Saturated nitrogen heterocycles TIMOTHY HARRISON Merck Sharp and Dohme Reseurch Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Hurlow, Essex CM20 2QR, UK Reviewing the literature published in 1995 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 209 Three-membered rings Four-membered rings Five-membered rings Six-membered rings Pyrrolizidines, indolizidines and quinolizidines Tetrahydroquinolines and tetrahydroisoquinolines Miscellaneous methods for the synthesis of nitrogen heterocycles of varying ring sizes Medium and large ring nitrogen heterocycles References 1 Three-membered rings Heteroaryl aziridines 2 (Het = 2-pyridy1, 2-quinolyl and 2-benzathiazoyl) of (E)-configuration have been prepared by the diastereoselective Darzens-type reaction of (heteroaryIchloromethy1)lithiums 1 with imines.The (heteroarylch1oromethyI)lithium species are readily available by lithiation of the corre- sponding chloromethyl heterocycles (LDA, THF, -78 "C), and the addition works well with both nonenolizable and enolizable imines.' Diary1 aziri- dines 4 can be prepared in moderate to good yields by reaction of cis-p-sultams 3 with SnCl,. The desired product is accompanied by smaller amounts of benzophenone derivative 5 . If the truns-/hultams are used, then the benzophenone derivatives predominate .2 1 2 n 3 4 5 Relatively sensitive N-tosyl vinyl aziridines 7 can be prepared in moderate to high yield by the Cu(acac)2-catalysed aziridination of 1,3-dienes using PhI=NTs. Both acyclic and cyclic dienes can be used, and in some cases the reactions appear to be stereospecific with retention of double bond geometry.For unsymmetrical dienes, the more electron rich double bond undergoes aziridination, and when two double bonds are electronically similar, steric factors govern the selectivity.3 Matano et al. have reported a direct route to 2-acylaziridines 11 starting from imines 10 utilising a bismuthonium ylide 9 generated in situ from bismuth salt 8. This mode of reaction stands in marked contrast to that of phosphonium ylides, and the cisltruns stereo- chemistry of the products can be controlled by proper choice of base and additi~e.~ -78 *c II c) 8 9 1 R2CH;NS0,R3 5 0 ~ ~ 3 r% R' + Ph3Bi 0 11 A number of papers detailing asymmetric syntheses of aziridines have appeared.Thus, Jorgensen et al. have reported the preparation of aziridines 13 via the addition of ethyl diazoacetate to imines 12 catalysed by simple copper complexes. The diastereoselectivity and yield of the reaction is very dependant on the nitrogen substituent R2, with phenyl giving the highest yields and silicon the highest diastereoselectivity. The incorporation of a chiral auxilliary in the diazoacetate portion produced products with a low de, and the use of Harrison : Sot ura ted nitrogen heterocycles 259Cu(OTf), in the presence of a chiral oxazoline ligand produced aziridines with low eek5 In a related study Jacobsen et al. have reported the same reaction using N-aryl benzylidine imines 14 as precursors and copper( I) hexafluorophosphate as the catalyst in the presence of homochiral bis-oxazo- lines.At present enantiomeric excesses are low to moderate, and efforts to extend this aziridination methodology to other classes of imines have not been fruitful. In some instances racemic pyrrolidines 15 are also produced in the reaction.6 HkZ2 R' 12 t 13 R' = Ph, Bu', H R2 = Ph, Pr', But, SiMe H 14 ' g - - H C02Et + Ar'--fyCO2Et c' N Ar' 'A? EtQC 'C02Et major (1 147% ee) mc -1 5 Both Davis7 and Ruano8 have reported the asymmetric synthesis of 2-substituted aziridines by addition of dimethyloxosulfonium methylide to enantiomerically pure sulfinimines 16. In the Davis work the de's proved to be relatively insensitive to the reaction conditions (58-70% de). After separa- tion of the diastereoisomers, the N-sulfinyl group can be removed by treatment with 1.5 equiv.of methyllithium at - 78 "C followed by quenching with sat. NH4Cl. Davis et al. have also reported an asymmetric synthesis of 2H-azirine 2-carboxylic acid derivatives 18 by LDA-induced deprotonation of aziridines 17 in the presence of iodomethane.' The 2H-azirine structural unit is found in a number of natural antibiotics. Me3S(0)CI, base H N A2 (W+)-16 MeLi. M F R2 = S(0)Ar -78°C H i. LDA, -78 "C ii. Me1 H Y H iii. H20, THF R H RXco2Me S(0)-tolyl-p 17 18 2 Four-membered rings Seebach et al. have described a new synthetic approach to the relatively unexplored azetidine- 3-one derivatives 20. Thus amino acid derived diazo ketone 19 undergoes Rh"-catalysed cyclisation to provide the products in 5040% yield after chromatography." R 19 20 3 Five-membered rings The asymmetric synthesis of pyrrolidine derivatives by 1'3-dipolar cycloaddition of azomethine ylides with alkenes in the presence of chiral controller groups continues to attract attention.Grigg et aZ. have shown that metallo-azomethine ylides 21, generated from imines by the action of amine bases, undergo cycloaddition with menthyl acrylate 22a at room temperature to give homochiral pyrrolidines 23 in excellent yield. The absolute configuration of the newly established pyrrolidine stereocentres is independent of the metal salt and the size of the pyrrolidine C(2)-substituent for a series of aryl aliphatic imines. In addition, other electron- withdrawing groups can replace the ester in the starting imine (e.g 24)." Similar work has also been reported by Waldmann et aZ.in which N-metallated azomethine ylides 21 add to N-acryloyl-(S)-proline 0 21 I R'OC- 0 R* I? . 