摘要:

Russian Chemical Reviews 70 (11) 897 ± 920 (2001) Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds { E N Prilezhaeva Contents I. Introduction II. Syntheses involving rearrangements of sulfoxides into sulfenates and sulfenates into sulfoxides III. Syntheses based on the Pummerer reaction IV. Use of the Ramberg ±BaÈ cklund rearrangement for the insertion of C=C bonds V. Conclusion Abstract. rearrange- important most the of applications on Data Data on applications of the most important rearrange- ments total stereoselective to sulfones and sulfoxides of ments of sulfoxides and sulfones to stereoselective total syntheses syntheses of The systematised. are compounds natural of natural compounds are systematised. The bibliography bibliography includes references 175 includes 175 references. I.Introduction Rearrangements of sulfoxides and sulfones along with other reactions of these compounds (see the review 1) are widely used in stereospecific total syntheses of natural compounds. The mechanisms of the rearrangements of sulfoxides and sulfones were detailed in the reviews.2, 3 In the present review, syntheses of natural compounds involving these rearrangements as the key stages are surveyed. In spite of the fact that the Mislow ± Evans rearrangement of sulfoxides can be applied only to the construction of allylic alcohol fragments, whereas the Ramberg ±BaÈ cklund rearrangement can be used only for the formation of C=C bonds, both these reactions are often utilised in the syntheses of complex natural compounds.An important point is that the sulfur-containing group is removed in both processes. The Pummerer reaction is used much more extensively. This rearrangement was discovered in 1910 4 and did not come to the attention of chemists for 50 years. Once Horner 5, 6 had demon- strated that this reaction has a general character, the Pummerer rearrangement gained wide acceptance. It should be noted that Pummerer appraised the essence of this reaction quite adequately and related it to the lability of the a-hydrogen atom and generation of the sulfenium cation.4 Later on, the assumptions made by Pummerer were supported by the fundamental studies of Oae et al.7, 8 devoted to the mechanism of this process.Different aspects of the synthetic applications of the Pum- merer reaction were considered in many reviews, for example, in the reviews 9± 13 published in the last decade. However, the data on the use of this reaction as well as of other rearrangements for the preparation of natural compounds have not been systematised. The only exception is the review 14 in which consideration was E N Prilezhaeva N D Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation. Fax (7-095) 135 53 28. Tel. (7-095) 938 36 21 Received 29 March 2001 Uspekhi Khimii 70 (11) 1013 ± 1038 (2001); translated by T N Safonova #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n11ABEH000593 897 897 902 914 918 given to the use of additive Pummerer conversions of enantiomeri- cally pure vinyl sulfoxides in asymmetric syntheses of natural compounds.II. Syntheses involving rearrangements of sulfoxides into sulfenates and sulfenates into sulfoxides The mechanisms of the rearrangements of sulfoxides into sulfen- ates and sulfenates into sulfoxides and the effects of the structures of the initial compounds and the reaction medium were detailed in a review.2 Thermal rearrangements of benzyl sulfenates into sulfoxides, which proceed in nonpolar solvents by an ion-pair mechanism, did not find wide use in synthesis. On the contrary, rearrangements of b,g-unsaturated aliphatic sulfoxides have assumed great importance. This is particularly true for the reversible allyl sulfoxide ± allyl sulfenate Mislow ± Evans rear- rangement and, to a lesser extent, holds for the propargyl sulfenate ± allenyl sulfoxide Braverman rearrangement.1. Syntheses based on the reversible rearrangement of allyl sulfoxides into allyl sulfenates (the Mislow ± Evans rearrangement) a. General observations The thermal reversible rearrangement of allyl sulfoxides into allyl sulfenates proceeds as a intramolecular process through a five- membered transition state and is accompanied by migration of the double bond. This rearrangement is presently among the best- studied [2,3]-sigmatropic processes. The structure of allyl sulf- oxide is thermodynamically more favourable than that of sulfen- ate due to which the equilibrium in the liquid phase under normal conditions is virtually completely shifted toward sulfoxide.The occurrence of this equilibrium was assumed 15 based on the fact that racemisation of optically active allyl sulfoxides proceeds much more rapidly than racemisation of saturated sulfoxides. This assumption was additionally supported by the fact that the reaction of allylic alcohol with sulfenyl chloride in the presence of a base afforded sulfoxide (rather than sulfenate). R R (AlkO)3P or B7 OH R PhS O PhSO A { Dedicated to Academician O M Nefedov with appreciation and on the occasion of his seventieth birthday.898 R 1) BuLi OH [A] R 2) PhSCl PhS O Both reactions proceeded through allyl sulfenate A, which is readily isomerised.The mechanism of the intramolecular com- pletely concerted process was proved by kinetic data and by the results of experiments using labelled compounds.15 The Mislow ± Evans rearrangement is used as a general procedure for the preparation of allylic alcohols.16 Trimethyl phosphite was proposed as the thiophilic reagent of choice.16 This reagent moves sulfenate off the equilibrium, which is virtually completely shifted toward allylic alcohol. In some cases, such bases as amines, thiolates or Na2S are used as thiophiles. This procedure was later modified 17 so that it involved the one-pot synthesis of allylic alcohol by oxidation of allyl sulfide with 30% H2O2 in the presence of a catalytic amount of SeO2 followed by treatment with 0.1 equiv.of TsOH (alcohols were obtained in*70% yields). For this procedure to be successfully employed in the synthesis of complex compounds, it was necessary to find appropriate conditions for a-alkylation of the simplest allyl sulfoxides. Evans and Andrews 16 revealed that selective a-alkylation (a/g 55 10) took place only in the case of allyl sulfoxides that contain the double bond in the ring or bear two terminal alkyl substituents; otherwise noticeable amounts (up to 50%) of g-alkylated products formed due to which the yield of the target allylic alcohol decreased substantially. R2 R2 R2 ArS(O) ArS(O) ArS(O) R3 R3 R3 R5X + 7 R4 R1 R4 R5 R1 R4 R1 R5 R1, R2, R3, R4=H, Alk; R5=Alk.To eliminate this problem, it was suggested 16 that alkylation of allyl sulfides bearing heterocyclic (for example, 2-pyridyl or 2-imidazolyl) substituents at the sulfur atom should be followed by oxidation of the resulting compounds to sulfoxides. These sulfides underwent predominantly a-alkylation due to the chelat- ing effect of the heteroatom. S 7 Li+ N Evans and Andrews 16 also established that deprotonation with alkyllithium in the case of alkylation of allyl sulfoxides with weak electrophiles, such as long-chain halides, must be performed in aprotic solvents at below-zero temperatures. The advantage of the allyl sulfoxide ± allyl sulfenate rear- rangement is the stereoselective formation of the (E )-C=C bond because the trans conformation (according to the nomenclature proposed by Mislow 15) in the transition state is more favourable.Recently, ab initio calculations for 2-methyl-3-phenylsulfinylbut- 1-ene confirmed that the formation of the (E)-C=C bond is energetically more favourable.18 However, the difference between the energies of the trans and cis transition states is small. Hence, isomerisation of sulfoxides can afford up to 10% of the (Z)- isomer depending on the character of the substituents. If the double bond is involved in the corresponding ring, the product with the (Z) configuration can be obtained in quantitative yield. Recently, it has been demonstrated that distant functional groups exert efficient (E )-stereocontrol. Thus the presence of branched groups in the b position19 or the hydroxy group in the g position 20 of allyl sulfoxide is favourable for (E)-stereoselectivity (80% ± 99%).Mislow was the first to note 15 that isomerisation of sulfoxides containing a chiral centre at the C(1) atom is accompanied by migration of this centre to the C(3) atom. The characteristic features of this asymmetric synthesis, which was called self- E N Prilezhaeva immolative, and the effects of the bulkiness and the character of the substituents were thoroughly investigated by Hoffmann.21 b. Syntheses of natural compounds involving the Mislow ± Evans rearrangement The [2,3]-sigmatropic Mislow ± Evans rearrangement was first applied to the syntheses of prostaglandins.22 ± 27 OH S(O)Ph OLi 1) RX S(O)Ph OH 2) Et2NH, H2O Et2NLi, THF, HMPA 740 8C 7 S(O)Ph OH OH HO OH R RS(O)Ph PhS(O) R 1 (35% ± 60%) HMPA is hexamethylphosphoramide; RX=C6H13I, BnBr, OCH2CH2OCH(CH2)6I, ButCO2(CH2)2C CCH2Br, ButCO2(CH2)6I, PhCH=CHCH2Br.This procedure was used for the preparation of cis-cyclo- pentene glycols 1, which are convenient starting compounds for preparing prostaglandins,22 and the stereocontrolled construction of the chiral centre at the C(15) atom in compound 2 was carried out. The latter compound was utilised in the synthesis of prosta- glandin PgA2 .23 O CO2Et 1) MCPBA, 778 8C 2) (MeO)3P SPh O CO2Et 12 15 2 (63%) OH MCPBA is m-chloroperbenzoic acid. This methodology was also employed for the preparation of racemic products: prostaglandin F2a (3),24 methyl ester of 11-deoxyprostaglandin E1 (4)25 and stable analogues of prosta- glandin PgI2, viz., 7-hydroxy- and 7-acetoxy-PgI2 (5a,b).26 OH CO2H HO 3 OH (CH2)3CO2Me O O CO2Me OR 4 OH HO OH 5a,b R = H (a), Ac (b).Of special interest is the study, which demonstrated high stereo- and enantioselectivity of the sigmatropic process.27 The methyl ester of rac-PgE1 (7), which is completely identical to the natural specimen, was prepared in high yield by a two-step899 Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds N S procedure starting from the readily accessible rac-(13Z)-prosta- glandin (6) through unstable sulfenate 8 and sulfoxide 9.In this study, both directions of the Mislow ± Evans rearrangement were utilised. 1) MCPBA 2) Et2NH, MeOH O 16 (85%) (CH2)6CO2Me 1) Et3N, H2O C5H11 4 steps 2) TolSCl OH OH (R)-14 H OAc 13 (46%) THPOrac-(13Z)-6 O (CH2)6CO2Me The ingenious short synthesis of yomogi alcohol 17 was carried out starting from sulfide 18, which was prepared by alkylation of tetramethyldiallyl sulfide 19 with methyl iodide.16 C5H11 c, d a, b THPO OSTol S 8 18 19 SMe O (CH2)6CO2Me 1) (MeO)3P, MeOH 2) AcOH, H2O OH C5H11 17 THPO S(O)Tol 9 (81%) (a) BunLi, TMEDA (1,1,4,4-tetramethylethylenediamine); (b) MeI; (c) NaIO4; (d) Et2NH, MeOH, 25 8C, 24 h. O (CH2)6CO2Me The sulfoxide ± sulfenate rearrangement was also used for the functionalisation of the isopropylidene group of farnesol, related isoprenoids 29, 30 and compounds of the terpene ± quinone series.31 C5H11 HO RCH2 RCH2 RCH2 1) Oxidation PhSCl Et3N OH rac-(E )-7 (79%) 2) P(OMe)3 PhS Cl PhS O.Tol=4-MeC6H4, THP= RCH2 CH2OH (60% ± 80%) Linear terpenoids and related compounds were synthesised using the above-mentioned alkylation at the stage of allyl sulfide. (E )-Nuciferol (10) and the terpenoid (E)-nuceferal (11) were prepared starting from methallyl imidazol-2-yl sulfide (12).16 Hence, the sulfoxide-sulfenate rearrangement can be per- formed as a one-pot procedure after oxidation of allyl sulfide to sulfoxide. Me N S BunLi + Tol Br 730 8C 12 N If quinones of the terpene series are used as the starting compounds, the functionalisation products containing o-hydr- oxyprenyl or -geranyl chains can serve as convenient building blocks in syntheses of biologically important compounds, such as ubiquinone or vitamins K.31 Tol 1) MCPBA N S 2) Et2NH, MeOH, 26 8C (95%, a :g&9 : 1) MeN The sulfoxide ± sulfenate rearrangement made it possible to perform one-pot epimerisation of 17b-hydroxy-17a-vinylsteroids of type 20 to produce the previously unavailable epimers 21 with the 17a-hydroxy-17b-vinyl group through sulfoxide 22 (the total yield was 88%, the isomer ratio 21 : 20=86 : 14).32 HO OH MnO2 O H CH2S(O)Ph Tol 11 (99%) Tol 10 (80% ± 85%, E :Z&97 : 3) P(OMe)3 PhSCl BunLi MeOH, 20 8C MeO 22 20 HO +20 21 MeO Alcohol (13), which is the key compound in the synthesis of the mealybug pheromone, viz., (R)-2,6-dimethylhepta-1,5-dien-3- ol acetate (14), was prepared in four steps starting from methallyl 2-pyridyl sulfide (15).28 After oxidation of intermediate 16 and rearrangement, the alcohol 13 was isolated by chromatography.The pheromone (R)-14 and its (S )-enantiomer were prepared in four steps involving asymmetric Sharpless epoxidation. This syn- thesis allowed the establishment of the absolute configuration of the natural pheromone. S N BunLi + The reaction has a general character and can be applied to steroids containing the A rings with different structures.32 Tandem processes involving other procedures for the prepa- ration of allyl sulfoxides were also described; among them the so- Br 15900 called SPAC reaction (Sulfoxide Piperidine and Carbonyl) 33 is noteworthy.This reaction proceeds under very mild conditions and is typical of sulfoxides containing an electron-withdrawing group in the a position. It is believed that the reactions of the latter compounds with carbonyl groups in the presence of bases proceed according to a cascade mechanism, which involves the Knoeve- nagel reaction yielding substituted vinyl sulfoxide A, its isomer- isation to allyl sulfoxide B and the subsequent Mislow ± Evans rearrangement into sulfenate C. In the presence of a base, the latter compound gives the reaction product D. a R2R3CHCH C(Z)SR1 R1S(O)CH2Z+R2R3CHCHO O A R2R3CCH CHZ R2R3C CHCH(Z)SR1 C B O OSR1 R2R3C(OH)CH CHZ D (a) NH, 20 8C.The SPAC reaction and its use in syntheses of natural compounds were considered in detail in a review.1 This procedure was followed in the preparation of compound 23, which is a key intermediate in the synthesis of brefeldin A,34, 35 protected seco acid 24, which is a precursor of (R,R)-pyrenophorin,36 and macrocyclic lactones of type 25.37 OH OMEM MEMO CO2Et 5 CO2Me OH OSiMe2But 3 23 24 Me MEM=MeO(CH2)2OCH2 . RO (CH2)nOH O 25 (R=H, Me; n=7, 9). Diene condensations of sulfinyl-substituted 1,3-dienes afford adducts containing the allylsulfinyl fragment due to which they can be used in tandem with the subsequent sulfoxide ± sulfenate rearrangement of the adduct (see the review 38).The first example of such a tandem process involving the Diels ±Alder reaction and the sulfoxide ± sulfenate rearrangement has been described in the early study of Evans et al.39 The authors prepared compound 26 with the skeleton of the alkaloid hasu- banan by the transformation (without isolation) of adduct 27, which was synthesised by the stereoselective reaction of 1-phenyl- sulfinylbuta-1,3-diene (28) with tetrahdydrobenzoindole (29). MeCN + 70 8C, 24 h S(O)Ph NMe 29 28 HO MeN MeN Na2S .9H2O, MeOH 65 8C, 8 h PhS(O) 26 27 E N Prilezhaeva This combination of the reactions offers promise for the synthesis of biologically important substituted cyclohexenols, which cannot be prepared by other procedures.39 However, this approach has received little use in the synthesis of natural compounds.There are several examples of the reactions, which do not belong to tandem processes because they involve rearrangements proceeding with the participation of adducts isolated in the pure form. Thus compound 30, which is a key intermediate in the total synthesis of chorismic acid, was prepared by the rearrangement of the adduct of 2-(tolylsulfinyl)pyrone with ethyl vinyl sulfide.40 The rearrangements of the adducts of 2-phenylsulfinylbuta-1,3- diene with 3,3-dimethylcyclopropene or methyl vinyl ketone afforded carenols 31 (a mixture of the a- and b-isomers in a ratio of 7.5 : 1) and a mixture of isomers of 4-acetyl-2-hydroxycyclo- hexanone (32), respectively.41 O O (O)STol O TolS(O) NaOMe H2C CHSMe O SMe CO2Me TolS(O) CO2Me SMe HO 30 OH OH PhS(O) HO P(OEt)3 MeOH PhS 31 O Ac Ac HO Me 1) Na/NH3 PhS(O) O 2) CrO3 3) P(OMe)3 32 The asymmetric tandem process consisting of the Diels ± Alder reaction and the sulfoxide ± sulfenate rearrangement can be performed with the use of enantiomerically pure 1-arylsul- finylbuta-1,3-dienes containing an electron-withdrawing substitu- ent at position 4.Thus one-pot thermal reactions of such dienes with an excess of N-methylmaleimide gave rise to enantiomeri- cally pure cyclohexene-containing compounds in high yields.38 This methodology has not been extended to the synthesis of natural compounds.However, the recent study carried out by CarrenÄ o et al.42 was devoted to the condensation of [SR]-1- (1E,3E )-1-(tolylsulfinyl)penta-1,3-diene (33) with 4-methyldihy- dro-1,2,4-triazole-3,5-dione in the presence of trimethyl phos- phite. This reaction proceeded in quantitative yield to form enantiomerically pure compound 34 serving as a key intermediate in the synthesis of optically active b-hydroxy-g-amino acids. O O S N Tol N P(OMe)3 NMe NMe + N N HO O Me 34 (91%, ee>98%) 33 Me There are also other examples of the use of alcohols, which were prepared by the Mislow ± Evans reaction, as key compounds in syntheses of natural products. Thus diol 35 was generated by the rearrangement of an epimeric mixture of sulfoxides, which was obtained by oxidation of sulfide 36, and served as a key inter- mediate in the synthesis of cembranoids.43Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds HO 1) Oxidation PhS 2) P(OMe)3 0 8C, 24 h 36 Bicyclic vinyl sulfide 37 was used for the preparation of derivative 38,44 which is a key compound in the facile synthesis of the sesquiterpenoid fragment of the active antitumour agent verrucarin.The scheme involves oxidation of the sulfide 37 to vinyl sulfoxide 39 followed by a cascade process consisting in the isomerisation of allyl sulfoxide 40 and the rearrangement of the latter into allylic alcohol 41, which is spontaneously isomerised with the ring expansion to give the final product.H CO2Me O 1) MCPBA SPh 2) P(OMe)3 CH2OMe 37 O CO2Me S(O)Ph 40 H O CH2CO2Me O 38 CH2OMe The general procedure for the preparation of b-hydroxy- and b-acetoxy-g-lactones 42, which are precursors of compounds possessing allergic action, is based on cyclisation of susbtituted allylic alcohols of type 43.45 The latter were prepared by oxidation and the rearrangement of allyl sulfides 4. This procedure was used in the first synthesis of tuliposide B, which is an agent of allergic dermatitis caused by prolonged contact with tulip bulbs. The precursor of tuliposide B 45 was synthesised starting from allylic alcohol 43a and acetobromoglucose. CO2R1 PhSCH2 1) MCPBA R2 2) P(OMe)3 HO 44 43a,b OAc OAc O AcO O 42 (20% ± 40%) R2 R1=Me, Et; R2=H(a), Alk (b).CO2R1 1) Ba(OH)2 43a OBn 2) Ag2O HO HO OAc O AcO AcO OC AcO O 45 Compound 46, which is a key intermediate in the route to the synthesis of an active antitumour drug taxol, was prepared starting from allenyl sulfoxide 47. Its treatment with lithium HO HO35 (92%) O CO2Me S(O)Ph 39 CO2Me H O H O CH2OMe 41 CO2R1 TsOH R2 OAc O AcO AcO CO2Ag AcO Br OBn OBn OH 901 phenoxide led to the cascade reaction accompanied by cyclisation and the rearrangement of intermediate 48 containing the allyl sulfoxide unit. Oxidation of the resulting tertiary allylic alcohol 49 afforded the target compound 46.46 It should be noted that the intermediate 48 was isolated in the reaction of the sulfoxide 47 with less basic nucleophile PhMe2Al.PhS(O) O PhS C a, b SPh O 47 O 48 O HO c SPh SPh O O 46 49 N. CrO3 . HCl, (a) LiSPh, THF, 0 8C; (b) H2O; (c) Me2N ClCH2CH2Cl, 100 8C 2. Syntheses involving the sigmatropic rearrangement of propargyl sulfenates into allenyl sulfoxides The rearrangement of propargyl sulfenates into allenyl sulfoxides discovered by Braverman (see Ref. 2) has received little use in syntheses of natural compounds as compared to the Mislow ± Evans rearrangement. The former rearrangement is a reversible [2,3]-sigmatropic reaction proceeding under mild con- ditions. This rearrangement is utilised in syntheses of natural products only as a convenient procedure for the preparation of allenyl sulfoxides starting from available propargylic alcohols.Allenyl sulfoxides can, in turn, be converted into substituted allyl sufoxides by the addition of a nucleophile at the activated C=C bond of allenyl sulfoxide. A procedure was developed 47 for the preparation of the antiinflammatory agent hydrocortisone acetate (50) bearing the COCH2OH group at position 17b, which is typical of cortico- steroids. O 1) ButOK 2) HC CH, THF 51 O CH CH HO C PhS(O) C PhSCl *2.3 Et3N, CH2Cl2 52 53 S(O)Ph H OMe PhS(O)CH2 C P(OMe)3 NaOMe MeOH 55 54 OH AcOCH2C(O) HO OMe OH ... H 50 56 (72%) O902 Readily accessible androst-4,9(11)-diene-3,17-dione (51) was used as the starting compound.The reaction of alcohol 52, which was prepared by the selective addition of acetylene to the carbonyl group at position 17 of compound 51, with PhSCl ± NEt3 afforded sulfenate 53. The latter is stable only below 740 8C and under- went the [2,3]-rearrangement to give allene sulfoxide 54 as a mixture of isomers. The addition of the methoxy group at the double bond of the sulfoxide 54 gave rise to an epimeric mixture of allyl sulfoxides 55, which were isomerised into allylic alcohol 56 through the Mislow ± Evans rearrangement. This process provides the basis for a general method for the conversion of ketosteroids to corticosteroids. The stereochemistry of all stages of this process was investigated.47 The addition of the alkyne fragment to the carbonyl group followed by desulfinylation of allenyl sulfoxides under the action of MeLi was used for the preparation of steroids containing allene substituents.48, 49 In the study,50 allenyl sulfoxides were utilised as the starting compounds in the development of a general method for the preparation of 2,5-dihydrofuranones 57 by cyclisation of substi- tuted allylic alcohols 58, which are products of the [2,3]-rearrange- ment of allyl sulfoxides 59.The compounds 59 were prepared by the addition of a sodium derivative of dimethyl malonate to allenyl sulfoxides. S(O)Tol R1 1) NaC(CO2Me)2, 20 8C, THF C 2) R3X R2 R1 R3C(CO2Me)2 P(OMe)3 MeOH R2 CH2S(O)Tol 59 CO2Me R3=H R1 R1 C(CO2Me)2 R2 O R2 R3 O 57 (87% ± 90%) OH58 R1=H, Me; R2=Me; R17R2=(CH2)5 .This procedure was also employed for the conversion of mestranol 60 to spiro lactone 61 via allenyl sulfoxide 62.50 S(O)Ph OHC CH C PhSCl ... MeO 60 62 MeO2C O O MeO 61 In the synthesis of sesquiterpenoid sterpurene [(+)-63], the key tetraene sulfoxide 64 was derived from propargylic alcohol 65.51 OH C PhSCl, Et3N, CH2Cl2 C 778 8C, 2 h; 20 8C, 38 h 65 E N Prilezhaeva PhS(O) H C 3 steps H (+)-63 64 (70%) Other examples of the synthetic applications of vinylallenyl- containing sulfoxides prepared in a similar way were presented in a review,52 which covered the use of vinylallenes in the synthesis of metabolites of vitamin D3 . III. Syntheses based on the Pummerer reaction The Pummerer reaction consists in the transformation of sulf- oxides bearing at least one a-hydrogen atom under the action of electrophilic reagents.The reactions of saturated sulfoxides resulted in reduction of the sulfinyl group to the sulfide group and oxidation of an a-hydrogen atom. It is believed 7, 8, 11, 53 that the reaction proceeds through successive equilibrium stages of the formation of the acyloxy sulfonium ion A, ylide B and the sulfenium cation C. The reactions ended in the attack of an internal or external nucleophile on the cation C. OAc O Ac2O +S R2 S R2 R1 R1 A OAc + + 7 R1SCHR2 R1 S CHR2 R1 7 S CHR2 OAc OAc B C All three main experimental versions of this reaction are employed in syntheses of natural compounds.The first version is the classical Pummerer reaction in which sulfoxides containing no unsaturated groups in the a,b positions react with acids or their derivatives (most often with anhydrides and sometimes in the presence of bases). As shown in the above scheme, these reactions afford a-acyloxy sulfides as the primary reaction products. The second version involves the so-called sila-Pummerer reactions. In this case, the substrate or the electrophilic reagent possesses labile Si7X bonds due to which the reactions often proceed under milder conditions (generally at below-zero temper- atures). Trimethylchlorosilane 54 or other silicon-containing elec- trophiles are used as silylating agents. The third version of the Pummerer reaction consists in additive processes involving vinyl sulfoxides as substrates, which undergo Pummerer-like rearrangements under the action of various inorganic or organic electrophilic reagents.55 The version proposed by Marino and Neisser 56 is of particular interest.In the latter case, dichloroketene generated in situ served as the electro- philic reagent. Examples of the use of the Pummerer reaction in syntheses of biologically active compounds are systematised below according to the nature of the nucleophilic reagent involved in the reaction with the sulfenium cation. 1. Syntheses based on hydrolytic cleavage of a-acyloxy sulfides Hydrolysis of a-acyloxy sulfides generated in the course of the classical Pummerer reaction provides a convenient way of trans- forming sulfoxides into carbonyl compounds.These reactions are generally performed under the action of alkalis with the addition of salts, such as HgCl2 or CaCl2 , which promote elimination of the RS group. This section is concerned with examples of the applications of this procedure to the construction of carbonyl groups in natural compounds or key intermediates for their syntheses.Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds (R)-(+)-Perillaldehyde (66) was prepared 57 starting from an enantiomeric mixture of optically active sulfoxides 67 [which were synthesised in two steps from (+)-limonene epoxide] by hydro- lysis of the Pummerer-reaction product 68 without its isolation.Side chain deacylation of the intermediate 68 afforded vinyl sulfide 69. CH2S(O)Ph O (CF3CO)2O ... 2,6-lutidine 67 SPh PhS OCOCF3 CHO HgCl2 + H2O 68 69 (22%) 66 (64%) 6-Acetoxy-2,5,7,8-tetramethylchroman-2-carbaldehyde (70), which is a key starting compound in the total synthesis of a-tocopherol, was derived 58 from sulfoxide 71 by hydrolysis of a-acyloxy sulfide 72 isolated in the individual form. Me AcO Ac2O NaOAc O Me CH2S(O)Ph Me Me 71 Me AcO 1) NaOH, EtOH 2) Ac2O, Py SPh O Me MeOAc Me 72 (92%) Me AcO CHO O Me Me 70 (65%) Me Racemic 5-desoxyleukotriene D [()-73] was synthesised with the use of aldehyde 74, which was prepared from sulfoxide 75 without isolation of intermediate acyloxy sulfide.The scheme of the synthesis of the aldehyde 74 involves the reaction of 1-phenyl- sulfinylpenta-2,4-diene 76 with methyl 5-formylvalerate in the presence of butyllithium followed by migration of the sulfinyl group in benzoyl derivative 77, which proceeds very readily through a two-step [2,3]-rearrangement.59 S(O)Ph a, b +OHC(CH2)4CO2Me 76 PhS(O) (CH2)4CO2Me c 77 OCOPh PhS(O) (CH2)4CO2Me d, e 75 OCOPh 903 OHC (CH2)4CO2Me ... 74 (65%) OCOPh (CH2)4CO2H C5H11 SCH2CHCNHCH2CO2H H2N O ()-73 (a) BunLi; (b) PhCOCl, 740 8C; (c) 25 8C, 3 h, (d) Ac2O, 2,6-lutidine, (CF3CO)2O, NaOH; (e) CaCO3, HgCl2, MeCN±H2O. In the key stage of the total synthesis of asteltoxin [(-78)], aldehyde 79 was generated from sulfoxide 80 also without isolation of intermediate acyloxy sulfoxide.60 OH OH PhSO a, b Et O O 80 H OH ...CHO O 79 O OH OH O OMe O Et O H (+)-78 (a) (CF3CO)2O, Ac2O, 2,6-lutidine; (b) CaCl2, HgCl2, MeCN±H2O. 3-Trichloroacetylaminohex-4-enal (81) was synthesised start- ing from sorbinic alcohol. 61 In this case, acyloxy sulfide 82 was isolated as an intermediate. Hydroxylation of the aldehyde 81 with OsO4 afforded the N-trichloroacetyl derivative of racemic dau- nosamine (83), which is a carbohydrate fragment of the antitu- mour antibiotic daunorubicin used in clinical practice. Variations of this procedure made it possible to synthesise the related carbohydrates, viz., racemic vancosamine and ristosamine.61 ...OH NHCOCCl3 (CF3CO)2O, Ac2O 2,6-lutidine S(O)Ph OAc NHCOCCl3 Cl3CCOHN OsO4 CaCl2 CHO SPh H2O 81 82 OH O NHCOCCl3 HO()-83 (66%) Branched sugar 84 was synthesised 62 in three steps from keto ester 85. The latter was obtained as the major product of the Pummerer reaction of sulfinyl-substituted ester 86, which was prepared by diene condensation of menthyl (S )-(2-pyridylsulfi- nyl)acrylate with furan.63 The Pummerer reaction involving the sulfoxide 86 afforded vinyl sulfide 87 as a by-product. Acid hydrolysis of the latter gave rise to the keto ester 85 in low yield (<25%).62 O OO (CF3CO)2O 40 8C, 0.5 h CO2Men 86 S(O)Py904 O MeO O OH OH OO CO2Men 3 steps O O 85 (62%) O 84 O OO CO2Men SPy 87 Men is menthyl.However, some of these reactions proceed readily; examples of such reactions were described in the literature. Thus vinyl sulfide 88, which was prepared by the Pummerer reaction starting from sulfoxide 89, was utilised in the synthesis of ketolactone 90. The latter is the direct precursor in the synthesis of the antitumour agent sarcomycin (91).64 SEt S(O)Et H2O (CF3CO)2O H H H H HgCN, MeCN 25 8C O O O 88 (89%) O89 O O ... H H O CO2H O 90 (90%) 91 Below is given a scheme illustrating additional potentialities arising from a combination of the classical Pummerer reaction and the subsequent transformation of its products without their isolation. A combination of hydrolysis of acetoxy sulfide and reduction of the intermediate carbonyl compound starting from sulfoxides 92 ±94 made it possible to prepare labile compounds, such as g-geraniol (95),65 dendrolasin (96)66 and enantiomerically pure penta-O-acetyl-L-arabinitol (97).67 SPh PhS(O) OH OAc b a (55%) 92 95 (84%) a S(O)Ph 93 SPh a, b 2 steps OH OAc (34%) O 96 (a) Ac2O, (CF3CO)2O (cat); (b) NaBH4, EtOH, H2O.OH OAc OH O b ± d, a a STol BnO STol OAc OH (4S,3R,2R,5R)-94 E N Prilezhaeva OAc AcO OAc AcO OAc 97 (40%) (a) Ac2O, AcONa; (b) Bui2AlH; (c) Ac2O; (d ) Pd/C, C6H10 . In more recent studies, for example, in the synthesis of 2-deoxy sugars 68 or in the construction of a fragment of the antibiotic nystatin A1 containing five chiral alcoholic centres, Solladie' et al.69 used yet another modification of the acyloxy sulfide group.The Pummerer-reaction product, which was purified only by column chromatography, was immediately subjected to desulfur- isation with Raney nickel. This procedure is exemplified by the preparation of derivative 98 of (2-deoxy-D-ribonic acid) starting from sulfoxide 99. OMEM O Tol 1) Ac2O, AcONa, 20 8C ButO S 2) Ni/Ra, EtOH TBSO 99 OOMEM O OAc ButO TBSO (3S,4R)-98 (68%) TBS=ButMe2Si. The procedure developed for the synthesis of substituted pyridines 70 involves a combination of four reactions, viz., oxida- tion of sulfide to sulfoxide, the classical Pummerer reaction, hydrolysis of a-acyloxy sulfide and the formation of the pyridine ring by the reaction of ammonia with intermediate 1,5-ketoalde- hyde.R3 R3 R3 R4 R2 R4 R2 R4 R2 c a, b CHO SPh R1 R1 R1 O O HN (a) NaIO4, MeOH, H2O; (b) (CF3CO)2O, Py; (c) NH3, MeOH, H2O. This procedure made it possible 71 to synthesise natural neuro- toxin, viz., acromelic acid A (101), starting from phenylthio- substituted pyrrolidine 100. Isomeric acromelic acid B was pre- pared analogously.72 More complex synthetic schemes involving the Pummerer reaction as the key stage are considered at the end of the section. Me O OTBS PhS(CH2)2 1) NaIO4 2) (CF3CO)2O, Py, 0 8C 3) NH3, H2O, 20 8C NBoc OTBS 100 N O HN HO2C OTBS CO2H 4 steps CO2H NBoc 101 OTBS NH Boc=ButOCO. 2.Syntheses based on intermolecular reactions of sulfenium cations with C=C bonds of alkenes The sulfenium cation is a highly electrophilic reagent, particularly, if the initial sulfoxide bears activating electron-withdrawingRearrangements of sulfoxides and sulfones in the total synthesis of natural compounds groups (most often carbonyl groups). This cation can react even with the weakly nucleophilic C=C bond. Analogous intermolec- ular processes were used in syntheses of predominantly linear unsaturated components of pheromones. In most studies, no consideration has been given to intermediates and hence, the mechanism of this reaction is unknown. Ishibashi and co- workers 73 ± 77 proposed the ene-type mechanism involving the sulfenium cation.The natural insecticide pellitorine (102) was prepared 73 by the reaction of oct-1-ene with the product of the Pummerer rearrange- ment of (methylsulfinyl)acetamide (103). (E)-9-Oxodec-2-enoic acid (the queen substance) (104) was synthesised analogously from methyl methylsulfinylacetate (105) and oct-1-en-7-one.74 Additional C=C bonds were generated by thermolysis of sulf- oxides prepared by oxidation of adducts 106 and 107. a, b Trideca-(4E,7Z)-4,7-dien-1-ol acetate (112), which is the potato moth pheromone, was synthesised 78 starting from phos- phorus-substituted sulfide 113. The latter was derived from (methylsulfinyl)phosphonate by the Pummerer reaction followed by the reaction with 5-heptyl acetate. The synthesis ended in oxidation of the sulfur atom in the adduct to the sulfonyl group, chain elongation by the Horner ± Wadsworth ± Emmons reaction with hexanal and a three-step modification of intermediate 114.MeS(O)CH2C(O)NHBui 103 SMe c, d CONHBui C5H11 MeS(O)CH2P(O)(OEt)2 106 CONHBui C5H11 102 (a) (CF3CO)2O; (b) C6H13CH=CH2; (c) NaIO4; (d ) D. a, b MeS(O)CH2CO2Me 105 O (a) (CF3CO)2O; (b) c, d, e CO2Me (e) BunLi; ( f ) 107 SMe O CO2H 3. Cyclisations based on intramolecular reactions of sulfenium cations with C=C bonds 104 O (a) (CF3CO)2O; (b) ; (c) NaIO4; (d ) D; (e) OH7. Intramolecular coupling of the Pummerer-reaction products and C=C bonds proved to be much more fruitful. The reaction of the sulfenium cation, which was derived from the sulfinyl fragment of compounds 115a,b, with the C=C bond of the indole fragment was the key step in the synthesis of tetracyclic pyrido[4.3-b]carb- azole alkaloids olivacine (114a) and ellipticine (114b).The target alkaloids 114a,b were prepared in rather high yields by ten-step transformations of intermediates 116a,b.79 R1 p-Chlorophenylmethyl sulfoxide proved to be a particularly convenient starting compound in such reactions. The Pummerer reaction involving primary product 108 afforded numerous bio- logically active compounds, for example, the sex pheromone of red cotton moth (109) with the ratio of the (E )- and (Z)-isomers identical to that observed in the natural substance,75 the pher- omone of some tortricids 110 76 and bicyclic exo-brevicomin 111, which is the aggregation pheromone of fir moth (in a mixture with 11% of the endo epimer).77 + a b, c, d 115a,b Cl S(O)Me Cl S CH2 7OCOCF3 108 CO2Me 2 steps OAc 109 (E:Z=81 : 19) Compound (a) (CF3CO)2O; (b) (CH2)8CO2Me; (c) MCPBA; (d ) D.a ± f 108 OAc 110 OTHP; (a) Et; (b) MCPBA; (c) BunLi; (d ) Br 116a 116b 114a 114b (e) EtNHLi; ( f ) AcCl, AcOH. 108+ 2 steps 4-ClC6H4S O OsO4, Py 4-ClC6H4SO2 Magnus and coworkers carried out systematic research into the synthesis of polycyclic indole alkaloids (see the review 80) and devised the [2,3]-quinodimethane strategy for constructing these alkaloids. ()-Aspidospermidine (117), which is the simplest representative of pentacyclic alkaloids from Aspidosperma sp.plants, was a convenient compound for the development of the methodology. Gallagher et al.81 synthesised tetracyclic precur- 905 O OH 2 steps 4-ClC6H4SO2 OH O O ()-exo-111 P(O)(OEt)2 d ± f a ± c OTHP MeS 113 SO2Me 3 steps OTHP 114 OAc 112 OAc ; (c) , H+; (d ) MCPBA; O O . (CF3CO)2O MeCN, THF S(O)Et O Bn N Me R2 R1 R1 N 10 steps O NH 114a,b Me Bn N Me SEt 116a,b Yield (%) R2 R1 MeH 5155 H Me 2823 H Me906 sors, viz., substituted octahydro-7H-pyrido[3,2-c]carbazole 119 and 120, starting from nitrogen-protected 3-formyl-2-methylin- dole (118). The compound 119 contains the sulfinyl-substituted exocyclic amide group, whereas the compound 120 bears the endocyclic amide group.Under the conditions of the Pummerer reaction, compounds 119 and 120 very readily undergo cyclisation to compounds 121 and 122 to form the E ring (apparently through intermediates 123 and 124, respectively). After deprotection of the indole nitrogen atom and reductive removal of the carbonyl and sulfide groups, racemic aspidospermidine 117 was obtained through the compounds 119 and 120 in total yields of 6.3% of 11.7%, respectively. Cyclisation proceeded with exceptional stereoselectivity resulting in the natural cis-fusion of the rings. Cyclisation proceeded readily due to the close arrangement of the sulfenium cation and the p-electron system of the nucleophilic indole fragment. CHO ... Me RN 118 O + PhS N H Et RN 123 O N H PhS Et NR 121 (91%) PhS(O)(CH2)2 ...118 RN O + PhS N H Et RN 124 ()-117 R=SO2C6H4OMe-4. The electronic or steric factors inhibiting the ring formation can (owing to the equilibrium character of this reaction) promote other conversions of a sulfenium-containing intermediate. Thus researchers failed to construct the E ring of indole alkaloids of the aspidospermine group under the standard conditions of the Pummerer reaction starting from model compound 125, which contains the electron-donating methoxy group in the benzene ring typical of alkaloids of the vinblastine and vindoline groups. Cyclisation was successfully performed under the action of trifluoroacetic anhydride in the presence of 2,6-di-tert-butyl-4- methylpyridine as a base.82 After thermolysis, compound 126 was obtained in rather high yield.MeO R=CO2Me; (a) (CF3CO)2O, PhS(O)CH2C(O)N H (CF3CO)2O Et RN 119 Magnus did not extend this discovery to natural alkaloids of the vinblastine and vindoline series, probably, because Langlois and coworkers 83 have reported an ingenious procedure for their preparation, which was also based on the Pummerer reaction but which utilised b-ketosulfinyl-containing tetrahydroindolo[2,3-a]- quinolizidines of type 127 as the starting compounds. Vindoline (128a) and vindorosine (128b) were prepared from the compounds 127a,b in which the indole nitrogen atom was protected with the methyl group.Under the conditions of the Pummerer reaction, the compounds 128a,b underwent a retrobiomimetic rearrangement via the intermediates A ? B ? C. The reaction started with the coupling of the sulfenium cation with the indole C=C bond and ended in the construction of the E ring in 129a,b, which are key compounds in the synthesis of the target alkaloids. If the indole nitrogen atom is not protected (as in the precursors 127c or 130a), the indoleC=Cbond can couple with the nearby sulfenium cation (via the intermediate D) under the conditions of the Pummerer O N DHE 3 steps R1 C A Et BHN ()-117 O N H (CF3CO)2O Et 120 O N H PhS 3 steps Et R1 NR 122 Compound 127a 127b 127c 128a 128b 129a 129b O PhS(O) N a, bMeO 125 RN But Me N ; (b) D.But H N R2=Me 21 TsOH RN2Et MeS(O)CH2CO 127a ± c H N R1 R1 Me NEt + O MeS A N H Et + R1 O SMe NMe H C 129a,b N H OH Et OAc R1 Me N CO2Me H 128a,b Yield (%) R2 R1 OMe 7 Me H Me 7 H H 7 OMe 10 (total) H 7 OMe 73 H 70 E N Prilezhaeva O N PhS H RN 126 (65%) H + N N Me MeS Et OB N H 7 steps Et O NMe SMeRearrangements of sulfoxides and sulfones in the total synthesis of natural compounds reaction giving rise to eburn-type alkaloids, for example, to compound 131. However, for this reaction pathway to become dominant, the indole C=Cbond must be additionally shielded by the b-hydrogen atom at the C(21) atom as in indoloquinolizidine 130a.84 The Pummerer reaction involving the epimeric compound 127c, which bears an a-hydrogen atom at the C(21) atom, afforded a mixture of aspidospermidine- and eburn-type alkaloids with the former predominating.85 H N 1) MeSO3H 21 MeO 2) Et3N RNEt MeS(O)CH2CO 130a,b H H N N N MeO MeO NH HO Et O Et + O MeS 131 (63%) R = H (a), Me (b). Vindoline 128a can be prepared with equal ease from the C(21)-epimeric precursors 127a or 130b.It was assumed 84 that the compound 130b was converted into the compound 127a due to rapid reversible Mannich-type isomerisation. Apparently, this reversible process is also responsible for racemisation, which was observed in attempting to prepare enantiomerically pure alkaloids of this series from optically pure indoloquinolizidines.84, 86 Further progress in studies on the synthesis of alkaloids of the aspidospermine group performed by Magnus and coworkers 87 was achieved owing to the employment of additional functional- isation of pentacyclic thio-containing amides.Thus racemic 8-oxotabersonine (132) was prepared 87 from pentacyclic com- pound 133 in five steps. O O N N H H PhS 5 steps Et NH NCO2Me 132 133 CO2Me The synthesis of heptacyclic alkaloids of the kopsan series was a more complicated problem. For this purpose, key compound 134a containing the diene system in the C ring was constructed. Under the conditions of the Pummerer reaction, aromatisation of the C ring competed with cyclisation due to which the use of the diene precursor 135 did not afford the target compound 134a.The reaction involving chlorine-containing analogue 136 took the desired path 88 and the intermediate A readily underwent de- hydrochlorination. Y O X PhS(O)(CH2)2N H DPhS E (CF3CO)2O C A BRN 135 134a,b RN R=SO2C6H4OMe-4; X=H, Y=O (a); X=O, Y=H (b). PhS(O)CH2CON (CF3CO)2O HCl RN ()-136 O N PhS HCl NRAO N H PhS 137 NR R=SO2C6H4OMe-4. The one-pot synthesis of heptacyclic compound 137 contain- ing all major elements of the kopsan system was carried out with the use of the pentacyclic compound 134b. For this purpose, the starting compound was allylated at the C(11) atom followed by intramolecular diene condensation involving the diene system of the C ring.The key alkaloid of this series, viz., ()-10,22- dioxokopsan (138), was synthesised from the compound 137 in four steps [the keto group at the C(22) atom was formed by the Pummerer reaction of the intermediate C(22)-sulfoxide]. C(22)-Oxokopsan and epimeric C(22)-kopsanols were readily derived from the compound 138. An analogous procedure was also used 89 for the preparation of optically active (+)-dioxokopsan [(+)-138] based on enantio- merically pure (taking into account the sulfinyl group) tetracyclic precursor (+)-139. In the cited study,89 the data on the optical O SCH2CON Tol H 7 steps HCl RN (+)-139 N H HN MeO2C H (7)-140 N H NH Et (7)-142 R=SO2C6H4OMe-4; N (a) , 2%HCl, D, 7 h.N Et OH H (7)-141 907 3 steps 134b 7HCl O 22 ON 11 H 4 steps 138 NH 5 steps (+)-138 a N H HN MeO2C H908 purity and absolute configurations of the products are lacking. However, the conversion into (7)-kopsinine (140) followed by its condensation with optically pure (7)-eburnamine [(7)-141] afforded bis-indole (7)-norpleiomutine [(7)-142] characterised by an optical rotation identical to that of the natural alkaloid. The application of Magnus's procedure to the construction of the fifth ring of the more strained systems of alkaloids from plants of the Strychnos family utilising either precursor 143a, which contains the exocyclic sulfinylamide group, or precursor 143b, which is an endocyclic amide, has not met with success.90 In the study of Bosch and coworkers,91 steric hindrances to the favour- able arrangement of the sulfenium ion relative to the indole C=C bond were overcome with the use of the more flexible sulfinyl- alkylamine group in tetracyclic precursor 143c.In the latter case, after the standard treatment with trifluoroacetic anhydride, the process was terminated at the stage of formation of a-acyloxy sulfide, which was converted without isolation into cyclisation product 144 under the action of boron trifluoride etherate. The yield was insufficiently high because the undesirable hydration product 145 was simultaneously obtained.However, the cited study 91 can be considered as a facile synthesis of strychnine alkaloids. Compound 146 was obtained in 50% yield. It is a 20-deethylated analogue of the final intermediate (which was prepared previously 92) in the synthetic pathway of the most important representatives of strychnine alkaloids, viz., tubifoline, tubifolidine, etc. C(X)CH2S(O)Ph Y H N a, b, c H NR 143a ± c N H N H PhS PhS + H H OH 145 144 RN RN N H d 144 e, f 145 H NR 146 (50%) R=CO2Me; X=O, Y=H2 (a); X=H2, Y=O(b);X=Y=H2 (c); (a) X=Y=H2 , (CF3CO)2O; (b) BF3 . Et2O; (c) CH2Cl2 , D, 4 h; (d ) Ni/Ra; (e) TsOH, 20 8C; ( f ) Ni/Ra. Sulfinylalkylamines were successfully used in syntheses of other groups of alkaloids.()-Deethylibophyllidine (147) was prepared 93 according to the standard Pummerer reaction from tetracyclic compounds 148 by the construction of the fifth ring. PhS(O)(CH2)2 N H (CF3CO)2O CF3CO2H, 80 8C, 2 h H 148 RN N N PhS 2 steps H H H H NH RN (63%) CO2Me ()-147 R=CO2Me. In the facile synthesis of ()-geissoschizine (149) starting from precursor 150, the six-membered ring was successfully constructed only under the conditions of the sila-Pummerer reaction.94 Under the conditions of the classical Pummerer reaction, the unexpected formation of hydroxy sulfide 151 from the compound 150 was observed instead of cyclisation. In a special study,95 it was demonstrated that such an anomalous Pummerer reaction is typical of C(3)-unsubstituted indole derivatives and is attributable to the prior formation of the seven-membered ring.