Heterocyclic chemistry 5 Mark F. Ward Department of Chemistry University of Aberdeen MestonWalk Old Aberdeen UK AB24 3UE This review covers the chemistry of heterocyclic compounds published during 1998 but focuses on the synthesis of such compounds rather than their reactivity. The subject is divided according to ring size and further grouped according to reaction type or nature of the heterocycle to guide the reader through the diverse material covered. Solid phase synthesis has largely been omitted because of the abstracting of much of this material in J. Chem. Soc. Perkin Trans. 1. 1 Three-membered rings Epoxides continue to receive substantial attention especially in the area of asymmetric synthesis. Further application of the dioxirane derived from 1 to asymmetric epoxidation has shown that it is e.ective in the asymmetric epoxidation of enynes (Scheme 1), dienes and silyl enol ethers or esters. Interestingly variations of the enantiomeric excesses with pH were observed for the epoxidation of alcohol-containing alkenes with 1. It was proposed that epoxidation by Oxone was facilitated by the hydroxy group in the substrate via hydrogen bonding thus allowing intramolecular attack.The ability of an -.uorine atom to in.uence the stereochemical outcome of an epoxidation has been demonstrated by treating alkenes with ketone 2 in the presence of Oxone (Scheme 2). Although research has focused on the use of chiral ketones as asymmetric mediators in this reaction iminium salts have also been used. Alkenes were converted to optically active epoxides in the presence of iminium salts 3 containing a chiral N-substituent (R) and Oxone (Scheme 3). In the search for structural types that would be amenable to asymmetric modi.cation 4 has been synthesised and shown to catalyse the epoxidation of alkenes (Scheme 4). Oxadiazepinium salt 4 shows a high rate of Oxone consumption as compared to cyclohexanone and high resistance to Baeyer—Villiger oxidation.Using salts 5 and 6 derived from Cinchona alkaloids phase-transfer catalysis has also been applied to this area in the guise of asymmetric epoxidations of ,-unsaturated ketones (Scheme 5) and asymmetric Darzens condensations (Scheme 6). The stereoselective preparation of cis-epoxyketones from cis-enones has proved troublesome because of the propensity of cis-enones to a.ord trans-epoxyketones during the oxidation process.Ytterbium based catalyst 7 has proved useful in applica- 157 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 Scheme 1 Reagents (i) Oxone 1 (20—30 mol%) NaHCO Na EDTA MeCN 0 or 10 °C. CO2Et N F H R3 R1 O 2 R2 Scheme 2 Reagents (i) Oxone 2 (10 mol%) NaHCO Na EDTA MeCN. R2 R3 R2 (i) 33-100% ee=29-83% BPh4 – N+ R1 3 (i) up to 78% ee=up to 73% R4 Scheme 3 Reagents (i) Oxone 3 (5—10 mol%) Na CO MeCN 0 °C. R4 + N O•H2O N+2TfO– 4 OBn (i) 96% conv. after 10h Scheme 4 Reagents (i) Oxone 4 (10 mol%) phosphate bu.er MeCN 0 °C. tion to this problem (Scheme 7), but a small amount of trans-epoxyketone is observed with some substrates.The current interest in immobilised reagents has led to the development of polymer linked versions of Jacobsen’s catalyst which epoxidise 1-phenylcyclohexene in up to 91% ee. Some notable methods for the asymmetric synthesis of epoxides by the use of ylides have been reported. Stoichiometric use of sul.mide 8 allows access to optically active epoxides or aziridines depending upon the nature of the heteroatom in the starting material 9 (Scheme 8). Another example of the stoichiometric use of sulfur ylides involves the generation of the C symmetric ylide in situ which reacts with aldehydes generating the trans-epoxide in most cases (Scheme 9). A particularly elegant catalytic procedure was provided by the copper(..) acetoacetate catalysed alkylidene transfer 158 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R3 R1 O R3 R2 O O OBn N BnO H Anthryl N+ O O Br– O 5 R2 R2 R1 R1 Scheme 5 Reagents (i) NaOCl 5 PhMe 25 °C. O H O O (i) 42-93% ee=69-87% N HO H N+ p-(CF3)C6H4 Br– 6 R Ph + Cl R O Ph O R2 R2 (i) 32-83% ee=42-79% Scheme 6 Reagents (i) LiOH·H O 6 Bu O 4 °C. OH O Yb(OiPr) O 7 R1 O O R1 Scheme 7 Reagents (i) MS 4Å 7 THF RT. X X (i) 51-80% ee=82-96% TsN– S+ Ar 8 R1 R2 R2 R1 9 Scheme 8 Reagents (i) NaH 8 DMSO usually 20 or 25 °C. O (i) up to 79% ee=6-70% S Me Me 10 PhCH RCHO 2Br + R Ph (i) 30-86% de=30-86% ee=86-94% (S,S) Scheme 9 Reagents (i) 10 NaOH H O BuOH RT.reaction to form a sulfur ylide derived from 11 which in turn