24 23 260 Contemporary Organic Synthesisesters 22b again with high diastereoselectivity furnishing pyrrolidines 23. l2 The homochiral oxazolidinone 25, which is a useful precursor for the synthesis of non-proteino- genic amino acids via Diels-Alder reactions, allenyl radical and nitronate anion 1 ,Zadditions, and cyclo- propanation, undergoes highly exo-diastereoselective 1,3-dipolar cycloadditions with azomethine ylides 26 derived from a-amino acids to provide cycloadducts 27. These are readily converted to polyfunctional prolines 28 (Na2C03, MeOH) with high enantio- meric purity.13 R' LiBr, DBU, THF PhANk:02R2 -780c L J 26 4 25 0 H 28 27 '*- -I- R2\[rNAF1' AgOAc, DBU R:, 0 0 THF 29 R ~ O C ~ R' H A full account of the diastereoselective synthesis of pyrrolidines by reaction of homochiral a, p- unsaturated ketones 29 bearing alkoxy or amino substituents in the y-position with azomethine ylides has appeared.I4 Harwood et al.have extended the scope of dipolar cycloadditions based on the morpholinone 30 by using ethyl glyoxylate as the condensing agent. The resulting (E)-ylide 31 under- goes highly diastereoselective cycloaddition with a range of dipolarophiles, and removal of the template from the cycloadducts 32 furnishes enantiomerically pure pyrrolidine-2,5-dicarboxylate derivative^."^ The use of formaldehyde as the condensing agent has also been de~cribed.'~~ Coldham et al.have described the synthesis of pyrrolidines by 1,3-dipolar cycloaddition of con- jugated azomethine ylides 34. These are generated in situ from a mixture of azido alcohols 33 by treat- ment with Ph3P to form the aziridine and then thermal ring opening. The ring opening is conrota- tory generating cis-2,5-disubstituted pyrrolidines 35. In all cases the endo-cycloaddition products were observed. l6 H H 30 31 32 Ph v C 0 2 E t ?H + Ph& .-' C02Et N3 33 OH 34 1 M e o 2 C ~ C o 2 M e Ph %CO2Et H Me02C 35 1,3-Dipolar cycloadditions using dipoles other than azomethine ylides can be used to prepare pyrrolidines. Treatment of aldehyde 36 with N-alkyl hydroxylamine gives the nitrone 37 which undergoes intramolecular cyclisation yielding the bicycles 38. The reaction proceeds with high diastereoselectivity.Cleavage of the cycloadducts with zinc in acetic acid-H20 at 70 "C provides the homochiral pyrro- lidin-2-ones 39, while reduction with LiAlH, provides pyrrolidines 40.17 Hassner et al. have described the Michael addition of secondary allylamines to nitroalkenes and subsequent trapping as the 0-silyl a-allylamino- alkylnitronates 41. These undergo stereoselective intramolecular silylnitronate-olefin 1,3-dipolar cycloaddition to provide highly functionalised pyrro- lidines in a one-pot operation.l8 The dithiolane-isocyanate imminium methylide 43, generated by desilylation of readily available salt 42, undergoes efficient cycloaddition to electron deficient dipolarophiles to yield lactams 44 following hydrolysis of the intermediate dithiolanes.l9 Enantiomerically enriched pyrrolidines 48 can be prepared by the Lewis acid promoted [4+2] cyclo- Harrison: Saturated nitrogen heterocycles 2610 L 36 37 39 40 addition with chiral vinyl ethers 46.20 The resulting cyclic nitronates 47 are reduced with H2 (160 psi) in the presence of PtO,. Yields are generally good. Coldham et al. have reported a new route to pyrrolidines by MeLi-promoted anionic cyclisation of the (aminomethy1)stannane 49 onto the proximal unactivated alkene. The resulting organolithium reincorporates trimethyltin to give the function- alised pyrrolidine 50. Cleavage of the trimethyltin group with ceric ammonium nitrate in MeOH provides the acetal 51.,' I 0.2 eq MeLi N,SnMe3 THF, %Me4 * LPh (70%) 49 50 i. HCI ii.CAN, MeOH I cat. TsOH MxoMe 51 41 In a reversal of the normal reactivity pattern, pyrrolidines 53 can be prepared by intramolecular R' R' ?SiMe3 nucleophilic substitution on nitrogen by a carbon- based anion, using the diphenylphosphinoxyl group as leaving group. The cyclisation precursors 52 are readily prepared from oximes.2' I R2Nb-FH * BU4NFSTHF R ~ N 3o R3 R3 42 + - 42? 