ISSN:0069-3030    

DOI:10.1039/OC99592FX001

出版商:RSC    

年代:1995

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC99592BX003

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (i) Pericyclic Reactions By 1. D. CUNNINGHAM Department of Chemistry University of Surrey Guildford GU2 5XH UK 1 Introduction The study of pericyclic reactions both experimentally and theoretically continues to be of considerable interest. Reviews have appeared covering the theoretical modelling of pericyclic transition states’ and the similarity approach to the theory of pericyclic macromolecules.’ Pericyclic reactions are included in reviews of tandem reactions for organic synthesis3 and of new reactions for forming heterocycle^.^ A theoretical study (RHF/6-3 lG* and B-LYP/6-3 1G*) has been applied to secondary kinetic isotope effects in a range of pericyclic reactions. It calculates for [4 + 21 cycloadditions large differences for the ‘in’ and ‘out’ diene terminal hydrogens and smaller differences for the endo and exo dienophile hydrogens for electrocyclic transition states large differences for the ‘in’ and ‘out’ hydrogens and for [3,3] sigmatropic transition states differences for the axial and equatorial hydrogens.The effects are due to differences in bending force constants.’ 2 Cycloadditions Many theoretical studies of cycloaddition reactions have appeared. The low reactivity of thiophene has been studied by ab initio (RHF and MP) methods,6 while its reactivity compared to thiophene 1-oxide and 1,l-dioxide has been studied using the AM1 meth~d.~ The AM 1 method also predicts that the thiophene-derived compounds (la) are less reactive towards dienophiles than the furan analogues (lb).’ (la) X = S Y = S CH2 0 (lb) X = 0,Y = S CH2,O 25 I.D. Cunningham The cycloaddition reactivities of 2H- 3H- and 4H-pyrazole along with protonated 4H-pyrazole7 towards ethene were studied by various theoretical methods (AM1 RHF and MP) including density functional theory (DFT).' Ab initiomethods were also used to examine transition state structures for the reaction of 4H-pyrazole with various heterodienophiles." Compared to the cyclopentadiene analogue a higher reactivity is predicted toward ethene but a lower reactivity with high endolexo selectivity toward cis-diazene. In the furan to cyclopropenone [4 + 25 cycloaddition a stabilizing interaction between diene oxygen and dienophile carbonyl favouring the em product both kinetically and thermodynamically is suggested by an ab initio study with reactants transition states and products studied at the MP4SDQ/6-31G*//MP2/6-31G* level.'' Differences in diene deformation energy (e.g.change in C-1 hybridization from sp2 to sp3) on going to the transition state rather than steric factors or orbital interactions are proposed on the basis of ab initio (e.g. HF/6-31G*) calculations to account for the observed syn or anti selectivity in the cycloaddition of ethene to 5-substituted cyclopentadienes (Scheme l)." SYn anfi Scheme 1 A combined AM 1and DFT approach to the generation of transition state structures in the reaction of cyanoethene with cyclopentadiene has been evaluated by comparison of predicted with experimental activation energie~;'~ a similar DFT approach has been applied to the reaction of ethene with butadiene or cyc10pentadiene.l~ Theoretical studies (AM1 and PM3) have been applied to the reactivity of allenes and fluoroallenes in [4 + 21 cycl~additions.~ Delocalization energies computed using an ab initio valence bond model derived from CASSCF/4-31G have been calculated for the transiton state structures of 171.4,+ 71.2,] and 171.2 + n2,] cycloadditions and used to rationalize the allowed or forbidden nature of these reactions.16 The tricyclic diene (2) normally unreactive towards [4 + 21 cycloaddition can be made to undergo Diels-Alder reaction with maleic anhydride N-phenylmaleimide and naphthoquinone via the rearrangement product (3).' 'The reactions requires pressures of up to 200 000 psi and the N-phenylmaleimide also requires acid catalysis (Scheme 2).The reaction between dienophiles such as N-phenylmaleimide and the fused furan (4) (X = 0)has been studied." Reaction Mechanisms (3) Scheme 2 Scheme 3 A range of novel Diels-Alder products are obtained from the reaction of vinyltetrathiafulvalenes(5)with reactive dienophiles such as tetracyanoethene (Scheme 3).19 Several novel heterodienophiles have been studied. Trichlorophosphaethene under- goes [4+ 23 cycloaddition with dienes yielding 1:1 adducts which undergo further reaction including further cycloaddition. Calculations (MNDO/PM3)categorize it as a normal electron demand dienophile and calculated and experimental regioselectivities agree.20 The selenoketones (6) undergo [4 + 21 cycloaddition with a reactive diene trans,trans-hexa-2,4-diene to give the cis-dimethyl-2H-selenopyrans (7) stereospecifi-cally (Scheme 4).However the less reactive cis,trans isomer gives only a small amount of the expected trans product mixed with predominant cis product and this is interpreted as evidence for a stepwise mechanism with reversible formation of an intermediate in the case of the less reactive diene.Under high pressure (12kbar) however the cis,trans diene reacts stereoselectively to give mostly trans 2H-sele-nopyran.* Analysis by 'H NMR spectroscopy of product mixtures from the dimerization of deuterium-labelled 1,3-diphenylbuta-1,3-diene has been interpreted as supporting a concerted rather than a diradical mechanism.22 The highly electron-rich dienes E,E-and E,Z-1,4-bis(dimethylamino)buta-1,3-diene have been allowed to react with a range of dienophiles of increasing electron-acceptor ability to provoke cycloaddition with I.D. Cunningham Scheme 4 preliminary electron-transfer. Several fail to give cycloaddition products but maleo- and fumaro-nitrile give adducts with retention of stereochemistry and dimethyl dicyano-maleate and -fumarate yield the same cycloadduct non-stereospecifically. There is evidence from ‘H NMR studies that electron transfer is taking place in these last two cases.23 The more constrained 2,3-bis(dimethylaminomethylene)-bi-cyclo[2.2.1]heptane and -bicyclo[2.2.2]octane give cycloadducts more cleanly and alkenes tetrasubstituted with cyano and methoxycarbonyl groups undero non-sterospecific cycloaddition with evidence from EPR and stopped-flow visible spectros- copy of prior electron transfer both in solution and in KBr.24 The tris(4-bro- mopheny1)ammoniumyl hexachloroantimonate [(4-BrPh),N+’SbCl,] catalysed Diels-Alder reaction of trans-stilbenes with 2,3-dimethylbuta-1,3-diene was analysed by Hammett-Brown plots.These show almost full positive charge on the dienophile consistent with a concerted cycloaddition involving a radical cation ([4 + l]) rather than the partial positive charge expected for an electrophilic me~hanism.~~ Pericyclic reactions involving cation radicals generated electrochemically have been studied.26 A theoretical study (RHF and MP2 or MP3/6-31G*) of the BH,-catalysed [4 + 21 cycloaddition of ethene to nitrosoethene predicts a low activation energy and inverse electron demand.27 Boron trifluoride-diethyl ether facilitates the cycloaddition of 2,3-disubstituted enals to dienes; the selectivity for alkene or carbonyl part as dienophile depends on the nature of the enal P-substituent.28 The effect of added inorganic (Li Na Mg etc.)perchlorate on pericyclic reactions has been studied and results have been rationalized in terms of effective internal pressure (Pi,erf) and specific cation interaction^.'^ Cycloadditions of nitrosoarenes (which are poor coordinators to Li+ etc.) to 2,3-dimethylbuta- 1,3-diene are accelerated only slightly in line with increasing Pi,err, while cycloaddition of naphthoquinones (better coordinators) and the diene is more strongly influenced by the nature and concentration of the cation although the effect is reduced in solvents [e.g.dimethyl sulfoxide (DMSO)] which themselves strongly solvate the cation. A similar strong variation with cation is observed for an intramolecular ‘ene’ reaction. Theoretical and experimental studies of cummulene cycloaddition have appeared. The theoretical studies are typified by an ab initio (RHFand MP2/3-21G 6-31G 6-3 1G*) treatment of the reaction between ethene and several i~ocyanates.~’ A study of isocyanate to alkene [n2 + (~2,+ n2,)] cycloaddition shows concerted transition state structures generated at various HF and MP levels having retained configuration and zwitterionic character and a reaction asynchronicity which can be modified by substituents and by solvent.31 A similar study of the catalysed and uncatalysed cycloaddition of chloroketene to acetaldehyde predicts trans- and a cis-oxetanone product for the uncatalysed and catalysed reactions re~pectively.~~ The AM 1 Reaction Mechanisms Scheme 5 \ Scheme 6 Bud (9) Scheme 7 approach was used to show that [4 + 21 cycloaddition of the C=C-CH=O system to the C=N of keteniminecompetes with addition to C=C.33 Based on kinetic data solvent effects LFER plots and activation parameters a concerted non-synchronous transi- tion state is proposed for the [2 + 21 cycloaddition of the cyanoketene (8) to styrenes (Scheme 5).34 The Diels-Alder reaction between pentamethylcyclopentadiene and electron-rich allenes is effected via the cation radical mechanism (Scheme 6).An argument based on low diene oxidation potential relative to that of the allene is made for a [3 + 2) rather than a ‘symmetry-allowed’ [4 + 13 mechanism although the fact that electron- withdrawing substituents to the allene reduce the yield suggests a possible cation radical intermediate (stepwise me~hanism).~~ An allene intermediate (9)is proposed in the base-catalysed intramolecular Diels-Alder reaction of furfuryl prop-2-ynyl ethers (10) (Scheme 7).36 1,3-Dipolar cycloadditions continue to attract much attention. An ab initio (MP2/6-31G*) and PM3 study of nitrone and pyridine N-oxide cycloaddition to isocyanates shows a high degree of asynchronicity in the concerted transition state for both reaction^.^' Transition state structures for the cycloaddition of azide ion to various carbon-carbon and carbon-nitrogen double and triple bonds have been calculated at the MP2/6-31 + G* level3* Conversion of enal carbonyl to acetal accelerates the 1,3-dipolar cycloaddition of I.D.Cunningham nitrile oxide to the C=C unit giving up to 99 1 regio~electivity.~~ Perturbation molecular orbital (PMO) theory has been applied to rationalize the regioselectivity of N-(phenylmethy1ene)benzenesulfonamidecycloaddition to the N-methyloxazolium- olates (I (ll)Rl R2=Ph,Me The synlanti selectivity in the reaction of the Baylis-Hillman adducts (12) with benzonitrile oxide or diazomethane (Scheme 8) has been analysed both experimentally and by PM3 calculations; the syn product is favoured in accord with the ‘inside alkoxy’ theory (see J.Am.Chern. Soc. 1984,106 3880).41 Steric factors are more important and stereoelectronic factors less important for diazomethane than for the oxide possibly due to the reduced negative charge on the terminal N; the observation that selectivity varies less with X for diazomethane than for the oxide is also consistent with this possibility. COzMe PkcE6-6 R,f$$Me Rf;Me w -N -N Ph Ph (12) X = H Bu’MezSi Ac SYn anti R = Me Pr Pri Ph Scheme 8 The nitrone (13) undergoes [3 + 21 cycloaddition to the alkynyl-chromium (14a) or -tungsten (14b) complex ca. lo4times faster than to the analogous alkynyl ester (14~).~~ Lewis acids enhance the dienophilicity of chiral acetylenic sulfoxides but do not A improve diastereo~electivity.~~ model for the selectivity of the asymmetric Diels-Alder reaction mediated by Ti-BINOLate and Ti-TADDOLate [e.g.(1 5)] has been proposed based on X-ray crystallographic The [2 + 21 and the [2 + 11 cycloadditions of hydrogen isocyanide to phos- phaethene have been studied by ab initio Ab initio calculations suggest that the reaction of cis-diazene with fumarate is a concerted [n2 + 02 + 021 pericyclic process. Rate constants have been determined experimentally for the reaction of in situ-generated aqueous trans-diazene with fumarate in its various protonation states React ion Mechanisms X Ph Ph (13) R = Me,Bd,Bu (14b) X = W(CO)s (14c) X = 0 and with maleate and range from 94-800dm3mol- 's-'; these values are composites of the constant for hydrogenation by cis-diazene and that for the trans-cis isomerization of the diazene (logK ca.-3.6).46 The use of a cyclopentadienyl iron complex as a hapten to generate antibodies for the regio- diastereo- and enantio-selective catalysis of the Diels-Alder reaction has been ~tudied.~' 3 Electrocyclic Reactions The ring-opening of cyclobutene has been studied by DFT methods which calculated the properties of starting material products and the transition state to an accuracy comparable with high level (e.g. MP4/6-311 + G**) nb initio theory.48 Ab initio and DFT methods have also been applied to the conrotatory ring-opening of 172-diformyl- 1,2-diazacyclobutene.A lower reactivity for the diformyl- compared to cis-1,2-dihydro-and other 1,2-diacyl- 1,2-diazacyclobutenes is predicted to be due to formyl-hydrogen to forrnyl carbonyl hydrogen bonding.49 Calculations at the GVB/6-3 1G** level predict a mechanistic gradation from diradical to aziridine-like pericyclic ring-opening as bulkier phosphorous substituents are introduced to phosphacyclopropane.50 Electrostatic stabilization (9.2-1 1.5 kcal mol- ') by Li+ of the transition state for the cyclization of (32)-hexa- 1,3,5-triene is predicted by theoretical methods (e.g.R M P4S DTQ/6- 31 G *//RM P2( fc)/6- 31G * and Bec ke 3 LYP/6- 3 11 + G*//M P2( fc)/6- 31G*).51 The effect of Li(H,O)+ and other metal cations on the reaction has also been examined and the aromaticity of the transition state has been studied by the individual gauge for localized orbitals (IGLO) method.The exo-endo isomerization of the deuteriated oxa- and aza-bicyclo[3.2.0]heptanes (16a,b) (Scheme 9) and the racemization of the thiabicycloheptene (16) has been interpreted in terms of an electrocyclic ring-~pening.~~ The value of AG* is cn. 35-39 kcal mol- ',compared to 18-27 kcal mol- 'for the related bicyclo[3.l.0]hexenes. The production of trans-dideuterioethene along with furan on further heating of (l6a) is interpreted as evidence for a 1,3-sigmatropic shift prior to a retro-Diels-Alder fragmentation. The introduction of a silyl substituent to the alkene [e.g.(17)] facilitates the electrocylization of vinylallenes (Scheme the fact that replacement of the trimethylsilyl group (TMS) by a tert-butyl group does not suggest that the effect is not steric. The electrocyclization of the azatriene (18) where R'-R3 are various H alkyl and aryl substituents has been studied (Scheme 11). Values of AS* (-11.5-2.8 cal mol- ') are similar to those found for the all carbon analogues but values of AH* I.D. Cunningham ex0 endo (16a) X = 0 (16b) X = NR (16c) X = S Scheme 9 (17) R = SiMes Scheme 10 Scheme 11 (17.5-22.5 kcal mol- ') 'are some 5-10 kcal mol- lower. The reaction is as expected disrotatory but slower where a syn arrangement of large terminal substituents occurs in the partially cyclized transition state.54 Torquoselectivity in cyclobutene ring opening where the cyclobutene is fused to a six-membered ring has been studied by ab initio (RHF/3-21G to MP2/6-31G*) and by force field (MM2* and MM3*) calculation^.^^ Calculations also show that cyc- lobutenes which are 3,3-disubstituted with a donor group and an acceptor group show torquoselectivity in which the donor has a larger outward rotation preference than the acceptor A further ab initio study (RHF and MP2 using 3-21G to 6-31G* basis sets) has shown that the model of torquoselectivity developed for cyclobutenes can be applied to the 1-substituted-hexatriene-cyclohexadiene electrocyclization although the hexatriene torquoselectivity is more affected by steric and less by stereoelectronic factor^.^' The ring closure of the vinylallene (19) (Scheme 12) is highly torquoselective.The effect is thought to be steric and replacement of the Bu' by Me removes the torquo~electivity.~~ Reaction Mechanisms cc c- R Scheme 12 4 Sigmatropic Rearrangements Theoretical studies have appeared including an ab initio study using various HF and MP methods of the [l,5] hydrogen shift across a l-thia-4-azapenta-l,3-diene.”A study (MP2/6-31G*//HF/3-21G) has compared [1,3] [1,5] etc. hydrogen shift activation barriers in conjugated alkenes with those in compounds where the terminal alkene is replaced by an allene.60 Barriers for the allene variants are calculated to be 10-12kcalmol-’ lower for [1,3] and [l,5] shifts but only 1-2kcalmol-’ lower for [1,7] and [1,9] shifts.This is attributed to vinyl stabilization of relatively high diradical character in the transition states for the [1,3] and [1,5] shifts. Calculations involving the PM3 semi-empirical method explore the possibility that the bicyclo[3.2.0]hept-2- ene to norbornene [1,3] carbon shift may proceed via a diradical mechanism with the inversion of configuration due to dynamic rather than orbital symmetry factors6’ The rate constant for [1,3] hydrogen shift in the ground-state of the phenyl acetate photo-Fries rearranged intermediate 6-acetylcyclohexa-2,4-dienone (3.6 s-’) has been found to be greater than that for the [1,5] shift of the intermediate 4-acetylcyclohexa- 2,Sdienone (0.065s-’). This apparent deviation from the Woodward-Hoffmann rule is due to the involvement of the carbonyl heteroatom; the importance of tunnelling for the [1,3] shift is considered.62 The [1,3] migration of chlorine across a S-C=C system has been described; the reaction is assisted by a ‘nucleophilic’medium which lowers the activation barrier by s~lvation.~~ Calculations at the MP4SDTQ/6-3 lG*//MP2/6- 31G* + ZPE level show that [1,3] suprafacial migration with inversion ([n2 + a2.J) of the phosphorus in triphosphabicyclo[2.1.O]pent-2-ene occurs with preferential breaking of the P-P rather than the P-C bond (Scheme 13).64 This is attributed to the relative weakness of the P-P bond and to the relative ease of inversion at P.The ‘ene’ reaction (a [1,5] intermolecular hydrogen shift) has received some attention.A theoretical study of the reaction between propene and ethene formaldehyde and maleic anhydride has compared the energetics and mechanism as calculated by various methods (RHF UHF UMP).65 The reaction between propene and maleimide has also been studied by computational methods; the use of the ab initio HF/3-21G or 6-31G* method for geometry optimization with MP2/6-31G* for single point energy calculation was found to give an activation energy in close agreement with that found experimentally for the analogous maleic anhydride reaction.66 The intramolecular ‘ene’ reaction of (20) gives the cis chroman (21) along with its trans isomer in aprotic solvent (Scheme 14).67 Addition of Li Ba or Mg perchlorates to the reaction solutions I.D. Cunningham Scheme 13 H Scheme 15 TMS ‘TMS Scheme 16 (acetone) gives up 106-fold rate enhancement and greater selectivity for the trans product. The intramolecular ‘ene’ reaction of the allenylsilane (22) gives the alkynylcyclopen- tanol(23) (Scheme 15); the allene C=C=C-H behaves as a 712~~2 unit for interaction with the C=O 7c2 system.68 A ‘metallo-ene-allene’ reaction has been proposed in which a metal (Zn) migrates from an allene terminus in the intermediate (24) (Scheme 16).69 An ab initio study of the Cope rearrangement shows it to be concerted and synchronous and to have an aromatic transition state.70 The use of a suitable heteroatom in the [3,3] (Claisen) rearrangement of ally1 ester enolates allows control of pre-transition state (25) configuration and formation of a Z-alkene product (Scheme 17).71 Reaction Mechanisms Scheme 17 (26a) X = CH2 V (26b) X = C=CMe2 X (27) Scheme 18 A novel homo-Cope rearrangement of (26a) has been described (Scheme 13);72 inclusion of an isopropylidene group (26b) results in a switch from a pericyclic to a diradical mechanism according to force-field (MM2) calculations.Supporting evidence for a pericyclic-diradical mechanistic switch is seen in the retro-Diels-Alder fragmenta- tion of the cis-dideuteriated norbornene analogues (27) where (27b) yields some trans-dideuterioethene product; the effect is attributed to allylic radical stabilization by isopropylidene. A novel acyclic aza-[2,3] Wittig rearrangement has been explored along with its potential for unnatural amino acid synthesis (Scheme 19).73 A [1,4] sigmatropic rearrangement along with a [2,3] rearrangement has been found for the '3C-labelled ammonium benzylides derived from (23).74 The proportion of [2,3] to [1,4] product depends on the nature of the base and solvent used (Scheme 20).Miscellaneous Several examples involving a sequence of pericyclic reactions have been described. For example a 1,3-dipolar cycloaddition followed by a [3,3] sigmatropic rearrangement,75 and a sequence of a [3,3] sigmatropic rearrangement a [1,5] hydrogen shift and an electrocyclic ring closure.76 The pericyclic cycloaddition of three ethyne molecules to form benzene has been examined by ab initio (MP2/6-31G*) method^.^' I.D. Cunningham I Boc Scheme 19 13CN 13CN WN RJ3yN ReN< 13CN (28a) R = H (28b)R = CI CN Scheme 20 An ab initio (MP2/6-31G*//HF/6-3 1G*) comparison of the cheleotropic ([02 + n4J) us. 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ISSN:0069-3030    

DOI:10.1039/OC9959200025

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (ii) Polar Reactions By I. W. ASHWORTH Zeneca Ltd. Process Studies Group Huddersfield Works Leeds Road Huddersfield HD2 lFF UK Solvolysis and Carbocations Carbocation-nucleophile combination reactions have been considered by Richard' in a report which advances a qualitative descriptive model based on experimental results. The ionic dissociation of carbon-carbon (T bonds to form hydrocarbon salts has been reviewed.2 Crystallographic studies of the structures of carbocations stabilized by hyperconjugation or bridging which included substituted norbornyl cations have been discussed by La~be.~ Studies of cubane derivatives in superacidic media have led to the characterization of a range of cationic species including the first report of a bridgehead halonium ion.4 Dimethyl cubyl- 1,4-dihalonium ions (1) prepared by treating the appropriate cubyl 1,4-dihalides with CH,F-SbF complex in SO at -70 "C were characterized by NMR spectroscopy at -40 "C.A number of cubyl carboxonium and acylium ions including (2) and (3) were also generated and the effect of the strained C-C ring bonds upon their stability discussed. 0 ;% (1) X = 1,Br Unstabilized benzylic cations have been generated solvolytically5 from (4) and shown to exist as an intimate ion pair by the use of salt effects l80labelling and polarimetry. Vinyl cations have been prepared under solvolytic conditions from phenyliodinio salts6 (5) which solvolyse via a process with a small positive.value of AS* positive Hammett p and exhibiting considerable internal return to an ortho-substituted iodobenzene (6).An intimate ion pair was proposed as the initial product of solvolysis. Carbocations stabilized by heteroatoms have been the focus of much attention with Jencks and co-workers determining lifetimes for iminium ions in aqueous sol~tion.~*~ 39 I. W. Ashworth X +I Inx cFT / 0 But (4) (5) X = CH3 H,CI (6)X = CH3 H Studies of common ion inhibition upon the solvolysis of anilino thioethers (7)and the amino thioether (8) gave rise to reported lifetimes of 1 x lo-' and 5.5 x lO-'s for (9)7 and (10)' respectively. Variation of the aryl substituents in (7)showed the solvolysis reaction to proceed via a late transition state with considerable electron donation from the nitrogen atom.The solvolyses of ring-substituted benzylic gem-diazides (11j were shown to proceed through a stepwise mechanism involving a cation stabilized by an a-azido group.g Added azide gave rise to common ion inhibition leading to the proposal of a diffusionally equilibrated ion pair. Comparison of the Hammett constants for the formation of the cation and its capture by water with those for the a-methoxy methylbenzyl cation suggest that the a-methoxy and x-azido groups have similar cation stabilizing abilities. Studies of the hydrolysis of thioacetals (12) led to the proposal of an A1 mechanism," in which initial protonation is followed by the generation of an a-thiophenylcarbocation (13) as shown in Scheme 1. Ph phFz (12) R = Et Ar 2 Other Nucleophilic Substitutions The reactions of anilino thioethers (14) with nucleophiles were shown to proceed by a Reaction Mechanisms Part (ii) Polar Reactions U Ph I slow Ph FSEt Ph Ph Ph Scheme 1 dissociative pathway observed with less electron withdrawing substituents on the aniline ring' and follows the hypothesis that an intermediate will become a transition state if it is sufficiently destabilized.Benzyl tosylate (toluene-p-sulfonate) solvolysis was found to exhibit a similar change from a dissociative to a concerted bimolecular substitution mechanism,'* which was investigated by the use ofion pair return solvent and subs tit uent effects. (14) X = 3-N02,4-N02 Investigations of the role of electron transfer in nucleophilic substitution reactions were discussed by Lund et al.13 It was concluded that non-chain electron transfer processes may participate in nucleophilic substitution reactions when the nucleophile is a good electron donor and steric hindrance excludes the classical S,2 pathway.Concerted intramolecular nucleophilic substitution reactions have been reported in the hydrolysis of N-phosphorylated nitrogen mustards (1 5)14 and in substitution reactions of 2-(pheny1thio)ethyl halides (16). l5 Mechanisms for these reactions involving intramolecular nucleophilic attack by nitrogen and sulfur respectively to yield three-membered ring intermediates [( 17) and (IS)] were proposed. Catalysis of the substitution reactions of alkyl and aryl sulfonate esters by metal ions has been studied in the presence of poly ether ligands.16 Crown ethers [(19) and (20)] were found to show unusually high reactivity which was rationalized as being due to the complexed alkali metal ion binding to the sulfonate group of the ester and aiding the attack of the halide ion nucleophile.3 Elimination Reactions The competition between nucleophilic substitution and concerted elimination has been studied in 9-ethylfluorene derivatives (21).'7,'8 It was found that [(Zl) X = I Br] I. W. Ashworth undergoes a solvent promoted E2 reaction to yield the more stable alkene product (22). In the presence of nucleophiles the ratio of elimination to nucleophilic substitution depends upon the leaving group and nucleophile-base combination with poor leaving groups such as brosylate (p-bromobenzenesulfonate) giving rise to the substitution product (23) with strong nucleophiles.(21) X = I Br CI OTs OBs (23)X = NU (22) Debromination of 1 -aryl- 1,2-dibromo-2-nitropropanes (24) by secondary amines has been shown to proceed via an E2 mechanism with considerable El, character by Cho et a1.” The reaction exhibited an uncatalysed and a base catalysed pathway in which a second molecule of amine aids the attack of another molecule of amine upon the C2 bromine. The asynchronicity of the transition state for the debromination reaciton was proposed on the basis of the observed activation parameters Hammett p Brarnsted p and ks,/kc ratio. Cevasco and Thea2’ have shown the alkaline hydrolysis of aryl 2-hydroxycinna- mates to involve an El, mechanism proceeding via an o-oxoketene intermediate (25).A change in mechanism to a B,,2 type process was observed when the pK of the leaving group rose above 6. Studies of the hydrolysis and aminolysis of a range of sulfamate esters2’ have implied the existence of a dissociative E l, pathway which proceeds through an N-sulfonylamine intermediate (26). The Hammett p activation parameters and deuterium solvent isotope effect are consistent with such a process proceeding via a transition state with considerable N=S bond formation. 4 Addition Reactions Studies of the nucleophilic vinylic substitution reactions of P-methoxy-a-nitrostilbene by Bernasconi et dZ2 have led to the direct observation of the intermediate (27).This intermediate was observed with weakly basic amine nucleophiles such as methoxyamine and N-methylmethoxyamine and was not observed in earlier studies using strongly basic amines such as piperidine. Reaction Mechanisms Part (ii) Polar Reactions An addition-elimination process was proposed for the reaction of E and 2 0-methylbenzohydroximoyl chloride with amine~.~~ The positive Hammett p (0.92) observed for the reaction with pyrrolidine Brsnsted p (0.38) and k,,/kcl ratio for the reaction of the 2 isomer were taken as evidence by the authors of a rate limiting loss of chloride from the tetrahedral intermediate(28). Interestingly retention of stereochemis- try about the double bond predominated in the reactions.The electrophilic bromination of a sterically hindered alkene (29) was shown to give rise to a bromonium ion by a reversible process.24 The bromonium ion was shown by deuterium labelling experiments to undergo a partially rate limiting deprotonation yielding the alkene (30) rather than the dibrominated alkane. Studies of the electrophilicreaction of alkenes with carbocations by Patz et al.*’ have led to the conclusion that electron transfer processes normally occur when the polar pathway has been slowed by steric effects. Exceptions to this generalization are also discussed. 5 Carbonyl Derivatives The use of cyclodextrins to catalyse ester and amide hydrolysis reactions has been probed by a number of groups. These studies included the hydrolysis of perfluoro- alkylamides,26 the role of potential inhibitors2’ and cooperative catalytic behaviour by different cyclodextrins.** Cross interaction constants have been used by Lee and co-workers to probe the mechanisms of the aminolysis reaction of dithiobenz~ates~~.~~ and the reactions of cinnamoyl chlorides with nu~leophiles.~’ Aminolysis of substituted dithiobenzoates (31) by substituted aniline nucleophiles in acetonitrile was shown to proceed via a stepwise addition-elimination mechanism (Scheme 2) in which the breakdown of the tetrahedral intermediate (32) was rate limiting.29 The large value of p,, (0.8) secondary deuterium kinetic isotope effect of less than 1 (for the use of deuteriated aniline nucleophiles) and the calculated cross interaction constants (pxu > 0 puz < 0 and pxz > 0) were taken as supporting this mechanism.Criteria for the differentiation I. W. Ashworth Scheme 2 RDS = rate determining step Scheme 3 RDS = rate determining step between stepwise and concerted mechanistic pathways on the basis of cross interaction constants and other mechanistic probes were proposed. These probes were applied to the reactions of cinnamoyl chlorides with methanol and anilines in acetonitrile leading to the conclusion that they proceeded via dissociative S,2 and addition-elimination pathways re~pectively.~' The use of secondary kinetic isotope effects for the investiga- tion of substitution reactions involving deuteriated nucleophiles has been reviewed by Lee. A UV-VIS spectroscopic study of the hydrolysis reactions of 1-aryloxyethyl-alkanoates (33) carried out by Hall and G~ulding~~ showed the mechanism of the reaction to be pH dependent.The acid catalysed hydrolysis was shown to proceed via an A*,-1 mechanism involving an alkoxycarbonium ion intermediate whilst under alkaline conditions the ester hydrolysed by a BAc-2mechanism. The reaction observed under neutral conditions was rationalized as an AAc-2reaction proceeding via a rate limiting attack of water on the carbonyl group followed by an intramolecular proton transfer (Scheme 3). Intramolecular amide hydrolysis by an amino group has been investigated as a potential method of prodrug activation in which the substituted amine released carries the active grouping.34 The hydrolysis of amides such as (34) was studied at around physiological pH.It was found that the use of a gem-dimethyl group increased the rate of the hydrolysis reaction 800-fold relative to the unsubstituted parent. A mechanism involving rate limitinggeneral acid catalysed attack of the amino group upon the amide followed by general base catalysed breakdown of the tetrahedral intermediate was proposed. The Schmidt reaction of flavanones (35)with trimethylsilyl azide in trifluoroacetic acid was studied kinetically by 'H NMR spectro~copy.~~ A mechanism was proposed on the basis of these studies which explained the observed regiochemistry and the formation of the tetrazolo (36) products observed. An iminodiazonium ion Reaction Mechanisms Part (ii) Polar Reactions 45 R' k' intermediate (37) formed by the action of azide on the flavanone was proposed which then undergoes a rearrangement with loss of nitrogen to generate a benzyl stabilized iminium ion.Indanone was found to have a pK of 16.96 for enolization to give the enolate anion.36 Studies of the rates of ketonization of 3-hydroxyindene and enolization of indanone coupled with the equilibrium constant for the deprotonation reaction of 3-hydroxyindene were used to determine the pK of indanone acting as a carbon acid. This value is lower by 1.4 than the previously determined carbon acidity of acetophenone in which coplanarity between the enolate and phenyl ring is not enforced. Richard and co-workers have reported a rate constant of 1.6 x lo6s-'for the intramolecular reaction between the enolate and aldehyde functions of (38).37 6 Reactive Intermediates The matrix isolation and IR spectroscopic study of low coordination carbon germanium and silicon species has been reviewed.38 Stable diaminocarbenes (39) and (40)have been synthesized and characteri~ed,~~.~~ a pK of 24 being determined from a study of the deprotonation reactions of (40) with hydrocarbons in dimethyl sulfoxide (DMSO).Reactions of phenylchlorocarbene with alkyl azides to generate chloro- imines which subsequently underwent a facile hydrolysis reaction were studied by laser flash phot~lysis.~' The activation parameters determined for the reaction with benzyl azide showed the activation barrier to the reaction to be principally entropic in origin.Mes Studies of the solvolysis of O-aroyl-N-acetyl-N-(2,6-dimethylphenyl) hydroxylamines (41) showed the reaction to proceed via a rate limiting ionization I. W. Ashworth It was proposed that the nitrenium-carboxylate ion pair intermediates undergo internal return to generate the cyclohexa-1,3-diene species (42). An estimate of 10 ps was made for the lifetime of this ion pair on the basis of trapping experiments with hydronium ions. The effects of trapping with bromide upon the product ratios led the authors to conclude that the mechanism for the solvolysis reaction must involve at least three short lived ion pair intermediates. An investigation of solvolytic behaviour of the reactive cyclohexa-1,3-diene species (42) showed meta and para substitution products (43) to be derived from acid catalysed and pH independent pathways re~pectively.~~ The pH independent reaction occurs by a rate limiting ionization to yield an ion pair (44) which undergoes nucleophilic attack or collapses at the para position.(41) (42) (43)R = H or COAr (44) The hydration of ketenes has been studied by a number of groups. Kresge and co-workers demonstrated the existence of an acid catalysed hydration pathway in their studies of aryl ketene~.~~ At low pH mesitylketene was shown to undergo a rate limiting protonation on the carbon for which the catalytic coefficient was determined by the Cox-Yates method. The value obtained is 2200 times lower than the catalytic coefficient for the acid catalysed hydration of ketene which was rationalized as being due to the stabilizing effect of the mesityl group.Studies of the hydration of ditipylketene (tipyl = 2,4,6 triisopropylphenyl) in ‘*Olabelled water showed consider- able incorporation of label into unreacted ketene providing evidence of the reversibil- ity of ketene hydrati~n.~’ The bis-ketene (45) was found to undergo an initial acid catalysed hydration reaction to yield the intermediate (46),which then reacts further by a pH independent intramolecular pathway (Scheme 4).46Evidence for the intermediacy of(46) was provided by its direct observation following generation in an NMR tube and its trapping by trifluoroacetate. A range of ynolate anions (47) have been generated from hydroxy cyclopropenones (48) by flash photolytic technique^.^^ Studies of the reaciions of the arylynolate anions in aqueous solution showed them to undergo a rate limiting protonation at the fi carbon to give a second short lived species which underwent hydration to yield arylacetic acids (Scheme 5).These intermediates were shown to be ketenes by comparison of the observed kinetics with the kinetics for the hydration of the postulated ketene intermediate generated by a photo-Wolff reaction. 7 Aromatic Addition and Substitution The reactions of unactivated aromatics in highly acidic media have been studied. Investigation of the Gattermann reaction between benzene and cyanide salts which gives rise to benzaldehyde via the hydrolysis of the imine intermediate (49),showed the 47 Reaction Mechanisms Part (ii) Polar Reactions MeaSi CcCo H+ H20 Me3sixc50- osc SiMe3 o,C xSiMe3 (45) (46) Scheme 4 Scheme 5 reaction to be accelerated under strongly acidic condition^.^^ Quantitative yields of benzaldehyde were obtained rapidly in trifluoromethanesulfonic acid (TFSA) contain- ing 5% SbF (H = -18 using the Hammett acidity function).The fact that reaction is slow under conditions which should protonate half of the hydrogen cyanide present (H = -12)is taken as evidence of the reaction with unactivated aromatics proceeding via the diprotonated species (50). Similar behaviour was observed in the Houben-Hoesch and Friedel-Crafts reactions of unactivated benzenes. Studies of the reaction of benzaldehyde with benzene under highly acidic conditions have led to the proposal of two different diprotonated species as the active electrophiles.Olah et aL4’ have proposed the 0,C-diprotonated benzaldehyde (51) on the basis of ab initio calculations at the correlated MP2/6-3 lG* level. The 0,O-diprotonated benzaldehyde (52) was proposed by Shudo and co-workers5’ on the basis of NMR studies and the lack of deuterium incorporation into the ring when benzaldehyde was treated with deuteriated TFSA. H,+ H dp.~~~ H-C=N\+ H @H +/H / dH HH Substitution reactions of 2-(4-nitrophenoxy)-4,6-dimethoxy-1,3,5-triazine(53) with substituted phenolate anions were shown to proceed by an unprecedented concerted me~hanism.’~ This proposal is made on the basis of the lack of curvature in a Brransted type plot for the pK of the nucleophile which implies a mechanism involving a single transition state.Further evidence was derived from the existence of a cross-correlation effect between b,, and the pK of the leaving group and pl and the pK of the nucleophile. Substituted pyridines however were found to react with the 1(4,6-diphenoxy-1,3,5-triazin-2-yl)pyridinium ion (54) by an addition-elimination mechan- ism.52 I. W. Ashworth The reaction of amine nucleophiles with phenyl2,4,6-trinitrophenyl ether in DMSO results in a rapid but reversible reaction to form products resulting from attack at the 3 position (55).53 A second slower reaction at the 1 position was then observed which gave rise to the expected substitution product (56).The regiospecificity of the amine attack was discussed. OPh NR’R~ Terrier et dS4 studied the interaction of nitroalkane anions and 4,6-dinitrobenzo- furoxan (DNBF) (57) in DMSO. The carbanions were found to add to the highly electrophilic aromatic ring system to generate a-adducts (58),which were characterized by NMR spectroscopy. Treatment of the a-adducts with base was found to yield the carbanions (59)by a fl elimination of HNO, rather than the expected dianions. Rate and equilibrium data for the formation of the a-adducts were obtained and showed the adducts with DNBF to be at least lo5 times more stable than those formed with 1,3,5-trinitrobenzene. A kinetic study has also been made of the reaction of a range of benzyl cyanide anions with 1,3,5-trinitrobenzene and DNBF.” A single electron transfer (SET) process was proposed for the reaction of 2,6-di-tert- butyl-4-methoxyphenyl 2-methoxybenzoate with organo-lithium and -magnesium specie^.'^ It was found that as the electron donating ability of the carbanion increased the level of the cyclohexadiene products [(60) (61)] over the expected substitution product (62) increased.The reaction of the trimethylsilyl anion to give purely the cyclohexadiene products was taken as further evidence of the proposed SET pathway. Reaction Mechanisms Part (ii) Polar Reactions 0Me OMe ? &02Ar &02Ar C02Ar R R References 1 J. P. Richard Tetrahedron 1995 51 1535. 2 K.Okamoto K. Takeuchi and T. Kitagawa Adv. Phys. Org. Chem. 1995 30 174. 3 T. Laube Acc. Chem. Res. 1995 28 399. 4 N. J. Head G. Rasul A. Mitra A. Bashir-Hashemi G. K. S. Prakash and G. A. Olah J.Am. Chem.SOC.,1995 117 12 107. 5 A. D. 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ISSN:0069-3030    