(CH2)2S(O)Ph N N H O H 150 SPhN N a H O(64%) H SPh (CH2)2OH N N b O 151 (a) Me3SiOCF3, 20 8C; (b) (CF3CO)2O, CF3CO2H. This research group 96 carried out the first synthesis of an alkaloid of the 3,4-secoakuammilan series by cyclisation of sulf- oxide 152 under the conditions of the Pummerer reaction. In this synthesis, the strongly strained quaternary centre at the C(7) atom was generated through the formation of the eight-membered lactam ring. R H Bn N Me N 152 O Bn NR 6 PhS 7 H Me N (23%) H (a) (CF3CO)2O, CH2Cl2; (b) NaCNBH3; (c) Ni/Ra, EtOH. 4. Synthesis of cyclic compounds by intramolecular reactions of sulfenium cations with various nucleophilic traps The Pummerer reaction is finding increasing use in the construc- tion of various rings, including those present in natural com- pounds, primarily, of heterocycles (see the review 12), and, to a lesser extent, of carbocycles.Natural heterocycles are constructed by intramolecular binding of the sulfenium cation to various nucleophilic traps. The C=C bonds other than those present in indoles can serve as nucleophiles as exemplified by the ingenious synthesis of the alkaloid ()-3-demethoxyerythratidinone (153).97 The latter was prepared starting from substituted sulfinylacet- amide 154, which was subjected to double cyclisation via inter- mediate A.E N Prilezhaeva N ... H NHMeO2C (+)-149 a, b CH2S(O)Ph O O NBn 7 c R Me N H H (80%)Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds MeOMeO 154 MeO MeO MeO MeO OO 156 O MeS (a) (CF3CO)2O; (b) SnCl4; (c) Ni/Ra; (d) H2, Pd/C. In the synthesis of the key starting compound 155 for the preparation of gibberellic acid, cyclisation also proceeded through the intramolecular coupling of the sulfenium cation with the double bond of compound 156.98 Ishibashi and coworkers used the intramolecular coupling of the sulfenium cation with the C=C bond in the development of a general facile procedure for the synthesis of pyrrolizidine alka- loids 99 and in the construction of the optically active (7)-trache- lanthamidine (157) from precursor 158.100 H Me N S(O)Me 158 O CH2OH HN (7)-157 (30%, ee*75%) Cyclisation can proceed through a Friedel ± Crafts-like coupling of the sulfenium cation with the aromatic ring containing activating alkoxy groups.Thus isoquinolone alkaloids, viz., dimethoxymethylisocarbostyril (159a) and doryanine (159b), as well as N-methylcorydaldine (160a) and oxyhydrastinine (160b) were synthesised starting from common precursors 161a,b.101 The latter were prepared by the reactions of Ac2O with alkylamides 162a,b. Cyclisation of a-acetoxy sulfides 161a,b under the action of TsOH afforded alkaloids 159a,b, whereas treatment of the compounds 161a,b with CCl3CO2H gave rise to intermediates O Me S N O TsOH O O O + N SMe 1) NaIO4 2) PhMe, D H O O A MeO O N N MeO 2 steps O O O ()-153 a, b OBz CH2S(O)Me O H H c, d OH O OBz O O 155 H (CF3CO)2O 4 steps SMe CH2Cl2, 20 8C N O (87%) 163a,b, which were subjected to desulfurisation to form the compounds 160a,b.O R1O NMe Ac2O, D R1O (CH2)2S(O)Ph R2O R2O 162a,b O R1O TsOH NMe R2O 159a,bO R1O NMe Ni/Ra CCl3CO2H R2O 163a,b SPh R1=R2=Me (a), R1±R2=CH2 (b). Analogous procedures were used for the preparation of the tetrahydroisoquinoline alkaloid hydrohydrastinine from the cor- responding aromatic amino sulfoxide 102 and for the facile syn- thesis of the polycyclic alkaloid chilenine (164),103 the seven- membered ring of the latter being constructed upon cyclisation of precursor 165.O O N OMe O S(O)Ph 165 OMe O N O SPh O N O O OH 164 (+)-Aphanorphine (166), which exhibited specific optical rotation identical to that of the natural alkaloid, was synthes- ised 104 from optically active sulfinyl-substituted lactone 167. The Pummerer reaction was accompanied by cyclisation to yield a 4-MeOC6H4 (CF3CO)2O H PhMe, D, 10 min O O S(O)Ph 167 O O MeO MeNH2 Me3Al H PhS H 168 O MeO NHMe 3 steps HOH SPh 169 H 909 O NMe CH2CHSPh OAc 161a,b O R1O NMe R2O 160a,b (CF3CO)2O PhMe, D O OMe ... OMe O OMe OMe NMe HO 166910 mixture of enantiomeric lactones 168.The lactone-ring opening was performed under the action of methylamine and the resulting bicyclic intermediate 169 was converted into the target alkaloid 166 in three steps. The short synthesis of gymnopusin (170),105 which is the first representative of natural phenanthrenes with the oxygen-contain- ing substituent at the C(10) atom, provides yet another example. It should be noted that the results of this synthesis proved the structure of natural gymnopusin. MeO PriO CCH2S(O)Me O PriO HO HO MeO (a) (CF3CO)2O; (b) Na/NH3; (c) (MeO)2SO4, CaCO3; (d ) BCl3, CH2Cl2. Oxygen-containing groups can also be involved in intramo- lecular coupling with the sulfenium cation to form oxacycles. Thus the involvement of the aldehyde group of sulfinyl-substituted a,b- unsaturated aldehyde 171 in cyclisation under the conditions of the Pummerer reaction made it possible to synthesise butenolides isodrimenin (172) or confertifolin (173) via intermediate com- pounds 174 or 175 containing substituted furan rings.106, 107 The possible mechanism of this process involves the free (under the action of Ac2O) or hydrated aldehyde group (upon heating in CH2S(O)Ph CHO H 171 PhS O H 174 K2CO3 171 H2O, PhMe H O H 175 OMe a, b OPri OMe MeO c, d OPri OMe MeO OH 170 +SPhCHO Ac2O D H AO O HgCl2 H3O+ H 172 +SPhCH(OH)2 7PhSH B OH H 173O O E N Prilezhaeva aqueous dioxane in the presence of K2CO3) (transition states A and B, respectively).The short one-pot synthesis of furanoterpene perylene (176) (a component of insect communication pheromones) was carried out using the sila-Pummerer rearrangement of hydroxy-contain- ing allyl sulfoxide 177, which was readily derived from the adduct of b-myrcene with benzenesulfinyl chloride.108 The authors of the cited study believed that the furan ring was generated from intermediate hydroxyaldehyde 178. a, b, c OH d, e, f S(O)Ph 177 OH O O 176 (52%) 178 (a) PhSOCl, 5 kbar; (b) AcOK, AcOH; (c) H2SO4 , MeOH; ( d) BunLi,785 8C; (e) Me3SiCl,785 to 25 8C; ( f) H2O, C5H12 . The synthesis of bicyclic lactones 179a,b, which are 3-nor- methylene analogues of avenaciolide and isoavenaciolide, respec- tively, provides an example of the involvement of the ester group in cyclisation of the above-mentioned type.109 The Pummerer reaction of optically active sulfenyl-substituted ester of tetrahyd- rofuranocarboxylic acid 180 afforded a mixture of diastereomeric bicyclic compounds 181a,b in a ratio of 5 : 1.Both these com- pounds were converted into the target compounds 179a,b in four steps. O (CF3CO)2O BnO2C CH2Cl2, 25 8C, 4 h Ph(O)SCH2 180 O O H H O O O + O H H PhS 181b (84%) PhS 181a (84%) 4 steps 4 steps O O H H O O O O O O H H H17C8 H17C8 179b 179a The ring closure can occur with the participation of the OH group. Optically active pyran derivative (+)-182 serves as the common key intermediate in enantiospecific syntheses of iridoid monoterpenes.This derivative was prepared 110 from bicyclic lactone 183 containing the required chiral centres. The compound 183 was converted into sulfide 184 by reactions in which the latter centres remained intact. Oxidation to sulfoxide and cyclisation, which occurred through the Pummerer reaction involving the enol hydroxy group, gave rise to compound 185 in which the SPh group was replaced by OMe. The methylacetal of iridoid aglycone sweroside 186 was prepared from the compound 182 in six steps.Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds CO2Me O OH 1) NaIO4 5 steps O 2) (CF3CO)2O, 2,6-lutidine 184 SPh (7)-(1S,5R)-183 CO2Me CO2Me 6 steps 2 steps O O 185 (+)-182 OMe SPh O O O (7)-186 OMe To construct the seven-membered oxathiazepine ring involved in the L-eudistamine molecule (187),111 which shows activity against Herpes simplex, the Pummerer reaction was carried out with the use of intermediate 188 in the course of which the sulfenium ion was coupled with the adjacent N7OH group.Br Br N O N OH 1) NCS 2) H+ H NH H S NH H H2N 188 187 CH2S(O)Me NHBoc NCS is N-chlorosuccinimide. The Pummerer reaction was used in the chemistry of penicilins and related biologically active lactams. This reaction allows one to convert rather inactive sulfoxides of the penam series into penem derivatives exhibiting high biological activities (see, for example, Refs 112 and 113).The most interesting results were obtained on cyclisation of b-amido sulfoxides in which intramolecular coupling of the sulfenium cations with the nitrogen atom of the imino group occurred to form substituted lactams. Thus Kaneko 114 was the first to perform intramolecular cyclisation in mild conditions of the sila-Pummerer reaction under the action of silyl trifluorome- thanesulfonate on b-amidosulfoxides 189a ± d and obtained 4-arylthio-substituted lactams 190a ± d. Kaneko demonstrated that the compound 189c containing one b-alkyl substituent produced predominantly cis-3,4-disubstituted lactam 190c, whereas enantiomerically pure precursors, viz., (R)- or (S )-189d, yielded optically active (R)- or (S )-lactams 190d with ee *67% (see Ref.115).{ These results provided supporting evidence for the assumption as to the correlation between the mechanism of the + R2 R2 SPh R1 R1 CH2S(O)Ph Me3SiOSO2CF3 NHR3 Me3SiO NR3 191a ± d O189a ± d R2 SPh R1 NR3 O 190a ± d R1=R2=Me, R3=OBn (a); R1=R2=H,R3=OBn (b); R1=Me, R2=R3= H (c); R1, R2, R3 = H (d). { Unfortunately, the absolute configurations of the compounds used in the investigation 115 were not established. 911 Pummerer reaction (involving sulfenium intermediate 191) and the first stage of the biosynthesis of lactam antibiotics. Kita and coworkers made a considerable contribution to the solution of the problems associated with the synthesis of b-lac- tams. The authors demonstrated that nitrogen heterocycles con- taining the thio group in the a position can be readily synthesised with the use of versatile silylating agents, viz., silyl ketene acetals.116 This methodology was first examined for the Pummerer cyclisation of o-amido sulfoxides to obtain intermediates utilised in the synthesis of pyrrolizidine and indolizine alkaloids.117 Later on, this procedure was extended to the synthesis of b-lactam carbapenems starting from o-amido sulfoxides.118 4-(Arylthio)- azetidin-2-ones 192, which were prepared by the reactions of methyl(trimethylsilyl) ketene acetal with amido sulfoxides 193, were used as the starting compounds.The compounds 192 were oxidised to sulfoxides 194. Under the action of the same ketene acetal, the latter compounds were transformed into trans-disub- stituted azetidin-2-ones containing ester groups at the C(4) atom [195, the ratio trans : cis= (89 ± 95) : (5 ± 11)], which are the key precursors in the synthesis of b-lactam antibiotics, carbapenems.This procedure was employed for the preparation of racemic carbapenem PS-5 (196)119 and b-methylcarbapenem.120 The enan- tioselective synthesis of thienamycin was carried out starting from enantiomerically pure b-amido sulfoxide of the type 193.121 O R1 SPh R1 R1 S(O)Pha S Ph b CH2 a O O O NR2 194 NR2 192 NHR2 193 OSiMe3 7 + CHCO2Me R1 SPh R1 N+R2 NR2 O O H CH2CO2Me R1 Et R2=H ... S(CH2)NH2Ac N NR2 O CO2H O 195 (52% ± 86%) 196 MeO , ZnI2 (cat), MeCN, 20 8C, (b) oxidation.(a)Me3SiO Kita et al.122 demonstrated that (S )-(tolylthio)lactams 198a ± d (ee 82%± 83%) can be prepared in high yields starting from optically active b-amido sulfoxides, for example, from (R)-197a ± d, whereas the corresponding (R)-lactams can be prepared with high enantioselectivity from (S )-197a ± d. Hence, the authors of the cited study not only improved the enantio- selectivity of this reaction compared to the method proposed by Kaneko,114 but also proved unambiguously that cyclisation was accompanied by the transfer of the asymmetric centre from the sulfinyl group to the C(4) atom of the lactam ring. O STol Tol S a NR NHR O O (R)-197a ± d (S )-198a ± d R=MeCHPh (a), Bn (b), CHPh2 (c), 2-BrC6H4CH2 (d); MeO (a) , ZnI2 (cat), MeCN, 20 8C.Me3SiO The mechanism of the first stage of the biosynthesis of penicillins consisting in the construction of the cis-disubstituted lactam ring by oxidative cyclisation of the tripeptide d-(L-a-912 aminoadipyl)-L-cysteinyl-D-valine (199) (LLD-ACV, which was assumed 123 as the direct precursor of isopenicillin N), has long been unknown. SH + NH H3NH O CO¡2O CO2H NH 199 (LLD-ACV) Under the conditions of the sila-Pummerer reaction, amido sulfoxides 200a,b, which contain substituents analogous to those in the compound 199, were demonstrated 124 to give predomi- nantly cis-disubstituted lactams 201a,b. This fact was seemingly evidence in favour of the possible occurrence of the Pummerer sulfenium intermediate in the first stage of the biosynthesis of penicillins. O MeO RNH RNH SPh Ph S , ZnI2 Me3SiO MeCN, 208C N NH O O MeO2C MeO2C cis-201a,b (R)-200a,b H CH2 (b).R=BnO2C (a); BnO2CHN O CO2Bn However, the results of the recent investigation performed by Baldwin and coworkers 125 gave conclusive evidence that the biosynthesis of penicillins takes quite a different path. The key stage of this process involves the attack of the Fe-activated enzyme IPNS on the thiol group of LLD-ACV (199). When analysing this problem, Shibata and Kita 126 admitted that their strategy 124 has not elucidated the mechanism of the biosynthesis of penicillins, but led to substantial improvement in Pummerer- type asymmetric cyclisation and in the Pummerer reactions of nonracemic sulfoxides.In earlier studies (see the review 14), high asymmetric induction was not achieved and ee was at most 30%. 5. Syntheses involving additive Pummerer reactions The most interesting results in the field of the asymmetric syn- thesis of natural compounds were obtained with the so-called additive Pummerer reaction (primarily using the procedure pro- posed by Marino). These investigations have been considered in detail in a previous review 14 and hence, they are only briefly outlined in the present review . The mechanism of the additive Pummerer reaction involves the initial attack of electrophilic dichloroketene, which is prepared in situ by the reaction of the zinc ± copper pair with trichloroacetyl chloride, on the sulfinyl oxygen atom 127, 128 as exemplified below Ar1 Cl2C C O Ar2S(O) Ar1 Ar1 Ar2 Ar2 +SCl +S Cl Cl 7 Cl O O O O7 B A Ar1 Ar1 Cl Cl Ar2S OD OC O O E N Prilezhaeva by disubstituted vinyl sulfoxide.Then the zwitterionic intermedi- ate A is converted into the Pummerer sulfenium-cationic inter- mediate B through the [3,3]-sigmatropic rearrangement involving the vinyl C=C bond. The intermediate B is stabilised through the intramolecular reaction with the carboxylate anion to give 3-arylthio-5,5-dichloro-g-lactone C. After dechlorination and desulfurisation, 3,4-disubstituted lactone D is obtained. The configurations of the chiral centres in the latter compound are completely controlled by the configura- tion of the chiral sulfinyl group in the initial vinyl sulfoxide. The synthesis of the key precursor of the neolignane porosin 202 starting from (S )-(dimethoxyphenyl)prop-1-enyl tolyl sulfoxide (203) 128 is an example of the additive Pummerer reaction.Thiosubstituted dichlorolactone 204, which was obtained in high yield, was dechlorinated with aliminium amalgam to obtain lactone 205. The latter was desulfurised with freshly prepared Raney nickel at 0 8C. The resulting enantiomerically pure g-lac- tone 206 was converted into the target compound (3S,4R)-202 in two steps. Cl Al/Hg Cl2C C O Cl Ar O Ar S THF O TolS O Tol (3R,4S )-204 (S )-203 Ni/Ra 2 steps Ar Ar O O TolS O (3S,4R)-206 (50%) O 205CO2Me (CH2)2COMe Ar O O 202 Ar=3,4-(OMe)2C6H3 .TolS O O Separation of the dechlorination and desulfation stages is important for a successful synthesis. For example, the synthesis of oak lactones 207 from (E,R)-3-(tolylsulfinyl)hept-2-ene (208),127 which involved one-step dechlorination ± desulfurisation of lac- tone 209 under the action of tributylstannane, afforded the final product as a mixture of enantiomers. TolO S Bun Bu3SnH Cl2C C O Bun Cl AIBN Cl 209 (R)-208 O O O Bun O Bun + (3S,4R)-207 (3S,4S)-207 AIBN is azodiisobutyronitrile. The additive Pummerer reactions can be performed with various nonracemic a,b-unsaturated sulfoxides. Thus lactone (+)-(R)-212, which is the key intermediate in the syntheses of a broad spectrum of lignane lactones, was derived from (Z,R)- piperonylvinyl sulfoxide (210) via lactone 211.129 O O Cl2C C O O S Tol (Z,R)-210Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds O Ar O O O O Cl O 3 steps O O Cl O STol (+)-(R)-212 cis-211 Ar=3,4,5-(OMe)3C6H2 .In the synthesis of (7)-physiostigmine (213) (the alkaloid used for the treatment of glaucoma), the reaction pathway was found to depend on the electronic and steric characteristics of the sulfinyl group and on the bulkiness of the protecting group at the nitrogen atom of the initial 2-sulfinylindole.130 5-Benzyloxy-3-methyl-2- (isopropylsulfinyl)indole [(S )-214] containing the protecting Boc group at the nitrogen atom proved to be the starting compound of choice.The reaction involving the above reagent proceeded through the tricyclic adduct with dichloroketene 215 to yield (7)-physiostigmine [(7)-213] exhibiting specific optical rotation identical to that of the natural compound. BnO Cl2C C O O S NBoc (S )-214 Pri MeNHC(O)O BnO Cl Cl 7 steps O O M Ne NMe NBoc SR 215 (7)-213 Sulfinyl-substituted triene 216 is an example of polyunsatu- rated sulfinyl precursors. This compound was utilised in the synthesis 131 of drimane-type sesquiterpenoids (+)-fragolide (217) and (+)-pereniporin (218). The process began with the addition of dichloroketene and the construction of p-tolylthiodi- chloro-g-lactone fragment in compound 219.The subsequent multistage transformation involved dechlorination and desulfur- isation along with cationic cyclisation with the participation of the vinylsilane group. O TolS O Me3Si Tol S Me3Si O 16 steps Cl2C C O HCl Cl 216 219 O O O O 3 steps HO H H OH O (+)-217 (7)-218 The advantages of the additive Pummerer reaction are the possibile subsequent transformations of primary g-lactones, which can be used in enantioselective syntheses of compounds with various structures. For example, in the facile synthesis of the pheromone with the linear structure, viz., (7)-(4S,6S,7S )-serricor- nin (220),132 starting from (E,R)-3-(tolylsulfinyl)pent-2-ene (221), g-lactone 222 was converted into the key intermediate, viz., 4,5- disubstituted valerolactone 223, with retention of the chiral centres.913 O O S 2 steps O Tol 3 steps 222 (+)-(E,R)-221O OAc O O ... (7)-(4S,6S,7S )-220 223 The product of the Pummerer reaction of b,b-disubstituted vinyl disulfoxide (R)-224 with dichloroketene was dechlorinated in situ and then converted into 4,4-disubstituted cyclohexenone 225, which was the key compound in the synthesis of the alkaloid (+)-mesembrin [(+)-226].133 O O O Ar 1) CCl2 C O 2 steps O O S 2) Zn, AcOH Ar STol Tol (R)-224 O Ar CH2CO2Me Ar 4 steps O N H Me (+)-226 O 225 Ar=3,4-(OMe)2C6H3 . Marino's procedure does not exhaust the synthetic possi- bilities of the additive Pummerer reaction. Iwata et al.134 found that a,b-unsaturated sulfoxides, including cyclic sulfoxides, underwent the Pummerer-like reaction under the action of allyl- magnesium bromide and applied this reaction to the enantiose- lective total synthesis of (7)-sibirine (227).135 The monoallylation product 228 of cyclohexene sulfoxide (7)-(S )-229, which was readily separated from diallylated compound 230, already con- tained the chiral quaternary carbon atom characteristic of (7)-sibirine 227.The latter was prepared by a multistage trans- formation; its specific optical rotation corresponded to that of the natural alkaloid. Tol S O MgBr 778 to 20 8C CH(OMe)2 (7)-(S )-229 STol STol CH(OMe)2 + CH(OMe)2 230 (20%) 228 (60%, ee 96%)OH ... 228 N 227 An analogous methodology was employed in the facile syn- thesis of the spirocyclic alkaloid (7)-perhydrohistrionicotoxin, which also contains the quaternary chiral centre.136914 6.Syntheses based on cascade processes involving the Pummerer reaction Examples of application of cascade processes involving the Pummerer reaction to syntheses of natural products were consid- ered above. It should be noted that Padwa and coworkers have obtained particularly impressive results in recent years.12, 137 ± 139 The tandem use of the Pummerer and Diels ± Alder reactions made it possible to develop a versatile procedure for the con- struction of polycyclic molecules. Thus treatment of sulfinyl- methyl-substituted diaryl ketone 231 with acetic anhydride and then with dimethyl maleate afforded 137 adduct 232 of the initially formed Pummerer-reaction product, viz., a-ethylthioisobenzo- furan 233, in high yield. Simple transformations of the adduct 232 gave rise to natural lactones of the naphthalene series, viz., taiwanin 234 and justicidin E 235.SEt CH2S(O)Et O O 1) Ac2O O CO2Me O O O 2) Ar CO2Me 231 Ar 233 SEt CO2Me O O O CO2Me 232 (85%) Ar Ar O 4 steps O O 234 OO O 2 steps O O 235 Ar O Ar= . O O SEt O CH2S(O)Et O Ac2O O TsOH COH N N 236 PhSO2 PhSO2 237 SEt OO N O PhSO2 238 (87%) Kappe and Padwa 138 used o-formyl-substituted indole sulf- oxide 236 as the starting compound. After the Pummerer reaction, the primary cyclisation product 237 was treated (without isola- tion) with maleic anhydride to obtain carbazole derivative 238 in high yield.This method can be used for the construction of natural carbazoles, for example, of ellipticine.12 The one-pot synthesis of the five-membered cyclic skeleton of the alkaloid erythrinane is a particularly elegant cascade proce- dure.139 For this purpose, compound 239, which was derived from polysubstituted aromatic sulfoxide 240 under the action of Ac2O in the presence of a catalytic amount of TsOH, was heated with an additional amount of TsOH. The process involved an intra- molecular Diels ± Alder reaction giving rise to adduct 241 fol- lowed by the oxabicycle opening yielding product 242 and, finally, cyclisation of the latter involving the N-acyliminium ion to give 3,4-benzoerythrinane 243 (the total yield was 70%).Padwa et al. 139 noted that the tandem process proceeded more or less readily depending on the reaction conditions. The best results were obtained with the use of Ac2O in toluene in the presence of catalytic amounts of TsOH, which efficiently suppressed the formation of acetoxy sulfide (a normal product of the Pummerer reaction). CH2S(O)Et O Ar(CH2)2NC(O)CH2 240 SEt O Ar(CH2)2N 239 SEt O Ar(CH2)2N 241 MeO MeO 243 Ar=3,4-(MeO)2C6H3 . IV. Use of the Ramberg ±BaÈ cklund rearrangement for the insertion of C=C bonds The Ramberg ±BaÈ cklund rearrangement (see the reviews 3, 141, 142), which is the oldest reaction 140 of all known sulfonyl rearrangements, proceeds with the participation of sul- fones of type 244 containing a substituent X in the a position as substrates.The substituent can be readily removed in the anionic form once carbanion 245 is generated through a-deprotonation. The mechanism of the process was confirmed by the results of numerous kinetic studies (see the review 3). X H SO2 244 SO2 246 The reaction gives rise to the C=C bond in the strictly fixed site of the molecule through the formation of episulfone 246, which readily eliminates SO2 . The involvement of the intermedi- ate 246 in the rearrangement was long judged from indirect evidence. Recently, episulfones, which are stable only below 720 8C, were prepared by the reactions of ButOK with some highly reactive a-iodosulfones primarily of the thiolane 1,1-di- oxide series.143 E N Prilezhaeva Ac2O TsOH (cat) CO2Me TsOH D O CO2Me O CO2Me CO2Me + Ar(CH2)2N O O 242 O CO2Me N O B 7 Slow 7X7 X HB SO2 245 Rapid 7SO2Rearrangements of sulfoxides and sulfones in the total synthesis of natural compounds The Ramberg ±BaÈ cklund reactions are traditionally carried out with the use of a-Cl and a-Br-substituted sulfones as the starting compounds.Halogenation with soft reagents, for exam- ple, with N-halogenosuccinimides, is often performed at the stage of the initial sulfide before its oxidation to sulfone. Meyers et al.144 devised a convenient modification of this reaction, which allowed the one-pot preparation of a-chlorosub- stituted sulfone and its subsequent rearrangement.In this version, sulfone was treated with powdered KOH in CCl4±ButOH. Unfortunately, this reaction is sometimes complicated by side processes, such as excessive halogenation or formation of chloro- carbene. To prevent these side reactions, Chen et al.145 used KOH adsorbed on Al2O3 in ButOH in the presence of CBr2F2 , which does not generate carbenes. The Ramberg ± BaÈ cklund reaction is actually a versatile procedure for the construction of the C=C bond; the configu- ration of the latter depends both on the structure of the initial sulfone and the reaction medium; in open-chain compounds, the resulting bond generally has the E configuration.The synthetic importance and applications of this reaction were covered in reviews.141, 142, 146 However, the data on use of this process in syntheses of natural compounds is systematised for the first time in the present review. Examples of the construction of isolatedC=Cbonds in open- chain natural compounds or in linear fragments of more complex molecules are considered below. Thus the ButOK-induced rear- rangement of a-chlorosulfone was used in the highly E-stereo- selective synthesis of D22-unsaturated steroids of types 247a,b starting from sulfides 248a,b, which were prepared based on 3a,5a-cyclo-6b-methoxypregnane.147 The structure of the com- pound 247a was proved by its conversion into the known steroid 249a. This synthesis was carried out in view of the fact that many exotic steroids from plants and animals contain unsaturated side chains. R S a, b, c H H MeO 248a,b H R d 249a AcO 247a,b (70% ± 75%) R = H (a), Et (b); (a) NCS, CCl4; (b) MCPBA, NaHCO3; (c ) 3 equiv.of ButOK; (d ) R=H, Zn(OAc)2, AcOH. Non-6-en-1-ol (250), which is a pheromone of Mediterranean fruit flies,148 was synthesised with the use of the rearrangement of linear a-bromosulfone 251, which was prepared by the reaction of 2-(n-propylsulfonyl)cyclohexanone (252) with bromine and NaOH. This reaction provided the basis for a general procedure O SO2Prn EtONa Br2, NaOH HO2C(CH2)4CHSO2CH2Et H2O EtOH 252 251 (98%) Br CHEt LiAlH4 HO2C(CH2)4CH (80%) OH 250 (95%) 915 for the synthesis of a-bromosulfones.The scheme of the synthesis ended in reduction of the carboxyl group to the alcoholic group in the initially formed non-6-enoic acid. The short synthesis of natural artemisia ketone (253) (the total yield was 86%) starting from methyl trifluoromethylsulfonyl- methyl sulfone (254) demonstrated that the triflate fragment is an excellent leaving group in the Ramberg ± BaÈ cklund reaction. The rearrangement of ketosulfone 255, which was prepared by alkylation followed by acylation of the sulfone 254, was carried out at room temperature under conditions of phase transfer catalysis.149 COCl Tf SO2Me TfCH2SO2Me MeI K2CO3 LDA 254 7 Bun4 NHSO4 Tf SO2CH NaOH, H2O, CH2Cl2 O 255 253 O Tf =CF3SO2; LDA is lithium diisopropylamide.Polyenes, including those containing conjugatedC=Cbonds, can be constructed by the Ramberg ± BaÈ cklund rearrangement starting from substituted diallyl sulfones. In an early study,150 sulfones 256a ± d were used for this purpose. It appeared that treatment of the sulfones 256a ± c with KOH and CCl4 at room temperature afforded mixtures of stereoisomeric polyenes 257a ± c in high yields, whereas the retinyl sulfone 256d did not enter into the reaction under these conditions. To prepare a mixture of polyenes from the latter compound, it was successively treated with butyllithium (it was assumed that dianion 258 was formed) and halogen. Isomerisation of a mixture of the compounds 257d under the action of iodine or upon heating gave rise to natural all- trans-b-carotene (259).R SO2 KOH, CCl4 R R 20 8C 2 257a ± c (78% ± 89%) 256a ± c SO2 R 2 equiv. of BunLi Hal2 256d 7 7 R 258 I2 or D 257d 259 (24%) (d). (c), (b), R=Me (a), Later, mixtures of substituted polyisoprenoids 261a ± c were obtained from diallyl sulfones 260a ± c containing polar substitu- ents Z according to Meyers's procedure.151 ButOK, CCl4 R CH2Z SO2 260a ± c R CH2Z 261a ± c (55% ± 91%) ; Z=OEt (a), CH2COMe (b), R=H, CH2C(Me)(OH)CH=CH2 (c).916 The synthesis of natural undecatrienes 262 and 263 and undecatetraenes 264 and 265 (the compounds 262 and 263 find use in perfumery) from the corresponding diallyl sulfones accord- ing to Meyers's procedure 152 also afforded mixtures of geometric isomers.Bun 262 264 Burger et al. 153 failed to elaborate the stereoselective synthesis by decreasing the basicity of the reaction medium through the generation of the required anion by the addition of the sulfinate anion to a-halogenovinyl- (266) or butadienyl sulfones 267 [the so-called MIRB process (Michael Induced Ramberg ± BaÈ klund)]. Starting from sulfones 268 and 269, this procedure also yielded mixtures of stereoisomeric isoprenoinds.153 The authors of the cited studies 150, 151, 153 did not examine the mechanisms of these processes. Hence, the stage at which Z-bonds are formed in the syntheses starting from all-trans compounds remains unknown. X SO2 +Nu 266 X SO2 Nu 7 X SO2 +Nu 267 Nu X SO2 7 Nu=SO2Ph; X=Cl, Br.Cl SO2 268 Recently, the problem of the construction of all-trans-polyene through the Ramberg ± BaÈ cklund rearrangement has been suc- cessfully solved 154 in the synthesis of natural b-carotene 259, which (along with its analogues) is finding increasing use as a food ingredient possessing simultaneously chemotherapeutic activity against some varieties of cancer. The scheme of the synthesis was based on alkylation of readily accessible sulfone 270 with di- chlorodiallyl sulfide, which was prepared from isoprene in four steps. In the alkylation stage, NaI was added to the reaction mixture to form in situ more reactive iodide. Then intermediate 271 was converted into sulfone 272 and the latter was subjected to the rearrangement into compound 273 under very mild conditions (oxidation with peroxyphthalic acid formed in situ and Meyers's rearrangement under an atmosphere of argon).The sulfonyl groups were removed from the intermediate 273 by reduction. Starting from isoprene, b-carotene 259 (all-trans) was obtained in a total yield of 13%. Judging from the results obtained in the cited study, the Ramberg ± BaÈ cklund rearrangement of the sulfone 272 gave rise exclusively to the (E)-C=C bond. The presence of sulfonyl groups in the radical R prevents isomerisation of the already existing (E)-C=C bonds. SO2Ph 270 Cl + S Bun 263 265 SO2 Nu Nu Nu SO2 269 + NaH, THF Cl NaI R R S 271 R R SO2 272 (75%) R R 273 (82%) SO2Ph.R=This procedure can also be used for the construction of other natural all-trans-polyenes. Thus, this procedure was employed 154 for the preparation of key intermediate 274 in the synthesis of carotenoids by the Wittig method. O O 274 In his review, Paquette 141 emphasised that the construction of unsaturated rings of different sizes is one of the problems, which can be solved by applying the Ramberg ± BaÈ cklund rearrange- ment. Examples of the use of this rearrangement in the synthesis of natural compounds are the preparation of both unsaturated carbocycles and oxygen-containing heterocycles. In the study,155 the cyclopentene ring in steroid 275 was formed starting from tetracyclic a-chloro-substituted sulfone 276, which was synthesised in two steps from the adduct of diene 277 and 2,3-dihydrothiopyran-4-one S,S-dioxide (278).O O S 150 8C + MeO 277 O 278O O S 2 steps O MeO O O H S Cl ButOK DMSO O O MeO MeO 276 Dehydrojasmone 279 was synthesised starting from (trifluo- romethylsulfonylmethyl)sulfone 254. The latter compound was converted into cyclic ketosulfone 280 containing the triflate group, which was eliminated to give the target product 279.156 O n-C8H17 ... Tf TfCH2SO2Me 254 O 280 Me 279 C8H17-n E N Prilezhaeva CO3H CO3H KOH, ButOH CCl4 Na, EtOH 259 D O O 275 O S Me K2CO3 THF, D ORearrangements of sulfoxides and sulfones in the total synthesis of natural compounds Meyers's method was successfully used 160 for the conversion of 1,4-oxathiane fragment of compound 287 (after oxidation of sulfide sulfur to sulfonyl sulfur) into the dihydrofuran fragment of compound 288.The latter compound was converted in three steps into acetogenin (+)-solamine (289). This procedure is applicable to syntheses of other acetogenins possessing various biological activities. HO An interesting procedure was developed 157, 158 for the syn- thesis of enantiomerically pure cyclohexene alcohols of type 281a ± c, viz., conduritols containing four chiral alcoholic centres. These compounds are inhibitors of glycosidases and also serve as the key compounds in the preparation of agents, which show promise for AIDS treatment. These alcohols were synthesised starting from sugar derivatives containing the required chiral centres.The latter compounds were converted into thiepanes whose oxidation to sulfones followed by the rearrangement under Meyers's conditions gave rise to conduritols in high yields. This procedure was used for the preparation of (7)-conduritol E derivative (281a) 157 from D-mannitol through thiepane 282 and its sulfone 283. All reactions proceeded in quantitative yields, the starting chiral centres remaining intact. Later, this procedure was extended 158 to the synthesis of derivatives of (7)-conduritol F (281b) and (+)-conduritol B (281c) starting from D-sorbitol and L-iditol, respectively. Conduritols (7)-F and (7)-E containing four unprotected hydroxy groups were obtained in 83% and 79% total yields, respectively, using readily removable benzyl instead of methyl as protecting groups.158 CH2OH S HO O O HO a, b OMe MeO HO OH 287 OH CH2OH S 282 OMe OMe O O OH O d c OMe MeO O OH S O OMe (94%) OMe 281a (94%) O 283 (98%) (a) MCPBA, 0 8C; (b) Na2S2O5 , CCl4 , 20 8C; (c) KOH, ButOH, CCl4 , H2O, 20 8C; (d ) 0.1 N H2SO4 .OMe OMe OH OH (a) MCPBA; (b) Me3SiCl, Et3N; (c) ButOK, ButOH, CCl4. OH OH OMe 281c OMe 281b In the course of the studies aimed at preparing polycyclic ciguatoxin, an efficient procedure was devised 161 for the prepara- tion of dioxabicyclic systems. For this purpose, trans-fused bicyclic intermediates 290a,b and 291a,b generated by thioanne- lation were successively subjected to a-chlorination, oxidation to sulfones and rearrangement without isolation of intermediates.The resulting oxabicyclic compounds 292a,b and 293a containing O In the synthesis of the strained nine-membered oxygen-con- taining ring of (+)-eremantholide (284), which exhibits antitu- mour activity in vitro, the final stages were carried out with the use of a-chloro-substituted sulfone 285.159 The latter was unstable in the presence of strong bases due to which the rearrangement was performed under the action of the weakly basic alkoxide of 3-ethylpentan-3-ol. Under these conditions, intermediate 286 was obtained in quantitative yield and was converted into the final product in one step.H 290a,b O O n = 2 (290a), 3 (290b); m = 1 (292a), 2 (292b). O O O O Et3COK 6MHCl O H THF H H DME, HMPA 70 8C O2S O O O O H 291a,b Cl 285 286 (82%) n = 3 (291a), 4 (291b); m = 2 (293a), 3 (293b). (a) NCS, CCl4; (b) MCPBA; (c) ButOK, THF. O OH O O HO O 284 (85%) 3 a, b, c O 3 Me3SiO 3 O Me3SiO 3 288 HO 3 O HO 3 (+)-289 H H O S a, b, c n O H 292a,b (37% ± 40%) H O S a, b, c n O H 293a,b (37% ± 48%) 917 3 steps O O H m OO m918 the newly formed six-, seven or eight-membered rings occurred as individual trans-fused molecules. Only compound 293b with the nine-membered ring was obtained as a mixture of cis and trans isomers.V. Conclusion The data surveyed in the present review show that rearrangements of sulfoxides and, to a lesser extent, of sulfones find many varied applications in the total syntheses of natural compounds, includ- ing enantioselective processes. In the coming years, one would expect the wider use of cascade processes involving these rearrangements. The extension of tandem processes, for example, the Diels ± Alder reaction followed by the sulfoxide ± sulfenate rear- rangement involving enantiomerically pure sulfinyl-substituted dienes, to the synthesis of natural compounds has considerable promise.162 The SPAC cascade process, which has been developed recently (by two research groups 163, 164 virtually simultaneously) and which provides a route to the synthesis of g-hydroxy-a,b- unsaturated sulfones, can find application in functionalisation of natural compounds.R1 CHCHO+PhSO2CH2R R2 R=4-MeC6H4, 4-ClC6H4. In particular, Trost and Grese 164 demonstrated that this process occurred under very mild conditions, which allow the successful use of even such a labile compound, as galactose derivative 294, as an aldehyde component. CHO O O PhSO2CH2SOC6H4Cl-4 O O O NH, MeCN 294 However, the reagents used in a particular stage of the tandem process must be chosen with caution. Thus attempt was made to synthesise the ethyl ester of 15-D2c-isoprostane (295) (which belongs to compounds structurally related to prostaglandins) starting from sulfide 296 through the Mislow ± Evans rearrange- ment.165 Generally (see Refs 23 ± 26), the oxidation ± rearrange- ment tandem processes give rise to the `lower branch' of the product with correct stereochemistry.However, the last-men- tioned process afforded C(12)-,C(15)-epimer 297 rather than isoprostane 295. OH 12 15 O OH 295 OH O 296 SPhOH O OH 297 OH MeCN R1 SO2Ph R2 NH, 20 8C (40% ± 90%) HO H O O PhSO2 O O O (73%) CO2Me 1) MCPBA CO2Me 2) P(OMe)3 CO2Me E N Prilezhaeva The authors believed that epimerisation was preceded by rearrangement under the action of residual amounts of m-chloro- perbenzoic acid. As for the Pummerer reaction, one would expect new examples of its application to the asymmetric synthesis of natural compounds both involving novel efficient inducing agents (for example, vinyl esters containing the ethoxy group in the a position proposed in recent years 166) and by designing new reagents for the additive Pummerer process.Investigations carried out by Padwa and coworkers with the aim of devising new cascade processes hold much promise. For example, the tandem use of the Pum- merer reaction and subsequent intramolecular [3+2]-cycloaddi- tion has been applied.167 One would expect that the Ramberg ± BaÈ cklund reaction will continue in use for the construction of unsaturated natural cyclic molecules. It is likely that the recent cascade process,168 which readily affords benzoannelated polycyclic molecules, will be extended to the synthesis of natural compounds.The process starts with the photochemical [6p+4p]-cycloaddition of various dienes to the chromium tricarbonyl complex of 1,1-thiepin dioxide (298) and ends in the Ramberg ± BaÈ cklund rearrangement of the resulting adduct 299.O O S hn + Cr(CO)3 298 SO2 1) ButOK, THF,7105 8C 2) NCS 3) ButOK, THF 299 (31% ± 81%) The characteristic feature of this process is that it makes possible both rapid assembly of the final polycyclic product (for example, in the synthesis of compound 300) and the stereospecific synthesis (for example, in the synthesis of compound 301) with the use of chiral nonracemic dienes. H SO2 a b, c, b H H MeO MeO MeO 300 (62%) SO2 a b, c, b H H 301 (45%) (a) 298, hn; (b) ButOK, THF, 7105 8C; (c) N-iodosuccinimide, THF. The investigations published in the very recent past 169 ± 175 (after the present review had already been written) demonstrated that the rearrangements of sulfones and sulfoxides continue in use in syntheses of natural products. The investigations of Padwa and coworkers devoted to the application of cascade Pummerer cyclisation ± deprotonation ± cycloaddition processes to syntheses of alkaloids were summarised in a review.169 Intramolecular Pummerer cyclisation was used as the key stage in the synthesis of bicyclic precursors for anthracyclinones.170 The PummererRearrangements of sulfoxides and sulfones in the total synthesis of natural compounds reaction was employed 171 in the stereoselective synthesis of 4b-thioribonucleosides.The procedure for the construction of the oxathiazepine ring using the modified Pummerer cyclisa- tion 111 was extended to the synthesis of (7)-eudistamines C, E, F, K and L.172 Other rearrangements were used more rarely. 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年代:2001

