R1 N R2 N2 H CO2Et N R1 CO2Et 42–93% i or ii or iii 3 2 1 R1 = Ar Bu t R2 = Ar PhCH2 + R2 Scheme 1 Reagents i BF 3 ·Et 2 O; ii AlCl 3 ; iii TiCl 4 6 Heterocyclic compounds By Peter W. Sheldrake SmithKline Beecham Pharmaceuticals Old Powder Mills Nr Leigh Tonbridge Kent UK TN11 9AN 1 Three-membered rings Formation of aziridines by the addition of a diazo compound to an imine has been reported by several authors. For example imines 1 react with ethyl diazoacetate 2 in the presence of a Lewis acid catalyst to give aziridines 3 usually as a mixture of cis- and trans-isomers,1 although conditions are reported which result in formation of only the cis-isomer (Scheme 1). 1,3,5-Triarylhexahydro-1,3,5-triazines (in e§ect formaldehyde imines) react with 2 the preferred catalyst in this case being tin(IV) chloride giving 3 R1\H in 50–86% yield.2 The reaction of imine 4 with phenyldiazomethane was carried out using rhodium acetate and 20 mol%of the chiral auxiliary 5.The predominant product was (R,R)-6 in 97% enantiomeric excess; it is unfortunate that it was accompanied by the corresponding cis-isomer (Scheme 2).3 A more complex example was provided by the conversion of 7 into 8 using rhodium acetate4 (Scheme 3). The diazabicyclo[3.1.0]hexane produced is envisaged as an intermediate in mitomycin synthesis. The rhodium acetate catalysed decomposition of N-(p-nitrophenylsulfonyl) iminophenyliodinane (NsN–– IPh) in the presence of olefins 9 a§ords aziridines 10 in up to 85% yield. For the most part olefin geometry is retained though there is partial loss of stereospecifity using cis-stilbene (Scheme 4).Chiral auxiliaries were investigated demonstrating potential for asymmetric synthesis.5 The bromo-amide 11 condensed with the diphenylphosphinylimine 12 gave a single Royal Society of Chemistry–Annual Reports–Book B 155 N Ph SO2(CH2)2SiMe3 N SO2(CH2)2SiMe3 Ph Ph O S 55% i 6 5 4 Scheme 2 Reagents i PhCHN 2 Rh 2 (OAc) 4 82% i 8 7 N H N OMe COMe N2 O H H H OMe O COMe N N Scheme 3 Reagents i Rh 2 (OAc) 4 9 10 i up to 85% H R1 R3 R2 Ns N R1 R2 H R3 Scheme 4 Reagents i NsN––IPh Rh 2 (OAc) 4 i 11 12 13 71% S O2 N Br O N N S O2 O H H Ph POPh2 N Ph POPh2 Scheme 5 Reagents i LiN(SiMe 3 ) 2 diastereoisomer of aziridine 13 in an aza-Darzens reaction (Scheme 5). The sultam can be hydrolysed using lithium hydroxide.6 Bromide 14 R\Ph condenses with a sulfonylimine 16 using a fairly large catalytic quantity of dimethyl sulfide with potassium carbonate in acetonitrile.The cis/trans ratio of the product 17 R\Ph was variable7 (Scheme 6). The ylide from 15 R\Ph is the intermediate. The isolated salt 15 R\CO 2 Et reacts in the same way to give 17 R\CO 2 Et; some stereoselectivity was achieved favouring the cis-product.8 Oxiranes 18 react with iminophosphoranes and a zinc halide catalyst to give the 156 PeterW. Sheldrake R = Ph CO2Et + Br– + 14 15 16 17 i ii N R Ar SO2Ar2 R R Br S Me2 Ar N SO2Ar2 Scheme 6 Reagents i,Me 2 S; ii K 2 CO 3 up to 84% i 19 18 R1 = aryl alkyl R2,3,4 = alkyl H R5 = Ph Pri O N R1 R2 R4 R3 R2 R1 R3 R4 R5 Scheme 7 Reagents i Ph 3 P––NR5 ZnCl 2 R1 R2 = alkyl 64–92% i 21 20 R1 OR2 N O TosO R1 CO2R2 N Scheme 8 Reagents i Et 3 N corresponding aziridines 19 (Scheme 7).Oxiranes with one CH 2 and those spiro to rings were found to be the most reactive.9 Tosylated* oximes 20 are e¶ciently cyclised by triethylamine in dichloromethane to give 2H-azirinecarboxylic esters 21 (Scheme 8). When quinidine was used as the base the (R) product was obtained with 81% enantiomeric excess but in only 40% yield. Borohydride reduction of 21 was found to give only the cis-aziridine.10 Irradiation of 22 in acetone below [60 °C caused decarbonylation to give a cyclohexadiene which by photofragmentation gave a phthalimide and N-ethoxycarbonyl Dewar pyrrole 23 (Scheme 9). This was demonstrated by carrying out the irradiation in the presence of 1,3-diphenylisobenzofuran thereby trapping 23 as its Diels–Alder adduct. Above[60 °C only 1-(ethoxycarbonyl)pyrrole was observed.11 The Darzens condensation of (-)-8-phenylmenthyl chloroacetate 24 with symmetrical ketones a§orded glycidic esters 25 in 77–96% diastereoisomeric excess (de) (Scheme 10).Using unsymmetrical ketones the (Z)-glycidic ester was the predominant product again formed in high de (93% for acetophenone).12 The sulfonium salt 26 is readily prepared from Eliel’s oxathiane by alkylation with benzyl alcohol–trif- *Tosyl (Tos)\toluene-p-sulfonyl. 157 Heterocyclic compounds i 23 22 NCO2Et NMe O O NCO2Et CO Et Ph Ph Et Scheme 9 Reagents i light 254nm + R* = (–)-8-phenylmenthyl R1 R2 = alkyl Ph 24 25 39–81% R1 R2 O R1 R2 H CO2R* O i OR* O Cl Scheme 10 Reagents i ButOK + OTf – i 38–58% O S Ph O H Ar Ph H 26 27 Scheme 11 Reagents i ArCHO NaH luoromethanesulfonic anhydride–pyridine.Ylide generation using sodium hydride and reaction with an aromatic aldehyde gave epoxides 27 in 97.9–99.9% enantiomeric excess (ee) though in 38–58% yield (Scheme 11). The auxiliary was recovered in good yield.13 The combination of nonafluorobutanesulfonyl fluoride and 1,8-diazabicyclo[5.4.0]- undec-7-ene (DBU) has been reported as a reagent for converting 1,2-diols into epoxides. Good yields were obtained even in sterically demanding situations.14 The dynamic kinetic resolution of epichlorohydrin 28 has been achieved using enantioselective ring opening with azidotrimethylsilane catalysed by chromium(III) azide complex 29 (Scheme 12). 