0":: - o,+ 0 H& R' 43 hydrolysis 1 E Me t F?? Tco2Et B"'oK_ or LDA pzo2Et ox R 53 0 I I X = H Et3N Ph2PCL I X = P(O)Ph2 52 44 In an extension of their work on the chemistry of diene-magnesium reagents, Rieke et al. have described a facile one-pot synthesis of y-lactams from conjugated dienes and imines (Scheme 1). The bis-organomagnesium reagent 54 reacts with complete regioselectivity in the 2-position in the initial step to give intermediate 55.Carboxylation and acidic hydrolysis provides lactams 56. The imine derived from cyclohexanone has also been used in this ~equence.'~ 0 + 0 R' R2 'V? .R2 -k 1:; LA R3 45 46 47 I %02 H The direct electrophile induced cyclisation of alkenylamines to nitrogen heterocycles has been R' R' 48 rarely employed in synthesis due to competing side- reactions associated with the process. However, 262 Contemporaly Organic Synthesis54 55 56 Scheme 1 imines 57, readily derived from primary homoallylic amines and aldehydes, undergo regioselective cycli- sation in the presence of electrophiles (Brz or phenylselenyl bromide) to provide pyrrolidines 58 in good yield. The bromine or selenium substituent is readily removed under radical reduction condi- tions.24 Electrophilic cyclisation can also be used to prepare bis-trifluoromethyl substituted 2-aryl pyrro- lidines 61.Thus ene reaction of 4-ally1 anisole 59 with N-tosylhexafluoroacetone imine provides the amine 60, which cyclises in the presence of toluene- p-sulfonic acid to give the pyrrolidine 61. The reaction appears to be limited to a-aryl substituted amines 61 which are able to form a benzylic cation.2s 57 9 Br2 or PhSeBr R'# R1' 50 Bu3SnH or Ph3SnH, E = Br, SePh PhCHB E = H "TS 'ene' @ + F3CACF3 N HTs OMe 59 60 gTsOH xylene I Ph q 2 3 I Ts 61 Radical-based methodologies for the synthesis of pyrrolidines continue to prove fruitful. Ikeda et al. have reported a 5-endo-trig radical cyclisation of acetamide derivatives 62 providing pyrrolidinones 63.In order for the cyclisation to proceed effect- ively, it is necessary that the developing x-acylamino radical in the transition state of the cyclisation must be stabilised by an aryl or an alkyl group (ie. R' is not H), otherwise simple reduction of the substrate is observed.26 Murphy et al. have described an elegant approach to the ABCE tetracycle of aspido- spermidine and related alkaloids 65 by tandem radical cyclisation of the iodo azide precursor 64, mediated by tris(trimethylsily1)silane (TTMSS) and AIBN. This work further demonstrates than an aryl C-I bond can be selectively reduced in the presence of an azide using TTMSS.27 * b0 R21Ni;;l R' Me AIBN R' Me Bu3SnH 62 (R' # H) 63 r N 3 r N H alyJ :;:s- Q-(J Y " 80 "C, PhH (95%) S02Me Y S02Me 64 65 Buchwald et al.have demonstrated that the pyrro- lidine ring system 67 can be assembled by reductive cyclisation of the enone 66 by a titanium catalyst.28 The key to the success of this approach is the use of Ph2SiH2 to cleave the Ti-0 bond in the metallocycle and regenerate the catalyst. The product is formed as a 1 : 1 mixture of diastereoisomers. lidines 69 through a five-step sequence which is formally equivalent to a disfavoured direct 5-endo- Homoallylic amines 68 can be converted to pyrro- 66 Ph 67 60 69 Harrison : Saturated nitrogen heterocycles 263Ph MeH R3R2NH pt+ ( R = I R2NH2 * C P f R 1 ')$-$NR2R3 * (R R' = = Me, Ph) R' =Me) 0 0 0 70 71 ,NR2R3 H N b 73 74 1 F' Scheme 2 trig ring closure from 68." The approach involves epoxidation, intramolecular epoxide opening by a carbamate group and a final zinc mediated reductive cleavage-reductive amination from an intermediate 1,3-0xazine-2-one.A series of publications by Meyers et al. has described the synthesis of pyrrolidine derivatives using the chiral bicyclic lactam 70 as starting material (Scheme 2). Thus, reaction of 70 (R =I) with a variety of primary amines afforded endo-aziri- dinolactams 71 (60-92% yield). Treatment of these lactams with AlH, provided the N-substituted pyrro- lidines 72 in which the angular methyl group has undergone facial inversion in the major diastereo- isomers (95 : 5). The N-substituent can be removed by hydrogenoly~is.'