Saturated nitrogen heterocycles TIMOTHY HARRISON Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essa CM20 2QR Reviewing the literature published between June 1993 and December 1994 1 1.1 1.2 2 2.1.1 2.1.2 2.1.3 2.2 3 3.1.1 3.1.2 3.1.3 3.2 4 4.1 4.2 5 5.1 5.2 5.3 6 Three- and four-membered rings Aziridines Azetidines Five-membered rings Pyrrolidines via 1,3-dipolar cycloaddition reactions Pyrrolidines via intramolecular cyclization Pyrrolidines via miscellaneous methods Pyrrolidinones Six-membered rings Piperidines via [4 + 21 cycloaddition reactions Piperidines via intramolecular cyclization Piperidines via miscellaneous methods Piperidones General methods for the construction of nitrogen heterocycles of varying ring sizes Monocyclic heterocycles Bicyclic and polycyclic heterocycles Pyrrolizidine, indolizidine, and quinolizidine ring systems Pyrrolizidines Indolizidines Quinolizidines References 1 Three- and four-membered rings 1.1 Aziridines A review detailing the synthesis of chiral aziridines and their uses in stereoselective transformations has recently appeared.’ An improved procedure for the generation of the useful nitrene NC02Et has been described which proceeds via a-elimination from NsONHC0,Et using an inorganic base without a catalyst; this nitrene is a convenient aziridine precursor.2 Homochiral aziridine-2-carboxylates, which are useful building blocks for the syntheses of modified amino acids, can be prepared by the Michael addition of amines to the bromo-acrylate 1 using the Oppolzer sultam as a chiral auxiliary.The enantio-differentiating step is asymmetric si-face protonation of the Michael adduct, leading to ( S ) - aziridine carboxylates 2, after removal of the auxiliary using Mg(OMe)2 in MeOH.3 1 R @ OMe H 2 Two reports detailing the asymmetric aziridination of olefins using PhI=NTs and a chiral catalyst have appeared. Katsuki et aE. have used optically active (salen) manganese(II1) complexes for the aziridination of styrene derivatives; however, at present the levels of asymmetric induction and chemical yields are Evans et al. have reported that cinnamate derivatives undergo highly enantioselective aziridination using PhI-NTs and a chiral bis (oxazo1ine)-copper ~omplex.~ At this time, however, the optimal conditions identified for the aziridination of cinnamate esters cannot be extrapolated reliably to other olefinic substrates.1.2 Azetidines A straightfonvard but extremely useful synthesis of 3,3-disubstituted azetidines 4 starting from an appropriate ketone is outlined in Scheme 1; the one-pot reduction-cyclization of the cyano-tosylate intermediate 3 is noteworthy.6 Both cyclic and acyclic ketones have been used in this sequence. 4 3 Scheme 1 A novel route to 3-substituted azetidines involving the addition of a reagent X-Y across the highly strained a-bond of the unusual bicyclic amine 5 has been de~cribed.~ The presence of the ethyl group Harrison: Saturated nitrogen heterocycles 209limits the generality of this procedure at this time, but the methodology can be used to prepare potentially useful azetidin-3-one derivatives such as 6.Y 5 6 2 Five-membered rings 2.1.1 Pyrrolidines via 1,3-dipolar cycloaddition react ions The 1,3-dipolar cycloaddition of azomethine ylides with olefins continues to be one of the most effective and useful methods for the construction of the pyrrolidine ring. Since these reactions are highly stereospecific the identification of chiral controller groups would allow the preparation of enantiopure pyrrolidine derivatives. N-Acryloyl proline benzyl ester 7 functions as an excellent chiral auxiliary in the cycloaddition with azomethine ylides 8 (readily derived from amino acids). In all of the examples studied the cycloaddition proceeds with almost exclusive endo-selectivity and also with excellent facial discrimination, providing highly functionalized pyrrolidine derivatives 