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Russian Chemical Reviews 70 (11) 921 ± 938 (2001) (Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis{ S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Contents I. Introduction II. Methods of synthesis and tautomerism of (het)aroylpyruvates III. Chemical properties of (het)aroylpyruvates IV. Biological activities of (het)aroylpyruvates and the products of their heterocyclisation V. Conclusion Abstract. and acids (het)aroylpyruvic of synthesis of Methods Methods of synthesis of (het)aroylpyruvic acids and their acyclic derivatives (esters, amides and hydrazides), and their their acyclic derivatives (esters, amides and hydrazides), and their reactions with various C-, N-, O-, S-nucleophiles are described. reactions with various C-, N-, O-, S-nucleophiles are described.Problems of activity biological and tautomerism of Problems of tautomerism and biological activity of (het)aroylpyr- (het)aroylpyr- uvates and products of their transformation are briefly consid- uvates and products of their transformation are briefly consid- ered. references 191 includes bibliography The ered. The bibliography includes 191 references. I. Introduction (Het)aroylpyruvic acids [(H)APA] and their derivatives, (het)- aroylpyruvates, [(H)AP] were discovered back in the XIX cen- tury.1, 2 They proved to be interesting and useful synthons permitting the preparation of a very broad spectrum of products, in particular, diverse heterocyclic compounds many of which possess biological activities.At present, this class of compound still remains attractive for researchers.3 ± 9 The chemistry of (H)AP is fairly extensive but the current state of investigations in this field is not covered in the world literature. This review is meant to fill this gap. Cyclic APA derivatives, 5-aryl-2,3-dihydrofuran-2,3-diones have been considered in reviews 7, 10 and will not be discussed here in detail. A review has been devoted to the chemistry of perfluoroaroylpyruvates;3 therefore we note below only specific features of these compounds not found for non-fluorinated analogues. II. Methods of synthesis and tautomerism of (het)aroylpyruvates 1. Methods of synthesis of (het)aroylpyruvates The Claisen condensation of the corresponding (het)aryl methyl ketones 1 with dialkyl oxalates in the presence of sodium metal or sodium (potassium) alkoxides is the main and the most convenient S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, ul.S Kovalevskoi 20, 620219 Ekaterinburg, Russian Federation. Fax (7-343) 274 59 54. Tel. (7-343) 249 34 91. E-mail: fc208@ios.uran.ru (S G Perevalov) Tel. (7-343) 249 34 91. E-mail: burgart@ios.uran.ru (Ya V Burgart) Tel. (7-343) 249 59 54. E-mail: saloutin@ios.uran.ru (V I Saloutin) Tel. (7-343) 274 11 89. E-mail: chupakhin@ios.uran.ru (O N Chupakhin) Received 15 June 2001 Uspekhi Khimii 70 (11) 1039 ± 1058 (2001); translated by Z P Bobkova #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n11ABEH000685 921 921 923 935 936 Scheme 1 Ar CO2R 1) B 2) H2O, H+ O O ArCOMe+(CO2R)2 1 H2 Ar CO2R Cu(OAc)2 H+ O 3 O Cu/2 Ar CO2H H2O O O H4 1 ± 4: Ar=Ph, 2-XC6H4 (X=NO2, OH), 4-XC6H4 (X=NHAc, Br, Cl, Ph, OH, OMe), 2-OH-4-OMe-C6H3, 2-OH-4-OEt-C6H3, 2,4-(OEt)2C6H3, 2,5-(OEt)2C6H3, 2,4-Me2C6H3, 2,4,6-(OMe)3C6H2, 2-OH-4,6-(OMe)2C6H2, C6F5, 2-naphthyl, 1-hydroxy-2-naphthyl, 3-phenanthryl, 2-pyrrolyl, 2,5-dimethyl-3-pyrrolyl, 2,3-dimethyl-4- pyrrolyl, 2-thienyl, 5-methyl-2-thienyl, methyl(phenyl)-2-thienyls, 2-furyl, Py, 5-X-indol-3-yls (X=H, OMe, Cl), 2-methyl-5-methoxy-3-benzo[b]- furyl, substituted 5-oxazolyls, 2,4-dimethyl-5-thiazolyl, 3-X-4-syd- nonyls (X=Me, Ph), cymantrenyl.B=Na, NaOR, KOR, LiH; R=Et, Me, Pr, Ph. method for synthesis of (H)APA esters 2 (Scheme 1). Alcohols, diethyl ether, benzene or toluene are used as solvents.1, 2, 11 ± 23 Pentafluorobenzoylpyruvates are prepared from pentafluoroace- tophenone in the presence of lithium hydride.3, 5, 24, 25 It is convenient to isolate and purify labile AP as their copper(II) chelates 3.1, 13, 14, 16 This is especially required in the case of pentafluorobenzoylpyruvates,5, 24, 25 which cyclise very easily to chromone derivatives due to the presence of ortho-fluorine atoms in the benzoyl substituent. Hydrolysis of the esters 2 to the corresponding acids 4 is normally carried out in an acid medium,1, 23, 26, 27 although examples of alkaline hydrolysis are also documented.2, 11 A method for the preparation of ethyl 4-(1,2-diaryl-4- hydroxy-5-oxo-1H-pyrrol-3-yl)-2-hydroxy-4-oxobut-2-enoates 5 { Dedicated to Academician O M Nefedov with appreciation and on the occasion of his seventieth birthday.922 by the reaction of diethoxalylacetone with diarylazomethines was proposed not long ago.28 O O O O O +RN CHC6H4X-4 20 8C OEt OEt H O O HO CO2Et O C6H4X-4 NR 5 (4% ± 36%) R=Me, 4-YC6H4 (Y=H, Me, OMe, Br); X=H, OMe, Br, Cl.The condensation of acetophenones 1 with esters of oxanilic acids is used for the synthesis of APA amides 6.29 Ar CONHAr MeONa MeOH O ArCOMe+ArNHCOCO2Et 1 H O 6 (32% ± 40%) Ar=4-XC6H4 (X=H, Me, OMe).Preparation of the amides 6 from the APA methyl esters 2 and N-phenylethylenediamine 30 or 2-aminopyridine has been described.31 Ar CONHR Ar CO2Me RNH2 O O O H O 6 (61% ± 85%) H2 Ar=4-XC6H4 (X=H, Me, OMe, Br); R=(CH2)2NHPh, 2-pyridyl. Methods for the synthesis of APA 4,32 the esters 2,32 ± 37 the amides 6,30, 31, 37 ± 64 and hydrazides 65 ± 74 based on the reaction of the corresponding 5-aryl-2,3-dihydrofuran-2,3-diones 7 38 with diverse nucleophiles have now become significant practically. The range of reagents used includes water,32 alcohols,32 oximes 33 ± 36 and amides of 2-hydroxy acids;37 amines,30, 31, 37 ± 39, 41 ± 44, 48, 51 ± 64 2-aminophenol,37 ethanolamine,37 amino acids,40, 49 thiols,44, 45 mercaptoethanolamine,44 amides of thioacids,50 acyl- and aroyl- hydrazides,65, 67 ± 69, 72, 73 hydrazine,66 and hydrazones.70, 71, 74 O Ar COR +RH O O Ar O H O 2, 4, 6 7 2: R=OAlk, OPh, ON=CR12 ; 4: R=OH; 6: R=NH2, NHAlk, NHAr, NHHet.The APA amides and hydrazides 6 have been prepared by acid hydrolysis of 5-aryl-2-imino-2,3-dihydrofuran-3-ones 8.75 ± 78 O CONHR Ar H2O, H+ O NR Ar H O 6 (64% ± 85%) O8 Ar=4-YC6H4 (Y=H, Me, OMe, Cl, Br); R=CH2SO2C6H4Me-4, 1-adamantyl, N=CHCOPh. Extensive hydrolysis of 1-aryl-4-aroyl-5-methoxycarbonyl- 2,3-dihydropyrrole-2,3-diones 9 affords the APA 4.79 S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin O O Ar Ar CO2H H2O, H+ O O O MeO2C NR H 4 (77% ± 82%) 9 Ar=4-XC6 H4 (X=H, Me, OMe), R=Ar (X=H, Me, OMe, NO2), etc.3-Halogen-substituted esters 10 (R=OEt, OMe) and amides 11 (R=NHPh) of APA are prepared by halogenation of the corresponding AP 2 (see papers 18, 80 ± 84) and 6 39, 85, 86 (Scheme 2). Scheme 2 Hal COR Ar Hal2 or SO2Cl2 Ar COR O O O H O 2, 6 10, 11 (83% ± 98%) Ar=4-YC6H4 (Y=H, Me, OMe, F, Cl, Br), 2,4,6-Me3C6H2, 2-naphthyl; Hal=Cl, Br; R=OEt, OMe, NHPh. The amides 11 can also be synthesised from 5-aryl-4-halo-2,3- dihydrofuran-2,3-diones 12 by introducing them into a reaction with diarylazomethines.87 Hydrolysis of the furandiones 12 read- ily gives 3-halo-APA 13.88 Hal Ar CONHPh PhN CHAr0 O O Hal O 11 (53% ± 94%) Hal Ar O H2O Ar CO2H O12 O O 13 Hal=Cl, Br; Ar=4-YC6H4 (Y=H, Me, OMe, Cl).The reaction of the APA esters 2 and amides 6 with diphe- nyldiazomethane gives rise to 3-diphenylmethyl-substituted AP 14 81, 89 and 15.90 It should be noted that APA 4 are esterified in this reaction to give the esters 2 (Scheme 3). Scheme 3 Ar CO2CHPh2 R=OH 20 8C O O COR Ar H2 Ph2CN2 CHPh2 O Ar COR R=OAlk, NHAr0 H O 2, 4, 6 70 ± 80 8C O O 14, 15 (7% ± 87%) Azo coupling of the APA 4 91 ± 93 and the esters 2 94 ± 96 with aryldiazonium salts is used to prepare 3-arylhydrazones of 4-aryl- 2,3,4-trioxobutanoic acids 16 and their esters 17 (Scheme 4). Scheme 4 NNHAr0 COR Ar Ar0Ná2 Cl7 Ar O 0± 208C O COR O 16, 17 (41% ± 91%) H O 2, 4 2, 17: R=OMe, OEt; 4, 16 : R=OH. The esters 17 are also formed in the alcoholysis of 1-aryl-3- aroyl-4,5-dihydropyrazole-4,5-diones (18).92 Treatment of the(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis pyrazolediones 18 with amines yields 4-aryl-2,3,4-trioxobutyra- mide 3-arylhydrazones 19 97, 98 and 20.98 NNHAr0 MeOH Ar O O CO2Me 17 (74% ± 95%) O O NNHAr0 Ar00NH2 O Ar CONHAr00 Ar N N O O 18 Ar0 19 (28% ± 99%)O Ar0HNN NH A Ar N A O O 20 (52% ± 92%) 2.Tautomerism of (het)aroylpyruvates Tautomeric equilibrium has been studied for a series of (H)AP (Scheme 5). According to 1H NMR data, the 3-unsubstituted (H)APA 4, their esters 2 and amides 6 exist in solution as enols.81, 99, 100 The enol structure of the benzoylpyruvic acid 4a has also been confirmed by X-ray diffraction analysis.101 Only ethyl 4-(3-indolyl)-2,4-dioxobutanoate in DMF-d7 is a mixture of ketone and enol tautomers in a ratio of*1 : 1.20 Scheme 5 R2 1 R2 3 1 2 4 R1 COR3 3 2 4 R1 COR3 O O O O H R1=Ar, Het; R2=H, Cl, Br, N=NAr, Alk, Ar; R3=OR4, NR42 , NR1NR42 (R4=H, Alk, Ar, COAlk). In the case of 3-alkyl- and 3-halo-substituted AP 10, 11, and 13 ± 15, the ketone form predominates.102 ± 105 Apparently, the hampered formation and energetic destabilisation of the enol form are caused by the presence of bulky substituents at the 3-position.The spectral data for the AP 16, 17, 19 and 20 available to date indicate that 3-arylhydrazone-substituted acids 16,92 esters 17 92, 96 and amides 19 and 20 97, 98 occur as equilibrium mixtures of Z- and E-tautomers of the ketone form relative to the C=N bond.Ar0 O COR N H N Ar N O Ar O NAr0 O COR H (E) (Z) III. Chemical properties of (het)aroylpyruvates (Het)aroylpyruvates contain three electrophilic centres, namely, the C(1) atom of the ester group and the C(2) and C(4) carbonyl atoms, and one nucleophilic centre, namely, the meso-position of the b-dicarbonyl fragment, i.e., the C(3) atom (see Scheme 5). Therefore, the (H)APA 4, their esters 2 and the amides 6 tend to react with nucleophilic reagents at the C(1), C(2) and C(4) atoms. In addition, (H)AP enter into reactions with electrophiles at the C(3) centre. These transformations are mainly considered in the previous Section concerned with the methods of synthesis of (H)AP (see Schemes 2 ± 4).A typical feature of (H)AP is the susceptibility to thermal transformation. Some (H)AP are able to undergo intramolecular cyclisations. 923 1. Thermal transformations and intramolecular cyclisations of (het)aroylpyruvates a. Thermal transformations Virtually all (H)AP are fairly labile compounds.O-Aroylpyruvoyl oximes 21 undergo decarbonylation at 1008C giving rise to O-aroylacetyl oximes 22.34 Ar ON CR1R2 Ar COON CR1R2 100 8C O O O 21 H O22 (65%± 75%) Ar=4-XC6H4 (X=H, Me, Et, Cl); R1=H, Me; R2=Ph, 2-HOC6H4, 1-adamantyl. Under similar conditions, O-aroylpyruvoyl oximes 23, con- taining an amino group, cyclise to 3-aryl-5-(3-aroyl-1-hydroxy- propenyl)-1,2,4-oxadiazoles 24.35 O Ar NH2 O N 100 ± 110 8C O H O R1 R2 23 Ar R1 N R2 OH O N O 24 (40% ± 60%) Ar=4-XC6H4 (X=H, Me): R1=R2=H, OMe; R1=H, R2=NO2.Arylamides of the 3-unsubstituted APA 6 are stable even at 220 8C.81, 106 N-(2-Hydroxyphenyl)-3-benzoylpyruvoylamide is an exception; on refluxing in mesitylene, this compound decom- poses into acetophenone 1a and 3,4-dihydro-2H-1,4-benzoxazine- 2,3-dione (25).37O Ph O O NH 164 8C 1a+ OH O H O O NH 25 (64%) Meanwhile, 3-methyl- (26) 106 and 3-diphenylmethyl-substi- tuted (15) 90 arylamides are decarbonylated on heating giving rise to N-aryl-2-methyl- (27) and N-aryl-2-diphenylmethyl-3-phenyl- 3-oxopropanamides 28.R1 R1 D Ar Ar CONHR2 CONHR2 O O 27, 28 (69% ± 95%) O 15, 26 26, 27: Ar=Ph, R1=Me, R2=YC6H4 (Y=H, 3-OMe, 4-OMe); 15, 28: Ar=4-YC6H4 (Y=H, Me); R1=CHPh2, R2= Ph, 4-MeOC6H4. b. Intramolecular cyclisations On refluxing in aqueous HCl, ethyl aroylpyruvates 29a ± d, con- taining a hydroxy group in the ortho-position of the benzene ring cyclise to give 4-oxachromene-2-carboxylic acids 30a ± d.16 R1 R1 O O H O H2O, H+ CO2Et OH R2 R2 O CO2R3 29a ± d 30a ± d R3=Et: R1=R2=H (a), OEt (b ); R3=H, R1=H (c ), OMe (d), R2=OMe.924 Pentafluorobenzoylpyruvates 31a,b cyclise either over a period of one month at 20 8C or rapidly on heating to give 2-alkoxycarbonyl-5,6,7,8-tetrafluoro-4H-chromen-4-ones 32a,b.3, 6, 24 Acid 31c (R=H) is stable under these conditions.27 It cyclises to be converted into chromone-2-carboxylic acid (32c ) only after treatment with anhydrous ammonia or triethylamine in dioxane at 20 8C.The copper(II) chelates 31d,e are also converted into chromones 32a,b on heating in DMSO at 80 ± 90 8C3, 4, 6, 24 (Scheme 6). Scheme 6 O F CO2R F O O CO2R O 32a ± e X 31a ± e 31: X = H: R = Et (a), Me (b), H (c); X=Cu/2, R=Et (d), Me (e); 32: R = Et (a), Me (b), H (c). Under conditions of acid hydrolysis, the ethyl pyrrolylpyr- uvates 5 undergo cyclisation which involves the hydroxy group of the pyrrole fragment and gives 5,6-diaryl-2-carboxypyrano[2,3- c]pyrrole-4,7(4H,5H)-diones 33.107 O H O O 4-XC6H4 HO H2O, H+ CO2Et RN O C6H4X-4 O CO2H NR O 5 33 (82% ± 96%) R=Me, Ph, 4-MeOC6H4, 4-BrC6H4; X=H,NO2, Br.Acid hydrolysis of APA N-benzoylmethylene- (34) 78 and APA N-benzimidenehydrazides 35 108 results in the formation of the same 6-aryl-4-hydroxy-2,3-dihydropyridazin-3-ones 36. OH Ar CONHN CHX Ar H2O, H+ O O H O 34, 35 NH 36 (71% ± 97%) Ar=4-YC6H4 (Y=OMe, Cl, H, Me); X=COPh (34), Ph (35). The amides 15 and 26 cyclise in boiling AcOH being thus converted into the corresponding 1,5-diaryl-4-diphenylmethyl- (methyl)-2,3-dihydropyrrole-2,3-diones 37 90, 109 and 38 110 (Scheme 7). The compound 37 (X=Me, Ar=R=Ph) recyclises on refluxing in ditolylmethane to afford 4-hydroxy-3-methyl-2- phenylquinoline (39).110 Scheme 7 O R1 R1 Ar R1=Me, Ar=R=Ph CONHR1 AcOH O Ar NR2 O (4-MeC6H4)2CH2 , 270 8C O 15, 26 37 (60% ± 79%), 38 (33% ± 92%) OH Me Ph N 39 (66%) 15, 37: Ar=4-YC6H4 (Y=H, Me), R1=CHPh2, R2=Ph, 4-MeOC6H4, 4-ClC6H4; 26, 38 : Ar=Ph, R1=Me, R2=YC6H4 (Y=H, 3-OMe, 4-OMe, 4-Me, 4-OH, 2-OH, 4-Br).S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin When heated in benzene with thionyl chloride (65 ± 70 8C) 38 or acetic anhydride (60 ± 70 8C),111, 112 the acids 4 undergo de- hydration to the furandiones 7. The two methods provide similar yields of the compounds 7. O 4 R O O 7 (49% ± 95%) R=Ar, Het. The APA 3-arylhydrazones 16 cyclise on treatment with thionyl chloride to give pyrazolediones 18.92, 93 The same com- pounds are produced on prolonged refluxing of the methyl esters 17 in acetic anhydride.113 O NNHAr0 O Ar O O Ar N N O CO2R Ar0 16, 17 18 (37% ± 95%) Ar=4-YC6H4 (Y=H, Me, OMe, NO2, Br, Cl); Ar0=4-YC6H4 (Y=H, OMe, Cl).A distinctive feature of pentafluorophenyl-substituted arylhy- drazones (17, Ar=C6F5) is their ability to undergo cyclisation either on heating with DMSO in the presence of potassium carbonate or in a mixture of triethylamine with chloroform; the reaction furnishes 1-aryl-5,6,7,8-tetrafluoro-3-ethoxalyl-1,4-dihy- drocinnolin-4-ones 40.95, 96 O NNHC6H4X-4 COCO2Et :B C6F5 CO2Et F N N O O C6H4X-4 17 40 (47% ± 80%) X=H, Me, OMe. Cyclodehydration of APA arylamides 41 49 and 42 64 with participation of the amide group capable of enolisation gives benzoxazines 43, 44.In the case of the amide 41, the reaction was carried out by heating the compound in benzene with thionyl chloride (withDMFas the catalyst),49 and for the compound 42, it was performed in acetic anhydride.64 O O O SOCl2 Ar Ar N HN O O O HO H O H O 41 43 (83% ± 98%) Ar=4-XC6H4 (X=OMe, OEt, Br, Cl). Ph Ph Ph Ph HOO O Ac2O Ar Ar N HN O O H O H O 42 44 (26% ± 30%) Ar=4-XC6H4 (X=H, Me, OMe). 2. Reactions of (het)aroylpyruvates with mononucleophiles Reactions with some C-, N- and O-mononucleophiles are known for the (H)APA 4 and their esters 2 and amides 6.(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis a.Reactions with C-mononucleophiles The reported reactions of AP with C-mononucleophiles are few in number because AP tend to decompose under conditions where nucleophiles are generated and/or are sufficiently reactive and heterocyclisation is precluded. Mention should be made of condensations of 4a with 2-hydroxyphenylacetic acid in the presence of PBr3 resulting in the product 45 and with 5-phenyl-2,3-dihydrofuran-2-one in the presence of acetic anhydride to give the compound 46.114 Ph O CO2H O OH PBr3 O O Ar CO2H 45 O Ph H O O 4a O Ph O O O Ac2O O Ph 46 (61%) b. Reactions with O-mononucleophiles Of the transformations of (H)AP in reactions with alcohols, only transesterification of the esters 2 is known.Most of the APA esters 2 (Ar is substituted phenyl) are unstable under conditions of alkaline hydrolysis and decompose yielding the corresponding acetophenone 1, alcohol and oxalate.1 The HPA esters 2 are more stable to this cleavage because the acids 4 [Ar=2-thienyl,2 3-(2,4- dimethylpyrrolyl) 11] can be prepared by alkaline hydrolysis of the corresponding esters 2. However, ethyl 3-indolyl- and 3-(5- methoxyindolyl)pyruvates are readily cleaved by alkalis and are even partially cleaved during recrystallisation from ethanol.20 Recently, ethyl pentafluorobenzoylpyruvate copper(II) chelate 31d was reported to undergo transesterification into the chelate of the methyl ester 31e. For the free AP 2, this reaction is unknown. c. Reactions with N-mononucleophiles The esters 2 are known 115 to react with ammonium acetate on refluxing in an AcOH± benzene mixture; the reaction involves the carbonyl group at the C(2) atom and gives ethyl 2-amino-4- arylbut-2-en-4-onoates 47 in*80% yield.Under mild conditions (at 20 ± 50 8C), both the (H)APA 4 and their esters 2 add aniline and its derivatives at the carbonyl group giving rise to 2-aryl- amino-4-aryl-4-oxobut-2-enoates 48 (the yields vary from 9% to 83%).79, 102, 116 Electron-withdrawing substituents and steric hin- drance in the reactants result in lower yields of the products 48. The structure of the compounds 48, stabilised by an intramolec- ular hydrogen bond (IMHB) in the b-amino vinyl ketone frag- ment, was confirmed by NMR spectroscopy.117 The APA arylamides 6 behave in a similar way in reactions with aniline, giving rise to arylamides of 4-aryl-4-oxo-2-phenylaminobut-2- enoic acids 49 in 60%± 93% yields.29, 118 COR1 Ar R2NH2 2, 4, 6 N O R2 H 47, 48, 49 2, 47: R1=OEt; R2=H; 2, 4, 48: R1=OH, OMe; R2=Ar0; 6, 49: R1=NHAr0; R2=Ph.The pyrrolylpyruvates 5 are also converted into amino esters 50b ± e when heated with arylamines to 60 8C.107 However, on stronger heating (150 ± 220 8C), these products cyclise to give compounds 51b ± e.107 The cyclisation is facilitated by electron- withdrawing substituents in the pyrrole ring of 5. Indeed, 1-meth- 925 ylpyrrolylpyruvate 5a readily cyclises with aniline at 20 8C giving rise to heterocycle 51a; the intermediate compound 50a cannot be isolated.107 H H Ar OH N O O O O O ArNH2 5 O CO2Et N R N NAr C6H4X-4 C6H4X-4 R 51a ± e (29% ± 58%) 50b ± e (87% ± 97%) Ar=Ph, R=Me, X=H (a); Ar=R=Ph (b ± d): X=H (b), Br (c), NO2 (d); Ar=R= 4-BrC6H4, X=Br (e).It has been reported that salts decarboxylated on refluxing in mesitylene (164 8C) to give 3-aryl-3-oxopropanal monoanils 52 can be isolated from the products of reaction between the APA 4 and aromatic amines at 20 8C.119 164 8C ArCOCH2CH NR 4+RNH2 52 (80% ± 83%) Ar=4-XC6H4 (X=H, Me, OMe, Cl, Br); R=4-XC6 H4 (X=H, OMe, Cl, Br). It is of interest that refluxing of methyl aroylpyruvates 2 in benzene with 2-aminopyridine results in APA 2-pyridylamides 53 instead of the 2-amino-derivatives such as 48, 49.31 The unusual pathway of 2-aminopyridine addition to AP is due, apparently, to the fact that in the transition state, the highly basic pyridine nitrogen atom of the nucleophile is coordinated to the C(2) carbonyl atom of the AP and the amino group is coordinated to the C(1) atom.N N NH2 Ar 2 NH2 OMe O H O O O N Ar NH O H O53 (82% ± 85%) Ar=4-XC6H4 (X=H, Me, OMe, Br). Unlike 3-unsubstituted esters 2, 3-arylhydrazones 17, which are efficiently stabilised by an IMHB, react with arylamines on refluxing in benzene; the reaction involves the ester group and gives the arylamides 19.98 X NNHX H N N RNH2 Ar Ar O O O O CO2Me CONHR 19 (40% ± 63%) 17 Ar=Ph, 4-EtOC6H4; R=4-YC6H4 (Y= H, Me, Cl); X=Ph.It is known 120 that APA arylamides containing a bulky group at the 3-position readily cyclise yielding 4-substituted 1,5-diaryl- 2,3-dihydropyrrole-2,3-diones 37, 38 (see Scheme 7).90, 109, 110 The tendency toward cyclisation is sometimes so pronounced that it is not always possible to isolate arylamides formed in the reaction of APA esters with amines.121 Indeed, the reaction of ethyl 3-phenyl- benzoylpyruvate (54) with methyl- or benzylamine in chloroform at 20 8C yields immediately the products of cyclisation of inter- mediate amides, 1-alkyl-4,5-diphenyl-3,5-dihydroxy-2,5-dihydro- pyrrol-2-ones 55. It is noteworthy that in this case, as for arylhydrazones 17, it is the ester group that is involved in the926 reaction with the amine.The products 55 are dehydrated to give 1-alkyl-4,5-diphenyl-2,3-dihydropyrrole-2,3-diones 56.103 Ph OH Ph O Ph AcOH Ph CO2Et RNH2 HO O O Ph Ph O O 54 NR 55 (91%± 98%) NR 56 (92%) R=Me, CH2Ph. Unlike the amides 6, APA b-aroylhydrazides 57 are cleaved by aromatic amines when fused together (160 ± 165 8C); this gives rise to acetophenones 1 and mixed amidohydrazides of oxalic acid 58.67 Benzylamine splits the hydrazides 57 even at 60 ± 65 8C. Ar CONHNHC6H4Y RNH2 O H O 57 O O Ar Me+ RHN NHNHC6H4Y O1 58 (20% ± 74%) Ar=4-XC6H4 (X=H, Me, OMe); R=4-XC6H4 (X=H, Me, OEt), CH2Ph; Y=H, 3-NO2, 4-OMe. Fluorine-containing AP behave quite differently in reactions with amines. Thus the pentafluorobenzoylpyruvates 31a,b rapidly cyclise to the chromones 32a,b when made to react with aqueous ammonia at 20 8C3, 121 (see Scheme 6); the reaction of the pyruvate 31a with cyclohexylamine on heating in DMSO does not stop at the cyclisation stage but proceeds as nucleophilic substitution with removal of the fluorine atom at the 7-position of the aromatic ring, thus yielding 5,6,8-trifluoro-7-cyclohexyl- amino-2-ethoxycarbonylchromen-4(4H)-one (59).121 O cyclo-C6H11NH2 F 31a O CO2Et cyclo-C6H11NH 59 (63%) As noted above, the reaction of pentafluorobenzoylpyruvic acid (31c) with anhydrous ammonia or triethylamine in dioxane at 20 8C leads to chromone-2-carboxylic acid (32c) (see Scheme 6).Heating of the acid 31c with aqueous ammonia and primary amines affords 2-(alkyl)amino-4-oxo-4-polyfluoroaryl-2-but- enoic acids 60.26, 27 The acid 60a cyclises reversibly into the chromone 32c on heating in an acid medium.On treatment with aqueous alkali, the acids 60b,c undergo cyclisation to give 1-alkyl- 2-carboxy-7-hydroxy-5,6,8-trifluoroquinolin-4(4H)-ones 61.26, 27 The structure of the quinolone 61b as DMSO adduct has been determined by X-ray diffraction analysis.104 + O NH2R RNH2 CO¡2KOH, H2O 31c F 90 ± 95 8C X 60a ± d (39% ± 65%) O F HO CO2H NR 61a,b (74% ± 75%) 60: X=OH, R=H (a); X=F: R=Pri (b), cyclo-C6H11 (c), Ph (d); 61: R=Pri(a), cyclo-C6H11 (b). S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Thus, the reactions of APA 4, their esters 2 and amides 6 with N-mononucleophiles mainly involve the oxo group at the C(2) atom, although in the case of esters having bulky substituents at the 3-position, the ester group becomes more reactive.3. Reactions of (het)aroylpyruvates with dinucleophiles The reactions of (H)AP with bifunctional nucleophiles are widely used in organic synthesis to prepare five-, six-, and seven-mem- bered heterocycles and their fused derivatives. a. Reactions with C,N-dinucleophiles Reactions with C,C-dinucleophiles are unknown. Of transforma- tions of (H)AP on treatment with C,N-dinucleophiles, the reac- tions with ethyl 3-aminocrotonate and cyanoacetamide are documented. Under mild conditions (at 20 8C in the absence of bases), the pyruvate 2a adds ethyl 3-aminocrotonate at the b-diketone fragment to give 3,4-bis(ethoxycarbonyl)-2-methyl-6- phenylpyridine (62).105 The most electrophilic centre of AP [the C(2) atom] reacts with the C-nucleophilic centre of the crotonate and the C(4) atom reacts with the amino group.O CO2Et H Me Ph CO2Et OEt + O CO2Et H2N Me Ph N H O2a 62 The reaction of the (H)AP 2 with cyanoacetamide proceeds in a similar way giving rise to 6-aryl-3-cyano-4-ethoxycarbonyl-2- pyridones 63.13,14, 122 The reaction was carried out by refluxing the reactants in ethanol in the presence of piperidine 122 or diethyl- amine.13, 14 The use of N-methylcyanoacetamide affords not only 6-aryl-3-cyano-4-ethoxycarbonyl-1-methyl-2-pyridones 64, but also 6-aryl-3-cyano-4-ethoxycarbonyl-2-methoxypyridines 65 as side products.13, 14 CO2Et H2N CN CN O O Ar NH :B 63 2 CO2Et CO2Et MeNH CN CN CN O + OMe Ar O Ar N65 NMe 64 2, 63: R=Et, Ar=Ph, 2-furyl, 4-diphenylyl; 64, 65: Ar=2-furyl, 4-diphenylyl.b. Reactions with N,N-dinucleophiles The reactions of (H)AP with N,N-dinucleophilic reagents possess the highest synthetic value; these reactions have been the best studied. Reactions with hydrazine and its derivatives. The acids 4, the esters 2 and the amides 6 react selectively with hydrazine at the b-dicarbonyl fragment [C(2) and C(4) atoms] to give 5-(het)arylpyrazole-3-carboxylic acid derivatives 66 in good yields. 3 ± 5, 11, 13, 14, 16, 17, 20, 21, 23, 31, 53, 59, 62, 67, 72, 73, 123 ± 126 The sol- derivatives vents used in these reactions are acetic acid, 1,4-dioxane, alcohols or water.The (H)AP 2, 4 and 6 react with monomethyl and arylhydrazines in a similar way, the reaction proceeding regio- selectively to give exclusively 1-methyl- 13, 14 and 1-aryl- 5-(hetero)arylpyrazole-3-carboxylic acid 67.1 ± 5, 13, 14, 20, 23, 67, 124, 127(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis COR Ar N2H4 .H2O HN N 66 (49% ± 97%) 2, 4, 6 Ar COR1 RNHNH2 N N R2 67 (15% ± 93%) 66: Ar=XC6H4 (X=H, 4-OH, 4-Me, 4-OMe, 4-OEt, 4-Br, 3-Br, 4-F, 4-Cl), 2,4-Me2C6H3, 4-diphenylyl, 3-phenanthryl, C6F5, 2-furyl, 3-indolyl, cymantrenyl, 3-methyl-5-phenyl-2-thienyl, 4-methyl-5-oxazolyl, 2,4- dimethyl-5-oxazolyl, 5-(2,4-dimethylthiazolyl); R=OEt, OH, NHPh, NH(CH2)2NHAc, 2-pyridylamino, 3-pyridylamino, 2-bromo-5-pyridyl- amino, 2-thiazolylamino, 2-pyrimidylamino, 3-cyano-4,5-tetramethylene- 2-thienylamino, NHNHCOAr0 (Ar0=Ph, 4-MeOC6H4), NHNHCOCO- CH=PPh3, NHNHCOC6H4Y (Y=2-methylphenylamino, 2-methyl-4- quinolyl); 67:Ar=Ph, 4-MeC6H4, 4-diphenylyl, C6F5, 2-pyrrolyl, 2-furyl, 2-thienyl, 5-methyl-2-furyl, 3-methyl-2-phenyl-5-thienyl, 2,4-dimethyl-5-oxazolyl, 2,4-dimethyl-5-thiazolyl, 3-indolyl; R1=OH, OEt, OPri; 2(3)-pyridyl- amino, 5-bromo-2-pyridylamino, NHNHCOC6H4Y-4 (Y=H, OMe); R2=Ph, 4-NO2C6H4, 2,4-(NO2)2C6H3, Me.For the synthesis of pyrazoles 66, the use of equimolar amounts of (H)AP and hydrazine hydrate or dihydrochloride is recommended.14 Some examples of cleavage of (H)AP upon the use of excess hydrazine have been reported.13, 20 In addition, under these conditions, the ester group in the final pyrazoles 66 is usually converted into a hydrazide group.11, 13, 17 Thus the reaction of 2-furoylpyruvate 2c 13 with excess hydrazine gives 5-(2-furyl)pyrazole-3-carbohydrazide together with the target pyrazole 66 (Ar=2-furyl, R=OEt) even under mild conditions.Note that the reaction of phenyl benzoylpyruvate with hydr- azine involves both the b-dicarbonyl fragment and the phen- oxycarbonyl group, resulting in 5-phenylpyrazole-3-carbo- hydrazide.16 Ph CO2Ph Ph CONHNH2 2 N2H4 .H2O HN N O O H 3-Arylhydrazono-APA 16 128 behave in reactions with hydr- azine and phenylhydrazine similarly to 3-unsubstituted analogues giving rise to 4-arylazo-(1-phenyl)-5-arylpyrazole-3-carboxylic acid derivatives 68.NC6H4X N Ar CO2R1 R2NH2 16, 17 N N R2 68 (49% ± 97%) Ar=C6H4Y (Y=H, 4-Me, 4-OMe, 4-Cl); R1=H, Et; R2=H, Ph. Conversely, the 3-chloroaroylpyruvates 10 are cleaved by hydrazine even under mild conditions without giving pyrazoles.80 Reactions of some esters of the (H)APA 2 with arylhydrazines at 20 8C catalysed by AcOH involve the C(2)=O group and result in the corresponding arylhydrazones 69 in good yields (87% for Ar=R2=Ph).127 Upon heating in an acid medium (AcOH, AcOH+HCl), these products cyclise almost quantitatively (93% for Ar=R2=Ph) 127 to give pyrazoles 70.11, 20, 124, 127 Ar CO2R1 Ar COR1 R2NHNH2 H+ 2 N N N O R2 67 69 N R2 H Ar=Ph, 3-indolyl, 2,4-dimethyl-3-pyrrolyl; R1=Et, Pri; R2=2,4-(NO2)2C6H3, Ph.927 The reactions of methyl aroylpyruvates 2 with N,N- dimethyl-,129 N-alkyl-N-arylhydrazines 130 and benzophenone and 9-fluorenone hydrazones 131 involve exclusively the C(2) centre and give AP N,N-dimethyl- (70) and N-alkyl-N-arylhydr- azones 71 and AP N-(di)arylmethylenehydrazones 72, respec- tively. Ar CO2Me R1R2NNH2 2 NNR1R2 O 70 ± 72 (27%± 69%) 70: Ar=XC6 H4 (X=H, 4-Me, 4-OMe, 4-Br, 4-Cl, 3-NO2, 4-NO2); R1=R2=Me; 71: Ar=Ph; R1=Me, Et, Pri; R2=4-XC6H4 (X=OMe, Me, H, Br, NO2); 72: Ar=XC6 H4; R1+R2=CPh2, 9-fluorenylidene. It was shown by 1HNMRspectroscopy 129 that the dimethyl- hydrazones 70 exist in solutions as equilibrium mixtures of b-ketoimine (syn-KI, anti-KI) and ketoenamine [(Z)-KEA, (E)-KEA] tautomers.In low-polarity aprotic solvents, the content of the KEA tautomer is higher. Electron-donating substituents X in the aromatic nucleus of the compounds 70 and an increase in the solvent polarity result in a higher content of the KI forms. The syn-KI form predominates in the KI pair, while in the KEA pair, the preferred form is (Z)-KEA, which is stabilised by an IMHB. The hydrazone 70 (X=H) was isolated from a solution as a mixture of the syn-KI and (Z)-KEA isomers, whereas other hydrazones 70 were obtained only as (Z)-KEA. Ar Ar CO2Me CO2Me O N O H N NMe2 NMe2 70, syn-KI 70, (Z)-KEA Ar CO2Me Ar NH NMe2 N O CO2Me O Me2N 70, anti-KI 70, (E)-KEA TheN-alkyl-N-arylhydrazones 71 are isolated as the (Z)-KEA tautomers.However, they exist in chloroform and pyridine solutions as equilibrium mixtures of the (Z)-KEA and syn-KI forms.130 In DMSO, the (E)-KEA form was also found. The influence of the nature of the solvent and the substituent X in the R2 group on the tautomeric equilibria has been elucidated. On passing from chloroform to pyridine, the content of the tautomer (Z)-KEA increases, while in DMSO, the total content of the KEA isomers increase, the (E)-KEA form being the preferred one. The content of (Z)-KEA increases with the enhancement of the 7M-effect of the group X on passing from OMe to NO2. The AP 2 react with benzoylhydrazine at the a-carbonyl group to give the corresponding hydrazones 73a ± h.132 Ar CO2R PhCONHNH2 2 NHCOPh N O 73a ± h (70% ± 86%) R=Me; Ar=XC6H4 (X=H (a), 4-Me (b), 4-OMe (c), 4-NMe2 (d), 4-Cl (e), 3-NO2 (f), 4-NO2 (g)); R=Et, Ar=Ph (h).A 1H NMR study of the tautomerism in the series of benzoylhydrazones 73 has shown 133 that these compounds exist in solutions as equilibrium mixtures of three tautomers, namely, Z-(A) and E-(B) ketohydrazones and 5-hydroxypyrazoline (C). Their proportions depend on the nature of the hydrazone 73 and the solvent. The electron-donating substituent X in the aryl group of the hydrazone 73 promotes an increase in the content of ketohydrazone. In CDCl3, Z-form A stabilised by IMHB is preferred, while in DMSO-d6, E-form B predominates.The928 hydrazones 73e ± g with electron-withdrawing groups X predom- inantly exist in solutions as cyclic form C. The content of tautomer C is higher in DMSO than in CDCl3. The benzoylhydrazones 73a ± d were isolated from methanol in form A, while 73e ± g, in form C. OMe OMe HO Ar CO2Me Ar O Ar O N N N H N O N Ph OHNCOPh B O C COPh A The synthesis of 2-isonicotinoylhydrazone 74 from ethyl 2-furoylpyruvate 2c and isonicotinic acid hydrazide has been reported.33 O N CONHNH2 N 2c O O N NH CO2Et 74 The reaction of the ester (H)AP 2c 13 and the acid 4a 134 with semicarbazide or its hydrochloride results in the formation of monosemicarbazones, which have, in our opinion, the structure 75a,b.These semicarbazones undergo thermal decomposition giving the corresponding pyrazoles 66a,b.On short-term refluxing in an aqueous solution of potassium carbonate, semicarbazone 75b is converted into 5-(2-furyl)-3-carboxypyrazole 66b.33 Ar CO2R Ar CO2H D H2NNHCONH2 2c, 4a N O HN N NH CONH2 66a,b 75a,b Ar=Ph, R=H (4a, 75a, 66a); Ar=2-furyl, R=Et (2c, 75b, 66b). The acid 4a reacts with thiosemicarbazide with participation of both carbonyl groups to give bis(thiosemicarbazone) 76. The alkaline hydrolysis of this product affords 1,2,4-triazine deriva- tives 77a,b.134 Ph NNHCSNH2 H2NNHCSNH2 4a NaOH, 20 8C NaOH, 100 8C N 76 CO2H NHCSNH2 N H2NSHCHN NHX PhO NH 77a,b X=S (a), O (b ). The reaction of the APA 4 and their methyl esters 2 with S-methylisothiosemicarbazide hydroiodide involves the a-dicar- bonyl fragment and affords 6-aroylmethyl-3-methylthio-1,2,4- triazin-5(2H)-ones 78 or 6-aroylmethyl-1,2,4-triazine- 3,5(2H,4H)-diones 79, depending on the nature of the aryl substituent and the reaction duration.135, 136 Thus refluxing in ethanol for 2 h gives 3-methylthio-1,2,4-triazinones 78; when the reaction time increases to 10 h, the products of their hydrolysis, 1,2,4-triazinediones 79, are formed.136 The compounds 78 are converted into the triazinediones 79 upon short-term refluxing in aqueous dioxane in the presence of catalytic amounts of HCl.According to the 1H NMR spectra, the compounds 78 in DMSO-d6 are mixtures of the imine (A) and enamine (B) tautomers in 4 : 1 ratio.135, 136 S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Ar H O N ArCOCH2 N NH NH NH.HI SMe O SMe O NA NB 2, 4 H2NNH SMe 78 (59% ± 80%) N ArCOCH2 H2O, H+ NHO O NH 79 (45% ± 69%) Ar=4-XC6H4 (X=H, Me, OMe, Cl, Br, I, NO2), 2,4-Me2C6 H3. On refluxing in dioxane, the acids 4 add selectively thiocarbo- hydrazide at the a-ketocarboxyl fragment to give 4-amino-6- aroylmethyl-3-thioxo-2H,4H-1,2,4-triazin-5-ones 80.136 Ar N H2NNH NH S 4+ O H2NNH O N S NH2 80 (52% ± 60%) Ar=4-XC6H4 (X=H, Me, Cl). Reactions with 1,2-diaminoethane and its derivatives. Both the APA 4 30, 137 and their esters 2 (see 21, 30, 137 ± 141) add 1,2- diaminoethane 21, 30, 138 ± 140 or its mono-N-methyl-,141 N-ben- zyl- 137 and N-phenyl-substituted 30, 141 derivatives in chemo- and regioselective reactions involving the a-dicarbonyl fragment [the C(1) and C(2) atoms] giving rise to 3-aroylmethylidenepiperazin- 2-ones 81 or their 1-alkyl(aryl) derivatives 82.The reactions are normally carried out on heating in toluene, ethanol or acetic acid. The piperazin-2-ones 81 can also be prepared by heating the sodium enolates of H(AP) 2 with 1,2-diaminoethane in glacial AcOH.140 Under mild conditions (ethanol, 20 8C) the AP 2 and 4 react with N-phenyl-1,2-diaminoethane at the a-carbonyl group to give acyclic 4-aryl-4-oxo-2-(2-phenylamino)ethylamino-2- butenoic acids or their esters 83. O R1 NR2 NHR2 H2N O H N D 81 (47% ± 98%), 82 (60% ± 96%) 2, 4 R1 CO2R2 NHPh H2N20 8C N O H NHPh 83 (80% ± 98%) 81: R1=Ar, Het, ferrocenyl, R2=H; 82: R1=Ar, Het, R2=Me, Ph, CH2Ph; 83: R1=Ar, Het, R2=H, Me, Et.However, on refluxing in ethanol, the pyruvate 2b reacts with N-phenyl-1,2-diaminoethane at the ester fragment [the C(1) atom] to give benzoylpyruvic acid 2-phenylaminoethylamide in 61% yield.30 1,2-Diphenylaminoethane does not react with AP.30 It is noteworthy that the reaction of pentafluorobenzoyl- pyruvate 31a with 1,2-diaminoethane gives, depending on the conditions, either 3-pentafluorobenzoyl- (84a) or 3-(2-hydr- oxy-3,4,5,6-tetrafluoro)benzoyl-methylidenepiperazin-2-ones (84b).3, 5 The piperazinone 84a is formed when the pyruvate 31a is treated with a large excess of ethylenediamine at 20 8C in a MeOH±AcOH mixture, and the product 84b is produced on refluxing equimolar amounts of the reactants in methanol.(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis O F NH2 H2N 31a NH D O X H N 84a,b X = F (a, 43%), OH (b, 18%).Non-symmetric 1-methyl- and 1-phenyl-1,2-diaminoethanes have been shown 142 to react selectively with the APA esters 2 on refluxing in an ethanol ± acetic acid mixture to give the corre- sponding 6-methyl- or 6-phenyl-3-aroylmethylenepiperazin-2-one 85 as the only reaction product.O R Ar NH2 H2N NH 2 N O R H85 (58% ± 93%) 3-aroylmethylidene-1,2,3,4-tetrahydroquinoxalin-2-ones Reactions with 1,2-phenylenediamine and other arylenediamines.The major process involved in the reaction of the (H)APA 4, their esters 2, and the amides 6 with 1,2-phenylenediamine (PDA) is a-dicarbonyl cyclocondensation at the fragment [the C(1) and C(2) atoms] giving rise to the correspond- ing (86).3, 5, 8, 12, 21, 44, 46, 58, 62, 67, 107, 115, 123, 126, 143 ± 149 O O Ar NH Ar NH2 R N O + H O O H NH2 2, 4, 6 86 (36% ± 99%) Ar=XC6H4 (X=H, 4-Me, 4-Et, OH, OMe, 4-Ph, 4-NO2, 3-NO2, 4-F, 4-Cl, 4-Br), 2,5-Me2C6H3, 2,4,6-Me3C6H2, C6F5, 1-naphthyl, 3-phen- anthryl, 2-furyl, 2-thienyl, 4-pyridyl, 4-hydroxy-5-oxo-1,2-diphenyl-2,5- dihydroxypyrrol-3-yl, cymantrenyl; 2: R=OMe, OEt, OBut, SCH2Ph; 4: R=OH; 6: R=N(Ar0)C(Ph)=CH2, NH2, NHNHAr0, NHAr0, 3-pyridylamino, 2-pyridylamino.Tautomerism of 2-quinoxalones 86 has been studied by spectro- scopy.145, 146 It was found that these compounds exist as IMHB- stabilised form A in the solid state and in solutions in DMSO-d6. Noticeable amounts of forms B ±D are found only in solutions in CF3CO2D.145 O O HN HN CF3CO2D N Ar Ar DMSO N O H O 86B 86A DMSO CF3CO2D HO O O Ar HN HN Ar N N OH 86D 86C 3-Substituted APA and their esters react with PDA similarly to unsubstituted analogues to yield 3-(1-X-aroylmethyl)-1,2-di- hydroquinoxalin-2-ones 87.80, 83, 89, 147 For instance, the 3-aryl- hydrazones 16,91 17 94 ± 96 and 3-alkyl-substituted APA esters 14 89, 147 readily react with PDA on refluxing in ethanol.The 3-halogen-containing AP 10 are more reactive and are converted 929 into quinoxalinones 87 on treatment with PDA at 20 8C.80, 83, 147 Heating of the reactants induces resinification 80 or formation of quinoxaline-2,3(1H,4H)-dione (88).83 O X Ar NH N O X Ar COR PDA 87 (45% ± 97%) O O 10, 14, 16, 17 O NH X=Br PhH, 50 8C O HN 88 (99%) 10: X=Cl, Br; Ar=4-YC6H4 (Y=H, Me, Br, OMe, F, Cl); R=OMe, OEt; 14: X=Me, Et, CHPh2; Ar=4-YC6H4 (Y=H, Me, Br, Cl, NO2); R=OMe, OEt; 16, 17: X=N=NAr 0; R=OMe, OEt, OH; Ar=C6H4Y (Y=H, 4-Cl, 4-Br), C6F5; 87: X=Me, Et, CHPh2, Cl, Br, N=NAr 0; Ar=4-YC6H4 (Y=H, Me, Br, OMe, F, Cl, NO2), C6F5. However, prolonged refluxing in ethanol of 3-bromo-substi- tuted ethyl benzoylpyruvate 10a (Ar= Ph, R=Et, X=Br) with PDA furnishes 3-benzoylmethylidenequinoxalinone 86a contain- ing no bromine.150 When the acid 4a has been made to react withPDAunder mild conditions (PriOH, 20 8C), a labile intermediate, 2-(2-ammonio- phenylamino)-4-oxo-4-phenyl-2-butenoate (89), has been iso- lated.On heating, this compound is quantitatively converted into quinoxalinone 86a.148 O 2 Ph Ph NH CO¡+NH3 PDA D N O N O 4a H H86a 89 (75%) It is notable that tert-butyl benzoylpyruvate prepared in situ from the acid 4a and isobutylene in the presence of H2SO4 reacts with PDA to give, apart from the quinoxalinone 86a, 2-tert-butoxy- carbonyl-4-phenylbenzo[b]-1,4-diazepine isolated as hydrochlor- ide 90. The product 90 results from the competing cyclocondensation of PDA at the b-dicarbonyl fragment of the pyruvate 4a.The diazepine 90 easily recyclises into the quin- oxalinone 86a upon dissolution.149 CO2But HN Ph CO2But 1) PDA 2) HCl + 86a + Cl7 O O H HN Ph 90 (51%) Unlike the APA 4 and their esters 2, the APA arylamides 6 react with PDA to give, depending on the reaction conditions, 4-arylbenzo[b]-1,4-diazepine-2-carboxylic acid arylamides 91 29, 151 instead of the expected quinoxalinones 86,115 or a mixture of these products.62, 149 The formation of the quinoxalinones 86 is promoted by performing the reaction in EtOH ±AcOH± H2O± HCl mixtures at pH 2.4 ± 4.6 and temperatures of 20 ± 65 8C.115 Meanwhile, short-term fusion of the reactants at 115 ± 130 8C furnishes predominantly the benzodiazepines 91.29, 115, 149 It was noted that electron-donating substituents in the aryl group of the initial amide 6 lead to higher yields of the benzodiazepines 91, while electron-withdrawing groups promote the formation of the quinoxalinones 86.149 The reaction of the 3-pyridylamide 6b with PDA on refluxing in a PriOH±AcOH930 mixture affords both the quinoxalinone 86a and the benzodiaze- pine 91 (R=3-pyridyl).62 86 (0% ± 100%) PDA Ar 6 NN CONHR 91 (39% ± 99%) 86: Ar=XC6 H4 (X=H, 4-Me, 4-OMe, 4-Cl, 4-Br, 4-NO2, 3-NO2); 91: Ar=4-XC6H4 (X=H, Me, OMe, Br); R=4-YC6H4 (Y=H, Me, OMe, Br), 3-pyridyl. 92 8, 143, 152, 153 N-Monoalkyl(aryl)-1,2-phenylenediamines react with the AP 2 and 4 similarly to PDA giving rise to 1-alkyl(aryl)-3-aroylme- thylidene-1,2,3,4-tetrahydroquinoxalin-2-ones stabilised by an IMHB.153 Note that these reactions proceed regio- and chemoselectively.O Ar NR NHR O 2,4+ H N NH2 92 (40% ± 84%) Ar=4-XC6H4 (X=H, Cl); R=Me, 4-XC6H4 (X=H, Me, OEt, Cl). Heterocyclisations of the AP 2 with 1,2-phenylenediamines containing various substituents in the benzene ring have been described. The addition pattern depends on the nature of the substituent in the benzene ring of the nucleophile. 1,2-Diamino- chlorobenzene 145 and 1,2-diamino-4-nitrobenzene 8 provide 3-benzoylmethylidene-7-chloro- (93a) and 3-benzoylmethyl- idene-7-nitro-1,2,3,4-tetrahydroquinoxalin-2-ones (93b), whereas 3,4-diaminobenzonitrile forms 3-aroylmethylidene-6-cyano- 1,2,3,4-tetrahydroquinoxalin-2-ones 94.51 O Ph X=Cl, NO2 NH O H N X NH2 X 2+ 93a,b (82% ± 84%) NH2 O Ar X=CN NH N O H 94 (82% ± 99%) CN X=Cl (a), NO2 (b); Ar=4-YC6H4 (Y=H, Me, Cl).2,3-Diaminonaphthalene reacts with the AP 2a similarly to PDA to give 3-benzoylmethylene-1,2,3,4-tetrahydrobenzo[g]qui- noxalin-2-one (95).145 HN O NH2 2a + N NH2 H O Ph 95 (61%) On treatment with 5,6-diaminoacenaphthene, the AP 2a,b and 4a are cleaved even under mild conditions (at 18 8C) to give 6,7- ethanoperimidine-2-carboxylic acid 96.154 S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Ph Me + 2a,b; 4a + N HN O 1a NH2 NH2 CO2R 96 (93% ± 98%) R=H, Me, Et.When the acid 4a is refluxed with 2(6)-substituted 8-amino- 1,2,3,4-tetrahydroquinolines 97a,b in ethanol, 2-benzoylmethyl- 4,5,6,7-tetrahydropyrido[1,2,3-d,e]quinoxalin-3(4H)-one deriva- tives 98a,b are formed.155 Ph N X X 4a + O O N R NH R NH2 98a,b (39% ± 68%) 97a,b R=Me,X=H(a); R=H, X=OMe (b). Reactions with heterocyclic diamines. Known reactions of the (H)APA 4 and their esters 2 with heteroaromatic ortho-diamines result in the preparation of annelated pyrazin-2-one derivatives 156 ± 162 (the products of addition at the a-dicarbonyl fragment of the AP) or [b]annelated 1,4-diazepines 160 (the prod- ucts of cyclocondensation at the b-dicarbonyl part of the AP), depending on the nature of the reactants. In the case of non- symmetric diamines, these reactions proceed regioselectively.Moreover, in some cases, both possible series of regioisomers can be prepared.157, 162 It has been reported 156 that refluxing the HPA 4b,c with 2,3- diaminopyridine (DAP) in an AcOH±H2O mixture results in the formation of (Z)-2-heteroaroylmethylidene -1,2,3,4-tetrahydro- pyrido[2,3-b]pyrazin-3-ones 99b,c. The researchers cited 156 con- firmed the structure of the heterocycles 99 by converting them into 3-heteroaroyl-1,2,4,5-tetrahydropyrrolo[1,2-a]pyrido[2,3-b]pyrid- azine-1,2,4-triones 100 upon condensation with oxalyl chlor- ide.156 Het O HN DAP, D ClCOCOCl 40a,c AcOH ±H2O O N NH 99a,b (85% ± 87%) O O Het N O O N NH 100a,b (69% ± 72%) Het=2-furyl (4b, 99a, 100a), 5-thiazolyl (4c, 99b, 100b).Unlike the APA 4, the esters 2 can yield two regioisomeric products, depending on the conditions, in the cyclocondensation with DAP. Thus 3-aroylmethylidene-1,2,3,4-tetrahydropyr- ido[2,3-b]pyrazin-2-ones 101 were prepared in an AcOH± EtOH ±H2O solvent mixture, whereas the use of an H2SO4 ± EtOH ±H2O mixture gave 2-aroylmethylidene-1,2,3,4-tetra- hydropyrido[2,3-b]pyrazin-3-ones 102.157 The structure of the heterocycles 101 and 102 was confirmed by hydrolysis of the compounds 101a and 102a followed by reduction to give the known methyltetrahydropyrido[2,3-b]pyrazinone 103, 104 iso- mers.163(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis HN O HN O AcOH N N Me N H O NH 103 DAP Ar 101a ± g (59% ± 81%) 2 EtOH Ar O H HN N Me H2SO4 N O N O NH NH 104 102a,c,d,f ± h (23% ± 60%) Ar=XC6H4 (X=H (a), 4-Me (b), 4-OMe (c), 3-OMe (d), 2-OMe (e), 4-OH (f ), 4-Br (g), 2-OH (h)).The reaction of the acid 4a with 4,5-diamino-1-phenyl- (105a) and 4-amino-5-methylamino-1-phenyl-1,6-dihydropyridazin-6- ones (105b) in boiling ethanol has been described.158 In the case of the diamine 105a, the reaction gives the product of cyclo- addition at the a-oxocarboxy group of the acid, 3-benzoylmethyl- 6-phenyl-1,2,5,6-tetrahydropyrazino[2,3-d]pyridazine-2,5-dione (106), while the reaction with 105b gives benzoylpyruvic acid N-(5-methylamino-6-oxo-1-phenyl-1,6-dihydropyridazinyl)amide (107).158 O Ph N NPh R=H N O O NH2 4a NH 106 (86%) NN O NHR Ph Ph NH R=Me O 105a,b O HN Me H O N O N 107 (83%) Ph R = H (a), Me (b).The reaction of the APA 4 with 1,2-diaminobenzimidazole in boiling AcOH occurs chemo- and regioselectively to yield 2-aroyl- methyl-3,4-dihydro-1,2,4-triazino[2,3-a]benzimidazol-3-ones 108.159 Refluxing of the same reactants in methanol affords salts, which are formed, apparently, at the pyridine N(3) atom of the diamine (yields 80%± 85%). When refluxed in AcOH, the salts cyclise to give heterocycles 108 in 80%± 87% yields.159 NH2 Ar N N N AcOH, D 4 + NH2 O N O N NH 108 (60% ± 74%) Ar=4-XC6H4 (X=H, Me, OMe, Cl, Br). The direction of the reactions of the AP 2, 4 with 4,5-diamino- 3-methyl-1-phenylpyrazole (109) depends on the conditions and on the nature of the a,b-tricarbonyl compound.160 At 20 8C in methanol, in the presence of a catalytic amount of HCl, both the APA 4 and their esters 2 add selectively the diamine 109 at the b-dicarbonyl fragment giving rise to 7-aryl-5-carboxy(methoxy- carbonyl)-3-methyl-1-phenyl-6H-pyrazolo[5,4-b]-1,4-diazepines 110.931 Me CO2R Me NH2 N MeOH, HCl (cat) N 2, 4+ N N NH2 N Ar Ph NPh 109 110a ± h (66% ± 84%) R=H(a ± c), Me (d ± h); Ar=4-X C6H4 [X=H(a, d), Me (b, e), Cl (c, f), NO2 (g)], 2,4-Me2C6H3 (h). When the reaction is carried out in benzene at 20 8C, the APA 4a and diamine 109 form 2-(5-amino-3-methyl-1-phenylpyrazol- 4-yl)amino-4-oxo-4-phenylbut-2-enoic acid (111), which cyclises to give pyrazolodiazepine 110a when heated to 50 8C in methanol in the presence of HCl.Unlike the acid 4a, the methyl ester 2b adds selectively the diamine 109 at the a-oxoester fragment under similar conditions; this furnishes 5-benzoylmethyl-3-methyl-1- phenyl-6,7-dihydropyrazolo[4,5-b]pyrazin-6-one (112). The prod- uct 112 can also be obtained by heating the acid 111 without a solvent at 130 ± 140 8C.160 Me Me CO2H N HNPh MeOH, HCl (cat) 4a N N 50 8C N N N CO2H O NH2 Ph Ph Ph 110a (82%) 111 (77%) PhH 109 20 8C 130 ± 140 8C Me Ph N 2b NN O O HN Ph 112 (61%) Although cyclocondensation at the a-dicarbonyl fragment is the major process in the reaction of both theAPA4 and the methyl ester 2 with 1,2-diamino-4-methyl-1,6-dihydropyrimidin-6-one on refluxing in AcOH, this process yields different regioisomers for these two types of substrate, namely, 2-aroylmethyl-6-methyl-4,8- dihydro-4H-pyrimido[1,2-b]-1,2,4-triazine-3,8-diones 113 and (Z)-3-aroylmethylidene-6-methyl-2,3,4,8-tetrahydro-1H-pyrimi- do[1,2-b]-1,2,4-triazine-2,8-diones 114, respectively.161 O Ar 4 N N O Me N O O NH NH2 AcOH N 113 (67% ± 91%) D O Me N NH2 Ar 2 NH O N O H N N Me 114 (64% ± 83%) Ar=4-XC6H4 (X=H, Me, OMe, Cl, OEt, Br, NO2).Heterocyclic amines such as 2,4,5,6-tetraamino- (115a) and 4-hydroxy-2,5,6-triaminopyrimidines (115b ) condense with the AP 2 similarly to o-diamines.When refluxed in a solution of AcOH, both amines react selectively with the AP 2 or with the corresponding sodium enolates at the a-oxoester fragment to give 2,4-diamino-7-aroylmethylidene-5,6,7,8-tetrahydropteridin-6-ones932 X NH2 N 2+H2N N. NH2 H2SO4 115a,b NH 121 116, 117, 119: Ar=4-YC6H4 [Y=H (a), Me (b), CN (c), OH (d), Cl (e), Br (f), CO2H (g)]; 118a: Ar=4-OHC6H4 . 116 in the case of the amine 115a or 2-amino-7-aroylmethylidene- 4-hydroxy-5,6,7,8-tetrahydropteridin-6-ones 117 in the case of 115b.162 When the reaction is conducted in aqueous NH3 (1 mol litre71, pH 8), derivatives of 4-aryl-2-(5-heteroaryl)- amino-4-oxobut-2-enoic acids 118a and 119a ± d, respectively, can be isolated.162, 164 In concentrated H2SO4, the compounds 119 cyclise into 2-amino-6-aroylmethylidene-4-hydroxy-5,6,7,8- tetrahydropteridin-7-ones 120, which are isomers of the pteridines 117.The structures of the products 119 and 120 were proved by hydrolysis, which gave rise to known 2-amino-4-hydroxy-6- methyl-7,8-dihydropteridin-7-ones (121) and benzoic acids (Scheme 8).162 Reactions with urea and sulfamides. The aroylpyruvic acids 4 react with urea at the a-oxocarboxyl fragment on fusion (120 ± 130 8C); this affords 5-aroylmethylidene-2,3,4,5-tetrahydroimidazole-2,4- diones 122.165 H2NCNH2 Ar O 4 O H N O 122 (68% ± 96%) Ar=4-XC6H4 (X=H, Me, But, OMe, F, Cl, Br). The direction of reactions of methyl 3-bromoaroylpyruvates 10 (X=Br) with urea is determined by the reaction conditions.Fusion of equimolar amounts of the reactants for 20 ± 30 min at 105 ± 120 8C results in the formation of 6-aroyl-5-hydroxy- 1,2,3,4-tetrahydropyrimidine-2,4-diones 123, whereas the use of a great excess of urea and a longer reaction time (2 h) gives 5-aryl- 4-methoxycarbonyl-2,3-dihydro-1H-imidazol-2-ones 124.166 ± 168 The researchers proposed a mechanism for the formation of the heterocycles 123 and 124, according to which the common first stage of the reaction is nucleophilic substitution of urea for the bromine atom in the initial AP 10.166 X HN O N AcOH, H2O N N H2N D H Ar O 116a ± d (X=NH2); 117a ± c,e ± g (X=OH) Ar O H X N NH3, H2O N D COOEt NH2 N H2N 118a (X=NH2); 119a ± d (X=OH) ONH S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Scheme 8 Ar O H OH N H2SO4 (conc.) N O N H2N NH 120a,b,d ± g H2O, cat.OH Me N H2O, Cat N O N H2N O HO 20 ± 30 min NH O Br O H2NCNH2 NH Ar CO2Me O Ar 123 (67% ± 89%) D O O 10 MeO2C HN 2 h O Ar HN 124 (61% ± 94%) R=Me, X=Br; Ar=4-YC6H4 (Y=H, Me, OMe, F, Cl, Br). The APA esters 2 react with sulfamide on refluxing in HCl- saturated ethanol at the b-dicarbonyl fragment to give 5-aryl-3- ethoxycarbonyl-2H-1,2,6-thiadiazine 1,1-dioxides (125).169 Simi- larly, N-methylsulfamide cyclocondenses selectively with the AP 2 giving rise to only one series of regioisomers, the position of the methyl group in which is not indicated in the study cited.133 The most probable structure is, apparently, 126, i.e., the structure of 6-methyl-substituted 1,2,6-thiadiazine dioxides 125.The products of reactions of the compounds 125, 126 with ammonia, primary amines and hydrazine possess biological activities.133, 169 O O X XNHSO2NH2 N S N 2 D Ar CO2Et 125 (X=H); 126 (X=Me) Ar=4-YC6H4 (Y=H, Cl, Me).(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis c. Reactions with N,O-dinucleophiles Reactions with hydroxylamine. The acids 4 and their esters 2 react with hydroxylamine hydrochloride at the b-dicarbonyl fragment to give isoxazoles of only one of the two possible regioisomer classes � 5-arylisoxazole-3-carboxylic acids 127.The reactions are usually carried out by refluxing in aqueous ethanol 13 ± 15, 123, 170, 171 or at 20 8C in the presence of Na2CO3 with subsequent short-term heating with either strong acids 15 or acetyl chloride.2 Less reactive arylamides AP 6 are converted into the corresponding amides 127 (R=NHAr) on refluxing with hydroxylamine hydrochloride in ethanol in the presence of KOH,62 while the AP hydrazides 58 produce hydrazides 127 (R=NHNHAr) in boiling dioxane.67 Under mild conditions (EtOH ±H2O, Na2CO3, 20 8C), it is sometimes possible to isolate 2-oximes 128 formed as intermedi- ates in the reactions of the (H)AP 2, 4 with hydroxylamine hydrochloride.2, 13, 15 The oximes 128 readily cyclise into isoxa- zoles 127 on heating or on treatment with strong acids 13, 15 or with dehydrating agents such as acetyl chloride.2 The formation of ethyl 3-pyridoylpyruvate (128h) requires more drastic condi- tions.17 COR Ar O N 127 (22% ± 99%) NH2OH 2, 4, 6 H+ COR Ar N OHO 128a ± h (40% ± 82%) 127: Ar=Ph, YC6H4 (Y=4-Me, 4-Cl, 2-OMe, 4-AcNH), C6F5, 4-diphenyl, 3-phenanthryl, 2-pyrrolyl, 2-furyl, 2-thienyl, 5-methyl-2- thienyl; R=OH, OEt, 3-pyridylamino, NHNHCOC6H4Z (Z=H, 4-OMe); 128: Ar=YC6 H4 [Y= H (a), 2-NO2 (b, c), 4-AcNH (d)], 2-furyl (e), 2-thienyl (f), 5-methyl-2-thienyl (g), 3-pyridyl (h); R=OH (a, b), OEt (c ± g), OMe (h).Reactions with 2-aminoethanol. The acids 4 add 2-aminoethanol at the a-oxocarboxyl fragment to give oxazine derivatives, the regiodirectivity of the reaction being dependent on the reaction conditions. The refluxing of the APA 4 with potassium 2-amino- ethoxide in anhydrous dioxane yields 3-aroylmethylidene-3,4,5,6- tetrahydro-2H-1,4-oxazin-2-ones 129;172 the reaction in anhy- drous ethanol affords 2-aroylmethylidene-3,4,5,6-tetrahydro- 2H-1,4-oxazin-3-ones 130.173 O Ar dioxane O O H N 129a ± d (83% ± 99%) H2N(CH2)2OH 4 D O Ar EtOH NH O O 130a ± c (68% ± 87%) Ar=4-XC6H4 [X=H (a), F (b), Br (c), Cl (d)].The acid 31c reacts with 2-aminoethanol in boiling dioxane also to give 3-pentafluorobenzoylmethylidene-3,4,5,6-tetrahydro- 2H-1,4-oxazin-2-one (129e). The structure of the compound 129e was confirmed by the fact that on heating in DMSO, it cyclises to yield 7,8,9,10-tetrafluoro-1,2-dihydro-1,4-oxazino[4,3-a]quino- line-4,6(4H,6H)-dione (131).On treatment with aqueous KOH, this product undergoes opening of the lactone ring, which gives 933 potassium 1-(2-hydroxyethyl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihy- droquinoline-2-carboxylate (132).26, 27 O F DMSO O H2N(CH2)2OH HN 31c 190 8C O 129e (46%) O O KOH, H2O F F O N N CO2K O CH2CH2OH 131 (46%) 132 (76%) Reactions with 2-aminophenol and its derivatives. The reactions of 2-aminophenol with the APA 4, their esters 2 and anilides 6 also involve the a-dicarbonyl fragment and give 3-aroylmethylidene-3,4- dihydro-1,4-benzoxazin-2(2H)-ones 133.3, 5, 9, 21, 29, 37,44, 45, 53, 174 ± 177 O NH2 Ar O OH 2, 4, 6 O H N 133a ± o (42%799%) 2: R=OMe, OEt; 4: R= OH; 6: R = NHPh.Ar=XC6H4 [X=H(a), 4-Me (b), 4-OMe (c ),OH(d ± f), 4-F (g), 4-Cl (h), 4-Br (i), 4-NO2 (j)], 2,4,6-Me3 C6H2 (k), 2-furyl (l), 2-thienyl (m), 4-pyridyl (n), cymantrenyl (o); The tautomerism of benzoxazines 133 has been studied by spectroscopy. 