DOI:10.1039/OC9959200039

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

3 Reaction Mechanisms Part (iii) Free-radical Reactions By STEPHEN CADDICK and KERRY JENKINS School of Chemistry and Molecular Sciences University of Sussex Falmer Brighton BNl SQJ UK 1 Introduction Contributions to the area of organic free-radicals have been made this year from a wide range of groups including synthetic physical-organic and bio-organic chemists reflecting the continuing importance of the field. The complex issues surrounding the origin of the P-oxygen effect in Barton deoxygenation reactions are discussed in an illuminating full paper by Crich et a!.' This informative report gives many useful clues to the nature of this well-known but little understood effect; perhaps one of the most important conclusions is that the stabilization of the carbon radical by the P-C-0 bond is not significant and that relief of unfavourable dipolar interactions in the transition state is an important feature.2 Initiators Promoters Reagents and Precursors The oxidation of alkanes continues unsurprisingly to attract considerable attention and the debate regarding radical intermediates in the Gif oxidation continued throughout 1995.2 In a short but very nice account Hill describes work carried out by his group in the area of alkane oxidation using polyxometallates based primarily on t~ngsten.~ The oxidation of alkanes using the increasingly popular dimethyldioxirane (DMD) has been shown fairly convincingly by Minisci and collaborators to proceed viu a radical based mechanism. They show that the oxidation of alkanes such as cyclohexane occurs with greater efficiency in the presence of an oxygen atmosphere and is significantly retarded in the presence of inhibitors such as TEMPO (2,2,6,6-tetramethylpiperidin- l-yl~xyl).~These exciting results are explained by the authors in a mechanism which involves alkane induced homolysis of the DMD as an initiation process (Scheme 1).These workers have also reported a similar radical mechanism for the DMD mediated oxidation of a range of functional groups including alkyl and aryl halide^,^ alcohols aldehydes and ethers. The intermediacy of carbon-centred radicals in the oxidation of some of these functional groups is supported by trapping experiments as 51 Stephen Caddick and Kerry Jenkins DMD Escape from solvent cage 1 Cross couplingI Carbon centred radicals trapped by O2essentiallyhalting radical chain transfer R-OH + Scheme 1 - Solvent cage a-a+&+ THF Y+ acetone 50 "C 0-(11 (2) (3) (4) 23% 3.2% 2.8% Scheme 2 illustrated by the oxidation of tetrahydrofuran (THF)with subsequent trapping with protonated quinolines6 (Scheme 2).Of course the use of organic halides as precursors to carbon-centred radicals is a widely used strategy by synthetic organic chemists. A number of interesting reports highlight some alternative reagents which might be used in certain instances to generate carbon radicals from these versatile precursors. For example Negrel and co-workers claim that alkyl bromides will react with lithium aluminium hydride under strictly anaerobic conditions to give carbon-centred radicals' and Wayner and Reaction Mechanisms co-workers describe the reduction of bromo esters with pentamethylpiperidine and mercaptoethanol which is claimed to be radical in nature.' Whilst interesting at present both methods suffer from some practical limitations; however further developments may lead to some synthetically useful and complementary new procedures.More traditionally group 14 metal hydrides have been used for the transformation of organic halides into carbon radicals although the associated problems are well-established and require further attention. In this area Clive and Yang have described full details of the preparation of reagent (5) which they use in a range of standard reductive transformation^.^ The yields of these transformations are compar- able with those obtained using more conventional tin based reagents but the authors claim that the ease of purification when generating non-polar products is a significant advantage.Chatgilialoglu and Ballestri have reported the use of tris(trimethy1-sily1)germane as a reducing agent lo which is commercially available and is a slightly more effective hydrogen atom donor than tributyltin hydride (TBTH) (K,, = 3.1 x lo6dm3s-mol-at 25 "C). The use of allylstannanes in radical allylation reactions has become a very popular synthetic methodology. However in order to transfer more elaborate ally1 derivatives the availability of the appropriate stannane may become an important issue.In an interesting report Fouquet and co-workers describe their preparation of monoalkylstannanes via oxidative addition using the known stannylene (6).The resulting compounds (7),are of particular interest since they are relatively stable if protected from water and will undergo very efficient radical transfer with alkyl radicals generated under 'standard' conditions as described in the paper. From a practical viewpoint it appears that these reagents may have some considerable advantage over more conventional allyltrialkylstannanes in that the displacement reactions proceed with a smaller excess of reagent (1.2 equiv.)." In addition the by-products are sensitive to hydrolysis and the desired products are easier to purify from the 'inorganic' tin residue.Another tin based reagent (8) has been described by Tada and Kaneko12 and the reagent has been used to effect cyclization under photochemical conditions. Kraus and co-~orkers'~ have developed the use of triethylamine zinc and sub- TMs ,N-Sn-N 'TMS &Sn[N(TMS)2]p TMS TMS (7) X = CI Br I R = H CI Ph CN C02Et Stephen Caddick and Kerry Jenkins 0 56% Zn,B12 (0.05 equiv.) cH302c+ F* cH30*c@Br Vitamin Et3N DMF Et Et Br Et0hoEt0 87%&OEt Vitamin B12(0.05 equiv.)Zn,EfN DMF 80% Scheme 3 stoichiometric quantities of vitamin B to effect the generation of bridgehead radicals which then undergo a range of addition reactions as illustrated in Scheme 3. The use of arenediazonium salts as precursors to aryl radicals is enjoying a revival and as Murphy and co-workers have shown tetrathiafulvalene (TTF) is a particularly useful catalyst for this purpose.14 In this work the aryl radical generated is trapped in a range of addition and substitution reactions.Furthermore Wassmundt and co- workers have trapped aryl radicals generated from arenediazonium species by addition to other aromatic groups as shown in Scheme 4. They use a variety of methods for generating the intermediate aryl radical and found that optimal yields were obtained using FeSO, although there is no mention of the results when TTF is used." A range of other methods for the generation of carbon radicals have been described. For example Minisci and co-workers have developed general procedures for intramolecular aromatic substitutions based on copper silver and ironI6 and systems based on lanthanide/zinc have been used to effect diene cyclizations with per- fluorinated alkyl iodides." The radical decarboxylation process has long been recognized as a useful method for the generation of carbon-centred radicals and this year two interesting new variants have been reported.One of these described by Binmore et a1.,18 is based on the generation of CO and a stable aromatic by-product and is illustrated in the transformation of (9) to (10) in Scheme 5. Motherwell and his collaborators have also developed an interesting procedure based on the reaction of 0-acylthiohydroxamates with thionitrite esters. l9 Thus Reaction Mechanisms R' R2 Yield (%) H CH3 80 H OCH3 82 CH3 CH3 80 CH3 H 77 H H 83 H CI 79 Scheme 4 treatment of hydroxamate (11)with trityl thionitrite gives the dimer (13) via a chain process involving a substitution reaction presumably via addition-elimination of the alkyl radical to the thionitrite (Scheme 6).The intermediate nitroso species then rapidly dimerizes.These materials can be converted into synthetically useful monomeric species in quantitative yield by heating in isopropyl alcohol or by catalytic hydrogenation. One of the limitations of the methodology is that it cannot be extended to tertiary carboxylic acids the authors rationalize this by comparing the ability of primary and secondary nitroso compounds to dimerize with that of tertiary nitroso compounds.3 Intramolecular Reactions Tosyl radical-mediated additions and/or cyclization reactions have been developed further; Hatem and co-workers show the cyclization of allylallenes (14a-c) to (15a-c) in good yield using tosyl bromide (Scheme 7).20 In a synthetic approach to forskolin Pancrazi and co-workers demonstrated the feasibility of an effective 6-endo-trig enyne cyclization as shown in Scheme 8.21 The generation and cyclization of indol-2-yl radicals has been reported by Jones and collaborators.22 The generation and manipulation of 2-halo-indoles enables the preparation of the precursors which then undergo smooth cyclization (Scheme 9). This approach nicely demonstrates an alternative to most of the known radical methods for making C-C bonds at the 2 position of indoles.Stephen Caddick and Kerry Jenkins TsBr AIBN PhH A 'CH3 R' Br (1 4a-c) (1 5a-c) R' R2 Yield (%I a CH3 H 82 b H H 24 cisll7 trans c H Et 53 cisl29 trans Scheme 7 HSnBu? AIBN toluene. A 0 55% Scheme 8 Translocations Simpkins and co-workers have explored the possibility of developing a radical based alkene synthesis involving a radical abstraction followed by p-sci~sion.~~ Somewhat surprisingly they found that the abstraction process was fairly slow and in a competition experiment found that cyclization was the preferred reaction. For example when (16) was treated with TBTH cyclization products e.g.(17) were isolated in reasonable yields (Scheme 10).The only examples in which the alkene synthesis was successful utilized precursors in which cyclization was not possible e.g. in the transformation of (18a) or (18b) to (19a) or (19b). The use of organosilanes as hydrogen atom donors in translocation reactions has been put to good use in controlling reactivity. Thus Clive and Cantir~~~ have cleverly exploited the propensity of silicon containing precursors to confer endo-selectivity in a 57 Reaction Mechanisms HSnBu3 AIBN toluene A * QT$ 70-80% Scheme 9 Bu3SnH AIBN PhH A 02 -PhSO; I RqoBz Ph (19a) R = H 39% (19b) R = CH, 42% (Z-isorner) (Bz = benzoyl) Scheme 10 very elegant sequence as illustrated in the transformation of (20) to (23) in Scheme 11.The first cyclization proceeds to generate the intermediate vinyl radical species (21) and thence the silicon centred radical (22) which then undergoes 5-endo-trig cyclization. The siloxane products are amenable to further synthetic manipulation as detailed in the paper. Curran and co-workers have also utilized efficient hydrogen-atom transfer from silanes to assist in mediating 'slow' bimolecular radical proce~ses.~' As shown in Scheme 12 addition of the radical derived from bromide (24) is very inefficient and either low yields of mixtures or large recovery of starting alkene results from more conventional reaction conditions. However simply modifying the silyl protecting groups as in substrate (26) results in an efficient addition process which after deprotection gives product (29) in good yield with only 5 mol% ditin required (Scheme 12).The propagating steps here involve fast intramolecular hydrogen atom transfer Stephen Caddick and Kerry Jenkins Ph3SnH,AIBN PhH,A (23) 57-72% Scheme 11 [(27) to (28)] and intermolecular bromine atom transfer which is slow. This cleverly designed process should have significant practical applications. Aromatics Jones and co-workers have shown that aryl radicals can add to pyrrole nuclei as exemplified in the transformation of (30a-c) to (31a-c) (Scheme 13).26 Aromatic Substitution Minisci and co-workers have shown that intramolecular carbamoylation of heteroaro- matics via ips0 substitution can be achieved." Addition of alkyl radicals to a range of heteroaromatics has been reported by Chuang and Wang as highlighted in the transformation of (32) to (33) using sodium toluene-p-sulfinate (TsNa) in the presence or absence of Cu(OAc) (Scheme 14).28 Substitution at the 2-position ofindoles can provide a useful method for the synthesis of functionalized and fused indoles.Two different approaches have been reported. The first involves the direct H-atom substitution which may in view of previous work by Ziegler be dependent upon the presence of substituents at the 3-po~ition.~' The second involves phenylthio and phenylsulfinyl substitution but takes place without substitu- tion at the 3-position (Scheme 15).30 Beckwith and Storey have very elegantly promoted aromatic ips0 substitution but have incorporated a H-atom transfer step in the ~equence.~' Thus oxindoles (35a) and (35b) result from treatment of aryl bromides (34a) and (34b) with TBTH-(Bu'O) (Scheme 16).Reaction Mechanisms PhO 0 (24) FAST PhOKCHJ + recovered (25) OTBS OTBS SLOW Br abstraction from (24)I P h O h Br OTBS 31% OSi(Bu'),H (27) (28) Br abstraction (24) SLOW 1 P h O OHh (29)71% Scheme 12 Stephen Caddick and Kerry Jenkins A Bu3SnH,AIBN R-toluene A I (30a-c) a R = CH3 (31a-c) a 28% b,R=H b 34% C R = CO~BU' c 12% Scheme 13 i or ii TsNa (10 equiv.) Ts (33) Scheme 14 Reagents and conditions i heat 48 h 66%; ii Cu(OAc) (2 equiv.) heat 24h 81% OBn OBn Bu3SnH,AIBN SLOW addition S(O)& toluene heat I Scheme 15 n = 1,47% n = 2,73% n = 3 29% n =O,m =l,24% n = 0 m = 2 50% n =l,m =1,40% n = 1 m = 2 50% n =l,m =3,30% Reaction Mechanisms Scheme 16 vs> Bu,SnH (5 equiv.) AIBN ms) cyclization fi-1 reduction1HSnBu3 (36) 70% Scheme 17 Cawademandem Reactions In a very elegant and efficient example of a tandem process Harrowven and Browne have developed an approach to condensed thiophenes as shown in Scheme 17.32 This sequence involves an unusual cyclization-fragmentation sequence which after reduc- tion undergoes intermolecular ips0 substitution to give the tributylstannyl substituted benzothiophene (36) in good yield.Parsons and co-workers have examined some complex but appealing tandem cyclization reactions toward pseudocopsinine and aspidosperma alkaloids as shown in the transformation of (37) to (38) and (39) to (40) respectively (Scheme 18).33 Bowman et al.have developed an approach to heterocyclic bicycles via tandem cyclization involving addition of an alkyl radical to an imine followed by addition of the nitrogen centred radical to an alkene. The use of a Lewis acid (MgBr,.Et,O) assists the cyclization of the aminyl radical intermediate and generally results in improved Stephen Caddick and Kerry Jenkins NC02CH3 HSnBu,AIBN PhH A 0-% a1EjH3 \ 0 0 (37) (38) 22% NC02CH3 Bu3SnCCNaBH4CNt AIBN 0-F OTBDMS BU‘OH A OTBDMS 0 (39) (40) 6% Scheme 18 MgBr2*Et20 Bu3SnH AIBN -toluene A 5 Ph/ Ph Ph (41) H abstraction 4 5Ph Ph (42) 33% Scheme 19 yields as highlighted in the cyclization of (41) to (42) in Scheme 19.34 Jahn and Curran have reported a rapid but low yielding tandem cyclization approach to the steroid skeleton as shown in the transformation of (43)to (44)(Scheme 20).The poor yield of this process is attributed with experimental verification to the more favourable translocation processes which can intervene.35 Reaction Mechanisms CN Bu3SnH(3mmol dm-3) AIBN SLOW addition PhH A TBDPSO TBDPSO (43) (44) 4% Yield 90% diastereoselectivity (ds) 93:7a:b (-)-8-phenylmenthyl Scheme 21 Stereoselectivity Stereoselective cyclizations are of great importance particularly in natural product synthesis and Ishibashi and co-workers have shown that using a matched pair of auxiliaries can lead to good stereoselectivity in asymmetric radical reactions.36 Nishida and co-workers have in a series of investigations illustrated that good levels of stereoselectivity can be achieved in the cyclization of vinyl radicals onto electron deficient alkenes bearing chiral auxiliaries.These workers show the importance of the nature of the Lewis acid particularly in view of the fact that in certain instances the Lewis acid appears to negate the use of a conventional initiator (e.9.Et,B) as shown in the transformation of (45) to (46a) and (46b) (Scheme 21);37at present it is unclear whether this is a general feature of this type of cycli~ation.~~ Reactions of this type are clearly quite complex and a more detailed understanding is essential prior to developing more general synthetic procedures.It would appear however that the Lewis acid simply enhances the levels of stereoselectivity in cyclizations of this type which can still proceed with fairly good levels of stereocontrol without Lewis acid as shown in the cyclization of (47) to (49a-d) (Scheme 22).,’ + TBDPSO TBDPSO Scheme 20 Stephen Caddick and Kerry Jenkins B"""""0 Bu3SnH Et3B /toluene 0 "C (47) Yield 77% ds (6:67:9:18) a:b:c:d R*= $,& (-)-8-phenylmenthyl Scheme 22 4 Intermolecular Reactions Further important contributions in this area have been made this ear.^'.^' In the general field of substrate control Giese continues to probe 1,2-stereoinduction and is attempting to derive some general rules regarding the stereochemical outcome for radicals of the general structure (50).He concludes that if X is a conjugating planar group then the A-strain model can be used to rationalize stereochemical outcome. If the substituent is linear or tetrahedral stereoinduction is negligible and if X is oxygen then the stereochemical outcome can be rationalized using the Felkin-Anh r~le.~~y~~ The problems associated with attempting to predict the stereochemical outcome of substrate-controlled reactions are made clear once again by Giese in the continuing developments in enolate radicals which have been shown to be sensitive to polar effects unless one of the substituents is extremely Guindon has examined similar systems which have yielded good levels of stereocontrol which can be reversed using Lewis Ogura and co-workers describe a system in which high 1,2-syn-selectivity can be achieved as illustrated in the transformation of (51)to (52)46 (Scheme 23) and Taguchi and co-workers have examined stereoselective radical additions to y-oxy-a,&un- saturated esters in cyclic and acyclic system^.^' Auxiliaries continue to attract considerable attention.Garner and co-workers have utilized carbohydrates as recoverable auxiliaries for use in diastereoselective radical addition reactions as shown in the formation of (54) from (53)48 (Scheme 24) and Hamon and co-workers detail in full some of their investigations into asymmetric radical additions of glycine derivative^.^' Reaction Mechanisms 65 OH OH SCH3 i (CH3),CHOHbenzophenone,hv S02T0l &so*TOl ii Raney Ni OH (52)84%; de 90% Scheme 23 BnO \ L (53) BnO\ uY02cH3 ds 11:l Scheme 24 Axon and Beckwith have developed a very practical and versatile approach to either enantiomer of a-amino acids utilizing oxazolidin~nes.~~ They exploit a very useful protecting group effect to prepare either enantiomer of a particular series; thus treatment of (55)or (57)with cyclohexyl radical leads to the 'pseudo' epimeric products (56)and (58)with good levels of stereocontrol (Scheme 25).Hydrogenolysis leads to the free amino acid. The ability to prepare either enantiomer by modifying the protecting group bodes well for the practical application of this strategy.Sat0 and co-workers have also used a diastereoselective approach to prepare carboxylic acid derivatives and are also able to prepare either epimeric product in this case by modifying the reaction condition^.^' They find that addition of alkyl radical to acceptor (59) using the appropriate hydrogen atom donor [in this case tris(trimethy1- sily1)silane (TTMSSH) is optimal] leads to the product in which the hydrogen atom donor approaches from the least hindered face as shown. The selectivity can be reversed Stephen Caddick and Kerry Jenkins +-<:x C-CaHtiHgH 0APh OAPh (55) (56) 89% 68% de Scheme 25 0 TTMSSH Bu PhP d 9 Ph (59) (60) 60% 96% de HSnBu3 OJ$bu Ph B*h 0.(61) 91% 20% de ‘AI-A -CI’ ‘Ar Scheme 26 by carrying out the reaction in the presence of a bulky Lewis acid such as (62),which coordinates to the carbonyl from the least hindered face forcing the hydrogen atom donor to approach from the opposite face to give predominantly the epimeric product (61)- The use of achiral auxiliaries as templates for chiral non-racemic promoters is an interesting and valuable strategy for asymmetric synthesis and Porter and co-workers have applied this approach to effect relative52 and absolute53 stereocontrol in radical addition reactions as shown in Scheme 27. Hoshino and co-workers have used an enantioselective halide reduction using a Reaction Mechanisms 00 Zn(OTf);$2 equiv.) eSnBu3 OANVR lNL 0u R-I * ____t u R = c-C6H11 92% 72% ee R = But 55% 88%ee Scheme 27 I i MgIz-EtzO(l-O equiv.) L' (1-0 equiv.) ii Bu3SnH DCM.-78 "C rac-(63) (64) a0% 62% ee L*= "" BnO 8 i \ / ii Bul Bu3SnH Et3B toluene -78420"C * OYBU (66)47% 28% ee Scheme 28 magnesium based system with good yields and promising ees [see reaction of (63) to (64) Scheme 28].54 Subsequently the use of a chiral non-racemic aluminium based Lewis acid to effect a similar asymmetric hydrogen atom transfer to an enolate radical has also been reported by Sat0 and co-~orkers~~ illustrated in the transformation of (65) to (66). Although the levels of enantioselectivity are moderate these are exciting developments in the area.The asymmetric oxidation of alkanes is of course one of the most fundamental types of transformation one can achieve in organic chemistry and Andrus and co-workers exploit the ubiquitous copper-bis-oxazoline systems to effect catalytic enantioselective allylic oxidation with modest yields but promising levels of enantioselectivity (4&60% yield up to 80%ee) as shown in Scheme 29.56 Stephen Caddick and Kerry Jenkins 0 OBz PhKOd0'Bu' Q Q 49% 81Yoee OTF MeCN. -20 "C OBz CSH,,.A9 C5Hll 50% 30% ee PhH 55 "C Scheme 29 au32,y* + // 14% 58% Scheme 30 5 Applications to Natural Product Synthesis Parsons et al. have developed an elegant synthesis of the sensitive cyclodecene core common to the periplanone class of insect attractant via a 10-endo-dig cyclization as shown in Scheme 30.57 In an approach to the aspidosperma class of alkaloids Kizil and Murphy have developed an azide terminated tandem cyclization of (67) to (68) and thence (69) (Scheme 31).58 The synthesis of ( +)-7-deoxypancratistatin by Keck and co-workers incorporates a radical cyclization of thiocarbonylimidazole precursor (70) to (7 1) in good yield (Scheme 32)." Finally this section would not be complete without mention of the transannular cyclization strategy toward 7,8-epoxybasmen-6-one described in full by Myers and Condroski and this strategy is highlighted in Scheme 33.60 Reaction Mechanisms TTMSSH AlBN PhH,A I I S02CH3 SO2CH3 (67) (68) dil.acid 1 I S02CH3 (69) 95% Scheme 31 OMOM TBSO Bu3SnH AlBN c (70) (71) 70% Scheme 32 References 1 D. Crich A. L. J. Beckwith C. Chen Q. Yak 1. G. E. Davison R. W. Longmore C. Anaya de Parrodi L. Quintero-Cortes and J. Sandoval-Ramirez,J. Am. Chem. SOC. 1995 117 8757. 2 F. Minisci F. Fontana S.Araneo F. Recupero S. Banfi and S. Quici J. Am. Chem. Soc. 1995 117,226. 3 C.L. Hill Synlett 1995 127. 4 A. Bravo F. Fontana G. Fronza A. Mele and F. Minisci J. Chem. Soc. Chem. Commun. 1995 1573. 5 A. Bravo F. Fontana G. Fronza F. Minisci and A. Serri Tetrahedron Lett. 1995 36,6945. 6 F. Minisci L. Zhao F. Fontana and A. Bravo Tetrahedron Lett. 1995,36 1895. 7 E. Peralez J.-C. Negrel and M.Chanon Tetrahedron Lett. 1995 36 6457. 8 M. Amoli M. S. Workentin and D. D. M. Wayner Tetrahedron Lett. 1995,36 3997. 9 D.L. J. Clive and W. Yang J. Org. Chem. 1995,60 2607. 10 C. Chatgilialoglu and M. Ballestri Organometallics 1995 14 5017. 11 E. Fouquet M. Pereyre and T. Roulet J. Chem. Soc. Chem. Commun. 1995 2387. 12 M. Tada and K. Kaneko J. Ory. Chem. 1995,60,6635. 13 G.A. Kraus T. M. Siclovan and B. Watson Synlett 1995 201. 14 R. Fletcher C. Lampard J.A. Murphy and N. Lewis J. Chem. Soc. Perkin Trans. 1 1995 623. Stephen Caddick and Kerry Jenkins H abstraction 51% cyclised products I t isornerization PhSH-heptane (1:3) AIBN hv,23-62 "C 74% Scheme 33 15 F.W. Wassmundt and R. Pedemonte J. Org. Chem. 1995,60,4991.16 S. Araneo F. Fontana F. Minisci F. Recupero and A. Serri Tetrahedron Lett. 1995 36 4307. 17 W.-Y. Huang G. Zhao and Y. Ding J. Chem. Soc. Perkin Trans. 1 1995 1729. 18 G. Binmore J. C. Walton and L. Cardellini J. Chem. Soc. Chem. Commun. 1995 27. 19 P. Girard N. Guillot W. B. Motherwell and P. Potier J. Chem. Suc. Chem. Commun. 1995 2385 20 F. El Gueddari J. R. Grimaldi and J. M. Hatem Tetrahedron Lett. 1995 36 6685. 21 C. Arnes L. Billot J. Lallemand and A. Pancrazi Tetrahedron Lett. 1995 36 7247. 22 A.P. Dobbs K. Jones and K.T. Veal Tetrahedron Lett. 1995,36,4857. 23 C. D. S. Brown A. P. Dishington 0.Shishkin and N.S. Simpkins Synlett 1995 943. 24 D.L. J. Clive and M. Cantin J. Chem. Soc. Chem. Commun. 1995 319. 25 D. P. Curran J. Xu and E.Lazzarini J. Am. Chem. Soc. 1995 117 6603. 26 K. Jones T.C.T. Ho and J. Wilkinson 36 6743. 27 F. Minisci F. Fontana F. Coppa and Y.M. Yan J. Org. Chem. 1995 60 5430. 28 C.-P. Chuang and S.-F. Wang Synlett 1995 763. 29 C.J. Moody and C. L. Norton Tetrahedron Lett. 1995 36 9051. 30 S. Caddick K. Aboutayab R. West J. Chem. Soc. Chern. Commun. 1995 1353. 31 A. L. J. Beckwith and J. M.D. Storey J. Chem. Soc.. Chem. Commun. 1995 977. Reaction Mechanisms 32 D.C. Harrowven and R. Browne Tetrahedron Lett. 1995,36,2861. 33 P. J. Parsons C. P. Penkett M.C. Cramp R. I. West J. C. Warrington and M.C. Saraiva Synlett 1995,507. 34 W. R. Bowman P.T. Stephenson and A. R. Young Tetrahedron Lett. 1995 36 5623. 35 U. Jahn and D. P. Curran Tetrahedron Lett.1995,36,8921. 36 H. Ishibashi C. Kameoka K. Kodama and M. Ikeda Synlett 1995,915. 37 M. Nishida H. Hayashi 0.Yonemitsu A. Nishida and N. Kawahara Synlett 1995 1045. 38 M. Nishida H. Hayashi Y. Yamaura E. Yanaginuma 0. Yonemitsu A. Nishida and N. Kawahara Tetrahedron Lett. 1995,36 269. 39 M. Nishida M. Nobuta K. Nakaoka A. Nishida and N. Kawahara Tetrahedron Asymmetry 1995,2657. 40 D.P. Curran and L. Balas Synlett 1995 119. 41 H. Urabe K. Yamashita K. Suzuki K. Kobayashi and F. Sato J. Org. Chem. 1995,60 3576. 42 B. Giese M. Bulliard J. Dichau R. Halbach C. Hassler U. HolTmann B. Hinzen and M. Senn Synlett 1995 116. 43 P. Renaud and M. Gerster J. Am. Chern. Soc. 1995 117 6607. 44 C. Hassler R. Batra and B. Giese Tetrahedron Lett. 1995 36 7639. 45 Y.Guindon B. Guerin C. Chabot N. Mackintosh and W. W. Ogilvie Synlett 1995 449. 46 K. Ogura A. Kayano N. Sumitani M. Akazome and M. Fujita J. Org. Chem. 1995,60 1106. 47 T. Morikawa Y. Washio S. Harada R. Hanai T. Kayashita H. Nemoto M.Shiro and T. Taguchi J.Chem. Soc. Perkin Trans. 1 1995 271. 48 P. P. Garner P. B. Cox and S.J. Klippenstein J. Am. Chem. Soc. 1995 117 4183. 49 D. P.G. Hamon R. A. Massy-Westropp and P. Razzino Tetrahedron 1995,51,4183. 50 J. R. Axon and A. L. J. Beckwith J. Chem. Soc. Chem. Commun. 1995,549. 51 H. Urabe K. Kobayashi and F. Sato J. Chem. Soc. Chem. Commun. 1995 1043. 52 R. Radinov C. L. Mero A.T. McPhail and N. A. Porter Tetrahedron Lett. 1995 36 8183. 53 J. H. Wu R. Radinov and N.A. Porter J. Am. Chem. Soc. 1995 117 11 029.54 M. Murakata H. Tsutsui and 0.Hoshino J. Chem. Soc. Chem. Commun. 1995 481. 55 H. Urabe K. Yamashita K. Suzuki K. Kobayashi and F. Sato J. Am. Chem. Soc. 1995,60 3576. 56 M. Andrus A.B. 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ISSN:0069-3030    