3-Azido-1-chloro-2-(trimethylsilyloxy)propane 30 was obtained in 76% yield and in 97% enantiomeric excess.15 In a study of metallating reagents for aromatic halides epoxide 31 was reacted at [78 °C with the zincate prepared from methyllithium (3 equiv.) and zinc thiocyanate to give 32 the product of a 5-exo ring closure along with a little 33 (Scheme 13).By contrast the corresponding cuprate prepared using copper(I) cyanide gave only 33 the 6-endo product. When chiral 31 was used the enantiomeric purity was unchanged in either reaction.16 A method has been reported for preparing solutions of dimethyldioxirane in chlorinated solvents at four to five times the concentration usually obtained in acetone. The more concentrated solutions were found to be no less stable.17 The ketone 34 derived 158 PeterW. Sheldrake 28 29 30 i ii Cl O Cl N3 OTMS O But But N But But N H O H Cr N3 Scheme 12 Reagents i 2mol% 29; ii 0.5 equiv.TMSN 3 by slow addition Scheme 13 Reagents i Li 3 ZnMe 3 (SCN) 2 ; ii Li 3 Cu(CN)Me 3 34 35 O O O O O O Cl Cl O O O O O O from fructose has been used with Oxone' in the asymmetric epoxidation of trans olefins and trisubstituted olefins. Enantiomeric excesses up to 95% were recorded.18 Dioxirane 35 prepared in situ from the ketone and Oxone' epoxidises trans stilbene in 95% yield and 76% enantiomeric excess.19 159 Heterocyclic compounds 36 37a X = I 37b X = OAc i HO Ar X O Ar Scheme 14 Reagents i Ag(collidine) 2 ClO 4 I 2 39 38 80–86% i X = Ph PhS FC6H4 CH2=CH C4H9 O O X O C4 H9 OH X Scheme 15 Reagents i BuLi Pr* 2 NH ButOK ii i 42 41 40 N N N But Ac Cl Cl Scheme 16 Reagents i Ac 2 O BF 3 ·OEt 2 ; ii KOH 44 43 N TBDMSO OAc H H O H N H O H H TBDMSO CO2H Me 2 Four-membered rings Iodocyclisation of dienols 36 gave oxetanes 37a predominantly (Scheme 14).The products were not conveniently separable but after displacement of iodide by acetate 37b was found to contain less than 10% of the alternative tetrahydrofuran product.20 Treatment of oxiranyl ethers 38 with a complex base forms an internal nucleophile that attacks the oxirane to give oxetanes 39 (Scheme 15). In the products the 2,3-anti configuration predominated except where X is a phenylthio group.21 1-Acetyl-3-chloroazetidine 41 was obtained by treatment of the tertiary amine 40 with acetic anhydride–boron trifluoride. Hydrolysis of the amide led to a transannular cyclisation giving azabicyclo[1.1.0]butane 42 (Scheme 16). In an NMRexperiment the 160 PeterW. Sheldrake R1 = Et i 45 46 N R1 O C6H4 OMe N C6H4OMe Ph S Ar O Br R1 SPh Ar OAc Scheme 17 Reagents i Bu 3 SnH AIBN i 30–70% R1 = Me BnO H R2 = Me H BnO R3 = Ph Me 47 48 X = Br I N R3 X H R2 R1 O O R1 R2 H N R3 Scheme 18 Reagents i Bu 3 SnH AIBN R1R2NH R1 R2 = H lower alkyl 49 50 51 N OTos Me O HO Me N OTos N H Me O R1R2N Scheme 19 Reagents i R1R2NH yield of 42 was quantitative.Reaction of 42 with ethyl chloroformate gave 1- ethoxycarbonyl-3-chloroazetidine.22 On the b-lactams the preparations of 43 and 44 pivotal intermediates for 1-b- methyl carbapenem synthesis have been reviewed.23 More examples of radical reactions in the b-lactam area are now appearing. Treatment of bromoamides 45 with tributyltin hydride and AIBN gave the b-lactam 46 (Scheme 17).24 In the case of 47 the same reagents were used to close the appended ring giving 48 (Scheme 18).25 The N-tosyloxyazetidinone 49 underwent an unusual addition of simple secondary amines with loss of tosylate.To explain this enolisation to 50 is suggested with attack of the amine by the mechanism shown in Scheme 19 leading to 51. In some cases by-products showed that nucleophilic attack can occur at all three of the ring carbon atoms.26 4-Formyl-b-lactams 52 well known from standard synthetic methodology are readily converted into formate esters 53 (Scheme 20). In a few cases oxidation to the 4-carboxylic acid was observed.27 161 Heterocyclic compounds 55 54 i ( )n ( )n N N O O O O Scheme 21 Reagents i Mo(––CHCMe 2 Ph)(––NC 6 H 3 Pr* 2 )[OCMe(CF 3 ) 2 ] 2 57 56 i ii N N CO2CHPh2 S S O O H H TBDMSO TBDMSO S S OH CO2CHPh2 H H Scheme 22 Reagents i MeSO 2 Cl Et 3 N; ii heat Na+ i 58 59 N S N O O H H H H TBDMSO TBDMSO O CO2CH2CH=CH2 O – CO2CH2CH=CH2 Scheme 23 Reagents i Ph 3 P NaH Scheme 20 Reagents i MCPBA A b-lactam will withstand the conditions under which an olefin metathesis reaction is used to close another ring as exemplified by the conversion of 54 into 55 (Scheme 21).28 Cyclisation of alcohol 56 was achieved by generation of an acyliminium ion with methanesulfonyl chloride and interaction with a ketene dithioacetal terminator to give 57 (Scheme 22).The ketene dithioacetal was removed by a singlet oxygen mediated cleavage to give the corresponding ketone.29 A new route to carbapenems relies on an Eschenmoser ring contraction applied to 1,3-thiazinones such as 58 conveniently prepared from thioesters of 44.Extrusion of sulfur on treatment with sodium hydride–triphenylphosphine gives enolate 59 162 PeterW. Sheldrake Scheme 24 Reagents i light 62 63 64 65 i ii iii iv N H H O OH MeO2C H N H N H H H N N Scheme 25 Reagents i soda lime; ii LiAlH 4 ; iii H 2 O 2 ; iv Bu5Li (Scheme 23).30 Capture of the enolate by diphenylphosphoryl chloride to permit subsequent displacement of the oxygen by a thiol was already known. Thioamide 60 is not chiral but its crystals are. When the powdered crystals are placed between Pyrex plates and irradiated azetidinethione 61 is formed e¶ciently (96% yield at 58% conversion) as a crystal and exhibits 94% enantiomeric excess (Scheme 24). The phenomenon arises from the chiral environment of the crystal lattice and minimal molecular motion of the intermediate radicals.31 3 Five-membered rings Amide 62 is easily available from a 2,5-disubstituted pyrrolidine.Closing the final ring using soda lime and reductive elimination of the alcohol in 63 gave the pleasingly symmetric amine 64 shown to be a relatively strong base though its precise pK! was not determined. The N-oxide of 64 treated with tert-butyllithium gave an azomethine which produced the remarkable dimer 65 (Scheme 25).32 Iodocyclisation of E-homoallylic tosylamides 66 leads to pyrrolidines 67 and/or 68. In the absence of base the product is 68; using potassium carbonate a strong preference ([25 1) for 67 was found (Scheme 26). The apparent violation of Baldwin’s rules (the overall process being