145, 146 It was shown that in the solid state and in DMSO-d6 solutions, they exist as form A stabilised by an IMHB. Noticeable amounts of forms B ±D are present only in CF3CO2D.145 O O O O CF3CO2D Ar Ar N DMSO N O H O B A CF3CO2D DMSO O O O O HO N Ar N Ar OH C D When the reaction of the acid 4a with 2-aminophenol was carried out under mild conditions (ethanol, 20 8C), a salt was isolated.On heating, this salt readily cyclised to benzoxazin-2-one 133a.37 It has been shown 37 that benzoxazinones 133 are thermo- dynamically less stable than quinoxalones 86. Thus the compound 133a is converted into the quinoxalone 86a almost quantitatively when fused with PDA; in solutions, this transformation occurs even at 20 8C. Pentafluorobenzoylpyruvate 31a can react with 2-aminophe- nol to give, unlike non-fluorinated analogues, not only 3-penta- fluorobenzoylmethylidene-3,4-dihydro-1,4-benzoxazin-2(2H)-one (133p), but also its mixture with 2-hydroxy-3,4,5,6-tetrafluoroben- zoylmethylidene-3,4-dihydro-2H-1,4-benzoxazin-2-one (133q). The compound 133p is formed under mild conditions (at 20 8C)934 in alcohol, while the product mixture is produced when the reactants are refluxed.3, 5, 176 O C6F6 O 20 8C O H N NH2 OH 133p (51%) 31a O F D O 133p (53%)+ O H O H N 133q (18%) 4(5)-Monosubstituted 2-aminophenols and 1-amino-2-naph- thol react with the AP 2 similarly to 2-aminophenol yielding 6(7)- derivativesf 3-aroylmethylidene-3,4-dihydro-1,4-benzoxazin- 2(2H)-ones 134a ± d and 3-benzoylmethylidene-3,4-dihydronaph- tho[2,1-b]-1,4-benzoxazin-2(2H)-one (135), respectively.145, 175, 177 O X OH Ar O Y NH2 O H N D X 2 Y 134a ± d (74% ± 86%) O NH2 OH Ph O O H N D 135 (89%) Ar=Ph (a ± c), 4-MeC6H4 (d); X=H (a ± c), Me (d); Y=Me (a), Cl (b), NO2 (c ), H (d).The reaction of the APA 4 with 2-aminobenzyl alcohol carried out by refluxing in toluene gives 4-aroylmethylidene-3,4-dihydro- 1H,5H-benzo[e]-1,4-oxazepin-3-one 136.178Ar O HN OH D 4+ O NH2 O 136 (76% ± 96%) The reactions of the APA 4 and their methyl esters 2 with 2-aminophenyldiphenylmethanol carried out by refluxing in ben- zene do not result in cyclisation products but give instead 4-aryl-2- [2-(1-hydroxydiphenylmethyl)phenylamino]-4-oxo-4-but-2-enoic acids and their esters 137.Unlike the ester 137d, the acids 137a,b cyclise when refluxed in acetic anhydride to 5-acetyl-4-aroyl- methylidene-1,1-diphenyl-3,4-dihydro-1H,5H-benzo[e]-1,4-oxaze- pin-3-ones 138.64, 179 S G Perevalov, Ya V Burgart, V I Saloutin, O N Chupakhin Ph Ph Ph Ph Ph Ph O OH OH O NH2 H R=OH O N O N 2, 4 2 Ac2O, D D Ac Ar ROC Ar 138a,b (53% ± 67%) 137a ± d (50% ± 84%) Ar=4-XC6H4 [X=H (a), Me (b, d), Cl (c)]; R=OH (a ± c), OMe (d).d. Reactions with N,S-dinucleophiles Reaction with 2-mercaptoethylamine. The acids 4 react with 2-mercaptoethylamine in boiling ethanol to give acyclic 4-aryl-2- (2-mercaptoethylamino)-4-oxobut-2-enoic acids 139, except for the APA having a methoxy group in the aryl substituent. In this case, the reaction yields cyclic 3-(4-methoxybenzoylmethylidene)- 2,3,5,6-tetrahydro-1,4-thiazin-2(4H)-one (140), which is due, apparently, to the strong electron-donating effect of the methoxy group.44 Ar CO2H O N(CH2)2SH H H2N(CH2)2SH 139 (69% ± 92%) 4 D O 4-MeOC6H4 S O H N 140 (83%) Ar=4-XC6H4 (X = H, Me, Cl, Br, NO2).Reaction with 2-mercaptoaniline. The aroylpyruvic acids 4 react with 2-mercaptoaniline on refluxing in toluene; the reaction involves the a -oxocarboxyl fragment and affords 2-aroylmethy- lidene-3,4-dihydro-1,4-benzothiazin-3(2H)-ones 141.180 Unlike the acids 4, their methyl esters 2 react with 2-mercaptoaniline on fusion to give the products of addition at the carbonyl group attached to C(2), i.e., 2-aroylmethyl-2-methoxycarbonyl-2,3- dihydrobenzothiazoles 142.180, 181 O Ar NH 4 S O NH2 141 (72% ± 98%) SH HN ArCOCH2 2 MeO2C S 142 (85% ± 98%) Ar=4-XC6H4 (X=H, Me, OMe, Cl, Et, F, Br). It is of interest that pentafluorobenzoylpyruvates 31b,d behave in a different way towards 2-mercaptoaniline. The pyr- uvate 31b is cleaved by the nucleophile under mild conditions (methanol, 15 ± 25 8C) to give ultimately 2-[4-(2-aminophe- nylthio)-2,3,5,6-tetrafluorophenyl]benzothiazole (143).Under similar conditions, the copper(II) chelate 31d reacts with 2-mer- captoaniline hydrochloride to give the product of selective cyclo- condensation at the a-oxoester fragment, 3-pentafluorobenzoyl- methylidene-3,4-dihydro-1,4-benzothiazin-2(2H)-one (144).3, 6(Het)aroylpyruvic acids and their derivatives as promising building blocks for organic synthesis N NH2 NH2 MeOH, 20 8C F 31b+ S S SH 143 (40%) O + F NH3Cl7 S MeOH, 15 ± 35 8C 31d+ N H O SH 144 (32%) 4. Miscellaneous reactions A specific feature of the APA 4 and their esters 2 in the formation of heterocycles is the ability to react simultaneously at the nucleophilic C(3) atom and one electrophilic center.Fusion of ethyl benzoylpyruvate 2a with benzylideneaniline is known 182 to result in the formation of 4-benzoyl-3-hydroxy-1,5- diphenyldihydropyrrol-2(5H)-one (145, Y=H, Ar=R=Ph). Borsche has shown 183 that the same pyrrol-2-ones 145 can be prepared from the APA 4 if an equimolar mixture of arylamine and aldehyde is used instead of N-arylaldimine. In subsequent studies dealing with the synthesis of pyrrolediones 145, all the three components, namely, (H)AP, aldehydes and amines were varied over wide limits.13, 184 ± 187 These reactions are usually carried out in alcohol, AcOH or dioxane at 20 ± 60 8C.The yields of the target products 145 can be increased by using an alde- hyde ± amine mixture, instead of the corresponding aldimine, and in the case where the AP 2, 4 contain electron-withdrawing substituents. It is of interest that pyrrolediones 145 are easily (AcOH, 20 8C) formed also from benzoylpyruvic acid 2-pyridy- lamide 6 (Ar=Ph, R=2-Py) and diarylaldimines.187 COAr HO 2, 4, 6+RN CHAr 0 O Ar0 2, 4+RNH2+Ar0CH O NR 145 (42% ± 96%) Ar=Ph, 4-XC6H4 (X=Me, OMe, OEt, Cl, Br, NO2), 2-furyl; R=Ph, 2-naphthyl, 4-MeC6H4, CH2CO2H, (CH2)2NMe2; Ar0=C6H4Y (Y=H, 4-OMe, 4-I, 4-Cl, 4-Br, 4-OH, 2-OMe, 2-F, 2-Cl). In the given reactions, the aldimine acts as an N-nucleophile and a C-electrophile with respect to AP. The enolysed structure of 145 has been confirmed by NMR spectroscopy.184 ± 186 It is notable that when 2-aminonaphthalene (or the corre- sponding aldimines) are used as the amine component, the acid 4a is not converted into pyrrolones 145 in boiling ethanol but forms (according to the Doebner condensation pattern) 2-substituted 3-benzoyl-4-carboxybenzo[ f ]quinolines 146.183, 188 In this case, the Schiff base acts as a C-nucleophile [the C(1) atom of the 2-naphthyl group] and a C-electrophile with respect to the AP.CO2H N CHR COPh 4a+ R N 146 (22% ± 62%) R=H, Me, Ph, 4-MeOC6H4, piperonyl. The reaction of ethyl 2-furoylpyruvate 4c with 2-amino- benzaldehyde gives 3-(2-furoyl)-2-ethoxycarbonylquinoline (147).13 935 CHO CO2Et O + O NH2 H O 4c O O N CO2Et 147 It has been reported 89 that refluxing of ethyl 4-chloroben- zoylpyruvate with diphenyldiazomethane in benzene induces cycloaddition of the ester at the C(2) and C(3) atoms without elimination of nitrogen to give 3,3-diphenyl-5-(4-chlorobenzoyl)- 4-ethoxycarbonyl-3H-1,2-pyrazole (148).CO2Et O + 7 4-ClC6H4 CO2Et Ph Ph2CN N 4-ClC6H4 O Ph N N H O 148 (17%) IV. Biological activities of (het)aroylpyruvates and the products of their heterocyclisation The interest in the (H)AP chemistry is related, first of all, to the broad spectrum of biological activities exhibited by representa- tives of this group of compounds and the products of their heterocyclisation. Thus sodium enolates derived from ethylbenzoyl- and 4-chlorobenzoylpyruvates possess an antimicrobial activity in vitro.189 Hetaroylpyruvic acids 23 and their esters 22, 33, 34, 36 have been found to display antiaggregation,23 antibacterial,23, 33, 34 antiviral,22 antiinflammatory 34 and analgesic 36 activities. 3-Halogenated esters of APA showed antibacterial 80, 84 and antifungal 18, 80 effects.The most diverse and the highest biological activities were found for (H)APA amides and hydrazides. Substances analgesic,31, 54, 59, 61, 62, 73, 94, 179, 190 with inflammatory,31, 42, 50, 54, 57 ± 60, 62, 69, 70, 72, 73, 85, 94, 179 convulsant,43, 61 and antiviral 69 ± 71 anti- anti- antibacte- rial 50, 51, 57, 58, 61, 62, 66, 69, 70, 73, 77, 86, 179, 190 activities have been found among this group.Many heterocyclic compounds obtained from (H)AP possess various types of physiological activities. The pyrazoles 66 (R1=NHR2) exhibit antiinflammatory,31, 59, 62, 73 analgesic 59, 73 and antibacterial 62, 69, 128 activities with low toxicity. 5-(3-Pyr- idyl)-3-hydrazinocarbonylpyrazole (66, Ar=3-pyridyl, R=NHNH2) has been patented as an antitumour agent.17 Antibacterial action has been discovered for a number of 1-phe- nyl-5-hetarylpyrazole-3-carboxylic acids 67.23 3-Aroyl- methylenepiperazin-2-ones 81 137, 139, 191 and their 1-methyl- and 1-phenyl- 82141, 191 or 6-methyl- and 6-phenyl-substituted 85 142 derivatives show antiinflammatory, anticonvulsant and analgesic activities in combination with low toxicity. Antiinflammatory 94 and analgesic 91, 94 effects of 3-(1-phenylazoaroylmethylene)- 1,2,3,4-tetrahydroquinoxalin-2-ones 87 (X=N=NPh) have been reported.N-Aryl-4-arylbenzo[b]diazepine-2-carboxamides 91 were patented as analgesics.151 Antibacterial and antiinflam- matory activities have been found for 3-aroylmethylene-6-cyano- 2-quinoxalinones 94.51 The tetrahydropyridoquinoxalinones 98 exhibited a tuberculostatic activity in vitro.155 It was found that 4-aryl-2-(5-heteroaryl)amino-4-oxobut-2-enoic acid 119 stimu- lates the cell growth of some microorganisms.162, 164 Some 5-aroylmethyleneimidazolidine-2,4-diones 122 possess an anti- convulsant activity while having low toxicity; they depress the central nervous system and, possibly, the activity of the micro- somal liver enzymes.165 A series of 5-aryl-1,2,6-thiadiazine-3-936 carboxylic acid 1,1-dioxide derivatives 125, 126 demonstrated antiviral and sedative activities.133 The benzoxazepinones 136 show antimicrobial action.178 An antibacterial activity has been noted for 4-aryl-2-[2-(1-hydroxydiphenylmethyl)phenylamino]-4- oxo-4-but-2-enoic acids and their esters 137.179 The benzothiazo- line 142 (Ar=Ph) has an antiinflammatory activity.181 In the case of some pyrrolones 145, antibacterial185, 186 and nootropic activ- ities have been found.185 V.Conclusion Analysis of the published data demonstrates that (H)AP represent an ample class of organic compounds containing carboxyl, ester, or amide functional groups. An indispensable structural feature of these substances is the presence of the b-dicarbonyl fragment.The structure of (H)AP accounts for their great synthetic potential. The availability of a wide range of (H)AP is ensured by facile and convenient procedures for their preparation, the main of them being the Claisen condensation or hydrolysis (alcoholysis) of 2,3- dihydrofuran-2,3-diones and -pyrrole-2,3-diones. When comparing the reactivity of the APA 4, the esters 2 and the amides 6, one cannot but note that the amides 6 are somewhat less reactive. Indeed, similar reactions require more drastic con- ditions in the case of theAPA amides 6. In all the (H)AP 2, 4 and 6, the C(2) centre, i.e., the a-carbonyl group, is the site of choice for the primary attack in the reactions with both mono- and dinu- cleophilic reagents (see Scheme 5).However, when a bulky sub- stituent has been introduced at the 3-position of (H)AP, some reactions involve the ester group. The transformations of (H)AP on treatment with dinucleophiles arouse the greatest interest because these reactions serve as the basis for the synthesis of various heterocyclic systems. The reaction can involve either the a- or b-dicarbonyl fragment. In the reactions with a-dinucleo- philes (hydrazines, hydroxylamine), the b-dicarbonyl moiety of (H)AP is involved in the process, while for most of other nucleophiles, the addition at the a-dicarbonyl residue is preferred. In the majority of cases, these processes are regio- and chemo- selective, which allows (H)AP to be used for targeted synthesis of heterocycles.Nevertheless, the chemistry of (H)AP is far from being exhausted. Further research into the properties of these com- pounds and into the prospects for using them in organic synthesis appears quite topical. These may be related, for example, to investigation of fluoro-containing (H)AP the chemistry of which has essential distinctive features. 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Yu S Andreichikov, V L Gein, I N Anikina Zh. Org. Khim. 22 1749 (1986) a 185. V L Gein, L F Gein, N Yu Porseva, E V Voronina, M I Vakhrin, K D Potemkin, V E Kolla, L P Drovosekova, A V Milyutin, N S Shchuklina, G A Veikhman Khim.-Farm. Zh. 32 (9) 23 (1998) c 186. V L Gein, N N Kasimova, E V Voronina, L F Gein Khim.-Farm. Zh. 35 (3) 31 (2001) c 187. A V Milyutin, V L Gein, Yu S Andreichikov Zh. Obshch. Khim. 62 2633 (1992) d 188. E A Robinson, M T Bogert J. Org. Chem. 1 65 (1936) 189. H Rinderknecht, J L Ward, F Bergel, A L Morrison Biochem. J. 41 463 (1947) 190. E N Koz'minykh, N M Igidov, E S Berezina, G A Shavkunova, I B Yakovlev, S A Shelenkova, V E Kolla, E V Voronina, V O Koz'minykh Khim.-Farm. Zh. 30 (7) 31 (1996) c 191. Russ. P. 2 067 579; Chem. Abstr. 126 312 261 (1997) a�Russ. J. Org. Chem. (Engl. Transl.) b�Chem. Heterocycl. Compd. (Engl. Transl.) c�Chem.-Pharm. J. (Engl. Transl.) d�Russ. J. Gen. Chem. (Engl. Transl.) e�Russ. Chem. Bull., Int. Ed. (Engl. Transl.) f�J. Struct. Chem. (En

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年代:2001

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Russian Chemical Reviews 70 (11) 939 ± 969 (2001) Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis N V Konovalova, R P Evstigneeva, V N Luzgina Contents I. Introduction II. Porphyrin dimers III. Multiporphyrin ensembles IV. Porphyrin ± carotenoid compounds V. Conclusion Abstract. photochemical and synthesis the on data published The The published data on the synthesis and photochemical properties which ensembles molecular porphyrin-based of properties of porphyrin-based molecular ensembles which repre- repre- sent models of natural photosynthetic light-harvesting complexes sent models of natural photosynthetic light-harvesting complexes are the of dependence The systematised. and generalised are generalised and systematised.The dependence of the transfer transfer of and donor between distance the on energy excitation of excitation energy on the distance between donor and acceptor acceptor components, and electronic arrangement, mutual their components, their mutual arrangement, electronic and environ- environ- mental energy of mechanisms Two discussed. are factors mental factors are discussed. Two mechanisms of energy transfer transfer reactions, consid- are bond', `through and space' `through viz., ., `through space' and `through bond', are consid- ered. references 96 includes bibliography The ered. The bibliography includes 96 references. I. Introduction Absorption of solar energy and its subsequent transformation by cells in the course of photosynthesis is the basis for the energy supply for vital activities of all living organisms.It is therefore not surprising that this problem arouses considerable theoretical and practical interest from investigators.1 ±6 Spectroscopic and theo- retical studies of photosynthetic processes are mainly focused on the fundamental analysis of photophysical and photochemical characteristics of biological energy-transforming systems and the construction of supramolecular ensembles for molecular pho- tonics and optoelectronics.7±10 Chlorophylls and related pigments as well as quinones and carotenoid polyenes are the major components of natural photo- synthetic systems. Their interactions are reduced to three basic photochemical processes, viz., singlet ± singlet energy transfer, triplet ± triplet energy transfer and photoinduced electron trans- fer.For example, antenna systems, which contain chlorophylls, carotenoids and other accessory pigments, collect light and trans- fer excitation energy to the reaction centres via a singlet ± singlet energy transfer mechanism.11, 12 Carotenoids are responsible for photoprotection of living organisms from destructive effects of highly reactive singlet oxygen by rapid quenching of the triplet state of chlorophylls via a triplet ± triplet energy transfer mecha- nism.13 The excitation energy derived from antenna complexes is transformed into chemical energy in the course of photoinduced N V Konovalova, R P Evstigneeva, V N LuzginaMV Lomonosov Moscow State Academy of Fine Chemical Technology, 117571 Moscow, Prosp.Vernadskogo 86, Russian Federation. Fax (7-095) 434 87 11. Tel. (7-095) 434 85 44. E-mail: httos.mitht@g23.relcom.ru (N V Konovalova) Received 1 June 2001 Uspekhi Khimii 70 (11) 1059 ± 1093 (2001); translated by R L Birnova #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n11ABEH000682 939 940 954 962 967 electron transfer mediated by chlorophylls and quinones, which, in turn, generates long-living states with transmembrane separa- tion of charges.14 ± 16 Recent studies have led to the synthesis of molecular systems which successfully simulate certain stages of natural conversion of solar energy, particularly, the above-mentioned singlet and triplet energy transfer reactions.The choice of pigments, donors and acceptors for such model systems is based of their spectral properties, which determine the energy characteristics of various excited states. Chromophores related to pigments involved in natural photosynthetic processes are the most promising compo- nents for such systems. The choice of the working principle, which regulates inter- actions between the individual fragments of a system, is no less important. These interactions, which are controlled by the spatial arrangement of the photosynthetic components and the nature of the separating medium, strongly affect the rates and quantum yields of photochemical processes. The spatial arrangement of pigments, donors and acceptors in natural photosynthetic systems is provided by their interactions with protein subunits. One of the strategies in the construction of artificial photosynthetic systems consists of the substitution of covalent bonds for pigment ± pro- tein interactions.1 ± 3, 6 An alternative strategy involves noncova- lent assembly of supramolecular complexes, mostly by virtue of the formation of hydrogen and coordination bonds.17 The con- struction, in the past few years, of models in which amino acids and peptides are used as connecting bridges (spacers) permitted one to study different regularities of energy and electron transfer in a protein matrix.18 The majority of supramolecular model systems described in the literature reproduce the photoinduced electron transfer step.Spectroscopic studies of donor ± acceptor model systems have made it possible to establish the dependence of rates of photo- chemical charge separation reactions on structural factors, such as the distance between the system components and their orienta- tion, on the interactions between the electronic systems of the donor and the acceptor, thermodynamic driving force of the electron transfer and environmental factors.1 ± 3, 6 Until very recently, much less attention was given to the development of model systems mimicking certain functional steps of light-harvesting antenna complexes. Light-harvesting antenna complexes inherent in natural pho- tosynthetic systems absorb low-intensity sunlight at wavelengths *280 ± 900 nm (up to 1040 nm in the case of some bacterial complexes) eventually resulting in the transfer of energy to the reaction centres.These complexes contain a large number of chlorophyll or bacteriochlorophyll molecules, carotenoid poly-940 Energy migration Light LH-2 LH-1 Energy transfer e7 LH-2 Reaction centre Figure 1. The structures of the bacterial light-harvesting complexes LH-1 and LH-2 responsible for the transfer of absorbed light energy to the reaction centres.11 enes and some other accessory pigments held at a small distance from one another by virtue of noncovalent interactions with the protein environment. Absorption of photons by pigments of antenna complexes is followed by migration of excited state energy generated by pigment ensembles until excitation reaches the reaction centre (Fig.1). The energy can be transferred over sufficiently large distances at record-breaking high speed and with nearly quantitative quantum efficiency (quantum yields).11, 12 The complexity of supramolecular pigment ± protein struc- tures of natural antenna complexes hinders detailed investigations of light-harvesting reactions at the molecular level and does not provide unambiguous answers to the following questions. How do electronic, photophysical and photochemical properties of pig- ments influence the efficiency of light-harvesting processes? How does energy migration depend on the three-dimensional config- uration of pigments (viz., the distance between the components, their orientation, spatial packing, etc.)? What are the mechanisms of electronic interactions between pigments and the role of local environment? What are the effects of these interactions on the synthetic ensembles after substitution of covalent bonds for pigment ± protein interactions between the components? What is the mechanism of functioning of the pigments as integral antenna systems within the ensembles and at what distances does energy migrate? Is it possible to increase the efficiency of energy migra- tion in artificial systems by varying the system structure or energy gradients and what are the structural limitations for directional migration of energy? These questions are of crucial importance for the correct understanding of light-harvesting processes occurring in photosynthesising organisms and purposeful utilisation of solar energy. In this context, artificial model systems offer convenient subjects for the study of regularities of energy transfer in natural antenna complexes. In this review, we consider the main principles of the con- struction of porphyrin-based model photosynthetic systems and the methods of their synthesis. The applications of these systems in the study of energy transfer in photosynthesis are also discussed.II. Porphyrin dimers Porphyrin dimers present special interest for investigation of pairwise interactions between pigments in larger ensembles as the simplest models for energy transfer studies. According to the type of their binding, these compounds can be divided into three groups, viz., covalently bound molecules with hydrocarbon spacers, complexes with amino acid and peptide spacers and systems linked by non-covalent bonds.N V Konovalova, R P Evstigneeva, V N Luzgina 1. Porphyrin dimers with hydrocarbon spacers a. Synthesis The synthesis of covalently bound pigment ensembles is the most popular approach to the design of bisporphyrin model systems. Covalently bound p-conjugated donor ± acceptor systems are convenient models for the study of regularities of energy transfer at large distances. The polyyne- and polyene-bound bisporphyrins 1a ± d and 2a ± d are examples of such systems.19 The strength of electron-exchange reactions between the donors and the acceptors in these compounds is largely determined by the `centre-to-centre' distance between two porphyrin macrocycles.This, in turn, is strictly correlated with the number of unsaturated bonds in polyyne-bound systems and can be measured, with a high degree of precision, for polyene-bound molecules taking account of rotation of porphyrin rings around the single bonds. C6H13 C6H13 C6H13 C6H13 But But N N HN N Zn X NH N N N But But C6H13 C6H13 C6H13 C6H13 1a ± d, 2a ± d, 3a ± c n n 1: X = p-C6H4( ) C C C6H4-p; n=1 (a), 2 (b), 3 (c), 4 (d); 2: X = p-C6H4( ) CH CH C6H4-p; n=1 (a), 2 (b), 3 (c), 4 (d); 3: X = p-C6H4C C Ar C CC6H4-p; Ar=1,2-C6H4 (a), 1,3-C6H4 (b), 1,4-C6H4 (c). The efficiency of intramolecular singlet energy transfer in the dimeric porphyrins 3a ± c and 4a ± c containing bis(phenylethy- nyl)phenylene bridges is determined by both the distance and mutual arrangement of the pigments.20, 21 But But But But But But N N N N X Zn Zn N N N N But But But But But But 4a ± c X=p-C6H4C:C7Ar7C:CC6H4-p; Ar=1,2-C6H4 (a), 1,3-C6H4 (b), 1,4-C6H4 (c).The polyyne-bound bisporphyrins 1a ± d were obtained by trichloroacetic acid-catalysed condensation of 3,5-di-tert-butyl- benzaldehyde (5), dipyrrolylmethane 6 and dialdehydes 7a ± d But C6H13 C6H13 Me Me + CHO+ NH HN 5 But 6 1a ± d CHO ( ) C C n + CHO 7a ± d n = 1 (a), 2 (b), 3 (c), 4 (d).Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis with subsequent oxidation with p-chloranil 22, 23 and metallation of one of the porphyrin rings.The yields of bisporphyrins ranged from 13% to 46%.19 Similarly, the dimers 2a,b and 3a,b were synthesised by condensation of dialdehydes with compounds 5 and 6.19, 20 This one-pot synthesis of bisporphyrins is both convenient and efficient. The formation of polymeric side products in the condensation is suppressed by a large excess of the terminal monoaldehyde; the polyyne and polyene groups, which are especially acid-sensitive, are not affected, since the reaction is carried out under mild conditions.22, 23 An alternative approach, which includes condensation of the formyl-substituted zinc-porphyrin monomer 8 with bisphospho- nates 9a,b, was used in the synthesis of bisporphyrins 2c,d.19 C6H13 C6H13Me Me But N N Zn CHO+ N N But Me Me C6H13 C6H13 8 O O P(OEt)2 2c,d + (EtO)2P n 9a,b n = 1 (a), 2 (b).Bisporphyrin 3c was synthesised by palladium-catalysed con- densation of ethynylporphyrin 10 [the latter was prepared by the reaction of 4-ethynylbenzaldehyde (11) with compounds 5 and 6 with subsequent oxidation by p-chloranil] with 1,4-diiodoben- zene.24, 25 The yield of the dimer 3c was 35%.20 C CH+5+6 OHC 11 C6H13 C6H13 Me Me But N HN 1,4-I2C6H4 3c C CH PdCl2 NH N Me But Me C6H13 C6H13 10 Similarly, bisporphyrins 4a ± c were synthesised in 49%, 55% and 84% yields, respectively, by the reaction of ethynyl-substi- tuted tetraarylporphyrins with 1,2-, 1,3- and 1,4-diiodobenzene in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri- phenylarsine.21 An approach to the construction of model light-harvesting systems has been developed, which makes use of porphyrin building blocks.Firstly, meso-substituted porphyrins are synthes- ised from aldehyde precursors (containing iodine atoms and ethynyl groups) and pyrrole (or dipyrrolylmethanes) with subse- quent palladium-catalysed condensation optimised for mild cou- pling of the porphyrin building blocks. In this case, spacers between porphyrins are formed directly in the condensation step.25 ± 27 This block synthesis was used to prepare the dimeric ensembles 12a ± i,27 ± 31 13a ± c 32 and 14a,b.33 These model systems were employed for the systematic analysis of structural and electronic factors and their effects on the degree of electronic interactions between tetrapyrrole macrocycles as well as for the synthesis of the amphiphilic porphyrin dimers 15a,b.34 The latter can be incorporated into lipid bilayer membranes for transmem- brane energy transfer studies.Condensation of the iodoporphyrin 16 free base and the zinc ethynylporphyrin complex 17 in the presence of tris(dibenzylide- neacetone)dipalladium(0) and triphenylarsine in a 5 : 1 toluene ± triethylamine mixture (35 8C) afforded the dimer 12a with a diphenylethyne linker (yield>70%). R N HN R NH N R 16 N + HC C N R=2,4,6-Me3C6H2. Bisporphyrins 12b ± h were synthesised analogously in 70%± 80% yields.27 ± 31 Since the palladium catalyst present in the reaction mixture is not involved in undesirable metallation reactions, free porphyrin bases can be used.If the reaction is carried out in neutral and weakly basic solvents at moderate temperatures, neither demetal- lation of zinc complexes nor oligomerisation of ethynyl-substi- tuted porphyrins take place.25, 27 The diphenylethyne linkers in the systems 12a ± i ensure a sufficiently large (*20 A) distance and relatively weak electronic interactions between the pigments, which excludes quenching of the excited state owing to the electron transfer, which competes with the energy transfer. However, in this case it is desirable to reduce the distance between the porphyrin chromophores in order to increase the rate of the energy transfer.It was shown 35 that the distance between the porphyrin components of a dimer can be reduced to 13 A if a para-phenylene linker is used, which significantly enhances their electronic inter- actions. Compounds 18a,b were obtained by one-pot condensa- tion of the corresponding aldehyde with terephthalaldehyde and pyrrole using boron trifluoride etherate as a catalyst and oxida- tion of the resulting product by 2,3-dichloro-5,6-dicyano-1,4- benzoquinone. R1 R2 R2 R1 R1 R1 R2 N N Zn R1 N N R1 R2 R1 R1 R2 R2 R1 18a,b R1=Me, R2 = H (a), R1=R2 = F (b). 941 I + R N R Zn 12a N 17 R R1 R2 R2 R1 R1 R2 R1 N NH R1 HN N R2 R1 R1 R1 R2 R2 R1942 R3 R5 R5 R3 R3 R3 R5 N N M1 R3 N N R5 R3 R1 R3 R3 R5 R5 R3 Et Et Me But N N Zn N N Me But Et Et X=1,4-C6H4 (a), 1,4-naphthylene (b), 9,10-anthracenylene (c).R1 R2 R2 R1 R1 R2 R1 N R1 N Zn N N R2 R1 R1 R1 R2 R2 R1 R1=Me, R2 = H (a); R1=R2 = F (b). CF3N N O Zn R N N CF3 R=OH (a), N(CH2)2SO¡3 Et3NH+ (b).R1 C C 12a ± i Me C C X Me 13a ± c C C 14a,bC C15a,b N V Konovalova, R P Evstigneeva, V N Luzgina R4 R5 R5 Com- R1 R2 R3 R4 R5 M1 M2 pound 12 R4 R4 R2 R5 R4 N N M2 R4 N N R4 R5 R2 R4 R4 abcdefghi H Me Me H Zn Mg H H Me Me H Zn 2H H Me Me H H Zn 2H Me H H Me H Zn 2H Me Me H H H Zn 2H Cl Cl H H H Zn 2H H H F F F Zn 2H H H Me Me H Mg 2H H H Me Me H Cd 2H H R5 R5 R4 Et Et Me Me But N HN C C NH N But Me Me Et Et R1 R2 R2 R1 R1 R2 R1 N R1 HN NH N R2 R1 R1 R1 R2 R2 R1 CF3 NH N OR HN N CF3Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis But But 21b M=2H(a), Zn (b).The `centre-to-centre' distance between two porphyrin frag- ments in the dimers 19a,b (Scheme 1) is equal to 16.5 A, whereas their spatial configuration is fixed by two-point addition of each macrocycle to a rigid bridge in such a way that the angle between the planes is 96 8.The synthesis of this system includes condensa- tion of porphyrin-2,3-dione 20 with 1,2-diamino-4-nitrobenzene resulting in nitroquinoxalinoporphyrin 21a. The latter is reduced by tin chloride in hydrochloric acid and the aminoquinoxalino- porpyrin 21b formed reacts with formaldehyde. The yield of the dimer 19a is 88%. Compound 19b was obtained by metallation of bisporphyrin 19a in 73% yield.36 Non-symmetrical porphyrin dimers containing two different macrocycles are promising models for the study of photosynthetic energy transfer. Studies into these compounds provide valuable information about the effects of electronic properties of porphyrin fragments on the yields and the direction of the energy transfer. For example, the covalently linked dimers 22a,b and 23a,b contain tetraphenylporphyrin and octaalkylporphyrin components; their p-systems possess different electronic properties.This allows their selective irradiation and elucidation of pathways of energy Ph 22: Ar=1,4-C6H4; 23: Ar=1,3-C6H4; M=2H(a), Zn (b). But But But But O NO2 H2N NH N + N O H2N NH But But But But 20 But But But But N But N But N N N But N CH2O N M N N N But But But But But 19a,b transfer following photoexcitation by light with an appropriate wavelength. The non-symmetrical dimers 22a,b and 23a,b were synthesised in the following way. The condensation of 8,12-diethyl- 2,3,7,13,17,18-hexamethylbiladiene-a,c dihydrobromide (24) with terephthalaldehyde resulted in porphyrin 25a with the formyl group in the para-position.The reaction of the latter with pyrrole and benzaldehyde gave the dimer 22a. Similarly, bisporphyrin 23a was synthesised using isophthalaldehyde in the first step.37 Et Et Me Me Ph Et Me N N N N M Ar M N N N N Et Me Me Me Ph 25: R=CHO (a), CH(OEt)2 (b). 22a,b; 23a,b Despite the similarity of many structural, chemical and photo- physical characteristics of synthetic porphyrins and natural chlor- But But N HN N N N NH But But 21a: R = NO2 21b: R = NH2 But But NH N N HN But But Me Me Me HN NH + 2Br7 + +NH HN Me Me Me 24Me Me Et N HN NH N Et Me Me 25a,b 943 Scheme 1 But R But CHOCHO Me R PhCHO 22a, 23a NH Me944 ins, their electronic properties differ considerably because of changes in the symmetry and conjugation pattern in chlorin due to the presence of a reduced pyrrole ring.The main difference between porphyrins and chlorophylls (or bacteriochlorophylls) constituting natural photosynthetic antenna complexes is in that the former absorb light strongly only in the blue region of the solar spectrum, whereas the latter absorb light in both blue and red regions. The orthogonal axes N7N in metalloporphyrins are degenerate (planar oscillator), whereas the dipole moment of the longwave transition in the metal complexes of hydroporphyrins is polarised along one of the N7N axes (linear oscillator), which favours directed transfer of energy. Therefore, the design of chlorin-containing donor ± acceptor systems is a promising approach for the modelling of natural light-harvesting complexes.In the ensembles 26a ± c and 27a,b, the porphyrin and chlorin macrocycles are linked through rigid aromatic spacers, which fix the macrocycles in parallel planes at a fixed `centre-to-centre' distance equal to*12.8 A.38, 39 O OMe N N N N M2 M1 N N N N OMe 26a ± c M1=M2=2H (a);M1=Zn,M2=2H (b);M1=M2=Zn (c). MeO N N N N M N Zn N N N MeO 27a,b M=2H(a), Zn (b). The macrocyclic ensembles 26a ± c were synthesised in the following way. Condensation of the aldehydes 28 and 29 with 3,30,4,40-tetraethyldipyrrolylmethane (30) resulted in the por- phyrin 31; its hydroxylation with osmium tetroxide and treatment with trifluoroacetic acid gave the oxochlorin 32.Condensation of compound 32 with p-tolualdehyde (29) and dipyrrolylmethane (33) and subsequent incorporation of zinc resulted in compound 26c (yield 18%); demetallation of the latter by hydrochloric acid afforded the product 26a in a quantitative yield. Treatment of the metal-free dimer 26a with an equimolar amount of zinc acetate resulted in the selectively metallated bisporphyrin 26b in quanti- tative yield.38 CHO OMe O + CHO+ O NH HN OMe 29 30 28 MeO N NH OO HN N MeO 31 N V Konovalova, R P Evstigneeva, V N Luzgina O MeO N NH OHC HN N MeO 32 26b 26a 26c The dimeric ensembles 27a,b were synthesised in a similar way.The chlorin component was obtained by condensation of tetra- ethyldipyrrolylmethane 30 with 2,6-dimethoxybenzaldehyde and 4-(5,5-dimethyl-1,3-dioxan-2-yl)benzaldehyde. The resulting por- phyrin was oxidised to oxochlorin, which was further converted into hydroxychlorin by treatment with methyllithium in ether according to Chang. Subsequent dehydration by boiling with trifluoroacetic acid in the presence of 2,2-dimethylpropane-1,3- diol gave methylenechlorin, which was condensed with dipyrrolyl- methane and p-tolualdehyde following hydrolysis of the protec- tive acetal group. The resulting metal-free dyad reacted with zinc acetate to give a mixture of mono- and dizinc-containing com- plexes 27a,b (yields 15% and 30%, respectively).39 The porphyrin ± chlorin heterodimers 34a,b containing ether bonds between the macrocycles have also been synthesised.The dimer 34a was prepared from 2-hydroxy-3,3,7,8,12,13,17,18- octaethyl-22H,24H-chlorin. This was treated with trifluoroacetic anhydride and the resulting trifluoroacetate reacted with 2-(1-hydroxyethyl)-3,7,8,12,13,17,18-heptaethylporphyrin.40 The heterodimer 34b was synthesised by condensation of the trifluoro- acetylated porphyrin component with the corresponding hydr- oxychlorin in the presence of catalytic amounts of 4-dimethylaminopyridine.41 Data from thin-layer chromatogra- phy, 1H NMR spectroscopy and computer modelling studies suggest that these compounds exist as two stable isomers. One of them has a sterically hindered structure due to the spatial proximity of the porphyrin and chlorin macrocycles, while the tetrapyrrole fragments of the other isomer do not virtually over- lap.40 ± 42 The effects of conformational mobility on spectroscopic and photophysical properties of the donor ± acceptor systems were studied using the porphyrin ± chlorin heterodimer 34a as an example.O HN N H H NH N NH HN N 34aO N NH H NH N H N HN HN N O HO 34b HO2C NH 29, NH 33 N OSynthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis Me N N Me M N N Me M=2H(a), Zn (b). The dimeric ensembles 35a,b, which contain an ordinary porphyrin and thiaporphyrin, have been synthesised.43 The sulfur atom in one of their macrocycles changes the electronic structure of the porphyrin backbone; therefore, the properties of the tetrapyrrole fragments in the ground and excited states of these systems differ considerably.The synthesis of the bisporphyrins 35a,b included the prepa- ration of a monomeric thiaporphyrin precursor by condensation of pyrrole and 2,5-bis(p-tolylhydroxymethyl)thiophene with p-hydroxybenzaldehyde and subsequent reaction of the resulting product with 5-[4-(5-bromopentyloxy)phenyl]-10,15,20-tritolyl- porphyrin.43 The ensembles in which the chromophores are linked through ethylene, ethyne or butadiyne linkers introduced directly into meso- or b-positions of the porphyrin macrocycles manifest interesting properties.These systems, in contrast to the above- described systems, are characterised by extraordinarily strong exciton and electronic interactions between the chromophores as can be evidenced from the significant changes in the electronic absorption spectra (splitting of the Soret band, pronounced bath- ochromic shifts, etc.).8, 44 ± 49 As regards photosynthesis, these compounds can serve as spectral models of antenna pigments possessing absorption in the red spectral region.44 However, dimers with conjugated ethylene, ethyne and butadiyne units between the chromophores are not used for the modelling of energy transfer; therefore, their synthesis and spectroscopic prop- erties are not considered in this review. b.Photochemical properties Studies of photochemical properties of model compounds have shed light on the dependences of the rates and efficiencies of energy transfer reactions on the distance between donor and acceptor components,19 ± 21, 35 their mutual arrangement 20, 21, 37 and extent of electronic interactions.21, 28, 29 Quenching of singlet excited states of porphyrin donors in the absence of acceptors can be effected in several ways (Fig. 2), viz., by radiative quenching through fluorescence emission with the rate constant kF and by non-fluorescent quenching including 1D* A kEN kNF+kF D 1A* D A Figure 2. Possible ways of quenching of the singlet excited state of the donor (D, donor, A, acceptor).19 O O (CH2)5 35a,b 945 OHN NH Me S N Me intersystem transition to the triplet state, inradiative quenching to the ground energy state, etc., with the rate constant kNF. For dilution commonly employed in photochemical studies (*1076 mol litre71), intermolecular quenching can be neglected.Attachment of an acceptor to the porphyrin donor provides an additional route of quenching of its excited state, viz., intra- molecular singlet energy transfer with the rate constant kEN.19 Emission spectra provide essential information about photo- processes occurring in model systems. Quenching of fluorescence of a porphyrin donor concomitant with enhanced fluorescence of the acceptor implies an intramolecular transfer of singlet excita- tion energy.19, 50, 51 High efficiency of energy transfer is a prerequisite for the normal functioning of natural light-harvesting antenna com- plexes.The quantum yields (F) of the energy transfer can be correctly determined by several methods. One of them includes detailed comparison of steady-state absorption and fluorescence excitation spectra. However, high quantum fluorescence yields, significant overlap of the donor and acceptor fluorescence spectra and the presence of residual amounts of the original monomers do not allow reliable estimation of energy transfer efficiency in molecular ensembles by static measurements alone. An alternative approach consists in comparison of the rates of the energy transfer and competing quenching channels of the donor excitation (see Fig.2). The use of this method for the determination of quantum yields of the energy transfer from the zinc-containing porphyrin to the free base in the dimeric ensembles 12a ± i has demonstrated extremely high efficiency of this reaction (F=87%± 99%) 28 ± 31, 51 despite of the large distance (20 A) and weak interactions between the chromophores. Similar results were obtained in the study of the model systems 18a,b where the quantum yields of the energy transfer were 599%.35 Efficient energy transfer from the octaalkylporphyrin to the tetraphenyl- porphyrin component was observed for the dimers 22 and 23 (F=79%± 99%).37 Analysis of these systems did not reveal any competitive electron transfer reactions. Thus, the energy transfer is a predominant channel of decay of the excited states of porphyrin donors in these ensembles. Energy transfer reactions follow two basic mechanisms.The first of them is the FoÈ rster `through-space' mechanism, which is determined by the interactions between transient dipole moments. In this case, the reaction rate depends on the mutual donor and acceptor arrangement, the `centre-to-centre' distance between them and the integral of spectral overlap of the donor emission and the acceptor absorption. The second route, viz., the Dexter `through-bond' mechanism, is realised in the presence of strong electron-exchange interactions in the case of close contacts between the donor and the acceptor or the presence of a p-con- jugated bridge between them.52946 It was shown that linear p-conjugated polyyne and polyene spacers enhance the `through-bond' electron-exchange interac- tions between two porphyrin macrocycles in donor ± acceptor bisporphyrin systems.19 The values of rate constants for the intramolecular energy transfer in the systems 3b,c containing porphyrin macrocycles in the meta- and para-positions of the aryl ring, are virtually identical despite the differences in the `centre-to-centre' distances between the chromophores, which is a clear evidence of electronic `through-bond' interactions in these compounds.Comparison of the energy transfer rates in the linear dimer 3c (kEN= 5.76108 s71 for the `centre-to-centre' distance of 26.2 A) and the diphenylpolyyne-bound bisporphyrin 1d (kEN=1.96109 s71 for the `centre-to-centre' distance of 27.0 A) has demonstrated that the 1,4-bis(phenylethynyl)phenylene bridge is less active in `through-bond' electronic interactions than diphenylpolyyne spacers of analogous lengths.19, 20 At the same time, the rates of the energy transfer in the bisporphyrins 13a,b, in which the arrangement of the porphyrin rings and the structures of spacers are similar to those in the dimer 3c, are comparable with that calculated in the framework of the FoÈ rster approximation (kEN=4.96108 s71).This suggests that the electron energy transfer in these compounds follows the `through-space' mechanism.32 Probably, in this case both mecha- nisms contribute to the interactions between the electronic sys- tems of these pigments. The energy transfer in the diarylethyne-linked ensembles 12a ± e predominantly occurs by the `through-bond' mechanism mediated by the p-electron system of the linker.This is supported by the fact that the rate constants for the energy transfer for all the dimers of this series (7.56109 s71<k<4.261010 s71) exceed markedly that predicted by the FoÈ rster theory for the `through- space' mechanism (1.46109 s71). In terms of the Lindsey hypothesis, the dihedral angle between the porphyrin ring and the aryl rings of the linker is a critical structural parameter, which determines the possibility of the `through-bond' energy transfer. Thus steric hindrances created by the introduction of ortho-substituents into the linker unit preclude coplanar arrangement of the aryl rings of the linker and the porphyrin rings.This diminishes orbital overlap and decreases fivefold the rate of the `through-bond' energy transfer. In the dimer 12e, this effect is predominant over other effects, such as withdrawal of the electron density and interactions of the p-or- bitals of ortho-chloro-substituents with the meso- carbon atoms of porphyrins.28, 51 Comparison of the rates of singlet ± singlet energy transfer in two series of bis(phenylethynyl)phenylene-linked bisporphyrins 3a ± c and 4a ± c gave similar results. The b-alkyl groups in the dimers 3a ± c adjacent to the bridge attachment site hold the bridge in the virtually perpendicular position relative to the porphyrin planes, which