~ Alternatively, bicyclic lactam 70 (R = H) undergoes highly diastereoselective conjugate addition of primary amines to afford homochiral 3-amino pyrrolidines 73 after reductive cleavage.Typical yields ranged from 80-90% with facial diastereoselectivities ranging from 95 : 5 to =- 98 : L3' Finally, addition of methylenedithiolane to 70 (R =H) occurred with very high endu-selectivity to give the cyclobutane adduct 74. Reductive removal of the sulfur (Raney Ni), cleavage of the chiral auxilliary with inversion of the angular methyl group (Et3SiH, TiC14) and removal of the phenyl glycinol moiety (Na-NH,) provided the enantio- merically pure pyrrolidine 75 (R' = Me).32 The ruthenium catalyst [Clz(PCy3)2Ru=CH- CH=CPh2], introduced by Grubbs for olefin metathesis, effects clean metathesis of the diene 76 leading to the unsaturated pyrrolidine 77.33 2-Substi- tuted pyrrolines can be prepared using the intra- molecular 'carbocation' version of the Schmidt reaction.Thus, 4-substituted but-3-enyl azides 78, CI~(PC~&RU=CH-CH=CP~~ (cat.) PhH, rt, 32 h - Bu'O (95%) 'OH 77 bH 76 78 R = Ar, ~r*' ArQ I A r G + NEN 79 upon treatment with CF3S02H at 0 "C, provide cyclic imines 79.34 Alper et nl. have described the Pd"-catalysed cycloaddition of stereochemically defined aziridines (e.g 80) with heterocumulenes (carbodiimides, isocyanates and isothiocyanates), leading to 5-membered ring heterocycles 81. The reaction is both regio- and stereo-specific, the cycloaddition occurring with retention of stereochemistry at the Wo2" Y + 1 80 X=C=Y R02C L Y 20 h, g-psi N2 a1 X Y ArN Am 0 ArN ArN S 264 Contemporay Organic Synthesisaziridine carbon centres, providing an enantio- specific general method for the synthesis of imidazolidinones, imidazolidinimines and thiazoli- dinimine~.~~ Finally, Watanabe et al.have utilised the deoxy- genating capability of carbon monoxide to effect a novel synthesis of 1 -pyrroline derivative 83 from aliphatic y-nitrocarbonyl compounds 82. The reaction is catalysed by a Ru3(CO),,-l,10-phen- anthroline system and is thought to proceed via a ruthenium nitrene intermediate.36 + 3 co 83 Ph Ph 88 R' ,-Qco2B"H b"' 89 90 4 Six-membered rings Ghosez et al. have described the Diels-Alder reaction of a, P-unsaturated hydrazones 84 bearing an ester or a nitrile at C-2 with electron-deficient dienophiles. Dramatic rate enhancements are observed if reactions are conducted in concentrated 2Ph3PCH3Br ~ f), R C02Bu' dph Bu;,DME Bu""2c> H R organic solutions of LiNTf, (a useful replacement for LiC104).37 Electron deficient 2-azadienes 86, which are prepared by aza-Wittig reaction of N-vinylic phosphazenes 85 with carbonyl com- pounds, undergo inverse electron demand Diels- Alder reaction with alkenes leading to the formation of tetrahydropyridines 87.38 x x 'y NMe2 84 X = CN, C02R 85 86 87 Trova et al.have utilised an asymmetric aza- Diels-Alder reaction in the construction of the bicyclic piperidine 88, a substructure found in a number of HIV-1 protease inhibitor^.^^ Both S ~ m f a i ~ ' ~ ~ ~ and C l d h a m ~ ~ ~ ~ ~ have used the aza-[2,3]-Wittig rearrangement for the construction of tetrahydropyridines. In the Somfai work, treat- ment of vinyl aziridines 89 with LDA resulted in smooth and rapid ( < 5 min) conversion to tetra- hydropyridines 90 in high yield and as a single diastereoisomer.Coldham et al. have utilised 2-keto 91 92 R = Me, Bu, Pt' aziridines 91 as starting materials. Treatment with 2 equiv. of a phosphonium ylide again generates vinyl aziridines which rearrange to provide cis-2,6-disub- stituted tetrahydropyridines 92. Muzart et al. have described the stereoselective synthesis of vinylmorpholines 94 by the palladium- catalysed tandem allylic substitution of butenediol derivatives 93 with enantiopure amino In a similar approach Achiwa et al. have demonstrated that both vinyl morpholines and vinyl piperazines 95 can be prepared with low to moderate ee's by reaction of the bis-acetate 93 with achiral amino alcohols and diamines in the presence of a chiral palladi~m(O)-catalyst.~~ Rhodium catalysts have also been used for construction of the piperidine ring system.Thus, intramolecular cyclohydrocarbonyla- tion of the unsaturated amine 96 in the presence of Rh(acac)(CO)2 (1 mol%) and BIPHEPHOS (2 mol%) provided the pipecolate derivative 97 in quantitative yield. The alkoxy group of 97 undergoes highly diastereoselective substitu- tion with cuprate reagents via an iminium ion inter- mediate to give trans-2,6-disubstituted MeNH kPh OH Pdo THF + - AcO Me-N kPh 93 94 95 Harrison: Saturated nitrogen heterocycles 265Rh(aca~)(CO)~ 96 97 Deziel et al. have described a very facile synthesis of heterocycles via asymmetric ring closure mediated by the chiral C2 symmetrical organo- selenium reagent 99.Thus, treatment of the carba- mate 98 with 99 in CH2C12 in the presence of 2.5% v/v methanol provides the piperidine 100 in 89% yield and with 25 : 1 diastereoselectivity. The selenium moiety is readily removed under radical conditions (Ph,SnH, AIBN).47 Ph- NHBoc 98 + OTf I w CHpClp cat. MeOH -78 + -90 "C I BOC 100 99 Overman et al. have described a carboxylate- terminated N-acyl iminium ion bis-cyclisation 101-+102 for construction of the D and E rings of the heteroyohimbine alkaloid ( - )-ajmalicine en route to a total ~ynthesis.~' A related cyclisation provides the central step in an approach to ( + )-e~iajmalicine.