DOI:10.1039/OC9959200051

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

4 Aliphatic and Alicyclic Chemistry By PETER QUAYLE Department of Chemistry University of Manchester M 13 9PL UK Introduction As stated in the last report the interplay between scientific disciplines becomes ever more apparent and again features heavily this year. In some quarters this interplay is regarded with suspicion as it is believed that it represents an erosion of the standing of the synthetic organic chemist within the scientific community at large. However this reviewer believes that such collaborations will provide fertile areas of research in which the traditional skills of the synthetic chemist can be used in tandem with other disciplines to provide a rational basis for the design and manipulation of complex systems. Such collaborations will hopefully generate new methodology which can then be applied to the more traditional areas of interest.A number of key papers have appeared this year which nicely illustrate this point. Bio-organic Chemistry The use of enzyme systems as reagents for organic synthesis is by no means a novel concept. Traditionally their utilization in organic synthesis has been primarily concerned with stereoselective transformations and is now relatively widespread.’-3 More significant however is the approach adopted by a number of interdisciplinary research groups who have by recombinant genetic engineering techniques begun to manipulate the enzyme systems themselves i.e. to prepare ‘tailor-made’ systems in order to divert natural biosynthetic pathways. The application of molecular biology to enzyme manipulation presents a number of exciting possibilities especially for the synthesis of ‘designed’ natural products which may have useful biological properties and therefore has far ranging implications in the pharmaceutical industry.This approach to ‘natural product’ synthesis is exemplified in the isolation of the novel tetracenomycin (1) by diversion of the normal polyketide assembly path~ay.~ The application of modern analytical techniques new developments in combinatorial synthesis’ and traditional synthetic methodology have enabled a number of groups to gain further insights into protein structure and protein-ligand ligand recognition by E-selecting and DNA binding of oligosaccharides. loAn understanding of such interactions is of prime importance for the development of new therapeutic agents.l1 Olefin Metathesis Olefin metathesis reactions have been extensively investigated by polymer chemists as a means of preparing polymeric systems from simple olefins.It is not until recently 73 Peter Quayle however that well characterized and highly efficient metathesis catalysts such as (2) have been described and in-depth investigations of their metathesis chemistry been undertaken.12 The potential utility of olefin metathesis in natural product synthesis as opposed to polymer synthesis is enormous but impossible to realize until the development of metathesis catalysts tolerant to polar functionality and which are also readily prepared using relatively unsophisticated anaerobic experimental procedures.Pioneering work from Grubbs' groupI3 has established that the stable but metatheti- cally active complexes such as (2) are readily prepared from simple intermediates with the result that a number of groups have begun to investigate their synthetic chemistry.14.15 A most striking feature of catalysts such as (2) is their degree of functional group tolerance in ring closing metathesis reactions (RCM). This type of reaction has been successfully applied to the synthesis of five-16 six-17 seven-18 and even in certain circumstances eight-membered rings,lg Scheme 1. Heteroatoms (e.g.N and 0,P) and polar functionality e.g. N-H bonds are also accommodated.20 Nugent and co-workers have demonstrated that the closely related catalyst system (3)enables metathesis of the diene (4)to the cyclopentene (5) on a multi-gram scale and with complete retention of optical activity Scheme l.17 Two further examples the preparation of a 'peptide cylinder' (6) by Clark and Ghadiri2' and the application of RCM to the synthesis of the macrocyclic lactam (7) by Hoveyda and co-workers22 clearly demonstrate the potential of this new technology to complex synthetic undertakings Scheme 2.The application of metathesis-type reactions in an inter-molecular sense is at present less well developed although initial investigations by both Grubbs and co-~orkers~~ indicate that such processes and Snapper and co-~orkers~~ provide a viable alternative to existing olefin syntheses. C-H Activation Catalytic C-H activation is the Holy Grail of organometallic chemistry and has many potential applications in organic ~ynthesis.~'-~' Recent results26 from Murai's group have convincingly demonstrated that C-H insertion of aryl ketones can be achieved under mild conditions using catalytic [Ru(H),(Ph,P),(CO)] (8).Furthermore reaction of the derived organometallics (9)with a variety of olefins and acetylenes to AIiphatic and Alicyclic Chemistry 0 BubKN (2) (Ref. 16) TH PhH,room temp: 92% 'OH -'"0 [cat.] (Ref. 17) 90"C 64% (99% ee) [cat.] = PhH 25 "C 99% [ Ref. 19(a)] RJ H OBn ,OBn / Qp-Qo 77% [Ref. 19(b) J yv I COCF3 COCF3 H I ( Ref. 20) I H ( Ref. 17) (4) (5) Scheme 1 Peter Quayle Covalent capture (Ref.21) Scheme 2 the formation of a variety of functionalized aryl ketones Scheme 3. Of note is the observation that the insertion-coupling sequence is catalytic in the complex (8). Although extensive investigations have yet to be reported these results nevertheless suggest that catalytic C-H insertion-coupling sequences may be relatively general as clearly demonstrated in an application of this methodology to C-H insertion of functionalized olefinic substrates as recently reported by Tr~st,~' Scheme 4.In a related series of experiment^,^^ Murahashi and co-workers have also shown that the complex (8)catalyses aldol and Michael reactions of nitriles with aldehydes and x,b-unsaturated Aliphatic and Alicyclic Chemistry (9) (Ref.28) [Rul + Y Si(OEt)3 H3 i cat. (8) t +cH3 (Ref. 29) NMe2 NMe2 + 85% @Si(OEt)3 ii (8) -(Ref. 30) + Si(OEt)3 @Si(OEt)3 -quantitative ____t iii (8) Et& + (Ref.31) '& \ 73% 27% + \ (9) Scheme 3 Reagents and conditions i PhCH, 135 "C 8 h; ii PhCH, 175 "C 1 h; iii PhCH, 135"C 4 h Peter Quayle C\02C2H5 i (8),ii 0 (Ref. 32) X-qo c ko pSi(0Et)s Scheme 4 Reagents and conditions i PhCH, 135"C (70%);ii H202 KHCO (63%) CN C02Et Ro2c+co2Et + 54%-(8) CH3 Scheme 5 carbonyl functionality respectively Scheme 5. Further investigations primarily with respect to 'fine-tuning' of the catalyst systems currently employed will hopefully expand the general utility of these transformations.General The development of new methodology for asymmetric synthesis continues to grow exponentially3L43 as do various applications of organ~metallics~~~' and heterogen- eous catalysis72 in organic synthesis. Carbohydrate chemistry poses many challenges to the synthetic organic chemist,73 although in recent years significant advancements in oligo- and poly-saccharide synthesis have been reported.74 Emerging technology in this area e.g. polymer-supported solution synthesis73 will doubtless be avidly scrutinized by workers in the field. Ho~t-guest,~~ molecular supra-molecular chemistry," including novel polymers' 'and multidisciplinary approaches aimed at understanding the role and synthesis of enzyme analogues again featured heavily.'* In related areas the synthesis of 'receptors' capable of enantioselective discriminationg3 or recognition of specific sugarss4 has been realized.Fullerene chemistry continues to grasp the imagination of chemists across the whole spectrum of the disciplines5 and has for example led to the synthesis of azafulleroids.86 Likewise the chemistry of enediynes continuesg7 to attract much attention from synthetic and mechanistic chemists. A timely overviews8 of combinatorial approaches to synthesis presents a rational view of one of the more frenzied areas of contemporary synthesis whereas articles on 'two-directional' ~ynthesis'~ and the use of tandem or cascade reactions in synthesisg0 discuss advances in more traditional aspects of the subject.The chemistry of oxyster~ls,~' acetogeninsg2 and oligotetrahydrof~rans,~~ antisense nu~leotides,'~P-la~tams,'~ fungal metabolite^,^^ duocarmycins,97 oxetan-2-0nes,'~ Aliphatic and Alicyclic Chemistry 0 A Hi' OH I Me.. Figure 1 80 Peter Quayle 2 \ \ C6H13 0 I 0x C6H13 93% liv (Ref. 112) Scheme 6 Reagents and conditions i AD-mix /3 (91%); ii SOIm, THF; iii RuCl, NaIO (82%); (iv) CH,CN-H,O 80 "C inositol~,~~ and organofluorine compounds"' have been reviewed in detail. The art of organic synthesis is embodied in the achievements of Gilbert Stork who for fifty years has been a master of his craft."' A splendid compilation'02 of reports on natural product synthesis has also appeared.Contrary to popular belief the development of new synthetic methodology should remain a paramount consideration as present day methodology is still lacking in terms of chemoselectivity as illustrated by the requirement to develop sophisticated protection-deprotection strategies in complex synthetic undertakings. '03 The total synthesis of complex natural products is now a relatively common event and this year has been no exception. Representative examples (Figure 1)include the synthesis of brevetoxin (10),'04 dynemycin (1 l),'" Taxol(12) milbemycins G 1069107 (13)''* and B, (14),'" sLeX tetrasaccharide glycals (15)"' and a full report"' on the total synthesis of rapamycin (16). The current drive to develop cascade processes in order to simplify the total synthesis of complex natural products is nicely demonstrated by Rychnovsky's polyepoxide-type cyclizations (utilizing Sharpless's asymmetric dihydroxylation methodology),' ' Scheme 6 and Eyrisch and Fessner's synthesis of dissacharide mimics which incorporates tandem enzyme-mediated aldol reactions,' '' Scheme 7.3 Aliphatic Chemistry Oxidations Sharpless-type dihydroxylation reactions continue to gain favour for the enantioselec- tive functionalization of alkenes.' 'u2'Care should be taken when invoking the Aliphatic and Alicyclic Chemistry HO -___ti "OhoH w " O W O H (Ref. 113) OHC CHO ii HE*: HO ii CHO ] OH OH OH R = PO:-iii( R = H Scheme 7 Reagents and conditions i 0,-MeOH -78 "C Me,S room temp.; ii 1.0 equiv.FBP FruA (500U) triosephosphate isomerase (500U) pH 7.2 7 days 40% conversion; iv acid phosphatase (50U) pH 5.8 16h i w R2 R3 >%yo (Ref. 123) RlxsiMe2R4 n ii -(Ref. 124) g C02Me 84% MOMOC02Me 85% Scheme 8 Reagents and conditions i DMDO acetone 20°C; ii DMDO CH2C1,-acetone; iii BF,-OEt,; iv DMDO acetone 0 "C empirical paradigm used to predict the stereochemical outcome of such reactions as to be expected in certain cases anomalous results have been reported.'22 Dimethyl- dioxirane (DMDO) and its derivatives continue to find applications for the chemoselective o~idationl~~-~~' of sensitive substrates Scheme 8. The in situ gener- Peter Quayle cF3 OMe H -~ i (Ref.128) \ CH3 0 80% (20% se) via Scheme 9 Reagents and conditions i KHSO, pH 7.5 CT".. 'CH3 98% Scheme 10 ation of the chiral non-racemic derivative (17)has been reported thus far epoxidations of prochiral alkenes with this reagent proceed with only modest levels of asymmetric induction (12-20% ee) Scheme 9.'" It is anticipated that these findings will serve as a catalyst for the development of more efficient and more discriminating enantioselective oxygen-transfer agents. Recent mechanistic investigations point to the intermediacy of free radical species during related oxidations using these reagent^.'^' The search for 'cleaner' (i.e. environmentally friendly) reagentsI3' has resulted in renewed interest in the development of hydrogen peroxide as a chemical reoxidant for a variety of catalytic oxidation rea~ti0ns.l~' Most notable are the reports concerning the use of an MTO-H,O system which appears to have much potential as a selective oxidizing agent for organic synthesis Scheme The use of a relatively innocent silicon A1ipha t ic and Alicyclic Chemistry &SiMe2Ph t c Oyo'n.0-/SiMe2Ph lii 71% OH 60%1v vi (Ref.135) Ph Scheme 11 Reagents and conditions i BF *OEt, CH,Cl, -78 "C; ii AcOOH Hg(OAc), AcOH; iii PhSeC1 Et,O -60°C; iv Bu,SnH AIBN PhH; v F- vi H,O ,-K F moiety as a masked OH group has been exploited to good effect this year. This methodology should gain further acceptance with the development of more versatile unmasking procedures Scheme 11.' 33-136 Corey and Palani have developed a simple method',' for the direct conversion of diols into lactols a transformation which until now required a multi-step sequence.Pflatz and co-workers have dem~nstrated',~ that cyclic alkenes can be converted directly into allylic benzoates with respectable levels of asymmetric induction (up to 82% ee) when reacted with PhC0,Bu' in the presence of chiral copper(1) complexes Scheme 12. Reich selenoxide elimination is recognized as one of the most valuable alkene- generating reactions. Note however should be made of subtle steric and/or electronic effects which may be operative in certain cases which can lead to either unexpected products'39 or enhanced levels of regiocontrol'08 in the synthesis of unsymmetrical alkenes Scheme 13.Peter Quayle 64% (77% ee) (Ref. 138) Scheme 12 Reagents and conditions i PhCO,Bu' Cu'OTf (5mol%) L* (6-8 mol%) ace tone C02Et qO2Et -(Ref. 108) HO CH3 HO OH OH OH 40 60 C02Et q02Et q02Et ____) BU'O~H 92% jQ jQ HOQCH3 SePh HO HO OCO,CCI3 RO OR 7 1 Scheme 13 Reagents and conditions i KOH-H,O,-MeOH Reductions Asymmetric catalytic hydrogenation reactions continue to be developed for the synthesis of a variety of useful synthetic intermediates. 140-144 Buchwald and co- workers have developed a catalytic method for the reduction of lactones to lactols Scheme 14,145whilst a versatile reducing reagent [LiH-Bu'OH-Ni(OAc),] prepared by activation of commercial lithium hydride has been reported by Fort.'46 Chirally modified boranes again have been used to good effect for the enantioselective reduction of prochiral or ('quasi' prochiral) carbonyl compounds Scheme 15.'47-'50 Finally catalytic hydrogenation of aromatic substrates provides access to polyalkylated cyclohexanes which are themselves of some synthetic utility Scheme 16.15' Aliphatic and Alicyclic Chemistry -BnoBOH Oxo CH3 \ CH3 CH3 CH3 \ CH3 CH3 94% 89% 94% ?oc ?OC 92% 'Ti complex' = [Ti+OoC1)2 Cpp] Scheme14 Reagents and conditions i 'Ti complex' (2 mol%) TBAF-Al,O (1mol%) PMHS PhCH, 20°C Ph Ph d C H 3 &OH i ,,h%r(0.1equiv.) H-B:OO0 (1.1 equiv.) 1 th ,-i+ ii H30+ (Ref.147) 82% ee 100% yield NHZ NHZ (SO% 2 95%de) Scheme 15 Peter Quayle Scheme 16 Reagents and conditions i Raney-Ni H + PhSnC13 -+ Pd" (Ref.153) Pd" + PhSnC13 -phwco2H Brwco2H (Ref. 154) I I H H 79% B(W2 \ 6 ox1' Pd" + R Scheme 17 Coupling Reactions R (Ref. 155) The direct synthesis of ketones from acyl bromides and Grignard reagents can be achieved' 52 in the presence of [Ni(dppe)CI,] [dppe = ethylenebis(dipheny1phos-phine)]. Palladium-mediated coupling reactions continue to dominate catalytic processes for C-C bond formation. The use of hydroxystannanes in aqueous Stille-type reactions palladacycles as modified catalysts high pressure techniques water soluble palladium catalysts vinylsilanes solid phase synthesis and immobilized palladium Aliphatic and Alicyclic Chemistry X X (trace) + X ii 'Uo OH PhP (Ref.161) Scheme 18 Reagents and conditions i [Pd(Ph,P),] (Pr'),NH CuI-THF; ii Ph,P (3 equiv.) [(Ph,P),Pd] (Pr'),NH CuI (0.01equiv.) THF 120"C catalysts are all apparently advantageous under certain conditions. l5'-l6' Note should be made however of potential problems which can be encountered when using such reactions as depicted above where preferential migration of a phenyl group from the ligand system to substrate occurs. 16' Nevertheless palladium-mediated cross coup- lings are exceedingly useful as exemplified above,' s ,-' 5,'62 Schemes 17-20.A seminal contribution from Falck et a!. underscores the potential of Stille-type coupling reactions at sp3 hybridized C-Sn bonds Scheme 20.'62d Aldol and related methodology is of major importance to organic synthesis; given this pre-eminence it is a little surprising that our understanding of 'simple' salt effects in such processes are still somewhat empiri~al.'~~-'~' Gallagher Lichtenhaler and co-workers have prepared well behaved sugar-derived enolates and found them to undergo a number of useful akylation reactions Scheme 21.'66 4 Alicyclic Chemistry Cyclopropanes A pleasing aspect in recent years has been the revitalized interest in the preparation of novel structures with a view to probing bonding theories and the design of new materials.For example Volhardt and co-workers have rep~rted'~' the preparation of the first [2.1.2.1.2.l]hexaannulene (19)from the cyclohexatriene (18).The hexaannu- Peter Quayle [Ref.162(a)] &J n = 6 24% n = 8 16% 0 0 [Ref. 162(b)] 71% 70% e-;" / Bu Bu 43% Scheme 19 Reagents and conditions i CO (1 atm); [C12Pd(PPh,),] (5mol%) Et,N Pr'OH 75°C lene (19) exhibits remarkable thermal (stable > 200 "C) and chemical stability. Diederich and co-workers have reported168 the synthesis of a number of radialenes (20) which possess interesting redox properties and Gleiter et al. have reported the preparation of the C5.5)biscyclopropanyliumphane (21) a new class of cyclophanes containing 2n-Hiickel aromatic^.'^' Most intriguing is the report by bio-organic chemists at MIT who have conclusively dem~nstrated"~ that the inactivation of thiamine hydroxylase by 5-ethynyluracil results in the formation of an unusually stable norcaradiene (22).The first synthesis of a marine sterol containing a cyclopropene Aliphatic and Alicyclic Chemistry [Ref. 162(d)] Scheme 20 Reagents and conditions i CuCN (8mol%) THF 80 “C -0 OBz (Ref. 166) OH -100% yield (8:l mixture of diastereoisomers) Scheme 21 Reagents and conditions i Zn-Cu THF -35 “C moiety has been reported by Wicha and co-workers Scheme 22.’” The isolation of FR-900848 has stimulated much interest in the development of reliable methodology for the enantioselective synthesis of cyclopropanes. Most work in this area has centred upon developing enantioselective/diastereoselectivevariations of the Simmons-Smith reaction as demonstrated by the work of Barrett and co-~orkers,”~ Armstrong and Ma~rer,”~ Scheme 23.In a characteristically detailed andTheberge and Zer~her,’~~ investigation Denmark et al. have studied17’ the effect of a variety of C,-symmetric ligand systems upon the enantioselectivity observed in the catalytic Simmons-Smith Peter Quayle (Ref. 170) C02H 0 &x { -CH2 H 0 (22) reaction (Scheme 24) whilst Charette and C6te have demonstrated the synthetic utility of their auxiliary-based Simmons-Smith methodology in the enantiodivergent syn- thesis of all four isomers of coronamic acid Scheme 25.58,176 Contamporaneous reports by Hoberg and B02ell'~~ and Nagarajan and co-i-iii (Ref. 171) A OMe Scheme 22 Reagents and conditions i CHBr,-NaOH; ii MeLi-Et,O -78 "C;iii MeI -78 "C Aliphatic and Alicyclic Chemistry /94% \ 100% Me2 N C,OdCO N M e2 Me2NCh,CONMe2 cat .1 = cat.2 = O\/ o\B/o I I Bu Bu Scheme 23 Reagents and conditions i Zn (CH21)2 CH2C12 0-25"C7 cat. 1; ii Zn(CH,I), CH2C1, 0-25"C7 cat. 2 + EtsZn + CH212 -i (Ref. 175) ph* OH phqOH 80% ee NHS02R cat. = 'NHSO~R Scheme 24 Reagents and conditions i CH,Cl, -25 "C cat. workers178 describe the preparation of 172-cyclopropanated sugars which themselves prove to be useful synthetic intermediates Scheme 26. Doyle Martin and co-workers have continued to probe the intricacies of intramolecular asymmetric cyclopropana- tion reactions using chirally modified rhodium catalysts.' 79 An elegant extrapolation of this chemistry has resulted in the development of a novel macrocyliz- Peter Quayle BnO OH (Ref.176) Scheme 25 RO' OR (Ref. 177) ca. 80% OAc Scheme 26 Reagents and conditions i Et,Zn CH212 Et,O or toluene; ii 40% TMSOTf TMSCN CH,CN; iii CHCl, 50% aq. NaOH BnEt,NCI; iv LiAlH, THF ation-cyclopropanation strategy as outlined in Scheme 27.180 Finally White and Jensen have validated the Corey-Brash cascade hypothesis for marine prostanoid biosynthesis in their total synthesislS1 of constanolactones A and B Scheme 28. Cyclobutanes Substituent effects in electrocylization reactions leading to cyclobutenes continue to generate interest. For example electrocyclization of the silicon-substituted allene (23) generates (24) in high yields (990/)under relatively mild conditions (toluene 145"C 2 h) whereas electrocylization of the unsubstituted compound (25) results in the Aliphatic and Alicyclic Chemistry cHTH3 (Ref.180) Scheme 27 SnC14 MeN02 C02H 1.5 h 0 "c HO\/e-.-47% /+ (Ref. 181) J % J Takai coupling HO Scheme 28 isolation of a mixture of (25)and (26) (as a 19:8 1 mixture) only after prolonged reaction times and under much more forcing conditions (360"C; 19 h) Scheme 29.lS2Vollhardt and co-workers have succeeded in preparing the C,-symmetric [7]phenylene (27) the largest member of its class yet prepared.18 Of note is that the central six-membered ring of (27)is completely bond localized (1.326 and 1.509A).Photochemical methods of cyclobutane formation are already widely utilized and two new this year will doubtless expand this methodology.Toda et al. have reported'84 that photoirradiation of a suspension of the inclusion compound (28) in water affords the [2 + 21 adducts (29) Peter Quayie pPh SiMe3 i 99% -SPh SiMe3 (Ref. 182) iii --(25) (26) 19 81 Scheme29 Reagents and conditions i PhMe 145 "C 2 h 99%; ii Bu,NF THF-H,O 70 "C; iii 360 "C 19 h in acceptable chemical yield (32-90%0) and more importantly in optical purities approaching 100%ee Scheme 30. Hoffman and Pete have described a formal "2 + 21' cycloaddition reaction of salicylate ethers which in one step generates the tricyclic system (30) in moderate to good isolated yield (35-80%) Scheme 31.185 Padwa et al.have demonstrated that the readily available dienes (31a,b) undergo a variety of [2 + 21 cycloaddition reactions affording a general route to a number of polycyclic cyclobutane-containing systems Scheme 32. lS6 Finally Olah and co-workers have provided the first experimental evidence for the generation of cubylcarboxonium ions such as (32). lS7 Aliphatic and Alicyclic Chemistry 95 90% (Ref. 184) PhbOH Ph (28) (29) 'Ph 100% ee Scheme 30 R (Ref. 185) Scheme 31 (Ref. 186) Cyclopen tanes The synthesis of cyclopentanes via the 5-exo-trig cyclization of carbon-centred radicals is now a well established method and numerous examples of this type of cyclization have again been reported this year.'88 A nice exemplification of Nugent's under- utilized reductive epoxide opening-olefin capture sequence is presented in Clive and Peter Quayle 0 I H H ii iii (Ref.189) I OH " \ Scheme 33 Reagents and conditions i MCPBA CH,Cl, 0°C; ii Cp,TiCl THF 20 "C; iii H30+ Magnuson's synthesis of ( f)-ceratopicanol Scheme 33.' 89 The first report of a radical cyclization onto a chromium bound aromatic substrate has also been describedlgO this year Scheme 34. The reductive cyclization of enones catalysed by titanocene complexes adds further credence to the potential of such processes in organic synthe~is.'~'*'~~ Recent practical improvements associated with the Pauson-Khand reaction indicate that it will no longer remain a curiosity but will increasingly be adopted as a viable method for the synthesis of functionalized cyclopentenones as (Scheme 35);'93-'95 in certain cases the adoption of [Mo(CO),] rather than [Co,(CO),] as the source of the 'CO' moiety may be ~referab1e.l~~ In a related sequence bis-acetylenes have been 97 Aliphatic and Alicyclic Chemistry OH (Ref.190) CH3-z:,0cH3 H H3 OCH3 Scheme 34 Reagents and conditions i SmI, THF; HMPT Bu‘OH -73 “C transformed into cyclopentenones using catalytic quantities of [Rh,(CO),,] in the presence of R,SiH under CO Scheme 35.”’ Synthetic applications of Fisher carbene complexes,’9’~’99 rhodium carbenoid,200 and alkylidene carbenes201*202 continue to show promise for the construction of cyclopentanes.The Ramberg-Backlund reac-tion,’ has been used in a synthesis of trans-carbovir and a pyranone-cyclopentenone rearrangement provides rapid access to functionalized cyclopentenones for use in the construction of neocarzinostain analogue^."^ Carbohydrates continue to be used as readily available as chiral non-racemic starting materials. It is a little surprising therefore that the first example205 of an intramolecular aldol reaction on a sugar template leading to formation of a cyclopentenone appeared only this year; these 00-20 5 are summarized in Scheme 36. Cyclohexanes The preoccupation of the synthetic community with Taxol has necessarily meant that the synthesis of densely functionalized cyclohexanes has been an area of intense activity Scheme 37.206-209 The Diels-Alder reaction still remains one of the most important methods for the construction of six-membered rings (Scheme 38).Discussions into the concerted nature”’ and stereochemical aspe~ts~~j-~~~ of these reactions continue to arouse interest. Again this year a variety of catalysts have been reported which enable such reactions to proceed with high levels of asymmetric indu~tion.~~~-~~~ Lithium perchlorate has been shown2j1 to have a profound effect upon the rate of certain Diels-Alder reactions whilst the addition of cyclodextrins to Diels-Alder reactions conducted in aqueous media may have substantial effects in terms of the regioselectivity of these reactions.232 Given the wealth of literature concerning Diels-Alder reactions in the laboratory it is surprising that the identifica- tion of biological equivalents is still at an embryonic state.However it was disclosed this year that the crude enzyme system extracted from Alternaria solani catalyses the intramolecular Diels-Alder reaction of (33) to the exo-adduct (34) with good levels of optical purity (92 f8% ee) Scheme 39.233Other cycloaddition reactions have also been used to good effect for the synthesis of polycyclic substrates e.g. Scheme 40.234 Organ~metallic-~~~~~~~ approaches continue to be used and radi~al-based’~’~~~’ extensively as have enzymatic strategies’,’ for the preparation of chiral non-racemic substrates Scheme 41. Medium and Large Ring Systems Boland et al. have shown239 that cycloheptadienes such (35),once thought to be the sex Peter Quayle OR .-0 ii-+ i ('+I I H&' '0-H (Ref.193) ca. 80% 40-92% -+o (Ref. 196) 47% \ SiMe3 TBDMS TBDMS 54% 14% Scheme 35 Reagents and conditions i [co2(co)8] CH2Cl, room temp.; ii CH,Cl, 10min; iii NMO (6 equiv.) CH2C1, 0 "c; iv [co,(c0)8] CH,Cl,; v [Mo(CO),] DMSO lOO"C PhMe; vi Bu'Me,SiH CO [Rh,(CO),,] PhH 95°C pheromones of marine brown algae are in fact degradation products of the divinylcyc- lopropanes (36) which are now believed to be the active pheromones Scheme 42. The halflife of cyclopropanes such as (36) is approximately 1 h at 8 "C which evidently is much longer than the sexual encounter in brown algae! Boger and Takahashi have described a highly convergent route to grandirubine (37) via an initial [4 + 21 cycloaddition reaction between the acetal(38) and the pyrone (39) Scheme 43.,,' Novel ring expan~ion,~~'.~~~ [3 + 4)-cycloaddi-organ~metallic,~~~ Aliphatic and Alicyclic Chemistry 0KO OX? (Ref.200) ___) 89% Me02CLx i Me02Cd ii 84% -iii 69% (Ref.201) I 'I' Ts SnBu3 TrO TrO iv (Ref. 202) -60% LQuOTBDMS ox0 ox0 v vi (Ref. 203) Ror= a" so2 BrHBoc HO 0-vii (Ref. 204) 71-76% &fH OR OR (Ref. 205) ix ___) CH3 CH3 Scheme 36 Reagents and conditions i [Rh,(octanoate),] (cat.) CH,Cl,; ii PhIC- NOTf; iii Bu'OK THF; iv TMSC(Li)N, THF 0°C; v Bu'OK(2.2 equiv.) THF -78 "C 77%; vi HCl MeOH 100%;vii Et,N DMF 80°C; viii PdCl, CuCl, 0, DMF 0.5 h 80%; ix Bu'OK 0.5 h 90% 100 Peter Quayle YOPMB-ii iii iv -POPMB -.CN (Ref.207) 0 TMSO -0 2 MeO-(Ref. 208) OMe OMe OMe Scheme 37 Reagents and conditions i BF -OEt, CHCI,; ii 140"C 72 h 38%; iii Na,S EtOH -78 "C 21%; iv TMSCN 90%; v piperidine HOAc PhH 70 "C 65% (Ref. 213) H Aliphatic and Alicyclic Chemistry (Ref. 216) (Ref. 217) r 1 OCH3 -@fly (Ref. 219) 0 L -I + (Ref. 221) Scheme 38 tion244 and rearrangement245*246 reactions have appeared this year for the synthesis of cycloheptanes. The asymmetri~ation~~’,~~~ of cycloheptadienes promises to be a valuable synthetic for the synthesis of chiral non-racemic building blocks.The ‘higher order’ cycloadditions of cycloheptatriene(tricarbony1)chromium complexes developed 102 Peter Quayle CHO Scheme 39 5:l (Ref. 235) Scheme 40 Reagents and conditions i i BuLi THF -78 "C; ii H,O 1 OMOM OMOM ___) (Ref. 237) 0 \ aoAc \ OH + aOAC OAc (Ref. 238) Scheme 41 Aliphatic and Alicyclic Chemistry (Ref. 239) Scheme 42 ?Me ?Me Me0 Me0 MeO%o t MO> 0 1 (39) OMe (Ref. 240) OH (37) Scheme 43 by Rigby et al.249and the related intramolecular Diels-Alder reactions pioneered by Shea and co-w~rkers~~~ provide ready access to functionalized cycloheptanes Scheme 44. The chemistry of eight-membered rings has once again been dominated by Taxol. Interestingly the isolation of the bicycloC9.3.llpentadecatriene canadensene (40) a putative biogenetic taxane precursor was reported this year.251 Whilst biological conversion of (40) into the taxane skeleton still remains a matter for conjecture a number of wholly synthetic routes to the ring B system of Taxol have appeared some of the more noteworthy examples are collated in Scheme 45.252-254 Paquette et af. have utilized a Claisen rearrangement to good effect in their synthesis of (+)-acetoxy~reunulide.~~~ There is continued interest in the synthesis of medium rings containing ene-diyne moieties as illustrated below Scheme 46. Of note is that the Nozaki-Kishi reaction was 104 Peter Quayle (Ref. 246) OH (Ref. 249) R (Ref. 250) OTBS OTBS Scheme 44 adopted as the optimal method for ring closure for all of these sensitive substra- te~.~~~-~~~ The same coupling procedure has also been adopted by Proctor and co-workers in their approach to the bicyclo[8.4.0] tetradecane skeleton of solenolide F S~heme47.~'~ The aromatic character of [lOlannulene isomers has once more been the subject of further scrutiny.Schleyer and co-workers have now provided arguments which suggest that a mono-trans-conformer of [lolannulene (41) should indeed be stable and exhibit aromatic properties.260 Clearly this debate will continue until a thorough re-evaluation of this system is undertaken. Finally Oppolzer et al. have developed a new macrocyclization strategy which has been utilized in a synthesis of (+)-aspicilin Scheme 48.261 References 1 C.Wong R. L. Halcomb Y. Ichikawa and T. Kajimoto Angew. Chem. Int. Ed. Engl. 1995 35 412. 2 C. 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ISSN:0069-3030    