reacts with benzaldehyde to form stilbene oxide (Scheme 10). Peroxycarboxylic acids such as m-chloroperbenzoic acid have various drawbacks because of the hazards associated with their preparation and use. Consequently there 159 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O + PhCHO O Ph Ph S 11 H Scheme 10 Reagents (i) Cu(acac) CH Cl RT. R2 O R1 R2 R1 + PhCHN2 O HN O 12 (i) 70-98% ee=68-94% O O H O R3 R3 R4 R4 Scheme 11 Reagents (i) 12 toluene or CH Cl or EtOAc usually 20 °C. Ph3N+ Br3 – R3 R3 R1 R1 13 NTs R2 R2 Scheme 12 Reagents (i) 12 TsNClNa MeCN 25 °C.H H N Mn (i) 98-100% N O R1 (i) 51-95% N O 14 Ts N R1 (i) 14-78% ee=31-94% Ph Ph R2 R2 Scheme 13 Reagents (i) 14 pyridine Ts O pyridine N-oxide CH Cl RT or 0 °C. is renewed interest in convenient methods for the epoxidation of alkenes. 5-(Hydroperoxycarbonyl) phthalimide 12 is a promising replacement for m-chloroperbenzoic acid (Scheme 11) because it is easy to prepare cheap and does not need bu.ering to overcome acid-induced side reactions. The use of carbodiimide promoted alkene epoxidation with aqueous hydrogen peroxide has also been reported. In a rare example of atom-transfer redox catalysis by a main group element bromine in the form of ammonium salt 13 catalysed the direct aziridination of alkenes in good to excellent yields (Scheme 12). Activation of nitridomanganese complex 14 by toluene-p-sulfonic anhydride causes it to e.ect the asymmetric transfer of an N-tosyl group to styrene derivatives (Scheme 13). Diastereoselective aziridination of alkenes with 16 has been shown to be greatly improved in the presence of titanium(..) tetra(tert-butoxide) (Scheme 14). It is postulated that chelation control is involved thus introducing a greater degree of steric control in the transition state.Intramolecular aziridination has been e.ected in high diastereoselectivity by the addition of iodine to the anion of N-tosyl allylamines (Scheme 15). Predominantly cis-vinyl aziridines have been prepared by the intramolecular closure of an N-sulfonylamine onto an -allyl complex(Scheme 16). Photolysis of N-alkylpyridinium 160 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R2 N N R1 15 tBu N (i) 53-85% dr>50:1 OH NHOAc ¡Ô R1NHOAc 16 H R2 Cl Ti(OBu) ,20 ¡ãC. TsN R1 R2 R3 I . R1 Scheme 14 Reagents (i) 15 CH R1 NHTs R2 (i) (ii) 63-95% R3 Scheme 15 Reagents (i) BuOK PhMe RT; (ii) I OCO2Me R1 (i) 50-88% cis:trans 94:6-98:2 N ArSO2NH SO2Ar Scheme 16 Reagents (i) Pd(PPh ) THF 60 ¡ãC. NR1 (i) 40-82% N+ Cl�C OH R1 17 O KOH externally cooled. OAc MeO2C MeO2C (ii) 48% (i) 80% N p-Tol N p-Tol Scheme 17 Reagents (i) h H 3 N 18 Scheme 18 Reagents (i) heptane reux; (ii) 1-acetoxybutadiene THF RT.salts yields aziridines 17 which have been elaborated to aminocyclopentanols (Scheme 17). Azirine 18 has been synthesised and shown to undergo Diels¡ªAlder reactions to produce bicyclic aziridines (Scheme 18). Tandem O,N-addition of hydroxamic acids to methyl propiolate produces N-acyloxaziridines (Scheme 19). N-Protected (trichloromethyl) oxaziridines have been synthesised and used as novel aminating agents (Scheme 20). A new and versatile method for the preparation of phosphirenes has been reported. Titanocene complexes and dialkoxytitanium complexes of alkynes react with dichlorophenylphosphine or phohorus trichloride to aord phosphirenes. (Scheme 21). Annu.Rep. Prog. Chem. Sect. B 1999 95 157¡ª182 CO2Me p-Tol 161 O O N R1 H O CO2Me (i) 86-95% + NHOH R1 CO2Me Scheme 19 Reagents (i) morpholine MeCN 40—45 °C. O (i) 93% Cl3C NBoc NBoc Cl3C Scheme 20 Reagents (i) Oxone K CO H O CHCl 0 °C. R5 (R1)2Ti(R2)2 P 19 R2 R2 R1 (i) 65-90% or (ii) 60-72% Scheme 21 Reagents (i) 19 (RCp RCi) BuLi THF alkyne PhPCl or PCl 78 then 50 °C; or (ii) 19 (RROPr) PrMgCl Et O alkyne PhPCl or R1 PCl 78 then50 °C. 2 Four-membered rings Highly sensitive oxetanes 20 and 21 have been isolated during investigations into the Mukaiyama crossed-aldol reaction (Scheme 22). These [2 2] cycloaddition intermediates form reversibly and prevent formation of the trimethylsilyl cation an achiral Mukaiyama catalyst thus in.uencing the enantioselectivity of the reaction.Enzymatic resolution has been used to prepare a .uorinated propiolactone in excellent optical purity (Scheme 23). Catalytic asymmetric [2 2] cycloaddition of silylketenes to aldehydes has been achieved using chiral titanium-TADDOL catalysts (Scheme 24). During the asymmetric syntheses of panclinins a silyloxy group has been shown to greatly in.uence the diastereoselectivity of the [2 2] cycloaddition process (Scheme 25). 