~' W N J Ar (HCHO), Tf 0- 1 : 1 TFA-CHC13 Tf "=Lm Tf "Go C02R 101 102 iq- 0 3-Hydroxy piperidines 104, which may contain a quaternary centre at C-3, can be easily prepared with ee's up to 97% by ring expansion of prolinol derivatives 103.The reaction likely proceeds via an aziridinium intermediate.49 Alternatively, optically pure cyclic enamides 105, available via a three-step sequence starting with Oppolzer sultams, undergo trans-selective hydroborations providing 3-hydroxy piperidine derivatives 106 in good yield and with high diastereoselectivity." Altenbach et al. have described a concise route to the highly functionalised dihydropyridine derivative 108, an intermediate which should prove to be useful in the synthesis of a range of polyhydroxy- lated piperidines (azasugars). Thus, the readily available protected amino alcohol 107 undergoes stereocontrolled oxidative cyclization in the presence of MCPBA providing 108 after acetal formation." i.(CF3CO)p0, THF, reflux ii. Et3N iii. NaOH (10%) R R OH R &OH I 103 104 i. BH3*SMe2, THF "O'G>- * R2 'R2 ii. H202,NaOH O A R ' OAR1 105 106 i. MCPBA CH Clp 30 "C, 4.k h (270%) OAc ii. EtOH, * EtO'. CdNH4)2(N02)6 Ts OAc rt, (95%) NHTs 1 07 108 The use of homochiral bicyclic lactams 110 for the synthesis of homochiral 2-substituted piperidines has been described by Meyers et al. Reduction of 110 using Red-A1 in refluxing THF provides N-substi- tuted piperidines 111 in high yield and with excellent diastereoselectivity. The N-benzyl substituent can be easily removed by hydrogenation. In order to improve the generality of this method Meyers has demonstrated that a range of 1,5-keto acids 109, the condensing partners with phenyl- glycinol in the preparation of bicyclic lactams 110, are readily prepared by low temperature addition of Grignard reagents to commercially available methyl 4- (chloroformy 1) butyrat e (Scheme 3).'* 0 C02Me 109 (S)-phenyl I glycinol t Red-Al, THF R' H OH 111 0 110 Scheme 3 Bicyclic lactam chemistry can be extended to provide a novel asymmetric route to homochiral cis- 2,6-disubstituted piperidines such as 114. Thus, the vinylogous urethane 113, which can be prepared from the bicyclic thiolactam 112 via Eschenmoser contraction, undergoes highly diastereoselective hydrogenation in the presence of Pd(OH),-C to provide 114 in a single step.53 266 Contemporary Organic SynthesisS 112 113 ‘C02Me C02Me H R’ 114 Finally, Jacobsen et al.have described methodo- logy (diastereoselective triflate alkylation and novel intramolecular Mitsunobu reaction) for the asymmetric synthesis of the complete series of enantiopure 2,6-methylated pipera~ines.~~ 5 Pyrrolizidines, indolizidines and quinolizidines Denmark et al. have described a general strategy for the synthesis of cis-substituted pyrrolizidine based alkaloids such as (-)-rosmarinecine 119. The key feature of this strategy is a tandem [4 + 2]/[3 + 21 cycloaddition sequence involving the fumarate- derived nitroalkene 115 and the chiral vinyl ether 116. The reaction proceeds with very high diaster- eoselectivity (25 : 1 exolendo) and in high yield (96%). The tricycle 117 is readily converted to the lactam 118 with recovery of the chiral auxiliary, and thence to (-)-rosmarinecine 119 following Mitsunobu inversion of the alcohol at C-6 (Scheme 4).’5 115 + ” v 116 U 117 Ph Ph 119 Scheme 4 118 Petrin et al.have used the homochiral nitrone 120, which is readily available in five steps from L-tartaric acid, in a stereoselective total synthesis of ( + )-lentiginosine 123. Addition of the Grignard reagent 121 to this nitrone proceeds with 90% de and in 82% yield to yield the hydroxylamine 122. Reduction and cyclisation then provides the natural product.’‘ 0- OH 120 122 It 1 23 Both the indolizidine and pyrrolizidine frame- works can be accessed via [2+2] cycloaddition of endocyclic enecarbamates 124 to alkyl ketenes 125. The endolexo ratio in the cycloadduct 126 is dependent on the reaction conditions and the struc- ture of the ketene.The exo-cycloadduct 126 (n = 1) undergoes highly regioselective Baeyer-Villiger ring expansion with MCPBA and the resultant lactone 127 is converted to the new, nonnatural indolizidine 128 (n = 1) in two simple stepss7 F? H \ ___) hexane *Ho reflux Z” Q + H t CI )n 124 125 c’ 126 n =0,1 MCPBA I 128 127 Both the amide 129a (X=O, R = H ) and the carbamate 129b (X = HZ, R = Boc) undergo highly diastereoselective intramolecular conjugate addition leading to piperidines 130, which are useful inter- mediates for the total synthesis of (+)-swainso- nine.58 Pilli et al. have described a one-pot preparation of quinolizidine-2-one and indolizidin- 7-one ring systems based on the addition of dienes 131 to cyclic N-acyliminium ions 132.59 Harrison: Saturated nitrogen heterocycles 267TBSO BU'OK, THF t &CO,Me 129a X=O,R=H 129b X = H2, R = BOC ir".