DOI:10.1039/OC9959200073

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

5 Aromatic Compounds By A. P. CHORLTON Zeneca Specialties Hexagon House Blackle y Manchester M9 8ZS UK General and Theoretical Studies The contentious issue of the D6h symmetry of benzene continues to be debated. Shaik and co-workers have postulated that the D6 symmetry is due to o bonding which overcomes the tendency of the .n electrons to distort the molecule to a D,h structure. This dual picture of benzene is in perfect agreement with its ‘aromatic’ behaviour.’ Haas and Zilberg have presented theoretical and experimental data which agrees with this picture.2 An intriguing aspect of aromaticity is the question of how much bending a benzene ring can tolerate without losing its aromatic character. This has been answered with respect to [4]paracyclophane (1).The structure strain energy and the magnetic susceptibility of [4]paracyclophane (1) and the activation energy for its interconversion with lP-tetramethylene Dewar benzene (2) have been calculated. This study has concluded that C4lparacyclophane (1) should have a weak ring current and is 9 kcal mol- more stable than the Dewar benzene isomer (2).3 A detailed study of the conversion of hexamethyl (Dewar benzene) to hexamethyl- benzene with thallium(II1) trifluoroacetate has been carried o~t.~,~ There is mounting evidence to suggest that strained bicyclic annulation induces significant bond alternation in benzene. Trisbicyclo[2.2.l]heptabenzene(3) shows mild bond localization supporting this view.6 Fusion of two cyclopentanone rings onto the bridged [14]annulene(4) with a cisoid relationship to each other and an odd number of bonds between the rings e.g.(5),substantially reduces the magnetic ring current. This observation is also interpreted as a bond fixation effect.’ According to Huckel’s (4n + 2)nelectron rule [lolannulene (6)is expected to be the next highest uncharged homologue of benzene. Earlier experimental studies reveal that [lolannulene (6) preferred a non-aromatic nonplanar structure. However recent 113 114 A. P. Chorlton oB \ /-/ @ \ 0 (4) (3) theoretical investigations have predicted that a new nearly planar aromatic [lo] annulene configuration should be stable.* Hypostrophene(7) is one of many (CH), isomers; it has been shown to undergo a degenerate Cope rearrangement to a new (CH), isomer (S).9 The first non-Kekule polynuclear aromatic compound has been synthesized the trioxy derivative (9) of triangulene is stable at ambient temperature which appears to cast doubt on the current suggestion that non-Kekule polynuclear aromatics are intrinsically unstable." The aromatic character of a transition state is often invoked as contributing to the 'driving force' of a reaction.Ab initio studies of the transition state for the trimerization of acetylene have been carried out." These predict that any n stabilization of the transition state is weak. Similar studies of the aromatic character of the transition states of allowed and forbidden cycloadditions concur with this observation.'* The relative stabilities of a number of o-benzyne derivatives of aromatic hydrocar- bons have been computed using AM1 orbital calculations.Their stability can be simply related to the steric and electronic properties of the parent hydrocarbons.' Extended ab initio calculations of the energy splitting of the singlet o- rn-and p-benzynes have been investigated showing that the former experimental values of the p-benzyne and o-benzyne energy splitting were overestimated.I4 Gavezzoti has correlated the melting point of a large number of mono- and di-substituted benzenes and naphthalenes. This study shows that with few exceptions ortho-and meta-disubstituted benzenes melt at lower temperatures than their para-isomers. However no significant trend was found between melting point and crystal density or packing energy." In related work Lenoir and co-workers have correlated the vapour pressure and enthalpy of sublimation for 30 polycyclic aromatic hydrocarbons.The results show that within a class of substances there is a relationship between structure and vapour pressure and structure and enthalpy of sublimation.'6 Aromatic Compounds The measurement of aromaticity continues to be addressed by a number of groups. Mitchell et al. have developed an NMR estimation of aromaticity relative to that of benzene.I7 Schleyer et al. have characterized five-membered ring systems by a combination of geometric energetic and magnetic criteria.' Si and Jiang have utilized valence bond calculations to predict bond lengths reactivities and aromaticities of benzenoid hydrocarbons.' Precise PPP molecular orbital calculations of the excita- tion energies of polycyclic aromatic hydrocarbons have been used as a correlation between their chemical softness and absolute hardness." Solid state 13CNMR examination of a single crystal of acenaphthene has revealed from experimental and calculated chemical shift tensors that the crystal contains two kinds of crystallographically unique molecules.This observation cannot be detected by diffraction methods.21 The intermolecular interactions between aromatic rings are of wide chemical interest. Although these interactions are relatively small they play important roles in many phenomena such as base-base interactions in DNA and the design of useful molecular recognition assemblies.The benzene-benzene interaction is the prototype of these interactions. NMR studies of these interactions using alignment of aromatics in strong magnetic fields has given evidence for both parallel and T-shaped dimers. However in water there is no clear preference for these dimers and it is likely that benzene is monomeric.22 n-Stacking effects are often invoked to explain asymmetric control in organic synthesis this subject has been comprehensively reviewed.23 Intermolecular interactions can also provide an insight into reaction mechanisms. 19F NMR investigations of interactions between amines and aromatic fluoro derivatives showed that the formation of the hydrogen bonding N-Ha-0 F may be an aid to the leaving group departure in solvents poorly able to solvate the F-ion.It is proposed that this interaction involves the leaving group in an equilibrium preceding the attack of the n~cleophile.~~ Picosecond optical grating calorimetry has been used to study the reaction of singlet methylene with benzene an initial transient species is formed which is believed to be a weak n-complex between singlet methylene and benzene.25 A face centred n-complex of the benzenium ion (10) has also been identified by collision- induced dissociation mass spectrometry (CID-MS).26 H 2 Preparation of Benzenes from Non-aromatic Precursors The Bergman cyclization and its variants continue to be of immense interest and have been the subject of a review.27 Recent advances in this area include low temperature high yielding tandem enyne allene radical cyclizations (Scheme l).28929 Enyne [3]cumulenals have been shown to undergo Bergman cyclization or an 116 A.P. Chorlton Scheme 1 intramolecular [2 + 21 cycloaddition depending on the nature of substituents on the yne carbon. A hydrogen substituted [3]cumulene (11) is cleanly converted to a naphthalene product (12) while a trimethylsilyl substituted substrate produces a cyclobutene product (13). These observations are in marked contrast to earlier studies which demonstrated that a [2 + 21 pathway occurs exclusively at the terminal cumulene bond giving rise to a 1,2,4-cyclohexatriene intermediate (14) (Scheme 2).30 Finn has developed an organometallic variant of the Meyers type Bergman cyclization (Scheme 3).31 A process related to a Bergman cyclization has been observed in the reaction of 6,6-dicyclopropylfulvene with isobutylidene (1 5) giving products derived from a rn-xylylene (Scheme 4).32 The utility of the Fischer carbene benzannulation methodology has been extended.The first example of phenol formation from the reactions of amino-stabilized a$-unsaturated Fischer carbene complexes with alkynes has been reported (Scheme 5).33 This process can also be rendered intramolecular by tethering the alkyne moiety through the nitrogen substituent of the carbene carbon. It was found that with complexes having three-carbon spacers the expected 6-hydroxytetrahydroquinolines (16) were produced however complexes with two-carbon spacers gave 1-aza-bicyclo[3.3.0]octanes (17) due to cyclization without carbon monoxide insertion (Scheme 6).34 The yield of the Fischer carbene benzannulation can be remarkably improved by photoirradiation employing a xenon lamp; this procedure also gives phenolic products free from metal imp~rities.~’ The effect of phosphine ligands on the benzannulation reaction of molybdenum carbene complexes with alkynes has been studied.36 A related process has also been developed in which zirconacyclopentadienes react with alkynes to give hexasubstituted benzene derivatives (Scheme 7).37 Turnbull and Moore and Koo and Liebeskind have continued to exploit the ring Aromatic Compounds R1=H,(llJ/R2 = SiMe3 * \ Ph (13) Scheme 2 CpRu(PMe&CI NH4PF6 * CH30H 25 "C t /CoZMe Scheme 3 118 A.P. Chorlton W,,e3 q] ~~~~-~~own-tj~ -t CDC13 __t & + [2,2]metacyclophane dimers Scheme 4 --Pr -(co)5cr< 80 benzene "C,14-18 h EX base R' R' R2 NMe2 (CO)&r' NMe2 Scheme 5 R Scheme 6 expansion of 4-acetoxycyclobutenones as a tool to provide highly oxygenated aromatic systems. (Scheme 8).38*39 Benzocyclobutenediones are key intermediates in the above process. A new methodology has been developed to provide annulated benzocyclobutenediones (Schemes 9).40 There have been a number of advances in Diels-Alder chemistry. Cochran and Padwa have designed a novel method for the synthesis of naphthalene derivatives. In Aromatic Compounds R’ R’ Scheme 7 OMe OMe Scheme 8 0 Scheme 9 this process the a-thiocarbocation generated from the Pummerer reaction of a o-benzoyl substituted sulfoxide is intercepted by the adjacent keto group to produce a a-thioisobenzofuran as a transient intermediate which undergoes a subsequent Diels-Alder cycloaddition with added dienophiles (Scheme 10).41742 An efficient synthesis of 4-amino-3-arylphenols via a Diels-Alder reaction has been reported (Scheme 1 l).43 4,5Dicyanopyridazine has been shown to participate in an inverse electron demand Diels-Alder reaction with a wide variety of dienophiles.This process is particularly effective for the synthesis of substituted phthalonitriles (Scheme 12).44 Several improved catalysts for the Pschorr phenanthrene synthesis have been discovered.Under traditional reaction conditions the ring closure of diazonium salts derived from substituted 2-(2-aminophenyl)cinnamicacids were induced by copper or by heating. Cyclization under these conditions required long reaction times and produced phenanthroic acids in variable yields. However the use of soluble substances which initiate free-radical reactions by electron donation considerably shorten the reaction time and increase the yield. The most effective catalysts were K,Fe(CN) in aqueous conditions and ferrocene in non-aqueous media (Scheme 1 3).45 A new methodology has been developed by Morrow for the synthesis of oxygenated phenanthrenes (Scheme 14).46 120 .P. Chorlton SrC2H5 I Scheme 10 i,Danishefsky's diene toluene reflux Ph Ph Ph NaOH-THF RT OH OH +R ,6M HCI reflux (+ R NH2 NHCOPh Scheme 11 Enynones have been found to undergo a novel acid catalysed transformation to phenols; this process was utilized in an efficient synthesis of the antimicrobial-cytotoxic agent juncusol (18) (Scheme 15).47 A similar cyclo-aromatization process has been found to proceed under base mediated conditions providing an easy two-step route to 3-alkylnaphthols (Scheme 16).48 Other syntheses of naphthalene derivatives are highlighted in Scheme 17.49-51 The annulation reaction with stabilized phthalide anions has been reviewed.52 The synthesis of radiolabelled benzene derivatives from non-aromatic precursors has been reported.Aromatic Compounds Re CN CN Scheme 12 Scheme 13 Scheme 14 3 Non-aromatic Compounds from Benzene Precursors The biotransformation of benzene and its derivatives to their corresponding cis- dihydrodiols has been exploited as a key step in the synthesis of highly oxygenated natural products.Two recent examples of this are the synthesis of aza-sugar ( + )-1-deoxygalactojirimycin ( 19y4 and pseudo-sugar (20) (Scheme 18)’’ Enantioselective bacterial biotransformation protocols to cis-dihydrodiols (21) of either configuration have been developed. 56 An extremely efficient chemical equivalent of the oxidative biotransformation of benzene has been developed by Motherwell and Williams. In this process benzene is irradiated in the presence of aqueous barium chlorate and a catalytic quantity of osmium tetraoxide and after a reductive work up do-inositol hexaacetate (22) was isolated in 31% yield along with conduritol E tetraacetate (23) in 5% yield (Scheme l9).” 122 A.P.Chorlton 0 II r -bR 'R L Scheme 16 Ref. 49 hv ~ Ar'QMe in CHPCIP /&A. Ref.50 1 -RwAc I/ Ac Ar Ar OH Ref. 51 Scheme 17 The direct oxidation of benzene to phenol with hydrogen peroxide has been achieved using a polymer supported V02+ Schiff base catalyst.58 Benzene has been biomimeti- cally oxidized to p-benzoquinone with magnesium monoperoxyphthalate and a fluorinated iron porphyrin catalyst.59 The [Co"'(salpr)(OH)] promoted oxygenation of 4-aryl-2,6-di-tert-butylphenols has been studied the position of dioxygen incorpor- ation is completely controlled by the nature of the solvent.Dioxygen incorporation occurring at the ortho-position in an uncoordinative solvent where dioxygen is incorporated into the para-position in amine solvents (Scheme 20).60The oxygenation of para-substituted phenolics to benzoquinone with a cobalt Schiff base complex catalyst6' and with ruthenium porphyrin have been examined.62 Nucleophilic addition of organometallics to arenes provides a useful procedure for the generation of non-aromatic compounds from aromatic systems for example the diastereoselective addition of organometallics to chiral naphthalene oxazoles has been used to prepare dihydronaphthalenes of high enantiomeric purity (Scheme 2 l).63 Aromatic Compounds 123 X 00"HO' 'OH Ho40TBs HO Scheme 18 OAc OAc / OAc OAc OAc OAc (22) (23) Scheme 19 Reagents 1 OsO, hv Ba(ClO,),; ii Ac,O Et,N DMAP 0 OH 0 The dichotomy between nucleophilic aromatic substitution and conjugate addition in the reaction of benzoic esters with organo-lithium and -magnesium reagents has been investigated.It was found that the addition products (24) and (24a) are preferred over the substitution product (25) as the electron-donating ability of the carbanion species increases (Scheme 22).64 The utility of conjugate addition to arenes is limited to those carrying electron withdrawing groups that do not undergo 1,2-nucleophilic attack. As can be seen in the above cases this is achieved by the use of unreactive oxazole derivatives or hindered esters.An advance in this respect has been demonstrated by Yamamoto and 124 A.P.Chorlton .Pi n* Scheme 21 OMe R OMe OMe C02BHA RMgBr or RLi bC02BHA J!JCO~BHA &CO2BHA R aCO"' R2 [ls2] R3-Li I R ,R3 acbH \ R2 (ATPH) ~3 1,2-adduct Scheme 23 co-workers where conjugate addition products were obtained for the first time with simple aromatic aldehydes and ketones by complexation with aluminium tris(2,6- diphenylphenoxide) as a carbonyl stabilizer (Scheme 23).65 When arenes are irradiated in the presence of alkenes they undergo [2+ 31 [2+ 41 and [2 + 21 addition processes. Tethering the alkene to the arene gives a degree of control in this process; Wagner and Smart have been very active in studying this area.66,67The synthetic utility of this process lies in its ability to yield products of a high degree of complexity from simple starting materials in a single step (Scheme 24).68 The complexation of benzene as the manganese carbonyl complex (26) results in its Aromatic Compounds Scheme 24 i 2O=C=CPh2 I ii [PPNICI .Mn-iii O2 0 oc-do'CO Scheme 25 Me0 0 Scheme 26 activation to cycloadditions diphenylketene undergoes a [2 + 2 + 21 addition to give dihydroisochroman-3-one (27) (Scheme 25).69 A new intramolecular spiro-endo-mode ring closure of allenyl (methoxypheny1)alkyl ketones has been developed (Scheme 26).70 4 Substitution in the Benzene Ring Electrophilic substitution The replacement of hydrogen by fluorine in aromatic compounds confers unique influences on physical chemical and biological properties.This has led to considerable interest in methodologies for site-specific fluorination of arenes. Direct electrophilic fluorination with elemental fluorine has not generally been successful due to a propensity for exothermic radical reactions. Chambers et a!. have demonstrated that the reactivity of elemental fluorine can be mediated by the use of protonic acids especially formic and sulfuric (Scheme 27). The regioselective bromination and iodination of activated arenes has been the subject of a number of investigations. Excellent para-selectivity was achieved using ultrasonically assisted bromination with N-bromosuccinimide (NBS).72The re-gioselective bromination of o-p-glycosylated aromatics has also been reported.73 A.P.Chorlton F F Scheme 27 Reagents i HC02H 10% F,-N Iodination of a wide range of phenols anilines and aryl ethers has been achieved by the action of bis(syrn-collidine)iodine(I) hexafluor~phosphate~~ and by a mercury(1r) oxide-iodine reagent. Direct iodination of aromatic compounds is very difficult especially for deactivated systems using current methodologies. A new direct iodina- tion protocol consisting of iodine sulfuric acid and elemental fluorine is an improve- ment in this respect even nitrobenzene being iodinated in 70% yield.76 Nitrogen dioxide in the presence of ozone acts as a powerful nitrating agent converting a wide range of aromatic compounds to their corresponding nitro derivatives.This process has been named the Kyodai nitration and its versatility is illustrated in a review article.77 Recent advances include its application to the nitration of anilides phenyl esters and trifluoromethyl-containing Studies on the mechanism have also been A n umber of other alternatives to traditional nitration conditions have been reported including ‘claycop’ a reagent made from an acidic montmorillonite clay impregnated with anhydrous cupric nitrate. Both yields and selectivities are superior to those obtained under homogeneous reaction conditions.82 The nitration of alkylbenzenes can be catalysed by mercury(r1) this leads to para-substitution being favoured.83 Strongly deactivated aromatics can be nitrated in good yield with a superacidic mixed nitric-tris(trifluoromethylsu1fonato)boricacid [HNO,-2CF3S03H-B(O,SCF),] for example pentafluorobenzene gave penta-fluoronitrobenzene in 99% yield.84 Resorcinol monoethers can be regioselectively nitrosated using solid sodium nitrite in anhydrous propionic acid high yields of the 2-nitroso products being obtained rapidly.85 The substituent effects of -NO and -NO2 groups in aromatic systems have been theoretically investigated using quantum mechanical methods.86 The Friedel-Crafts (F-C) reaction proceeds by preliminary protonation of the alkenes by Lewis acids followed by addition of the carbenium ion formed or a polarized complex to the arene [Scheme 28(a)].An alternative mechanism has been suggested in which alkylation occurs within a complex formed upon addition of an arenium ion to the alkene [Scheme 28(b)].Evidence for this process has been obtained in the gas phase with Fourier transform ion cyclotron resonance (FT-ICR) and GC-MS. The implications of these results are that the scope of aromatic alkylation can be widened to allow substitution by carbenium ions that would undergo isomerizations in conventional bimolecular reaction^.^' It has been demonstrated that F-C benzylation proceeds readily at room tempera- ture using K 10 clay-supported zinc chloride the rates being significantly improved with sonication.88 Direct alkylation of aromatic compounds under F-C conditions usually leads to complex mixtures of products.A solution to this problem is provided by the use of a supported reagent system ZnC1,-Si0,-K,C0,-Al,03 (Scheme 29).89 Aromatic Compounds Scheme 28 + CI Scheme 29 WN AIC13(2.5 equiv.) @R Ref. 94 ~ X + RCH2N02 70-80°C(N2) 0 4-6h X TICI., sym-tetrachloroethane 70 "C,6 h + ACN Me0/o Me0 Scheme 30 Advances have been made towards a catalytic F-C acylation reaction acylation of phenol and 1-naphthol derivatives with acyl chlorides proceeds smoothly in the presence of 5-20mol% of Sc(OTf) to afford the corresponding ketones in high yields." The Fries rearrangement of acyloxynaphthalenes has also been effected catalytically using SC(OT~),.~' Complementary to this is the use of hafnium tri- fluoromethanesulfonate as a catalyst in the F-C reactions of substituted benzenes with acid anhydride^.^^ The F-C acylation of activated aromatics has also been achieved under mild conditions using the system (RCO),O-Me,S-BF,.It is thought that dimethylacylsulfonium salts RCOS' Me + RC0,BF; are the active agents.93 A number of interesting Lewis acid mediated electrophilic substitution reactions related to the F-C reaction have been reported (Scheme 30).94*95 Leblanc and Boudreault haveextended the utility of the amination reaction of arenes with electron-deficient azodicarboxylates to produce diamines (Scheme 3l).96 A novel mild direct sulfenylation method for aromatic compounds has been reported involving treatment of substituted phenol ethers or naphthalenes with phenyliodine(II1) bis(trifluor0acetate) and thiophenols furnishing the unsymmetric diary1 sulfide (Scheme 32).97 128 A.P.Chorlton OMe 00 OMe 0- NR-NHR -CI,CCH,0KN=NKOCH2CCI i HOAc QNHAc ii CH2C12 NR-NHR NHAc Scheme 31 OMe OMe R R Scheme 32 Reagents i PhSSiMe or PhSH (2.0 equiv.) (CF,),CHOH; ii PhI(OCOCF,) (1.2-1.5 equiv.) Scheme 33 Nucleophilic substitution Many aromatic nucleophilic substitution reactions are induced by light by solvated electrons or by electrons from an electrode.The mechanism for this radical process is termed SRN1 and is depicted in Scheme (33). 174-Dichlorobenzene has been shown to undergo reactions with various nucleophiles upon electrochemical initiation.98 Saveant and co-workers have demonstrated that the photochemical induction of the reaction of iodoadamantane with arenethiolate ions is an example of SRN1 substitu- ti~n.~~ In the study of the nucleophilic aromatic substitution of glutathione and l-chloro- 2,4-dinitrobenzene it was established that if the reaction is effected in the presence of a surfactant with a positively charged polar head group (cetyltrimethylammonium bromide) then the reaction rate is increased by a factor of about 20.It is proposed that this rate enhancement is due to the formation of reversed micellar systems which because of their positive nature stabilize the negatively charged Meisenheimer complex. This observation may have implications for the catalysis of other nucleophilic processes.loO The mechanism of the nucleophilic substitution of phenyl aryl ethers with aliphatic amines in dimethyl sulfoxide (DMSO) has been studied.It was found that butylamine shows a first-order dependence on the amine concentration indicating that nuc-leophilic attack is rate limiting. However the reactions with pyrrolidine and with piperidine are subject to general base catalysis."' Primary and secondary amines have Aromatic Compounds Scheme 34 Scheme 35 OMe Scheme 36 been found to react with 1,2-dihalo-4,5-dinitrobenzene to give only nitro substitution at moderate temperatures. The halogen substituents on the ring are unaffected making them available for further synthetic elaboration. (Scheme 34). lo2 The rate of fluorination of 2,4-dichloronitrobenzene to give 2,4-difluoronitroben- zene can be significantly enhanced by the use of activated solid KF.The KF is activated by slow recrystallization from methanol which gives KF with a large surface area." 2,6-Difluoro-4-nitroanisole has been recommended as an improved biochemical probe for photoaffinity labelling because it can react with a large number of nucleophiles under photochemical conditions without photoreduction occurring. lo4 Aromatic nucleophilic substitution with carbon nucleophiles is an important method for the formation of carbon-carbon bonds. The displacement of a methoxy group from an aromatic nucleus by Grignard reagents is a recent advance in this area (Scheme 35).lo5 In a related process the addition of carbon nucleophiles to ortho-alkylated anisole-[Cr(CO),] derivatives the methoxy substituent is lost by a tele-substitution process (Scheme 36).'06 The nitroarylation of phenylacetonitrile has been reinvestigated.Earlier workers had reported that the phase transfer catalysed reaction of phenylacetonitrile with 4-chloro-3-(trifluoromethyl)nitrobenzene (28) gave the product of nitroarylation (29). Makosza and Tomashewskii have refuted this claim and presented evidence that proves that the benzisoxazole (30)is the major product (Scheme 37).'07 The kiiletics of 130 A. P. Chorlton Scheme 37 CI PPh2 6:"-Scheme 38 the addition of the anion of phenylacetonitrile to aromatic nitro-compounds has also been studied.lo8 Vicarious nucleophilic substitution methodologies continue to be developed.A recent example of this is the synthesis of benzylphosphine oxide (31). The versatility of this protocol is highlighted by quenching the intermediate(32) with aromatic aldehydes giving access to (E)-stillbenes uia a one-pot process (Scheme 38).'09 Substitution via Organometallic Intermediates Directed ortho-metallation (DOM) continues to be exploited as one of the most potent methodologies for the elaboration of polysubstituted aromatics. MNDO and PM3 semi-empirical methods have been used in predicting the regioselectivity of DOM reactions. The experimentally observed regioselectivities are reproduced in certain examples however care must be exercised in using these semi-empirical methods because they are based on agostic interaction (33)parameters which over estimate the stability of these adducts.' ''9' '' In depth studies have been carried out on the DOM of anisole and p-dimethoxyben- zene.Significant disproportionation between the mono- and 2,5-bis-metallated inter- mediates resulting from metallation of p-dimethoxybenzene was observed. Experimen- tal conditions involving incremental addition of N,N,N',N'-tetramethylethyl-enedianine (TMEDA) allows the generation of each of these intermediates.'12 In a similar manner significant increases in both rate and yield of metallation of p-methoxyanisole are afforded by use of incremental amounts of TMEDA." The synthetic utility of DOM of aromatic tertiary amides has been extended by the Aromatic Compounds 131 Agostic interaction-use of their ortho-lithio cuprate species.These ortho-lithio cuprate species react with ally1 bromides benzyl bromides and methyl bromoacetate to give good yields of ortho-substituted benzamides. This is in contrast to their corresponding lithio derivatives which are reported to give poor yields using these ele~trophiles.''~ In a similar manner the use of manganese species has allowed the synthesis of thio- amides.' l5 DOM of unprotected benzoic acids provides easy access to multi-function- alized products.' 16,117In an analogous fashion ortho-lithiated anilines have been used to provide a new route to acridine (Scheme 39).'18 Fluorine can also act in a DOM capacity;'lg the lithiation of fluorinated benzenes and its dependence on solvent and temperature have been studied.12' N-Fluoroben- zene-o-disulfonimide has been used as an effective electrophilic source of fluorine in the reaction with ortho-metallated aromatic compounds.12' DOM chemistry has been combined effectively with a palladium-catalysed cross acylation reaction (Scheme 40).'22 Transition metal-catalysed cross-coupling reactions continue to be widely used for the functionalization of aromatic compounds. Most of these processes involve reaction OH L 0' iii Scheme 39 Reagents i water; ii HCI THF; iii water then NaOH 132 A.P. Chorlton Scheme 40 5 mol% ArMgX Ni(acac)2* aAr X X Scheme 41 of aryl or vinyl halides (or equivalents) with alkenes or hetero-substituted vinyl compounds or arenes with the Heck and Stille/Suzuki coupling reactions the most commonly used.The major advances in this area have been driven by a desire to carry out this process economically on an industrial scale. Aryl diazonium salts have been used as alternatives to the more costly aryl bromides and iodides. Homogeneous catalysts have been replaced by heterogeneous catalysts that are easier to re~yc1e.l~~ Aqueous Heck reactions have been developed using polymer bound aryl iodides and also using water-soluble phosphorous ligands. 124 The palladium-catalysed cross-coupling between aryl or vinyl halides and triflates with organostannanes known as the Stille coupling has been the subject of a number of publications. The coupling can be effected with Pd/C if copper iodide is used as a c0cata1yst.l~~ Combinatorial libraries of biaryls can be produced by a solid-phase Stille rea~tion.'~~.'~~ The coupling can also give rise to product mixtures arising from aryl halide-phenyl exchange with the triphenylphosphine ligand.'28.'29 When the organostannane is replaced by arylboronic acid the reaction is known as the Suzuki coupling.Recent advances include the use of aryl mesylates which were previously considered too unreactive. However nickel catalysis renders aryl mesylates amenable to the Suzuki coupling and symmetrical and unsymmetrical biphenyls have been prepared by this methodology.' 30-133 Nickel catalysis has also been utilized for the coupling of allylamines with arylboronic The use of thallium(1) hydroxide in a Suzuki coupling enables the reaction to be effected at ambient temperature.These modifications may prove useful for the coupling of heat sensitive molecules or the synthesis of atropisomers. 135 A novel synthesis of unsymmetrical biaryls has been developed by Julia and co-workers (Scheme 41).'36 Transition metal-catalysed cross-couplings have primarily been focused on aryl-aryl or aryl-alkene/alkane bond formation. Recent innovations include the arylations of amine~,'~~-'~~ and thiols141 and some of these are illustrated in phosph~nates'~~ Scheme 42. A number of novel procedures for substitution in the benzene ring via organometallic intermediates have been reported. Phenylcalcium iodide reacts with N20 in 1,2-dimethoxyethane (DME) to give azobenzene in 61 % yield (Scheme 43).'42 [Pt(P(OCH,),CEt)] complex catalyses the ortho-silylation of benzylidenamines Aromatic Compounds L2Pdor L2PdC12 ArBr + HNRR' ArNRR' Refs.137 138 LiN(SiMe3)12 0 I I CH (OEt) DBr (EtO)&HP[(O)OEtJH mp\OEt Ref. 140 R' SH SH + Ref. 141 Scheme 42 Scheme 43 SiMe2Y xm:-R .+ -YMe2SiSiMe2Y-xQ+;-R -+ --I3 SiMe2Y SiMe2Y Scheme 44 with disilanes via intramolecular C-H activation; both mono- and bis-silylated products are formed (Scheme 44).'43 Substitution via Aryl Radicals Aryl radicals can be generated by pulse radiolysis of aryl bromides in aqueous solution. 134 A.P. Chorlton H H H ____) DMF or CI DMA CI H H H (35) (34) Scheme 46 The aryl radicals then react rapidly with 0 giving rise to aryl peroxyl radicals (Scheme 49.144 The replacement of a diazonium group by hydrogen in N,N-dimethylformamide (DMF) can be catalysed by substances that act as electron donors and initiate free-radical reactions.A general procedure has been developed in which FeSO increases the rate of this reaction and leads to higher yields.14' Tetrathiafulvalene has also been used to generate aryl radicals from arene diazonium salts which on subsequent quenching give products arising from radical cyclization and nucleophilic substitution.'46 The reduction of aryl halides by sodium borohydride is catalysed by titanium complexes. The scope of this reaction is solvent dependent. In DMF an adduct of DMF and sodium borohydride is formed which reduces simple aryl halides by a non-radical mechanism.Dimethylamino-substituted products (34) are formed as are dechlorinated species (35).However in dimethylacetamide or in ethers a radical based reaction involving activated titanocene borohydride takes place and only de- chlorinated products result (Scheme 46).'47 3-Arylpropyl hydroperoxide in the presence of iron(rr) and copper(I1) generates the 3-phenylpropan-I-oxyl radical. The major products from these reactions are the alcohol (36) and aldehyde (37) the yield of radically substituted products (38) and (39) are only moderate to poor (Scheme 47).'48 5 Condensed Polycyclic Aromatic Compounds Benzenoid Aromatics The highly challenging goal-the rational total synthesis of C,,-has captured the interest of a number of groups.The most critical step in these approaches is the synthesis of aromatic intermediates that possesses a significant degree of curvature. 149 C,,H, (40)and C30H12 (41)are both viewed as rational precursors to the synthesis of the c6 skeleton. Rabideau and co-workers have synthesized C3oH1 (41) via the vapour phase cyclization of (42)(Scheme 48).150Mehta and co-workers' quest for the Aromatic Compounds Scheme 47 H (42) Ref. 150 lF"P C Ref. 152 Ref. 151 Ref. 153 Scheme 48 136 A. P. Chorlton >300"C (43) Scheme 49 synthesis of these c60 precursors is not complete; progress to date is shown in Scheme (48)-l-l Zimmermann and co-workers have synthesized the bowl-shaped polycyclic aro- matic hydrocarbon (43) (PAH) which represents a curved subunit of C, (Scheme 49).lS4 Mullen has developed a cycloaddition-cyclohydrogenation strategy from stil- benoids which gives access to extended PAHs (Scheme 5O).ls5 Symmetrical hexasubstituted triphenylenes have been widely studied as discotic liquid crystals.However the unsymmetrical derivatives have not been subjected to detailed examination because of difficulties encountered with their preparation. Bushby and co-workers recently developed a simple methodology for their prepara- tion and this has allowed the synthesis of many new analogues (Scheme 51).156 Selective ether cleavage has also been used to prepare di- and tri-functionalized triphenylenes.'" The first synthesis of the elusive perchlorotriphenylene (44) albeit in low yield came via trimerization of tetrachlorobenzyne (generated in the vapour phase from tetrachlorophthalic anhydride)."* PAHs are ubiquitous environmental contaminants produced in the combustion of fossil fuels and other organic matter.Some PAHs are relatively potent mutagens and carcinogens. They are activated enzymatically to bay or fjord region diol epoxides metabolites which induce tumours. These reactions occur mainly though not exclusive- ly via addition of the exocyclic amino group of deoxyguanosine and deoxyadenosine to the benzylic carbon of the epoxide function (Scheme 52). Harvey and others have disclosed synthetic routes to these PAHs and their metabolites. These include benz0[5]picene,'~~ benzo[~]pyrene,'~~-'~~ 4H-cyclo-benz~[g]chrysene,'~~-'~~ penta[def)chrysene'66 and 7,12-dimethylben~[a]anthracene.'~' The non-alternant cyclopenta-fused PAHs are often implicated as carcinogens.However because of limited synthetic methods for their synthesis they have not been extensively studied. Two new synthetic routes to polycyclic fluoranthrenes have been published (Schemes 53).168.169 Aromatic Compounds iii I Scheme 50 Reagents i (a) BuLi THF -78°C; (b) ZnBr, THF -78°C; (c) [Pd(dba)J THF -78 +25 "C; ii PhMe 100 "C; iii DDQ PhH 78 "C Non-benzenoid Aromatics The [18]annulene (45) can be regarded as being derived from benzene (46) by the insertion of the linear acetylenic group (-C=C-) at the position a and the linear cumulene group (=C=C=)at the position b.[18]Annulenes have been synthesized (Scheme 54). These compounds were found to be stable and to have aromatic character by the existence of a diamagnetic ring current on the basis of NMR spectral data and to conform to the D, symmetry group.'70 138 A. P. Chorlton OHx I OHx Scheme 51 *o cl@ CI / 550-700% w CI '\ CI CI \ / / CI CI 0 CI \ CI CI CI (44) __c __L HO" "OH Scheme 52 In a similar study the C14lannulene (47) has been synthesized and been shown to be considerably aromatic in spite of only nominal stability.' 71 The dimethano-bridged octahydro [20]annulene (48) and the trimethano-bridged dodecadehydro[30]annu- lene (49) have been prepared by Glaser coupling methodology (Scheme 55).'72 The area of novel porphyrinoids has been reviewed; this includes the superarenes with up to 34n e1ectr0ns.l~~ The 14 electron non-benzenoid aromatic dihydropyrene (50)undergoes nitration to give the unexpected o-dinitro-product (51) in contrast to benzenoid systems in which rneta-nitration is generally observed (Scheme 56).'74 Aromatic Compounds Ref.168 -8Ref.169 Scheme 53 R OR CH,O Ph (45) Scheme 54 Reagents i (a) PhMgBr CeCI, THF 0°C; (b) OHC-C=C-C(OMe)(Ph~CX-CHO;ii PPTS MeOH 55 "C;iii Dess-Martin room temp.; iv PhMgBr THF 0 "C; v SnCl, HCl Et,O 0 "C 140 A.P. Chorlton Scheme 55 But Bur .NO2 Scheme 56 Me0 \ 1 \ / OMe hv Me0&-&Me Me0 \ / L\ / OMe H H Scheme 57 Aromatic Compounds - hv >80% Scheme 58 Scheme 59 6 Cyclophanes [2.2]Biphenylophanes with two biphenyl units arranged face-to-face are interesting molecules because of the intramolecular interaction between the n-electron systems of the two biphenyl units.The electronic properties of these cyclophanes are greatly affected by the dihedral angle between the two benzene rings and the substituents on them. An in depth study of this phenomena has been limited due to the difficulties of their synthesis. Nishimura and co-workers have reported on an intermolecular [2 + 21 photocycloaddition approach which give ready access to C2.23 biphenylophanes (Scheme 57).”’ [2 + 2)Photocycloadditions have also been used in an intramolecular fashion to give the ladderane (52).This process is unique in the respect that it is an example of a topochemical controlled reaction in solution. 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ISSN:0069-3030    