4-Exo nickel-mediated radical cyclisation of 23 produced a -lactam (Scheme 26). -Lactam-4-ylidene based methodology was employed to prepare a benzo-fused oxapenem (Scheme 27). Standard [2 2] cycloaddition methodology was used to construct the -lactam core of a range of non-conventionally fused bicyclic -lactams 24 and 25.Subsequent functional group manipulation allowed incorporation of the fused ring (Scheme 28). Although these were of an interesting structural type they exhibited little or no antibacterial activity against a variety of micro-organisms. Employing a diastereoselective Staudinger reaction -lactam 26 was synthesised en route to the paclitaxel side-chain (Scheme 29). Oxazolidinone 27 combined with 2-chloro-1-methylpyridinium tosylate 28 as a dehydrating agent e.ected a stereoselective Staudingertype reaction (Scheme 30). Another chiral auxiliary based method allowed the asymmetric construction of -lactams by a three-component domino procedure (Scheme 31). 162 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 OSiMe3 + PhCHO OMe Scheme 22 Reagents (i) [Eu(hfc) ] C D 20 °C. O O C + H H H ClF2C (i) 67% (ii) ee=99.0% at 58% conv. ClF2C O Scheme 23 Reagents (i) ZnI Et O 30 °C. O O C + H H R1 SiMe3 R1 Scheme 24 Reagents (i) 22 (20 mol%) CH Cl 15 °C. O C tBuMe2SiO O + H R2 SiMe3 tBuMe2SiO (i) 57-84% dr=83:17-94:6 R1 Et O CH Cl 50 °C; (ii) Lipase PS n-C H OH (i) 39-79% dr=35:65->95:5 ee up to 80% major isomer Me R2 O O Ph Ph Ph Ph O O Ti Cl Cl 22 O O R1 SiMe3 O O R2 H SiMe3 Scheme 25 Reagents (i) EtAlCl Cl SPh N Bn 23 Cl (i) 60% O Scheme 26 Reagents (i) Ni AcOH PrOH re.ux.O Ph N Ph N O HO N O N (i) 53% O Ph Ph Scheme 27 Reagents (i) C H 100 °C. Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O Ph (i) 56% dr(20:21)=38:62 O Ph Et O 50 to 4 °C. Cl O NBn OSiMe3 OMe 20 + OMe OSiMe3 21 O 163 O R1 N N 24 25 H O R1N S O (i) 88%; (ii) 95% trans:cis 10:1 Ph + SBn N (iii) trans:cis 1:2 Cl R1 Ph H I Scheme 28 Reagents (i) Et N CH Cl 78 °C; (ii) I CH Cl re.ux; (ii) BuLi THF,78 °C then AcOH O . Ph Ph O N + AcO Et NH O MeO 26 N; (ii) recrystallisation; (iii) Ce(NH ) (NO ) MeCN R2 R1 O R1 N Cl TsO– (iii) 87% Cl N O N O N + (i) 78% dr=73:27 AcO (ii) 52% (S)-26 N+ Me 28 O R2 Ph Ph Ph Ph (i) 54-100% 81:19->99:1 27 Scheme 30 Reagents (i) Et N CH Cl 0 °C to RT.iPr R2 O (i) 60% trans:cis=100:0 ee(trans)=>99% or N (ii) 57% trans:cis=98:2 ee(cis)=>99% N O R1 Scheme 29 Reagents (i) Et H O. O CO2H S O O Scheme 31 Reagents (i) (a) Me CuLi Et O,78 °C (b) BocNCHPh THF 0 °C; (ii) (a) Me CuLi Et O,78 °C (b) (p-MeOC H )NCHCO Me THF 0 °C. 3 Five-membered rings Ring closing metathesis (RCM) has exerted considerable in.uence on the synthesis of heterocyclic rings of .ve atoms or more.A prominent example of RCM is the 164 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R1 tBu N Mo Me Ph O O O O Me Me tBu R2 R2 R3 R3 R3 30 Me R3 R4 (i) 28-91% ee=10-99% R4 (S)-29 R4 Scheme 32 Reagents (i) 30 (5 mol%) toluene 20 or22 °C. OBn OBn O O (i) 95% or BnO BnO (ii) 55% dr=4:1 O O R1 R1 OBn BnO BnO 31 ) RuCHPh toluene 60 °C; (ii) RMe OBn Scheme 33 Reagents (i) RH Cl (PCy Cl (PCy ) RuCHPh toluene 60 °C. MeO2C F3C (i) 50% N N MeO2C F3C Cbz Scheme 34 Reagents (i) Cl (PCy Cbz ) RuCHPh (11 mol%) CH Cl . desymmetrisation of achiral trienes via ring closing metathesis a.ording optically active dihydrofurans (S)-29 or (R)-29 (Scheme 32). The stereochemical outcome of the reaction appears to be determined by the size di.erential between R and the enantiotopic alkenyl moieties.Dihydrofuran (S)-29 is obtained whenRH however when a large group such as cyclohexyl is present predominantly (R)-29 is obtained. Pyranose spiroacetal derivatives 31 have also been prepared by ring closing metathesis of the corresponding non-conjugated acyclic dienes (Scheme 33). Modifying the ole.nic side-chains in the starting material allows the preparation of six- to eightmembered analogues of 31. Cyclic amino acid derivatives containing a tri.uoromethyl group have been prepared via RCM (Scheme 34). Five-membered N-heterocycles have been prepared by enyne metathesis which proceeds in substantially better yields if ethene is present (Scheme 35). Enyne metathesis followed by a Diels—Alder reaction has led to the e.cient formation of a highly substituted hydroisoindole ring system.The reaction sequence was performed on Wang resin and using a split/mix protocol to prepare a 104516 isoindoline