- -55 "C X 130 The indolizidine (-)-slaframine 135 can be accessed via the bicyclic lactam 134 which in turn can be prepared by intramolecular aldol reaction of ketoaldehyde 133.60 The ketone carbonyl in 134 can be reduced with high diastereoselectivity using the Corey oxazaborolidine. Suitably activated proline derivatives such as 136 undergo 5-exo-trig cyclisation to provide the pyrrolizidine ring system 137 with retention of optical integrity. If the corresponding methyl ester is used in the cyclisation then racemisa- tion occurs.61 do 0 uo HNZ 133 piperidine, THF, t 6 ~ rt, 24 h then H30+, 1 h 0 NH2 HNZ 134 135 t 'N' y" THF.-78 "C 0 A 2h 0 P 136 137 The lactam 139 is a pivotal intermediate which can be used to prepare a range of indolizidines containing alkyl substituents at the 3-, 5- and 8-positions. This intermediate is readily prepared from the dianion of 4-(phenylsulfonyl)butanoic acid 138.62 f alkylation/deprotection cyclisation, 0 chain extension 138 chain introduction 139 The umpolung of reactivity offered by electron transfer has been utilised in an approach to indolizi- dine and quinolizidine derivatives based on cathodic cyclisation. Thus the pyridinium salt 140 undergoes diastereoselective cathodic cyclisation to give a mixture of regioisomeric hydroxy alkenes 142 with the same relative stereochemistry. The diastereose- lectivity of the reaction may occur through the hydrogen-bonded transition structure 141.63 U 1 40 - le- t ___) %OH+% H 141 1 42 6 Tetrahydroquinolines and tetrahydroiso- quinolines Kobayashi et al.have demonstrated that rare earth metal triflates [Ln(OTf)3 or Sc(OTf),] are excellent catalysts for the reaction of imines with silyl enolates and for the Diels-Alder reaction of imines with d i e n e ~ . ~ ~ , ~ ~ The latter reaction can provide tetrahydroquinolines 143 in good yield. Alterna- tively, cationic 2-azabutadienes 144, which are considerably more reactive and selective than their neutral counterparts, undergo highly regio- and diastereo-selective [4n+ + 2n] cycloaddition with various dienophiles to give tetrahydroquinolines 145 in good yield.66 Sc(0Tf)s (20 mot%) MeCN,rt, "Ph A,, + Ph 85% Ph 143 R QNfisR Tic14:pph3*[ Q,] L pJ$ I I 144 1 45 l-Formyl-1,2-dihydroquinolines 148 are readily accessed in a reasonably efficient manner by the BF3-catalysed cyclisation of phenyl isocyanides 147.These intermediates are in turn prepared from (0-acylpheny1)formamides 146 following Grignard addition and dehydrati~n.~~ 268 Conternporaly Organic Synthesisp3 R3 0 146 1 47 0.1 BF39Et2 1 CH2CI2,O O C t I CHO 148 Over the years, the Pictet-Spengler reaction has developed into one of the most important methods for the synthesis of nitrogen heterocycles. Nakagawa et al. have reported that the homochiral tryptamine derivative 149 undergoes diastereoselective Pictet - Spengler reaction providing tetrahydro-P-carbolines 150 with de's of up to 72%.68 Waldmann et al.have reported that diastereoisomeric ratios of > 99 : 1 can be achieved in the same reaction by using N-acyli- minium salts such as 151 which bear an N,N-phtha- loyl amino acid as chiral auxiliary which can be readily removed by reduction of the amide bond 'using LiAlH4.69 Two reports from Katritzky describe novel routes to both 1,3- and 1,4-disubstituted tetrahydroq~inolines~' and 4-(dialky1amino)tetra- hydroq~inolines~' starting from benzotriazole-based precursors. (S )-149 1 50 + c1;- 0 0 cr Meyers et al. have extended their chiral bicyclic lactam chemistry to provide a general route to 1-alkyl- and 1-aryl-tetrahydroisoquinolines. The application of this chemistry to the synthesis of the isoquinoline alkaloid ( + )-cryptostyline 154 is outlined in Scheme 5.Condensation of the keto acid 152 with (S)-phenylglycinol provides the diastereo- isomerically pure bicyclic lactam 153 in 61% yield. Reduction (LiAlH4, 14 : 1 mixture of diastereo- isomers) followed by debenzylation and methylation provides 154 in exellent yield.72 Finally, Heaney et al. have provided a full account of their work on the synthesis of N-(arylmethy1)tetrahydroisoquinolines starting from bis-amino1 ethers.73 (S )-phenylglycinol OMe Me0 t PhCH3, reflux I OMe 152 Scheme 5 It 0 153 i. LAH, THF ii. HP, Pd-C iii. H2C0, HC02H 1 I OMe Me0 Q OMe 154 7 Miscellaneous methods for the synthesis of nitrogen heterocycles of varying ring size The use of N-acylnitroso Diels-Alder methodology for the synthesis of nitrogenous natural and the use of amino acid esters as chiral auxiliaries for the asymmetric synthesis of nitrogen hetero- c y c l e ~ ~ ~ has recently been reviewed.Pearson et al. have utilised their 2-azaallyl cycloaddition methodology in an extremely concise synthesis of the amaryllidaceae alkaloids ( - )-amabiline and (-)-augustamine. In a key step the 2-(azaally1)- stannane 155 undergoes intramolecular cyclo- addition upon transmetallation at - 78°C to provide a 5 : 1 mixture of the diastereoisomeric hexahydro- indoles 156. The major isomer undergoes further cyclisation in the presence of Eschenmo~ers~s salt to give (-)-amabiline 157 in excellent yield.76 In a series of two publications Livinghouse et al. have described the scope of acynitrilium ion initi- ated cyclisations in heterocycle s y n t h e ~ i s .