DOI:10.1039/OC9959200113

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

6 Heterocyclic Compounds By PETER W. SHELDRAKE SmithKline Beecham Pharmaceuticals Old Powder Mills Nr Leigh Tonbridge Kent TN11 9AN UK Three-membered Rings Oxiranes maintain their eminent position as synthetic intermediates and work on their asymmetric preparation makes them ever more available in chiral form. The scope of chiral manganese(II1) salen [H,salen = bis(salicylidene)ethylenediamine] catalysed epoxidations continues to expand. With a rn-chloroperbenzoic acid (MCPBA)-N- methylmorpholine N-oxide oxidant,' di-substituted and tri-substituted olefins are epoxidized at -78 "C in good yield and in high enantiomeric excesses [98% in the case of (Z)-3-phenylprop-2-ene]. The same catalysts with a sodium hypochlorite-4-phenylpyridine N-oxide oxidant2 epoxidize tetra-substituted olefins in up to 97% enantiomeric excess.In the case of ct,P-unsaturated aldehydes a chiral auxiliary has been used to prepare a derivative (l) then reaction with N-bromosuccinimide (NBS) followed by base treatment gives the epoxide (3)in greater than 95% diastereoisomeric ex~ess,~ oia intermediate (2) (Scheme 1). Preparation of an epoxide (6)using (S)-sulfimide (4) and an aldehyde or ketone (5) gives moderate yields4 and enantiomeric excesses of 21% to 74% (Scheme 2). meso-Epoxides (7) react with trimethylsilyl azide in the presence of a chiral chromium(sa1en) complex to give azido alcohols (8);enantiomeric excesses are 81 YOto 98% (Scheme 3). The same system5 gave kinetic resolution of racemic styrene oxide (98% ee) and epichlorohydrin (97% ee).Epoxides (9) are used as precursors of the metallated epoxides (10) though a very low temperature is required.6 Products (11) from a useful range of electrophiles are obtained (Scheme 4).The stereochemistry of the precursor is maintained. Another unstable epoxide is (13) formed from enamide (12) using dimethyldioxirane (Scheme Scheme 1 Reagents i NBS 172-dimethoxyethane(DME) H,O; ii NaOEt EtOH 145 Peter W. Sheldrake (5) R' = Ph PhCH2CH2 cyclohexyl R2 = H Me Scheme 2 Reagents i NaH THF i ii m 6590% (7) (8) R = Me (CH2)n CH2CH=CHCH2 Scheme 3 Reagents i Me,SiN with chromium(sa1en); ii CSA MeOH i 0 (9) R' R2= alkyl aryl Scheme 4 Reagents i Bu'Li or EtMgC1 THF -100"C; ii electrophile; elec- trophile = aldehyde ketone trimethylsilyl chloride (TMSCI) EtOCOCl PhCON(H) PhCON(H) i phcoN(H)l Me - Me x~'~~)COPh (12) Scheme 5 Reagents i dimethyldioxirane -50 "C; ii warm 5).' It is stable at -50 "C (characterized by low temperature NMR) but on warming gives the dioxane (14).Reaction of imine (15) with ethyl diazoacetate in the presence of a copper(1) complex and chiral auxiliary (17) gives aziridine (16)as the major product* (Scheme 6)but both the yield and enantiomeric excess (44%) are low. The aza-Payne rearrangement of activated aziridine-2-methanols and 2,3-ep-oxyamines has been ~tudied,~ as exemplified by the conversion of (18)into (19)shown in Scheme 7. Preparation of azirines by elimination (and trapping by iodomethane) of a Heterocyclic Compounds Scheme 6 Reagents i N2CHC02Et CuPFJMeCN) (17) H PkWHN CH20H i 94% c Ts TS(H)N (18) Scheme 7 Reagents i KH (20) (211 Scheme 8 Reagents i LDA -78 "C; ii MeI; iii H20 sulfenic acid from a suitable aziridine is described," thus (20) is converted into the antibiotic dysidazirine (21) (Scheme 8).,S02Ph Ph (22) When oxaziridine (22) is used to hydroxylate carbanions excess lithium diiso- propylamide (LDA) causes its decomposition with the emission of light." Not all strong bases produce the phenomenon which is ascribed to ring opening of the conjugate base of (22). 2 Four-membered Rings It appears that in 90 years or so since its discovery'2 the Darzens reaction has only now been attempted with a phenyl ester.I3 Interestingly the chloro ester (23) with a suitable lithium amide base and a ketone gives via (24) not an oxirane but lactone (25) (Scheme Peter W.Sheldrake (24) (25) R1,R2= alkyl (CH2)n Scheme 9 Reagents i LDA; ii R'COR' i c R2?02ph = alkyl or H Scheme 10 Reagents i R3COR4,In H i HyN2 -PG"+O Scheme 11 Reagents i Rh,(OAc) (30) n = 1,2,3 (311 Scheme 12 Reagents i (Ph,P),Pd Bu3N CO 9). Corresponding bromo esters (26) and ketones are converted into di- tri- or tetra-substituted /?-lactones (27) using indium powder or electrochemically using a sacrificial indium anode14 (Scheme 10). Yields are variable but usually good. Treatment of diazo ketones (28) derivable from wamino acids with rhodium acetate gives azetidin-3-ones (29) (Scheme 11).The products react as expected with sodium borohydride ester enolates Grignard reagents or Wittig reagents. The compounds so derived are obtained in (mostly) good yield and have high diastereoisomeric excess.' Vinyl trifluoromethanesulfonate (triflate Tf) [(30) n = 11 undergoes palladium(0) catalysed carbonylation and ring closure16 to give p-lactam [(31) n = 11.The reaction can also be used to prepare larger rings (Scheme 12). The prop-2-ynylamine (32) produces a p-lactam (33) when reacted with carbon monoxide using a palladium(0) Heterocyclic Compounds 0 (33) Scheme 13 Reagents i CO air (22atm) KI 10% Pd on C MeOH (34) (35) R' R~ = alkyl Scheme 14 Reagents i R2NH, MeOH reflux i H02C/-(c02CH2Ph 28-83% NH2 (36) (37) Scheme 15 Reagents i R'CHO R2NC Scheme 16 Reagents:i CH,=C(OEt)OTBDMS BF,.OEt, MeCN Et,O -78 "C; ii H, catalyst; iii KOH MeOH; iv 2-chloro-l-methylpyridinium iodide (TBDMS = tert-butyldimethylsilyl) catalyst (Scheme 13).17 It was found impossible to extend the reaction to unsubstituted or to acylated amines.Unsaturated esters (34) give p-lactams (35) on treatment with a primary amine in refluxing methanol (Scheme 14).18 The aspartate monoester (36) is closed to give p-lactams (37) using an aldehyde and an isonitrile (Scheme 15).19 The benzyloxycar- bony1 group was then subjected to further transformation. The versatile intermediate (38) is reacted with an ester-enolate equivalent to give (39).After deprotection of the nitrogen by hydrogenolysis lactamization to (40)is achieved by conventional means but in.only 22% yield (Scheme 16).20 Peter W.Sheldrake TBDMSO TBDMSO OTBDMS 33% i +pCH0 97 C02Me C02Me (41) (42) Scheme 17 Reagents i AgBF, CH,Cl, -78 “C TBDMSO TBDMSO i 70-1 00% *OB2 C02Et E C02Et (43) E = COZEt SPh (44) Scheme 18 Reagents i Pd(OAc), ethylenebis(dipheny1phosphine) (DPPE) base TBDMSO TBDMSO WcOsR i.5542% ii iii iv 0 ~ WSR C02allyl C02allyl (45) (46) Scheme 19 Reagents i NaN(TMS),; ii TMSCl; iii (PhO),P(O)Cl; iv tetrabutylam- monium fluoride (TBAF) Starting from the chloroazetidinone (41) the precursor of the required iminium ion the aza-Cope Mannich cyclization tactic gives the carbapenem (42) (Scheme 17).” Cyclization of (43) by intramolecular closure of a malonate anion onto a rc-ally1 palladium complex gives (44) in respectable yield (Scheme 18)., Strong base initiates ring-closure in (45) (Scheme 19) but in the one-pot process thiolate anion returns to ‘counter-attack’ the vinyl phosphate intermediate giving (46) in good yield considering all that has occurred.23 Reaction of the well-known acetoxyazetidinone (47) with a Grignard reagent and carbon disulfide in the presence of copper(1) iodide gives the dithioester (48).Formation of a 2-substituted penem (49) was completed using methyl oxalyl chloride followed by treatment of the oxalimide with diethyl methylphosphonite (Scheme 2O)., A preparation of 2-aryl or 2-heteroaryl substituted penems (51) involves coupling the 2-tributyltinpenem (50)with aryl halides using palladium(0) (Scheme 21).Triphenylar- sine is necessary as a ligand.25 The cycloocta-1,5-diene origin of (52) is evident. Attacking the p-lactam with Heterocyclic Compounds TBDMSO TBDMSO TBDMSO R NH 31-75% 0 C02Me (47) (48) (49) Scheme 20 Reagents i RMgX CuI; ii CS,; iii CICOC0,Me; iv MeP(OEt) TBDMSO TBDMSO i y+*. b$snBu3 t0737! * C02Me C02Me (50) (511 Scheme 21 Reagents i Ar-X Pd,(dba);CHCl (dba = dibenzylideneacetone) AsPh, toluene reflux I ph8 ., , OH 0 (53) (52) Scheme 22 Reagents i MeLi THF -25 "C methyllithium permits transannular attack by the liberated amide on the oxirane26 (Scheme 22) giving (53) which was converted into ( +)-anatoxin-a.Sequential reaction of prop-2-ynyl bromide with triphenylphosphine and then a primary or secondary amine gives the phosphonium salt (54) which with diborane produces (two geometric isomers of) (55);the first four-membered heterocycle of its type (Scheme 23). Some simple reactions of (55) are de~cribed.,~ 3 Five-membered Rings Aromaticity and anti-aromaticity in five-membered heteroaromatics containing one heteroatom,28 the coupling of terminal alkynes and halides using palladium or palladium-copper catalysts yielding heterocycle^,^' and the stereoselective synthesis of oligo- te tra h ydrofurans have been reviewed. The series of reviews on the synthesis and reactions of lithiated monocyclic azoles now covers isothiazoles and thiazoles3' and triazoles tetrazoles oxadiazoles and Peter W.Sheldrake Me - Ph3p2~R'R2 i Br- H2 Br- (54) (55) R' R2= -CHMePh H -CHMePh -CHMePh (CH2)4 or 5 Scheme 23 Reagents i BH;THF CH,Cl thiadia~oles.~, It is known that 2-lithiooxazoles give reaction products of ring opening; however transmetallation to a zinc species allows the oxazole to be coupled with aryl iodides using a palladium catalyst'j or using zinc chloride-copper(1) iodide to be a~y1ated.j~ Copper(1) iodide is essential in the latter case as the simple zinc species is unreactive to acyl chlorides. (56) The three oxygen atoms in (56) were shown by 13C and "0 NMR to be transposable by sequential rearrangements brought about by ultra-violet i1-radiati0n.j~ Rearrangement of the aminoalkylfuran derivative (57) under oxidative conditions gives the dihydropyridine (58) of 95% enantiomeric excess (Scheme 24)j6 thus providing a route to aza-sugars.Reaction of 2-fury1 phenyl thioketone (59) with diazobis(phenylsulfony1)methane gives the furo[2,3-c]thiophene (60) in 62% yield (Scheme 25).j7 Phenyliodonium bis(phenylsulfony1)methane brings about the same reaction and a thiophene a pyrrole or their benzo-derivatives can take the place of the furan moiety. An alternative synthesis of furo[2,3-c]pyrroles is described3* and their Diels-Alder reactions are investigated. For example (61)gives a 1:2 adduct with dimethyl acetylenedicarboxylate yielding (62) (Scheme 26). Scheme 24 Reagents i MCPBA; ii CAN EtOH Heterocyclic Compounds i 62% (59) Scheme 25 Reagents (PhSO,),CN, Cu(acac) (Hacac = acetylacetone) toluene heat Me02C i WR -%Me Me0& C02Me (61) (62) R = Bn Pi But (CH2J30H Scheme 26 Reagents i MeO,CCZCO,Me (63) (64) R = Ph PhCH=CH Scheme 27 Reagents i PhSeC1 K,CO, Et,O -60 "C to 0 "C R' R2 i PMBoACHO 7578% * C02Et (65) (66) R' R2 = H Me Et Scheme 28 Reagents i N,CHCO,Et SnCl, -78 "C to 0 "C The 2-silylalk-3-enols (63) undergo 5-endo-trig selenoetherification in moderate yield but high diastereoselectivity (>98% de) to give tetrahydrofurans (64) (Scheme 27).39 Tetrahydrofurans (66) are formed from aldehydes (65) and ethyl diazoacetate (Scheme 28) in a reaction which might have been expected to produce a /?-keto ester.40 Variable behaviour of y-butyrolactone under Friedel-Crafts conditions is re-ported.41 The acylation of 1-methylpyrrole (67)to give (68) (Scheme 29) is contrasted with alkylation of benzene under the same conditions.2-Formylbenzoic acid (69) reacts with phenethylamine to give (70). On treatment with thionyl chloride and then methanol the a-methoxyisoindolone (71) is formed (Scheme 30) utilizable as an acyliminium ion prec~rsor.~ (2)-/?-Iodoenones such as (72) are carbonylated under palladium catalysis and cyclization leads to lactones (73) Peter W. Sheldrake Scheme 29 Reagents i tetrahydrofuran-2-one AICl Scheme 30 Reagents i PhCH,CH,NH,; ii SOCl,; iii MeOH i -EtCH2 80% ’X Et (72) (73) Pr Pr i P hX s r 77% PhGo (74) (75) X=O,NH Scheme 31 Reagents i CO (2WO atm) (Ph,P),PdCl, NEt, 100“C (Scheme 31); imines react in an analogous way to give lac tarn^.^ Starting materials such as (74) cannot react in this way but an additional reduction then occurs to give (75).Reaction of p-tolyllead triacetate with azoles (or their anions) under copper(1r) acetate catalysis gives N-tolyl derivatives usually in high yield.44 Pyrroles (77) are formed by reduction of the nitro group in nitro ketones (76)to the imine then cyclization (Scheme 32).45 The reducing agent in this instance is formamidinesulfinic acid and the ester (or other electron withdrawing group geminal to the nitro group) was found to be necessary for successful reaction.The ability to form nitrogen-containing heterocycles using nitrogen as the only nitrogen source may sound like the heterocyclic chemist’s Philosopher’s Stone! The complex formed from titanium tetrachloride lithium and chloro trimethylsilane is reported46 to convert nitrogen and (78) in the presence of caesium fluoride into (79) amongst other examples (Scheme 33). Boron tribromide is the unusual choice of catalyst for the high-yielding Friedel-Crafts-like cyclization of pyrrole diester (80) to (81) (Scheme 34).47 155 Heterocyclic Compounds Et02CGo Et02CbR2 * N 7549% NO2 H (76) (77) R' R~ = atkyl aryl Scheme 32 Reagents i H,NC(=NH)SO,H Et,N isopropylamine (IPA) I Ph Scheme 33 Reagents i TiC1,-Li-Me,SiCl CsF N Scheme 34 Reagents i BB, CH,CI, 5°C ii (82) (83) (84) Scheme 35 Reagents i PPA; ii EtO,CCZCO,Et Friedel-Crafts reactions starting from the corresponding acids tend to give relatively poor results.Polyphosphoric acid (PPA) brings about the cyclization of (82) to oxygen-sensitive thieno[2,3-flindolizine (83) in good yield considering its 14n-electron system and potential rea~tivity,,~ demonstrated by reaction with diethyl acetylenedicarboxylate to give (84) (Scheme 35). Hydrobromic acid induced cyclization of (85) gives 3-bromopyrroles (87) bearing a 5-substituent (Scheme 36).49 Alternative placement of the substituent in the starting material (86) for convenience prepared and used as the acetal gives a 3-bromopyrrole with a 2-substituent (88).2-Methylpyrroles bearing a variety of other alkyl acyl and/or ester substituents are oxidized by ceric ammonium nitrate (CAN) in THF-acetic acid-water to the corresponding 2-formylpyrroles in moderate to good yields5' Peter W. Sheldrake Br i or ii * R' 4 R' o-NHR2 R3 6679% R3 R2 (85) R' = alkyl R3 = H (87) R3 = H (86) R' = H R3 = alkyl furyl thienyl phenyl (88) R' = H R~ = BOC or TS Scheme 36 Reagents:i HBr HOAc CH,Cl, 0 "C; ii HBr(aq) toluene 20 "C-60 "C Me I OTBDMS (92) Scheme 37 Reagents i maleic anhydride MeCN 25"C 5min; ii PhCHO TBDMSOTf Scheme 38 Reagents i trifluoroacetic acid (TFA) The preparation of osmium(1r) complexes of some simple pyrroles is de~cribed.~' These complexes react readily in dipolar cycloadditions as exemplified by conversion of the parent complex (89) into (90) (Scheme 37).Yields are high and the osmium can be removed from the product using ceric ammonium nitrate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). P-Electrophilic additions of these pentaamine osmium(I1) q2-pyrrole complexes are also reported;52 the conversion of (91) into (92) is typical (Scheme 37). An intramolecular Schmidt reaction converts keto azide (93) into the bicyclic lactam (94) (Scheme 38).s3 There is only a slight loss of chiral purity in the reaction. The base-induced cyclization of 5-(diphenylphosphinyloxyamino)valeric esters (95) readily prepared from the hydroxyamines gives pyrrolidines (96) (Scheme 39).54 Heterocyclic Compounds R’ = Me CH2Ph R2 = H C02Et Scheme 39 Reagents i LDA; ii Bu’OK ,x (97) R = Ph (98) (100) R=H X = C02Me efc.Scheme 40 Reagents i (HCHO), XCH=CHX xylene sieves heat; ii (HCHO), XCH=CHX MgBr, THF sieves; iii H, Pd(OH), TFA MeOH i D 96% C02Me (101) (102) Scheme 41 Reagents i MeO,CCzCCO,Me CHCl, room temp. Ring-formation by displacing a leaving group from nitrogen is relatively uncommon. The homochiral oxazin-2-one (97) has been used as the source of an azomethine ylide which was converted into adduct (98). Cleavage of the chiral auxiliary leaves pyrrolidinecarboxylic acid (99)(Scheme 40).” The oxazin-2-one (100) is also available and has been used in analogous reaction^.'^ The reaction of 1,8-diazabicyclo[5.4.O]undec-7-ene (DBU) (101) with dimethyl acetylenedicarboxylate is reported57 (Scheme 41).The adduct (102) is formed in excellent yield. 1,5-Diazabicyclo[4.3.O]non-5-ene (DBN) under the same conditions gives ‘an intractable red mixture’. 2-Haloarylalkylamines (103)are cyclized rapidly and in high yield by palladium(0) giving (104) (n = 1-3) (Scheme 42).58 Tributyltinalkynes such as (105) are precursors of alkynyliodonium salts (106) which are themselves isolable but are best treated immediately with strong base to deliver a cyclized amine such as (107) (Scheme 43).59 Photochemical irradiation of trimethylsilylmethylphthalimide ( 108) gives an azomethine ylide which undergoes typical reactions giving for example (109) (Scheme 44). An azomethine ylide can also be generated photochemically from (1 Peter W.SheIdrake (103) n = 1,2,3 X = Br I Scheme 42 Reagents i (PPh,),Pd NaOBu' K2C0, toluene heat Scheme 43 Reagents i PhI' CN TfO-; ii Bu'OK; iii lithium bis(trimethylsily1)amide (LiHMDS) @ T;02Me 02Me 0 0 (108) R = SiMe (109) (110) R=COZH Scheme 44 Reagents i UV MeCN dimethyl fumarate (1 11) (112) Scheme 45 Reagents i trifluoroacetic anhydride (TFAA) THF reflux; ii NEt,; iii NaOH N-Benzylprolinol (N-benzylpyrrolidine-2-methanol)(1 1 1) undergoes ring-expan- sion (Scheme 45) to give piperidinol(ll2) of 97% enantiomeric excess.61 Acyl azide (113) was heated in the expectation of obtaining an isocyanate.62 However 1,1,7-trimethylindazol-3-ium-5-olate (114) is found to be the product; its structure is confirmed by X-ray crystallography (Scheme 46).The triazolium salt (1 15) adds methoxide to give (1 16). At just 80 "C this undergoes a-elimination to give carbene (117) (Scheme 47) which is thermally stable to 150 "C; it reacts with alcohols or secondary amines by inserting into the X-H bond.63 Reaction of an imidate such as (118) with formylhydrazine is known and the final Heterocyclic Compounds 159 0- i c Me Me Scheme 46 Reagents i heat benzene Ph Ph Ph Ph I. Ph (115) (116) (1 17) Scheme 47 Reagents i NaOMe MeOH; ii 80°C (1 18) (119) Scheme 48 Reagents i H,NN(H)CHO 0 "C; ii Scheme 49 Reagents i Bu,SnH AIBN C,H, heat product (1 19) would be expected to be a triazole.However at 0"C a triazole does not form and (1 19) is treated with nitrous acid to give a tetrazole (120) (Scheme 48).64 The oxidation of a number of diazoles triazoles and tetrazole with a peracid or perborate is reported65 in a survey of the preparation of N-hydroxyazoles. A reinvestigation into the polychlorination of thiophene is reported., The chemistry of the thiophenetricarbonylchromium(0)complex is described it is used to prepare di- tri- and tetra-substituted thiophenes.,' Treatment of 1,3-dithiane derivatives such as (121) with tributyltin hy-dride-azoisobutyronitrile (AIBN) gives benzothiophenes (122) with a 2-tributyltin substituent convenient for further elaboration (Scheme 49).68 Treatment of 1,4-naphthoquinone with ethyl carbamate thionyl cloride and pyridine gives the 1,2,5-thiadiazole (123) in 81 % yield;,' experiments leading to the identification of the reactive species were described.Peter W. Sheldrake 0 Nitro esters such as (124) cyclize in refluxing xylene containing molecular sieves to give isoxazoles such as (125) (Scheme 50).70A mechanism is suggested and partially validated by independent generation of a proposed intermediate. The anion (127) reacts with 2-chloromethylbenzothiazole(126) with enlargement of the heterocyclic ring to give a benzo-1,4-thiazine (128) (Scheme 51). Similar azine anions were found to react in the same way.71 Low temperature ozonolysis of enol ethers (129) is used as a source of carbonyl oxides (130)which react with imines to give 1,2,4-dioxazolines (131) (Scheme 52).Many of the yields are good and most of the products are stable to column chromatogra- ph~.~~ (124) (125) Scheme 50 Reagents i 5A molecular sieves xylene reflux H Scheme 51 Reagents i THF -78 "C R" = H alkyl phenyl Scheme 52 Reagents i 0,,CH2Cl, -70 "C; ii R4R5C=NR6 Heterocyclic Compounds The preparation of the hitherto unsynthesized 1,2-diphospholide anions (132) is reported.73 This completes the series of phosphorus-containing five-membered heteroaromatic rings. (132) R = Ph Et 4 Six-membered Rings There is a review on computer-assisted design of heterocyclic syntheses with emphasis on the direct identification of starting materials.74 Recent syntheses of aromatic heterocycles are reviewed75 and the use of such compounds as intermediates in natural products synthesis is covered.76 Alcohols (133) react with an acetal and the resulting mixed acetal forms an oxonium ion onto which the allylsilane moiety readily cyclizes to give pyran (134)of the indicated stereochemistry (Scheme 53).77 Amides (135) are readily prepared by alkylation of the unsubstituted phenyla~etamides.~~ Lithium aluminium hydride reduction gives alco- hols which are cyclized in good yields to 3-substituted benzopyrans (136) of 9499% enantiomeric excess (Scheme 54).(133) R' = Me Et Ph (134) R2 = alkyl Ph Scheme 53 Reagents i R2CH(OEt) (135) R' R2 = H OMe Scheme 54 Reagents i LiAlH,; ii Ph,P EtO,CN=NCO,Et (MOM = methoxymethyl) Peter W.Sheldrake (137) R = CHO C02Me only R = H OMe N02,CH0 C02Me Scheme 55 Reagents i NaH THF; ii H + (140) R = alkyl benzyl Scheme 56 Reagents i POCl, N,N-dimethylformamide (DMF) R@&-0 Scheme 57 Reagents i NaOH The diarylacetylenes (137) are cyclized by strong base to give either a product of 5-exo-dig cyclization (138) or apparently a 6-endo-dig cyclization forming (139) according to the nature of the s~bstituent.~~ In fact the primary product is always (138) and in certain cases this undergoes a rearrangement (Scheme 55). 4-Aminocoumarins (140) are cyclized by the Vilsmeier reagent to give [l]benzopyrano[4,3-b]pyridin-5-ones (141) (Scheme 56).80 4-Chloromethylcoumarins (142) are rearranged by sodium hydroxide to give benzofuran-3-ylacetic acids (143) (Scheme 57).8' 4-Alkylamino-3-formylcoumarins (144) react with secondary amines to give 4-amino-3-dialkylaminomethylcoumarins (145) (Scheme 58).After imine forma- tion there is an intramolecular hydride transfer and subsequent loss of an aldehyde.82 The 1,4-dioxane (146) is substituted by allysilanes to give for example (147) of the specific stereochemistry shown in over 98% diastereoisorneric excess.83 Chirality is transferred from the auxiliary diol to a new diol which is released by hydrogenolysis Heterocyclic Compounds 163 Scheme 58 Reagents i HNR,' Scheme 59 Reagents i CH,=CHCH,SiMe, TMSOTf MeCN 0 "C Scheme 60 Reagents i see text (Scheme 59). An extension of the method84 using 3-acetoxy-5,6-diphenyl-l,4-dioxan-2-one permits the introduction of two different groups into the new diol.Hydroperoxide (148) can be cyclized to 1,2-dioxane (149) using one of three reagents that prepared from samarium iodide and oxygen (79% yield) di-tert-butyl per- oxyoxalate (66%) or di-tert-butyl peroxyoxalate-tert-butyl hydroperoxide (89Y0) (Scheme 60).85 Useful palladium(0) catalyzed cyclizations are described86 including the formation of 1,2-dihydroisoquinoline (1 5 1) from (1 50) and of isocoumarin (1 53) from (152) (Scheme 6 1). Benzopyrans and benzofurans were also prepared. The trifluoroacetylketene (1 54) is prepared from the appropriate acid chloride trifluoroacetic anhydride and pyridine. It reacts with enamines or vinyl ethers to give 2-trifluoromethyl substituted pyran-4-ones (1 55) and (156) and with dimethylcyanam- ide to give 1,3-oxazin-4-one (157) (Scheme 62).87 A trifluoromethyl substituent is thus attached to heterocycles capable of further elaboration or transformation.The product of acetylation of 2-~yano(cyanomethyl)benzene(158) is shown to be an isocoumarin derivative (159). Among other reactions this is readily transformed to isoquinolone (160) or l-aminoisoquinolines (161) (Scheme 63).88 The oxidation of benzylacetone oximes such as (162) giving quinoline (163) by stoichiometric tetrabutylammonium perrhenate(vr1) is de~cribed.~' A more conveni- Peter W. Sheldrake 0 Scheme 61 Reagents i PhCzCC0,Et; ii Bu‘CfCMe; iii Pdo 0 ii 57% 1 0 CF3 YiOEt Scheme 62 Reagents i 1-morpholinocyclohexene; ii CH,=CHOEt; iii Me,NCN ent more efficient reagent using less perrhenate with 4-chloranil was developed (Scheme 64).An efficient synthesis of 2-chloro-3-ethoxycarbonylpyridine (165) is described.” The immediate precursor (164) is itself readily prepared in 77% yield from acrolein and ethyl 2-chloro-2-cyanoacetate (Scheme 65). The pyridine (166) is cyclized by tert-butoxide to give 5-amino- 1,2-dihydrofur0[3,2- fl[177]naphthyridine(167) attack on the ring by the carbanion adjacent to the cyano group being the clue to the mechanism.’l In a further idiosyncratic reaction (167) on acid hydrolysis gives (168) (Scheme 66). Simple imines such as (169) enter into 4 + 2 cyclizations with vinyl ethers ultimately giving quinolines in this case (170) (Scheme 67).Ethyl vinyl ether dihydropyran and dihydrofuran were also used as the 2n component.92 Improved methods for two well-known and fundamental reactions of heterocyclic chemistry are reported. The preparation of some azine N-oxides using rn-chloroper- benzoic acid is preferentially carried out in dimethylformamide-methanol containing Heterocyclic Compounds CN CN Scheme 63 Reagents i Ac,O; ii NaOH; iii RNH (162) (163) Scheme 64 Reagen ts i Bu,NReO, CF,SO,H chloranil 5 8 molecular sieves ClCH,CH,Cl heat i CHO CN Et 65% fic& Scheme 65 Reagents i PCI, DMF hydrogen fluoride thereby improving reaction time and/or yield.93 The displacement by cyanide of reactive chlorine substituents in pyrimidines purines quinoxalines and quinazolines (though strangely not isoquinolines) is catalysed by sodium toluene-p- ~ulfinate.~, Another variant on a classical reaction is the use of triflic anhydride-4- dimethylaminopyridine (DMAP) to effect a Bischler-Napieralski reaction.95 The new reagent converts (171) to (172) in 92% yield (Scheme 68) whereas there is no reaction with phosphorus oxychloride even at 200 "C.Hantzsch dihydropyridines (1 73) are routinely oxidized with a variety of reagents. Peter W. Sheldrake Scheme 66 Reagents i Bu'OK dioxane; ii conc. HCI reflux 74% i D qph Scheme 67 Reagents i CH,=C(OMe)Me Yb(OTf) "Me I i / C02Me 92% Scheme 68 Reagents i Tf,O DMAP However where the substituent R is a secondary alkyl or a benzyl group use of manganese dioxide causes loss of the substituent leading to the 4-unsubstituted pyridine (174) in good yield (Scheme 69).96 Two methods of forming 4-methoxypyridyne (176) are reported97 (Scheme 70) using strong base to eliminate hydrogen chloride from (175) or a fluoride initiated elimination from the silyl derivative (177).The latter method gave better yields of trapped product. 2-Chloro-3-oxiranylmethoxypyridine(178) is metallated by LDA at the 4-position. The epoxide is then attacked intramolecularly to yield furopyridine (179) efficiently (Scheme 71)." 3-Trichloromethylpyridine (180) reacts in unusual fashion with oxygen sulfur and nitrogen nucleophiles to give 6-substituted 3-dichloromethyl products (181) (Scheme 72).The N-oxide and 3,5-bis(trichloromethyl)pyridine react in the same way.99 Both 2-bromo-3-trifluoromethylsulfonyloxypyridine(1 82) and the 3-bromo-2-trifluoromethylsulfonyloxypyridine (1 84) react at the 2-position with 1-ethoxyvinyl(tributy1)stannane and a palladium(0) catalyst giving (183) and (185) respectively (Scheme 73). The 2-position is inherently the more reactive and this knowledge was then used as synthesis of dimethyl sulfomycinate.'OO Heterocyclic Compounds 167 RH 8043% Me Me H (173) R = benzyl or 2" alkyl Scheme 69 Reagents i MnO OMe N OTf Scheme 70 Reagents i lithium tetramethylpiperidide (LiTMP); ii CsF HO i 77% Scheme 71 Reagents i LDA (2 equiv.) tetrahydrofuran (THF) -78 "C Simple imines (186) prepared in situ react with l-methoxy-3-trimethylsilyloxybuta-1,3-diene and a lanthanide triflate catalyst to give dihydro-4-pyridones (1 87) (Scheme 74).The same imines can also react as aza-dienes with alkenes to give tetrahyd- roisoquinolines (188) (Scheme 74).'" Dihydro-4-pyridones (189) pretreated with chlorotrimethylsilane and a copper catalyst react with Grignard reagents. The intermediates (190) can be re-oxidized to reform pyridones (191) now with an additional substituent (Scheme 75).'02 The carboxylate-terminated N-acyliminium ion bis-cyclization of (192) to (193) (Scheme 76) exemplifies the principle of the key step used in a total synthesis of ( -)-ajmalicine.'03 The diastereoselectivity of such cyclizations is high (93% de in this instance).The tetrahydroisoquinolinium salt (194) is quantitatively rearranged by sodium methoxide to tetrahydroisoquinoline (195) (Scheme 77).'04 The features of the suggested mechanism are ring fission with formation of a quinonemethide trapping of the quinonemethide by methoxide and C-alkylation of the resulting phenolate. Hydrazones (196) prepared from aryl trifluoromethyl ketones cyclize in good yield on treatment with potassium hexamethyldisilazide (KHMDS) to give 3-aryl-4- aminocinnolines (197) (Scheme 78). lo' Peter W. Sheldrake CHC12 i or ii or iii Nuc Scheme 72 Reagents i PhOH; ii RSH; iii R,NH i OEt (182) R=H X=OTf Y=Br (183) R=H X=OTf (184) R=Me X=Br Y=OTf (185) R=Me X=Br Scheme 73 Reagents i CH,=C(OEt)SnBu, Pdo R'- N Ph ~ ii 'N'-Ph - f) N Ph H Ar (188) (1 86) (187) Scheme 74 Reagents i C H ,=C( OSi Me,)CH=C( H)O Me Ln(OTf), MgSO, MeCN; ii CH,=CHR, Ln(OTf),; Ln = Sc or Yb; R1 = H OMe; R2 = SPh OEt Scheme 75 Reagents i CuBr,-SMe, Me,SiCl; ii R2MgX; iii Pd(OAc), MeCN Reaction of 2-chloropyridine (198) and 2-aminobenzenethiol(l99)at high tempera- ture in the presence of iodine gives 4-azaphenothiazin (200) (Scheme 79).It is thought that sequential attack at the pyridine 2-position by the two heteroatoms of (199) forms a spiro intermediate which by rearrangement and oxidation gives the product.lo6 Primary aromatic amines (201) react with phenylsulfinylselenyl chloride to form transient selenonitroso species (202). These can be trapped with 1,3-dienes to give 1,2-selenazines (203) (Scheme 80).The yields are low and the products are stable at 0 "C for only a few hours.'07 3,6-Diiodopyridazine (204) is desymmetrized by reaction with fluoride methoxide dimethylamine or methanethiolate.Yields are good and the products (205) are Heterocyclic Compounds Bn Scheme 76 Reagents i (HCHO), TFA MeNO HO a Me0 p e ,- 100%i Me0 &NMe LCN HO (194) (195) Scheme 77 Reagents i NaOMe MeOH reflux 2 h (196) (197) Scheme 78 Reagents i KHMDS THF -78 "C; ii H,O (198) (199) (200) Scheme 79 Reagents i I, high-boiling solvent 210 "C convenient for further reactions (Scheme 81). Examples are given of palladium catalysed cross-coupling reactions with acetylenes boronates and heteroaromatic stannanes.lo* The syntheses and spectroscopic properties of (206 a b) are reported.'Og The delocalized 12n system is formally antiaromatic.The preparation of lithium borataben- zene (207) is reported.' lo The compound reacts with deuterium oxide liberating H-D reduces aldehydes and opens an oxirane ring. The first gallatabenzene derivative (208) is reported characterized by 'H and I3CNMR which reveal aromatic character in the new heterocycle.' '' Peter W. Sheldrake 1-1 Scheme 80 Reagents i PhSO,SeCl Et,N CH,Cl, 0°C; ii CH 2=C( Me)-C( Me)=CH 67-99% Nuc-l N-N N-N (204) (205) Scheme 81 Reagents i nucleophiles such as MeO- F- Me,NH MeS- Bu But -Q Li+ .i+ B"" but (206a) X=N (206b) X=P 5 Seven-membered Rings The development of methods required for the total synthesis of brevetoxin B has led to reports of the photochemical cyclization of bis-thioester (209) to oxepine (210) and the reductive cyclization of hydroxy ketone (211) to oxepane (212) (Scheme 82).'12 The more complex examples used in the actual natural product synthesis and the story of the heroic synthetic achievement also appear.' '3*114 Reaction of 7-hydroxyhept-1-enes (213) with bis(syrn-collidine)iodine(r)hexa-fluorophosphate (sym-collidine = 2,4,6-trimethylpyridine) induces em-mode cycliz- ation giving oxepanes (214) in good yield (Scheme 83).'" The method is much less efficient when challenged to produce an oxetane.4,5-Dihydro-2,5-dimethoxy-1,3-dioxepine (215) is readily prepared from (Z)-but-2- ene-1,4-diol by bromination in methanol cyclization with orthoformate and dehyd- robromination.Treatment with silica in refluxing benzene yields a mixture of the (inseparable) dihydrofurans (216) and (217) (Scheme 84). Both of these slowly eliminate methanol in the presence of an acid catalyst producing furan-3-carbaldehyde in good overall yield.'I6 2H-Azepine (219) has been prepared for the first time; the key step being the deprotection-cyclization of (218) (Scheme 85). The yield was just 1 %! Proton and I3C NMR spectra are reported; the compound is stable for 48 h at room temperature.'" Bicyclic azepines are available by intramolecular trapping of didehydroazepines. Heterocyclic Compounds i P 63% OMe Me ii b 85% Me Scheme 82 Reagents i Pyrex-filtered UV toluene 70°C; ii Et,SiH TMSOTf CH,Cl, 0°C (213) (214) Scheme 83 Reagents i (collidine),I 'PF; CH,Cl Scheme 84 Reagents i silica benzene reflux Thus for example photolysis of azide (220) gives 2,3,4,4a-tetrahydro-l H-pyrido- [2,3-b]azepine (221) in moderate yields dependent on the solvent (Scheme 86).' l8 Reaction of cyclohexanone (222) with 2-azidoethanol gives N-hydroxyethylcaprolac- tam (223) in 98% yield (Scheme 87).The work goes on to study the diastereoselectivity of the reaction between readily available chiral azido alcohols and 4-tert-butylcyc- lohe~anone."~ Cyclic enol ethers (224) are converted into azides (225) with trimethyl- silyl azide and thence by photolysis to the ring-expanded lactams (226) (Scheme 88).''O Dehydroamino acid derivatives (227) undergo palladium(0) catalysed cyclization to give seven- eight- or nine-membered rings (228) (Scheme 89).I2l The 7-endo Heck cyclization is rare and the 8-endo Heck cyclization even more so and formation of the nine-membered ring is the first such example.Photocycloaddition of ( -)-8-phenylmenthyl acrylate and tricarbonyl[N-(methoxycarbonyl)azepine]chromium(0)(229) gives the endo-adduct (230) in 58% yield and 98% diastereoisomeric excess (Scheme 90). There is also a smaller yield (15%) of Peter W. Sheldrake Scheme 85 Reagents:i TFA CH,Cl, -10"C; ii DMAP or 1,4-diazabicyclo[2.2.2]-octane (DABCO) i UPto 69% H (220) (2211 Scheme 86 Reagents i light > 350nm various solvents (222) Scheme 87 Reagents i HOCH,CH,N Scheme 88 Reagents i Me,SiN, pyridinium toluene-p-sulfonate (PPTS);ii UV the unexpected em-adduct of similarly high diastereoisomeric purity.'22 Benzothiazolium salts (23 1)(readily available using a,w-dihaloalkanes) on treatment with sodium hydroxide suffer ring-opening of the thiazole and recyclization to form a new larger heterocyclic ring (232) (Scheme 91). The scope of the reaction includes a,o-dihaloalkanes of chain lengths 2 to 8 and therefore new rings of up to 12 members can be formed.lZ3 Yields vary from 11% to 84%. Larger rings A review'24 on syntheses of large-ring compounds (12 or more membered) includes heterocyclic examples beyond simple lactones and lactams and there is a review covering medium ring lactones.' 25 Heterocyclic Compounds Scheme 89 Reagents i Pd(OAc), NaHCO, Bu,NCl 3 A molecular sieves MeCN ?O2Me HM&C02R* H i P 0 -Cr(CO) 58% (229) (230) Scheme 90 Reagents i ( -)-8-phenylmenthyl acrylate UV CH2CH2CH2CI YHO (2311 Scheme 91 Reagents i NaOH H,O TCE i HO= 50% Me kO"*-Me Me- '-Me Bi (2333 (234) Scheme 92 Reagents i Ph,PCH,CH,PPh,-Br, CH,Cl, reflux When the A5-oxonene (233) is brominated using the l72-bis(dipheny1phos-phino)ethane-bromine complex a 50% yield of the ring-contracted A4-oxocine (234) is found (Scheme 92).The mass balance is completed by two compounds of unchanged ring-size.'26 When the diene(tricarbony1)iron complex (235a) is treated with Amberlyst 15 cyclization to oxocine (236) occurs (Scheme 93).A separate deprotection step is not required. The reaction is stereospecific the diastereoisomer (235b) yields only the diastereoisomer of (236) and the potential of optically active complexes is ~1ear.l~~ The iron is removed from the product using ceric ammonium nitrate. Attempted bromination of enediyne (237) initiates a comprehensive rearrangement leading to (239) (Scheme 94). Careful investigation permitted isolation of the 2-bromo Peter W. Sheldrake (235) a R'=H R2=OTBDMS b R2=H R'=OTBDMS Scheme 93 Reagents i Amberlyst 15 CH,Cl 0 -0Me Br F OMe 0 (237) R = H (239) (238) R=Br Scheme 94 Reagents i Br2 CHCl derivative (238) rearrangement of which was found to depend on hydrogen bro- mide.128 -NMe (240) The conformation of enediyne (240) is determined by coordination to the mercuric ion and Bergman cyclization occurs at 418K.Without the metal ion Bergman cyclization needs a temperature of 510K. The authors speculate that even more strained systems might respond to a chemical signal at room temperat~re.',~ It is convenient to mention here an enediyne system (241) in which cyclization is triggered by hydrolysis of a fi-la~tarn.'~' Heterocyclic Compounds i m * NH2 NH2 NH2 100% Scheme 95 Reagents i HCHO water And finally 1,3,5triaminopentane (242) reacts with formaldehyde to produce in just 30 min a quantitative yield of (243) (Scheme 95).13' The conformations of (243) were studied by X-ray analysis and 13C NMR-possibly in less time than it takes to work out its name! Acknowledgements.I am grateful to my immediate managers at SmithKline Beecham for regarding the preparation of this and previous chapters as part of my normal work. I must convey my thanks to Helga Clunie for transcribing my original scribbling both speedily and with remarkable accuracy into typescript. 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ISSN:0069-3030    