combinatorial library (Scheme 36). A large number of palladium-catalysed methods for the synthesis of .ve-membered 165 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 CH (i) 21% or (ii) 90% N N Ts Ts ) RuCHPh (1 mol%) CH Cl Ar; (ii) R1 O R3 (i) (ii) N R4 Scheme 35 Reagents (i) Cl (PCy Cl (PCy ) RuCHPh (1 mol%) CH Cl CH CH .O R1 N O O R2 R2 ) RuCHPh (5 mol%) C H 75 °C; (ii) R3 CN CN O (i) 58-94% dr=52:48-61:39 R2 CN R2 R1 Scheme 37 Reagents (i) Pd(PPh ) THF 40 °C. R2 CH R1=Me R1=H Scheme 36 Reagents (i) Cl (PCy RCHCHR toluene 105 °C. CN R3 1 O R + R2 O HN CO2Me (i) 22-87% N Ts CO HN (ii) 23-66% 2R1 O Ts Scheme 38 Reagents (i) RX Pd(PPh or DMF 40—81 °C; (ii) RX Pd(OAc) Et Ts ) K CO or K CO —TBAC THF or MeCN or Pd(OAc) —PPh or Pd(PPh ) Et N or N—TBAC THF or MeCN 40—81 °C. heterocycles have appeared. Palladium-catalysed reaction of Michael acceptors with vinylic epoxides produced tetrahydrofuran derivatives as [3 2] cycloaddition products (Scheme 37). Using either the amino or acid functionality of acetylene-containing amino acids as a nucleophile O- or N-heterocycles were prepared (Scheme 38). Palladium-catalysed coupling of N-substituted 2-iodoaniline with a variety of internal alkynes results in 2,3-substituted indoles (Scheme 39). The reaction exhibits good regioselectivity with the less sterically demanding end of the alkyne being coupled to the aromatic ring.Indolines have been prepared from aryl Grignard reagents in a two-step sequence involving titanocene-based methodology followed by palladium catalysed aryl amination. In this way dibromo compound 32 was smoothly transformed into indoline 33 under the appropriate conditions (Scheme 40). The construction of complexmolecules by metal-mediated processes continues to 166 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R2 NHR1 N + R2 (i) 27-98% I R3 R3 Scheme 39 Reagents (i) Pd(OAc) (5 mol%) base DMF 100 °C. R3 R2 R2 R3 Br (i) 18-54% based on Cp2TiCl2 Br N Bn R1 32 R1 33 Scheme 40 Reagents (i) Pd (dba) P(o-tol) NaOBu BnNH PhMe. CH + X CH 34 Scheme 41 Reagents (i) Cp*Ru(cod)Cl 40 °C. R1 R1 O O O X (i) 50-90% 3 O Ph Cu R1 O O O R (i) 65-76% Scheme 42 Reagents (i) [Rh(DIPHOS)(CH Cl ) ]SbF CH Cl 25 °C.Me N O 2 35 O C R3OH + O C (i) Conv=83-99% R2 R1 R2 Scheme 43 Reagents (i) 35 toluene 25 °C. generate interest. Hepta-1,6-diynes undergo cycloaddition with allylic ethers in the presence of a ruthenium catalyst (Scheme 41). No cycloadduct is observed when 34 is substituted by cyclopentene or conformationally restricted allylic ethers which led the authors to postulate that ruthenium co-ordination of the oxygen atom and double bond in 34 is essential to the progress of the reaction. Rhodium—phosphine complexes have been used for the synthesis of variously substituted isobenzofuran derivatives (Scheme 42). Modi.cation of the phosphine ligand has made this a highly enantioselective process. Dihydrofuranones have been prepared by the copper-catalysed reaction of 1,2-bisketenes with alcohols (Scheme 43). No asymmetric induction was observed despite the use of a chiral catalyst.Nitrogen .xation has been used in the synthesis of N-heterocycles (Scheme 44). After sequestration of atmospheric nitrogen by the TiX —Li—Me SiCl system amination occurred across not only 1,4-diketones 167 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O O (i) 56% air O O NH or Ti(OPr) Li Me SiCl THF nitrogen or air. 3 2 HN 2 (i) 86% N2 MeNd SiMe 36 (i) 90% Scheme 44 Reagents (i) TiCl NH2 • D sealed tube 140 °C. O R1 R3 R1 (i) 54-92% dr=1:1->20:1 R2 OH O Scheme 45 Reagents (i) 36 C O X + R3M R2 Scheme 46 Reagents (i) MLi or MgBr or CeCl no other conditions given.O O (i) 78% H HO H 37 Scheme 47 Reagents (i) NaOH H O 25 °C. O R1O2C O O OSO2(3-NO2C6H4) (i) 41-70% ee=92-99% (R)-38 Scheme 48 Reagents (i) CH (CO R) CsF DMF. but from a ketone onto an activated acetylenic or an activated ester. Under catalysis by lanthanide complex 36 hindered alkenes have been intramolecularly hydroaminated to produce heterocyclic compounds (Scheme 45). Nucleophilic approaches to furans pyrrolidines and related compounds have seen some elegant developments. Stereocontrolled formation of tetrahydrofurans has been accomplished via S O-cyclisation (Scheme 46). Addition of an organometallic reagent to an aldehyde or ketone generates a nucleophilic alkoxide which attacks the allyl halide in an intramolecular sense to yield the product.The carbonyl group has also been reduced to the same ends. Bis-epoxide 