e§ectively 5-endo-trig) can be explained by the reaction being electrophile rather than nucleophile driven.33 Asymmetric deprotonation of Boc-protected amines 69 using sec-butyllithium–([)- 163 Heterocyclic compounds i R1 R2 = H Me Et Ph 66 67 68 N N NH R1 R2 Tos Tos Tos R1 R1 R2 I R2 I Scheme 26 Reagents i I 2 base Scheme 27 Reagents i BusLi (-)-sparteine 72 71 67–85% R1 R2 = H Me MeO i ii N R1 R2 Br N E R1 R2 Scheme 28 Reagents i BuLi; ii electrophile E 74 73 i ii N SnBu3 N H E Scheme 29 Reagents i BuLi; ii electrophile E sparteine in toluene at [78 °C (the choice of solvent being important) led to cyclisation and formation of the (S)-2-arylpyrrolidines 70 in up to 75% yield and 96% enantiomeric excess (Scheme 27).34 Transmetallation of the allylated bromoanilines 71 with butyllithium brought about anionic cyclisation to indolines 72 where the intermediate cyclised carbanion could be captured with various electrophiles35 (Scheme 28).Oxidation of the products 72 to indoles was also reported.36 The stannane 73 has been used in a similar fashion (Scheme 29). Where the electrophile was a proton the product 74 is pseudoheliotridane. Note that the stereochemistry is preserved in the reaction.37 The preparation of 3-substituted pyrrolidines using the same principle was also reported.38 Radical ring closure reactions are useful for forming pyrrolidine rings. The (phenyl- 164 PeterW. Sheldrake 78 77 i I – I – i 76 75 N+ SePh Me Me N+ Me Me N+ N+ I Scheme 30 Reagents i Bu 3 SnH initiator R = Me Ph H X = Cl Br I 80 79 i N Bn R N R X O CO2Me O CO2 Me Bn Scheme 31 Reagents i Bu 3 SnH AIBN R1 = H Ph R2 = H alkyl Ph i ii 81 82 R1 CO2Me NH Bn N Bn CO2Me R1 R2 Bt N R1 R2 CO2Me Bn Scheme 32 Reagents i R2CHO benzotriazole (Bt); ii SmI 2 selenenylethyl)allylammonium salt 75 illustrates the tactic for forming the 3,4 bond39 (Scheme 30); other more complex examples were described.40 Using homoallyl iodomethylammonium salts such as 77 the pyrrolidine 2,3 bond was formed.41 Radicals formed from a-haloamides 79 undergo a 5-endo-trig closure to give pyrrolidinones 80 (Scheme 31).42 Amines 81 condense with an aldehyde and benzotriazole (Bt) giving the adducts; subsequent treatment with samarium iodide yields pyrrolidines 83 in 51–70% yield (Scheme 32).Where the possibility exists the reactions produce mixtures of diastereoisomers. 43 Cyclisation of unsaturated sulfonamides such as 83 induced by palladium acetate –oxygen gives products incorporating an allylamine moiety e.g.84 (Scheme 33). 165 Heterocyclic compounds i i 93% 86% 83 84 85 86 NH N Tos Tos Tos HN N Tos Scheme 33 Reagents i Pd(OAc) 2 O 2 DMSO 87 i ii 88 89 COCF3 N N COCF3 N OTBDMS COCF3 OTBDMS OTBDMS Scheme 34 Reagents i ruthenium carbene catalyst; ii molybdenum carbene catalyst Scheme 35 Reagents i NaOEt; ii LDA Similarly 85 gives the dihydroquinoline 86. This is in contrast to the previously reported cyclisation of 2-allylaniline with palladium chloride which gave 2-methylindole. 44 The triene 87 is set up to undergo pyrrolidine formation in an olefin metathesis reaction. A ruthenium carbene catalyst produced the 2,5-trans disubstituted product 88 whereas a molybdenum carbene catalyst gave the corresponding cis-isomer 89 (Scheme 34).Yields were high in each case.45 When aziridine 90 was exposed to a catalytic quantity of sodium ethoxide in ethanol the internal malonate anion opened the aziridine to give pyrrolidinone 91 (Scheme 35). In contrast the use of excess lithium diisopropylamine (LDA) brought about attack by 166 PeterW. Sheldrake 98 R = alkyl PhCH2 H 99 i ii 71–86% N N Boc N Boc N O O R Scheme 37 Reagents i Na NH 3 ; ii RX 95 94 93 R1 = Cl Me MeO NO2 ; R2 = alkyl iii i ii N N Cl Cl N CHO O O R2 R1 R1 R1 R2 Ar R2 R2 Scheme 36 Reagents i (COCl) 2 ; ii Pr* 2 NEt; iii Br 2 97 96 N O O N Cl N O Cl Cl the amide nitrogen on the tert-butyloxycarbonyl group generating the bicycle 92.46 On treatment with oxalyl chloride followed by Hu� nig’s base N-formylanilines gave intermediates 94 which on further treatment with bromine formed isatins 95 (Scheme 36).The reaction also succeeded with N-formylindoline giving a tricyclic product.47 Phosphorus pentachloride treatment of isatin itself has always been said to give &lsquosatin chloride’ 96. This compound has now been shown48 to be a ‘phantom’ and the true structure of the product is 97. This discovery is remarkably reminiscent of the ‘misbehaviour’ of pyrrolidin-2-one with phosphorus pentachloride.49 The Birch reduction is applicable to electron deficient pyrroles such as 98. It was shown that the intermediate anion can be protonated or trapped with an alkylating agent to give 99 (Scheme 37).50 An attempted double acetamidomalonate displacement on 1,4-dichlorobut-2-yne using excess base gave pyrrole 100.It was postulated that the reaction proceeds via intermediates 101 and 102 (Scheme 38).51 Treatment of the vinylamidinium salt 103 with sarcosine ethyl ester and base produced 3-aryl-1-methylpyrrole-2-carboxylate 104 (Scheme 39). Interestingly use of ethyl glycinate gave the 2,5-disubstituted pyrrole 10552 Titanium tetrachloride mediated condensation of silyl enol ethers 106 and hydrazones 107 followed by acid catalysed cyclisation and removal of the 167 Heterocyclic compounds + 100 101 102 i NH CH3 CO2Et Ac NH CO2Et CO2Et Cl Cl O NH C C H2C CO2Et CO2Et O N CO2Et Scheme 38 Reagents i NaOEt + X – i ii 103 104 105 Me2N Ar NMe2 NH CO2Et Ar N Me Ar CO2Et Scheme 39 Reagents i MeN(H)CH 2 CO 2 Et NaH DMF; ii H 2 NCH 2 CO 2 Et NaH + R1 R2 R3 = lower alkyl aryl 106 107 108 i ii iii 33–65% NH R1 R2 R3 R1 OSiMe3 R2 N NMe2 R3 AcO Scheme 40 Reagents i TiCl 4 ; ii TsOH; iii Na NH 3 dimethylamino group with sodium–liquid ammonia led to 2,3,4-trisubstituted pyrroles 108 (Scheme 40),53 in an overall yield of 33–65%.The position of acetylation of 3-substituted 1-phenylsulfonylpyrroles 109 depends on the