DOI:10.1039/OC9959200145

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

7 OrganometalIic Chemistry the transition elements By G. R. STEPHENSON School of Chemical Sciences University of East Anglia Norwich NR4 7TJ UK Organometallic structures If one factor must be chosen to illustrate the vitality of research in organometallic chemistry it would be the huge scope available for structural variation by the judicious selection of metal and ligand types and the inclusion of organic functionality. As methods of organometallic synthesis become more assured so chemists are becoming increasingly adventurous in their choice of target structures. New applications of organometallic complexes Metal-ligand assemblies can be custom designed and tailor-made for particular purposes ranging from materials science and bioorganic chemistry to catalyst- and reagent-optimization.Recognition pockets incorporating organometallic units illus- trate the point. The combination of 4-aminopyridine arms with the cobaltocinium cation in (1) affords an anion recognition pocket that is able to recognize C1- HSO and H,PO anions detected by exploiting the electrochemical properties of the cobalt complex.' Amide-linked bis-cobaltocinium structures have also been prepared.2 In the same paper a calixC41arene structure bearing two cobaltocinium units serves as a receptor for dicarboxylate dianions. Ferrocene units are also popular redox-active organometallic addends; four are attached to the tetraazacyclotetradecane receptor in structure (2).3The tables are turned in (3) in which a redox-active anthraquinone unit has been incorporated to interact with 19-electron organometallic radicals generated photochemically from the dimolybdenum dimer.4 When the receptor structure is a large protein the organometallic moiety can become the guest.In an extension of a long-term research programme exploring the properties of organometallic molecules that bind to the estradiol receptor the Jaouen group has developed a selection of organorhenium steroid derivatives such as (4)for use as radio pharmaceutical^.^ The half-life and emission profile of 186Re and 188Re are optimal for tissue penetration and radio-element tracking. Thus these metal complexes offer properties that would be unavailable without the inclusion of the organometallic complex. With the chloromethyl unit at ring C the structure(4) showed a better affinity for the estradiol receptor than the natural hormone itself showing that the presence of the bulky metalcarbonyl unit is not incompatible with efficient binding to the protein.The attachment of the organometallic labels to the surface of proteins is also of 179 G.R. Stephenson ?3GN @I co+ I I Fe Fe &nA 0 WNUN% I I ie interest. A series of organometallic pyrylium derivatives have been prepared for this purpose.60 Organometallic units have also been included within the strands of polymers as in the polyimine copolymer (5) which was easily prepared by condensation of the bisaldehyde starting material with 1,3-diaminoben~ene.~~ Palladium-catalysed coup- ling of the alkyne substituents on the cyclobutadiene cobalt complex (6) with a diiodoarene affords the polymer (7) which has thermotropic liquid crystal properties.' Organometallic clusters based on cobalt carbonyl units have been attached as pendent groups to polyacrylate resins.' More ambitious still from the point of view of the architecture of the organometallic structures is work currently underway in several research groups to prepare alkyne- linked organometallic balls and mats.Hay coupling has been used to prepare a Organometallic Chemistry the transition elements SiMe SiMe3 ,C6H13 I I 'COCD PdC12(PPh3)2 Cul SiMe3 piperidine selection of oligomers such as (8) in work that aims ultimately to produce poly(tricarbony1manganese)-substituted Cl,o-fullerenynes.9 Metallation of iron-bound cyclobutadienes followed by iodination with 1,2-diiodoethane provided pre- cursors for palladium-catalysed coupling with tin-substituted alkynes.This led ultimately to the dimeric building block (9)." A more extended polyyne organometallic (10) was prepared by linking two platinum bis-acetylide complexes by Hay coupling. The product contains tetraethynylethene units bound as ql-ligands. l1 Alkyne links themselves provide excellent ligands and are employed to form an unusual complex (11) in which the central nickel atom was introduced by reaction with [Ni(cod),] G.R. Stephenson SiMe3 SiMe SiMe3 SiMe3 (9) (cod = cy~loocta-1,5-diene)'~ With alkynes it is still possible to encounter new bonding modes.In (12) cyanoethyne is bound to tungsten in a novel fashion as a four-electron donor ligand.' The rod-like structure (13)contains a ferrocenyl moiety and a thioether donor group separated by an arylethynyl oligomer. As is typical with these complexes the unsaturated substituent was built up sequentially again employ- ing palladium-catalysed coupling procedures.14 Electronic communication in ethynylallyl units and ethynyl aryl-platinum complexes has been examined with simple mono-alkynyl substituted ferrocenes. Absorption maxima have been found to correlate with the Hammett constants of substituents on the aryl ligand.I5 The same study demonstrated that anodic potentials in cyclic voltammograms of the platinum complexes also correlate with the Hammett constants.Complexation of a terthiophene by reaction with [CpRu(MeCN),]PF affords the dicationic diruthenium complex (14) Organometallic Chemistry the transition elements I I RU+ I which was found to be stable in the solid state and in dichloromethane solution but partially dissociated when dissolved in acetone. l6 Since thiols bind to gold and carboxylate or phosphonate groups associate with In20,/Sn02 (ITO)electrodes thesimple expedient of mixing alkylthiol- and alkylcarb- oxylate- (or phosphonate-) substituted ferrocenes in electrolyte solutions provides an approach for orthogonal self-assembly of electroactive monolayers on the electrodes. l7 Organometallic sandwich molecules have been placed between the lamellae of zinc sulfide and selenide lattices for an investigation of their electronic and magnetic properties," and cation exchange has been used to introduce positively charged organoiron complexes into montmorillonite clays.l9 Aligned cyclopentadienyl com- plexes are also accessible through the construction of polynuclear ladder complexes such as (15). A study of the redox properties of these structures has been reported.20 Silicon atoms as links provide another strategy for electronic communication. Dinuclear vanadium and chromium complexes linked by a 1,3-disilacyclobutane spacer have been prepared.2' In this study @-ligands were employed. Research on silicon-linked q5-ligands such as indenylzirconium complexes2' or even ferrocene ring ~ysterns'~ continues.G. R. Stephenson Cationic polymetallic structures raise interesting issues about bonding. In structure (16) for example three dicarbonylcyclopentadienyliron units contribute to the stabilization of positive charge in the cyclopropenium The dimer (17) illustrates charge stabilization by iron. Both iron atoms can contribute to stabilization of charge. The corresponding rhenium dimer (18) can be protonated to form a bis-carbene dication but does not deprotonate to form a disubstituted cyclobutadiene when reacted with b~tyllithium.~~ Oxidation of neutral structures such as (19) can produce dications in which cummulene-linked structures contribute to the bonding picture.26 The trimetallic structure (16) was directly prepared by reaction of the classic dicarbonylcyclopentadienylironanion with C,CI,SbF,.Similar treatment of prop-2-ynoic acid with this anion affords the neutral enolyl-linked bimetallic complex (20).27 Much effort has been directed to the synthesis of polymetallic complexes of extended hydrocarbon ligands. Cationic tricarbonyliron cyclopentadienyl complexes linked to chromium-bound arenes are accessible by a step-wise route which starts with fluoride oc co n+ Organometallic Chemistry the transition elements 185 @\ Fe displacement from (21). Complexation of the resulting mixture of cyclopentadiene regioisomers followed by hydride abstraction affords (22). Since tricarbonylchromium complexes are effective at stabilising negative charge the cyclopentadiene intermedi- ates can be deprotonated and the substituted cyclopentadienyl anion employed with electrophilic sources of transition metals.In this way the neutral q5tricarbonylman-ganese analogue of (22) was obtained by reacting the anion with [Mn(CO)5Br].28 Tricarbonylchromium complexes of diben~ofulvalenes~~ and iron complexes of dihydr~phenanthrene~' have also been prepared. In the latter case interconversion between the phenanthrene and dihydrophenanthrene ligand series affords a switchable molecular-electronic device. q4-Cyclobutadiene complexes bearing tricarbonyl-chromium-bound aromatic rings,31 and hexanuclear derivatives of the cyclopenta- dienyl dicarbonyl dimer (for example with two tricarbonylmanganese-complexed cyclohexadienyl substituents on each of the iron-bound ligand~)~~ illustrate more extensive examples of these structures.Taking high nuclearity even further large organoruthenium dendrimers have been prepared in which a tree of benzyl ether linked aromatic rings terminate with 48 dicarbonylcyclopentadienylrutheniumend-gr~ups.~~ Properties of Organometallic Structures Microwave spectroscopy is an unusual technique for the study of organometallic complexes but can give highly accurate structural information. An examination of tricarbonyl(benzene) chromium in the 4-12 GHz range reveals alternating car- bon-carbon bond lengths in the aromatic ring.34 Mass spectrometry is also increasing- ly used. CI and EI methods have been compared for the study of salen [H2-salen = bis(salicylidene)ethylenediamine] complexes.35 With iron carbonyl and cyclo- pentadienyl complexes the use of electrospray mass spectrometry has been inves- tigated.36 Thermochemical studies have been reported in the ligand exchange chemistry of benzylideneacetone(tricarbonyl)iron37~38and cyclopentadienyl(q6-arene)iron cation complexes.39 Kinetics is another crucial classical technique for the elucidation of reaction mechanisms.Reductive elimination of titanocene complexes has been studied in this way.40 With fluctional processes NMR spectroscopy is often brought into play. An example this year defines the fluctional properties of cyclopenta- G.R. Stephenson dien yliron-su bs tit u ted cyclooc ta trien yl c~mplexes.~’ In metal carbonyl complexes the carbon monoxide ligand can sometimes be difficult to detect by 13CNMR spectros- copy.Polarization transfer has been employed for this purpose.42 Infrared spectros- copy operates on a faster time-scale and is suitable for the study of very rapid fluctional motion. The effect of temperature on the vibrational spectra of tricarbonyl(norbor- nadiene)iron has been described.43 Infrared methods are also used for the study of surface interactions. Another organoiron example is provided by a study of the cyclopentadienyl(dicarbony1)iron dimer on alumina surfaces. The spectroscopic prop- erties vary considerably depending on the acid-base nature of the surface.44 Pressure can also be used to influence the vibrational properties of metalcarbonyl complexes. This has been studied by both the IR and Raman technique^.^^ Time-resolved Raman spectroscopy and matrix isolation studies have been used to probe the anti-syn photoisomerization properties of metal carbonyl carbene c~mplexes.~~ Resonance Raman provides a method to study photoreactive states and intermediate^.^^ It is the study of nonlinear optical properties where most growth has been occurring with attention turning particularly to third-order coefficients.Transition metals can be attached to conventional functionality on the dipole,48 or can form an integral part of an extended .n-system. The bis-titanium complex (23) for example has the largest ^J value yet measured.49 Other studies include investigations of metal dithiolene olig~mers,’~ tetraaryl-asymmetrically substituted dithiolene complexes of ni~kel,~‘ substituted dithiolene complexes,52 and bis-dithiolene c~mplexes.’~*~~ Gold nickel platinum and palladium were used in this work.A range of transition metal phosphine complexes have also been examined and large non-resonant second-order molecular hyperpolarisabilities were measured.” y= 92x esu Theoretical Investigation of Organometallic Structures Density functional calculations offer big steps forward in the understanding of organometallic mechanisms. A dynamic study has been made of C-H activation steps in the carbonylation of methane which provides a typical example. Photochemical activation is believed to produce a 14-electron rhodium complex (24) which is sufficiently reactive to insert into the C-H bond of methane.’6 Density functional calculations have also been used to compare carbene and silylene complexes demonstrating that the latter have only weak n-bonds with the metal centre.57 Acetylene insertion in cationic zirconocene complexes has been studied using RMP2 ab Organometallic Chemistry the transition elements 187 H initio calculation^.^^ MM2 calculations have been used to examine conformational equilibria in q3-cyclohexenylpalladium cornplexe~,~~ and a qualitative molecular mechanics approach probes stereoselectivity in intramolecular Pauson-Khand cycliz- ations in an attempt to account for the powerful control of relative stereochemistry in these reactions.60 2 Stoichiometric Strategies for the use of Organometallic n-Complexes in Organic Synthesis Organotransition metal catalysts are easily incorporated into the reaction sequences of organic synthesis because the conventional procedure for a particular transformation is simply replaced by the new organometallic approach.In the case of the most powerful organometallic methods several key steps are run together into one reaction. Approaches that employ stoichiometric metal complexes are difficult to apply and it is harder to achieve the full potential of the methodology. Typically a ligand attached to the metal centre becomes stoichiometrically incorporated into the target structure. An issue in this type of chemistry is the efficiency of introduction of the transition metal and if this can be performed in a reaction which forms the n-bound ligand itself there is no otherwise unproductive complexation step in the synthetic route.General methods are not yet available for this purpose but examples of reactions that relate to this objective are becoming increasingly common-place. n-Ligand Preparation during Complexation The preparation of the ligand tropone by carbonylative combination of three molecules of ethyne proceeds in a step-wise fashion but the overall transformation builds the n-bound ligand in (25) by a sequence of insertion reactions.61 Dimerization of alkynes to form cyclobutadiene(cyclopentadieny1)cobalt complexes provides a related case.62 Substituted cobaltacyclobutene complexes react with alkynes to form q4-cobalt complexes of substituted cy~lopentadienes.~~ A vinylcarbene iron complex reacts with ethoxyethyne to form a related q4-tricarbonyliron structure.64 In the case of an alkynylcarbene reaction with an amine effects carbonyl insertion and cyclization to the q4-pyrone structure (26).65The corresponding cyclohexadienone complex in the 0 G.R.Stephenson F&$OMe .. Fe (CO) ph$?h Ph Ph CI(Pri3P)2Rh=C MeMgl * (Pi,P)2Rh- Ph Ph cp(co)*w{+\ Ph co OH triphenyl-substituted series is obtained by ring-opening of trisubstituted vinylcyclo- propenes.66 Addition of a vinyl Grignard reagent to a ruthenium carbene complex affords an q3-allyl ligand67 and in the case of an iridium carbene complex direct reaction with ethene or a substituted alkene again forms an q3-structure.68 Vinylidene complexes react with methylmagnesium iodide in a related fashion to form (27).69 Acid rearranges the q1-prop-2-ynyltungsten complex (28) to produce the q3-complex (29) as Organometallic Chemistry the transition elements a single stereoi~omer.~' Further acid treatment liberates metal-free a$-unsaturated lactone structures.Carbonyl insertion in the case of (30) follows a different course but again forms an q3-product.71 Allenes reacting with acyl cobalt complexes proceed to similar q3-structures but in the cases rep~rted~~,~~ these are intercepted by intra- molecular nucleophile addition to afford a metal-free product. The variety of these reactions reinforces the point that side-on n-bound ligands can be fashioned in many ways during the process that attaches the metal though in some examples the starting material is another organometallic structure of a different class.It is the cyclization chemistry of alkynes that currently offers the most general prospects for n-ligand creation during complexation and it is revealing to compare these stoichiometric reactions with related procedures for the cyclotrimerization of alkynes. Wilkinson's catalyst has been used in a cyclotrimerization to afford (31) and the method has been applied to the synthesis of C-arylglyc~sides.~~ Iridium complexes can effect the cyclotrimerization of ethyne to form benzene and cyclooligomerizations with ethene to form he~atriene.~~ Zirconacyclopentadienes insert alkynes to form sub- stituted aromatic rings.76 Replacing an alkyne with a nitrile leads to the formation of substituted pyridines.A cobalt-catalysed example combines ethyne and benzonitrile and can be performed in water.77 Me (31)54% BnO. Bn:&H CIRh(PPh& Brio BnO BnO BnO 89% The Dotz cyclization provides one of the most general procedures by which a ligand is built during complexation. Diastereoselective conversion of the carbene complex (32) into the q6-arene complex (33) has been rep~rted.~' In this reaction chirality in the hydrocarbon ligand of the starting materials controls the diastereoselectivity of the attachment of chromium to the aromatic ring. Photochemical assistance of the cyclization reaction offers a highly efficient route to (34)." A more unusual process takes a simple Fischer carbene complex and effects cyclization with an enyne.*' Other modifications include the incorporation of a benzenesulfonyl substituent on the vinyl carbene component'' and the cyclization of alkynyl carbene complexes with isonitriles to afford aminonaphthalene structures.82 A step-wise procedure has been proposed in which an isonitrile replaces a carbonyl group at chromium to produce an intermediate G.R.Stephenson 1) -2) PPh3 DEAD (32) (33) Me0 95% (34) Cr( CO)*CN R \ Et-CZC-Et q:r(co)4cNR R = 2,6-dimethylphenyl Me0 (35) (36) (35)that cyclises by reaction with hex-3-yne with migration of the chromium to the aryl substituen t. Ligand Modification during Decomplexation the Pauson-Khand Reaction The Pauson-Khand reaction combines an alkyne and alkene with carbonyl insertion to produce a cyclopentenone.The cyclization of (37) to form a linear fused triquinane structure provides a typical e~ample.'~ The reaction proceeds by initial complexation of the alkyne to form a dicobalt hexacarbonyl adduct. In intermolecular examples careful investigation of steric and electronic effects is necessary." A double Pauson-Khand procedure has been used to prepare ethene-linked biscyclopen- tadienes. Currently it is the stereoselectivity and asymmetric modification of the Pauson-Khand cyclization that is receiving the main attention. The ascorbic acid- derived enyne (38) can be made to cyclise diastereoselectively to afford (39) in 93% yield.87 In this case use of trimethylamine N-oxide to promote cyclization reduced the yield to only 7%.Pre-forming the cobalt alkyne complex and then exchanging a carbon monoxide ligand with a chiral phosphine has provided a strategy for an enantioselec- tive variant. This chirality induces asymmetry in the cobalt cluster and has a profound effect on the reaction pathway. Cyclization with norbornene affords a cyclopentenone in greater than 99% enantiomericexcess (ee)." In this case the product (40)was formed Organometallic Chemistry the transition elements 191 OAc 60% (38) (39) 90% ee in 76% yield using the trimethylamine N-oxide procedure. Since the alkyne dicarbonyl cluster is chiral introduction of achiral phosphine followed by resolution [by separation of diastereoisomers with R = menthyl in the case of (41)] can be equally effective in affording a precursor for an enantioselective Pauson-Khand process.Replacement of menthol with allyl alcohol provided an optically pure precursor for cyclization into (42) in 70% yield.*' Another approach for an asymmetric Pauson-Khand reaction relies on chirality in the ether to control the formation of the ring. With an alkoxyalkyne as the starting material this ether-linked chirality is as close as possible to the sites of bond formation. The procedure has been employed in a formal total synthesis of brefeldin A." The Pauson-Khand cyclization is performed with norbornadiene. Conjugate addition to the enone followed by a retro Diels-Alder fragmentation of the cycloadduct affords a fresh r,P-unsaturated ketone for the second conjugate addition step.In this way the 3,4-disubstituted cyclopentenone (43)is formed in the correct relative stereochemistry. Other metals can also be used to promote cyclopentenone formation. A good example employs a reagent derived titanium tetraisopropoxide and two equivalents G.R. Stephenson ROE 1) cu OSiMe2Buf BF,.OEt 2) Sml or Zn-Cu kCO~BU 4 1) MeAICI 2)+OB" OSiMe2Buf LiCIO H H of isopropylmagnesium chloride." A zirconocene-mediated cyclization has also been described but in this case the zirconocycle is intercepted by carbon monoxide and an electrophile in an unusual metal-removal step.'* Cyclizations of diynes with iron pentacarbonyl have been further developed.q4-Cyclopentadienone complexes are formed and if the metal is removed with trimethylamine N-oxide bicyclic dienones with an alkene link in each ring can be isolated.93 If the metal is retained in the molecule this cyclization provides a further example of ligand synthesis during complexation. The decomplexation reaction to form (44) proceeded in 61% yield. Similar dienone structures are available by the use of Pauson-Khand conditions with allenic compounds.94 The product (45) was obtained in this way from the dicobalt hexacarbonyl complex of hex-4-yne in 69% yield. Intramolecular versions of the cyclization with allenes have been examined. Reaction of (46) with molybdenum hexacarbonyl affords the cyclization product (47).95 A similar starting material with the silyl group on the allene has been cyclised photochemically by reaction with [Fe(CO)4(NMe3)].g6 The Nicholas Reaction and Related Carbocation Chemistry An intramolecular example of the Nicholas reaction in which the nucleophile is the trimethylsilyl enol ether portion of (48) illustrates the process." The metal can be removed from the cyclization product to afford the free ligand by oxidation with cerium(iv) sulfate.The sugar-derived starting material (49) can be employed in a similar fashion with silver tetrafluoroborate to open the pyranose ring. The intermediate is an alkynyl-substituted ally1 cation. Nucleophile addition lacked complete regioselectiv- Organometallic Chemistry the transition elements (44) 51me3 CSiMe3 \\ (47) 68% H 75% (49) it^.'^ A simple prop-2-ynyl alcohol complex has been used with dialkyl amines to afford intermediates that cyclise to pyrroles upon oxidation with iron(m) nitrate.99 Double stabilization of carbenium ions by ferrocene and bimetallic alkyne complexes has been examined,"O and heterobimetallic cation complexes have been prepared."' With a terpene-based carbocation Wagner-Meerwein rearrangements have been observed despite the stabilization available from the bimetallic unit.lo*An unexpected deprotonation of (50) affords a bimetallic alkylidene structure (51).lo3 Prop-2-ynyl chlorides can also be used as starting materials for cobalt-stabilized cation^."^ A nice series of organocobalt examples of the carbonyl-ene reaction have been rep~rted."~ In the case of the formation of (52) the product was obtained in 79% yield.G.R. Stephenson cp cp (50) Cycloaddition Chemistry of Metal n-Complexes Even when n-bound to transition metals double bonded systems can still undergo cycloaddition reactions. Cyclooctatriene and cyclooctatetraene complexes of tricar-bonylchromium have been used in recent developments of these reactions. Photolytic procedures are employed to promote [6 +2) cycloadditions.'06 With cyclohepta- trienes carrying chiral auxiliaries diastereoselective complexation followed by [6 +23 cycloaddition has been examined. In the case leading to structure (53) good diastereoselectivity has been achieved.'" With a heterocyclic chromium complex a chiral dienophile has been employed.Diastereoselectivity was excellent at 98% and a simple stereocontrolled thallium(Ir1)-mediated ring-contraction afforded (54)in a highly efficient fashion. This compound has been used as a key intermediate in an enantioselective synthesis of (+)-ferruginine (55).Two steps were required to remove the ester and its chiral auxiliary and functional group exchange at nitrogen was also needed. A final functional group change was achieved by hydrolysis of the acetal addition of a methyl group from methylmagnesium bromide and oxidation to afford the acetyl substituent in the natural product (5.9.''' An azirine-derived dienophile has been used in a [6 +31 heterocycloaddition to the chromium complex of cycloheptat-riene.log Heteroatom-containing dienophiles have also been employed in cycloaddi- tion reactions at alkynes adjacent to Fischer carbene complexes."' Similar addition reactions with masked azomethine imines have been described."' In contrast reactions with enamines afford metal-free cyclization products.' ' The bicyclic structure (56) was obtained in this way.Vinylcyclopropanes and alkynes have been combined in a transition metal catalysed reaction that is homologous to the Diels-Alder rea~tion,''~ and a [3 +3 +21 cycloaddition produces the iridium complex (57).' ' Metathesis Reactions Molybdenum complexes have become popular in metathesis reactions. A nice application forms an eight-membered ring in an approach to an antiturnour alkaloid.The second product is ethene. In this reaction the carbene complex (58) is employed as the catalyst to link together the two alkenes in the starting material to introduce the Organometallic Chemistry the transition elements 70% A hv (+)-(53)65% 82% 58% TI(NO& MeOH aH I C02Me Steps H \ Me0 / alkene link in (59).'15 The same alkylidene complex (58) has been used in cross- metathesis in which acrylonitrile and alkyl-substituted terminal alkenes are linked.' l6 Metathesis strategies for the synthesis of azasugars' ''and conformationally restricted dipeptides,'I8 have been described. In this latter case alkene-containing substituents on the amino groups of two adjacent amino acids are linked.Amino acid side-chain alkenes have also been joined. q2-Complexes Cyclopentadienyldicarbonyliron is a typical metal-ligand unit to promote elec- G. R. Stephenson CP* + Ph-ph !-) OBn / (59)77% trophilicity in stoichiometric alkene complexes. A nice route to such cations forms a carbon-carbon bond by Lewis acid catalysed addition of aldehydes to y~ '-allyliron starting materials.' l9 The products can be functionalized by nucleophile (e.g.alkoxide) addition or utilised in intramolecular cyclization reactions. 120 This is illustrated by the formation of (61) from the q'-ally1 precursor (60). The decomplexation step is conceptually significant since a carbon-carbon bond is formed during the metal removal procedure. When used in an organic synthesis this is not just a wasted step.In some cases with BF as the catalyst intermediate $-cation complexes can be isolated as the N-BF adducts.'20 q3-Complexes Tetracarbonyliron groups are commonly employed to stabilise cationic stoichiometric $-structures. Nucleophilic transfer of an ally1 group from allyltrimethylsilane has been used in an enantioselective synthesis of 5-substituted pyrrolinones. An enantiopure neutral q4-alkene complex with an allylic leaving group was the starting point for this route. Enol acetates have been employed as nucleophiles in a similar way."' A seriesof far less common tris(pyrazolyl)borato(allyl)dicarbonylmolybdenum complexes have Organometallic Chemistry the transition elements h I Ts L J (61) 55% been prepared.Athermodynamic preference for the anti stereoisomer was observed.122 Palladium complexes are rarely used in stoichiometric reactions but an example for the interconversion of morphine alkaloids has been published.' 23 The morphine- derived starting material contained an allylic chloride. The same allyl chloride starting material can be converted by reaction with hexacarbonylmolybdenum into neutral q3-organomolybdenum complexes. In a similar introduction of a tricarbonyliron unit an intermediate cationic q3-allyl structure has been proposed. This proceeds by deprotonation to afford a neutral q4-diene complex.'24 The opening of allyl epoxides by [Fe,(CO),] is commonly used in reaction sequences that lead ultimately to lactonization.Treatment of the ferralactone intermediate with barium hydroxide has now been employed to divert this chemistry in a synthesis of P-dimorphecolic acid (63) in which stereochemistry of the secondary alcohol was established by a metal-controlled reduction adjacent to the q3-allyliron portion of the ferralactone. Overall in this process chirality is relayed from Sharpless epoxidation to a different position in the natural product.12' The opening of the epoxide produces a mixture of two diastereoisomers which were not separated. Reduction with the unusual agent triisobutylaluminium was performed on the mixture but the major stereoisomer had the correct relative stereochemistry to afford (62)for reorganization to produce the 0 Steps C5Hll -OH -C5H1 1 a(CH2)80SiPh2Bu' Steps I G.R. Stephenson q4-intermediate. Removal of the tricarbonyliron unit was performed next to produce a metal-free intermediate which required only a series of functional group interconver- sions to complete the carboxylic acid in (63). Opening of allylic epoxides with [Fe(CO),NO]Bu,N affords neutral [q3-Fe(CO),NO] complexes. These have now been employed in reactions with nucleophiles to produce difunctionalized alkene products. In this case syn addition of the iron to the allylic epoxide and trans nucleophile addition control the relative stereochemistry of the products.'26 Insertion of dicarbonylcyclopentadienylcobaltinto allylic epoxides has also been e~arnined.'~ Cobaltalactone complexes have been converted into cationic carbene complexes e.g.(64) which retain the q3-allyl moiety.'28 Reactions with nucleophiles have been examined. q4-Complexes Neutral tricarbonyliron diene complexes are poor electrophiles but since their reaction with nucleophiles can be coupled with carbonyl insertions to combine decomplexation with two carbon-carbon bond formations their electrophilic properties are strategi- cally important. It has now been found that the control of the carbonyl insertion step can be adjusted by the provision of phosphine ligands in the reaction mixture.'29 Vinylketene complexes (65) should be better electrophiles since the oxygen of the ketene moiety activates the ligand as an electrophile. Reaction with anions obtained by deprotonation of alkyl (aryl) phosphoramidates promotes the formation of vinyl- ketenimine complexes of type (66).l3' Addition of imines forms metallacyclic q3-c~mplexes.'~~ The same paper describes the addition of substituted alkenes which proceed by decarbonylation again affording cyclic structures but in this case complexes that lack the acyl substituent next to the metal-bound portion of the ligand.In a parallel study comparison of imine nucleophiles identified the dihydrooxazine (67) as particularly suitable. The intermediate (68) was converted into a substituted pyridone by oxidation first with iodine and then with trimethylamine N-0~ide.l~~ This reaction sequence provides a further example of metal removed during a skeletal bond formation step. Introduction of sulfur into (65) (R = phenyl) employing Davy's reagent formed a thioester-linked metallacycle not a vinylthioketene c0mp1ex.l~~ The prepara- tion of vinylallene complexes of Fe(CO) has been re~0rted.l~~ +Complexes Organoiron-mediated routes to carbazoles are still finding new applications.The synthesis of hyellazole (69) provides a typical example. The iron-mediated part of the reaction sequence begins by nucleophilic addition of an activated aromatic ring to a tricarbonyl(cyclohexadieny1)iron cation. Oxidation with the ferrocinium cation com- Organometallic Chemistry the transition elements \=N (67)w P h 40 (1) 12 -[(65),R = Me] '9 (CO),Fe-( I> (2)Me3N0 0 (68)87% OMe OMe I @Me FygMe r; I Ph Ph NH2 NH2 Me H Ph Ph (69) f (1) Me,NO; 95% (2) K&O Mel; 93% pletes the cyclization.Although some of the final product (69)is obtained in this step demetallation does not go to completion and the route can be improved by employing MnO and a second oxidation using trimethylamine N-oxide.' 35 Similar oxidative procedures have been used in an iron-mediated total synthesis of cara~ostatin'~~ and a variety of other 3-hydroxycarbazole structure^.'