37 has been regioselectively opened to produce an optically active tetrahydrofuran (Scheme 47). Sodium sul.de e.ected ring-opening of 37 to a.ord an inseparable 5 1 mixture of the corresponding tetrahydrothiophene via a 5-exo opening of the second epoxide and a tetrahydrothiopyran via a 6-endo opening of the second epoxide. Caesium .uoride promotes the addition of various malonate derivatives to (S)- or (R)-glycidyl nosylate 38 to produce cyclopropanolactones in good yields (Scheme 48). A small loss in optical purity indicates 168 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 O O OAlEt2 O (i) 45-76% + (ii) 81-99% R1 OtBu R1 ( )n ( )n Scheme 49 Reagents (i) THF,35 °C; (ii) TsOH·H O CHCl . Me CO2Me H CO2 Me SePh (i) 55-71% dr=71:29-93:7 O R1 SePh MeO2C O 39 40 Scheme 50 Reagents (i) MeLi Et O,70 °C then RCHO. I I R1 (i) 45-82% (ii) 40-75% CO CO R1 R1 2Me 2Me TsHN CO2Me N Ts N Ts 41 42 43 K CO MeCN; (ii) I MeCN. R3 R2 (i) 85-99% Me R1O2C Me N Scheme 51 Reagents (i) I OMs N R2 R1O2C R3 R1O2C R1O2C Cl DBU 0 °C. Scheme 52 Reagents (i) CH that initial displacement of the nosylate by the malonate can not be totally discounted. Spiro -lactones have been prepared by ring opening of spiroepoxides by aluminium enolates followed by acid catalysed lactonisation (Scheme 49). Using 2-selenofumarate 39 butano-4-lactone derivatives 40 have been assembled by a tandem Michael—aldol induced ring closure (Scheme 50). Methyllithium adds to 39 in an exclusively 1,4 fashion the resultant anion reacts with an introduced aldehyde and the resultant adduct undergoes an instantaneous lactonisation.Iodine has been used to activate double and triple carbon—carbon bonds to nucleophilic ring closure by an N-tosyl moiety. For example allylglycine derivative 41 undergoes ring closure to 2,5-trans-diastereoisomer 42 in the presence of iodine and base whereas in the presence of iodine alone the 2,5-cis-diastereoisomer 43 is formed (Scheme 51).Nucleophilic approaches to .ve-membered N-heterocycles usually involve a nucleophilic nitrogen atom with examples involving an electrophilic nitrogen somewhat less common. One such approach involving cyclisation onto an O-methanesulfonyl oxime by an active methine group a.ords dihydropyrroles (Scheme 52). Free radical methods have found use in the synthesis of nitrogen- and oxygencontaining .ve-membered rings. Radical cyclisations using a glucopyranosyl auxiliary have resulted in the construction of quaternary stereocentres with high stereopurity (Scheme 53). Mechanistic investigations into the pathway involved in the formation 169 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 CH Et O O O Br Me Me H O O OAc OR1 O (i) 61% O R1 ¡Ô OAc OAc OAc Scheme 53 Reagents (i) 1-ethylpiperidinium hypophosphite AIBN toluene reux.O Et 16O 2N NO2 18O (i) 49% MeO O OMe MeO O N O O S 45 Scheme 54 Reagents (i) h C 44 H reux. R1 R1 R2 O (i) 40-52% R2 dr=1.0:1-1.6:1 N N SO2Ph SO2Ph Scheme 55 Reagents (i) Bu SnH AIBN C H 80 ¡ãC. of spirodienone 44 have shown that the biaryl ether oxygen of the starting material 45 does not emerge as the carbonyl group oxygen in the product (Scheme 54). This and other evidence suggests that the spirocyclisation most likely involves the formation of a cyclohexadienyl radical which is subsequently trapped by a nitro group. Direct evidence of oxygen atom transfer from the nitro group to the carbon radical centre and hence to the carbonyl oxygen can not be realised until suitable methodology for the preparation of O labelled aryl nitro groups exists.Hydroxypyrrolidines have been prepared by tin hydride-mediated cyclisation of -amino aldehydes (Scheme 55). The use of -amino aldehydes under similar conditions aorded piperidines. Generation of acyl radicals from phenylselenocarbamates and subsequent 5-exo cyclisation leads to -lactams (Scheme 56). 