catalyst. Boron trifluoride gave substitution at the 5-position but use of aluminium chloride led to 2-acylation forming 110 and 111 respectively (Scheme 41).54 N-Arylalkenesulfinamides 112 were prepared from N-sulfonylarenamines and alkenyllithiums. On heating they undergo a [3,3] rearrangement to 113 which cyclises with loss of sulfinic acid to give indoles 114 in up to 83% yield (Scheme 42).55 Tolylsulfonyl derivatives 115 of a number of heterocycles are converted into the corresponding stannanes 116 on treatment with tributyltin hydride (Scheme 43).Examples were given for pyrrole indole pyrazole furan thiophene and their benzo derivatives.56 168 PeterW. Sheldrake i ii 109 110 111 N R SO2Ph N SO2Ph R N R PhSO2 O O Scheme 41 Reagents i Ac 2 O BF 3 ·OEt 2 ; ii Ac 2 O AlCl 3 i R1 R2 = H Me (CH2)4 112 113 114 NH S R2 R1 O N H R1 NH S+ O – R2 R1 R2 Scheme 42 Reagents i heat i X = O S N 115 116 X SnBu3 SO2Tol X Scheme 43 Reagents i Bu 3 SnH AIBN i X = NH; R = H Me Cl Br X = O S; R = H 117 118 X CO2H CO2H X R R Cl CHO Scheme 44 Reagents i POCl 3 DMF Reaction of diacids 117 with DMF–phosphoryl chloride gave 118; the reaction being equally applicable to the synthesis of indoles benzofurans and benzothiophenes (Scheme 44).57 Reaction of acetylenic diols 119 with iodine induced (electrophile driven) 5-endo-dig cyclisation to iodofurans 120 (Scheme 45).58 Reaction of thiophenes such as 121 with acetic anhydride–toluene-p-sulfonic acid gave thieno[2,3-c]furans in this example 122 (Scheme 46).The products are reactive dienophiles; it is easy to contrive examples where the ensuing 4]2 reaction is intramolecular. Furo[3,4-b]indoles have been prepared by the same methodology.59 The combination of phenyliodonium acetate–iodine cyclises alcohols 123 via an alkoxyl radical forming the aryl–oxygen bond of ethers 124 (Scheme 47). The starting alcohols can be primary secondary or tertiary.60 Aryl–oxygen bond formation was 169 Heterocyclic compounds i 121 122 79% S S O SEt Ph S+ Ph O O – Et Scheme 46 Reagents i Ac 2 O TsOH 22–70% i 124 123 n = 1,2,3 R1 R2 = H alkyl ( ) n ( ) n R2 OH R1 O R1 R2 Scheme 47 Reagents i PhI(O 2 CCH 3 ) 2 I 2 up to 93% i 126 125 n = 1,2,3 ( ) n ( ) n Me Me OH O Br Me Me Scheme 48 Reagents i Pd(OAc) 2 Tol-BINAP K 2 CO 3 120 119 R1 = Ph Me CO2Me; R2 = Bu Ph i 47–88% O R1 R2 I R2 OH R1 HO Scheme 45 Reagents i I 2 NaHCO 3 brought about by palladium(0) catalysis in the conversion of 125 to 126 (Scheme 48).All reported examples except one were of tertiary alcohols; the sole case of a secondary alcohol gave a 32% yield.61 Construction of a cyclic ether by an addition–elimination reaction on the iodotolylsulfonylalkene moiety of 127 is a simple but e§ective tactic (Scheme 49). Note that in the five-membered product 128 the double bond remained exocyclic but moved into the six-membered ring of product 129.62 Treatment of 130 with caesium fluoride gave the carbonyl ylide 131 which reacted with alkenes allenes aldehydes ketones and imines.63 Bis(chloroalkyl)ethers 132 are precursors of unstabilised carbonyl ylides 133 samarium diiodide being the reagent.64 These carbonyl ylides were reacted with alkenes and alkynes (Scheme 50).Treatment of thiophene 134 with potassium fluoride e§ected an elimination of both 170 PeterW. Sheldrake 129 128 127 n = 2 i n = 1 i ( ) n I O O SO2Tol HO SO2Tol SO2Tol Scheme 49 Reagents i KN(SiMe 3 ) 2 R1 R2 = alkyl 133 132 ii _ _ i 131 130 _ Ar O Cl Me3Si Ar O+ Cl O R2 R1 Cl O+ R2 R1 R1 O+ R2 Scheme 50 Reagents i CsF; ii Sm I 2 136 135 134 ii i S S Me3Si I(OTf) Ph S Scheme 51 Reagents i KF 18-crown-6; ii C 6 H 6 substituents to give a species depicted (unsatisfactorily) as 135 (Scheme 51).It is highly reactive giving 136 in benzene and reacting with furan or anthracene in a 4]2 manner. With 2,3-dimethylbuta-1,3-diene it underwent a 2]2 addition and an ene reaction.65 Diallyl sulfide undergoes an olefin metathesis reaction with a molybdenum carbene catalyst giving 2,5-dihydrothiophene 137 in essentially quantitative yield (Scheme 52). Diallyl ether behaved in the same way.66 Sulfides 138 n\1 form dihydrobenzothiophenes 139 on treatment with phenyliodonium trifluoracetate. The reaction is capable of producing larger rings (Scheme 53).67a The same reagents were used for intramolecular aryl–aryl bond formation where the chain linking the aromatic groups may optionally contain a heteroatom.67b Pyrazoles 141 were formed from aromatic carboxylic acid chlorides 140 in a one-pot 171 Heterocyclic compounds 137 i S S Scheme 52 Reagents i Mo(––CHCMe 2 Ph)(––NC 6 H 3 Pr* 2 )[OCMe(CF 3 ) 2 ] 2 i ii 139 n = 1,2,3 x = 0,1,2 138 ( ) n ( ) n S S R R Bn MeO MeO (MeO) x (MeO) x Scheme 53 Reagents i PhI(OCOCF 3 ) 2 BF 3 ·OEt 2 ; ii MeNH 2 141 140 21–58% i ii iii Ar Cl O N N Ar CN NH2 R Scheme 54 Reagents i CH 2 (CN) 2 NaH; ii Me 2 SO 4 ; iii RNHNH 2 Et 3 N R = alkyl aryl 143 142 42–88% i N N N N Me Me Me Me R O Scheme 55 Reagents i CO CH 2 ––CHR Ru 3 (CO) 12 three-step procedure summarised in Scheme 54.Although more than one regioisomer is in principle possible only that shown was formed the regiochemistry being established by X-ray crystallography.68 The reaction of 1,2-dimethylimidazole 142 with an alkene and carbon monoxide catalysed by triruthenium dodecacarbonyl gave the acylated imidazole 143 in 68% yield (Scheme 55).There are relatively few approaches to such acylated imidazoles.69 Treatment of N-butyl-2,6-dinitroaniline 144 with sodium hydroxide gave the benzimidazole N-oxide 145 in 95% yield (Scheme 56). Both nitro groups are needed and displacement of the butylamino group by hydroxide can be a competing reaction; otherwise the authors did not comment on the reaction mechanism.70 The 4-chloro-2-oxopyridine-3-carbaldehydes 146 react with azide by chloride displacement and cyclisation giving the 5,6-dimethylisoxazolo[4,3-c]pyridin-4(5H)-ones 147 (Scheme 57). When R\Me the