^^ Oxidative cyclization with ferric chloride closes an amino alkyl substituent to a cyclohexadienyl complex completing the 2,3,3a,7a-tetrahydroindolenucleus.'38 The starting material for this reaction was also derived from nucleophile addition to q5-dienyl complexes. These nucleophile addition reactions generally proceed at the metal-bound dienyl complex.An exception has been rep~rted'~' in which a metal acyl results from the reaction of orthometallated aryllithium reagents to substituted cyclohexadienyliron complexes. Deprotonation of q5-cyclohexadienyl complexes to aromatic structures might appear likely but until this year had not been encountered. Now with l-aryl substituted cyclohexadienyl com- plexes treatment with base allowed the preparation of metal-free biar~1s.l~' Tri-carbonyliron complexes lacking the aromatic substituent do not deprotonate in this fashion. q5-Cyclohexadienylmolybdenumcomplexes incorporating a tridentate phos- phine can be formed by protonation of a neutral q6-arene complex and easily revert by deprotonation. Deuterium labelling studies however show that in this case the deprotonation pathway can proceed by hydrogen transfer to the metal as well as by direct loss of a proton from the exo face.'41 Acyclic tricarbonyliron complexes have provided an example of a new directing effect on an q5-ligand.The l-cyano substitution pattern has been examined with heteroatom nucleophiles and found to direct the site of reaction to the far end of the G.R. Stephenson dienyl This work is of particular importance since it illustrates the possibility that the iron carbonyl control group might progress through a ligand placing chiral centres one by one in its trail. With pentadienyl complexes a comparison of tricarbonyliron and dicarbonyliron triphenylphosphine metal-ligand systems has been made.Regioselectivity for addition at the substituted terminus at the pentadienyl cation was increased by the use of the triphenylphosphine group. The reactions proceeded by the normal trans addition of the nucleophile and afforded cisoid metal complexes as the products.'43 When phosphines are used as the nucleophile with pentadienyltricarbonyliron complexes reversible nucleophile addition is observed in some cases.144 Nucleophile addition to an q5-cross-conjugated pentadienyl unit proceeds preferentially to form trimethylenemethane structures. Allyltrimethylsilane in the presence of Lewis acid catalyst was used for the in situ generation of the electrophile by exploitation of an allylic leaving group. 145 A sequence of two such allylations has been re~0rted.I~~ Primary amines have been used as nucleophiles with tricarbonyl- manganese complexes of pentadienyl and hexadienyl ligands.'47 With dicar-bonyl(trimethy1phosphite)manganese as the metal-ligand system and an unusual cyclohexadienone starting material nucleophilic introduction of a phenyl substituent was followed by trapping of the anionic organometallic intermediate by acetylation at oxygen. The nucleophile addition occurred at a metal-bound carbon atom not at the electrophilic centre of the ketone to provide a 1,2-disubstitution pattern on the six-membered ring. Removal of the metal by oxidation with Jones reagent allows this procedure to produce disubstituted aromatics. 14* By the use of heptadienyl complexes of iron internal nucleophile addition affords o,n-ally1 structures.Metal removal by carbonylation produces two carbon-carbon bonds during the step which detaches the metal. An application of this chemistry to bicyclo[3.2.l]oct-2-en-8-oneshas been reported. 14' q6-Complexes Some of the most significant applications of electrophilic arene complexes this year have been aimed at syntheses of polyaryl cyclic peptides. A cyclic peptide model for the B,C and F rings of ristocetin A has been completed. Nucleophilic replacement of chlorine from the aromatic ring of (71)was possible through the activation provided by the cyclopentadienylrutheniummoiety. The phenolic nucleophile in (70)was generated by deprotonation using a hindered phenoxide base. The metal can be detached from the substitution product by photolysis in acetonitrile.Several steps were then needed to convert the metal-free product into the model structure (72).150In another example the metal-mediated nucleophilic aromatic substitution reaction was used to close a new cyclic peptide by construction of the diary1 ether unit.'51 The product (73)is a model for the ring system of vancomycin. The use ofchiral aminal substituents on aromatic rings activated by tricarbonylman- ganese units allows transfer of chirality to the $-metal complex in the product. Diastereoselectivity as high as 10 1 has been 0bser~ed.I~~ Substituted metallated arenes have been found to be particularly effective nucleophiles with cationic tricarbonylmanganese benzene c~mplexes.'~~ q6-Cycloheptatrienyl complexes are also good electrophiles.Their use with functionalized zinc-copper coupling reagents has been described.' 54 With terpene-derived aromatic ligands tricarbonylmanganese complexes have been used with a variety of nucleophiles including organolithium and Organometallic Chemistry the transition elements 201 ?Me EtO + c'p3::Br 'RuCp 0 OMe OMe ?Me steps -NHBoc 0 0 OMe BocN H OR (73) Grignard reagents. Good regioselectivity was observed in the functionalization of methyl 0-methylpodocarpate. ' A detailed investigation of nucleophilic aromatic substitution of neutral tricarbonyl- chromium arene complexes has been re~0rted.I~~ Nucleophile addition to a neutral arene complex produces an anionic intermediate.In this study the metal-centred anion has been trapped by a means of an organotin reagent. The Smiles rearrangement proceeds via nucleophilic attack at an aromatic ring and this too can be promoted by complexation of the arene by tricarbonylchromium.l 57 Reactivity Adjacent to the Metal Complexed Portion of pComplexes An example of stereocontrolled reduction of a ketone adjacent to an qj-metal complex G.R. Stephenson was discussed in the preceding sections. With larger metal n-complexes the strategy of using the metal-bound portion of the ligand as a chiral auxiliary to control reactions of functionality at adjacent positions is a well explored and on-going area of research. This is a typical application of tricarbonyliron complexes.Products often have labile oxygen functionality which can be replaced via intermediate metal-stabilised cations but not necessarily involving rearrangement to $-dienyl structures. Esterification of protected glycine has been performed in this way.”* Tetrahydrothiopyran can also be obtained by intramolecular reaction with thiols.’” Ether rings have been formed in a model study for a synthesis of laurencin.’60 An unusual cyclization of the tricar- bonyliron complex of a diazoester forms the substituted cyclohexadienone (74).16’ Turning to the patent literature the conversion of the iron complex of p-ionone into a triene complex by enolate addition and elimination has been described.’62 0 (1) TMSCI (75) (76) (1) BuLi (2) Me1 (1) BHfSMe then H202 OMe * (2) TsCl (3) TBAF OMe (78) (77) Manipulation of functionality adjacent to an q6-arene complex of the tricarbonyl- chromium group has allowed an enantioselective route to functionalized hydronaph- thalene derivatives in a model study for routes to secopseudopterosins.The optically pure $-complex (75) was obtained by diastereoselective complexation of the ligand temporarily modified by addition of a proline-based chiral auxiliary. Nucleophile addition employing isopropenyllithium proceeded trans to the chromium and the resulting alkoxide was trapped by silylation to produce (76). Two equivalents of the Organometallic Chemistry the transition elements alkenyllithium reagent are needed since metallation also occurs on the aromatic ring and overall two silyl groups are introduced.This is an important feature of the synthetic route since the aromatic ring is now protected against further metallation. Deprotonation adjacent to the metal-bound arene is still possible and by reaction with butyllithium the benzyl anion complex is formed. Electrophilic alkylation with methyl iodide produced (77) in a stereocontrolled fashion. A second chiral centre is now introduced by functionalization of the alkene. Anti-Markovnikov hydroxylation of the isopropenyl substituent was diastereoselective and produced a terminal alcohol that was cyclised to the benzylic positions. To produce (78) the aromatic silyl group was also removed by reaction with tetrabutylammonium fluoride.The closure of the four-membered ring does not proceed by a benzyl cation intermediate but rather by tosylation of the primary alcohol with concomitant detachment of the silicon from oxygen and esterification. The relative stereochemistry of (78)was confirmed by X-ray crystallography. The chemistry of indan-2-one chromium complexes has been explored. The q6 structure could not be obtained by direct complexation of the indanone but its acetal was efficiently complexed and could be hydrolysed in dilute acid. Both reduction and cerium-mediated methyllithium addition to the carbonyl group were stereocontrolled as was the alkylation of the chromium-stabilised enolate. All three reactions proceeded on the face of the ligand opposite to the Stereocontrolled reduction of a 1-oxobenzocyclobutene complex of tricarbonylchromium has also been reported.Despite the presence of the chromium carbonyl group ring opening and trapping of o-quinodimethane intermediates is re~0rted.l~' Conjugate addition of tert-butyl- lithium to the double bond of an o-methoxystyrene complex of tricarbonylchromium produces a benzyl anion that can be stereoselectively alkylated with methyl iodide. This chemistry was demonstrated in an enantiopure series of metal complexes.'66 Diastereoselective metallation of chromium complexes with chiral substituents has been used to induce asymmetry in the incorporation of an acyl substituent. This induced chirality of the metal complex can then control reduction of the acyl group with lithium triethylb~rohydride.'~~ Removal of the metal and the inducing chirality (an ether derived from 1-phenylethanol) afforded an ortho-substituted phenol with a side-chain chiral centre in greater than 92% enantiomeric excess.A similar strategy for inducing asymmetry in the metallation step has been employed with functionalized chiral aminals producing substituted benzaldehyde complexes.' Progress has also been made with asymmetric deprotonation using chiral lithium amide bases. Products in up to 97% enantiomeric excess have been re~0rted.l~' Valuable bond forming reactions can take place through the properties of metal centres attached to transition metal-complexed aromatic rings. Optically active biaryls have been obtained by palladium-catalysed coupling of chiral bromoarene complexes with arylboronic acids.'70 This chemistry has also been applied to the synthesis of naphthyltetrahydro- isoquinoline alkaloids.' 71 With the tricarbonylchromium complex of tributylstannyl- benzene palladium coupling with iodoarenes is combined with carbonyl insertion to produce biaryl ketones.17' These reactions proceed by oxidative addition at the metal-bound aromatic ring.In the cationic tricarbonylmanganese series the product of oxidative addition into a chloroarene ligand has been studied by NMR spectroscopy. Carbonylation did not occur in this series of cornpo~nds.'~~ 204 G. R. Stephenson 3 Uses of Carbene Complexes in Organic Synthesis Examples of the Dotz cyclization and alkene matathesis both ofwhich involve carbene chemistry have already been discussed.In this section further examples of carbene chemistry are reviewed. The Hegedus photochemical functionalization of chromium carbene complexes continues its development. Dipeptides have now been produced by the photolytic coupling reaction by combining aminocarbene complexes with amino acids.' 74 Photolysis of poly(ethy1ene glycol) (PEG)-supported peptides with aminocar- bene complexes detaches the peptide from the polymer ~upport.'~' Butenolides have been prepared by the photolysis of enamines with Fischer carbene complexes. With a chiral auxiliary incorporated in the enamine a stereoselective route is a~ailab1e.I~~ Cyclic tungsten carbene complexes have been dimerised to make 5,5'-diphenyl-2,2'- bifuran.' 77 Fischer carbene complexes can stabilise anions adjacent to the carbene unit.Reaction of this anion with a tropone derivative has afforded an extended bicyclic carbene derivative."* By the use of a chiral auxiliary in an aminocarbene complex stereoselective conjugate addition reactions have been examined.179 Rhodium carbene complexes are popular intermediates in metal-catalysed organic synthesis. Typical starting materials are diazo ketones and esters. The carbene intermediates which are not isolated can insert into a carbon-hydrogen bond. An example of the use of this chemistry to produce chiral tertiary alcohols from secondary alcohol derivatives has been described. 180 Dipolar cycloaddition can also be promoted by rhodium carbene complexes.A chirally disposed OH group in an allylic alcohol has been used to control the stereochemical course of this reaction.'*' Cyclization of cyanamides with the rhodium carbene complexes obtained from diazo ketones affords 2-alkylaminooxazoles.'82 A vinylogous Wolf€ rearrangement has been promoted under rhodium catalysis,'83 and tandem cyclization-cycloaddition reactions show promise in a route to Aspidosperma alkaloid^.'^^ In the presence of chiral auxiliaries such as methyl 2-oxopyrrolidine-5-carb- or ~xylate'~~phox { tetrakis[(4S)-tetrahydro-4-phenyloxazol-2-0ne]~,'*~an enan- tioselective cyclopropanation of alkenes can be performed with diazoacetate esters. In an intramolecular example,'85 an enantiomeric excess as high as 95% can be achieved in the product.C~pper,'~' cobalt18* and ruthenium'*' illustrate the variety of metals currently popular for enantioselective control of diazoester-mediated cyclopropan- ation. The copper catalyst (79)was used in an intramolecular cyclization which again proceeded in excellent ee. The cobalt system (80) was somewhat less efficient than the ruthenium pybox complex (8 1) in an intermolecular cyclopropanation which in one case using (8l) achieved 93% enantiomeric excess. Intermolecular reactions with 172-disubstituted alkenes still suffer from problems with cisltrans stereoselectivity. In a recent ruthenium-catalysed example using a bis(2-oxazolin-2-yl)pyridine ligand sys-tem trans selectivities as high as 98% have been achieved.'" An iron carbene complex adjacent to a chiral auxiliary in the form of a chromium arene complex has also been used in enantioselective cycl~propanation.'~' Chromium carbene complexes themselves can be used directly in the cyclopropanation of diene~,'~~ or through an enyne metathesis procedure to combine cyclization with cyclopropanation affording bicyclic products from acyclic starting mate1-ia1s.I~~ Aformal total synthesis of carabrone (86) relies on the formation of polycyclic Organometallic Chemistry the transition elements CN CN C02Me I (79) cyclopropanes from stoichiometric alkene-containing chromium carbene complexes in an intermolecular reaction with propyne.lg4 The starting material (82) was easily obtained by the addition of two alkenyl bromide electrophiles to anions developed by deprotonation of a methyl-substituted Fischer carbene complex.The cyclization to (83) correctly controls the stereocentres in the cyclopropane ring but leaves the centre adjacent to the ketone in the wrong configuration. This requires epimerization via the enolate before reduction of the ketone to establish the two stereocentres on the right-hand side of (84). Nonetheless this is an ingenious route since the remaining alkene links in the symmetric starting material are now utilised by ozonolysis to introduce oxygenation at the correct positions in the two side-chains. Oxidation of the aldehyde in the right-hand portion of the molecule and lactonization completes (85) which is capable of conversion into (86) by established literature procedures.As a formal total synthesis this work was performed in a racemic series of complexes from (83) onwards but since (82)is prochiral the route should be capable of enantioselective modification. 4 Catalytic Strategies for the use of Organometallics in Organic Chemistry In Section 3 stoichiometric and catalytic procedures for the use of carbene complexes in organic synthesis were compared. Useful as these reactions are they are mostly quite specialized procedures. The Annual Report this year ends with consideration of enantioselective metal-catalysed reactions which have a far more central role in G.R. Stephenson (CO)&r OMe Me+ x-, / \ H’ (83)60% Steps <-o H‘ synthesis design.First come two palladium-catalysed procedures asymmetric allylic displacement (which should be compared with the stoichiometric q”-chemistry surveyed in Section 2) and coupling reactions. Finally reductive and oxidative functional group interconversions are discussed. Asymmetric Modification of Palladium-catalysed Allylic Substitution Nucleophile addition to the terminus of a symmetrically substituted q3-allyl complex can be controlled by the presence of the chiral ligand at the metal. The 1,3-diphenylallyl ligand still remains the most popular proving ground for this chemistry. Racemic allylic acetate starting materials can now be converted into nucleophile addition products with high optical purity. The range of ligands currently in use in catalysis systems is wide.Examples include the chiral ferrocene-based diphosphine (88),19’ diamine systems such as (89)Ig6 and sulfoxide-based ligand systems (90).19’ In some cases monodentate ligands offer advantages if their structure ensures that bulky groups are judiciously placed. The example (91) is an unusual (dihydrobenzazaphos-ph0ly1)borane.”~ With dimethyl malonate as the nucleophile these auxiliaries give enantiomeric excesses of the product (87) in the range 64-99%. A chiral bis(dihydrooxazo1e)palladiumcomplex has proved similarly efficient.”’ In the case of (89) an NMR investigation of palladium complexes has indicated that the bisaziridine Organometallic Chemistry the transition elements 207 MeO2CVCO2Me Pd catalyst a L* cPh&Ph L*= p -Tot H,B' Ph..R M e Fe d p-To1 SiBu'Ph optical purity of (60) 85% ee [(R)-(87)1 Fe 'PPh2 FPPh2 C02H (93) adopts a conformation that forces the q3-portion of the ligand out of the normal square planar geometry.196 An X-ray crystallographic study has defined the structural parameters for a simple N,N,N',N'-tetramethylethylenediame (TMEDA) palladium complex of the 173-diphenylallyl ligand. Based on these results molecular mechanics techniques have been used to explore chiral pockets in a range of chelating phosphine ligands.200A chiral auxiliary derived from borneol is employed in an investigation of the isomerization of allyl and diphenylallyl ligands.*'' When three phenyl groups are placed at the termini of the allyl unit the starting material can be either a prochiral 1-acetoxy- 171,3-triphenylallyl compound or the racemic chiral 173,3-regioisomer.Asymmetric induction in these cases has been examined using the chiral auxiliary (92). O2 Attention this year is beginning to move away from the 173-diphenylallyl system to a wider variety of allylic alkylations. A study of asymmetric induction with cyclic substrates such as cyclohexenyl acetate has employed the chiral auxiliary (93).203 With allyl acetate itself no chiral centre is built by alkylation of the substrate unless the G.R. Stephenson nucleophile itself is prochiral. This is a more difficult form of asymmetric induction. With a 2-nitrocyclohexanone and rubidium fluoride as the base the unusual ferrocenyl diphosphine (94) gives an optical yield of 41Y0.~'~ Covalent attachment of a chiral auxiliary to the nucleophile renders the reaction diastereoselective and has been used in a route to a-allyl-or-amino acids.205 The de of the product was greater than 90%.Alternatives to palladium are also under investigation. With a carbonyltungsten catalyst the prochiral starting material (95) is converted into a 4 1 mixture of two regioisomers. The chiral isomer is the major product so asymmetric induction can be achieved.206 p -To1-0 ! -P(OEt)2 NaCH(C02Me)2 - (95) 95% ee Woc' I 'co MeozcYC02Me C0 P -To1 92% yield Regiocontrol in Metal-catalysed Allylic Substitution The example given at the end of the preceding section raises an important general issue when unsymmetrical substitution patterns are present on the allyl substrate.After displacement of the leaving group the unsymmetrical metal complex (96) reacts preferentially at the substituted terminus. In a series of palladium complexes with para-substituted aromatic ligands at C-1 of the allyl unit NMR chemical shifts have been used to estimate charge density on the ligand and these properties have been related to the Hammett constants for the sub~tituents.~'~ The alkoxy substituent in (97) is also charge stabilising and similar ipso-selective nucleophile addition has been observed in palladium-catalysed allylic substitution.208 In these examples stabilised enolate nucleophiles were employed. As one might anticipate a fluoro substituent at C-1 as in (98),209directs in the opposite sense.Similar results have been obtained with 1,l-difluoroallyl structures. Switching the nucleophile however can completely change the regioselectivity. When phenylzinc chloride was employed the phenyl group was transferred to the terminus of the allyl moiety which carried the fluorine atom. In this reaction the nucleophile is transferred to the ligand via the palladium atom. The electron withdrawing substituent in (99)directs nitrogen-centred nucleophiles to the far The substrate (100)puts the ipso-directing effect of oxygen substituents to work in a chiral environment. With both palladium or nickel catalysts nucleophile addition proceeds at the oxygen-substituted end to give (101) despite the use of phenylmagnesium bromide as the nucleophile.2 ' ' Palladium and nickel give opposite stereoselectivity.Synthetic Applications of Palladium Ally1 Complexes A total synthesis of the Sternona alkaloid (-)-stenhe (104) employed the reduction of a n-ally1 palladium complex derived from the intermediate (102) which was easily Organometallic Chemistry the transition elements BnO1 BnOl PhMgBr BnO PdClz(dPPf) or NiC12(dppe) Pd cat 01 isomer Ni cat p isomer 1 accessible by an oxidative cyclization of a protected tyrosine. The key feature was stereoselectivity with normal trans displacement of the leaving group combined with palladium-mediated delivery of the hydrogen atom from a metal-bound formate. The product (103) was obtained in 68% yield together with the alternative regioisomer (1 1 YO)and a diene produced by elimination YO).^ l2 This same formate-mediated reduction procedure has been employed in a deletion of a chiral centre from optically active allylic alcohol^.^' In a synthesis of the antidepressant (R)-rolipram (108) a further trick to manipulate stereochemistry of nucleophile addition is encountered.The key step is the conversion of(105)into (106) by displacement of the allyliccarbonate and addition of the stabilised enolate nucleophile. Both are typical steps in palladium-mediated allylic displace- ments. With regard to the benzylic chiral centre however substitution has proceeded with overall inversion of stereochemistry not the normal retention. The explanation is to be found at the right-hand end of the ally1 unit where the stereochemistry of alkene substitution has changed from cis in (105) to trans in (106).This stereochemical change proceeds via a o-bound intermediate in which rotation about a carbon-carbon single bond allows the stereochemistry of alkene substitution to change and in the same process swings the palladium atom around to the opposite face of the n-system. This HO' HC02H-Et3N ' HO' (-141 02) (103)68% (-)-(104) G.R. Stephenson Steps - (108) right-hand portion (and with it the inducing chirality) is discarded in the steps leading to the intermediate (107) which can be lactamised to complete the target structure (108).2l4 A palladium-mediated route to the cyclic ether (111) also manipulates the allyl stereochemistry but in the opposite fashion.The major product (110)has a cis-alkene whereas the chiral starting material (109),which was obtained in a series of steps from two optically pure building blocks has a trans-alkene. Intramolecular nucleophile addition of the sulfone-stabilised anion however picks up the less favoured anti stereoisomer of the intermediate q3-allyl complex so producing the required eight-membered The palladium-mediated displacement of allyl groups is now a common deprotec-tion strategy. Selective deprotection of an N-ally1 structure in the presence of an N-benzyl group has been reported.2l6 Allyloxycarbonyl substituents at nitrogen are also popular in palladium-mediated deprotections and this has now been applied in trans-protection for peptide bond formation.21 In another application of this method its compatibility with conventional amino acid protection strategies have been demonstrated.218For example an allyloxy protected amino acid has been combined with a Fmoc-Gly-OPFP to afford a protected dipeptide.Palladium-catalysed elimination reactions encountered as a side reaction in the production of (103)can also be valuable in their own right as a defunctionalization step. As an alternative to the use of formate (see above) to reduce an allylic chiral centre diene structures can be obtained by elimination2l9 Steps ''6H13 Organometallic Chemistry the transition elements 21 1 Asymmetric Palladium Coupling Reactions The most important current developments in the field of palladium coupling reactions focus on the asymmetric modification of this chemistry.Intramolecular coupling to a prochiral alkene constitutes a strategy based on enantioface recognition. The conver- sion (112)into (113) was performed efficiently with (R)-BINAP [(R)-2,2’-bis(diphenyl- phosphino)-1,l’-binaphthyl]as the chiral auxiliary. A mixture of alkene regioisomers was obtained as an intermediate but oxidation afforded the single dienone (113).220 In the starting material (114) two enantiotopic alkenes are present. Asymmetric Heck coupling to afford (115)has now been used in a route to (116)which is an intermediate in the synthesis of ( -)-oppositol.221 In the starting material (1 17) two enantiotopic aryl trifluoromethanesulfonate (R)-BINAP I * + K2C03 (113) 95% ee 1) BHs-THF then H202 2) FeC13 3) BnBr NaH Steps * Steps 0 BnO-@ a) -BnO-’ BnO-OH G.R. Stephenson (triflate) groups are present so that stereodifferentiation occurs in the oxidative addition step. By sequential replacement of these two units in reactions mediated by palladium coupling asymmetric induction to establish the axial chirality of the biaryl unit was achieved.222 Until recently BINAP has been almost universally used as the chiral auxiliary for asymmetric palladium coupling. In this case the phefos ligand (1 18) has been employed. Another variant uses o-iodoarenes equipped with nucleophilic substituents e.g. (1 19). Coupling to allenes proceeds by C-C bond-formation to produce an q3-allyl intermediate which reacts with the nucleophilic side-chain group.The initial coupling step establishes the chirality of the q3-intermediate. The chiral auxiliary (120) employed in this work achieved enantiomeric excesses in the range 61-82%. With terminal allenes this is a case of enantioface recognition. Racemic internal allenes can also be used as substrates.223 Coupling stereochemically-labile chiral Grignard reagents such as (121) with vinyl halides locks the interconverting stereoisomers of the nucleophile. Efforts to optimise this difficult dynamic kinetic resolution continue. In the case of the chiral auxiliary( 122),enantiomericexcesses up to 45% have been achieved. An X-ray crystallographic analysis of a palladium complex of the chiral auxiliary has been reported.224 TfO OTf (1 19) X =OH NHTs Me PhAMgCI Ph-' Ph Asymmetric Hydroformylation and Hydrogenation Work continues with asymmetric hydroformylation using rhodium catalysis225 and systems and asymmetric hydrosilylation with rhodium229 and palladium.230A wide variety of chiral auxiliaries are now in use in these investigations.The highest enantioselectivity yet achieved in a rhodium-catalysed asymmetric hydroboration has been described in studies using a heterocyclic derivative of a ferrocene-based chiral amin~phosphine.~~' Enantioselective hydrogenation of alkenes continues as a popular method for the induction of asymmetry in the synthesis of amino acids. The reaction has been applied Organometallic Chemistry the transition elements to branched amino and a study of dynamics of intermediates in hydrogenation reactions of this type has been reported.233 Palladium catalysts can also be useful in the preparation of substrates for the hydrogenation step as in an enantioselective total synthesis of clavicipitic Competing elimination in the macrocyclization step required correction to give efficient access to the trans and cis isomers (123) and (124).(123)trans (124) cis Steps H Other substrates for asymmetric hydrogenation include unsaturated carboxylic acids235 and lac tone^.'^^ With terpene-derived starting materials competing isomeriz- ation and hydrogenation has been in~estigated.’~~ Mechanistic investigations of vinylcarboxylic acid derivative^,'^^ kinetic studies of hydrogenation of ligands in catalyst precursor^,'^^ developments of water-soluble hydrogenation catalysts which function as phase-transfer ligand~,’~’ and an asymmetric hydrogenation system that breeds a counter-configurated ligand,241 have all been reported this year.Ruthenium catalysts have been popular for the enantioselective hydrogenation of carbonyl ~ompo~nds.’~’-’~~ There are also examples of the asymmetric hydrogena- tion of p-ke to esters ’ and p-ke to phosphona tes.’ Iridium -ca t a1 ysed enan tioselec- tive hydrogenation of x,p-unsaturated ketones has been rep~rted.’~’ The reverse of hydrogenation is C-H activation. Enantioselective modification of these transition metal-catalysed procedures is of growing importance.Methods that employ dirhodium complexes with x-diazo ketones lead the way.248*249 Asymmetric oxidation Turning to oxidations the development of manganese-catalysed epoxidations by the Jacobsen and Katsuki group25 1,252 continue and other contributors describe variants such as the use of periodate salts as re oxidant^^^^ (with alkene substrates) and oxygen as the re~xidant~~” (in the oxidation of an aryl thioether). A quite different approach to metal-catalysed epoxidation employed sulfur-based yl-ides.255*256 Rhodium carbene complexes are employed in this ingenious double 214 G.R. Stephenson catalytic cycle. Applications,257 and development^^^^*^^^ of enantioselective dihydr- oxylation are also notable.The growth point however in enantioselective oxidation this year has been with developments in allylic oxidation. Copper complexes are employed for this purpose.260-262 A copper promoted asymmetric Kharasch reaction has been described.263 5 Concluding Remarks The Annual Report this year has concentrated on the use of enantioselective procedures and ongoing work in a number of fields described last year has not been covered. Palladium-catalysed oxidative cyclization/l,4-difunctionalizationand cas- cade procedures and development of Heck Stille and transmetallation-based and [sp + sp2] palladium-catalysed coupling procedures have not been surveyed. 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Hossain Tetrahedron Lett. 1995,36 5113. 192 M. Buchert M. Hoffmann and H.-U. ReiBig Chem. Ber. 1995 128 605. 193 S. Watanuki and M. Mori Organornetallics 1995 14 5054. 194 T.R. Hoye and J.R. Vyvyan J. Org. Chem. 1995 60 4184. 195 H. C. L. Abbenhuis U. Burckhardt V. Gramlich C. Kollner P. S. Pregosin R. Salzmann and A. Togni Organometallics 1995 14 759. 196 P.G. Anderson A. Harden D. Tanner and P.-0. Norrby Chem. Eur. J. 1995 1 12. 197 R. Tokunoh M. Sodeoka K. Aoe and M. Shibasaki Tetrahedron Lett. 1995,36 8035. 198 G. Brenchley M. Fedouloff M.F. Mahon K.C. Molloy and M. Wills Tetrahedron 1995 51 10581. 199 P. von Matt G.C. Lloyd-Jones A. B. E. Minidis A. Pfaltz L. Macko M. Neuburger M. Zehnder H. Riiegger and P. S. Pregosin Helv. Chim.Acra 1995 78 265. 200 P. Barbaro P.S. Pregosin R. Salzmann A. Albinati and R. W. Kunz Organometallics 1995 14 5160. 201 J. Herrmann P. S. Pregosin R. Salzrnann and A. Albinati Organornetallics 1995 14 331 1. 202 G. J. Dawson J. M. J. Williams and S.J. Coote Tetrahedron Lett. 1995 36 461. 203 G. Kniihl P. Sennhenn and G. Helrnchen J. Chem. Soc. Chem. Cornmun. 1995 1845. 204 W.-M. Tang Youji Huaxue 1995,15,202. 205 K. Voight A. Stolloe J. Salaun and A. de Meijere Synlett 1995 226. 206 G.C. Lloyd-Jones and A. Pfaltz Angew. Chem. Int. Ed. Engl. 1995,34,462. 207 R. Malet M. Moreno-Mafias T. Parella and R. Pleixats Organometallics 1995 14 2463. 208 N. Vicart B. Cazes and J. Gore Tetrahedron Lett. 1995 36 535. 209 G. Shi X. Huang and F.-J. Zhang Tetrahedron Lett.1995 36 6305. 210 E. ohler and S. Kanzler Synthesis 1995 539. 211 C. Moineau V. Bolitt and D. Sinou J. Chem. Soc. Chem. Commun. 1995 1103. 212 P. Wipf Y. Kim and D. M. Goldstein J. Am. Chem. Soc. 1995 117 11 106. 213 S.-K. Kang D.-C. Park H.-S. Rho C.-M. Yu and J.-H. Hong Synth. Commun. 1995 25 203. 214 M. Braun K. Opdenbusch and C. Unger Synlett 1995 1174. 215 H. M. R. Hoffman and A. Brandes Tetrahedron 1995 51 155. 216 S. Lemaire-Audoire M. Savignac J. P. Gent3 and J.-M. 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Fabbri and L. Kollar J. Organornet. Chern. 1995 491 91.229 M. Sawamura R. Kuwano J. Shirai and Y. Ito Synlett 1995 347. 230 Y. Uozumi K. Kitayama T. Hayashi K. Yanagi and E. Fukuyo Bull. Chem. SOC. Jpn. 199568,713. 231 A. Schnyder L. Hinterrnann and A. Togni Angew. Chem. Int. Ed. Engl. 1995 34 931. 232 M. J. Burk M. F. Gross and J. P. Martinez J. Am. Chem. Soc. 1995 117 9375. 233 J.A. Ramsden T.D. W. Claridge and J. M. Brown J. Chem. Soc. Chem. Commun. 1995,2469. 234 Y. Yokoyarna T. Matsumoto and Y. Murakarni J. Org. Chem. 1995,60 1486. 235 D. J. Ager D. E. Froen S.A. Laneman Chem. Ind. (Dekker) 1995,62 145. 236 T. Ohta T. Miyake N. Seido H. Kumobayashi and H. Takaya J. Org. Chem. 1995 60 327. 237 Y. Sun C. LeBlond J. Wang D. G. Blackrnond J. Laquidata and J. R. Sowa Jr. J. Am. Chem. Soc. 1995 117 12647. 238 A.S.C.Chan C.C. Chen T.K. Yang J.H. Huang and Y.C. Lin Inorg. Chim. Acta 1995 234 95. 239 D. Heller K. Kortus and R. Selke Liebigs Ann. 1995 575. 240 H. Ding B. E. Hanson and J. Bakos Angew. Chem. Int. Ed. Engl. 1995 34 1645. 241 H. Brunner and A. Terfort Tetrahedron Asymmetry 1995 6 919. Organometallic Chemistry the transition elements 242 T. Ohkuma H. Ooka T. Ikariya and R. Noyori J. Am. Chem. SOC.,1995,117 10417. 243 S. Akutagawa Chem. lnd (Dekker) 1995,62 135. 244 T. Ohkuma H. Ooka S. Hashiguchi T. Ikariya and R. Noyori J. Am. Chem. Soc. 1995,117 2675. 245 J. P. Genet V. Ratovelornanana-Vidal M. C. Caiio de Andrade X. Pfister P. Guerreiro and J. Y. Lenoir Tetrahedron Lett. 1995 36 4801. 246 M. Kitamura M. Kokunaga and R. Noyori J.Am. Chem. Soc. 1995 117,2931. 247 C. Bianchini E. Farnetti L. Glendenning M. Graziani G. Nardin M. Peruzzini E. Rocchini and F. Zanobini Organometallics 1995 14 1489. 248 N. Watanabe Y. Ohtake S. Hashimoto M. Shiro and S. Ikegami Tetrahedron Lett. 1995,36 1491. 249 M. P. Doyle Q.-L. Zhou C. E. Raab and G.H. P. Roos Tetrahedron Lett. 1995,36 4745. 250 B.D. Brandes and E.N. Jacobsen Tetrahedron Lett. 1995,36 5123. 251 T. Fukuda R. 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ISSN:0069-3030    