2-Aziridinyl radicals undergo ring opening to generate a nitrogen centred radical which triggers o a cyclisation cascade to yield pyrrolizidines (Scheme 57). Five-membered heterocycles have been assembled using carbenes and carbenoids as 170 Annu. Rep. Prog. Chem. Sect.B 1999 95 157¡ª182 OMe OH O O R4 TsN SePh R1 TsN (i) 31-68% R2 R3 R4 R1 R2 R3 Scheme 56 Reagents (i) (Me Si) SiH AIBN PhMe re.ux. R1 R2 H R1 Me (i) 49-63% N R2 N Br Scheme 57 Reagents (i) Bu SnH AIBN C H heat. O O O (i) 58% O O 46 47 Scheme 58 Reagents (i) Me SiC(H)N BuLi DME hexanes. O O 48 O EtO2C R1 CO2Et Et3SiO (i) 53-87% dr=3:1->20:1 + N2 CHO R1 HO ·OEt 78 °C no solvent given. Scheme 59 Reagents (i) BF reactive intermediates. Addition of lithio(trimethylsilyl)diazomethane to ketal 46 followed by treatment with mild acid upon work up produced the bicyclic ether 47 (Scheme 58). Intermediate 48 was observed by NMR but was not isolated and indicates that this method may provide the basis for a synthesis of zaragozic acid/squalestatins.The Lewis acid induced reaction of ethyl diazoacetate and protected -alkyl--(triethylsilyl)oxyaldehydes has resulted in the synthesis of 2,3,4-trisubstituted tetrahydrofurans (Scheme 59). Generation of rhodium carbenoids from diazoesters and their N—H insertion reaction has been used in a modi.ed Bischler indole synthesis (Scheme 60). -Lactams 49 have been prepared from diazoketones 50 containing an N-tosylamine (Scheme 61). Wol. rearrangement of 50 leads to the corresponding ketene which is trapped in an intramolecular fashion by the nitrogen nucleophile. Cycloaddition processes including tethered Diels—Alder reactions and [3 2] 171 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 R2 R2 (i) 60-89% R1 + CO R1 2R3 (ii) 31-87% N2 NHMe CO O 2R3 N Me Scheme 60 Reagents (i) Rh (OAc) PhMe or CH Cl heat; (ii) Amberlyst PhMe heat. NHTs O O R1 N R1 CHN2 (i) 81-93% 50 Ts 49 Scheme 61 Reagents (i) PhCO Ag Et N MeOH or THF. R1 R1 H BnN BnN (i) 69-83% SO2Ph SO2Ph 51 52 H re.ux. O (ii) 2.5:97.5 53 54 Scheme 63 Reagents (i) RH toluene or xylene 110 or 135 °C; (ii) RPh C toluene or xylene 110 or 135 °C. R2 N N R2 R1 C + CO2Me (i) 26-96% Scheme 62 Reagents (i) C (i) 100:0 or O R1N R1N R1 CO2Me 55 56 C H RT. Scheme 64 Reagents (i) PPh cycloadditions have been used in the construction of .ve-membered heterocycles.N-Tethered diene—dienophile systems have led to fused pyrrolidines. Diels—Alder reaction of amino acid derived triene 51 led exclusively to hydroisoindole 52 (Scheme 62). The size of the nitrogen substituent in 53 determined the position of the equilibrium between 53 and the cycloadduct 54 (Scheme 63). Cycloaddition processes have provided convenient approaches to nitrogen heterocycles. A novel phosphinecatalysed [3 2] cycloaddition of imines with methylbuta-2,3-dienoate 55 produced the cycloaddition product 56 regiospeci.cally (Scheme 64). It is postulated that the 172 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R2 R1 N R1 N R2 O (i) 55-91% R3 OH R4 Scheme 65 Reagents (i) PSP RCH——CHR CH Cl or CDCl .Ph O O S PPh3 (i) 58% S S 57 Scheme 66 Reagents (i) 600 °C 0.01 Torr. Me3Si SiMe3 Me3Si P P – P SiMe3 P P (i) 54% P Me3Si Me3Si 58 Scheme 67 Reagents (i) (Me Si) CHBr DME,78 °C. phosphine undergoes conjugate addition with 55 to produce a reactive dipolar intermediate which then goes on to react with the imine. Solid-supported reagents are of considerable importance in the solution phase synthesis of chemical libraries as they can be used in excess but obviate the need for extensive puri.cation of the product mixture. Polymer-supported perruthenate (PSP) has been used in mild and selective oxidations of secondary hydroxylamines to nitrones which undergo a [3 2] cycloaddition with dipolarophiles (Scheme 65). Other interesting approaches to .ve-membered heterocycles have been reported.Flash vacuum pyrolysis of phosphorus ylide 57 yielded benzothiophene (Scheme 66). Although extrusion of phosphines from stabilised ylides to give carbenes is unusual it is proposed that the carbene thus generated undergoes a 1,5-insertion process followed by homolytic degradation to yield the products. Phospholes are generally accepted not to be aromatic but alkylation of 3,5-bis(trimethylsilyl)-1,2,4-triphospholide anion 58 produced the .rst example of a fully delocalised 1,2,4-triphosphole (Scheme 67). 4 Six-membered rings Alkene metathesis has been found to be particularly applicable to the construction of polycyclic ether natural products.An elegant application of enyne metathesis has not only led to the synthesis of the desired cyclic enol ethers but has also extended the substrates known to undergo enyne metathesis to include alkynyl ethers (Scheme 68). An iterative approach to polycyclic ether systems involved conversion of ester 59 173 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 H H O PMP H H O PMP R1 (i) 20-77% O O O H O H R1 ) RuCHPh (10 mol%) CH Cl re.ux. BnO O BnO R1 (i) up to 65% of 70 BnO BnO O O 60 59 (iii) 15% (ii) up to 85% BnO O BnO R1 BnO O 61 Zn CH Br PbCl TMEDA THF 0 then 60 °C; (ii) bis(hexa.uoro-tert- R2 Scheme 68 