intermediate azido compound was isolable.71 The 172 PeterW. Sheldrake Scheme 56 Reagents i NaOH R = H Me 146 i 147 N N O N Cl Me O R O Me Me Me O R Scheme 57 Reagents i NaN 3 100% 96% 150 149 148 ii i N N N N O Ph O Ph Ph O N3 NH2 Scheme 58 Reagents i PhI (OAc) 2 ; ii heat similar 3-phenylisoxazolo[3,4-c]pyridine 149 was prepared by treatment of 3-amino- 4-benzoylpyridine 148 with phenyliodonium acetate or by thermolysis of the azide 150 (Scheme 58).72 A novel synthesis of 3-amino-1,2-benzisoxazoles 152 involved a nucleophilic aromatic substitution reaction by hydroxamate anion on the activated ortho substituent in benzonitriles 151 followed by ring closure and deacetylation (Scheme 59).This procedure73 is claimed to be superior to other methods. It has not usually been possible to use 2-lithiooxazoles synthetically as they ring open to form an isonitriloenolate.Now it has been reported that the borane complexes of a number of 5-substituted oxazoles can be deprotonated reacted with an electrophile and recovered from the complex to give the 2-substituted oxazoles in good yield.74 A usable degree of asymmetric induction in the reaction of a nitrone and allyl alcohol was reported when the reaction was carried out as indicated in Scheme 60. The chirality is derived from a tartrate ester–zinc complex. The reaction was carried out in chloroform but usable enantiomeric excess in the isoxazoline product 153 was only obtained when small quantities of another oxygen containing solvent were added.75 The selenium dioxide promoted oxidative rearrangement of 2-alkyloxazolines 154 173 Heterocyclic compounds X = F Cl NO2 R = H Halogen MeO BnS 152 151 43–80% i N O X CN NH2 R R Scheme 59 Reagents i AcN(H)OH ButOK 153 i ii iii OH R OH N O Scheme 60 Reagents i Et 2 Zn; ii (R,R)-DIPT; iii RC(Cl)––NOH 155 154 i R1 = H Me Ph R2 = Ph Pri O N R1 R2 N O O R1 R2 Scheme 61 Reagents i SeO 2 i i 158 156 157 R = Me Ph n = 1,2 Z E ( ) n ( ) n ( ) n R O N O OH N+ O O – Me O R O O NH H O Scheme 62 Reagents i heat via the 2-acyl derivative to dihydrooxazinones 155 represents a convenient preparation of these compounds including 3-unsubstituted examples which are otherwise not readily accessible (Scheme 61).76 Further studies on the reaction mechanism have been reported.77 The oximes 156 are configurationally stable at elevated temperatures.The (E)- oximes reacted via a concerted 1,3-azaprotio cyclotransfer reaction to give six- and seven-membered cyclic dipoles 157 whilst the Z-isomers gave fused isoxazolidines 158 via 1,2-prototropy and cycloaddition (Scheme 62).78 Thiobenzamide 159 and alkynyl(phenyl)iodonium methanesulfonate form thiazoles 160 according to the sequence outlined in Scheme 63.79 Thioamides 161 can be converted into benzothiazoles 162 by reaction with butyllithium which initiates a sequence of directed lithiation aryne formation cyclisation 174 PeterW.Sheldrake 57% .. 160 159 i Ph NH2 S N S C4H9 Ph S I Ph Ph HN S IPh C S HN Ph C4H9 Ph C4H9 C HN C4H9 Scheme 63 Reagents i PhI(OSO 2 Me)C–– – C–C 4 H 9 162 161 X = Cl F R = Bu t OPri i ii S N X HN R S E R Scheme 64 Reagents i BuLi; ii electrophile E 164 163 R = alkyl aryl 36–95% i Cl N N Ar N R N N R Ar Scheme 65 Reagents i NaN 3 and quenching (Scheme 64).Considerable variety was exemplified in the final quenching electrophile.80 Imidoyl chlorides 163 react with sodium azide in a two-phase system to form 1,5-disubstituted tetrazoles 164 (Scheme 65).81 From a discussion (covering the furanofurans thienothiophenes benzofurans and benzothiophenes) of whether the most stable fused heterobicycles in a series are the most aromatic it was concluded that there need not be any direct relationship in such isomers between the thermodynamic stability and their aromaticity since thermodynamic stability is influenced by strain and other e§ects.82 4 Six-membered rings It was known that pyridine and butyllithium in a 3 1 molar ratio produce an isolable complex 165 but now a new complex a bis(pyridyl)dihydropyridyllithium dimer 166 175 Heterocyclic compounds 166 165 py py N Bu H Li N N H H H H Li Li py py py py 167 69% i N N OH OH CO2Bn Scheme 66 Reagents i ClCO 2 Bn NaBH 4 NaHCO 3 MeOH,[80 °C 97% 99% 170 169 168 ii i N N Ph Ph Ph O O Me N Me Me Scheme 67 Reagents i L-Selectride; ii LiAlH 4 TiCl 3 has been isolated from the same reactants in the presence of excess pyridine.The complex has been characterised both in solution and as a crystal.83 Alkylation of 2-pyridone with benzyl chloride produces the 1-benzyl derivative no matter what form of heating is used. The use of benzyl bromide or benzyl iodide without solvent or base in a microwave oven gave mixtures of the 3-benzyl and 5-benzyl derivatives.84 Reduction of 3-hydroxypyridine with benzyl chloroformate–sodium borohydride led regiospecifically to the tetrahydropyridine 167 (Scheme 66); complexation of borohydride to the hydroxy group is believed to occur.85 The reduction of pyridone 168 can be controlled by the choice of reagent Selectride' gave exclusively the dihydropyridone product 169 while lithium aluminium hydride–titanium trichloride led to the tetrahydropyridine 170 (Scheme 67).86 Lithium aluminium hydride gave both products.Permutations of lithium aluminium hydride/deuteride reductions with methanol/methan[2H]ol quenches were used to gain mechanistic information. After N-oxidation the pyridylacetylene 171 reacted with oxygen sulfur or nitrogen nucleophiles (Scheme 68) via 172 to give 173 in an intramolecular Reissert–Henze-type reaction.87 176 PeterW. Sheldrake 173 172 171 ii i AcO– + N Ph N Nuc Ph O N O Ph Scheme 68 Reagents i H 2 O 2 AcOH; ii nucleophile (see text) i 175 174 N O CO2H CO2H O N H N H O CO2H O CO2H N Scheme 69 Reagents i NaBO 3 ·4H 2 O 176 i CF3CO2 – + N NH2 N NH H H Scheme 70 Reagents i HCHO TFA cyclopentene Palladium(0) couplings of 2-chloroquinoline have been reported; Stille Suzuki and