DOI:10.1039/OC9959200179

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

8 Synthetic Methods By N. J. LAWRENCE Department of Chemistry UMIST PO Box 88 Manchester M60 lQD UK 1 Introduction The predominant theme of new synthetic methods this year has been the development of cleaner reactions and transformations. Methods for asymmetric catalysis and selective processes have as in recent years been prominent in 1995. The number of reports describing deliberately unselective synthesis in the guise of combinatorial chemistry has increased this year and has included some very useful reviews.ly2 Many impressive total syntheses of complex and important natural products have been reported this year including the construction of avermectin Bla,3tax01,~ curacin A,5 rapamycin6 and (+)-pancratistatin.' A candid report of the total synthesis of taxol disclosed last year by Nicolaou and Guy' is also well worth reading.Specialist reference works that have been published in 1995 include volume 49' of Organic Reactions which this year reviews aromatic lithiation reactions promoted by heteroatomic substituents,'" and the intramolecular Michael reactiongb A new major reference work The Encyclopaedia ofReayentsfor Organic Synthesis was published this year. This excellent work which comprehensively reviews over 3000 commonly encountered reagents will undoubtedly soon be indispensable to all those with an interest in organic synthesis. 2 Carbon-Carbon Formation The asymmetric catalytic addition of organozinc reagents-whose stereoselective reactions have been reviewed recently"-to aldehydes has proved as popular as ever this year (Figure 1).Some of the catalysts used include the diselenide (1)12 and the titanate complex (2).' The versatility of this type of reaction is being advanced by the development of new methods for the preparation of diorganozinc reagents. For example Knochel and co-workers report a useful nickel-catalysed conversion of alkenes to functionalized dialkylzinc reagents [e.y. (3) +(4)] (Scheme l).I4 An attractive feature of this reaction is that a large number of organozinc reagents can be made from diethylzinc (one of the few commercially available dialkylzinc reagents). The organozinc reagent can be trapped with various electrophiles or be used efficiently for the catalytic asymmetric addition to aldehydes. Two reports describing the direct oxidation of organozinc reagents with oxygen or dry air have been reported by the 22 1 N.J. Lawrence CI (1) (S)1 mol% 91% 98% ee Cl (2) (S)5 mol% 79% 91% ee Fig. 1 Selectivity in the addition of ZnEt to PhCHO neat 50 "C 2 Ft-+ Et2Zn (R+2zn + 2 CH2CH2 Ni(acac)2(1 mot%) (3) COD(1 mot%) (4) Scheme 1 groups of Kno~hel'~*'~ and Normant" respectively. Secondary and tertiary alkylzinc bromides have been found to add conjugatively to a$-unsaturated ketones in the presence of trimethylsilyl chloride and BF,*OEt, without a copper catalyst." Examples of the asymmetric catalytic addition of organolithium reagents to carbonyl compounds are rare. However Thompson et a!. have shown that the lithium acetylide (7) adds enantioselectively to the trifluoromethyl ketone (5)in the presence of the ephedrine alkoxide (8) to give the alcohol (6),a key intermediate in the synthesis of the reverse transcriptase inhibitor L-743,726 [Scheme 2(a)].I9 Normant and co-workers have developed a different strategy for the use of organolithium reagents in asymmetric carbon-carbon bond forming reactions.They have developed a potentially useful and intriguing process by finding that the asymmetric carbolithiation of cinnamyl derivatives can be performed using sparteine as a chiral promoter [e.g. cinnamyl alcohol -+(9) [Scheme 2(b)].,' The allylation of aldehydes by organometallic reagents provides useful homoallylic alcohols as products. Several new methods for achieving this transformation have been reported in 1995.The asymmetric allylation of aldehydes with diallyltin dibromide is promoted by chiral diamines,2 'for example the proline-derived diamine (10)[Scheme 3(a)]. Charette et af. have shown that the addition of allyltributylstannane to ketones of the type (1 1) [Scheme 3(b)] possessing the 2-benzyloxytetrahydropyranylgroup is highly selective in the presence of MgBr,.OEt,., New reagents for the allylation of aldehydes and ketones include allyl br~mide-tin-Me,SiCl-MeOH,~~allyl bromide and commercial zinc and allyl bromide and CUC~,.~H,O-M~.~~ Isaac and Chan describe a useful and related protocol for the coupling of aldehydes with prop-2-ynyl bromides in aqueous media mediated by indium to give allenyl alochols Synthetic Methods 0 CI CIecF.NHR NHR (5) (6) 82% 97% ee i BuLi-hexane (-)-sparteine 0 "C 1 h PhyOH Ph&OH ii H30+ B" (9)8l% 78% ee Scheme 2 f\\PhCHO (10) (1.1 equiv.) - Br2Sn \ CHzCIz -78 "C Phu 93% 79% ee MgBr2.0Et2 SnBY - Me OHa? \ (b) 90% 92% de = Br Me c J H In H,O R R =C8H17 99% Scheme 3 [Scheme 3(c)]. As with other processes that can be carried out in water this procedure offers the benefits of a cheap non-toxic non-flammable solvent; there is no need for hydroxy protecting groups; substrates that show minimal solubility in organic solvents can be used; and selectivity changes often occur.26 Aldehydes can be coupled with ally1 N.J. Lawrence bromides in a similar fashion.27 3-Bromo-2-bromomethylprop-1-ene and indium provide a water compatible trimethylenemethane dianion equivalent.28 A general useful review of synthetic organoindium chemistry29 has appeared this year.The addition of an organometallic reagent to carbonyl derivatives is promoted by ultrasound. Luche and co-workers3' report the use of the sonochemical Barbier reaction to make ketones. A mixture of alkyl chloride lithium carboxylate and lithium metal in tetrahydrofuran under sonication gives the required ketone in high yield. The rare earth triflates (trifluoromethanesulfonates)have been used to promote a variety of carbon-carbon bond forming reactions this year; their general utility has been reviewed by Mar~hrnan.~' Many reports have detailed further applications for this remarkable class of catalysts.For example hafnium triflate-catalysed Friedel-Crafts acylation reactions have been performed in lithium perchlor-ate-nitr~methane.~~ Lanthanide triflate-catalysed imino Diels-Alder reactions pro- vide a convenient synthesis of pyridine and quinoline derivatives. 33 Fries reactions of phenol and 1-naphthol derivatives with acyl chlorides proceed smoothly in the presence of a small amount of Sc(OTf) (5-20mol%) to afford the corresponding ketones in high yields.34 Lanthanide triflates are also effective for the allylation of imines with allyltrib~tylstannane.~~novel Mannich-type reaction between an A aldehyde amine and a vinyl ether is catalysed by lanthanide triflates in aqueous media.36 0 (12) Ph The design of new chiral auxiliaries and the improved syntheses of old ones for the asymmetric construction of carbon-carbon bonds has featured prominently this year.For example the oxa~olidinone~~ (12) derived from diphenylalinol (itself made from ~-serine~') is an excellent auxiliary for aldol alkylation and Diels-Alder reactions. McKillop Taylor and co-workers report a novel simple and efficient procedure for the synthesis of Evans-type oxazolidinones that avoids the use of borane and the intermediacy of water soluble 1,2-amino alcohols.39 The protected amino acid (13) is reduced with sodium borohydride in the presence of calcium chloride to give an alcohol (14) that is not water soluble; simple heating in toluene with potassium carbonate then gives the oxazolidinone (1 5) in high yield (Scheme 4).The process is very efficient and is well suited to the large scale preparation of this type of chiral auxiliary. Myers et al. have extended their elegant use of p~eudoephedrine~'as a chiral auxiliary to include the synthesis of r-amino acids.41 Treatment of the gly~inamide~~ (16) with lithium diisopropylamine followed by alkylation and hy- drolysis generates the amino acid (17) with high enantioselectivity (Scheme 5). Replacement of the hydrolysis step by treatment with a Grignard reagent generates r-amino ketones.43 Kise et al. report a very selective method for the construction of 2,3-disubstituted succinic acids by oxidative homocoupling of chiral en~lates.~~ The lithium enolate of the Evans oxazolidinone (18) is treated with the oxidant titanium Synthetic Methods (15) 91% Scheme 4 Me 0 i 2 x LDA LiCl Php+/NH2 4b HOLNH* I ii OH Me I iii H20 (16) (17) 63% > 97% de Scheme 5 X i,ii LDA .GX0 TiCI Et 0 x=ov (a) (18) (19) 95% 90% de 0 i LDA Y X ii I2 70% > 98% de Scheme 6 tetrachloride to give the coupled diester (19) with high diastereoselectivity [Scheme 6(a)].Helmchen and co-workers have also reported the synthesis of similar diesters (21) by coupling the enolate of the chiral imidazolidone derivative (20) with iodine as the oxidant [Scheme 6(b)]-45 Masamune et a!. have introduced benzopyranoisoxazolidines as a new class of chiral auxiliary.46 The auxiliary is very efficient in controlling the stereochemistry of alkylation of the acyl derivatives (22) in the manner (22) -,(23) (Scheme 7).In addition the new auxiliary offers many advantages over other auxiliaries such as oxazolidinones for example the acyl derivatives are simply made by combination of the isoxazolidine and the appropriate acid chloride in the presence of triethylamine. The alkylation with P-branched electrophiles can be performed by using the appropriate triflates. The N. J. Lawrence 1 > 90% de R' Scheme 7 auxiliary is removed (and recovered) in a variety of ways to release alcohols aldehydes or ketones. 1 lr-Binaphthyl-2,2'-diol a commonly used but expensive auxiliary has been resolved by reaction of its phosphoryl chloride with a variety of homochiral arnine~.~' De Lucchi and co-workers also report a convenient procedure for the resolution of racemic binaphthalene derivatives via fractional crystallization of the dia-stereoisomeric menthyl carbonate^.^^ 171'-Binaphthyl-2,2'-diolhas also been resolved by separation of its neomenthyl thi~acetates.~' Charette and Brochu have developed a new strategy for the Lewis-acid catalysed cyclopropanation of allylic alcohols.50 They found that treatment of an allylic alcohol with an (iodomethy1)zinc reagent-a class of reagent which has recently been reviewed' '-followed by addition of a Lewis acid triggered the cyclopropanation reaction.Enantiomerically enriched cyclopropylmethanol derivatives are obtained in the presence of homochiral Lewis acids.For example the titanium catalyst (24)effects the efficient enantioselective cyclopropanation of cinnamyl alcohol +(25) (Scheme 8). Radical-based Methods Majetich and Wheless have reviewed recent examples of remote intramolecular free radical functionalizations including those that involve carbon-carbon bond forma- ti~n.~~ Clive and Yang have introduced the polar stannane (26) for use in radical chemistry in much the same way as tributyl- and triphenyl- stannanes are It has been used to effect radical promoted dehalogenation Barton-type deoxygenation and deselenation reactions. The stannane being non-polar and relatively immobile on silica gel allows for the easy chromatographic separation of products from tin- containing by-products.Alkene Synthesis A practical synthesis of (2)-a,P-unsaturated esters using the new Horner-Emmons reagent (27) ethyl diphenylphosphonoacetate has been reported by and^.'^ The Synthetic Methods Zn(CH,I) (1 equiv.) (24) (0.25 equiv.) Ph*OH CHpCIp 0 "C 1.5 h * Ph (25)80% 90% ee Ph Ph Scheme 8 00 i KHMDS. 18-Crown-6 ~ Ph? (4 (pho)2b'doEt ii PhCHO -78 "C 1 h C02Et (27) (28) 98% Z:E 99:l 0 PhCHO CsF DMSO mC02Et do,, room temp. 35 min then * Ph \ (b) 100 "C 1 h (29) (30) 93% E:Z > 98:2 Scheme 9 reagent (27Fprepared from triethyl phosphonoacetate PCI and phenol-when deprotonated by a variety of bases at low temperature reacts with aldehydes with exceptionally high (Z)-selectivity (27) +(28) [Scheme 9(a)].Bellassoued and Ozanne have introduced a modification of the Peterson olefination reaction in which the coupling of the silyl reagent (29) and aldehyde and subsequent elimination of 'Me,SiOH' are both catalysed by fluoride ion in dimethyl sulfoxide (DMSO) in a one-pot operation (29) +(30) [Scheme 9(b)].55 N.J. Lawrence (31) (R) 1 mol% 8O% 93% ee (32)(R) 10mol% 90% 94% ee (33) (R) 10 mol% 89% 95% ee Fig. 2 Selectivity in the borane reduction of PhCOMe 3 Reduction Much effort has been spent on the development of new reagents for the selective reduction of carbonyl compounds and their derivatives especially ketones.56 Estab- lished asymmetric protocols using oxazaborolidine catalysts have seen widespread use for the borane reduction of ketones.57 Among the many new oxazaborolidine catalysts introduced this year are the p-amino alcohol (3 1),58 the serine-derived hydroxy aziridine (32)59 and cis-2-amino-1-acenaphthenol(33) (Figure 2).60 Two other organoboron reducing agents diisocamphenylchloroborane6' and diisobutyl-chloroalane62 have been used to chemoselectively reduce aldehydes in the presence of ketones.Wandrey and co-workers report the use of chiral titanium alkoxides as catalysts for the enantioselective reduction of ketones with boranes (Scheme For example the (r,sc,r',a'-tetraaryl- 1,3-dioxolane-4,5-dimethanol) TADDOL-like ligand (34) catalyses the catecholborane reduction of p-bromoacetophenone (35) with high selectivity to give the alcohol (36). The development of modified borohydride reagents has also been a particularly active area of research this year.For example titanocene borohydride [prepared in siru from Cp,TiCl and NaBH in 172-dimethoxyethane(DME)]has been shown to reduce ketones efficiently to the corresponding alcohols. The reduction of 4-terr-butyl- cyclohexanone is highly trans selective (trans cis = 97 3).64 Mukaiyama and co- workers have shown that the (p-oxoaldiminato)cobalt(rr)complex (37) is a highly efficient catalyst for the reduction of prochiral ketones with sodium borohydride e.g. (38) -P (39) (Scheme 1l).65Zinc borohydride (from ZnC1 and NaBH,) reduces carboxylic acids in refluxing tetrahydrofuran (THF) easily66 whilst calcium borohydr- ide reduces both aliphatic and aromatic esters to alcohols completely in the presence of alkene catalysts.67 A mixture of NaBH and BiCI has been used for the selective Synthetic Methods loo% 82% ee Ph (34) Scheme 10 (37) (5 mol%) NaBH [EtOH (3% in CHCI,)] (39)94% 92% ee Scheme 11 reduction of the carbon-carbon double bond of a,&unsaturated esters with high selectivity.68 The selective reduction of the carbon-carbon double bond of other x,P-unsaturated acid derivatives is also achieved using borohydride exchange resin-copper sulfate in methanol.69 The chemoselective 1,4-reduction of cx,p-un-saturated aldehydes or ketones is achieved with sodium dithionite in H,O-dioxane at 50°C in the presence of unsaturated (non conjugated) and saturated aldehydes or ketones.70 Diisobutylchloroalane effects the same change.71 Several useful modifications of the Meerwein-Ponndorf-Verley (MPV) reduction of ketones have been reported this year.Trifluoroacetic acid (TFA) has been found to greatly accelerate the MPV reaction of ketones with aluminium isopropoxide at room temperature in toluene.72 The aluminium reagent can be used in sub-stoichiometric N. J. Lawrence (411 A 99% 97% ee B:92% 93% ee [gives ent -(41)] A [BINAP-Ru"-(42)-KOH (1:1:2 mole ratio)] (0.2 mol%) H2 (4 atm) Pr'OH B:[RuC12(mesitylene)]2-(43)-KOH (1:2:5 mole ratio)] (0.5 mol%) Pr'OH Scheme 12 quantities in the presence of 1 mol equivalent of isopropyl alcohol (IPA) (i.e. IPA 100 mol%; Al(OPr'), 8 mol%; TFA 0.3 m~l%).~~ In the presence of the co-catalyst NaOH [NiCl,(PPh,),] acts as an efficient Meerwein-Ponndorf-Verley-like catalyst for the transfer of hydrogen from isopropyl alcohol to ketones and aldehydes.74 Noyori and co-workers report a useful related transfer hydrogenation reaction in which isopropyl alcohol is the ultimate source of hydrogen.They use a ruthenium(r1) catalyst in the presence of the sulfonamide (42) TsDPEN for the highly selective process A (40) +(41) (Scheme 12).75 A related process B using a catalyst system with a higher substrate catalyst ratio has been disclosed by the same group. The ruthenium catalyzed hydrogenation is highly enantioselective with the 2,2'-bis(dipheny1phos- phino)-1,l'-binaphthol (BINAP-Ru" complex is used in combination with the chiral diamine (43) and potassium hydroxide.76 Cutler and co-workers have shown that the manganese carbonyl complex [Mn(CO)(PPh,)Ac] (44) and related materials effect the catalytic hydrosilylation of carboxylic esters to the corresponding ether (45) -+ (46) [Scheme 13(a)].77 The modestly enantioselective radical-mediated reduction of the dihydrocoumarin (47) +(48)is achieved by combining Bu,SnH the chiral diamine (49) and magnesium iodide [Scheme 13(b)].'* The asymmetric induction is thought to derive from the close association of the enol radical with the Lewis acid and chiral ligand.Several new methods for the synthesis of amines by reduction have been developed this year including many involving the reduction of azides. For example lithium N,N-dimethylaminoborohydride reduces aliphatic and benzylic azides to the corre- sponding amines in excellent yield.79 Dichloroborane-dimethyl sulfide also reduces a variety of organyl azides with higher selectivity (halides esters nitriles and nitro groups are compatible with this process).*' Azides are transformed to N-boc-amines by treatment with tributylphosphine in the presence of di-tert-butyl dicarbonate.'' Organic azides are also efficiently reduced to primary amines with samarium Synthetic Methods 23 1 EtOhoEt (44) (3 mol%) PhSiH3 CsH6 24 "c (4 (45) 0 (46) 68% I Bu3SnH Mglo (1 equiv.) aoMe (49) (1 equiv.) (b) (47) (-)-(48) 88% 62% ee Scheme 13 dii~dide.'~,'~ Samarium diiodide also effects the reductive cleavage of N-0 bonds in hydroxylamine and hydroxamic acid derivatives.' Several new methods for the reductive amination of aldehydes and ketones have been reported in 1995.A general preparatively efficient simple method for the preparation of N,N-dimethylalkylamines via reductive alkylation of aldehydes and ketones with dimethylamine using titanium(1v) isopropoxide and NaBH has been reported by Bhatta~haryya.'~ Other amines can be used in this reaction.86 Dimare and co-workers report a simple and mild reductive amination protocol using methanolic pyridine-borane and 48 molecular ~ieves.'~ Amines are reductively methylated by the action of ZnCI, NaBH and formaldehyde in dichloromethane.88 Nitro compounds often function as precursors to amines in synthesis; new selective methods for achieving this transformation are desirable.For example anilines are prepared by the reduction of nitroarenes using catalytic FeCl,.H,O and N,N-dimethylhydra~ine.'~ The procedure is mild and compatible with a wide assortment of functional groups. Nitroarenes are also reduced to anilines by the binary combinations NaBH,-SbCl and NaBH,-BiC1,.90 Nitroarenes and nitroalkanes are reduced to anilines and alkylhydroxylamines using Na,S,O and octylviologen as an electron transfer reagent.g1 Aromatic aldehydes are reduced to the corresponding hydrocarbon (ArCHO -f ArMe) with borohydride exchange resin and nickel acetate in methan01.~' The same system reduces aromatic oximes to amine~.~, Aromatic ketones are reductively deoxygenated by the action of NaCNBH,-BF,*OEt, providing a practical alternative to the Clemmensen reduction and related processes.94 The reduction of sulfoxides and active halides is achieved with a mixture of Cp,TiCI or TiCl and samari~m.~~.~~ N.J.Lawrence (50) (DHQD)2DP-PHAL R = Ph (51) (DHQD)2-PHAL R = H ?H (DHQD),-PHAL oso, (01 (53) 63% ee with (50) 35% ee with (51) Scheme 14 Oxidation One of the most successful oxidative synthetic methods of recent years the Sharpless asymmetric dihydroxylation (AD) reaction has been highlighted as part of a review of ligand-accelerated catalysis.97 The method has been refined and exploited extensively this year. Sharpless and co-workers have extended this powerful reaction by making new ligands that possess a diphenylphthalazine spacer group (Scheme 14).98For example the ligand (50)(DHQD),DP-PHAL generally gives greater enantioselectivi- ties than those obtained from the PHAL series (51).cis-Olefins give improved selectivities [e.g. (52)-+ (5311 with (50). The diphenylphthalazine ligands are the most general for the asymmetric dihydroxylation reaction described to date. Among the many olefinic substrates studied this year are polyene~,~~,'~~ cyclopentene deriva- tives,"' polycyclic aromatic hydrocarbons,'02 vinylpho~phonates'~~ and cyclo- propylidene derivative^."^ The AD protocol has been used to make (20s)-cam- ptothecin,"' rhodinose derivatives,lo6 a bicyclic acetal apple aroma c~nstituent,"~ spiroacetals,' O8 bis(hydroxymethy1)piperidine derivative^,'^^ goniobutenolides A and B,' 'O tetrahydroxybutylimidazoles' '' and oxazolidinediones.' l2 Torii et a/.have described a procedure for the asymmetric dihydroxylation of olefins using a Sharpless method that incorporates a catalytic amount of potassium ferricyanide K,Fe(CN) which is recycled by electrooxidation.' ' New protocols for highly enantioselective dihydroxylation reactions using polymer supported cinchona ligands have been described this Warren and co-workers report a Sharpless-like racemic dihydroxylation protocol for the reaction of various alkenes (stilbenes sulfides and phosphine oxides).' '' Dihydroxylation with solid OSCI to provide the catalytic oxidant K,Fe(CN) as stoichiometric oxidant quinuclidine as the accelerating ligand with added K,CO and Synthetic Methods methanesulfonamide in a two-phase system (water and tert-butyl alcohol) gives excellent yields of racemic syn diols.An asymmetric version of the protocol incorporating the DHQD,-PHAL ligand has been used in the dihydroxylation of allylic phosphine oxides. l6 Many new catalysts and oxidants have been developed for the clean and efficient transformation of alcohols to their corresponding carbonyl compounds. For example benzylic and allylic alcohols are oxidized to ketones with Bu'OOH and catalytic [COC~,(PP~,),]."~The oxidation of alcohols is also effected by the catalytic use of palladium chloride and Adogen 464; the stoichiometric oxidant is 1,2-dich-loroethane.' l8 Rajendran and Trivedi have used ruthenium tetroxide and a phase- transfer catalyst in a biphasic system [CCl,-NaCl (as.)] for the oxidation of aromatic primary alcohols and aldehydes.The spent ruthenium oxidant is regenerated at a platinized titanium anode.' '' Secondary alcohols are rapidly oxidized to the corresponding ketones by the action of RuCl (2mol%) and peracetic acid in ethyl acetate.120 1,2-Diols are efficiently oxidized to the corresponding 1,2-diketones with aqueous hydrogen peroxide in the presence of catalytic peroxotungstophosphate. '" Alcohols are also oxidized by the 1 1 complex of N-bromosuccinimide and tet- rabutylammonium iodide,', by K,FeO and K10 Montmorillonite clay.123 18- Crown-6 complexes of N-butylammonium and pyridinium chlorochromates (PCCs) have been prepared and used as mild and selective oxidizing-agents for alcohols.'24 Unlike PCC these complexes oxidize benzylic alcohols more rapidly than primary alkyl alcohols.Dimethyldioxirane (DMDO) has been used to selectively mono-oxidize 1,2- and 1,3-diols to the corresponding hydroxy ketones in high yield.'25 The protocol exploits the inhibiting effect of carbonyl groups on DMDO promoted alcohol oxidation. A cheap efficient method for the oxidation of thiols to disulfides uses sodium chlorite.' 26 Transformation of sulfides to sulfoxides is effected by mercury(I1) oxide and iodine'27 and nitric acid catalysed by FeBr,.'28 Page et a/. report a highly enantioselective protocol for the asymmetric catalytic oxidation of sulfides to sulfoxideswith hydrogen peroxide.12' They used a series of acetals of oxocamphorsul-fonylimines as oxygen atom transfer mediators (Scheme 15). The sulfonylimine (54) generally gives the best selectivity [e.g. (55)+(56)]. The oxidation of electron-deficient sulfides to sulfones is achieved using excess HOF*CH,CN complex.'30 The related transformation of selenides to selenones is effected mildly and efficiently by Oxone (potassium peroxymonosulfate). ' ' The use of dioxiranes for the epoxidation of alkenes has seen much activity this year. Yang et a/. report a useful protocol for the epoxidation of olefins by methyl(trifluoromethy1)dioxirane which is generated in situ in a mixture of MeCN-H,O from trifluoromethylacetone and 0x0ne.l~~ Denmark et a/.have used a variety of ketones as catalysts for the epoxidation of alkenes with Oxone (Scheme 16).The best catalyst under biphasic reaction conditions was found to be the N-dodecyl-4- oxopiperidinium salt (57) in CH,CI2 at pH 7.5-8.0 [cinnamyl alcohol gave (5S)J.'33 Oxone in acetone is also a mild oxidant for the conversion of various substituted aniline derivatives to the corresponding nitroarenel, and the oxidation of the C-B bond of boronic acids and boronic esters.'35 New protocols for the epoxidation of alkenes using salen [H,salen = bis(salicy1idene)eth ylenediamine] complexes have been developed this 234 N. 3. Lawrence (55) (56) 100% >96% de Scheme 15 (57)(10 rnol%) Oxone CHzCIz-H,O Ph-*H pH 7.5,O"C,24 h * Ph&OH (58)83% 0 Scheme 16 year. Jacobsen and co-workers report the low temperature asymmetric epoxidation of unfunctionalized olefins by [Mn"'(salen)J complexes such as (59) [Scheme 17(a)].The combination of rn-chloroperbenzoic acid (MCPBA) and 4-methylmorpholine N-oxide (NMO) proved to be the best primary oxidant system for efficient asymmetric epoxidation of (60)to give (61).136The low temperature reaction allows epoxidation of a variety of alkenes with a significant increase in enantioselectivity relative to reaction using aqueous bleach. Katsuki and co-workers have also reported a low temperature epoxidation reaction [Scheme 17(b)]; using a solution of NaOCl saturated with NaC1 a reaction temperature of -18°C is possible. At this temperature and with the manganese complex (62) the epoxidation of cyclopentadiene is highly enantioselec- tive.' 37 Epoxidation of olefins can also be achieved with formamide-hydrogen peroxide in an aqueous medium,13* a synthetic hydrotalcite clay and hydrogen peroxide' 39 and silica treated with Ti(OPr') in combination with tert-butyl hydr~peroxide.'~' or,/?-Unsaturated ketones are rapidly converted to epoxy ketones by sodium perborate in the presence of a phase transfer reagent.',' The general use of sodium perborate in organic synthesis has been reviewed by Mu~art'~' and McKillop and Sander~0n.l~~ Synthetic Methods 235 (59) (2-8mol%) MCPBA / NMOGH&I, -78 "C (a) (60) (61)89% 96% ee (88% ee with NaOCI) PhHph TIPSO$-:;:$:boTl PS Bur But (59) NaOCl (aq.NaCI) 4-phenylpyridine* QO Koxide (20mol%) 82% 93% ee Scheme 17 Sanchez and Roberts have used poly-L-leucine and poly-D-leucine as catalysts for asymmetric epoxidation of a variety of a$-unsaturated ketones and dienones Ce.9.(63) -+ (64)] as an extension of the work of Julia (Scheme 18).'44 It has been known for some time that a phenyldimethylsilyl group can act as a latent hydroxy group. Taber et al. report a useful modification of the silyl-to-hydroxy conversion that is compatible with alkenes [Scheme 19(a)].145 The phenyl group in (65) is first reduced to the cyclohexa- 1,4-diene (66)with lithium in ammonia the cyclohexadiene group replaced by fluoride by reaction with tetrabutylammonium fluoride then the silyl fluoride is oxidized by hydrogen peroxide to the alcohol (67).This process has been used in the synthesis of a-dictyopterol. 146 Disilanyl groups are also readily converted to a hydroxy group by a simple two-step one-pot operation involving successive treatment with tetrabutylammonium fluoride (TBAF) and alkaline hydroperoxide [(68)-+ (69)] N. J. Lawrence ply-L-leucine Ph& *A Ph H2O2-NaOH4H2CI2 Ph Ph (63) (64)ee > 98% Scheme 18 i TBAF ii. H20 OH $30. (67)66%' OH OH Ph&SiMe2SiMe3 i TBAF THF room temp. ii H202 KHC03 MeOH. 40 "C Ph (68) (69)90% Scheme 19 [Scheme 19(b)].'47 Dirnethyl(5-methylthienyl)~ilyl'~~ and dimethylcl-(phenyl-thio)cyclopropyl)]silyl'4g groups have also been used as masked hydroxy groups. Resek and Meyers report the synthesis of x,P-unsaturated ketones nitriles and lactams from the saturated carbonyl compound using methyl phenyls~lfinate.'~~ The sulfinate is prepared by the treatment of diphenyl disulfide with bromine in the presence of methanol.a-Sulfinyl carbonyl compounds (71) are formed upon treatment 237 Synthetic Methods X= 0or NR Me3Si0 $J3) :::::2 -.;" OJ OJ (74) 86% Scheme 20 of a mixture of the methyl phenylsulfinate and the carbonyl compound (70) with potassium hydride. Thermal elimination of the sulfinate (71) generates the a$-unsaturated carbonyl compound (72) [Scheme 20(a)]. Larock et al. report a simple new effective palladium catalysed oxidation of silyl enol ethers to enones. For example the enol ether (73) is converted to the a$-unsaturated ketone (74) by treatment with Pd(OAc) (10mol%) in the presence of one atmosphere of oxygen in DMSO as the solvent [Scheme 20(b)].Pfaltz and co-workers have found that the copper(1) complex prepared in situ from the chiral bisoxazoline (75) and CuOTf effects the asymmetric allylic oxidation of alkenes. For example the bisoxazoline CuOTf and tert-butyl perbenzoate gives the allylic benzoate (76) from cyclopentene with good enantioselectivity (Scheme 2l).ls2 Chen and co-workers describe the potentially useful enzyme-mediated oxidation of substituted toluene derivatives to the corresponding aldehydes (77) -+(78).lS3 The enzyme used laccase (applications of which have recently been reviewedlS4) requires an artificial cofactor diammonium 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) [ABTS(NH,),] (79) [Scheme 22(a)].Titanium silicates (TS-1 and TS-2) efficiently catalyze the oxidation of cyclic ethers into the corresponding lactone (e.g. THF -+ 7-butyrolactone) in combination with H,O,. Ishii et a/.report the aerobic oxidation of a variety of organic substrates using N-hydroxyphthalimide as a novel catalyst [e.g. (80) +(81)] [Scheme 22(b)].155 This process is potentially very useful since no metal is involved in the oxidation reactions. Other advances in aerobic oxidation have been detailed by Mukaiyama and Yamada.lS6 Finally Hamelin and co-workers report a protocol for the rapid promotion of Beckmann reactions. Microwave-promoted reaction of cyclic ketones with hy- droxylamine-0-sulfonic acid over silica gives the corresponding lactams quickly and in high yield.15' Other microwave-assisted reactions have been extensively reviewed this year. 158,159 Two reviews of other specialized but important areas of synthetic chemistry serve as good introductions to synthesis in supercritical fluids,160 and the use of ultrasound.161 N. J. Lawrence (75) (6 mol%) CuOTf (5 mol%) PhCO,Bu' -20 "C 22 d MeCN * Q=ocoph (76)61Yo,84% ee But BU' (75) Scheme 21 "Y" laccase-ABTS( NH&02 87-1 00% (77) (78) Et SOSNH~ 02 PhCN 100 'C (b) (80) (81) 83% Scheme 22 Synthetic Methods 5 Protection and Functional Group Interconversion The use of protecting groups is essential in most organic syntheses.New developments in the use of protecting groups have recently been reviewed by Jarowicki and Kocienski.'62 New protecting groups and new methods for the manipulation of old ones described this year are outlined below. Alcohols and thiols Many new methods involving silicon based protecting groups have been detailed. Diphenyl-tert-butoxysilyl derivatives of alcohols are cleaved by sodium sulfide in ethanol [tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS)] groups remain ~naffected).'~~ Deprotection of diphenylmethylsilyl ethers of allylic or benzylic alcohols is achieved by UV irradiation in the presence of ~henanthrene.'~~ Lee et a!. report the chemoselective deprotection of tert-butyldimethylsilyl benzyl ethers in the presence of silyl ethers of secondary and tertiary alcohol^,'^^ by subjecting a 0.25 mol dm- solution of the silyl ether in CH,OH-CCl (1 1) to ultrasound.The use of various benzyl and ally1 protecting groups has seen much activity including the report of Srikrishna et ul. that sodium cyanoborohydride and boron trifluoride-diethyl ether provides a new convenient reductive procedure for the conversion of 4-methoxybenzyl (MPM) ethers to alcohols.'66 The combined use of tert-butyldimethylsilyl trifluoromethanesulfonate and triethylamine cleaves p-methoxybenzyl ethers to give the corresponding tert-butyldimethylsilyl ether direc- tl~.'~~ Benzyl ethers of o-substituted phenols are deprotected using hydrobromic acid in presence of a phase-transfer catalyst.16* Ammonia pyridine and ammonium acetate were found to be extremely effective as inhibitors of Pd/C catalysed benzyl ether hydrogenolysis while olefin benzyloxycarbonyl benzyl ester and azide groups are smoothly hydr~genated.'~' The use of iodine in methanol is described as a simple non-vigorous selective method for the cleavage of p-methoxybenzyl ethers in the presence of benzyl ethers.' 70 A 4,4'-dimethoxytrityl derivative of the levulinyl group has been developed for protection of nucleophilic functionalities such as hydroxy groups by reaction of its symmetrical anhydride.I7' It is rapidly removed under mild conditions using a hydrazine-pyridinium acetate buffer at near neutral pH.This protectinggroupcan bedetected withhighsensitivityat 513nm(~ = 78 600dm3mol-' cm-').Ally1 ethers are cleaved electrochemically using a nickel(I1) bipyridine com- plex.' New chemistry of acetal protecting groups include that from Srikrishna et ul. who report the simple reductive deprotection of tetrahydropyran-2-yl (THP) ethers using a combination of NaCNBH and BF,.OEt in THF.'73 x o-Diols are selectively mono-protected as a THP ether using a strongly acidic ion-exchange resin in a mixture of 3,4-dihydro-2H-pyran and toluene.' 74 Other catalysts used to promote the tetrahydropyranylation of alcohols include the Envirocat EPZG resin'75 and dicyanoethylene acetal. 76 THP ethers are readily hydrolysed to their corresponding alcohols in wet acetonitrile in the presence of a catalytic 2,3-dichloro-5,6-dicyano- 1,4- benzoquinone (DDQ).'" Related THF ethers are made by treating an alcohol with toluene-p-sulfonyl chloride and sodium hydride in THF.'78 Ley's new bisdihyd- 240 N. J. Lawrence ropyrans which can be used to protect alcohols as dispiroketals have been reviewed this year.'79*'80 The year has seen the introduction of some interesting new methods for the synthesis of esters. For example alcohols (as part of a polyol array) can be rapidly converted to esters using an acid chloride in the presence of sub-stoichiometric catalytic dibutyltin oxide under microwave heating.18' Yamamoto et al. report the use of scandium triflate as a remarkable acylation catalyst.'82 Hindered alcohols including tertiary ones are conveniently acetylated using acetic anhydride in acetonitrile at room temperature in the presence of scandium triflate (0.1mol%) (82 -+ 83) [Scheme 23(a)].The process is reported to be superior to the commonly used basic catalysts 4-dimethylaminopyridine (DMAP) and tributylphosphine. Scandium triflate was also used by the same group to effect the esterification of alchohols with carboxylic acids in the presence of p-nitrobenzoic anhydride. A similar protocol for the direct combination of carboxylic acids and alcohols using octamethylcyclotetrasiloxane and Ti"Cl(OTf) (cat. 10mol%) has been described by Mukaiyama and co-~orkers.'~~ Barrett et a!. report a useful Mitsunobu-like procedure for the acylation of alcohols. '84 They found that secondary alcohols are converted into benzoate esters with inversion of configuration via sequential reaction with (chloromethylene)dimethylammoniumchloride and po- tassium benzoate.An efficient procedure for the acylation and perfluoroacylation of activated aromatic substrates under mild conditions uses (RCO),O-Me,S-BF,.' 85 N-Formylbenzotriazole prepared by the reaction of benzotriazole and formic acid in the presence of dicyclohexylcarbodiimide is a superior N-and 0-formylating agent. '86 Alcohols are regenerated from their corresponding sulfonyl (mesyl) ester by simple treatment with methylmagnesium bromide in THF.18' Phenols are often protected as ethers Lee et al. have described the use of alkyl halide-caesium carbonate in acetonitrile for the efficient alkylation of phenols.' 88 Dodge et a[.have observed that methyl ethers of phenols para to electron withdrawing groups are selectively removed by alkaline thiolate in the presence of other methyl phenol ethers.189 Lemaire and co-workers report an alternative catalytic method for the synthesis of ethers (84) -+ (86) [Scheme 23(b)],190 made reductively from alcohols and ketones by the hydrogenolysis of the intermediate hemiketal(85) using Pd/C as the catalyst. Yamashita and co-workers have developed the optically active diazacyclophos- phamide (87) as a reagent for the determination of absolute configuration of optically active alcohols and amines by 'H and 31P NMR.lgl Finally thiols may be protected as the corresponding methoxymethyl (MOM) derivative by treatment with bromochloromethane and methanol under phase-transfer catalysis with benzyltriethylammonium ch10ride.l~~ Ketones and Aldehydes By far the most common way of protecting a ketone or aldehyde is formation of an acetal or ketal.Acetals can be made using microwave irradiation and ethylene glycol in the presence of toluene-p-sulfonic acid ferric chloride or acidic alumina. '93 Tartaric acid has been used as the acid catalyst for the efficient acetalization of acid-sensitive a$-unsaturated aldehydes.194Deprotection of dimethyl acetals of r-halo aldehydes is achieved with a mixture of acetic anhydride-acetyl chloride-sodium acetate trihydrate in refluxing chloroform. 19' The dithioacetalization of ketones and aldehydes is Synthetic Methods 241 I I Ac20 (1.5 equiv.) Sc(OTf) * CH,CN room temp.1 h 'OAc (4 9. 2- (82) (83) O=P-N Ph C6H13 CI (87) (86)92% Scheme 23 catalysed by BiX (X = C1 Br I) or Bi,(S0,),.'96 The cleavage of acetals is catalysed by a variety of reagents including copper sulfate supported on silica gel,lg7 [MoO,(a~ac),]'~~ and NO in CCl and silica Dilute methanolic HC1 in anhydrous THF promotes the cleavage of acetals and ketals without affecting tert-butyldimethylsilyl ethers.," A variety of other derivatives of ketones and aldehydes are converted to the parent carbonyl compound by new protocols. For example enol ethers are converted to aldehydes by Bu,NF-BF,.OEt catalysed hydrolysis.20' Ketones are oxidatively regenerated under neutral conditions from tosylhydrazones by treatment with tetrabutylammonium peroxydisulfate,202 and from oximes by treatment with activated manganese dioxide.*' Although not strictly a functional group interconversion the deracemization of chiral ketones is nevertheless an important process.Fuji et al. have used a series of binaphthalene derivatives as novel chiral proton sources for the enantioselective protonation of en~lates.~' The carbamate (90)is a particularly good proton source for the protonation of magnesium enolates (88) -,(89) [Scheme 24(a)]. The Kemp's acid-derived imide (93) also acts as a chiral proton source for the asymmetric protonation of enolates (91) -+ (92) [Scheme 24(b)].,05 In this case the imide is used catalytically. The imide is regenerated by the slow addition of the bulky phenol (94) to the reaction mixture.Carboxylic Acids and Derivatives The dicyclopropylmethyl (DCPM)group has been used to protect carboxylic acids and N. J. Lawrence (89) 72-85% 90% de (90) Ph OSiMe3 ii (93) (0.1 ~uIv.) ' -78 "C --u-'' iii (94) (1 equiv.) -78 OC 2 h (911 (92) 72-85% 90% ee ' (93) OH Scheme 24 carboxamides. DCPM esters are hydrolysed exploiting the exceptional stability of the cyclopropylmethyl cation with trifluoroacetic acid (1 YOin CH2C1,).206 Sibi et a!. describe a convenient synthesis of N-methoxy-N-methylamides from carboxylic acids using inexpensive 2-chloro- l-methylpyridinium iodide as the coupling agent.207 Nitriles are selectively converted into amides on unactivated alumina at 60 0C.208 Chloro iminium salts derived in situ from amides react with the new sulfur transfer reagent benzyl triet h ylammonium tetra thiomol ybda te to give the corresponding thioamide in very high yield.209 The overall process is a good method for converting an amide to a thioamide.Kende and Liu report that trifluoroacetyl groups attached to a carbon atom devoid of hydrogen undergo facile high-yield conversion to nitriles by reaction with MeAlClNH followed by KOBu' (95) +(96)+(97) [Scheme 25(a)]."' Seebach et al. have developed a very efficient procedure for the enantioselective opening of meso anhydrides of cyclic dicarboxylic acids [Scheme 25(b)]. The product hemiesters provide very useful building blocks for further elaboration. For example Synthetic Methods 243 Ph PcF3 phkcF3 MeAICINH2 BubK ph&c'N (a) I I I Me Me (95) (96) (97) Me 91% (100) Ar = p-CIOHI Scheme 25 Scheme 26 the anhydride (98)is converted to the isopropyl ester (99)upon reaction with the chiral Lewis acid r-Diazo esters (103),valuable synthetic intermediates can be prepared simply from an ester (101) by benzoylation to give an a-benzoyl ester (102) followed by diazo transfer (Scheme 26).2'2 A similar process transforms 2-benzoyl ketones via the same debenzoylation-diazo transfer strategy.213 Amines and phosphines The tetrachlorophthaloyl group has been used by Fraser-Reid and co-workers to protect amines.It is removed more easily than a phthaloyl group by simply heating with excess ethylenediamine in ethanol at 50 0C.214Davis and Gallagher introduce the tetraethyldisilaisoindoline (TEDI) group (104) (Figure 3) as a chromatographically (silica) stable group for the protection of primary amine~.~" Low-valent titanium can be used to facilitate the cleavage of N-allyl- and N-benzyl-amines.216 N,N-Di- allylamines are selectively deprotected using a Pdo catalyst and 2-thiobenzoic acid as the n~cleophile.~~~ The first ally1 group is cleaved at room temperature whilst the N.J.Lawrence ,Si Et \Et Fig. 3 second is cleaved at 60 "C. The pyridine-2-sulfonyl group is used to protect amines. The N-S bond is cleaved under mild conditions (SmI, room temp. THF) unlike that of the corresponding N-phenylsulfonylamines which requires much harsher conditions.21 * Gage and Wagner have found that treatment of a variety of aromatic amines with isobutylene in 1,4-dioxane in a pressure tube (90-140 "C) in the presence of HBr (as.48%) conveniently gives the N-tert-butyl aromatic amine.219 Trichloroethoxycar- bony1 (TROC) protected amines are efficiently reductively cleaved under neutral conditions with a cadmium-lead couple.220 The diethoxymethyl group is a useful nitrogen protecting group for lactams and amides. Treatment of lactams and amides with triethyl orthoformate leads to the N-diethoxymethyl substituted derivatives.221 The diethoxymethyl group is easily removed by subsequent treatment with trif- luoroacetic acid and NaOH. Amines are made from alcohols by a new protocol developed by Knight and co-workers where N-benzyltriflamide is used as a novel Mitsunobu nucleophile.222 Various primary and secondary alkyl azides potential precursors to amines have been synthesized in high yields by the fluoride anion induced S,2 substitution reactions of the corresponding alkyl halides phosphates or toluene-p-sulfonates (tosylates) and trimethylsilyl a~ide.~~~ Phosphines can be protected by formation of a tungsten pentacarbonyl complex [RPh,P.W(CO),] which is stable to alkylati~n.~~~ Aliphatic isocyanates react success- ively with mercury acetate and sodium borohydride to give aliphatic primary amine~.~~~ The selective mono-deprotection of phosphate phosphite phosphonate and phosphoramide benzyl esters is effected by stoichiometric amounts of 1,4-diazabicyclo[2.2.2]octane (DABCO) or quinuclidine in refluxing toluene.226 Ahman and Somfai report a simple procedure for the efficient preparation of the widely used base potassium bis(trimethylsily1)amide (KHMDS).227When a mixture of bis(trimethylsily1)amine and potassium in THF is sonicated for several hours a good yield of KHMDS is reliably obtained.KHMDS reacts with alkyl bromides iodides tosylates benzylic chlorides and allylic chlorides to give the corresponding N,N-bis(trimethylsily1) amines in high yields. Subsequent deprotection of the trimethylsilyl groups is performed under mildly acidic conditions to afford primary amines.228 A related procedure generates arylamines by the palladium catalysed coupling of KHMDS and an aryl halide.229 6 Organo Halides The year has seen many new methods for the synthesis of halogen-containing organic compounds many of which are included in a recent review.230 Synthetic Methods 245 Fluoro Compounds General organofluorine ~hemistry~~',~~~ and the asymmetric synthesis of fluoro- organic compounds233 has been reviewed this year as has the use of xenon difluor- ide234 and N-fluoropyridinium salts235 in synthesis.Perfluorohexane has been used as a replacement of carbon tetrachloride due to be phased-out as part of the Montreal Protocol as the solvent for bromination reactions. Perfluorohexane offers the advantages of being non-toxic non-ozone-depleting and readily a~ailable.~ 36 Fluorine is generally perceived to be too reactive to exhibit useful selectivity.However Chambers' group has demonstrated that elemental fluorine has great potential as a selective reagent for organic synthesis. For example elemental fluorine has been used as an enabler for the generation of powerful electrophiles; a combination offluorine diluted in nitrogen and iodine creates a system that will iodinate unactivated aromatic compounds in sulfuric acid.2 1,3-Dicarbonyl compounds react directly with elemental fluorine at room temperature to give the corresponding 2-fluoro derivatives.238 The electrophilic fluorination of aromatic compounds is achieved by the use of elemental fluorine in formic acid.239 In addition diaryl- 1,3-dithiolanes are converted into gem-difluoromethylene compounds by a combination of elemental fluorine and iodine.240 Aryltrifluoromethyl ketones are prepared conveniently by the palladium(0) catalyzed cross-coupling of aryltrialkyltin reagents-derived from aryl halides-with trifluoroacetic anhydride.241 Several uses of electrophilic fluorinating reagents have been described this year.Davis et al. report the synthesis of N-fluoro-o-benzenedisulfonimide (1054 and describe its use as a selective electrophilic fluorinating agent.242 It has been used to fluorinate enolates silyl enol ethers (106)-+(107) P-dicarbonyl compounds and aromatic compounds. Umemoto and Tomizawa have developed a series of N-fluoropyridinium- 2-sulfonates including (108)and illustrated their potential as highly selective fluorina- tion agents by their reaction with a variety of nucleophilic substrates such as activated aromatics enol trialkylsilyl and alkyl ethers [e.g.(109) -+ (1lo)] [Scheme 27(a)] activated olefins and sulfides.243 Poss and Shia have described the ./-fluorination of a$-unsaturated ketones [similar to the transformation (109) + (1 lo)] using N-fluorobenzenesulfonimide (1 11) [Scheme 27(b)].244 In their protocol the r,B-un- saturated ketone is first converted to a conjugated boron enolate. Many reports have detailed uses of the new electrophilic fluorinating agent Selectfluor F-TEDA-BF,245 (1 12) including ones describing the fluoro-decarboxylation of x-pyrrolecarb~xylic~~~ and x-furoic the fluorination of P-dicarbonyl compounds 248 nucleo~ides~~~ and substituted pyrimidine^.^^' The reagent has also been used to effect the conversion of 1-phenyl-substituted acetylenes to r,r-difluoro ketones.251 The related compound Accufluor NFTh (1 13) is reported to be highly effective for the fluoro-methoxylation and fluoro-acetylation of phenyl substituted alkene~.~~~ The novel fluoride source tetrabutylammonium (triphenylsily1)difluorosilicate (TBAT) is an excellent reagent for the nucleophilic substitution of halides mesylates and triflate~.~~~ Chloro Compounds The combination of trimethylsilyl chloride (TMSCl) and DMSO provides a new reagent system for the quick convenient and inexpensive conversion of alcohols to N.J. Lawrence TMSO 0 Me (105) CH&I, room temp. 2.5 h (106) (107) 86% room temp. 90 h * TIPSO 0 F (109) (110) 93% 3.8:l) I F (112)X=CH2CI (113)X=OH Scheme 27 Synthetic Methods chlorides.254 The efficient reverse conversion of an alkyl halide to an alcohol is achieved using triethylammonium formate to give first an alkylformate followed by acid or base ~atalysed-hydrolysis.~~~ Bromo Compounds Carrefio et a/.have shown that the use of N-bromosuccinimide (NBS) in acetonitrile provides an efficient method for the bromination of methoxybenzenes and naphtha- lenes with absence of side-chain reactions.256 x-Bromination of unsaturated ketones and dibromination of alkenes is effected by the polymeric bromine source poly(4- methyl-5-vinylthiazolium) hydrotribromide (114).257 Iodo Compounds Alcohols are converted directly to alkyl iodides (with inversion of stereochemistry) by reaction with iodine in refluxing light petroleum (60-80 0C).258 The method is mild and efficient and most importantly does not require an expensive iodine precursor.Iodination of phenols is achieved efficiently by the use of bis(syrn-collidine)iodine(I) hexafluor~phosphate.~~~ The same reagent also serves as an excellent source of ‘I” in the synthesis of oxepanes260 from hept-6-en-1-01s and the iodoacetylenes261 from terminal acetylenes. 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ISSN:0069-3030    

DOI:10.1039/OC9959200221

出版商:RSC    

年代:1995

数据来源: RSC