minimises the electronic interactions between the porphyrins and the bridge.This conformational restriction is not so severe in the dimers 4a ± c, which is a reason for enhanced electronic interactions between porphyrins and increased rates of the `through-bond' energy transfer in these systems in comparison with the bisporphyrins 3a ± c.21 The superexchange mechanism, which involves the binding chromophore, is also responsible for increased energy transfer rates in the systems 19a,b characterised by strictly fixed mutual spatial arrangement of the porphyrin macrocycles and the bridge.53 At the same time, the decrease in the degree of conjugation between the p-electron systems of the linker and the porphyrins is accompanied by somewhat enhanced contribution of the `through-space' energy transfer to the overall process.Thus the contribution of this mechanism to the energy transfer in the dimers 12d,e where the rotation of the linker's aromatic rings is restricted by the substituents, exceeds 10%.28, 51 The experimental values of the rate constants for the energy transfer for the dimers 22a (2.46108 s71), 23a (8.56108 s71) and N V Konovalova, R P Evstigneeva, V N Luzgina 23b (2.561010 s71) are in good accord with those predicted by the FoÈ rster theory. This can apparently be explained by the fact that the macrocycles in the above models cannot lie in the same plane with the binding phenylene groups due to steric hindrances; therefore, direct conjugation between the p-systems of the por- phyrins and the linker is excluded while the contribution of the `through-space' mechanism to the overal energy transfer process increases in accordance with the Lindsey hypothesis.37 Energy transfer in natural photosynthetic systems occurs at very fast rates.One of the ways to accelerate this process in synthetic ensembles is to reduce the distance between the porphyr- ins. Thus the rate constant for the energy transfer in the bispor- phyrin 3a exceeds by about an order of magnitude that in the dimer 3c, which has an identical spacer, but the distance between chromophores is twice as long.20 In the case of the dimer 4a with closely located porphyrin fragments, the energy transfer rate is higher than in the system 4c, but the effect is far less pronounced.21 The rates of the energy transfer in the p-phenylene-linked dimers 18a (2.961011 s71) and 18b (161011 s71) are much higher than in structurally similar ensembles containing the diphenyl- ethyne linker, viz,.4.261011 s71 for 12a and 4.26109 s71 for 12f. The observed increase in the reaction rate is mainly due to enhancement of the electronic interactions between the porphyrin components which, in turn, is due to shortening of the distance between the chromophores in the former case.35 Analysis of spectral properties of the heterodimer 34a revealed that the efficiency of the energy transfer in the `folded' conformer characterised by spatial closeness of the two macrocycles (the `centre-to-centre' distance determined by computer simulation studies is*6 A) is close to 100%.At the same time, the quantum yield of the energy transfer for the isomer having an `open' conformation of the macrocycles (the distance between the chromophores is >10 A) is lower (74%) (see Ref. 54). It was shown that direct dipole ± dipole `through-space' inter- actions become predominant in the energy transfer in the ensem- bles 3a,20 18a,b 35 and 34a 54, 55 with decreased distances between the donor and acceptor components. Whereas the effects of steric factors on the rates and mecha- nisms of energy transfer have been studied in sufficiently great detail, the contribution of spacers to the electronic structure of the excited state has been studied to lesser extent.It is known, however, that the strength of the electronic interaction depends not only on structural parameters, such as the distance between the chromophores constituting the system and their mutual arrangement, but also on the relative orbital energies of the donor, the acceptor and the spacer group. Investigation into the effect of the electronic structures of bridges on the rate of energy transfer has been carried out 32 with the systems 13a ± c with identical distances between the macro- cycles, well-defined mutual arrangements of two porphyrin ring planes and minimum degree of conjugation between the donor, the bridge and the acceptor, which allowed consideration of the system components as individual chromophores. Spectral studies of the model bisporphyrins 13a ± c revealed the strongest quenching of donor emission in the case of the anthracenylene-linked dimer 13c, which suggests the higher effi- ciency of the energy transfer in this compound.Moreover, the rate constant for the energy transfer for the dimer 13c (k=109 s71) exceeds approximately twofold those for the bisporphyrins 13a,b (5.86108 and 5.46108 s71, respectively) with phenylene- and naphthylene-containing spacers. These results indicate stronger electronic interactions in the dimer with anthracene-containing spacer, apparently due to the proximity of the energy levels of the lower singlet excited states of the donor, the acceptor and the anthracene chromophore (17 500, 16 000 and 21 600 cm71, respec- tively).However, splitting of the energy levels between the donor and the bridge as well as between the bridge and the acceptor is large enough to prevent stepwise energy transfer with the involve- ment of the intermediate excited state of the binding chromo- phore.32Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis Comparison of photochemical properties of the dimeric ensemble 12f containing pentafluorophenyl groups in all the non-binding meso-positions of the tetrapyrrole macrocycle and its non-fluorinated analogue 12a was carried out in order to elucidate the effects of electronic factors on the extent of inter- actions of the porphyrin components in the ground and excited states.The rate of the energy transfer in the bisporphyrin 12f was 10 times lower than that in the dimer 12a despite identical diphenylethyne linker in both compounds. The lower rate of the energy transfer in the former dimer is attributed to weakened electronic interactions between Zn-porphyrin and the free base in the S1 excited state. The degree of the `through-bond' energy transfer between components of dimeric ensembles depends on the electronic and oscillation matrix elements. In the dimers 12a,f possessing identi- cal linkers, oscillator contributions are the same and interactions between the porphyrin components are predominantly deter- mined by electronic factors. Their magnitude depends on the nature and distribution of the electron density of molecular orbitals involved in bonding.In compound 12a, as in most meso- substituted porphyrins, HOMO has the a2u symmetry character- ised by considerable electron densities on meso-carbon atoms including those attached to the linker. In contrast, the penta- fluorophenyl groups in the dimer 12f stabilise the orbital with the a2u symmetry, which changes theHOMOsymmetry to a1u. Such a change in the orbital ordering diminishes the electron density on the peripheral meso-atoms of the macrocycle where the linker is attached, and thus reduces the electronic matrix element. Thus, the rate of the energy transfer between the zinc-containing porphyrin and the free base of the dimer decreases. Redistribution of the electron density from the meso-carbon atoms of the a2u orbital to the strongly electron-withdrawing pentafluorophenyl rings is yet another factor inducing appreciable decrease in the rate of the energy transfer in the dimer 12f.29 In the case of the fluorine-containing dimer 18b, a threefold decrease in the rate of the energy transfer was observed in comparison with the non-fluorinated analogue 18a (161011 and 2.961011 s71, respectively).This effect correlates with the above- described fluorine-induced changes in the orbital characteristics of porphyrin components in the case of meso-diarylethyne-linked dimers.35 An opposite effect was observed for the b-linked dimers 14a,b in which the presence of pentafluorophenyl groups in the non- binding meso-positions promotes stronger electronic interactions.As a result, the rate of the energy transfer in the dimer 14b (k=4.261010 s71) exceeds more than twofold that in the mesi- tyl-substituted ensemble 14a (k=1.861010 s71). This, too, is due to enhanced contribution of the a1u orbital characterised by higher electron density on the b-pyrrole atoms, where the linker is attached, to the wave function of the excited electronic state in pentafluorophenyl-substituted dimers.33 A 17-fold decrease in the rate of the energy transfer in the meso-diphenylethyne-linked b-alkyl-substituted dimer 1a (see Ref. 19) in comparison with the meso-aryl-substituted bispor- phyrin 12a possessing the identical linker is mainly due to the electronic factors determined by the differences in the orbital ordering.29 In particular, eight b-alkyl substituents and two aryl groups in the meso-positions of each porphyrin fragment in the dimer 1a determined the a1u HOMO symmetry characterised by the absence of electron density on the meso-carbon atoms to which the linker is attached.In addition, the steric hindrance due to the b-methyl groups in the pyrrole rings of the porphyrin macrocycle limit the rotation of the aromatic rings of the linker and prevent their coplanarity with the porphyrin macrocycles. This diminishes the conjugation of their p-electron systems and thus makes an additional contribution to the weakening of the electronic inter- actions between the dimer components.947 The enhancement of `through-bond' electronic interactions and the increase in the rate of singlet energy transfer upon substitution of the tetraarylporphyrin component in the systems 4a ± c for the 10,20-diaryloctaalkylporphyrin component in the dimers 3a ± c are explained in a similar way.21 Thus, the site of attachment of the linker should be chosen with due regard to the general pattern of substitution in the tetrapyrrole macrocycle in order to ensure optimum electronic interactions. For porphyrins with the a2u HOMO symmetry, the strongest electronic interactions are provided by linkers attached to the meso-positions of the macrocycles, whereas stronger electronic interactions between the pigments with the a1u HOMO symmetry are provided by spacers introduced into b-pyrrole positions.It should also be considered that the electron densities of the eight b-pyrrole carbon atoms with the a1u orbital symmetry are much lower than those of the four meso-atoms with the a2u orbital symmetry. Consequently, the electronic interactions through spacers connecting b-positions of the porphyrin macro- cycles should be less efficient than those through spacers connect- ing meso-carbon atoms.29, 33 The LUMO characteristics also contribute to linker-mediated electronic interactions between chromophores. The electronic factor is determined by the overlap of the eg orbitals of porphyrin with the dp-orbitals of the metal. Thus an increase in the rate of the energy transfer in the cadmium-containing ensemble 12h (k=6.761010 s71) in comparison with the magnesium-contain- ing dimer 12g (k=3.261010 s71) reflects the putative role of cadmium d-orbitals in the electronic interactions.31 Stronger `through-bond' interactions in the zinc-containing diporphyrin 19b in comparison with its non-metallated analogue 19a is thought 53 to be due to the interaction of the metal dp-orbitals with the porphyrin ring, which increases the electron density on the pyrrole carbon atoms bearing the spacer group.53 The effect of the bridge topology on the electronic interactions between porphyrins in the ground and excited states was studied in the example of the conjugated dimers 36 and 37.The energies of absorption maxima in the region of the Q-bands of the b,b-linked ensembles 36a,b are essentially the same as those of the isolated zinc-containing tetraphenylporphyrin complex, which points to weak electronic interactions between the chromophores in the ground and the lowest singlet electron-excited states.Contra- riwise, a pronounced bathochromic shift and enhanced low- energy absorption in the region of the Q-bands in the meso,meso- linked dimer 37 suggest the presence of strong electronic inter- actions between the porphyrin macrocycles. These data are in good agreement with the order of changes in the strength of the electronic interaction (meso,meso>meso,b>b,b) for meso-sub- stituted porphyrins at a fixed twist angle between the tetrapyrrole planes predicted on the basis of the above-described analysis of the electronic structure.Moreover, the rotation barrier around the ethyne linker in the meso,meso-linked ensemble 37 is a minimum in comparison with b,b-linked dimers. This suggests that the con- formers in which the components of the meso,meso-linked dimer have planar structures and maximum conjugation predominate in solutions at room temperature.44, 45 Ph Ph Ph N Ph N N Zn N ( C C )n N Zn N N Ph Ph N Ph Ph 36a,b n=1 (a), 2 (b).948 Ph Ph N N N N Zn C C Zn N N N N Ph Ph 37 These data suggest that the electronic structure together with steric factors are essential for efficient electronic interactions and high rates of the energy transfer in dimeric ensembles. Zinc-containing porphyrin complexes analogous in structural, chemical and photophysical characteristics to those of chloro- phylls and bacteriochlorophylls are widely employed in photo- synthetic model systems.However, natural photosynthetic pigments contain magnesium atoms in their chlorin rings. Spectral properties of the ensembles 12a,g,h, which contain zinc, magne- sium and cadmium in one of their macrocycles, were compared in order to examine the effects of metal substitution on the photo- dynamic behaviour of bisporphyrins. The rates of the energy transfer for the three dimers were very close, which can be attributed to the similarity of electronic interactions between the chromophores in the magnesium-, zinc- and cadmium-containing bisporphyrins.However, the quantum yield of the energy transfer for the Mg-containing dimer (F=99.7%) is higher than that for the Zn-containing dimer (F=99%) due to the longer lifetime of the excited state of the Mg-porphyrin (10 ns) in comparison with that of the Zn-porphyrin (2 ns). Although this difference is insignificant in the case of the isolated dimer, this may be multi- plied in multiporphyrin ensembles, which perform more energy transfer steps.30Amore significant decrease in the efficiency of the energy transfer in the case of the cadmium-containing dimer (F=87%) is almost exclusively due to the very short (*100 ps) lifetime of the Cd-porphyrin excited state, which, in turn, may be a result of acceleration of the singlet ± triplet intersystem transition, which competes with the energy transfer due to the presence of a heavy metal.31 Moreover, magnesium- and especially cadmium- containing bisporphyrins are more labile with respect to demetal- lation and photochemical oxidation and are more prone to electron transfer, whereas zinc-containing dimers are rather stable against these side reactions.These data suggest that synthetic ensembles capable of highly efficient energy transfer may contain both Mg- and Zn-porphyr- ins; the choice of a metal should be made with due regard to all the factors mentioned above.30 Moreover, the extremely high rate (k=1.161011 s71) and the nearly quantitative efficiency of the R1 R5 N O N R2 Zn NH C N N R5 R1 38a,b R1=Me, R2=NHCOMe, R3=H, R4=R5=Cl (a); R1=R2=NMe2, R3=R4=F, R5=H(b).N V Konovalova, R P Evstigneeva, V N Luzgina energy transfer in the dimer 12i, which contains Zn- and Mg- tetraarylporphyrin complexes, confer attractive properties on the combination of these complexes within a single ensemble. At the same time, the use of cadmium complexes in artificial energy- transforming systems is limited due to reduced efficiency of the energy transfer and lability of these compounds.31 The effects of environmental factors, such as viscosity, solvent polarity and temperature, on the photodynamic behaviour of the diarylethyne-linked ensembles 12a ± d have been discussed.51 These studies have shown that the rates of energy transfer in viscous media (e.g., castor oil) are 1.3 ± 1.9 times lower than in toluene. This can be explained by the fact that higher viscosity of the medium impedes probably the rotation of the aromatic rings of the linker around a single bond, which prevents their copla- narity with the porphyrins and thus weakens electronic `through- bond' interactions between the porphyrin macrocycles. With a decrease in temperature to 150 K, the rates of the energy transfer in these dimers show a slight decrease.Presum- ably, the mobility of the aromatic group and a concomitant change in the average dihedral angle between the linker and the porphyrin are also decreased due to freezing of the solvent. The degree of thermoinduced conformational changes depends on rotational restrictions of the linker.Therefore, the most appreci- able (2.5-fold) decrease in the rate of the energy transfer is observed for the dimer 12a where a broad range of dihedral angles is possible due to the lack of torsional restrictions. No such changes were observed for the ensemble 12d.51 The dynamics of singlet ± singlet energy transfer in the por- phyrin ± chlorin system 34a containing ether bond between the macrocycles changes with temperature. At 293 K, the excitation energy migrates repeatedly between the interacting donor and acceptor components over the lifetime of acceptor fluorescence, since the rates of forward and reverse energy transfer reactions exceed the deactivation rates of S1 states of porphyrin and chlorin by more than an order of magnitude.In contrast, the transfer of excitation energy from porphyrin to chlorin at 77 Kis irreversible, for in this case the calculated rate of the reverse transfer is much lower than the deactivation rate of the acceptor S1 state.55 It was shown that the polarity of the solvent affects only slightly the efficiency and rate of energy transfer in diarylethyne- linked dimers. However, significant quenching of fluorescence of the porphyrin free base in the dimers 12a,b observed in polar solvents (e.g., dimethyl sulfoxide) is ascribed to the charge transfer from the neighbouring metal complex.51 Magnesium-containing ensembles are even more sensitive to this process due to increase in the driving force of the electron transfer process.30 Similar photoinduced electron transfer to the excited singlet state has also been observed in the hybrid porphyrin ± chlorin dimer 26b (see Ref. 38) and the bisporphyrins 38a,b (see Ref.56). R3 R3 R3 R4 R5 R4 R5 R5 R4 NH N N HN R4 R5 R5 R4 R5 R4 R3 R3 R3 R3 R3 R3Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis It should be emphasised that the charge transfer occurs after the excitation has reached the acceptor and has no appreciable influence on the energy transfer between the donor and acceptor components in the above-described ensembles.51 The fluorescence spectra of bisporphyrins linked by flexible hydrocarbon chains can be interpreted by the existence of two conformations, viz., the `open' conformation where quenching of the donor fluorescence is fairly ineffective and the `folded' conformation characterised by effective quenching of donor emission owing to the transfer of singlet energy to the acceptor.57 ± 59 Changes in the solvent polarity bring about tran- sition of one form into another.Thus the `open' conformation is predominant for solutions of bisporphyrins 35 in toluene, whereas in dimethylformamide the `folded' conformation is preferable in which the `centre-to-centre' distance between two porphyrin components is 18.7 A. Such conformational transition results in the enhancement of the efficiencies and rates of energy transfer in polar solvents.59 The knowledge of regularities of the energy transfer depend- ing on structural, electronic and environmental factors is useful for the design of more complex model donor ± acceptor systems.2. Porphyrin dimers with peptide spacers All the bisporphyrins described above contain hydrocarbon spacers. However, chlorophyll and bacteriochlorophyll in photo- synthetic antenna systems exist in a protein environment, which affects the photophysical properties.11, 12, 60 Synthetic porphyrin dimers with the macrocycles linked through amino acid or peptide spacers represent convenient model subjects for the study of intramolecular interactions and energy transfer between tetrapyr- role chromophores within natural pigment ± protein complexes. a. Synthesis The porphyrin dimers 39a,b and 40a,b linked through amino acid bridges served as models for the studies of spectral properties of chromophores in biological photosynthetic systems.61 These com- pounds were synthesised in 10%± 15% yields by condensation of 5-o-(2-bromoethoxy)phenyl-10,15,20-triphenylporphyrin with glycine or racemic phenylalanine in dimethylformamide in the presence of a phase-transfer catalyst.R1 R1 R2 R2 R2 R2 N N N R1 M X M N N N R2 R2 R2 R2 R1 R1 41a,b; 42a,b 41: R1=Me, R2=H; 42: R1=H, R2=But;M=2H (a), Zn (b). O H p-C6H4CH2O HN D,L-41, D,L-42: X= HO O H p-C6H4CH2O HN L,L-41, L,L-42: X= NH HO R2 R2 N R1 N R2 R2 NH OCH2C6H4-p OCH2C6H4-p 949 N O N M N N N NH N C M C R2 O N R1 O N O 39a,b; 40a,b 39: R1=R2=H; 40: R1=Bn (H), R2=H (Bn);M=2H (a), Zn (b).The porphyrin dimers with macrocycles covalently linked through cyclic dipeptides, viz., piperazine2,5-diones (compounds 41a,b and 42a,b),62 b-folded oligopeptides (dimers 43a,b, 44a ± d, 45a,b) 63 and the oligo-L-proline spacers 46a ± i and 47a ± i,64 were synthesised for studies of intramolecular interactions and energy transfer between the porphyrin components. In these dimers, two porphyrin rings are held in specific conformations by rigid peptide spacers. Thus rigid b-folded structures of the dipeptides in the molecules 43a,b, 44a ± d and 45a,b are determined by the formation of hydrogen bonds between the carbonyl groups of the porphyrins and amino groups of amino acid residues of the peptides.63 Due to the cyclic side chain, the oligo-L-proline spacers in the dimers 46a ± i and 47a ± i acquire fairly stable helical conformations provided the number of amino acid residues is no less than four.18, 64 The general strategy of the preparation of these compounds is based on the use of standard protocols of the peptide synthesis.The symmetrical bisporphyrins 41a,b and 42a,b, which are cova- lently linked to tyrosine residues by ether bonds to form piper- azine-2,5-dione, were obtained from the zinc-containing porphyrins 48a,b, which in turn were synthesised by the conden- sation of the corresponding aromatic aldehydes with methoxy- carbonylbenzaldehyde and pyrrole followed by reduction of the ester groups to hydroxy groups, substitution of bromine for R R R R N N N N M N N M N N R R N O H O N NH O 43a,b R=p-MeC6H4; M = 2H (a), Zn (b).; .950 Me NM1 N N Me M1=M2=2H (a), Zn (b);M1=Zn,M2=2H (c);M1=2 H,M2=Zn (d). Me N N M1 N N Me M1=2 H,M2=Zn (a); M1=Zn,M2=2H (b). But But N N M1 N N But But 46: M1=Zn,M2=2H; 47: M1=2 H, M2=Zn; n = 0 (a), 1 (b), 2 (c), 3 (d), 4 (e), 5 (f), 6 (g), 7 (h), 8 (i). hydroxy groups and introduction of zinc into the porphyrin rings.62 Condensation of benzyloxycarbonyl-protected L- or D-tyro- sine with L-tyrosine methyl ether afforded dipeptides, which were converted into piperazine-2,5-diones following deprotection. Reactions of the latter with the porphyrins 48a,b afforded the diastereomerically pure zinc-containing dimers 41b and 42b; their demetallation resulted in compounds 41a and 42a.62 An alternative approach was used in the synthesis of the porphyrin dimers 43a,b, 44a ± d and 45a,b linked through b-folded peptides.In this synthesis, 5-(p-carboxyphenyl)-10,15,20-tri-p- tolylporphyrin (49) and 5-(p-aminophenyl)-10,15,20-tri-p-tolyl- porphyrin (50) were used as the porphyrin components, while Me Me N N O O O NH HN HN O 44a ± d MeO N N OO H NH O N O Me 45a,b Me But N NH O O n But 46a ± i, 47a ± i N V Konovalova, R P Evstigneeva, V N Luzgina Me N N N M2 N Me Me Me N N M2 N N NH Me But But But N N M2 N N But But But Ar N N M Ar R N N Ar 48a,b; 49; 50 48: R = CH2Br,M =Zn, Ar=4-MeC6H4 (a), 3,5-But2C6H3 (b); 49: R = CO2H, M=2H, Ar=4-MeC6H4; 50: R = NH2,M=2H, Ar=4-MeC6H4.Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis the amino acid sequences D-Pro-Gly and D-Pro-L-Asp were used as the b-folded peptide spacers.The acid 49 was converted into its acid chloride, which reacted with D-proline to yield compound 51. Me Me HN 1) (COCl)2 2) D-Pro 49 N N NH N Me O 51 CO2H The reaction of the amine 50 with tert-butoxycarbonylglycine (Boc-Gly) using dicyclohexylcarbodiimide (DCC) as a coupling reagent resulted in the derivative 52a. The last step included condensation of the acid 51 with the amine 52b under the action of DCC in the presence of 1-hydroxybenzotriazole.This reaction afforded the porphyrin dimer 43a linked through a b-folded dipeptide (yield 76%). The bisporphyrin 43a was easily converted into the dizinc complex 43b by treatment with an excess of zinc acetate.63 Me Me HN Boc-Gly N 50 N NH NHCCH2NHR Me O 52a: R = CO2But 52b: R = H 43a 51 + 52b 43b The dimers in which both porphyrin residues are linked to aspartic acid were synthesised in the following way. First, the b-carboxy group of Boc-L-Asp(OH)-OH was selectively protected followed by protection of the a-carboxy group. Subsequent hydrolysis of benzyl ester afforded the amino acid derivative 53 with a free b-carboxy group; its reaction with the amino acid component 50 yielded the derivative 54a.Condensation of the acid 51 with the amine 54b (obtained in 66% yield by deprotection of compound 54a) gave the dimer 44a, which gave further the complex 44b (yield 58%). CH2CO2H 50 BocNHCHCONH BocNHCHCO2H CH2CO2CH2 Me 53 951 Me Me N NH HN Me N RHN Me NHCOCH2CHCONH 54a: R=Boc 54b: R = H 54b + 51 44b 44a The selectively metallated dimers 44c,d were synthesised by the condensation of the zinc-containing porphyrin component with the porphyrin free base.63 The synthesis of the dimer 45a included condensation of 5-(p- carboxyphenyl)-10,15,20-tri-p-tolylporphyrin (49) with piperi- dine-4-carboxylic acid, reaction of the product with D-proline to yield the amino acid derivative 55 and condensation of the latter with the zinc ± porphyrin complex 54b in the presence of DCC.63 Me O N NH N Me N C CO2H O HN N Me 55 The bisporphyrin 45b was synthesised from the zinc complex of compound 55 and the porphyrin free base 54b in a similar way.63 This strategy was also used in the synthesis of the bisporphyrin donor ± acceptor model systems 46a ± i and 47a ± i linked by oligoproline spacers.Porphyrin components differing in the positions of their functional groups used in the synthesis of peptide-linked bispor- phyrins made it possible to obtain meso-b-linked ensembles 56a ± c.65, 66 An interesting feature of these systems is that their spacers contain an aromatic amino acid, viz., phenylalanine.Incorporation of aromatic amino acids into model photosynthetic systems is an important issue, since it was found that such aromatic amino acids as tyrosine and tryptophan mediate inter- actions between tetrapyrrole chromophores by virtue of electronic coupling of their molecular orbitals. Substitution of aliphatic amino acids for aromatic ones enables one to establish the dependence of the strength of interchromophore interactions and the efficiencies of photoinduced processes on the nature of the amino acid components of the spacers. The bisporphyrins 56a ± c were synthesised from the amino acid derivatives of 5-(p- aminophenyl)-10,15,20-triphenylporphyrin and 2-(2-carboxy)- vinyl-5,10,15,20-tetraphenylporphyrin using the dicyclohexylcar- bodiimide method.952 Ph O N NH Ph Ph CH CHCXNH HN N N NH Ph Ph Ph HN N 56a ± c Ph O O X=NHCHCNHCH2CO (a), NHCHCNHCH2CO (b), CH2Ph CHMe2 O O NHCH2CNHCHCNHCH2CO (c).CH2Ph The covalently linked mesoporphyrin dimers 57a-g containing a lysine residue as the spacer were synthesised to study chloro- phyll ± protein interactions. UV-Vis and circular dichroism spec- troscopic studies revealed that these dimers form complexes with polypeptides of natural light-harvesting systems owing to axial coordination of zinc and nickel atoms with histidine and the formation of hydrogen bonds between the ester groups of the dimer and the polar amino acid residues of the peptides. In the synthesis of the dimers 57a ± g, the mesoporphyrin IX mono- methyl ester was condensed with Boc-L- or Boc-D-lysine using N-hydroxysuccinimide ±DCC as the activating reagents.The product formed reacted with the second molecule of the meso- porphyrin monomethyl ester under identical conditions.67 N N M1 N N N N M2 N N CO MeO2C CO HN CO2Me HC NH (CH2)4 CO2R 57a ± g R Compound 57 M2 M1 abcdefg HHHH (D-isomer) Me Me H 2H 2H Zn Zn 2H Zn Ni 2H Zn Zn Zn 2H Zn Zn b. Photochemical properties Photochemical studies of the piperazine-2,5-dione-linked systems 41a,b and 42a,b revealed that the chromophores of the L,L-dimers 41a,b having p-tolyl substituents interact more efficiently than the chromophores of the L,L-dimers 42a,b with 3,5-di-tert-butyl- phenyl substituents.This difference is due to the fact that the bulkier 3,5-di-tert-butyl groups in the molecules 42a,b disturb interactions of the porphyrin rings. N V Konovalova, R P Evstigneeva, V N Luzgina It was also found that the porphyrin components in the L,L-dimers 41a,b and 42a,b interact more efficiently in compar- ison with the D,L-dimers. This can be attributed to the localisation of both tyrosine phenylene groups in L,L-isomers on one side of the piperazine-2,5-dione plane, whereas in D,L-isomers these groups are localised on different sides of this plane. Thus the porphyrin components of the L,L-dimers are closer to each other than in the D,L-dimers. It thus follows that the strength of intramolecular interaction depends on the `centre-to-centre' dis- tance between the porphyrin rings.62 Evidence for the dependence of interactions between chromo- phores on the `centre-to-centre' distance was also obtained for the dimers 43a,b and 44a ± d.63 The efficiency of intramolecular energy transfer from zinc complexes to porphyrin free bases in the asymmetrical dimers 44c,d (F=86%) and 45a,b (F=76%) depends on the distance between tetrapyrrole components rather than on the nature of the spacer.The efficiency of quenching of the excited states of zinc- containing porphyrin complexes in compounds 46 and 47 decreases with an increase in the number of proline residues, i.e., the average distance between the chromophores, in the course of energy transfer irrespective of its direction.These findings prompted a conclusion that singlet energy transfer in dimers linked by peptide spacers occurs predominantly `through- space'.63, 64 The dipole ± dipole `through-space' interaction described by the FoÈ rster approximation is the most probable mechanism of energy transfer from the zinc complex to the nickel-containing porphyrin in the dimer 57g. The most efficient energy transfer was noted between the porphyrin rings that form coordination and hydrogen bonds with polypeptides of natural light-harvesting complexes. This suggests that polypeptides induce efficient intra- molecular energy transfer between pigments in model photo- synthetic compounds.67 3.Non-covalently linked bisporphyrin systems The above-described methods for the construction of model photosynthetic systems are based on the formation of covalent bonds between chromophores, but they are not always suitable for the synthesis of muticomponent ensembles. An alternative approach consists in the assembly of supramolecular aggregates due to non-covalent interactions, such as the formation of hydro- gen bonds, salt bridges and coordination bonds between metals and ligands.17 The strategy of synthesis of non-covalently linked ensembles consists first in the synthesis of chromophores possessing specific recognition sites and their subsequent self-assembly into highly ordered multicomponent structures. According to the type of their binding, these model systems resemble those discovered in the light-harvesting antennae.The design of non-covalently linked supramolecular complexes can be based on pairwise interactions between comple- mentary heterocyclic bases. The complex 58 ± 59, which is stabi- lised by hydrogen bonds between guanine and cytosine residues, was among the first ensembles of this kind described in the literature.68 However, high flexibility of this first-generation system prevented detailed studies of the energy transfer mechanism observed. The synthesis of the rigid dimeric porphyrin ensemble 60 ± 61 in which the donor and the acceptor are linked directly to guanosine and cytidine residues through phenyl groups has been described.69 The arrangement of its two porphyrin residues is such that the angle between the planes of their macrocycles is *90 8 and the `centre-to-centre' distance was estimated 69 to be *22.5 A.The porphyrin fragments can rotate by *45 8 around the C7C bond linking the phenyl ring to the heterocyclic base. The nucleoside-substituted porphyrin 60 was prepared by the Lindsey condensation of the guanosine-containing benzaldehyde 62 with benzaldehyde and 3,30-dibutyl-4,40-dimethyldipyrrolyl-Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis N N Zn N N 58 R=(CH2)2O(CH2)2OMe. * R2O O R1= , R2=SiMe2But. OR2 R2O methane (64) with subsequent removal of the isobutyryl group, introduction of the tert-butyldimethylsilyl group and metallation. O N HN N N R2HN R1O O OR1 R1OBu Me N N Zn Ph N N Me Bu The nucleoside-substituted metal-free porphyrin 61 was syn- thesised in a similar way from the cytidine-containing benzalde- hyde 63.The reaction of the cytidineporphyrin 61 with the guanosine- containing zinc complex 60 in dichloromethane results in the formation of a three-point hydrogen bond between the comple- mentary bases. According to 1H NMR spectroscopic data, the binding constants of the guanosine and cytidine derivatives in the ensemble 60 ± 61 are equal to 22 0002000 litre mol71 (see Ref. 69). The photoactive non-covalent complexes 65 ± 66a and 65 ± 66b (see Ref. 70) were assembled from carboxylate-contain- ing porphyrins and the monoprotonated pentapyrrole chromo- N Me CHO 62 (R1=R2=Me2CHCO) Bu Me Me R1O Bu R1O 60 (R1=SiMe2But, R2=H) H R N N H N O N H N N O H NH NZn N N N O N R1 N 60 N H N H Bu Me Bu NH NH 64 ... PhCHO O phore sapphirine through the salt bridge formed.These systems are prepared by mixing porphyrin and sapphirine (in the form of a free acid and a free base) in dichloromethane; their binding constants determined by 1H NMR spectroscopy are *103 lit- re mol71. The two chromophores in these ensembles are oriented perpendicularly to each other in such a way that porphyrin is localised above the plane of sapphirine, while the `centre-to- centre' distance between the chromophores is equal to 12.5 A.N NH N N NHR2 O OR1 N HN N N N NH N R 59 N NH HN N H N H N H 61 N O R1 NHBz CHO N N O BzO O BzO 63 OBz Bu Bu N Me O O7 Et Et N NH HN +Me N NH HO(CH2)2 Et Et 65 953 64, PhCHO 61 Me N Me N M Bu N Me 66a,b Bu M=2H (a), Zn (b). Me (CH2)2OH954 It was shown 69, 70 that the non-covalently linked bisporphyrin systems described above can be used as models in studies of photoinduced energy transfer between pigments. The singlet ± singlet energy transfer from the zinc complex to the porphyrin free base in the ensemble 60 ± 61 is effected to a distance of *22.5 A and is characterised by the rate constant k&9.16108 s71 and 60% efficiency, which is consistent with the parameters calculated on the basis of the FoÈ rster approximation.These results suggest that dipole ± dipole `through-space' interac- tions are the most probable mechanism of singlet energy transfer. In this case, the role of hydrogen bonds between complementary bases is solely to bind chromophores and not to promote singlet energy transfer. On the other hand, the triplet energy transfer in the ensemble 60 ± 61, which follows from the appearance of an absorption band at 545 nm characteristic of triplet states of metal-free porphyrins, seems to be effected through hydrogen bonds which play in this case a more active mediatory role.69 Irradiation of porphyrin subunits in the ensembles 65 ± 66a and 65 ± 66b induces singlet ± singlet energy transfer from por- phyrin to sapphirine within the complexes; this process is charac- terised by lower energy of the first excited singlet state.The calculated rate constants for the energy transfer in systems, which utilise metal-free bases and zinc ± porphyrin complexes as donors, were equal to 4.361010 and 1.161011 s71, respectively, which is consistent with the FoÈ rster mechanism. Rapid energy transfer in the ensembles 65 ± 66a and 65 ± 66b is due to higher values of spectral overlap integrals of porphyrin emission and sapphirine absorption.70 The donor ± acceptor ensembles described in this Section can be incorporated into more complex multicomponent systems mimicking natural light-harvesting complexes.III. Multiporphyrin ensembles Natural photosynthetic light-harvesting complexes contain sev- eral hundreds of pigments responsible for the migration and transfer of excitation energy to the reaction centres. Therefore, an ideal model system should include a great and strictly defined number of chromophores with known photophysical properties. The molecular organisation of such a system should allow accurate control over the mutual arrangement of pigments in the integral ensemble. This, in turn, will ensure efficient transfer of excited state energy. Limited solubility of multiporphyrin ensembles is one of the main difficulties in their design. The approaches to the solution of this problem include incorporation of long alkyl groups into b-pyrrole positions and of alkyl, 3,5-di-tert-butylphenyl or ortho- disubstituted phenyl groups into more accessible meso-positions of terrapyrrole macrocycles.The porphyrins thus substituted are less susceptible to aggregation and, correspondingly, are more readily soluble in organic solvents, which facilitates the synthesis, chemical and spectroscopic analysis of the multiporphyrin ensem- bles based on them.27 Yet another problem is related to the quenching of excited states by photoinduced electron transfer which competes with the energy transfer. One of the ways to limit the energy transfer envisages the design of porphyrin ensembles with sufficiently long fixed `centre-to-centre' distances where electronic interactions between the pigments are relatively weak.1. Synthesis Two promising approaches to the synthesis of multiporphyrin ensembles include building block synthesis of covalently linked systems and self-assembly of pigments possessing special recog- nition sites. Building block synthesis, which consists in condensa- tion of substituted iodoaryl- and ethynylarylporphyrins under mild conditions in the presence of a palladium catalyst, was used for the preparation of linear trimers 67 25 and 68,27 the linear amphiphilic ensemble 6934 and the star-like five-porphyrin N V Konovalova, R P Evstigneeva, V N Luzgina ensemble 70 30, 71 in which the macrocycles were linked through diarylethyne spacers. The synthesis of a dithiaporphyrin (N2S2) block and its further use in the construction of the model light-harvesting system 71 have been reported.72 The preparation of the N2S2-porphyrin includes the reaction of 4-(trimethylsilylethynyl)benzaldehyde (2 equiv.) with dilithiothiophene (1 equiv.), condensation of 2,5-bis[4-(trimethylsilylethynyl)phenyl(hydroxy)methyl]thiophene with pyrrole in the presence of boron trifluoride etherate and removal of trimethylsilyl protective groups.The reaction of the dithiaporphyrin formed with 5-(4-iodophenyl)-10,15,20-tris(3,5- di-tert-butylphenyl)porphyrin in the presence of a palladium catalyst and triphenylarsine affords the pentamer 71 in 37% yield. As mentioned previously, one of the main tasks in photo- synthetic modelling is the construction of molecular ensembles which, like natural antenna complexes, are characterised by high molar absorption coefficients in both blue and red regions of the visible spectrum and significant overlap of absorption spectra of the acceptor and emission spectra of the donor.These properties are inherent in systems containing porphyrins and phthalocya- nines, which differ in their electronic characteristics. Yet another attractive feature of the combination of porphyrin and phthalo- cyanine chromophores within a single ensemble is that the energy of the first singlet excited state of phthalocyanine is lower than that for porphyrin. The light-harvesting complexes 72 and 73 contain four and eight porphyrin components, respectively, which are covalently linked to phthalocyanine to form a star-like structure.The use of a phenylethyne linker between the porphyrin and phthalocyanine components makes it possible to reduce the distance and to enhance interchromophore electronic interactions in the above systems in comparison with their structural analogues, viz., the diphenylethyne-linked pentamers 70 and 71. The ensembles 72a,b were synthesised in 45% and 15% yields by cyclotetramerisation of ethyne-linked porphyrin ± phthaloni- trile in pentan-1-ol in the presence of 1,8-diazabicyclo[5.4.0]un- dec-7-ene and MgCl2 or Zn(OAc)2, respectively. Subsequent selective demetallation and metallation reactions afforded the pentads 72c ± e, which contain different metals in their tetrapyr- role macrocycles.73 Asimilar approach was used for the synthesis of the ensembles 73a ± c.In this case, cyclotetramerisation was preceded by palla- dium-catalysed preparation of the porphyrin dimer containing a phthalonitrile fragment.74 Miller et al.75 have carried out the synthesis of the linear chromophore ensemble 74, containing perylene, bisporphyrin and phthalocyanine components, which manifests enhanced light- harvesting properties owing to strong absorption in all the visible region of the spectrum. This system can function as a cascade transferring excitation energy towards the acceptor. The ensemble 74 was synthesised in four steps: (1) synthesis of trans-substituted AB2C-porphyrin building blocks, each possessing only one non- substituted meso-position; (2) oxidative meso,meso-condensation of the porphyrin monomers to yield the bisporphyrin containing the phthalonitrile and iodophenyl fragments; (3) synthesis of bisporphyrinphthalocyanine ensembles by mixed cyclisation of the bisporphyrin and 4-tert-butylphthalonitrile and (4) palladium- catalysed condensation of the resulting product with ethynylper- ylene.X-Ray diffraction analysis of antenna complexes of photo- synthesising bacteria revealed that these consist of two concentric circular ensembles of bacteriochlorophyll molecules non-cova- lently bound to apoproteins (see Fig. 1).11 The planes of over- lapping bacteriochlorophyll a molecules in the inner ring containing two thirds of all chromophores are perpendicular to the plane of the tylakoid membrane, whereas the planes of chromophores in the outer ring are almost parallel to the membrane surface.Such spatial arrangement ensures the most efficient energy transfer through dipole ± dipole resonance inter- actions between pigments in the photosynthetic subunit.Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis R1 N R1 Zn N R1 67: R1=2,4,6-Me3C6H2, R2=H,M1=2 H,M2=Zn; 68: R1=2,4,6-Me3C6H2, R2=Me,M1=Zn,M2=2H. HO2C R R NM N N N R R NM N N N R RR=2,4,6-Me3C6H2;M=Zn (a), Mg (b). N C C N 67, 68 CF3N N Zn C C N N CF3 C C NH N N HN C C 70a,b R1 R2 N N M1 C C N N R2 R1 CF3 Me Me N NH HN N Me Me CF3 69 R R NM N N N R C C R C C C C R NM N N N R R 955 R1 N N R1 M2 N N R1 CF3N N Zn C C CO2H N N CF3 RCC N S R C C S N CCR 71a,b ArN N M R=C6H4 Ar, Ar=3,5-But2C6H3, N N Ar M=2H(a), Zn (b).956 R2 R1 R3 R3 N N M1 N R1 N R3 R1 R2 72: R1=R2=Me, R3=2,4,6-Me3C6H2; 73: R1=H, R2= M1=M2=Mg (a), Zn (b), 2H (c), M1=2 H,M2=Mg (d), M1=Zn,M2=Mg (e).O But N But O R1 R3 NM1 N N N C C N NM2 N C N N C 72a ± e, 73a ± c C But NH C C N But C N C NN C C NM1 N N R3 R3N N M1 C N N R3 But But N NH HN HN N But But N V Konovalova, R P Evstigneeva, V N Luzgina R2 R1 R3 N R1 M1 N N N R3 R3 N R1 R1 R2 R3; R3=2,4,6-Me3C6H2; But But But N N NH N N HN N N N C C But But 74Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis Ph Ph HN N N NH PhPh N N Zn N N Ph Ph The multiporphyrin ensemble 75 was designed for simulation of spatial arrangements of chromophores in the inner rings of natural antenna complexes.In this model, six porphyrin rings are covalently linked through rigid ethynyl linkers to six positions of the benzene ring, which functionally replaces protein matrices of natural complexes. The diameter of the cyclic ensemble 75 is 46.7 A and the `centre-to-centre' distance between chromophores is 13.2 A, i.e., it is higher than the average distance (*9 A) between magnesium ions of bacteriochlorophylls in natural sys- tems.The three-step synthesis of the hexaporphyrin ensemble 75 includes reaction of the zinc-containing complex of 5-(4-iodo- phenyl)-10,15,20-triphenylporphyrin with the 1,3,5-tris(trime- thylsilyl) derivative of hexaethynylbenzene in the presence of a palladium catalyst under standard conditions, removal of protec- tive groups and reaction of the star-like trimer formed with a large excess of the metal-free porphyrin. The total yield of the resulting ensemble 75 is 11%.76 The hexagonal cyclic ensembles 76a,b have been described 77 in which the six porphyrin rings are linked rigidly through six meta-diethynylphenyl bridges to form a cavity with an internal diameter of *46 A: A multistep synthesis of these ensembles is based on the use of only one building block (77) in which two protected, reactive positions, viz., the ethynyl group and the carbon atom of the phenyl ring, can be activated selectively (Scheme 2).Cross-condensation of porphyrins 78a and 79, which are readily prepared from compound 77 by treatment with methyl iodide or sodium hydroxide, respectively, in the presence of a palladium catalyst results in the bisporphyrin 80a. Iteration of this three-step reaction sequence yields porphyrin tetramers; their condensation with dimeric fragments and cyclisation result in the formation of the hexameric ensembles 76a,b. N Ph N C CC C N Ph NHPh N Ph Zn N CC C CC C CCHN Ph N Ph 75 Eight chromophores in the system 81 are linked to the polypeptide chain, which may form a secondary a-helical struc- ture after certain degree of oligomerisation.This conformation is determined by the natural trend of porphyrins for aggregation and is characterised by overlap of the chromophores, which ensures electronic interactions sufficient to enhance migration of excita- tion energy within the ensemble. The synthesis of the octamer 81 is based on the use of the L-lysine-containing porphyrin 82, which was prepared by con- densation of carboxy and amino components in the presence of DCC and 1-hydroxybenzotriazole (HOBT) (yield 94%). The strategy of oligomer synthesis involves selective removal of protective tert-butoxycarbonyl and allyl groups under mild con- ditions (Scheme 3).Thus treatment of the porphyrinlysine 82 with a solution (1 mol litre71) of chlorotrimethylsilane and phenol in dichloromethane results in the removal of the protective Boc group (yield 91%). Removal of the allyl protection from the carboxy group of compound 82 was carried out in a dimethylacet- amide ± piperidine mixture in the presence of tetrakis(triphenyl- phosphine)palladium in 84% yield. The dimer 83 was synthesised by condensation of the amine and the acid in the presence of DCC and HOBT. Iteration of this three-step procedure affords the tetramer 84 and the octamer 81 in 86% and 80% yields, respec- tively.78 A strategy based on an ordered assembly of chromophores owing to specific non-covalent interactions, was used in the design of a model photosynthetic system 85.This is formed as a result of pairwise interactions between complementary heterocyclic bases upon mixing of guanosine and cytidine porphyrin derivatives in dichloromethane.69Ph N NH HN N Ph Ph N N Zn N N Ph 957 Ph Ph958 Et2N3 Zn C C But 77 But 78a,b + 79 80c 80a ; 80d R1 But 80c,e+80d,f But N Zn = N I But 78a,b M=Zn (a), 2H (b). C CSiMe3 Et2N3 But R1 C C Zn C C But 80e 80b 80f C C Zn C C C C But But M1 C C C C Zn C CCC M2 CC Zn C C But 76a,b ArN Zn , Ar=2,4,6-Me3C6H2.N Ar M C C Zn C C79 C M C C80a,b C C M But C C C C C C But N V Konovalova, R P Evstigneeva, V N Luzgina C CSiMe3 Compound 80 C CH CR2 abcdef But C C Zn C C But C ZnCC But M1=M2=2H (a), M1=2 H,M2 =Zn (b). C C M2 C Scheme 2 M R2 R1 SiMe3 SiMe3 SiMe3 SiMe3 Zn 2H Zn H Zn2H H 2H N3Et2 N3Et2 IN3Et2 IN3Et2 CSiMe3 C M 80d,f C CSynthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis O NH2 O O NHBoc O 82 O NHBoc HO O * * = HN NZn N N N N R1 * R2O O R1= , R2=SiMe2But.OR2 R2O 2. Photochemical properties Photochemical studies of the system 70a have shown that the emission from the central porphyrin free base predominates in the fluorescence spectrum. The quantum yields of emission of zinc- containing complexes within the ensemble (F=0.38%) were 12- fold smaller than that of the corresponding monomeric zinc- porphyrin complex. At the same time, the presence of four peripheral metal-containing porphyrin fragments virtually did O O O NH2 O O NH O O O NHBoc O O NH 83 O O O NHBoc HO HO NH But But But N NH . O HN N But But But N NH HN N H N N H O N H N N N O H R1 N H 85 not influence the emission yield of the central porphyrin free base (F=12%).It was noted also that the whole fluorescence excitation spectrum coincided almost completely with the absorp- tion spectrum. Based on these data, the yield of the energy transfer from the peripheral zinc complexes to the porphyrin free base was estimated to be equal to 90%. Thus, the pentamer 70a can accumulate and concentrate the energy of photons in the centre of the ensemble.71 O O O NH2 NH NH NH O O O NHBoc NH NH NH 84O O O NHBoc NH NH NH H R1 H N O N N N H N N O H N N H 959 Scheme 3 BocHN O NH O NH O NH O NH O NH O NH O NH O O 81 R1 NZn N N N960 Similar results were obtained for the ensembles 71a,b where the efficient energy transfer occurs from the peripheral porphyrin fragments to the central dithiaporphyrin subunit.72 The quantum yields of the energy transfer from the photo- excited porphyrin components to the central phthalocyanine in the model systems 72b ± e exceed 99%.However, the efficiency of energy transfer in the ensemble 72a is decreased by 40%, which is attributed to the contribution of the charge transfer from the excited porphyrin to the ground state of phthalocyanine due to probable easier oxidation of magnesium-containing porphyrins in comparison with zinc-porphyrin complexes and free bases.73 An approach to the targeted transfer of energy to the terminal acceptor includes a cascade of energy transfers along the ensemble of pigments linked in succession.Studies of spectral properties of the linear molecular system 74 revealed an ultrafast (k53.361011 s71) and nearly quantitative cascade-like energy transfer from perylene to bisporphyrin and further to phthalo- cyanine. The directional energy transfer in this rigid structure is determined by the nature of the donor and acceptor chromo- phores, type of spacers and strong electronic interactions between the pigments in the bisporphyrin energy-transferring subunit. In addition, the ensemble 74 is characterised by significant overlap of absorptions of the components in the visible region of the spectrum, which determines its high light-harvesting capacity.75 The effective transfer of singlet excitation energy from zinc- containing complexes to porphyrin free bases was observed in the ensembles 75 (F=98%) and 76a (F=91%) in which the spatial configuration of the chromophores mimicks the mutual arrange- ment of pigments in light-harvesting complexes of natural photo- synthesising organisms.76, 77 At the same time, the energy transfer from five zinc-containing chromophores to the single acceptor in the hexamer 76b occurs with the quantum efficiency of 40%.77 Such a significant difference is explained by the increase in the number of non-productive stages in the energy transfer between zinc-containing porphyrins in the ensemble 76b.In contrast with the above-described systems, the singlet energy transfer in the non-covalently linked ensemble 85 where two zinc complexes and one porphyrin free base are held at a distance of 22.5 A from one another due to pairwise interactions between guanine and cytosine follows the FoÈ rster `through-space' mechanism (k&96108 s71) with a 60% efficiency. The quantum efficiency of the energy transfer in this system can be optimised by reducing the distance (by *5 A) between the porphyrin compo- nents.69 Fast migration of excitation energy between isoenergetic pig- ments takes place in natural light-harvesting complexes.It was of interest to determine the rate of this process. In an attempt to study the dynamics of this process and the feasibility of a reversible energy transfer, Hsiao et al.51 have performed com- puter-assisted simulation of the photodynamic behaviour of the trimer 68 with some admissions.First, considering that absorp- tion characteristics of two zinc-containing chromophores are identical, the authors admitted that primary excitation is distrib- uted uniformly between these two porphyrins. Second, it was assumed that the two-photon absorption was negligible under the conditions used. Third, it was suggested that the rate of energy transfer from the terminal zinc porphyrin (ZnP) to the central one (k1) is equal to that of the reverse process (k71). And, finally, the rate of the energy transfer between the central zinc-containing complex and the porphyrin free base (H2P) (k2) was taken to be equal to the rate measured for the analogous dimer 12c (Scheme 4). The temporal evolution of the energy transfer between the chromophores in the trimer is described by a system of differential equations which, for a fixed value of k1 with a time interval of 0.5 ps, is solved with respect to the concentrations of singlet excited states for each of the three individual chromophores at a given moment of time.The decay curves constructed on the basis of the calculated values should correlate with the experimental monoexponential curves of absorption bleaching of the metal-free N V Konovalova, R P Evstigneeva, V N Luzgina Scheme 4 k1 k2 1(ZnP)* ± ZnP ±H2P k71 ZnP ± 1(ZnP)* ±H2P B ZnP ± ZnP ± 1(H2P)* C A k3 k3 k4 ZnP ± ZnP ±H2P D porphyrin in the ground energy state and of decay of the singlet state of zinc-containing porphyrins.The rate constant for the energy transfer between two isoenergetic zinc-containing por- phyrins estimated in this way, k1=k71=(2.20.8)61010 s71, is comparable to that for the energy transfer between a zinc- containing complex and the free base.51 The total quantum yields of energy transfers in multicompo- nent porphyrin ensembles are difficult to predict, even if the efficiencies of individual steps of these processes are known. As the synthesis of such ensembles is very time and material consum- ing, rational design of efficient energy-transmitting molecular structures demands reliable prediction of their properties. Van Patten et al.79 have developed a general analytical technique for simulation of the kinetics of energy migration in weakly bound multipigment ensembles containing several donors but only one terminal acceptor. This approach is based on the system of differential equations which describe the temporal evolution of the energy transfer between the neighbouring chro- mophores.Thus in the case of the trimeric porphyrin ensemble 68, these processes include energy migration between the donors (k1, k71), energy transfer to the terminal acceptor (k2), relaxation of the singlet state of the donors (k3) and the terminal acceptor (k4) (see Scheme 4). In this specific case, it is necessary to consider four configurations the interaction of which is described by the follow- ing system of differential equations: dA/dt=(7k17k3)A+(k71)B, dB/dt=k1A+(7k717k27k3)B, dC/dt=k2B7k4C, dD/dt=k3A+k3B+k4C, where A±D are the concentrations of states A±D, respectively.In the general case, the energy transfer for a multiporphyrin ensemble ZnPN71±H2P can be regarded as an analogous first- order task for a series of reactions with N+1 configurations. These equations are constructed with allowance for irreversibility of the energy transfer to the acceptor, whereas excitation energy migrates between isoenergetic donors in both directions (see Scheme 4). By varying the initial conditions for excitation and the empirical data for the rates of energy transfer in all stages, it is possible to find solutions for the given system with respect to the concentrations of singlet excited states for each particular chro- mophore at a given moment of time. Their subsequent summation in time makes it possible to determine the general quantum efficiency of the energy transfer, i.e., the percentage of ensembles in which the excitation reaches the terminal acceptor.This method allows prediction of the quantum efficiency depending on the rates, lifetimes of excited states and structures of ensembles. The results of these calculations showed that the quantum efficiency of the energy transfer to the terminal acceptor in linear ensembles during random excitation of isoenergetic donor pig- ments with fixed rates of the energy transfer in each step decreases rapidly with an increase in the molecule length. The quantum efficiency strongly depends on the changes in the rates of the energy transfer between isoenergetic pigments.For example, the quantum efficiency of excitation capture for a linear twenty- porphyrin ensemble (the rate constant for the energy transfer between its isoenergetic pigments, k1, is 261010 s71) is as low as 35%. However, with an increase in the transfer rateSynthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis (k1=171012 s71) the quantum yield of the energy transfer for this ensemble increases to 70%, whereas that for the linear fifty- porphyrin ensemble is 43%. Thus, the increase in the rate of the energy transfer results in a significant increase in the quantum efficiency. The energy transfer becomes more efficient provided the migration of energy competes successfully with relaxation of the excited state.With this in mind, van Patten et al.79 have studied the dependence of the efficiency of the energy migration in linear ensembles on the lifetime of the singlet excited states. A compa- rative study for different rates of competing deactivation has demonstrated that the quantum efficiency increases significantly with an increase in the lifetime (t) of the excited singlet state of the donor. Calculations have shown that the quantum yields for ten- component linear ensembles containing zinc- and magnesium ± porphyrin complexes as donors (t=2.4 and 9 ns, respectively) are 62% and 85%, respectively. Qualitatively similar results were obtained in simulation of linear ensembles where the excitation and energy capture occur at different ends of the molecule.Since the quantum yields are determined by the competition between the energy migration and relaxation of the excited state, the efficiency of the energy transfer increases significantly in cyclic and branched ensembles with the minimum number of non- productive energy transfer steps. For example, the quantum efficiency for a tri-branched ten-component ensemble shown in Fig. 3 c (F=91%) is similar to that for a linear tetramer, whereas that for a linear ensemble comprising nine zinc-containing por- phyrins and one free base is as low as 63%.79 It should be noted that the quantum efficiency estimated for a cyclic porphyrin decamer with an integral acceptor (F=84%, see Fig.3 b) exceeds markedly the experimental value for the hexamer a ZnP ZnP ZnP ZnP ZnP H2P ZnP ZnP ZnP ZnP c ZnP ZnP ZnP ZnP ZnP ZnP H2P ZnP ZnP ZnP Figure 3. The effect of architecture on the quantum yields (F) of energy migration to a single acceptor in cyclic (a, b) and branched (c, d ) ensembles containing nine donor pigments. All donor pigments have similar absorp- tion patterns: k1=k71=261010 s71, k2=2.161010 s71, k3= 4.26108 s71; F=76% (a), 84% (b), 91% (c), 98% (d).79 bZnP ZnP ZnP ZnP H2P ZnP ZnP ZnP ZnP ZnP d ZnP ZnP ZnP ZnP ZnP H2P ZnP ZnP ZnP ZnP 961 76b with an identical structure (F=40%). There are several explanations for this phenomenon: (1) different sizes of the macrocyclic ensembles in theoretical and synthetic models; (2) decreased (in comparison with theoretical value) rate of intra- molecular energy transfer in the synthetic ensemble where por- phyrin subunits are linked through meta-positions of aromatic rings of the linkers; (3) predominant excitation, under the exper- imental conditions, of only one zinc-containing chromophore in each multiporphyrin ensemble with the resulting loss of excitation energy in the reversible energy transfer between neighbouring zinc porphyrins and (4) possible rotation of porphyrin chromophores in the synthetic hexamer.77 Introduction of different types of donors into model systems increases the ratio of rates of forward and reverse energy transfer processes between the donors (k=k1/k71>1), which, in turn, leads to a directed energy transfer (Fig.4) and sharp increase in the quantum efficiency. Modelling of such cascade ensembles demonstrated that a twofold decrease in the rate of the reverse reaction (k=2) results in an increase in the quantum efficiency which is commensurate with a 50-fold increase in the rate of direct energy transfer in the linear ensemble under conditions of random migration of the excitation energy.79 P1 k1 P2 k2 P3 k3 P4 k4 H2Pk6 k5 k5 k5 k5 Figure 4. A five-membered cascade ensemble containing several types of donor pigments (P1±P4) and an acceptor (H2P).79 (Here and in Figs 5 and 6 ki are the rate constants of the corresponding energy transfer). An important characteristics of light-harvesting model sys- tems is their antenna effects, which represent products of the number of donor pigments in an ensemble with the quantum efficiency of the energy transfer.For example, the dimer 12a and the corresponding star-like pentamer 70 have identical quantum efficiencies (98%),51, 71 but the antenna effect of the former ensemble is 0.98, whereas that of the latter is 3.92, which points to a higher light-harvesting capacity of the pentamer.79 The antenna effect provides a possibility for the choice of strategies in the design of multicomponent ensembles. From the standpoint of energy capture by the acceptor, the most efficient architecture of the ensemble is the one which ensures maximum antenna effect.Thus the addition of three donors to a ten- component tri-branched ensemble (see Fig. 3 c), which manifests an antenna effect of 8.19 and a quantum efficiency of 91%, can be effected in two ways. Attachment of one zinc-containing por- phyrin each to the ends of branches decreases the quantum efficiency to 87%, while the antenna effect increases to 10.44. An alternative route consists in direct addition of the fourth linear ensemble consisting of three zinc-containing porphyrins to a free base resulting in the formation of a symmetrical cross-shaped structure. This procedure does not influence the level of quantum efficiency, since all the four linear branches are independent structures, but enhances the antenna effect to 10.92.These calculations have shown that the appearance of a new individual route for the direct energy transfer from additional donors to the acceptor does not increase the number of non-productive energy transfers in the existing set of donors and is therefore the most efficient way to enhance the light-harvesting properties of the ensemble. Systems with star-like architecture (see Fig. 3 d) mani- fest the best light-harvesting properties, their quantum efficiencies are comparable with those of the corresponding dimer and the962 antenna effect depends linearly on the number of the attached donors. The results of theoretical modelling pave the way to the synthesis of multicomponent ensembles with anticipated high efficiency of the overall energy transfer process.79 IV.Porphyrin ± carotenoid compounds Carotenoids (Car) are present in the composition of antenna complexes and reaction centres of natural photosynthetic systems. They function as light-harvesting pigments by absorbing light in the spectral regions where the extinction coefficients of chloro- phylls (Chl) and bacteriochlorophylls (BChl) are low and by supplying the excitation energy to these pigments through a fast singlet ± singlet transfer.12, 80 ± 82 1Car*, Car+hn 1 Car+1Chl*, Car*+Chl (BChl) 1Chl* Chl+hn (fluorescence). Contrariwise, in the case of high light intensity carotenoids dissipate excesse energy through singlet energy transfer from chlorophyll to the carotenoid and thus control the intensity of singlet energy flow to photosynthetic reaction centres.83 In addition, carotenoids fulfil the photoprotective function.Upon irradiation of photosynthetic complexes with high-intensity light, primary electron donors (special pairs) obtain excitation energy from antenna systems and effect primary electron transfer prior to regeneration of the quinone component of the electron transport chain. Under these conditions, the primary charge- separated state, which involves the radical cation of the special pair and the radical anion of bacteriopheophytin (BPh), is not subject to ordinary conversions and undergoes recombination with the formation of the triplet state of the special pair. Triplet states of chlorophylls are usually long-living and are highly energetic.They can also react with other compounds, particularly, with molecular oxygen to generate singlet oxygen. Sensitisation of singlet oxygen represents an energy transfer from the triplet state of chlorophyll to the ground state of oxygen according to an electron-exchange mechanism. hn 1BChl*, BChl 1 BChl+.+BPh7., BChl*+BPh 3 BChl+.+BPh7. BChl*+BPh, 3 BChl+1O2*. BChl*+O2 Singlet oxygen is known to be extremely reactive and causes the destruction of plant tissues. Carotenoid polyenes prevent the deleterious effects of singlet oxygen by quenching the triplet states of chlorophylls and bacteriochlorophylls prior to their reaction with oxygen. This represents a triplet ± triplet energy transfer and results in the formation of a low-lying triplet state of a carotenoid, which is harmless for plant tissues.Studies of the temperature dependences of the decay rate of the triplet state of the primary donor and the quantum yield of the triplet carotenoid have led to the discovery of a transient excited state which was attributed to the triplet state of the monomeric bacteriochlorophyll localised on the inactive side of the reaction centre. Thus, the triplet energy is transferred from the special pair to the neighbouring bacteriochlorophyll in a thermally activated step; the triplet state of bacteriochlorophyll generated in this process is rapidly quenched by the carotenoid.84 3 BChl2+3BChl*, (BChl2)*+BChl+Q 3 BChl+3Car*, BChl*+Car 3 Car+Q, Car* where Q is heat.N V Konovalova, R P Evstigneeva, V N Luzgina Carotenoids behave also as photoprotectors by directly quenching singlet oxygen.84, 85 3Car*+3O2 , Car+1O2* 3 Car+Q. Car* Biomimetic model compounds containing porphyrin or chlor- ophyll derivatives covalently linked to carotenoid polyenes have been developed for the study of photochemical characteristics of carotenoids, particularly, their photoprotective and antenna functions. 1. Synthesis The carotenoid ± tetraarylporphyrin dyads 86a,b linked by the ester bond, were described in 1980. With these compounds it was shown for the first time that the efficient intramolecular singlet ± singlet energy transfer from carotenoids to porphyrins requires that strict conformational demands be met.86, 87 The models 86c ± f were subsequently prepared for the study of singlet ± singlet and triplet ± triplet energy transfer between carotenoids and porphyrins.2, 85 Me N NH R3 Me HN N R2 R1 86a ± f Me R1=R2=H, R3=CO2CH2X (a), NHCOX (c), O(CH2)3OCOX (f); R2=R3=H,R1=CO2CH2X (b), NHCOX (e); R1=R3=H, * R2=NHCOX (d); X= .2 * 2 The synthesis and investigation into photodynamic behaviour of the dyads 87a ± k and 88a ± k in which the carotenoid and the porphyrin are linked through aromatic groups have been reported.88 Owing to steric repulsion between the meso-aryl rings and methyl groups in the adjacent b-pyrrole positions, the aromatic bridge occupies an almost perpendicular position rela- tive to the porphyrin plane and the `centre-to-centre' distances between the pigments in the majority of models are fixed.These conformational restrictions permit one to establish the depend- ences of the rates of dynamic processes of the photoexcited state on geometric parameters of the molecules. Yet another essential feature of these models is conjugation of carotenoid and por- phyrin p-electronic systems in the systems 87a ± g and 88a ± g containing phenylene, naphthylene and biphenylene spacers, which help realisation of considerable `through-bond' electronic interactions between the chromophores. The dyads 87a ± k were prepared by trichloroacetic acid- catalysed condensation of the carotenoid-substituted aromatic aldehydes 89a ± k, which in turn were synthesised by the Wittig reaction from the corresponding arylphosphonium salt and b-apo-80-carotenal, with 4-methoxycarbonylbenzaldehyde (90) and dipyrrolylmethane 6 (Scheme 5).Despite the lability of the carotenoids in acidic media, this method afforded carotenoid- linked porphyrins in quite acceptable yields. Metallation ofSynthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis Me Me Me X 2 CHO+6+ OHC Me 2 Me 90 89a ± k C6H13 Me H13C6 N N M Me N Me Me Me N X 2 Me 2 Me Me C6H13 87a ± k:M=2H; 88a ± k: M = Zn X=1,4-C6H4 (a), 1,3-C6H4 (b), 2,6-naphthylene (c), 2,7-naphthylene (d), p-C6H4±C6H4-p (e), m-C6H4±C6H4-p (f), p-C6H4±C6H4-m (g), * (i), p-C6H4±CH2±C6H4-p (h), * * compounds 87a ± k by zinc acetate results in the model systems 88a ± k.88 The carotenoid ± pyropheophorbide dyads 91 ± 95 (see Refs 89 ± 91) were prepared to study the interactions of the carotenoid and chlorophyll in the excited state.The natural carotenoids fucoxanthin and zeaxanthin used in these model studies fulfil different functions in the photosynthetic apparatus. It was found that fucoxanthin transfers energy to chlorophyll a in natural systems with high efficiency, whereas zeaxanthin, which is a member of the xanthophyll cycle, quenches excess energy during intense illumination. Studies of electronic interactions of these carotenoids with chlorin-type pigments are important for gaining insight into the mechanisms of photochemical processes under- lying biological functions of natural carotenoids.The use of different pyropheophorbide components allows one to vary the energy levels of their S1 states and the extent of `through-bond' electronic interactions between the two pigments. The dyads 91 ± 95 were prepared by the reaction of chlorophyll a derivatives with fucoxanthin and zeaxanthin in the presence of 4-dimethylaminopyridine using 2-chloro-1-methylpyridinium iodide as a condensing reagent. These reactions occurred with acceptable yields (15% ± 30%) without formation of side products and cis ± trans-isomerisation of the carotenoid component. According to 1H NMR spectroscopic data, these dyad molecules have extended conformations in solution. Me COX Me COX Me Et Et Me N NH N NH R HN N HN N Me Me Me Me O CO2Me 93a,b CO2Me 91a,b: R =H; 92a,b: R =Cl 963 Scheme 5 CO2MeCO2Me Me C6H13 *( j ), p-C6H4±CONH±C6H4-p (k).H2C R1 Me Et N NH HN N Me Me O COR2 94a,b: R1=Me, R2=X; 95a,b: R1=COX, R2=OMe. OH O O C O CH X= (a), O O OH(b). 2 2 O 2. Singlet ± singlet energy transfer Despite the large number of publications devoted to the studies of light-harvesting function of carotenoids in photosynthesising organisms, the detailed mechanism of the transfer of solar energy to chlorophylls is still obscure. Among a variety of factors hampering the understanding of singlet ± singlet energy transfer mechanisms mediated by carotenoids, special mention should be made of the following: (1) experimental problems connected with determination of energy levels of the lowest excited singlet states of carotenoids; (2) fast time scale of the energy transfer; (3) difficulties in estimation of the energy transfer rate constants for individual chromophore pairs within multicomponent ensembles; (4) lack of detailed information about the structures of light- harvesting antenna complexes.A characteristic feature of carotenoids is the presence of two low-lying singlet excited states. Intense colour of carotenoids, e.g., b-carotene, is due to a strictly allowed electric dipole transition to the second excited singlet state S2. The radiative rate constant for * *964 this state is rather high, but its lifetime is*200 fs and, corre- spondingly, the quantum yield of fluorescence is very low.The first excited singlet state S1 is characterised by a longer lifetime (*10 ps), but is strictly forbidden and is seldom detected in ordinary absorption spectra. The radiative rate constant for this state and quantum yield of fluorescence are usually very low.80 As a consequence, spatial requirements for effective singlet ± singlet energy transfer from carotenoids to chlorophylls or porphyrins are very strict, which imposes strong limitations on molecular structures of artificial photosynthetic systems. The very first studies of energy transfer in porphyrin ± carote- noid compounds revealed that sreric factors influence strongly the efficiency of this process.Thus the carotenoid unsaturated chain in the dyad 86a, which contains tetraarylporphyrin linked to the carotenoid through the para-position of the meso-aryl ring, is removed from the tetrapyrrole macrocycle as a result of which singlet ± singlet energy transfer does not take place. At the same time, the folded carotenoid chain in the ortho-isomer 86b lies above the porphyrin macrocycle with an interchromophore dis- tance of *4 A and the p-electron systems of the two chromo- phores are in contact with one another. In this case, the singlet ± singlet energy transfer occurs with *25% efficiency (see Refs 2, 86 and 87). Singlet ± singlet transfer of excitation energy from carotenoids to porphyrins can be studied by fluorescence excitation spectro- scopy.In these studies, the fluorescence intensity of porphyrin depends on the excitation wavelength. If porphyrin fluorescence is induced by the light absorbed by the carotenoid, the energy transfer from the carotenoid to porphyrin follows the sing- let ± singlet mechanism.2 The use of this technique has made it possible to detect this type of intramolecular energy transfer in compounds 87a ± k. The efficiency of this process was estimated from the ratio of excitation to absorption spectra and is equal to 9%± 35% (see Ref. 88). The energy transfer from the carotenoid to pyropheophorbide in the fucoxanthin-containing compounds 91a ± 95a occurs with the quantum efficiency of 12%± 44% (see Ref.91). Elucidation of the mechanism of the singlet ± singlet energy transfer from the carotenoid to chlorophyll in photosynthesising organisms is a topical problem in the study of the light-harvesting function of carotenoids. The existence of close orbital contact needed for the singlet ± singlet energy transfer in the dyad 86b calls into question the applicability of the FoÈ rster dipole ± dipole approximation, which has been formulated for complexes where the distances between chromophores are larger than their sizes. Thus, the probability of energy transfer through electron- exchange interactions which demand orbital overlap becomes higher. In the carotenoid ± porphyrin dyad 86c, the chromophores are linked by a partially conjugated amide bond and the energy transfer yield is *13%. This is rather high, especially with reference to a very short lifetime of the excited singlet state of the carotenoid.Electron-exchange interactions caused by partial overlap of p-electron systems of carotenoid and porphyrin through the amide bond appeared to play a crucial role in the energy transfer in this model system. Similar results were obtained for the dyads 96a,b in which the carotenoid is linked to the pyropheophorbide derivative. The quantum yield of the energy transfer in compound 96a is <5%; the lifetime of the corotenoid singlet state (16 ps) remains unchanged upon attachment of pyropheophorbide. In contrast, the lifetime of the carotenoid S1 state in the dyad 96b decreases to 7 ps due to energy transfer to pyropheophorbide which occurs with the quantum efficiency of *50%.These results are inter- preted by the fact that in the molecule 96a saturated carbon atoms separate the p-orbitals of the two chromophores and thus prevent electron-exchange interactions required for effective singlet energy transfer. In the molecule 96b, partial conjugation of the p-electron systems of the carotenoid and porphyrin through the amide bond ensures electron-exchange interactions; therefore, energy transfer occurs with high efficiency.2, 85 N V Konovalova, R P Evstigneeva, V N Luzgina Me Et N Me R1 HN NH Me N O Me COR2 96a,b R1=CH=CH2, R2=NHX (a), R1=CONHX, R2=OMe (b); * X= . 2 2 In the model compounds 87a ± g, the conjugation of the p-electron system of the carotenoid with the porphyrin macro- cycle through the aryl bridge enhances electronic interactions between the chromophores.The rates of singlet ± singlet intra- molecular energy transfer in these dyads depend on the site of attachment of the carotenoid to the aromatic spacer. Thus comparison of the energy transfer rates in the dyads 87a,b revealed that this process occurs faster in a para-linked structure than in the meta-isomer (k=561010 and 361010 s71, respectively). This can be rationalised by stronger electronic interaction between chromophores in the former case due to much greater orbital density in the para-position. Analogously, distribution of the electron density on the molecular orbitals of spacers provides an explanation for the observed dependence of the rate of the energy transfer on the carotenoid-binding site in naphthylene- and biphenylene-bound systems.The results obtained suggest that `through-bond' electronic interactions represent the most essential mechanism of intramolecular singlet ± singlet energy transfer. This conclusion is consistent with the dipole-forbidden nature of the carotenoid S1 state, since energy transfer involving such forbidden states can only be effective in the presence of electron- exchange interactions in the system.88 Effective orbital overlap, is possible where chromophores are in van-der-Waals contact. In the case of bound chromophores (see above), orbital overlap occurs in folded conformations, where the p-systems of the donor and the acceptor are in direct contact with one another.The orbitals of the linkers and the environment (e.g., the solvent or a protein) also take part in electron-exchange interactions. Orbital contacts of non-bound pigments in solution require molecular collisions; therefore, the rates of electron- exchange interactions depend directly on the rate of diffusion. However, the lifetime of the S1 state of carotenoids is so short (tens of picoseconds) that no collisions with the expected energy accept- ors (viz., porphyrins or chlorophylls) can take place. It thus follows that carotenoids are inefficient donors of the singlet state energy in non-bound systems in solution.85 The results illustrating the necessity of electron exchange for singlet energy transfer from carotenoid pigments are very impor- tant for the design of more complex photosynthetic model systems in which chlorophylls and carotenoids are bound to the protein.Functioning of carotenoids as antennae in the transfer of singlet excitation energy to chlorophylls requires that two protein-bound pigments were in a van-der-Waals contact with one another. Although the predominance of electron-exchange interactions in `through-bond' singlet energy transfer from the carotenoid to porphyrin has been confirmed experimentally, one should not rule out some contribution of dipole ± dipole interactions. The two p-electron systems in the fucoxanthin ± pyropheophorbide dyads 91a ± 95a are separated by at least five saturated carbon atoms and there is no evidence of folded conformation.In this case, direct orbital overlap required for `through-bond' electron-exchange interactions is insignificant and its contribution to the singlet ±Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis singlet energy transfer observed is very low. However, in non- symmetrical carotenoids, such as fucoxanthin, the S1 state can `borrow' oscillating dipole energy from the S2 state and thus become weakly dipole-allowed. The rate constants and the effi- ciencies of energy transfer in the dyads 91a ± 95a estimated with the use of the FoÈ rster approximation are in good agreement with the experimental results.These studies suggest that dipole ± dipole interactions play a crucial role in the intramolecular singlet ± sing- let energy transfer from fucoxanthin to pyropheophorbide in these compounds.89, 91 According to Sadovnikova et al.,92 the energy transfer in model compounds 97a,b is also described in terms of the FoÈ rster theory. The efficiency of energy transfer in these systems varies depending on the lengths of the conjugated bonds in the polyene and changes from 33% to 55% on going from compound 97b to compound 97a, apparently due to the increased spectral overlap integral of the donor fluorescence and the acceptor absorption in the latter case. Ph O N NH Ph N C R H HN N 97a,b Ph * * (b).(a), R= OMe OMe Elucidation of the role of two excited singlet carotenoid states in the energy transfer is yet another important problem, which attracts keen attention of investigators. An analysis of time resolved fluorescence spectra showed that the quenching time of the carotenoid S1 state in compound 96b (7 ps) coincides with the time of formation of the singlet state of the pyropheophorbide component.85 A similar phenomenon was observed for the fuco- xanthin-containing dyads 91a ± 95a. Besides, the decrease in the efficiency of the energy transfer in the series 92a>91a>93a is commensurate with the decrease in the spectral overlap between the fluorescence of the S1 state of fucoxanthin and Qy-absorption of pyropheophorbide.88 ± 90 The lifetime of the carotenoid S2 state does not exceed several hundreds of femtoseconds and therefore cannot contribute to the energy transfer, which proceeds on a picosecond time scale.These findings point to the involvement of the carotenoid S1 state as an energy donor in the singlet energy transfer.80, 85, 89 The energy transfer from the carotenoid S2 state is also possible as was the case with the light-harvesting antenna complex B800-850 of the purple bacterium Rhodobacter sphaeroides; how- ever, in this case the process proceeds on a femtosecond time scale.80 The S1 state of zeaxanthin in the dyads 91b ± 95b is energeti- cally lower than the singlet state of pyropheophorbide and cannot therefore take part in the energy transfer to pyropheophorbide.An alternative route of the energy transfer from the singlet-excited state to pyropheophorbide is that from the S2 state of zeaxanthin. This hypothesis is corroborated by the fact that the fluorescence spectrum from the S2 state of zeaxanthin overlaps with the high- energy absorption Qx-band of pyropheophorbide. The quantum yields of the energy transfer from the S2 state of the carotenoid to the S1 state of pyropheophorbide in compounds 91b ± 95b do not exceed 15%. The strictly allowed nature of the S2?S0 transition permits the contribution of dipole ± dipole interactions to this mechanism. However, the rate constants for the energy transfer estimated with the use of the FoÈ rster model correlate weakly with experimentally determined values.The FoÈ rster theory of dipo- le ± dipole interactions assumes that the excitation is followed by 965 oscillatory relaxation of the donor state prior to its deactivation through energy transfer. However, no complete oscillatory equi- librium can be reached in zeaxanthin-containing compounds in which the rapid energy transfer is effected from the short-lived S2 state. Therefore, the use of the FoÈ rster model for the description of the energy transfer mechanism is not correct in this case. It should be noted, however, that the carotenoid and pyropheophorbide components of the dyads 91b ± 95b are separated by fewer saturated carbon atoms in comparison with the components of the corresponding fucoxanthin-containing compounds 91a ± 95a.This structural difference can favour somewhat stronger `through-bond' electronic interactions in those cases where the energy is transferred from zeaxanthin to pyropheophorbide.89 ± 91 Thus, highly efficient transfer of excitation energy from carotenoids to chlorophylls can follow several mechanisms. Their detailed study in each concrete case depends on the structures of the carotenoid and chlorophyll and their mutual arrangement in the protein environment. Efficient singlet ± singlet energy transfer is thermodynamically possible in those cases where the singlet state energy of the donor (carotenoid) exceeds that of the acceptor (chlorophyll or bacterio- chlorophyll). In the case of partial degeneracy of excited singlet states of the carotenoid and chlorophyll, the overall efficiency of the energy transfer may depend on the lifetimes of their singlet states.The reduction of the lifetime of the S1 state of chlorophyll in natural photosynthetic systems owing to the fast electron transfer to an additional acceptor, e.g., accessory chlorophyll, can enhance the efficiency of the energy transfer from the carotenoid to chlorophyll. On the other hand, in the absence of additional fast photochemical processes, which quench the singlet state of chlorophyll, the efficiency of the energy transfer from the carotenoid to chlorophyll can be less than optimum.85 In addition to the key light-harvesting function discussed above, an opposite process, viz., photochemical quenching of the first excited singlet state of porphyrin or chlorophyll by the carotenoid, was discovered in the studies of carotenoid-containing model compounds.This phenomenon is similar to energy dis- sipation after excessive irradiation of chlorophylls in vivo. A comprehensive analysis of mechanisms of quenching of porphyrin fluorescence by carotenoids will shed additional light on the ability of the latter to control the intensities of singlet energy fluxes to photosynthetic reaction centres. Spectroscopic studies of the dyads 91b and 94b have demon- strated that zeaxanthin diminishes the intensity of pyropheophor- bide fluorescence by 20% and 45%, respectively, and noticeably reduces the lifetime of the excited singlet state of pyropheophor- bide (5.6 and 3.9 ns, respectively) in comparison with dimethyl esters of free pyropheophorbides (6.8 and 7.8 ns, respectively). This points to the existence of an additional pathway of quenching of the singlet excited state of pyropheophorbide in carotenoid- containing systems.89 A possible explanation of this phenomenon is electron transfer from the carotenoid to the singlet excited state of pyropheophorbide with subsequent ultrafast recombination of charges.93 An alternative mechanism of quenching of pyropheo- phorbide fluorescence consists in reverse singlet ± singlet energy transfer from the excited S1 state of pyropheophorbide to zeax- anthin. This route is thermodynamically allowed, since the S1 state of zeaxanthin possesses lesser energy than that of pyropheo- phorbide.The ability of zeaxanthin to quench the singlet excited state of pyropheophorbide corresponds with the role played by this carotenoid in the quenching of excess energy of chlorophyll under conditions of the excess irradiation in vivo.89, 90 Similar quenching of porphyrin fluorescence by the carote- noid was observed in the dyads 87a ± k and 88a ± k. Thus the lifetime of porphyrin fluorescence in compound 87a decreases to 850 ps, i.e., becomes close to the time of formation of the carotenoid S1 state (930 ps), which reflects the intramolecular energy transfer from the excited singlet state of porphyrin to the carotenoid. The carotenoid S1 state generated is subjected to reversible energy transfer to porphyrin, which competes with its966 b a k1 k5 1 1 Car* ±H2P Car* ± ZnP Car ± 1H2P* Car ± 1ZnP* k2 k3 k3 k4 k6 Car ±H2P Car ± ZnP Figure 5.A scheme of singlet energy transfer in the porphyrin ± carote- noid compounds 87a ± k (a) and 88a ± k (b).88 fast internal transition to the ground state. The singlet ± singlet energy transfer between the carotenoid and the metal-free por- phyrin in compounds 87a ± k is reversible (Fig. 5 a) assuming that the S1 states of the two chromophores are nearly isoenergetic. At the same time, the unidirectional singlet ± singlet energy transfer from zinc porphyrin to the carotenoid (Fig. 5 b) observed in systems 88a ± k indicates that the S1 state of the carotenoid is energetically lower than that of the zinc ± porphyrin complex.88 The above-described approach, which is based on the changes in positions of the S1 energy level of porphyrin or chlorophyll induced by chemical modifications, e.g., metallation, introduction of appropriate substituents and changes in the p-electron system, makes it possible to estimate the true localisation of the non- radiative S1 state of carotenoids provided the lifetime of the singlet excited state is determined exclusively by the intramolecular energy transfer between the carotenoid and the tetrapyrrole pig- ment.89 3.Triplet ± triplet energy transfer Photoprotection of plant tissues from the destructive action of singlet oxygen is provided by quenching of triplet states of chlorophylls through the transfer of energy to carotenoids.In contrast to singlet ± singlet energy transfer, triplet ± triplet transfer is forbidden as regards the dipole ± dipole mechanism and occurs exclusively in the presence of electron-exchange interactions, which demand orbital overlap of the donor and the acceptor. The triplet ± triplet energy transfer in porphyrin ± carotenoid dyads can be studied by monitoring the quenching of transient absorption of the triplet state of porphyrin around*440 nm and the concomitant increase in the carotenoid triplet absorption at *550 nm. The triplet ± triplet energy transfer in the isomeric dyads 86c,d in which the carotenoid is linked to porphyrin through the para- and meta-position of the meso-aryl group, respectively, was studied in order to determine structural and photophysical parameters of effective photoprotection.In these systems, elec- tron-exchange interactions are mediated by p-electrons of the amide bonds. The rate constants for the triplet energy transfer in compounds 86d and 86c determined by laser-flash spectroscopy for solutions of these compounds in toluene were equal to 26107 and 16108 s71, respectively. The calculated yield of the singlet oxygen generated by the triplet state of porphyrin in the meta- linked dyad 86d was 30%; singlet oxygen was not formed in the case of the para-isomer 86c. These findings suggest that in the former case the carotenoid fails to entrap the bulk of the singlet oxygen sensitised by the attached porphyrin.As a result, singlet oxygen avoids direct contacts with the quencher even if the former is localised in immediate proximity to the latter. It thus follows that the triplet energy transfer from porphyrin to the carotenoid should proceed at a very fast rate in order to suppress completely the formation of singlet oxygen. Thus the triplet of the special pair of bacteriochlorophyll in the reaction centres of Rhodobacter sphaeroides is quenched by the energy transfer to the carotenoid with the rate constant k>108 s71. In the absence of conjugation between the chromophores, rapid triplet transfer takes place in a molecule with a folded conformation in which all the p-electron systems are in close contact with one another.Fast triplet ± triplet energy transfer was N V Konovalova, R P Evstigneeva, V N Luzgina observed