carbonylation reactions were exemplified but a Heck reaction (which presumably relies on the same organopalladium species) unaccountably failed.88 Keto-acids of the type 174 can be oxidatively decarboxylated by perborate (Scheme 69) to give acids 175.89 2-Aminopyridine (and other similar aminoheterocycles) reacts with formaldehyde together with an alkene to give tricycles of which 176 is a typical example (Scheme 70).90 Pyridyl ketone 177 reacted with an iminium salt to form an intermediate 178 which can progress in two ways (Scheme 71).The Michael pathway (preferred when R1\H) led to a U-shaped terpyridine 179. Reaction by an aldol pathway led to an S-shaped product 180 and predominated when R1\alkyl.91 When ketone 181 was reacted with phosphorus oxychloride in the expectation of preparing 4-(trifluoromethyl)quinoline 2-(trifluoromethyl)quinoline 182 (Scheme 72) was obtained. No rearrangement of benzene ring substituents was observed. No 177 Heterocyclic compounds R1 = H alkyl aryl 180 179 178 177 i N O O N R1 N N N R1 N N N R1 Scheme 71 Reagents i R1CH––N`Me 2 X~ NH 4 OAc 182 181 i NH O CF3 N CF3 Scheme 72 Reagents i POCl 3 184 183 i R1 R3 = H Me R2 = Me Ph R4 = Me EtO R2 N Bn N Bn Me R1 R3 R1 R2 R3 O R4 Scheme 73 Reagents i R4COCH 2 COCH 3 information was provided on whether the trifluoromethyl shift is intra- or intermolecular.92 1-Azabuta-1,3-dienes 183 can react with acetylacetone or ethyl acetoacetate to give unsymmetrically substituted 1,4-dihydropyridines 184 (Scheme 73). Unfortunately not all combinations of substituents gave acceptable yields.93 Camptothecin analogues were prepared using intramolecular [4]2] cycloadditions of N-arylimidates (and 4H-3,1-benzoxazin-4-ones) acting as 2-aza-1,3-dienes. The key step is illustrated by the conversion of 185 to 186 (Scheme 74).94 Addition of the lithium enolate of 187 to the pyridinium species 188 gave 189 after 178 PeterW. Sheldrake 82% 186 i 185 NH N O O Me CN N N MeO MeO O CN Me Scheme 74 Reagents i,Me 3 O`BF 4 189 188 187 i NH N+ CO2But O O But O N NH O O But H H CO2But O H Scheme 75 Reagents i LDA 191 60% 190 i NH OBn OH H N OBn I H OH Scheme 76 Reagents i NaI (CH 2 O)n H 3 O` further cyclisation of the first-formed intermediate as a single diastereoisomer (diastereoisomeric excess 95%) (Scheme 75).95 In the synthesis of pumiliotoxins A and B the crucial step was the iodide promoted iminium ion–alkyne cyclisation which converted 190 to 191 (Scheme 76).96 Reaction of diene 192 with a trimethylsilylimine gave after aqueous work-up the highly substituted 4-piperidone 193 (Scheme 77).Enantiomeric excess was in the 80–98% range though yields were only moderate.97 The trifluoromethanesulfonamides 194 were cyclised by phenyliodonium acetate –iodine giving 195 by formation of the aryl–nitrogen bond (Scheme 78).98 This should be compared with the analogous formation of an aryl–oxygen bond in Scheme 47.Cyclisation of trifluoroacetamides 196 (Scheme 79) produces tetrahydroisoquino- 179 Heterocyclic compounds 193 192 R = Me MOM TMS TBDMS i N OMe OR NH O Ar OR Scheme 77 Reagents i ArC(H)––NTMS ZnCl 2 ; ii H 2 O 13–84% 195 194 X = CH2 O R = H lower alkyl n = 1 2 i ( ) n ( ) n X HN X N SO2CF3 R SO2CF3 R Scheme 78 Reagents i PhI(OCOCH 3 ) 2 I 2 197 196 X = Br CO2Me NO2 85–94% i N X X HN COCF3 COCF3 Scheme 79 Reagents i (HCHO)n HOAc H 2 SO 4 i 31–86% 198 199 N O O Me NH NH Scheme 80 Reagents i tryptamine 1M HCl lines 197 in a manner complementary to the Pictet–Spengler reaction in that electrondonating groups on the benzene ring are not necessary.99 Azalactones 198 have been used in a Pictet–Spengler reaction to give tetrahydro-b- carbolines 199 (Scheme 80).Phenylpyruvates were detected in solution but the reaction may still involve the enamides.100 Thioamides 200 undergo a novel Reformatsky reaction to give 201 which were cyclised by polyphosphoric acid to quinolines 202 (Scheme 81).101 The reaction of salicylaldimines 203 with alkenes gave tetrahydroisoquinolines 204 in 70–91% enantiomeric excess when a catalytic (20 mol%) quantity of a chiral ytterbium complex was used (Scheme 82). The catalyst was prepared from ytterbium 180 PeterW. Sheldrake i ii 200 201 202 N N N O CO2Et EtO2C CO2Et S R R R Scheme 81 Reagents i BrCH(CO 2 Et) 2 Zn; ii PPA i 203 204 OH N Ar NH R2 R1 Ar OH Scheme 82 Reagents i cis-R1CH–– CHR2 Yb(OTf) 3 (R)-(])-BINOL DBU X = NH O 205 206 207 + i XH X X CO2Me CO2Me CO2Me Scheme 83 Reagents i see text trifluoromethanesulfonate and (R)-binaphthol.This is the first example in which an aza-Diels–Alder reaction of this type employs less than a stoichiometric amount of the chiral catalyst.102 Amines 205 (X\NH) cyclise spontaneously (they are generated in situ by reductive amination of the corresponding ketone). (E)-Geometry in the Michael acceptor gave 206 (X\NH) exclusively while the (Z)-isomer gave 207 (X\NH) (Scheme 83). The corresponding alcohols which cyclised using sodium hydride in THF showed reversed selectivity. Thus (Z)-205 (X\O) produced 206 (X\O) in a 97 3 ratio while (E)-205 (X\O) shows only a 3 1 preference forming mainly 207 (X\O).103 Many challenging synthetic targets of current interest possess complex polycyclic polyether systems for which general synthetic methods are being sought.Ester–alkenes such as 208 can be converted to isolable enol ether–alkenes 209 by Tebbe’s reagent (Scheme 84) and further treatment with the same reagent brings about cyclisation by olefin metathesis to 210. The sequence can be accomplished in one-pot using excess reagent and is also applicable to the formation of a seven-membered cyclic ether.104 Acyl radical induced cyclisation of 211 gave 212 as the major product (Scheme 85). In this case the functionality is such that iteration is possible the methyl ester was converted into an acyl selenide the ketone reduced and the resulting alcohol reacted with methyl propiolate.105 Ring