Reagents (i) Cl (PCy BnO BnO O O R1 tBu N R1 Scheme 69 Reagents (i) TiCl (2,6-diisopropylphenylimido)neophylidenemolybdenum(..) butoxide) hexane 60 °C; (iii) conditions as for (i) but extended reaction time.N R1 + (i) 65-99% R3 I R2 R3 Scheme 70 Reagents (i) Pd(OAc) (10 mol%) PPh Na CO DMF 100 °C. into the enol ether 60 using Takai’s procedure and produced the desired cyclic enol ether 61 in low yield (Scheme 69). A two step procedure involving Schrock’s molybdenum alkylidene proved to be more e.cient. Isoquinolines and pyridines have been prepared via the palladium-catalysed iminoannulation of internal acetylenes (Scheme 70). Palladium methodology has previously been employed in the preparation of substituted isoquinolines but these older methods have been stoichiometric with respect to palladium.Intramolecular 1,4-dialkoxylation of cyclohexa-1,3-dienes under palladium catalysis has been shown to be an e.cient process for the preparation of fused pyrans (Scheme 71). Low valent early transition metal co-cyclisation of N-tethered enynes 62 produced piperidines 63 after hydrolytic workup (Scheme 72). Work up with carbon monoxide or iodine resulted in more highly functionalised N-heterocycles. Cyclohydrocarbonylation of heptadiene 64 under rhodium catalysis yielded dehydropiperidine 65 (Scheme 73). 4-Substitution of 64 with a methyl group resulted exclusively in the 174 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 (i) 76-96% 82->97% cis R1O O Scheme 71 Reagents (i) Pd(OAc) (5 mol%) MeSO H benzoquinone RT.R2 R1 OH + R1OH 2 N R R1 N (i) 30-90% R3 R3 63 62 Scheme 72 Reagents (i) Cp ZrBu THF,78 °C to RT then MeOH H O. 4 (i) 88% HNTs N Ts 64 65 CHO Scheme 73 Reagents (i) Rh(acac)(CO) BIPHEPHOS CO H THF 65 °C then SiO . Me HNTs CHO OHC 66 desired ring closed product after 16 h at 45 °C but the dialdehyde 66 was obtained as the predominant product at 60 °C after 24 h. Nucleophilic approaches to pyran and piperidine derivatives have used heteroatom and carbon nucleophiles to e.ect ring closure. The stability of -silyl cations has been harnessed in the synthesis of pyrans.Enantiomerically enriched allyl silanes 67 possessing a distal alcohol were treated with an aldehyde or ketone to yield optically active pyrans 68 (Scheme 74). Intramolecular attack of a nucleophile upon 2- phenyloxetan-3-ols led to heterocycles containing di.erent heteroatoms and having varying ring size. For example removal of the pivaloyl protecting group of 69 with methyllithium generated the corresponding lithium alkoxide which when heated yielded pyran 70 (Scheme 75). Some oxetane 71 was also recovered. Ring opening of epoxides 72 has been used to prepare pyrans 73 (Scheme 76). Stabilisation of propynyl cations by alkyne—dicobalt complexes caused ring closure to proceed via the endo mode rather than the normally expected exo mode. Preparation of an allenyl derivative of pipecolic acid utilised a chiral auxiliary to orchestrate the nucleophilic asymmetric intramolecular addition of a propargylsilane moiety onto an iminium ion 175 Annu.Rep. Prog. Chem. Sect. B 1999 95 157—182 SiMe2Ph HO 2 O R R1 Bu (i) 72-99% 67 + Bu ee=91.5-93.6% trans/cis=9:1->99:1 O 68 R2 R1 Scheme 74 Reagents (i) Me SiOTf CH Cl 78 °C. O CO CO 2 tBu 2 tBu O O + (i) 54% (70) Ph 13% (71) Ph OH Ph OSiMe3 OH OH 69 71 70 Scheme 75 Reagents (i) MeLi DME then re.ux. OH (i) 65-98% O trans:cis=1:99-99:1 OH O R1 R1 (CO)6Co2 72 73 Scheme 76 Reagents (i) Co (CO) CH Cl then BF ·OEt ,78 °C to RT. SiMe3 OH OH H C N Ph NH Scheme 77 Reagents (i) CHOCHO THF H O RT.MeO NHBoc MeO NBoc MeO MeO (i) 70% Et – 75 Ph OH OTf Se+ SeAr (i) 66% de=79% 74 76 O,100 °C. Scheme 78 Reagents (i) 75 Et which was generated in situ (Scheme 77). Intramolecular aminoselenation of the alkene in 74 with the novel selenide 75 a.orded tetrahydroisoquinoline 76 (Scheme 78). It was established that the counter ion in.uenced the diastereomeric excess attained in the product. Using radical based methodology -lactones have been prepared from saturated alcohols and carbon monoxide (Scheme 79). The reaction is believed to involve a 1,5-hydrogen transfer from the -carbon to an alkoxy radical which is formed via a single electron oxidation of the alcohol.Subsequent carbonylation of the -carbon 176 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 O R3 R1 O R4 (i) 32-75% R1 R4 R2 OH R2 R3 Scheme 79 Reagents (i) Pb(OAc) C H CO (80 atm) 40 °C. 2 R2 O Me3SiO H R (i) 65-98% + O ee=70-96% O OMe Scheme 80 Reagents (i) 