~ ~ , ~ ~ The application of this methodology to alkaloid synthesis is demonstrated by the spiroannulation of the iso- nitrile 158 to provide bicycle 159, a potentially Harrison: Saturated nitrogen heterocycles 269xo&NvSnBu3 0 155 i. 1.9 eq BuLi ii. H20 THF, -78 "C 74% I H I H + ) L o O.C;;;? H I H 5 1 156 i. Me2N=CH2 r, MeCN, A ii. HCI, MeOH, I + 85% Hwo \ / 9 1 57 L + 'R 158 Me0 (-yo 0 159 useful intermediate for the synthesis of the alkaloid serratine. An alternative entry into polycyclic alkaloid skeleta has been reported by Feldman in which the unique ability of an iodonium species to form two bonds in tandem by nucleophile capture and subse- quent C-H insertion is exploited. The reactive iodonium species 160b is generated from the stannane 160a and undergoes cyclisation-insertion to provide bicycles 161.The reaction is successful for n = 1-3 (but not 4) and subsequent alkylidine carbene insertion occurs into a range of C-H bonds (primary, secondary and tertiary) in line with the high reactivity of these specie^.'^ Negishi et al. have reported an approach to bicyclic and tricyclic lactams 163 in which acyl palladium intermediates, the products of carbo- palladation of alkynes 162, are trapped intra- molecularly using an internal nitrogen nucleophile. I 160a X = SnBu3, A = H 160b X = IPh' OTf, A =a ii. Bu'OK, THF i. PhICNOTf Ts H 161 9' I - R' CO, cat. PdL,, base LNHZ d 162 163 R', R2 = 2 or 3 atom tether 2 = H, alkyl, acyl, sulfonyl Scheme 6 Both modes of cyclisation have been demonstrated (Scheme 6).80 A similar approach to a, P-unsaturated lactams 165 by Pd-catalysed intramolecular carbonylative coupling of amino vinyl triflates 164 has been described by Crisp." 0 Pd(Ph3P)o Bu~N c or CO (1 am) or MeCN, 65 "C OTf &;HBn 164 0 h k n 165 An unusual synthesis of lactams has been described by Mori et al.in which alkynyl amino derivatives 166 react with Fischer chromium carbene complex 167 to generate a vinyl ketene complex which is attacked by the tethered sulfonarnide. Yields are good for the synthesis of 4-7 membered ring lactams.82 The use of zirconium y2-imine complexes for the construction of nitrogen hetero- cycles has been reported by W h i t b ~ . ~ ~ 270 Contemporary Organic SynthesisOEt Me i. (co),cr=( 167 THF, reflux ii.[FeClp(DMF)d[Fe&] ( I HF;' Ts Ts 166 X The intramolecular aza-Wittig reaction is a powerful method for the construction of nitrogen heterocycles and has recently been used to prepare 174-benzodiazepin-5-one derivatives 168 in moderate to good yield, (Scheme 7).84 Pearson et al. have extended the scope of the intramolecular Schmidt reaction of carbocations with azides to include aliphatic azides. This method can be used to prepare a variety of saturated nitrogen heterocycles of varying ring sizesE5 168 Scheme 7 Scheme 8 169 The synthesis of azacycles using radical based methodology continues to attract interest. Lee et al. have reported an efficient synthesis of 5- and 6-membered heterocycles 170 by radical cyclization onto @-amino acrylates 169. In general diastereo- selection is not high, and 7- and &membered rings are not readily accessible.However, starting with cyclic amino acids as precursor the indolizidine and pyrrolizidine skeleta can be readily accessed, and stannyl ketyl radical precursors 171 can be employed in the radical cyclization although the reaction is slower (Scheme In contrast to aryl radicals, which prefer to cyclise onto imines in a 6-endo sense, sp3 carbon-centred radicals undergo predominantly 5-exo or 6-ex0 cycli- sation onto either the carbon or nitrogen atom of imines. This finding has been utilised in a synthesis of nitrogen heterocycles 172 using tandem radical cyclisation of imines. Addition of Lewis acid facili- tates the tandem reaction, and a number of cyclisa- tion modes have been demonstrated leading to a variety of ring systems (Scheme 9).87 Ikeda et al.have described a synthesis of the bridged azabicyclic compounds 174 and 175 using radical translocation of the proline-derived bromo- benzoyl derivatives 173. The regiochemistry (5-exo vs. 6-endo) of this cyclization can be controlled by 170 I C02Me 171 Bu3SnH, AIBN, PhH (0.025 mol dm -3), reflux, 24 h C02Me C02Me 65% 32% (mR1 / \ * (mR, ' \ R2 MgBr2 R2 MgBr2 A2 1 72 . Scheme 9 substitution of the prop-2-enyl group, and substituents at the 2- and/or 4-position(s) of the pyrrolidine ring play an imporant role in this cyclisation." Harrison: Saturated nitrogen heterocycles 271Me02C