expansion of epoxides is a potentially versatile strategy; thus bromo bis(epoxide) 213 underwent rearrangment to 215 using silver ion 181 Heterocyclic compounds i 208 X = O 209 X = CH2 210 O O O O O H H H H H H H H H BnO BnO BnO BnO O X H H H Scheme 84 Reagents i Tebbe’s reagent ( ) n ( ) n i 211 212 n = 1 2 O CO2Me COSePh CO2Me O H H O Scheme 85 Reagents i (Me 3 Si) 3 SiH Et 3 B air ii i i 215 214 213 R = CH2OTBDPS Br R R R O OTf O O O O O H H H H H OH H Scheme 86 Reagents i AgOTf; ii Tf 2 O i 218 217 216 O O OTBS H O O OTBS OTf OTBDPS H H H H O H H OTBDPS SO2Ph O Scheme 87 Reagents i TsOH either directly or via 214 depending upon the conditions (Scheme 86).106 Compound 217 was formed by alkylation of an oxiranyl anion with 216; subsequent rearrangment of 217 by acid gave 218 (Scheme 87).Reduction of the ketone followed by protecting group manipulation can be used to re-establish the silyl ether–trifluoromethanesulfonate arrangement allowing iteration of the process.Three rings were constructed in this way.107 An acylated Meldrum’s acid 219 reacted with enol ethers giving 220 which underwent rearrangement and decarboxylation in acid to give 2,5-disubstituted pyran-4- ones 221 (Scheme 88).108 A fairly general coumarin synthesis is exemplified in Scheme 89.109 182 PeterW. Sheldrake R1 = Me Et Bn 221 220 219 R2 = H alkyl ii i O O O O OOH R1 O R2 BuO O O O R2 R1 OH R1 Scheme 88 Reagents i BuOCH–– CHR2; ii TsOH 82% i 223 222 MeO MeO OH MeO MeO O O Scheme 89 Reagents i H–C–– – C–CO 2 Et Pd(OAc) 2 NaOAc HCO 2 H 226 225 224 i ClO4 – O CHO CO2Me O CO2Me O MeO MeO O O N Ph N+ N Ph Scheme 90 Reagents i K 2 CO 3 228 227 X = Br I i O O X N O O N Scheme 91 Reagents i imidazole K 2 CO 3 An asymmetric intramolecular Stetter reaction can be e§ected using 224 with 225 as catalyst (Scheme 90).The catalytically active species is the nucleophilic carbene formed by deprotonation. Products 226 showed enantiomeric excess in the range 41–74%.110 3-Iodochromone 227 underwent an addition–elimination reaction with imidazole (and other azoles) giving the 2-substituted chromones (Scheme 91).111 Oxidative rearrangement of hydroxyalkylfuran 229 was used to produce 230a (Scheme 92); the corresponding acetate 230b is a precursor to a pyrylium ylide which 183 Heterocyclic compounds 230 a R = H b R = Ac i ii iii 229 231 Me O O RO O OTBS Me OTBS OH Me O OTBS O Scheme 92 Reagents i ButOOH/VO(acac) 2 ; ii Ac 2 O Et 3 N DMAP; iii DBU i 232 233 ii dienophile = cyclopentene N-phenylmaleimide S Ph HN N Ph S Ac S Ph H X X N Ac Ar Me Ar Ar Me Me Scheme 93 Reagents i AcCl pyridine; ii dienophile 234 235 236 i ii N N O O O Ar1 Ar2 Ar1 Ar2 O O N N O Ar2 Ar1 O+ Ar1 Ar2 O – Scheme 94 Reagents i norbornadiene BF 3 ·OEt 2 ; ii heat cyclised to give 231 as the main product an intermediate in an approach to taxanes.112 Thioamides 232 derived from an optically active amine can be activated by N-acetylation and then undergo [4]2] addition to give thiopyrans 233 in excellent yield and with[98% diastereoisomeric excess (Scheme 93).113 Disubstituted 1,3,4-oxadiazin-6-ones 234 undergo [4]2] addition with norbornadiene giving 235 (Scheme 94).Sequential loss of nitrogen and cyclopentadiene leaves 3,6-disubstituted pyran-2-ones 236.114 a-Formylamides 237 are simple to prepare; they react with aldehydes under acidic conditions in the first convenient route to 6-unsubstituted 2,3-dihydro-1,3-oxazin-4- ones 238 (Scheme 95).115 (1R,2S)-Ephedrine condenses with phenylglyoxal to give a diastereoisomeric mix- 184 PeterW.Sheldrake R1 = alkyl R2 = H Me 238 237 ii i Ph NH R1 O O NH R1 Ph O N Ph H R1 R2 O OH Scheme 95 Reagents i HCO 2 Et NaH; ii R2CHO HCl i 240 239 Ph Me Ph Me N Me N Me O Ph O O O Ph N Me O Ph Me Ph O Scheme 96 Reagents i room temp. R = H TBDMS 243 242 241 i N N NH2 Cl H2N O RO O HN RO O Cl NH2 N N HO N N N NH2 Cl RO OH Scheme 97 Reagents i AcOH ture of 2-benzoyloxazolidines 239. On standing this mixture was transformed into (3R,5S,6R)-4,5-dimethyl-3,6-diphenyloxazin-2-one 240 (Scheme 96). The driving force and mechanism were not elucidated.116 When the 3@-keto pyrazine nucleoside 241 was treated with acetic acid the pyrido[ 2,3-b]pyrazine 243 was formed via hemiaminal 242 (Scheme 97).The closely analogous compound with an ester group in place of the chlorine does not undergo rearrangement.117 185 Heterocyclic compounds ii iii i 245 244 N S S N MeO MeO Cl CN N N CN OR MeO MeO MeO MeO HN CN S CN Scheme 98 Reagents i Ph 3 P; ii ROH heat; iii ROH NaH R1 = H alkyl 249 248 247 246 Y = OEt NR2 iii ii i N Cl N CO2Et HN Cl CO2Et N Cl Ar Ar N N CO2Et Ar Y Cl H R1 N N Ar R1 Scheme 99 Reagents i,Pr* 2 NEt; ii R1CH––CHY; iii KOH EtOH or ButOK ButOH Reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with o-aminobenzonitriles gives adducts such as 244 (Scheme 98). Then in one or two steps the sulfur–sulfur bond cleaves and a quinazoline-2-carbonitrile 245 was formed.118 Hydrazones 246 can be dehydrochlorinated to give the diazadiene mixture 247.This reacted regioselectively with an electron-rich alkene to give a tetrahydropyridazine 248 (Scheme 99). Treatment with strong base induced two eliminations forming the pyridazine 249119 Treatment of 250 with formaldehyde gave pyrrolo[1,2-a]quinoxaline 251 (Scheme 100). It is at first slightly puzzling that benzaldehyde gives the same product but this fact should make it easier to discern the mechanism.120 A set of group additivity parameters has been devised which permits prediction of enthalpies of formation of azines.121 They also have some application to fused fivemembered heterocycles. 