77 4Å MS BuOMe then CH Cl and TFA. (i) 87-99% + R2 R2 OEt O O OEt O O Scheme 81 Reagents (i) 78 3Å MS THF 0 °C. P(p-Tol)2 P(p-Tol)2 OMe Ts R1 Ts R1 N ee=95-99% 81 N + O CO2Et (i) 68% ee=80% (ii) 70% ee=96% EtO2C Me3SiO R1 R1 79 ·4MeCN (1 mol%) THF,78 °C. 80 Scheme 82 Reagents (i) RH 81 CuClO·4MeCN (10 mol%) THF 78 °C; (ii) RMe 81 CuClO radical produces an acyl radical.Oxidation and deprotonation liberate the -lactones. Considerable advances in the area of hetero-Diels—Alder reactions have been made with a number of groups presenting work in this area. Chiral (salen)chromium complexes 77 catalyse the cycloaddition of Danishefsky’s diene and aldehydes in good to excellent enantiomeric excesses (Scheme 80). Copper complexes of C -symmetric bisoxazoline ligands brought about the addition of activated ketones to analogues of Danishefsky’s diene with high enantioselectivity. Asymmetric inverse electron demand hetero-Diels—Alder reactions of enol ethers with ,-unsaturated -ketoesters catalysed by 78 exhibit high enantioselectivities (Scheme 81). The reaction can tolerate reaction temperatures up to 0 °C without a large drop in enantiomeric excess and signi.cantly in the presence of .orisil the catalyst is adsorbed and may be recycled.An asymmetric variant of the aza-Diels—Alder reaction has been developed (Scheme 82), in which the ethyl glyoxylate-derived imine 79 reacts with 177 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R1 R2 R2 S S (i) 4-98% R4 R3 R4 R3 R2 R2 R1 R1 82 Cl 20 °C. O O + – N N Cr OTf N N Scheme 83 Reagents (i) CH Danishefsky’s and related dienes 80. Of the metal—ligand combinations screened 81—CuClO ·4MeCN proved to be the most active and to provide the best enantiomeric excesses. Thioketones underwent [4 2] cycloadditions to dienes to produce the corresponding cycloadducts 82 (Scheme 83). When monosubstituted dienes were used the preferred regioisomers obtained were ‘meta’ and ‘para’ cycloadducts 83 and 84 respectively.1,3-Dithia-2-ylium ions react with 1,3-dienes (Scheme 84). Mechanistic investigations suggested a stepwise process but did not rule out a concerted pathway involving highly unsymmetrical transition states. Bicyclic phosphines 85 have been prepared by [4 2] intramolecular cycloadditions involving in situ generated carbon —phosphorus dienophiles (Scheme 85). H H R1 R1 O O X tBu H2O Cu OH2 tBu OTf tBu tBu 78 77 3-Hydroxypiperidine N-oxide derivatives 87 have been synthesised via the reverse Cope cyclisation of -hydroxy hydroxyamines 86 (Scheme 86). Previously this reaction has been somewhat neglected due to its reversible nature.In this example the judicious placement of a hydroxy group may stabilise the amine oxide in 87 by hydrogen-bonding. 5 Seven-membered and larger rings Once again ring closing metathesis has been shown to be a versatile method for the construction of rings containing at least seven atoms. The .rst example of RCM on a phosphate template has led to the synthesis of six- to eight-membered heterocycles. For example triene 88 is smoothly transformed into 89 with Grubbs’ catalyst (Scheme 87). A traceless linker strategy allowed immobilised diene 90 to be cleaved by RCM to produce 91 (Scheme 88). Ring closing metathesis of functionalised alkyne derivatives has led to surprisingly good yields of twelve-membered or larger rings (Scheme 89). A range of functionality is tolerated in this transformation resulting in the formation of lactones lactams and cyclic silyl ethers.Finally RCM has been used to 178 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 R1 R2 S S R4 R3 R4 R3 83 84 R1 R1 BF4 S+ S+BF4 + (i) 64-84% S R2 R2 S Cl 25 °C. R1 R2 P R2 85 Scheme 85 Reagents (i) C H N,60 to 20 °C or Et N30 to 20 °C. R1 R1 HO (i) 51-82% Scheme 84 Reagents (i) CH Cl R1 P (i) H HO N Bn OH N+ Bn O– 86 87 re.ux. O O P O O P O Scheme 86 Reagents (i) CHCl O (i) 75% 88 89 ) RuCHPh (3 mol%) CH Cl re.ux.SO2(p-NO2C6H4) N SO2(p-NO2C6H4) (i) 54% CO2Me CO2Me 91 Scheme 87 Reagents (i) Cl (PCy O O N O 90 Scheme 88 Reagents (i) Cl (PCy ) RuCHPh (5 mol%) styrene PhMe 50 °C. 179 Annu. Rep. Prog. Chem. Sect. B 1999 95 157—182 X X R2 R1 Scheme 89 Reagents (i) [W(— (i) 52-97% — — CCMe )(OCMe ) ] C H Cl 80 °C. X X Leu Aib Val Leu OMe Boc Val O O (i) 85% or (ii) 90% H BocN O O MeO2C Scheme 90 Reagents (i) XOHSer Cl (PCy ) RuCHPh (20 mol%) CHCl 25 °C; (ii) XOHHse Cl (PCy ) RUCHPh (20 mol%) CHCl 25 °C. cross-link peptides (Scheme 90). 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