in the porphyrin ± carotenoid system 86b characterised by good spatial orbital overlap of the two chromophores.2, 85 The energy transfer from the triplet excited state of pyropheo- phorbide (Ppd) to the attached carotenoid was observed in model compounds 91a,b and 94a,b. It was found that the rates of energy transfer in these systems did not depend on the type of the carotenoid, but were determined by the flexibility of the bond linking the chromophores. In this case, `through-bond' electron- exchange interactions are weak due to the presence of saturated carbon atoms between the p-systems of the chromophores and the orbital overlap required for such triplet transfer should be effected `through-space'. However, according to 1H NMR data the extended conformations of these dyads are the most stable where the carotenoids are spatially separated from pyropheophorbide.Folded conformations may appear exclusively in the case of intramolecular mobility of chromophores in solution. The molec- ular structures 91a,b are little flexible. To some extent, this restricts their intramolecular movement, which would bring the p-systems of the two chromophores into close contact. Corre- spondingly, the rates of the triplet ± triplet energy transfer in these compounds are lower than those in the more flexible molecules 94a,b.89 The triplet ± triplet energy transfer mediated by intramolecu- lar movements was also observed in the porphyrin ± carotenoid dyad 86f containing flexible polymethylene spacer between the chromophores.2 This dynamic process is similar to that observed between non-bound donors and acceptors upon collision in solution.Fast quenching of the triplet state of the special pair in Rhodobacter sphaeroides is a two-step process, which includes a triplet energy transfer from the bacteriochlorophylls of the special pair to the auxiliary bacteriochlorophyll with its subsequent transport to the carotenoid.84 The photochemical properties of the molecular triads 98a,b and 99, which consist of a carotenoid covalently linked to porphyrin, which, in turn, is linked to a pyropheophorbide derivative (Car ± P ± Ppd) in the system 98 and the fullerene (Car ± P ±C60) in the system 99, were studied in order to elucidate the structural and dynamic parameters of multistep triplet energy transfer.94, 95 The excitation of porphyrin or pyropheophorbide in com- pound 98a dissolved in acetone results in the population of the first excited singlet state of pyropheophorbide, which accepts singlet energy from the excited porphyrin with*100% efficiency (Fig.6). Subsequent intersystem transition gives rise to the triplet state of pyropheophorbide (the quantum yield is *1), which sensitises the formation of singlet oxygen in air (k& 2.56109 s71). The quantum yield of the singlet oxygen in the triad 98a (F=36%) is much lower than that for the free pyropheophorbide (F =80%), which reflects competitive quenching of the triplet state of pyropheophorbide in the triad by intramolecular energy E /eV Car ± 1P ± Ppd 2.0 k2 Car ± P ± 1Ppd k3 Car ± 3P ± Ppd Car ± P ± 3Ppd k6 k8 k7 1 k4 k1 O2 1.0 3Car ± P ± Ppdk5 k9 Car ± P ± Ppd 0 Figure 6.A scheme of energy transfer in the triad Car ± P ± Ppd.94Synthetic molecular systems based on porphyrins as models for the study of energy transfer in photosynthesis O N N M XC NH N N M=2H(a), Zn (b); R=CO2Me; * X= 2 N NH HN N 99 O C * R1 R1= NH 2 * N . R2=Me transfer with the formation of a carotenoid triplet state. The rate constant for this triplet transfer, k6, is equal to 2.96106 s71. The linear structure of the triad prevents the appearance of conforma- tions where orbital interactions of the carotenoid with pyropheo- phorbide required for the triplet ± triplet energy transfer are possible.It was suggested 94 that intramolecular triplet energy transfer in compound 98a is a two-step process. Its first step consists in the energy transfer from the triplet state of pyropheo- phorbide (*1.33 eV) to the attached porphyrin, while the second step includes fast quenching of the porphyrin triplet state formed (1.44 eV) by the carotenoid (k8>108 s71) (see Fig. 6). The rate of the overall process is determined by the endoergic step of the triplet energy transfer from pyropheophorbide to porphyrin. The temperature dependence of the formation of the carote- noid triplet state was studied in order to gain an insight into the two-step mechanism of triplet energy transfer.No triplet absorp- tion of the carotenoid was observed upon excitation of cooled (to 77 K) solution of compound 98a in butyronitrile, which points to the lack of the energy transfer. Consequently, this process requires sufficient activation energy for its realisation, which correlates with the putative two-step mechanism of the triplet energy transfer with the first endoergic step. The height of the potential barrier in such endoergic transfer can be varied by chemical modification of the system. The presence of a zinc atom in the porphyrin macrocycle of the triad 98b increases the triplet state energy of porphyrin from 1.44 to 1.59 eV with a concomitant increase in the activation energy by 0.15 eV.In this case, the transfer of triplet energy is too slow to compete with sensitisation of singlet oxygen. As a result, the O N HN O N NH R HN C 98a,b. 2 R2 , 2 967 carotenoid loses its ability to afford photoprotection by quench- ing the triplet state of pyropheophorbide.85, 94 The quantum yield of singlet oxygen in the triad 98b is commensurate with that obtained for the corresponding pyro- pheophorbide ± porphyrin dyad. Consequently, in the absence of energy transfer the proximity of the carotenoid to the site of singlet oxygen generation does not provide effective photoprotec- tion. This clearly demonstrates that rapid quenching of the triplet state of the sensitiser is a much more efficient means of photo- protection than deactivation of singlet oxygen that has already formed.94 The triplet excitation energy in the fullerene-containing triad 99 is transferred from the fullerene component (Car ± P ± 3C60) to the carotenoid polyene resulting in the generation of state 3Car±P±C60.As in the previous case, the activation energy Ea=0.17 eV is necessary for the energy transfer, which is consistent with the two-step mechanism where the energy migrates from the excited triplet state of fullerene to porphyrin with the formation of Car ± 3P±C60 in a slow thermally activated step, fast transfer of energy from the porphyrin triplet to the carotenoid culminates in the generation of the terminal state.95 Thus, there are several strict structural and energetic limita- tions for the stepwise triplet energy transfer, viz., electronic interactions between the donor chromophore, the intermediate porphyrin and the carotenoid should be sufficiently strong; in addition, the thermodynamic barrier to migration of the triplet energy should not be too high.In contrast to the triplet state of chlorophyll, the excited triplet state of the carotenoid does not sensitise singlet oxygen, which is a prerequisite for photoprotection. Thermodynamic analysis of this process suggests that the energy of the lower triplet state of a potential sensitiser should exceed that of the singlet oxygen (0.98 eV) for the latter could be formed.The published data on the energy of the triplet states of carotenoids are very scarce, which can be attributed to the difficulties in the detection of phosphor- escence of the carotenoid chromophore. Moore et al.85 have carried out a series of photoacoustic laser- flash experiments using the dyad 86c as an example and calculated the energy of the lowest triplet state of the carotenoid by measur- ing heat energy released upon relaxation of 3Car ± P into the ground state in solution. The triplet energy of the carotenoid determined in this way (0.640.04 eV) is much lower than that of chlorophyll (*1.3 eV) and bacteriochlorophyll (*1 eV) in pho- tosynthetic reaction centres. This allows directed transfer of triplet energy to the carotenoid trap, which makes the transfer fast and irreversible.Low triplet energy of carotenoids also explains the lack of sensitisation of singlet oxygen by the triplet state of the carotenoids needed for effective functioning of natural photo- protective systems. V. Conclusion The porphyrin-containing ensembles described in this review are convenient models for the study of photoinduced energy transfer. These data suggest that optimisation of efficiency of electronic interactions between pigments and the rates of energy transfer in these models should take into account structural characteristics altogether, such as mode and the character of substitution in macrocycles, the type of coordination metal ions, the nature and binding site of the linker, etc.By varying these features, it is possible to gain control over electronic and steric factors, which determine various parameters of photodynamic processes and to obtain compounds with predetermined spectral characteristics and energy levels of excited states of pigments. The data on the structure of natural light-harvesting antenna complexes combined with fundamental energy transfer theories provide a basis for the construction and fine tuning of model molecular photosynthetic systems.2, 29, 35 The use of the multistep energy transfer strategy is an efficient approach to the reproduction of natural photosynthetic processes.968 The development of novel methods for the synthesis of covalently linked ensembles 27 and the principles of non-covalent self-assem- bly of pigments 17 has made possible the synthesis of a great variety of multicomponent structures.Preliminary reliable esti- mation of expected photochemical properties of each target structure allows the design of highly efficient model photosyn- thetic systems.79 The synthesis of multicomponent clusters with several isolated sets of donors which provide independent routes of energy trans- fer to the terminal acceptor is a promising approach to the modelling of energy transfer. Such systems possess the most efficient light-harvesting properties, although their application is limited for steric reasons. Yet another promising strategy consists in incorporation of several types of donor pigments into a single ensemble, which may lead to directed energy transfer and a sharp increase in the quantum efficiency of energy migration.The construction of such cascade ensembles has become possible owing to fine tuning of energy levels of excited states of pigments. For example, cascade ensembles may include linear compositions of porphyrin, chlorin and bacteriochlorin pigments; their longest wavelength absorption bands are shifted from 646 to 740 nm.79 Synthetic light-harvesting complexes reproduce only some of the structural and functional characteristics of natural objects, which opens up new possibilities for their investigation. Further approximation of artificial photosynthetic schemes to biological transmembrane energy-transducing processes is aimed at reaching a definite level of supramolecular organisation of cofactors, which is controlled by polypeptide subunits of natural photosystems.Elucidation of factors providing effective control over the rates and mechanisms of biological energy transfer occurring in the protein matrix still continues to be a central problem. Only a few synthetic models containing peptide-linked chromophores have been designed so far in order to elucidate the effects of protein components on interpigment interactions and regularities of energy transfer processes.67, 78 However, the usefulness of this approach demands further investigations. And, finally, it seems very tempting to use multiporphyrin ensembles in non-biological objects, such as molecular photonic and optoelectronic devices.The feasibility of incorporation of such systems into highly ordered structures, e.g., liposomes, micelles, polymers and monolayers deposited onto conducting supports, significantly increases the efficiency of molecular devi- ces due to limited intramolecular migrations of pigments. Multi- component ensembles able to function as molecular photonic wires and optoelectronic switches have already been devised.10, 96 Hence, the basic principles of photosynthesis can successfully be employed in the design of synthetic molecular devices. Their versatility and main characteristics are comparable to, and some- times surpass, those of the natural systems. This review has been written with financial support of the Russian Foundation for Basic Research (Project Nos 01-03-06155 and 00-15-97866).References 1. M R Wasielewski Chem. 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N Solladie, A Hamel, M Gross Tetrahedron Lett. 41 6075 (2000) 79. P G van Patten, A P Shreve, J S Lindsey, R J Donohoe J. Phys. Chem. B 102 4209 () 80. R J Cogdell, T Gillbro, P O Andersson, R S H Liu, A E Asato Pure Appl. Chem. 66 1041 (1994) 81. H A Frank, R J Cogdell Photochem. Photobiol. 63 257 (1996) 82. Y Koyama, M Kuki, P O Andersson, T Gillbro Photochem. Photobiol. 63 243 (1996) 83. B Demmig-Adams Biochim. Biophys. Acta 1020 1 (1990) 84. A Angerhofer, F Bornhauser, V Aust, G Hartwich, H Scheer Biochim. Biophys. Acta 1365 404 (1998) 85. T A Moore, D Gust, A L Moore Pure Appl. Chem. 66 1033 (1994) 86. G Dirks, A L Moore, T A Moore,D Gust Photochem. Photobiol. 32 277 (1980) 87. A L Moore, G Dirks, D Gust, T A Moore Photochem. Photobiol. 32 691 (1980) 88. A Osuka, H Yamada, K Maruyama, N Mataga, T Asahi, M Ohkouchi, T Okada, I Yamazaki, Y Nishimura J. Am. Chem. Soc. 115 9439 (1993) 89. A Osuka, S Shinoda, S Marumo, H Yamada, T Katoh, I Yamazaki, Y Nishimura, Y Tanaka, S Taniguchi, T Okada, K Nozaki, T Ohno Bull. Chem. Soc. Jpn. 68 3255 (1995) 90. S Shinoda, A Osuka, Y Nishimura, I Yamazaki Chem. Lett. 1139 (1995)

ISSN:0036-021X    

出版商:RSC    

年代:2001

数据来源: RSC

摘要:

Russian Chemical Reviews 70 (11) 971 ± 990 (2001) Silica gel in organic synthesis A K Banerjee,M S Laya Mimo',W J Vera Vegas Contents I. Introduction II. Cyclisation reactions III. Rearrangements IV. Reduction V. Oxidation VI. Condensations VII. Formylation VIII. Hydration and dehydration reactions IX. Protection of functional groups X. Deprotection of functional groups XI. Miscellaneous reactions Abstract. are synthesis organic in gel silica of use the on data The The data on the use of silica gel in organic synthesis are presented. intra- (both cyclisation of features specific Some presented. Some specific features of cyclisation (both intra- and and intermolecular) reduction, rearrangements, reactions, intermolecular) reactions, rearrangements, reduction, oxidation, oxidation, condensation, dehydration, and hydration formylation, condensation, formylation, hydration and dehydration, protec- protec- tion are gel, silica of presence the in functional of tion of functional groups, groups, etc., ., in the presence of silica gel, are discussed. references 96 includes bibliography The discussed.The bibliography includes 96 references. I. Introduction Silica gel represents a uniform, non-deformable, three-dimen- sional network consisting of densely packed colloidal silicon oxide particles.1 It contains substantial amounts of water which is retained tenaciously in the gel network even after drying, which points to the presence of hydrates or silicic acids. Owing to its highly developed surface (5 ± 800 m2 g71) and high porosity, silica gel is generally used as a sorbent for dehydration of gases and fluids, chromatographic separation of organic compounds, as a catalyst support, an enhancer of thixo- tropic properties of fluids, etc.Various chemical applications of silica gel have been described in the monograph of Vail.2 In addition, silica gel plays an important role in fine organic synthesis. Chemical reactions catalysed by silica gel usually proceed under mild conditions and with high chemo-, regio- and stereoselectivities and involve operationally more simple proce- dures for the isolation of final products in comparison with the corresponding homogeneous reactions. A vast number of papers published over the past 20 years have been devoted to the use of silica gel in organic synthesis (see, e.g., Ref. 3), and their number is steadily increasing.This review is an A K Banerjee,M S Laya Mimo',W J Vera Vegas Centre of Chemistry, Venezuelan Scientific Research Institute, 1020-A Caracas, Apartado 21827, Venezuela. Fax (58-212) 504 13 50. Tel. (58-212) 504 13 24. E-mail: abanerje@quimica.ivic.ve (A K Banerjee) Tel. (58-212) 504 13 29. E-mail: mlaya@quimica.ivic.ve (M S Laya Mimo') Tel. (58-212) 504 13 85. E-mail: wvera@quimica.ivic.ve (W J Vera Vegas) Received 23 November 2000 Uspekhi Khimii 70 (11) 1094 ± 1115 (2001); translated by R L Birnova #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n11ABEH000642 971 971 978 979 980 981 981 982 984 986 986 attempt to generalise the published data.The overwhelming majority of studies in this area were aimed at obtaining maximum yields of target products rather than at elucidating mechanisms underlying catalytic (or any other) effects of silica gel in these reactions. Although this review does not give an exhaustive account of reactions on silica gel, it sheds more light on its usefulness for organic synthesis. II. Cyclisation reactions Most of the studies published over the past 20 years and devoted to various applications of silica gel in organic synthesis provide a description of various cyclisation reactions. This can be explained by the fact that these reactions have found wide application in the synthesis of diverse physiologically active compounds, particu- larly, of alkaloids.1. Intramolecular cyclisation reactions A simple procedure for the synthesis of isoquinoline and naph- thalene fragments of an unusual alkaloid, viz., ancistrocladein (1), has been proposed by Bringmann.4 OMe OMe Me Me HO N Me MeO 1 This synthesis employed the indan derivatives 2 and 3 as the starting compounds. They were converted into the corresponding polyketones 4 and 5 by mild ozonolysis (in the absence of oxygen) followed by cyclisation into the phenolic derivatives 6 and 7 in the presence of silica gel.{ { The possibility of cyclisation of polyketone 4 under the action of bases was postulated long ago by Birch et al.,5 however, the reaction products have not been studied.972 The conversion of phenol 6 into the isoquinoline derivative 8 was carried out by consecutive methylation by dimethyl sulfate and cyclisation by concentrated ammonia in methanol.Selective removal of the 2-hydroxyethyl group afforded 6-hydroxy-8- methoxy-3-methylisoquinoline (9). In turn, treatment of the phenol 7 with a base resulted in 1,8-dihydroxy-3-methylnaphtha- lene (10);{ its methylation by dimethyl sulfate gave the dimethoxy derivative 11. Further reaction of isoquinoline 9 with naphthalene 11 resulted in ancistrocladein 1. Me Me O O SiO2 O3 778 8C Et2O, 25 8C O O O Me OO 2 Me O 4 (82%) 1) Me2SO4, K2CO3, Me2CO, 25 8C Me O 2) conc. NH3, MeOH, 25 8C O O HO OH Me 6 (58%) Me HO Me O KH, THF N N 25 8C HO Me OMe8 OMe Me 9 O O Me MeO O3 SiO2 MeMe 778 8C Et2O, 25 8C H Me MeO O O 3 5 (89%) OH OH O OH KOH,MeOH, Me2SO4 MeMe 25 8C Me O 10 7 OMe OMe Me 11 The use of silica gel in the synthesis of the sesquiterpene pallescensin A (12) has been described.6 Trimethylcyclohexanone 13 and furylacetylenide 14 were used as the starting compounds.The addition of acetylenide 14 to cyclohexanone 13 and subse- quent dehydration of the reaction product followed by hydro- genation over Lindlar's catalyst yield the derivative 15; its cyclisation on silica gel affords the trans-fused tricyclic product 16. Selective hydrogenation and desilylation of the product 16 yield pallescensin A (12).It is of note that hydrogenation is accompanied by partial reduction of the furan ring. C CLi Me Me3Si + O O Me Me 13 14 { The derivative 10, which is extremely sensitive to oxidation, was found in the berries Diospyros mollis possessing anti-helminthic activity. A K Banerjee, M S Laya Mimo',W J Vera Vegas SiMe3 Me BF3 . Et2O C6H6, D, 12 h O Me MeOH SiMe3 Me H2/Pd, BaSO4 O EtOAc Me Me O Me SiO2 C6H6, 200 8C SiMe3 Me Me 15 O O 1) Pt, EtOH Me Me SiMe3 2) Bu4NF, THF 16 H Me Me H Me Me 12 In this reaction, silica gel not only facilitated the cyclisation of the furyl derivative 15 but also ensured control over the stereo- chemistry of ring fusion, which made this procedure attractive on the whole.The synthesis of five-membered lactams 17a ± c by photo- cyclisation of N,N-dibenzyl-2-benzoylcarboxamides 18a ± c adsorbed on silica gel has been reported.7 O R1 OH O CH2Ph Ph R2 hn N Ph SiO2 Ph O R1 R2 N CH2Ph CH2Ph 18a ± c 17a ± c Yield of 17 (%) R2 Compound R1 SiO2 C6H6 abc 83 91 63 80 90 65 HHMe HMe Me It is suggested that this reaction, similar to that performed in solution,8 occurs as an intramolecular 1,3-hydrogen shift towards the carbonyl oxygen atom. The rate of consumption of the starting b-oxo amides 18a ± c depends on their surface densities, i.e., the amount of b-oxo amide adsorbed per g of silica gel. If solid b-oxo amides are irradiated in the absence of silica gel, the yields of lactams are low.The use of silica gel as adsorbent in photoconversions of b-oxo amides is very effective, since it ensures uniform distribution of the latter over the whole surface of silica gel. The yields of lactams 17a ± c obtained by photocyclisation on silica gel are comparable to those obtained in solutions.9 Reductive cyclisation on silica gel of a series of 2-nitro-b- piperidinostyrenes 19a ± g prepared } by condensation of substi- tuted 2-nitrotoluenes 20a ± g with tripiperidinomethane has been described.10 In this study, the Fe ±AcOH system was used as the reducing agent and toluene as the solvent. The yields of the reaction products, viz., indoles 21a ± g, were 62%± 94%. } This procedure for indole synthesis is a modification of the Leimguber ± Batcho method,11 which includes aminovinylation of 2-nitrotoluenes followed by reductive cyclisation of trans-b-dialkylamino-2-nitrostyrenes formed.Silica gel in organic synthesis R1 Me R2 +HC N R3 NO2 20a ± g R1 R2 R3 NO2 19a ± gR1 R2 R3 21a ± g Compound R1 R2 abcdefg H H H 82 F H H 87 H H 90 OMe H 94 OCH2Ph H 85 H H 81 H OCH2Ph In the absence of silica gel, the yields of indoles are much lower, which can be ascribed to intramolecular reactions involving b-dialkylamino-2-nitrostyrenes.12 This approach was successfully employed in the synthesis of 5,6-bis(benzyloxy)-4-fluoro-, 5,6-bis(benzyloxy)-7-fluoro- and 4,7-difluoro-5,6-diphenylmethylenedioxyindoles (yields 61%, 53% and 53%, respectively); these products are intermediates in the synthesis of halogeno-substituted analogues of pharmaceuti- cally useful neurotoxins, viz., 5,6- and 5,7-dihydroxytryptamines.If TiCl3 ±AcONH4 and Ni-Raney ±N2H4 are used as reducing agents in the condensation, the yields of indoles are much lower. Thus the yields of 5,6-bis(benzyloxy)-7-fluoroindole were as low as 19% and 23%, respectively, apparently due to side reactions,13 whereas these undesirable intramolecular reactions are suppressed in the processes carried out in non-polar solvents (e.g., toluene) in the presence of silica gel. It is noteworthy that the use of silica gel together with toluene increases sharply the yields of indoles in reductive cyclisation with Fe ± AcOH.Thus the yield of indole 21a was 82%, while that obtained with the Fe ±AcOHsystem in ethanol was as low as 17%. The system mentioned (iron+acetic acid, toluene and SiO2) was used by Corey et al.14 in the synthesis of a substituted tryptamine, a starting compound in the synthesis of the indole alkaloid aspidophytin 22. NO MeO N H 22 OMe Me Dinitrostyrene 24 was used as the starting compound in the synthesis of tryptamine 23. NO2a, b MeO NO2 OMe 24 3 N Fe7HOAc, SiO2 PhMe, boiling, 1 h NH Yield of 21 (%) R3 Cl HHOMe OCH2Ph 62 O c, d N MeO Me OMe MeO (a) Fe ± HOAc, SiO2, MePh, D; (b) MeI, KOH, Bu4NI, THF, 23 8C; (c) POCl3, DMF, 35 8C, 1 h, NaOH(aqueous), D; (d ) MeNO2, NH2OAc, D, 1 h; (e) LiAlH4, THF, D, 1 h.The use of silica gel for cyclisation of several ketene acetals resulting in polyfunctional bicyclo[2.2.2]octanones has been described.15 Ketene mixed acetals 25a ± c were prepared from 3-methoxy- cyclohex-2-enone (26a) and its 6-methyl- (26b) and 2,6-dimethyl derivatives (26c). To this end, cyclohexenones following treatment with lithium diisopropylamide (LDA) at low temperature reacted with methyl acrylate with subsequent silylation. In this case, the reaction of cyclohexenones with methyl acrylate was stopped in the step of formation of mixed ketene acetals 25a ± c; no twofold Michael addition products were detected. The cyclisation of acetals 25a ± c was carried out in two ways, viz., by passage through a short column packed with silica gel and by treatment with titanium tetrachloride at low temperature.In the former case, the reaction is stereoselective and the yields of the corresponding bicyclo[2.2.2]octanones 27a ± c exceed 98%. The yields of reaction products prepared by an alternative route are much lower. R2 MeO Compound abc Bicyclooctanones 27 present certain interest as precursors of cyclic products having several asymmetric centres. To this goal, compounds 27 are converted into lactones 28 by regioselective Baeyer ± Villiger oxidation. Opening of the lactone ring affords the cyclic products 29, which contain three asymmetric centres with defined configurations. MCPBA 27 CH2Cl2 NO2e N MeO Me OMe 1) LiNPri2,778 8C O CO2Me R1 2) 3) Me3SiCl 26a ± c O OSiMe3 R1 R2 OMe MeO 25a ± c OR1 R2 CO2Me MeO H 27a ± c R2 R1 Yield of 27 (%) SiO2 >98 >98 >98 HHMe HMe Me O O R1 R2 MeO7 CO2Me MeO H 28 973 NH2 NMe OMe 23 SiO2, 20 8C or TiCl4,778 8C TiCl4 72 83 54 HO R1 CO2Me R2 H OMe OMe O 29974 Later, Schinzer and Kalesse 16 used this method to obtain other bicyclo[2.2.2]octanone derivatives.3-Vinyl- and 3-(N- methyl-N-tosylamino)-substituted cyclohex-2-enones were used as the starting compounds. It was found that the former derivative reacts with methyl acrylate similarly to the 3-methoxy derivative, viz., first, the corresponding ketene acetal is formed, which is then cyclised on silica gel into the final vinyl-substituted bicy- clo[2.2.2]octanone. On the other hand, the amino derivative affords directly bicyclooctanone at778 8C as a result of twofold Michael addition.Acid-catalysed cyclisation of unsaturated carbonyl com- pounds in the presence of Lewis acids has been studied in sufficiently great detail (see, e.g., the review 17 and references cited therein). This approach is very attractive in the generation of a new C7C bond. However, the use of ordinary Lewis acids does not always ensure high selectivity, the reactions are accom- panied by the formation of side products. The use of silica gel as a catalyst for this reaction has been recommended by Marshall et al.18 Thus, silica gel catalyses efficiently the cyclisation of unsatu- rated aldehydes 30.19, 20 R1 R2 H R1 R2 H R3 CHO SiO2 R4 CH2 H H CH2 30a,b Me R3=H,R4=OH (from 30a), R3=OH, R4=H (from 30b).30a: R1=Me, R2=H, 30b: R1=H, R2=Me, The results of studies 21 of different reagents absorbed on silica gel provide convincing evidence that silica gel always contains some amount of bound water molecules, particularly as silicic acid. It is known that high pressure increases the pKa of acids. Although we still have no direct proof of the effect of high pressure on the acidity of silica gel, it can be assumed, with a high degree of certainty, that the acidity of silica gel will increase with pressure. According to Dauben and Hendricks,22 oven-dried silica gel efficiently catalyses the cyclisation of various unsaturated car- bonyl compounds.Acid-catalysed cyclisation on silica gel as a mild acid catalyst under a pressure of 15 kbar was used in the synthesis of six- and five-membered carbocycles.Me Me Me SiO2, CH2Cl2 + R4 R3 R1 R3 R4 Me R2 R2 R2 CH2 CH2 33a ± d 32a ± d 31a ± d Yield (%) R4 R3 R2 R1 Com- pound 33 32 H 585 46 HHMe CHO CHO COMe 15 20 20 H 66 7 Me OH OH Me OH CH=C(CO2Me)2 Me CH(CO2Me)2 abcd The cyclisation of unsaturated carbonyl compounds 31a ± d yields the six-membered stereoisomeric cyclic products 32a ± d and 33a ± d. The yields of the carbocyclic products from compounds 31a, 31c and 31d on silica gel at 15 kbar are comparable to those obtained previously with Me2AlCl 23 and ZnBr2.24, 25 In the case of the aldehyde 31b, the yields of the cyclisation products 32b and 33b are low (5% and 20%, respectively), whereas the yield of the product 32b prepared with Me2AlCl is 90%.Under normal A K Banerjee, M S Laya Mimo',W J Vera Vegas pressure, compound 31c is not cyclised on silica gel; compound 31a is cyclised but the yields of the reaction products are <10% after 7-day exposure on silica gel. No cyclisation of compounds 31a and 31d takes place at 15 kbar in the absence of silica gel. The unsaturated aldehyde 34 undergoes cyclisation on silica gel at 15 kbar to yield a mixture of five-membered cyclic products 35 ± 37. The methyl ketone homologue of the aldehyde 34 is not cyclised under these conditions. Me Me H Me Me H H OH H OH CHO + + OH H H CH2 CH2 CH2 Me Me Me 37 (38%) Me36 (26%) Me 35 (14%) 34 The unsaturated ester 38 yields the cyclic derivatives 39 and 40 under identical conditions.MeCH C(CO2Me)2 Me Me 38 H Me Me H H CH(CO2Me)2 + H CH(CO2Me)2 CH2 CH2 Me Me 40 (8%) 39 (75%) The use of silica gel in combination with a pressure of 15 kbar was also found to be helpful in the cyclisation of the labile vinylcyclopropane-containing aldehyde 41 into compounds 42 and 43. An attempt to cyclise compound 41 under the action of zinc bromide failed, the products 42 and 43 were detected but in trace amounts. Me Me Me Me Me Me OH OH + CHO Me Me Me H H Me Me Me Me CH2 CH2 43 41 42 It was shown 22 that the yields and selectivities in ene-type cyclisations on silica gel at 15 kbar are comparable to those obtained by other methods (see, e.g., Refs 26 and 27).The conditions mentioned proved to be of choice in certain cases, as in the cyclisation of the aldehyde 41. Treatment of g-halogeno-substituted esters 44a,b and their vinylogues 45 and 46 with silica gel in xylene results in high yields of g-butyrolactones 47a,b, 48 and 49, respectively.28 R R O Br CO2Et 44a,b O 47a: R =H (66%), 47b: R=n-C6H13 (79%). CO2Et O O Cl3C CO2Et EtO2C Cl Cl 45 48 (63%)Silica gel in organic synthesis CO2Et Cl3C CO2Et Me 46 The silica gel used in this reaction was dried for 3 h at 200 ± 250 8C and 20 Torr.The reactions were performed by heating the substrates with silica gel in xylene for 3 ± 15 h. The efficacy of silica gel was demonstrated in the conversion of ethyl 4-bromobutyrate (44a) as an example. Boiling of com- pound 44a in xylene in the presence of SiO2 results in g-butyro- lactone 47a in 66% yield, whereas heating of the haloester in xylene in the absence of silica gel affords no lactonisation product. Acid-catalysed lactonisation of g-halogeno-substituted car- boxylic acids is one of the most attractive methods for the synthesis of g-butyrolactones. However, this is inapplicable to substrates containing easily hydrolysable functional groups. The use of silica gel not only lifts these restrictions, but also increases the yields of the target products.Previous reports describe moderate yields of g-butyrolactones prepared upon heating of g-halogeno esters in the absence of solvents. It is of note that the conditions for this reaction (170 ± 180 8C) are more drastic than those used for the lactonisation on silica gel. This method was also used in the synthesis of bis-g-butyro- lactones. Thus the triester 50 and the diester 51 are converted into dilactones 52 and 53 in high yields by treatment with silica gel. Me Cl CO2Et Me CO2Et O CO2Et O50MeO2C MeO2C O Me O I 51 Me . . . Compound 53 is the key intermediate in the synthesis of (+)- canadensolide (54), a metabolite isolated from Penicillium cana- dense. Anovel method of the synthesis of g- (compounds 55a ± e) and d-lactones (compounds 56a ± e) by conversion of methyl 4-aryl-5- tosyloxyhexanoates 57a ± e in the presence of silica gel in hexane has been reported.29 Ar Me CO2Me OTs57a ± e CO2Et Me Cl2HC O O 49 (46%) O O Me MeH CO2Et O O 52 (70%) O O Me H CO2Me O O 53 (78%) O O H H O CH2 O 54 + R SiO2 C6H14 2 1 Me O OMe A O O + Me Ar 55a ± e Ar Compound abcde 4-MeOC6H4 2-MeOC6H4 3,4-(MeO)2C6H3 4-MeO-2-MeC6H3 2-MeO-4-MeC6H3 The structures of the resulting lactones were determined from spectroscopic data.In all cases studied, the yields of d-lactones exceeded those of g-lactones. The stereochemistry of d-lactones 56a ± e suggests that these compounds, like g-lactones 55a ± e, are formed via an intermediate phenonium ion (A), rather than by direct substitution of the tosyloxy group by the ester group.It was concluded that the regioselectivity of the lactonisation reaction, which proceeds via the intermediate phenonium ion (A), is controlled by electronic factors. It was also found that the lactonisation of compounds 57a ± e under conditions of thermodynamic control is selective and yields g-lactones 55a ± e, whereas that under conditions of kinetic control yields predominantly d-lactones 56a ± e. It should be noted that methyl 4-(4-methyl-2-methoxyphenyl)-5-tosyloxypentanoate (58) is converted exclusively into g-lactone 59 upon lactonisation on silica gel in hexane.Me OMe TsO O OMe 58 Me O 59 (86%) We believe that lactonisation on silica gel will find broad application in synthetic organic chemistry. A simple procedure for lactam synthesis, which includes cyclodehydration of the corresponding amino acids by treatment with silica gel in boiling toluene, has been described.30 H2N(CH2)nCOOH SiO2 PhMe n=3 (97%), 4 (99%), 5 (75%). The corresponding lactams are formed in very high yields. This reaction proceeds smoothly on alumina as well. 975 Ar Me O O 56a ± e 56 Yield (%) 55 42 67 36 30 11 347 7368 14 Me + OMe SiO2, C6H14 2 days O OMe OMeO HN (CH2)n CO976 An efficient procedure for the synthesis of nitrogen hetero- cycles, which includes cyclisation of N-(D4- or D5-alkenyl)carba- mates under the action of PhSeCl in the presence of silica gel, has been developed (Table 1).31 Presumably, this reaction proceeds in two steps, viz., initial rapid addition of PhSeCl in CH2Cl2 to the double bond of the urethane and subsequent cyclisation of the adduct formed on the surface of silica gel.The PhSe-groups were removed by treatment of the selenides with triphenyltin hydride in boiling toluene. It was noted that the ring closure occurs more easily in the presence of predried silica gel (Merck 60 PF-254) and the yield of the target products (the corresponding pyrrole and piperidine derivatives) is increased (Table 1). In the case of N-ethoxycar- bonyl-2-(3-methylbut-2-enyl)aniline both 5-exo- and 6-endo-cyc- lisation products were obtained.32 This method provides a reasonable alternative to Hg2+-in- duced cyclisation commonly used in the synthesis of nitrogen heterocycles and a good supplement to palladium-assisted cycli- sation, which affords products at a different level of hydrogena- tion.Table 1. Cyclisation of urethanes. Urethane NH COOEt NH COOEt MeMe NH COOEt NH COOEt NHCOOEt NHCOOEt DD NHCOOEt C11H23 NHCOOEt C10H21 Me NH COOEt Product Yield (%) in solution on SiO2 SePh 93 77 NCOOEt SePh 85 73 NCOOEt ± 76 N MeMe SePh COOEt SePh + Me Me NH H 82 59 N H SePh COOEtSePh 87 52 N COOEt H ± 94 N H H PhSe COOEt H D ± 83 D N H H PhSe COOEt ± 84 N C11H23 PhSe COOEt C10H21± 35 Me N CHSePh COOEt A K Banerjee, M S Laya Mimo',W J Vera Vegas 2. Intermolecular cycloaddition reactions The efficiency of silica gel in intermolecular cycloaddition reac- tions has been described in numerous papers (see, e.g., reviews 3, 21 and references cited therein).Here we shall consider only some of the most interesting studies devoted to [4+2]-cycloaddition reactions (the Diels ± Alder reaction). A new methodology for [4+2]-cycloaddition of dienes 60 to dienophiles 61 on the surface of chromatographic adsorbents (e.g., SiO2, MgO. SiO2, Al2 O3) under solvent-free conditions has been described.33, 34 R1 R3 R1 R3 SiO2 + R2 C(O)R5 R4 R2 R4 C(O)R5 61 60 62a ± i R5 R4 R3 R2 R1 Yield of 62 (%) Com- pound H Me Me HH Me H Me H Me Me H H H H Me 85 H H H H 67 H H H Me 72 H H H H 5692 89 83 H H H Me 73 H H H H 66 HHMe Me Me Me Me (CH2)2CH=CMe2 (CH2)2CH=CMe2 abcdefghi With SiO2, the yields of the [4+2]-adducts 62a ± i were 56%± 92%.Condensation of these compounds in the liquid phase in the absence of catalysts usually requires drastic condi- tions (120 ± 160 8C, 3 ± 6 h). If the reaction is carried out on SiO2 without solvents, the temperature can be decreased considerably (e.g., by 50 ± 100 8C). In some cases, the Diels ± Alder diene products are obtained in higher yields. Presumably, the role of silica gel is to ensure polyfunctional catalysis (due to multicentre adsorption), and the absence of a solvent favours formation of pre-reaction complexes due to weak van-der-Waals interactions of adsorbed substrates devoid of shielding solvation shells.If the reaction is carried out on the surface of SiO2 in the presence of solvents (e.g., C6H14, CH2 Cl2), the efficiency of cycloaddition decreases considerably, presumably due to partial desorption of the reactants from the surface of SiO2. It is suggested that the activity of silica gel depends critically on the water content. The highest yields were obtained with silica gel dried at 200 8C for 6 h in order to remove physically adsorbed water. Florisil (MgO . SiO2, Florisil) tested in this reaction appeared to be less efficient. With MgO.SiO2, the reaction temperature had to be increased by 20 ± 30 8C in order to make the yields of [4+2]-adducts comparable to those obtained with dried SiO2. The main advantage of this method is that cycloaddition reactions on silica gel in the absence of solvents are highly regio- and stereoselective, whereas reactions in liquid media yield mixtures of isomers. Thus the SiO2-catalysed addition of methyl vinyl ketone and acrolein to cyclopenta- and cyclohexadienes results in the predominant formation of the endo-isomers 63, whereas the liquid-phase reaction involving these substrates yields a mixture of isomers where the exo-isomer content is>20%. (CH2)n CH2 (CH2)n + CH C R C R O 63 O R=H, Me.The reaction of furan (64a) and silvane (64b) with methyl vinyl ketone occurs differently under these conditions. This reaction is fast, but yields exclusively addition products, viz., compounds 65Silica gel in organic synthesis and 66, respectively. This can be attributed to high lability of methyl vinyl ketone on such a sorbent as silica gel. At the same time, the use of florisil (MgO . SiO2) as a sorbent affords the expected [4+2]-cycloaddition products 67a,b. R=H CH2 CH + R SiO2 R=Me O C Me O 64a,b MgO. SiO2 R=H, Me. An illustrative example of the high efficiency of the dry- adsorption method is provided by the hetero-Diels ± Alder syn- thesis.35 It was found that the cycloaddition of alkoxyallenes 68 to a,b-enals and a,b-enones 69 results in the [4+2]-adducts 70.O R3 R1 R2 C + C R4 R5 CH2 69 68 R2 R1 Com- pound a H EtO b H EtO c H EtO def HMe3Si Me3Si EtO MeO MeO gh MeO MeO Me3Si H i H MeO j H MeO In addition to the dihydropyran derivatives 70, which repre- sent [4+2]-cycloaddition products, this reaction affords a small amount of [2+2]-cycloaddition by-products, viz., the cyclobutane derivatives 71. The highest yields of the [4+2]-cycloaddition products were obtained when dried silica gel deactivated with triethylamine (0.2% ± 0.5%) was used. It is of note that the acidity of ordinary silica gel is a factor which is responsible for the destruction and polymerisation of cycloaddition products.The use of more basic florisil as a medium for the hetero-Diels ± Alder reaction helps avoid undesired side reactions,34 but the reaction rate decreases. Alumina manifests no catalytic activity in this reaction. The 2-alkoxy-5-methylidene-3,4-dihydro-2H-pyrans 70 for- med are the starting products in the synthesis of valuable derivatives of glutaraldehyde. According to Posner et al.,36 preparative [4+2]-cycloaddition of commercial 3-methoxycarbonyl-2-pyrone (72) to vinyl ethers 73 and 74 is strongly accelerated under the action of silica gel (EM Science 60) at room temperature, resulting in endo-bicyclic prod- ucts (75 and 76) diastereoselectively and in extremely high yields. SiO2 O Me Me O O O 65 (43%) R=Bun (73, 75), PhCH2 (74, 76).Me Me O O 66 (76%) O C(O)Me The endo-adducts 77 (the diastereomer ratio is*4 : 1) are also formed upon cycloaddition of benzyl vinyl ether (74) to the enantiomerically pure (R)-methyl pyrone-3-carbonyl lactate 78. This reaction was carried out on dried (200 8C, 16 h) silica gel (Syloid 221) in toluene. R 67a,b O O O 78 R1 R2 R1 O R3 R2 + R4 CH2 R5 O R4 70a7j R3 No [4+2]-cycloaddition products are formed in the absence of silica gel. The above-described silica gel-catalysed cycloaddition reac- tions are operationally simple, stereoselective methods for the synthesis of bicyclic lactones and represent `atom-economical' procedures } in which all the atoms of both reactants are incorpo- rated into the final products.71a7j R5 R4 R3 Yield of 70+71 (%) H H H H H Me Despite the immense diversity of synthetic methods used to obtain nitrogenous heterocycles, the interest of investigators in simple and convenient procedures does not fade, since nitro- genous heterocycles are constituents of many physiologically active compounds. Recently, Ranu et al.37 have developed a simple and efficient method for quinoline synthesis from anilines and alkyl vinyl ketones by treatment with indium(III) chloride on silica gel under microwave irradiation without any solvent. H Me H R1 HHH HHMe HHHH Me H HH Com- pound H H Me 71 (with pre- dominance of 70) 68 (with pre- dominance of 70) 58 (with pre- dominance of 71) Me <5 47 (70)+26 (71) 47 (with pre- dominance of 70) 38 (70)+43 (71) 47 (with pre- dominance of 70) 65 (with pre- dominance of 70) 82 (1 : 1) H Me H abcdefghijklmno} This term was originally suggested by B Trost.977 COOMe COOMe O O OR R + O O 72 75 (98%), 76 (80%) 73, 74 O O C HMe COOMe CO O O HMe COOMe OCH2Ph + CH2Ph O 77 (60%) R4 R3 R4 R3 InCl3 / SiO2 R1 MW O R2 + NH2 R2 N 79a ± o R4 R3 R2 R1 Yield of 79 (%) Me Me Me Me Me Me Me Me Me Me Me HHHHHHHHHHH 2-Me 3-Me 4-Me 2-OMe 4-OMe 3-OH 3-Cl 4-Cl 4-Br 2-Me-4-I C4H4 3-Cl n 8581 84 85 80 83 81 87 80 80 83 82 81 83 55 H H H Me HHHHHHHHHHH H MeH p-MeOC6H4 Me H H Pr Et p-MeOC6H4 Me978 This method allows one to obtain quinolines 79a ± o in high yields irrespective of the nature of substituents in the anilines and alkyl vinyl ketones.This reaction includes the Michael addition of aniline to vinyl ketone followed by cyclisation and aromatisation catalysed by InCl3/SiO2. When InCl3 is used without silica gel, the reaction is sluggish, while imines are formed on silica gel in the absence of InCl3. The same authors have developed a convenient one-step method for the synthesis of polysubstituted pyrroles.38 It was found that the reaction of a,b-unsaturated carbonyl compounds with amines and nitroalkenes on the surface of silica gel (HF 254) under microwave irradiation without any solvent affords various polysubstituted pyrroles 80a ± p.R2 R3 O R1 Com- pound Ph Ph Ph HHPh Ph Ph abcdefghi O j O Prn Prn klmnop Ph H Ph H Ph H 7(CH2)47 Heating of mixtures of starting compounds in the absence of silica gel results in resinification. When this reaction is carried out in solution (e.g., boiling in THF), the yields of the reaction products decrease significantly, whereas the reaction time increases. In our opinion, the one-step syntheses of quinolines and pyrroles from readily available compounds developed by Ranu et al.37, 38 are among the best methods presently available.To obvious advantages of these methods one can relate simple procedures, high product yields, high reaction rates and the possibility to obtain a broad array of quinolines and pyrroles. A convenient procedure for the preparation of quinoxaline di- N-oxide derivatives 81a ± f from b-dicarbonyl compounds and benzofuroxan in methanol in the presence of silica gel has been proposed.39 O N O + N R2 R1 SiO2 R1+R4NH2+MeCH2NO2 MW Me R3 NR4 80a ± p Yield of 80 (%) R4 R3 R2 SiO2 THF, D 30 32 35 31 32 33 33 35 HPh Me Me Me HMe H PhCH2 PhCH2 PhCH2 PhCH2 cyclo-C6H11 C(Ph)HMe C(Ph)HMe Pri 60 65 64 60 60 62 66 64 HHHHHHHH i H Me Pr 36 68 40 72 Me H PhCH2 Et Et 28 35 31 40 32 40 HHHMe HMe PhCH2 cyclo-C6H11 Prn Bun Bun Bun 60 65 62 65 61 68 O O N O O R2 MeOH, SiO2 20 8C R2 R1 N R1 O 81a ± f R1 Com- pound OMe Me Ph Me Ph Me abcdef This reaction is carried out as follows.Benzofuroxan and the b-dicarbonyl compound are dissolved in methanol, the solution is mixed with silica gel and concentrated at 20 8C. The resulting mixture containing the adsorbed reagents is kept at room temper- ature for 1 ± 2 weeks without drying after which the correspond- ing quinoxaline di-N-oxide is isolated. The efficacy of this reaction strongly depends on the type of silica gel used. Convenient gels are Wako gel C-200 (Wako Pure Chemical Industries) and Silica gel 60 (Merck).It is assumed that the yields of the products 81a ± f correlate with the per cent content of the enol form of the carbonyl compound. When alumina (basic, neutral or acidic) was used instead of silica gel, the yields of quinoxaline di-N-oxides 81a ± f were much lower. In all cases studied, the main product appeared to be contaminated with side products. III. Rearrangements Many organic compounds undergo diverse molecular rearrange- ments under the action of acids and bases. The papers published before 1979 provide examples of interesting rearrangements of certain classes of organic compounds, such as aminopyrroli- dines,40 hydroxycyclopropanes,41 oxazolidines 42 and aldehydes, on silica gel.18 A great variety of interesting rearrangements induced by silica gel have been described in the review of McKillop and Young,21 therefore we shall omit them from consideration and shall confine ourselves to a few cases only.43 ± 45 Thus multiple passage of addition products of methyl-sub- stituted 1-acetoxybuta-1,3-dienes 82 ± 85 to chlorobenzoquinones 86 ± 89 through a column with silica gel leads to rearrangement and