5 Seven-membered rings Optically active 2H-azepines 253 can be prepared from precursors 252 available through a simple sequence starting with amino acids (Scheme 101).The 2H-azepines 186 PeterW. Sheldrake 251 250 i or ii N NH2 NH2 N N Scheme 100 Reagents i HCHO; ii PhCHO 252 253 i R1 R2 = Alkyl N NH Boc O R2 R2 R1 H R1 H AcO Scheme 101 Reagents i TFA i ii 254 255 M = P As Sb Bi Br Br Li Li M Ph Scheme 102 Reagents i ButLi; ii PhMCl 2 undergo an easy isomerisation into 3H-azepines.122 Dibromide 254 can be dilithiated with tert-butyllithium and the intermediate reacted with any of a number of dichlorides to give 3-benzoheteroepines 255 (Scheme 102). The products were shown to have half-lives varying from 82 h (M\P) to under one minute (M\Bi).123 The aldehydes and imines 256 were converted thermally into dihydroazepines 257 and/or the bridged structures 258 (Scheme 103).124 Further studies showed that the mechanism involves a [1,6]hydride-shift (antarafacial) forming 259 followed by a conrotatory 1,7-cyclisation.125 The allylsilane 260 was prepared by an allylsilane–imine cyclisation; on treatment with formaldehyde it formed 261 which underwent another such cyclisation to give the azabicyclo[3.2.1]octane 262 (Scheme 104).126 Azepine 263 was converted into 264 under Mitsunobu conditions (Scheme 105).On treatment with methanesulfonyl chloride however it underwent ring contraction to the chloromethylpiperidine 265.127 The indole derivative 266 cyclised to 267 using sodium hydride the combination of the ketone and phenylsulfonyl substituents permitting by addition–elimination an overall nucleophilic substitution of the indole (Scheme 106).128 Naphtho[2,1-b][1,8]naphthyridine 268 gave on treatment with hydrogen peroxide the 1,4-oxazepine 269 together with its N-oxide (Scheme 107).No similar reaction was observed with 1,8-naphthyridine or acridine.129 187 Heterocyclic compounds 256 Y = O NR2 + 257 258 i _ 259 N N O Y N R1 H Bn H N N N O Bn N Bn O N N YH R1 R1 Y H N+ Bn R1 YH O N N Scheme 103 Reagents i heat R = H Pri Bui 262 261 260 i ii + HN R SiMe3 SiMe3 R N N R Scheme 104 Reagents i HCHO; ii TFA 56% 94% 265 264 263 R = Bn CH2CH2Ar ii i N HO OBn BnO OH R N BnO OH OBn Cl R O N BnO OBn R Scheme 105 Reagents i Ph 3 P DEAD PhCO 2 H; ii MeSO 2 Cl Et 3 N Simple amidrazones can be cyclised with formaldehyde to give 1,2,4-triazoles. The same was shown to be true if both ortho positions of the N-3 aryl substituent in 270 are blocked.However with an ortho position free 270 and formaldehyde cyclised to give a benzotriazepine 271 (Scheme 108).130 6 Larger rings The 3]1 approach to the porphyrins depicted in Scheme 109 is the subject of a short review131 and specific examples.132,133 A limitation of the synthesis is that one component must be symmetrical:otherwise the problem of isomer formation o§sets 188 PeterW. Sheldrake 267 266 n = 0,1 i ( ) n ( ) n PhSO2 N NH N O HN PhC O PhC O O Scheme 106 Reagents i NaH i 43% 268 269 N N O NH N H OAc Scheme 107 Reagents i,H 2 O 2 AcOH Scheme 108 Reagents i HCHO TsOH H H H H H N N N N N R2 R1 R2 R1 R3 R4 R3 HN CHO CHO R4 N N CO2H CO2H Scheme 109 the convergent character of the approach. An interesting o§shoot involves the use of 3-hydroxypyridine-2,6-dicarbaldehyde to form the porphyrinoid 272 in which the pyridine unit adopts a quinomethane form.134 The 1,5-diazacyclooctane 273 was prepared in good yield from toluenesulfonamide and 1-chloro-2-(chloromethyl)prop-2-ene.Much of its reactivity involves transannular 189 Heterocyclic compounds H H 272 Me Et Et Et Et Me N N O N N 68% 82% 275 274 273 ii i TosN NTos NH HN Me Me TosN NTos Br Br Scheme 110 Reagents i LiAlH 4 ; ii Br 2 (slow addition) 277 276 i O O Ph Ph O O Ph Ph O I OMe Scheme 111 Reagents i I`(collidine) 2 ClO 4 ~ MeOCH 2 CH 2 OH cyclisation e.g.lithium aluminium hydride reduction to 274 or bromination to 275 (Scheme 110).135 Treatment of but-2-enyl-1,3-dioxolane 276 with a positively charged iodine compound formed 1,4-dioxocane 277 with remote asymmetric induction (Scheme 111).The methoxyethoxy unit is displaceable using a Grignard reagent and the iodide by a nucleophile hydrogenolysis then yielded a chiral 1,4-diol.136 The tetrathiacyclooctadiene 278 was prepared from the disodium salt of ethene-1,2- dithiol by treatment with iodine. It is thermally stable in refluxing xylene but in acetonitrile–chloroform solution it was converted into the remarkable 16-membered ring 279 (Scheme 112).137 Pyrrolidine 280 was acylated by a suitable acid chloride to give the salt 281 which rearranged stereoselectively via its enol form to give the nine-membered lactam 282 (Scheme 113).138 Diazacyclodecadiyne 283 underwent an extensive rearrangement on treatment with 190 PeterW. Sheldrake 278 279 i ii S S S S S – Na+ S S S S S S S S S – Na+ Scheme 112 Reagents i I 2 KI; ii MeCN–CHCl 3 + Cl – 280 281 282 R1 = H Ph R2 = H Me Ph Cl OBn NPhth i N CO2Et R1 R1 CO2Et N O R2 O N CO2Et R2 R1 Scheme 113 Reagents i R2CH 2 COCl Scheme 114 Reagents i 5%Pd on charcoal MeOH i 286 285 O O O O O O O O O O Scheme 115 Reagents i Ru(–– CHPh)(PCy 3 ) 2 Cl 2 palladium on charcoal to give 3,3@-bipyrrole 284 (Scheme 114).The mechanism involves the formation of two new carbon–carbon bonds the cleavage of one triple bond two allylic rearrangements and two dehydrogenation steps and the yield is still 95%!139 The versatility and scope of the olefin metathesis reaction is further illustrated by the 191 Heterocyclic compounds 288 287 iii iv i ii H H H H N N N N N N N N NH2 NH2 S S Scheme 116 Reagents i EtBr; ii H 2 N(CH 2 ) 2 NH(CH 2 ) 2 NH(CH 2 ) 2 NH 2 ; iii DIBAL; iv NaF 289 Pr3+ N N N N CO2 – CO2 – CO2 – MeO high-yielding conversion of the diallyl polyether 285 into the crown ether 286 (Scheme 115).140 Tricycle 287 was readily prepared from dithiooxamide and triethylenetetramine.Reduction forms a cleverly conceived bis-aminal which by aminal opening and further reduction completed an e¶cient synthesis of ‘cyclen’ 1,4,7,10-tetraazacyclododecane 288 (Scheme 116).141 And finally there is the cyclen–praeseodymium complex 289 using which it is possible to estimate temperature from the 1H NMRspectrum. 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