NBz &Me 10-20% Pd(0AC)p NaHC03 (2.5 eq) Bu~NCI (1 .O eq) 3 A molecular sieves, MeCN, 95 "C, 16.5 h Bu3SnH, AIBN, 174 c PhCH3, reflux and/or 173 175 8 Medium and large ring nitrogen heterocycles A range of methods have been reported over the last year for the construction of medium and large ring nitrogen heterocycles. Aryl iodides tethered to dehydroalanine units by two to four methylene units 176 undergo endo-selective Heck cyclisation under anhydrous Jeffrey conditions to provide 7-, 8- and 9-membered heterocycles 177.89 Rigby et al.hav 176 n =1-3 Qco2Me 177 reported that the enamide 178 undergoes predominantly the expected exo-cyclisa- tion under 'standard' Heck conditions [Pd( OAc)* (10 mol%), (o-Tol)'P (20 mol%), Et,N (2 equiv.), MeCN-H20 (10: l), 80 "C] to give the six- membered ring product 179 but remarkably under- goes exclusively endo-cyclisation under Jeffrey conditions [Pd(OAc):! (10 mol%), Bu,NCl (2 equiv.), KOAc (5.5 equiv.), DMF (0.2 mol dm-'), 100 "C)] to provide the seven-membered ring product 180 (Scheme 10).Thus the possibility exists for affecting either endo- or exo-selective Heck reaction from the same substrate by appropriate choice of reaction condition^.^^ Clark et al. have described an enantioselective approach to the CE ring system of the manzamines in which the spiro-fused bicyclic ylide 182, generated from a copper carbenoid, undergoes [2,3]-sigma- tropic rearrangement generating the bicycle 183 with >98% ee.91 and 13-membered rings) from protected amino The synthesis of medium ring lactams (7-, 9-, 11- n M e O & v N t i R Me0 0 179 Conditions 'Jeff ery' - 'standard' 46% Scheme 10 Cu(acac)p (2 mot %) C6H6;, reflux 56 /o 1 78 I NHR I Me0 180 26% 48% 183 acids via cyclization using polymer bound l-hydroxy- benzotriazole (HOBt) has been reported.92 Grubbs et al.have shown that eight-membered rings (e.g. 185) can be formed from acyclic precursors 184 by ring closing metathesis provided the cyclisation precursor contains a suitable conformational constraint to facilitate cyclisation (in this case an aromatic ring). Structures related to 185 can be converted to the anticancer agents mitomycin and FR-900482.93 Ph OTBS r i rd @- yJ= 59% OTBS Boc Boc 184 185 Optically active nine-membered lactams 187 can be prepared in good yield and with complete 1,3-chirality transfer starting from allylic amines 186 by a zwitterionic aza-Claisen reaction.94 The reaction can be carried out in the presence of acidic protons without epimerisation. Johnson et al.have utilised a Pd-mediated 71-ally1 alkylation for the synthesis of the ten-membered lactam 189 starting from allylic acetate 188. The use of benzyltrimethylammonium methyl carbonate 272 Contemporary Organic Synthesis?2 R ' c t 7 ?-fOEt 0 1 86 1 87 N AC02Me Me02C,,pNJ Pd(Ph3P)* (cat.) - O H O H Me02C 1 88 189 (BTMC) as a source of slowly generated methoxide is crucial to the success of this cyclisation. The allylic acetate moiety of 188 is generated by Ag' catalysed addition of NaOAc to the corresponding allene.95 A number of reports deal with the synthesis of nitrogen-containing macrocycles. Thus Kise et al. have described the synthesis of diazacrown ethers 191 by intramolecular coupling of bis(imino ethers) 190 promoted either by electroreduction or chemical reduction with Zn powder in the presence of methanesulfonic acid.Proton-bridged inter- mediate diiminium salts have been invoked to explain the relatively high yields in these cyclisa- tions.96 More highly functionalised systems have been examined and the diastereoselectivity of these cyclisations is discussed. / Ph-NWo reduction MsOH 190 191 The 17-membered ring of the macrocyclic spermi- dine alkaloid ( - )-oncinotine has been successfully closed using an iminium cyclization as the key step. Thus, treatment of the aldehyde 192 with H2 over a Pd(OH)2 catalyst under high dilution (4 x lo-' mol dm-' in MeOH) leads to in situ generation of the transient iminium ion 193 which is further hydro- genated to provide 194 in 66% yield in a single step .97 Finally, Vogtle et al.have described the synthesis of l-aza[2.2]metacyclophane 196, the hitherto most strained cyclophane with a free NH group in the NHBOC 192 L NHBOC J NHBOC 193 194 PhLi (exces. EtpO rt, 58% Br-0NKCF3 / o H' 195 196 bridge, from dibromide 195. Crucial to the success of this synthesis is the use of the trifluoroacetate group for N-protection, with subsequent C-C bond formation via a phenyllithium coupling reaction. Under these conditions the N-protecting group is removed following C-C bond formation, and the product is formed in a remarkable 58% yield." 9 References 1 S. Florio, L. Troisi and V. Capriati, J. Org. Chem., 2 T. Kataoka and T. Iwama, Tetrahedron Lett., 1995,36, 3 J.G. Knight and M. P. 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