concomitant aromatisation leading to naphthoquinones 90 ± 96.43 R1 R2 +Cl R3 OAc 82 ± 85 R2 R3 Reaction Pro- duct 90 91 92 92 91 82+87 83+86 83+87 84+86 84+87 A K Banerjee, M S Laya Mimo',W J Vera Vegas R2 Yield of 81 (%) Enol content (%) OMe OMe OEt Me 0 16 63 58 66 88 012.6 27 84 90 ± 100 94 Ph Ph O O R1 H R4 R2 R4 SiO2 R5 R3 R5 Cl AcO O O 86 ± 89 O R1 R4(5) R5(4) O 90 ± 96 R5(4) R4(5) Yield (%) R3 R2 R1 927965 88 80 H H H Cl H H H Me Cl H(Cl) H(Cl) Me (H) Cl (H) HMe H Me H HHHSilica gel in organic synthesis R5(4) R4(5) Yield (%) Reaction R3 R2 R1 Pro- duct 93 94 95 96 80 90 96 79 HCl H(OMe) Cl (H) OMe (H) HH Me H Me H Me H Me H HH 85+86 85+87 84+88 84+89 This method is especially convenient for the synthesis of substituted naphthoquinones which represent fragments of many natural alkaloids.Yet another interesting rearrangement coupled with aromati- sation has recently been observed in studies of the conversion of ketone 97.44 This was first transformed into alkene 98 by the Wittig reaction and then into the target diol 99 by treatment with Woodward's reagent (MeCOOAg, I2, MeCOOH, H2O) followed by alkaline hydrolysis.An attempt to purify the diol 99 on a column with silica gel (Silica gel 60, Merck) gave unexpectedly tetralin 100 in 90% yield. Apparently, during its passage through the column diol 99 first undergoes dehydration and then rear- rangement. OH OH Me MeO MeCH2 CH2=PR3 SiO2 Me Me H Me Me H Me Me H 99 98 97 Me Me MeCH2 Me Me Me Me H 100 A simple procedure for flavanone synthesis from esters (the Fries rearrangement) has been proposed.45 This rearrangement is effected by microwave irradiation in the presence of the catalytic system AlCl3 ± ZnCl2 ± SiO2.O Ph O Ph O AlCl3 ± ZnCl2 ± SiO2 R R MW O IV. Reduction Reduction of nitrostyrenes 101a ± e to nitroethylbenzenes 102a ± e was carried out by treatment with sodium borohydride in chloro- form ± isopropyl alcohol in the presence of silica gel.46 NaBH4 R1C6H4CH2CHR2NO2 R1C6H4CH=CR2NO2 SiO2 102a ± e 101a ± e Yield of 102 (%) R1 R2 Compound H H 93 H Me 9399 92 92 2-Me 4-Me 3-Me abcde HHH The reduction results in highly polar negatively charged intermediates 103. In the absence of silica gel, such intermediates bind a proton or a second molecule of the original styrene 979 resulting in a mixture of products 102 and 104 in a nearly equal ratio.The formation of the dimer 104a in solution shown in the scheme below is an example. NaBH4 NO2 Ph 101a O7 O + + N N Ph Ph 7 O7 O7 103a NO2 Ph NO2 Ph 104a In the presence of silica gel, the intermediates 103 are formed most probably on the surface. In this case, the addition of the second styrene molecule is hindered, and the reaction yields nitroethylbenzenes 102 as the main products. The use of chloroform as a solvent in this reaction is more preferable than the use of dichloromethane, ether or benzene. The reason is that the dissolution of the intermediate in this solvent is minimal due to the low dielectric permeability of chloroform, whereas its high density favours uniform distribution of silica gel in the reaction mixture.For the same reasons, the use of isopropyl alcohol is more preferable than the use of methanol and ethanol, for it dissolves sodium borohydride to a lesser extent and, correspondingly, the formation of the dimeric side products 104 is less probable. The reduction of bicyclic diketones 105 and 106, tricyclic ketone 107 and several steroidal ketones (5a and 5b-androstane- 3,17-diones, methyl esters of di- and trioxocholanoic acids, etc.) by treatment with the BH3 .NMe3 complex has been described.47 It was shown that the reaction carried out in the presence of silica gel impregnated with FeCl3 .6H2O or ZnCl2 resulted in selective reduction of only one keto group.Thus diketones 105 and 106 are reduced to the corresponding hydroxy ketones 108 and 109 in good yields; this reaction does not require protection of the second carbonyl group. Me Me O O COOMe COOMe H H HO O 105 108 (74.8%) MeO MeO HO O H 109 (66.5%) H 106 Me Me Me HO O Me Me H Me Me H 107 (48.2%) The presence of a small amount of water (5%) in silica gel accelerates the reaction, apparently due to enhanced adsorption of the amine. Compounds containing several carbonyl groups can be regio- selectively adsorbed on silica gel. Thus IR-spectroscopic studies of 5a- and 5b-androstane-3,17-diones revealed that during adsorp- tion of these steroids on silica gel one of the carbonyl groups, viz., C(17)O, forms stronger hydrogen bonds with the OH groups980 present on the surface of silica gel in comparison with C(3)O.Thus, the former becomes protected from reduction with the BH3 .NMe3 complex. In the cases of all steroidal ketones studied, it was the carbonyl group at position 3 that underwent reduction preferentially to the carbonyl groups at positions 7, 12, 17 and 20. Three catalytic systems, viz., SiO2 . FeCl3 ± PhH, SiO2 ± ZnCl2 ± PhH and ZnCl2 ± PhH, were tested in the reduction of 5a- and 5b-androstane-3,17-diones with BH3 .NH3. All these reactions afforded mixtures of 3a- and 3b-hydroxy derivatives. The catalytic system SiO2 ± FeCl3 ± PhH proved to be the best as the reaction was complete within 2 h, whereas reduction in the presence of the other two systems required 18 ± 20 h.It should be noted also that in the absence of silica gel (the third catalytic system) the yields of steroid alcohols were very low. Ranu and Das 48 have proposed an excellent method for the synthesis of cyclic and acyclic allylic alcohols by reduction of the corresponding conjugated unsaturated ketones and aldehydes by zinc borohydride supported on silica gel. This reaction was carried out with unsaturated aldehydes (crotonic aldehyde, citral, etc.) and ketones (substituted 3-methylcyclohex-2-enones, a-ionone, pent-2-enone, etc.); in most cases, the yields of the corresponding allylic alcohols were quantitative. Thus the yields of alcohols in the reduction of substituted 3-methylcyclohex-2-enones exceeded 80%.OH O Zn(BH4)2, SiO2 THF,75 to710 8C, N2 Me Me R R R=H (80%), COOEt (82%), COOMe (85%). Zinc borohydride manifested high selectivity in hydrogena- tion, which affected exclusively carbonyl groups, but no double bonds. Later, Ranu et al.49 recommended this reagent for use in reductive amination of conjugated aldehydes and ketones in the presence of silica gel (substitution of the amino group for the carbonyl group is a very important process in organic synthesis). O R3NH2, SiO2 Zn(BH4)2 R1CH CHC NR3 R2 R1CH CHC DME R2 NHR3 R1CH CH CH R2 R1, R3=Alk, Ar; R2=H, Alk. Attempts to use other catalysts, e.g., BF3 . Et2O or ZnCl2, in this reaction were unsuccessful; good yields (75% ± 90%) of the corresponding imines were obtained only in the case when the reaction was carried out on silica gel.Among other recent studies devoted to hydrogenation of carbonyl compounds, special mention should be made of the one 50 where the reduction of ketones and aldehydes into the corresponding alcohols was effected with sodium borohydride in the presence of silica gel in an aprotic solvent (hexane). The main advantages of this reaction are easy availability, low cost of reagents and catalysts, mild reaction conditions, ease of isolation of final products and, which is even more important, high yields. V. Oxidation The use of inorganic oxidants in organic synthesis is often limited by their poor solubilities in low-polar media.One of the most popular oxidants is ozone. Dry ozonisation in the presence of silica gel for the insertion of oxygen atoms into non-activated C7H bonds has been described in sufficiently great detail by Basyuk;3 therefore, we shall not discuss this process in this chapter A K Banerjee, M S Laya Mimo',W J Vera Vegas and shall confine ourselves to the consideration of some other inorganic oxidants. 1. Oxidation of alcohols The use of bis(trimethylsilyl) chromate supported on silica gel for the oxidation of some alcohols to carbonyl compounds has been described.51 This reaction is initiated by microwave irradiation and takes place in the absence of solvents. (Me3Si)2CrO4 ± SiO2 RCHO RCH2OH MW R=p-MeC6H4 (98%), n-C7H15 (86%). Me Me (Me3Si)2CrO4 ± SiO2 MW O OH Me Me Me Me (84%)O OH (Me3Si)2CrO4 ± SiO2 MW Me Me n-C6H13 n-C6H13(89%) The reaction is complete within a short period of time.High yields of carbonyl compounds, simple methodology, easy isola- tion of reaction products and stability of the oxidant make this procedure especially attractive for synthetic chemists. Oxidation of alcohols in CH2Cl2 with bis(trimethylsilyl) chromate supported on silica gel had been described earlier.52 2. Oxidation of phenols Despite the great diversity of methods employed in quinone synthesis, studies in this field are currently under way, since many quinones possess biological activities and some of them are valuable semi-products in the synthesis of medicinal drugs. Recently, Hashemi and Bni 53 have proposed a very convenient, from our point of view, procedure for quinone synthesis which consists in oxidation of phenols with oxygen in the presence of a mixture of manganese and cobalt salts of 4-aminobenzoic acid supported on silica gel.OH O R2 R1 R2 R1 O R1=R2=H (64%); R1=Me, R2=H (53%); R1=R2=Me (57%) O OH (65%) O Benzene, toluene and ethylbenzene can be used as solvents in this reaction. 3. Oxidation of silyl ethers Bis(trimethylsilyl) chromate supported on silica gel was also used for the oxidation of trimethylsilyl ethers of primary and secondary alcohols.54 This reaction was run in dichloromethane. RCHO RCH2OSiMe3 (Me3Si)2CrO4 ± SiO2 CH2Cl2 R=Ph (95%), PhCH=CH (71%). Ph2CHOSiMe3 (Me3Si)2CrO4 ± SiO2 CH2Cl2 Ph2C O (92%)Silica gel in organic synthesis OSiMe3 Me (Me3Si)2CrO4 ± SiO2 CH2Cl2 It is worth noting that in addition to the expected cinnamic aldehyde, the oxidation of 3-phenylallyl silyl ether yielded an appreciable amount (28%) of benzaldehyde, which points to the vulnerability of the double bond under these conditions.Special mention should be made of the oxidation of trime- thylsilyl ethers by atmospheric oxygen which is catalysed by manganese and cobalt salts of 4-aminobenzoic acid supported on silica gel.55 This reagent is also effective in the transformation of acetals and ketals into the corresponding carbonyl compounds. 4. Oxidation of sulfides An effective procedure for the synthesis of sulfoxides by oxidation of sulfides in the absence of solvents has been developed.56 The oxidation is carried out with manganese dioxide in the presence of a catalytic system, H2SO4 ± SiO2.MnO2, H2SO4 ± SiO2 R1SR2 without solvent VI. Condensations Silica gel is an efficient catalyst for the Knoevenagel condensation. The condensation of peptidylacetonitriles derived from N-acetyl- L-phenylalanine, N-acetyl-L-leucyl-L-phenylalanine and N-ace- tyl-L-leucyl-D-phenylalanyl-L-phenylalanine with aromatic alde- hydes and ketones has been described.57 O H RN ER=Ac: E=CN, CO2Me, NO2; R=N-Ac-L-Leu, E=CN; R=N-Ac-L-Leu-D-Phe, E=CN. When this reaction is performed under homogeneous con- ditions, it requires weak bases, but even in this case the yields of reaction products are moderate.High yields can be achieved in heterogeneous conditions, viz., on silica gel. It is assumed that silica gel, which is acidic, catalyses enolisation of cyanomethyl ketones R1CH2CN and activates electrophilic carbonyl com- pounds. O CN + R1 R2 R1 L-PhCH2CH C AcNH O L-PhCH2CH C (N-Ac-L-Leu)NH O O L-PhCH2CH C H (N-Ac-L-Leu-D-Phe)NH O Me (88%) R1S(O)R2 CN R1 SiO2 R3 R3 R2 R2 R3 Yield (%) 100 The Vilsmeier ± Haack reaction is widely employed for the intro- duction of aldehyde groups into aromatic rings. Taking into account the great importance of this reaction in organic synthesis, Paul et al.59 made an attempt to find optimum conditions for its performance.It was found that irradiation in a conventional microwave oven of substituted aromatic compounds and the Vilsmeier ± Haack reagent (POCl3 ±DMF) supported on silica gel affords maximum yields of the corresponding aldehydes and decreases reaction time to 1.5 ± 2.5 min (Table 2). The amount of the reagent is crucial for achieving maximum yields. For liquid substrates supported on silica gel, the amount of the Vilsmeier-Haack reagent may not exceed 2 equiv., whereas 85 formylation of solid substrates requires no less than 3 equiv. The amount of silica gel pre-irradiated for 5 min at 700 W needed for the formylation also depends on the amount of the reagent. Evidence for the important role of microwave irradiation in this reaction follows from the fact that the yields of aromatic alde- hydes formed upon microwave irradiation exceed significantly those obtained upon conventional heating of the reactants at the same temperature. H 4-MeOC6H4 H Ph H 4-Me2NC6H4 H 4-O2NC6H4 H 2-HO2CC6H4 H 3-MeO-4-HOC6H3 7(CH2)57 7(CH2)47Me Me Me HOCH2 MeC(OH)H Me H 58 37 97 93 46 35 44 80 61 98 4-MeOC6H4 94 4-MeOC6H4 981 This reaction holds great promise in the synthesis of peptide inhibitors of a-chymotrypsin by virtue of its operational simplic- ity, high yields of the reaction products and the fact that it is not accompanied by epimerisation. The condensation of (N-acetyl- phenylalanyl)acetonitrile with 2-formylbenzoic acid and vanillin has demonstrated that no preliminary protection of functional groups is necessary when this reaction is performed on silica gel. These data altogether suggest that silica gel is a mild selective acidic catalyst of the Knoevenagel reaction.In addition to peptidylacetonitriles, other compounds, such as R1CH2E (E=CN, CO2Me, NO2; R=CN, NO2, C(O)Ph, CO2Me, CO2Et and SO2Ph) containing activated methylene groups, were tested in this reaction. It was found that the reaction takes place only if compounds with E=CN and R1=CN, NO2 and C(O)Ph are used; compounds with E=CO2Me and R1=CO2Me, CO2Et and SO2Ph do not enter into this reaction, presumably, due to steric hindrances. The reaction of malonic acid with carbonyl compounds is an important synthetic route to the preparation of valuable unsatu- rated acids.a,b-Unsaturated acids are formed upon heating of the starting compounds in the presence of bases (pyridine and piperidine). The Knoevenagel condensation catalysed by SiO2 was recommended for the synthesis of b,g-unsaturated acids.58 This reaction was performed under microwave irradiation with- out any solvent. SiO2 RCH2CHO+CH2(CO2H)2 RCH CHCH2CO2H MW, 3 ± 5 min 110 ± 118 119 ± 127 R=Et (110, 119, 84%), Prn (111, 120, 83%), Bun (112, 121, 84%), n-C5H11 (113, 122, 84%), n-C6H13 (114, 123, 88%), n-C7H15 (115, 124, 86%), n-C8H17 (116, 125, 90%), Ph (117, 126, 92%), Bn (118, 127, 89%). Thus the reactions of aldehydes 110 ± 118 with malonic acid afforded unsaturated acids 119 ± 127. The target products are formed in high yields and are stereochemically pure.The method is distinguished by the ease of preparation and rapidity. VII. Formylation The use of microwave irradiation in combination with silica gel is an excellent procedure for the rapid (within 1.5 ± 2.5 min) and quantitative Vilsmeier ± Haack reaction.982 Table 2. The Vilsmeier ± Haack reaction. Starting compound RMeN PhHN RR1 VIII. Hydration and dehydration reactions Dehydration of alcohols resulting in the formation of alkenes and the inverse reaction, viz., hydration of alkenes, are valuable synthetic conversions widely applicable in organic synthesis. A general method for the selective anti-Markownikoff addi- tion of water to alkenes in the presence of silica gel has been described in detail by Ranu.60 An alkene supported on preacti- vated silica gel (200 8C, reduced pressure) was treated with a solution of Zn(BH4)2 in 1,2-dimethoxyethane (DME) at room temperature and then hydrolysed.This reaction gives good yields of primary and secondary alcohols (Table 3). Yield (%) Product Me CHO R Cl O 79 75 88 R=Cl R=Br R=OMe CHO MeN 66 O Cl N N Ph Ph Cl O 64 PhHN CHO S S CHO R R NH NH R=Ph R=4-MeC6H4 R=4-ClC6H4 71 68 75 CHO R NHCOMe Cl N 79 58 65 75 68 R=H R=6-OMe R=6-Me R=8-Me R=7-Me CHO 89 CHO 92 72 CHO CHO 78 R2 R1 R2 CHO 81 85 78 R1=R2=OH R1=R2=OMe R1=NMe2, R2=H A K Banerjee, M S Laya Mimo',W J Vera Vegas Table 3.Anti-Markownikoff addition of water to alkenes. Product Yield (%) Starting compound CH2OH Me(CH2)6CH2 Me(CH2)6CH CH2 95 Ph CH CH2 85 Ph CH2 CH2OH+ Ph CH Me 4 : 1 OH Me Me 90 Ph Ph CH2OH CH2 Me Me 80 OH cis : trans=3:7 Ph Ph 70 OH cis : trans=1:3 70 Me Me OH cis : trans=3:7 The obvious advantages of this method include ease of performance, mild conditions, lack of side reactions and high yields of reaction products. The reaction mechanism is not quite clear, but the authors exclude the possibility of conventional hydroboration ± oxidation. The efficiency of silica gel in the dehydration of alcohols is determined by the acidic properties of its surface (SiO2 is a weak Lewis acid).Thus application of iron(III) chloride hexahydrate dissolved in a volatile solvent (methanol, ether, etc.) onto the surface of commercial silica gel (Kieselgel 60, Merck) and subsequent evap- oration of the solvent under high vacuum (0.1 Torr) yield a catalyst for selective dehydration of tertiary, allylic and sterically hindered secondary alcohols.61 The corresponding alkenes are obtained in quantitative yields (Table 4). This reaction is carried out under mild conditions using ether and acetone as solvents. The content of water affects the catalytic activity: the addition of H2O (2 mass%) to the dry catalyst changes only slightly the catalytic activity, whereas at higher water content (>10%) the activity is completely lost. The FeCl3 .6H2O± SiO2 system containing 2% of water also catalyses the epoxide ring opening and certain rearrangements (see below): R R O (>90%) OHOH OAc O COOH OAc OH AcO AcO (>90%) H H Later, the FeCl3 ± SiO2 system prepared from anhydrous iron chloride by simple grinding of components was recommended for dehydration of alcohols.62 This system proved to be efficient inSilica gel in organic synthesis Me OH MeMe FeCl3 ± SiO2 Me 1608C, DMSO Me Me 128 130 dehydration of tertiary alcohols where the yields of reaction products were quantitative. Me OH Me R R R=Me (95%), But (91%). Me Me Me Me OH Me Me (90%) The reaction is carried out in the absence of the solvent. 1-tert- Butylcyclobutan-1-ol 128 undergoes an interesting rearrangement with ring enlargement and formation of 1,5,5-trimethylcyclopen- tene (129) (Scheme 1).In this case, the dehydration occurs via carbocations A, B and C. If the dehydration of the alcohol 128 is carried out under different conditions, viz., by heating in DMSO at 160 8C, com- pound 129 is formed in low yield (5%), while the yield of the alkene 130 reaches 95%. Table 4. Selective dehydration of alcohols by iron(III) chloride on silica gel. Product Yield (%) Starting compound Me HO Me Me OH >90 + Me Me Me OH OH + + >90 H H Me Me Me Me OH HO >90 Me Me Me Me COMe Me COMe Me OH OH Me Me >90 OH O O Me Me Me Me Pri Pri Me >90 Me HO 983 Scheme 1 Me Me Me Me Me + Me Me Me + + Me Me Me Me B A C 129 (100%) The dehydration of the alcohol 131 in the presence of the FeCl3 ± SiO2 system also proceeds via the intermediate cyclopentyl cation 132 and results in the cyclic ether 133.The same product (133) is obtained in good yield upon dehydration of the alcohol 134 under identical conditions. Me Me OH Me Me Me Me Me FeCl3 ± SiO2 + Me O MeCH2OH 131 CH2OH 132 133 (75%) Me Me 133 (85%) Me CH2OH 134Thus, the FeCl3 ± SiO2 system catalyses efficiently both dehy- dration reactions and rearrangements including ring enlargement. Some rearrangement products are key precursors in the synthesis of sesquiterpenoids. Toluene-p-sulfonic acid supported on silica gel is an excellent catalyst in dehydration of secondary and tertiary alcohols (pri- mary alcohols do not react under these conditions).63 Thus alcohols 135 ± 138 are converted into alkenes 139 ± 142 in high yields.OH TsOH± SiO2 Ph Ph 135 139 (91%) TsOH± SiO2 OH Ph Ph 136 140 (94%) TsOH± SiO2 OH C10H21-n C10H21-n 137 141 (98%) OH TsOH± SiO2 But Ph But Ph 138 142 (98%) Dehydration of the alcohol 143 gave alkene 144 in somewhat lower yields under identical conditions.{ OBz OBz Me Me TsOH± SiO2 HO Me Me Me Me 143 144 (82%) This system was also used for dehydration of 3-hydroxyste- roids. The reaction occurred via carbocations and resulted in D2-alkenes and D3,5-dienes. { The authors' unpublished data.984 Me Me TsOH± SiO2 HO H H (90 ± 97%) Me Me TsOH± SiO2 HO (68 ± 75%) It was found 64 that silica gel-supported copper(II) sulfate is an efficient catalyst in smooth dehydration of secondary and tertiary alcohols into alkenes.The catalyst was prepared by mixing chromatographic silica gel with an aqueous solution of copper(II) sulfate with subsequent evaporation by heating at 2 Torr. The catalytic activity depended on the evaporation time and temper- ature and was maximum when the catalyst was dried at 200 8C for 3 h or at 240 8C for 1 h. With a further increase in the evaporation temperature (300 8C, 1 h), the catalyst lost its activity completely. The dehydration rate depended on the SiO2 : CuSO4 ratio (the optimum ratio is 4 : 1).Under these conditions, alcohols 145 ± 148 are converted into alkenes 149 ± 153 in high yields. OH CuSO4 ± SiO2 145 149 (98%) Me CH2 MeOH CuSO4 ± SiO2 + 146 151 (52%) 150 (48%) CuSO4 ± SiO2 PhCH=CH2 152 (83%) PhCH(OH)CH3 147 CuSO4 ± SiO2 OH Me Me 148 153 (88%) Tertiary alcohols are dehydrated more easily than secondary ones. The mechanism of this reaction is still unclear, but it is reasonable to assume the formation of carbenium cations, since dehydration rates of tertiary alcohols are higher than those of secondary and primary ones. This system can also be used for dehydration of 3-hydroxysteroids. Special mention should be made of a detailed study 65 of dehydration of various primary, secondary and tertiary alcohols catalysed by transition metal sulfates supported on silica gel.The activities of various brands of silica gel in this reaction have been compared. The highest activity was manifested by Silica gel BW- 300 (Fuji-Davidson). The catalytic activities of metal sulfates supported on silica gel decreased in the following order: Fe(III)=Ce(IV)=Ti(IV)>Sn(IV)>Al(III)>Cu(II)>Zn(II)> Co(III)>Ni(II)>Fe(II)>Mn(II)>Cd(II). The optimum con- ditions (time, temperature) for treatment of catalysts providing maximum yields of dehydration products have been found.65 The effects of solvents, reagent ratios and reaction conditions on the product yields have been investigated. Some suggestions on the possible mechanism of this reaction have been put forward.Interesting examples of the preparation of a-methylidenecar- bonyl compounds from derivatives of cyclic b-(hydroxyalkyl)- vinyl ethers, b-alkylthio- and b-arylthioacroleins have been described,66 which involved dehydration of intermediate alcohols in the presence of silica gel as one of the steps. The following catalytic systems, viz., SiO2±H2O±HOOCCOOH± HgCl2, A K Banerjee, M S Laya Mimo',W J Vera Vegas and SiO2±H2O±HOOCCOOH and SiO2±H2O±H2SO4 dichloromethane as a solvent, were employed. O OMe SiO2 ± H2O ± (COOH)2 CH2 CH2OH (94%) O OMeMe SiO2 ± H2O ± (COOH)2 Me OH (65%) Me Ph Me Ph 1) NaBH4, MeOH 2) SiO2 ± H2O ± HX SPh H2C O (62%, from Z) (65%, from E) OHCZ or E HX=(COOH)2, H2SO4.Ph Me Ph Me 1) NaBH4, MeOH 2) SiO2 ± H2O ± H2SO4 OHC SEt Z+E H2C O (50%) IX. Protection of functional groups The use of silica gel as a catalyst for introduction of protective groups is a popular procedure in organic synthesis. 1. Tetrahydropyranylation of alcohols The tetrahydropyran-2-yl group (THP) is one of the most popular groups used for the protection of alcohols and phenols. Many methods have been devised for its introduction. It has been found 67, 68 that sulfuric acid adsorbed on silica gel can be used as a catalyst in tetrahydropyranylation of alcohols and phenols. Dichloromethane is generally used as a solvent in this reaction. H2SO4 ± SiO2, CH2Cl2 ROH+ O O RO R=Ph (95%), PhCH2 (96%), a-C10H7 (98%), PhCH CHCH2 (96%), PhOCH2CHC:CH (94%).This simple and inexpensive method gives the reaction products, as a rule, in high yields. Recently, this reaction has been carried out 69 using micro- wave irradiation in the presence of the same catalyst but without solvent. This permitted one to obtain reaction products in a pure state and in high yields. The absence of solvents makes it possible to run this reaction under mild conditions. Other advantages include short reaction time (10 ± 15 min), omission of the aqueous workup and environmental safety. 2. Thioacetalisation and acetalisation Protection of carbonyl groups as acetals or thioacetals is a common procedure in the synthesis of organic compounds, in particular, of complex polyfunctional compounds.However, protic and Lewis acids and some silicon reagents 70 commonly used in (thio)acetalisation do not afford selective protection of aldehyde groups in the presence of keto groups. Silica gel treated with thionyl chloride effects their protection. It was found that this silica gel effectively catalyses thioacetalisa- tion { of many aldehydes and ketones by 1,2-ethanedithiol or 1,3- { The inverse reaction occurs upon treatment with sulfuryl chloride in the presence of wet silica gel.985 Silica gel in organic synthesis Yield (%) A R n propanedithiol and affords selective protection of aldehyde groups when both these groups are present simultaneously.71 7C6H47 S SOCl2 ± SiO2 RCHO +HS(CH2)nSH RHC (CH2)n SO2Cl2 ± SiO2 (moist) S 7(CH2)37 n Yield of thioacetal (%) R 7CH2CH(Ph)CH27 C6H13 7CHMe7 90 99 78 89 98 98 99 92 92 Me Me Ph Me Me Me Me Ph Ph 232232323 PhCHMe H2C=CH(CH2)8 MeCH=CH PhCH=CH Ph All these reactions proceed with high selectivity and do not require complex equipment.The unusual chemoselectivity of this method can be attributed to the differences in spatial interactions of the aldehyde and ketone groups with the porous surface of silica gel. 222232 S H SH R1 S S R2 R1 R1 R1 R2 S + SH R2 O R2 Cl7 O O Cl OH SiO2 SiO2 SiO2 SiO2 2 99 3 99100 100 100 97 100 100 3 97 2 98 2 99 2 98 2 88 2 98 2 98 2 93 4-MeC6H4 4-ClC6H4 4-MeOC6H4 4-HOC6H4 4-HO2CC6H4 4-Me2NC6H4 2-O2NC6H4 By itself, silica gel (without SOCl2) does not manifest any noticeable catalytic activity in thioacetalisation of aldehydes.Treatment of heptanal with 1,2-ethanediol afforded the corre- sponding 1,3-dithiolane in as low a yield as 11%. This method holds especially great promise for multistep syntheses of complex molecules. The synthesis of thioacetals from aldehydes (or ketones) and 1,2-ethanedithiol in the presence of catalytic amounts of cop- per(II) trifluoromethanesulfonate supported on silica gel in the absence of solvents has been described.72 All thioacetals were obtained in high yields. S R1 R1 Cu(OTf)2 ± SiO2 O +HSCH2CH2SH The reaction with ketones in benzene proceeds very slowly; however, this can be completed within 24 h in boiling toluene.R1 S without solvent, 25 8C R1 SOCl2 ± SiO2 R2 R2 S O+ HSCH2CH2SH R2 R2 S Yield (%) R1 R2 Yield (%) R2 R1 Ph 91 100 93 31 Me 7(CH2)57PhCH2 Ph PhCH2 Ph The difference in the rates of thioacetalisation of aldehydes and ketones permits selective protection of aldehydes in the presence of ketones (Table 5) as well as selective thioacetalisation of oxo aldehydes. Ph n-C6H13 H 91 cyclo-C6H11 H 92 2-Furyl H 91 2,5-(MeO)2C6H3 H 98 PhCH=CH H 89 2-HOC6H4 H 96 2-O2NC6H4 H 93 4-ClC6H4 H 98 4-MeC6H4 H 99 4-MeOC6H4 H 99 4-HOC6H4 H 94 Me 92 7CH2CH2CHButCH2CH27 94 93 Table 5. Thioacetalisation of mixtures of aldehydes and ketones in the presence of SOCl2 ± SiO2. 7CH2CH(CO2Me)CH(CO2Me)CH27 Conversion Ketone Aldehyde In most cases, the reactions proceed selectively and at room aldehyde ketone temperature.This reaction can also be performed in the presence of the CuCl2 ± SiO2 system (in the absence of solvent), however, in this case the reaction rate and the product yields are lower. PhC(O)Me PhC(O)Me (PhCH2)2C=O Bui2C=O 100 96 100 100 83 100 PhCHO 4-ClC6H4CHO Bun(Et)CHCHO 4-MeOC6H4CHO Ph(Me)CHCHO C6H13CHO PhCH=CHC(O)Me PhC(O)C(O)Ph 000000 S SOCl2 ± SiO2 A C RC (CH2)n A CH RC +HS(CH2)nSH In addition to thioacetals, cyclic acetals, which are stable in alkaline or weakly acidic media, are used to protect aldehydes and ketones in multistep syntheses.73 The reaction of aldehydes with ethylene glycol in the presence of strong protic or Lewis acids is a common procedure for their synthesis; however, this method is characterised by low yields and long reaction time.Other methods for acetal synthesis require drastic conditions, the use of expensive or hazardous reagents, sophisticated synthetic and isolation procedures, etc. S H O O O An efficient method for protection of the aldehyde and ketone groups by treatment with ethylene glycol with microwave irradi- ation without any solvent has been developed.74 Here, metal sulfates [Ce(SO4)2, MgSO4 and NaHSO4] supported on silica gel are used as catalysts.986 NaHSO4 ± SiO2 RCHO +HO(CH2)2OH MW, without solvent R=Ph (85%), 2-O2NC6H4 (98%), 2-MeOC6H4 (82%), 2-ClC6H4 (90%), 3-NCC6H4 (97%), 3-PhOC6H4 (85%), 3-BnOC6H4 (81%), PhCH(CN) (90%), b-C10H7 (87%), 4-[PhC(O)CH2O]C6H4 (75%), [X =O (94%), S (81%)], PhCH=CH (81%), X MeCH=CH (82%), MeC(O)CH2CH2 (82%), n-C6H13 (90%), n-C10H21 (87%), ClCH2CH=CH (78%), MeO2C(CH2)4 (85%).This technique provides selective protection of aldehyde groups in the presence of keto groups (the latter proved to be fairly resistant to microwave irradiation). X. Deprotection of functional groups There is a vast body of evidence concerning the use of silica gel as a catalyst in hydrolytic reactions aimed at removal of protective (trityl, ketal, ester, etc.) groups.3, 21 Some examples of these reactions will be given below. Very good yields of carbonyl compounds were obtained upon removal of the thioacetal group by boiling the dithioacetals in organic solvents with silica gel-supported copper(II) sulfate.75 S CuSO4 ± SiO2 S S CuSO4 ± SiO2 S S CuSO4 ± SiO2 S S CuSO4 ± SiO2 S The reaction is generally completed in 2 ± 20 h.Its mechanism is still unclear. Many oximes are converted into the starting carbonyl com- pounds under the action of chromium trioxide supported on silica gel.76 These reactions occur on heating in such solvents as toluene, benzene or ether. Mitra et al.77 have proposed to use sodium bismuthate supported on moist silica gel for removal of the oxime protective group. This reaction is initiated by microwave irradi- ation. R1 NaBiO3 ± SiO2 (moist) NOH MW R2 Yield (%) R2 R1 Me Bui7(CH2)57 Ph C10H7 Ph 4-MeC6H4 Ph Me Me Me 4-MeOC6H4 Me Me 81 73 90 90 89 85 94 82 4-O2NC6H4 O R O COOH (90%) O (60%) O (50%)O (80%) R1 O R2 A K Banerjee, M S Laya Mimo',W J Vera Vegas This reaction is quantitative and is completed within several minutes at normal pressure.Later, the same authors used this reagent to convert semi- carbazones into the original carbonyl compounds.78 Hydrolysis of esters, which is usually carried out by heating in aqueous solutions of acids or bases, is one of the most common reactions in organic synthesis. These conditions can result in hydrolysis of compounds containing acid- or base-sensitive groups.Therefore, studies in this field are aimed at the search for conditions of ester hydrolysis in neutral media. An original procedure for ester hydrolysis by microwave irradiation on moist silica gel impregnated with indium triiodide has been proposed recently.79 This approach made it possible to hydrolyse various acyclic and carbocyclic esters to the corresponding acids in high yields. RCO2H RCO2Me R=PhCH2 (92%), n-C17H35 (70%), Ph2CH (70%). COOH O COOMe O MeO MeO (83%) COOH COOMe COOMe COOH (89%) The duration of this reaction was 25 ± 80 min. This reaction proceeded smoothly even in the case of sterically hindered esters and diesters. Mild reaction conditions make this reaction suitable for hydrolysis of compounds containing additional functional groups, e.g., keto and hydroxy groups, as well as C=C bonds.XI. Miscellaneous reactions Among other reactions, we shall consider the Nef, Ritter, Wittig and Prins reactions as well as acylation, substitution, halogen- ation and ring-opening reactions. These types of conversions will be outlined below. 1. The Nef reaction The use of silica gel in the Nef reaction has been described.80 Nitroalkanes were converted into the corresponding carbonyl compounds in high yields by treatment with sodium percarbonate in the presence of silica gel in aqueous DMF (40 8C, 1 h). Na2CO3 . 1.5H2O2 ± SiO2 R1R2C=O R1R2CHNO2 Yield (%) R2 R17(CH2)47 7(CH2)57 n-C5H11 PhCH2 73 68 H 65 Me 81 In the absence of silica gel, the reaction proceeds at a slow rate (12 ± 15 h). If sodium carbonate is used instead of percarbonate, the reaction does not take place.2. The Ritter reaction The Ritter reaction of benzyl alcohols with nitriles initiated by iron(III) chloride supported on silica gel results in the correspond- ing amides in high yields.81 R2 R1 H FeCl3 ± SiO2 O R1 +R37C:N OH R2 HN R3Silica gel in organic synthesis Yield (%) R3 R2 R1 Ph Ph Ph 4-MeOC6H4 4-ClC6H4 4-O2NC6H4 Ph Me 94 Me Me 95 Ph PhCH2 92 H Me 80 H ClCH2 91 H Ph ± This reagent has a number of advantages over concentrated sulfuric acid commonly used in this reaction; it is non-hygroscopic and does not require any special precautions. All reactions were conducted under solvolytic conditions using nitrile as a solvent. The iron salt and the substrate were used in equimolar amounts.p-Nitrobenzyl alcohol does not enter into the reaction under these conditions. 3. The Wittig reaction The Wittig reaction with the use of silica gel 82 allows one to selectively synthesise a,b-unsaturated carbonyl compounds in high yields from stable phosphorylides and aldehydes. Thus irradiation of mixtures of ethoxycarbonylmethylidenetriphenyl- phosphorane with aldehydes in a microwave oven in the presence of silica gel yielded esters of the corresponding a,b-unsaturated carboxylic acids. + 7 RCH CHCOOMe RCHO +Ph3P7CHCOOMe SiO2 n-C6H14, MW R=Prn (87%), But (78%), cyclo-C6H11 (90%), MeOCH2 (85%). The use of silica gel not only accelerates the reaction, but also promotes the separation of the triphenylphosphine oxide formed.As a result, target products are formed in high yields and do not contain admixtures. In addition to aldehydes, ketones can also be involved in the reaction. 4. The Prins reaction The Prins reaction, which includes condensation of alkenes with aldehydes (usually, formaldehyde), affords 1,3-diol derivatives. This reaction is catalysed by mineral acids, soft Lewis acids and solid catalysts, such as ion-exchange resins, zeolites and clays (montmorillonite K-10). Recently, the Prins reaction has been carried out with micro- wave irradiation under solvent-free conditions using TaCl5 sup- ported on silica gel as a catalyst.83 Under these conditions, alkenes were converted into 1,3-diol derivatives in high yields.O R1 O R2 R1 R2 +HCHO TaCl5 ± SiO2 MW, 3 ± 4 minR3 R3 Yield (%) R3 R2 R1 88 H MeH H H 90 H H Me H 86 Me Cl HH HH 88 85 H H NO2 80 H Me Me 90 H Ph H 85O O TaCl5 ± SiO2 OMe OMe 7 7 MW, 4 min O O (78%) These reactions are usually completed within 3 ± 4 min, whereas under conventional conditions (in dioxane) it takes 10 ± 13 h and the yields do not exceed 80%. 5. Substitution reactions Thioamides were converted into the corresponding amides under mild conditions by treatment with Caro's acid (peroxymonosul- furic acid) supported on silica gel. The reaction was carried out in acetonitrile at room temperature in air.84 R1C(S)NHR2 R2 R1 Ph 4-O2NC6H4 Ph Me CH2Ph CH2Ph Bun C6H4Me This reaction is operationally simple.However, it is not suitable for conversion of primary thioamides which yield a mixture of products difficult to identify. Despite this limitation, Caro's acid supported on silica gel allows mild conversion of secondary and tertiary thioamides into amides in the yields comparable and sometimes exceeding those described previously. This reaction is successfully employed in the chemistry of thio analogues of nucleic acids and nucleosides.85 6. Synthesis of nitriles from aldehydes Nitriles are used as starting components in the synthesis of many biologically active compounds; therefore, elaboration of effective methods of their synthesis is a topical problem.The conversion of aldehydes into the corresponding nitriles represents an important transformation of functional groups. A simple and efficient procedure for the synthesis of nitriles from aldehydes and hydr- oxylamine using microwave irradiation in the presence of NaHSO4 supported on silica gel has been described.86 NH2OH± HCl RCHO NaHSO4 ± SiO2, MW R=Ph (84%), 4-HOC6H4 (90%), 4-MeOC6H4 (91%), 3-Me-4-HOC6H3 (96%), 3-HOC6H4 (91%), 3,4-(MeO)2C6H3 (97%), 3,4-(CH2O2)C6H3 (95%), PhCH=CH (85%), n-C7H15 (81%), n-C8H17 (80%). This reaction proceeds very fast (1 ± 3 min) and final products are formed in high yields. Presumably, the aldehyde is converted into the corresponding aldoxime which is immediately dehydrated to yield the nitrile.7. Acylation, alkylation and esterification The use of solid adsorbents in organic synthesis provides high selectivity in many chemical reactions including alkylation, acy- lation, esterification, etc. The most essential feature of these reactions is that they can be applied for selective protection of one functional group in bi- and polyfunctional compounds. Thus acetylation of a series of symmetrical 1,n-diols adsorbed on silica gel (Wako gel C-200, Wako Pure Chemical Industries) by heating with acetyl chloride in cyclohexane resulted in monoacetyl deriv- atives in quantitative yields.87 HO(CH2)nOH n46810 12 16 987 H2SO5 ± SiO2 R1C(O)NHR2 Yield (%) 84 76 82 87 RCN AcCl, cyclo-C6H12 AcO(CH2)nOH 2 h, boiling Yield on SiO2 (%) Yield in the homoge- neous reaction (%) bis mono 52.3 58.6 54.3 56.5 66.5 30.2 99.5 99.5 99.8 99.8 99.0 99.9 00001.0 0988 n Yield on SiO2 (%) Yield in the homoge- neous reaction (%) bis mono 32.6 40.8 29.9 OH HO 52.5 47.5 36.0 CH2OH HOCH2 Under identical conditions, cyclic diols [cyclohexane-1,4-diol and 1,4-bis(hydroxymethyl)benzene] yield predominantly diol diacetates. The dependence of reaction selectivity on temperature was studied in the example of cyclohexane-1,4-diol; the yields of monoacetylated and bisacetylated products at 80 8C were 29.9% and 40.8% and at 0 8C, 52.4% and 19.3%. The silica gel used in this reaction seems to play a protective role for one of hydroxy groups of the diol which is adsorbed on the silica gel surface. It is thought that the diol is adsorbed on the surface of silica gel resulting in the formation of a monomolecular layer, which has been demonstrated in the methylation of alcohols (1-decanol, geraniol and cyclohexanol), phenol, a- and b-naph- thols, 2,6-di-tert-butylphenol, etc., by diazomethane.88 Presum- ably,88 it is alcohols (in the form of alkoxides) adsorbed on the surface of SiO2 that enter into the reaction.This reaction does not take place in the absence of silica gel. Ogawa et al.88 determined the maximum amount of the alcohol adsorbed on silica gel beyond which the reaction rate does not change further.For 1-decanol, it was equal to 4 mmol g71 SiO2, which corresponds to the for- mation of a monomolecular layer of the alcohol molecules on the surface of silica gel. It was found that 2,6-di-tert-butylphenol, which cannot be adsorbed on the surface of SiO2 due to steric hindrances, is not methylated under these conditions. An alternative procedure 89 for selective monoacylation of diols by reaction with esters (ethyl acetate, ethyl formate, methyl propionate, methyl isobutyrate) has been developed;89 this reac- tion is catalysed by metal sulfates [NaHSO4, Ce(SO4)2] supported on chromatographic silica gel. This method was used to prepare monoesters of ethylene glycol, butane-1,4-diol, pentane-1,5-diol and hexane-1,6- and -2,5-diols. The reaction occurs in the presence of hexane at the control- lable hexane : ester ratio of *1 : 4.The yields of monoesters decrease with the increase in this ratio. This phenomenon is attributed to the effect of solvent polarity on the adsorption of alcohols and esters. With the above ratio, only alcohols are adsorbed, which are more polar than the monoesters. A selective procedure for esterification of aliphatic carboxylic acids in the presence of aromatic acids has been developed;90 an interesting example of selective esterification of dicarboxylic acid 154 into the monoester 155 has been described. CH2COOH CH2COOMe COOH NaHSO4 ± SiO2 COOH+MeOH 25 8C 154 155 (96%) 8. Halogenation of aromatic compounds Preparation of novel effective reagents for electrophilic chlorina- tion of aromatic compounds has been described.91 It was found that many chlorine-containing organic compounds acquire strong electrophilic properties in the presence of silica gel, although they differ substantially in reactivities.The systems based on N,N- dichlorourethane, dichloramine-T and tert-butyl hypochlorite appeared to be the most active. They quantitatively chlorinate aromatic compounds under controlled conditions. The tert-butyl hypochlorite ± chromatographic silica gel (BDH) system proved to be very convenient for monochlorination of some aromatic compounds.91 In some cases, the yields of ortho- and para- chlorinated derivatives reached 100%. A K Banerjee, M S Laya Mimo',W J Vera Vegas ButOCl ± SiO2 PhR o(p)-ClC6H4R CCl4, 25 8C ortho : para Ratio Yield (%) R 65 : 35 57 : 43 44 : 56 15 : 85 30 : 70 56 : 44 100 86 100 70 100 70 Me Et Pri But OMe Ph This reaction has significant advantages over classical electro- philic chlorination reactions involving chlorine and sulfuryl chloride and is characterised by high yields, ease of isolation of reaction products and the absence of HCl.The nature of silica gel is very important for the successful implementation of this reaction. Satisfactory results were obtained exclusively with strongly acidic (pH<5) chromatographic silica gel dried at 120 8C. The dichlorourethane ± silica gel system in acetonitrile was used for chlorination of benzene and the dichloramine ± silica gel system in carbon tetrachloride was used for chlorination of toluene.The addition of silica gel to N-bromosuccinimide in carbon tetrachloride resulted in a catalytic system, which allows selective monobromination (presumably, in the para-position) of some alkoxybenzenes.92 Hal R1 R1 R2 R2 R3 R3 Yield (%) R3 R2 R1 99 98 87 78 90 90 96 OMe HOMe OMe OMe OMe OEt HOMe HHHHH OMe OMe Me Pri Et HH Thus bromination of m-alkylmethoxybenzenes (Alk=Me, Et, Pri) occurs exclusively in the para-position relative to the methoxy group. 4-Bromo-3-tert-butyl-1-methoxybenzene is the major product even in the case of m-(tert-butyl)methoxybenzene. Quite unexpectedly, the ratio of 4-Br- to 6-Br-derivatives was found to be equal to 74 : 26, considering the large size of the tert- butyl substituent (bromination of this compound in the presence of Fe-catalysts yields exclusively the 6-Br derivative).The rate of this reaction strongly depends on the amount of silica gel and the mixing rate; this points to the heterogenous character of the reaction. No bromination occurs in the absence of silica gel. Many types of silica gels manifest catalytic activities in this reaction; noteworthy, acidic silica gels are more reactive, whereas neutral and basic ones are more selective. The acidic chromato- graphic silica gel Microbead 3A (Fuji ± Davidson) exhibited the highest efficiency. Availability of the commercial reagent, ease of performance, excellent yields of reaction products and the absence of hydrogen bromide make this method especially attractive.92 This reagent has been used in previous studies for the bromination of indoles and benzoimidazoles.93 9.Ring opening A convenient method for the synthesis of high-boiling alkenes (b.p.=250 8C) from b-lactones by heating the latter in benzene or cyclohexane in the presence of chromatographic silica gel has been proposed.94989 Silica gel in organic synthesis Me O O R Me R R=H (90%), Me (88%), CO2Et (97%), CH2OH (77%). O R1 R3 R1 O SiO2 (moist) R2 R4 R2 R4 R3 7. T Hasegawa, J Moribe, M Yoshioka Bull. Chem. Soc. Jpn. 61 1437 (1988) 8. T Hasegawa, H Aoyama, Y Omote J. Chem. Soc., Perkin Trans.1 963 (1979) 9. T Hasegawa, H Aoyama, Y Omote J. Chem. Soc., Perkin Trans. 1 2054 (1976) 10. M Kawase,A K Sinhababu,R T Borchardt J. Heterocycl. Chem. 24 1499 (1987) 11. A D Batcho, W Leimguber Org. Synth. 63 214 (1985) 12. J Harley-Mason J. Chem. Soc. 200 (1953) 13. A K Sinhababu, R T Borchardt J. Org. Chem. 48 3347 (1983) 14. F He, Y Bo, J D Altom, E J Corey J. Am. Chem. Soc. 121 6771 Yield (%) R4 R3 R2 R1 Me Me (1999) 15. D Schinzer, M Kalesse, J Kabbara Tetrahedron Lett. 29 5241 (1988) 16. D Schinzer, M Kalesse Synlett 34 (1989) 17. B B Snider Acc. Chem. Res. 13 426 (1980) 18. J A Marshall, N H Andersen, P C Johnson J. Org. Chem. 35 186 H 95 H H 9395 H 75 Me Me Me Pri Ph(CH2)2 SiMe2But cyclo-C6H11 H Me n-C7H15 (1970) 19.N H Andersen, D W Ladner Synth. Commun. 8 449 (1978) 20. J A Marshall Synthesis 517 (1972) 21. A McKillop, D W Young Synthesis 401 (1979) 22. W G Dauben, R T Hendricks Tetrahedron Lett. 33 603 (1992) 23. B B Snider,M Karras, R T Price, D J Rodini J. Org. Chem. 47 4538 (1982) 24. L F Tietze, U Beifuss Tetrahedron Lett. 27 1767 (1986) 25. L F Tietze, U Beifuss Liebigs Ann. Chem. 321 (1988) 26. B B Snider, D J Rodini, M Karras, T C Kirk, E A Deutsch, Distillation of lactones over moist silica gel is the best procedure for the preparation of alkenes with b.ps<200 8C.95 Silica gel was used to accelerate the decarboxylation of b-lactones; this is an excellent procedure for stereoselective synthesis of alkenes.Anhydrous silica gel fire-dried in vacuo is not always suitable for decarboxylation, since this may cause isomerisation of alkenes formed. In the above-described experiments, silica gel was used in the amount of 10 mass %, since the amount of water released in the course of distillation decreases with the silica gel dose. R Cordova, R T Price Tetrahedron 37 3927 (1981) 27. S Sakane, K Maruoka, H Yamamoto Tetrahedron 42 2203 (1986) 28. S Tsuboi, H Fujita, K Muranaka, K Seko, A Takeda Chem. Lett. 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ISSN:0036-021X    

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年代:2001

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