9 via a highly ordered, chelated transition state.8 Garner and Dogan have investigated the Oppolzer sultam as a dipole based chiral auxiliary in cycloaddition reactions with achiral dipolaraphiles." The desired carbonyl stabilized azomethine ylides 14 and 15 were generated by thermolytic ring-opening of the aziridine derivatives 12 or by condensation of the glycine derivative 13 with an aldehyde followed by tautomerization.The endo-ao selectivity and regioselectivity were found to be somewhat dependent on the structure of the dipolarophile; however, moderate to good face selectivity (5:l to 11:l) was achieved (Scheme 2). 13 Scheme 2 The dipolar cycloaddition reactions of non- stabilized azomethine ylides are generally restricted to reactions with electron-deficient alkenes.However, ethylenic compounds bearing a trifluoromethyl group are sufficiently activated to allow the formation of 3-trifluoromethylated pyrrolidines in good yield.'' A new method for the generation of non-stabilized azomethine ylides involves electrochemical oxidation of N , N- bis (trimet hylsilylmet hyl) benzylamine 16. Electrochemical reduction of enone receptors is a competing side-reaction.12 Alternatively, azomethine ylides can be generated under thermal conditions without using a catalyst starting from a benzotriazole derivative such as 17.13 Bn I TMS-N-TMS DMF An alternative approach to obtaining asymmetric induction in these cyclizations is to use an enone bearing a chiral alkoxy or amino substituent in the y-position, e.g.10, as the dipolarophile. In this way Patzel and co-workers' observed extremely high regio- and diastereo-selectivity in cycloaddition reactions with azomethine ylides, providing pyrrolidines 11 as single diastereoisomers. 0 14 9 16 10 11 15 H20 ? BtH + CH20 + Me3SiCH2NHR TMS-N-Bt r.t., 2h 17 toluene reflux L J The synthesis of pyrrolidines by the [n4s + n2s] cycloaddition between highly reactive non-stabilized 2-aza-ally1 anions and electron-rich alkenes complements azomethine ylide chemistry, where an electron deficient alkene is normally used. In an 210 Contemporary Organic Synthesisextension of earlier work, Pearson et al. have described the generation and cycloaddition reactions of heteroatom-substituted 2-aza-ally1 anions 19 with alkenes and alkynes leading to 1-pyrrolines 20.14 The aza ally1 anions are generated by tin-lithium exchange starting from stannyl imidates or thioimidates 18 (Scheme 3).E+Y+ -R * X I R 18 X = OR', SR' 19 Li I -x- t E = Ts, NO2, Ar R = alkyl, aryl, C02R' 24 X = OAc, OC02Me The intramolecular oxime-olefin cycloaddition of the unsaturated oxime 25 derived from L-serine provides the unusual tricyclic intermediate 26 in a highly stereoselective cyclization. l7 The tricycle 26 was then converted into the highly functionalized pyrrolidine 27, following reduction and hydrolysis. The reason for epimerization at C-2 during the $-k~ [ *R= *R hydrolysis is being investigated. t 20 ii Scheme 3 Jones et al. have reported an improvement to their earlier procedure for the preparation of pyrrolidines 23 by the 1,3-dipolar cycloaddition of 4,5-dihydroimidazolium ylides (21) with alkenes, followed by reduction of the resulting adduct 22.15 25 170 "C __c H N - 0 OK &*'= 0 26 27 This one-pot procedure utilizing a t-butyl ester as quarternizing agent provides experimental simplification and improved stability of the products 23.2.1.2 Pyrrolidines via intramolecular cyclization The propensity Of cyclizations onto proximate alkene bonds has made this an attractive method for pyrrolidine synthesis. to undergo I I rN< f02Me DBU (714b) L" \ 3'. 21 I But026 22 (60%) Thus Takano et al. have reported a highly diastereoselective radical cyclization of the densely functionalized precursor 28 leading to the pyrrolidine 29 en route to an enantiospecific synthesis of (-)-kainic acid.18 TMSl M e y i c e OTBDPS 602Me 28 Bu3SnH 23 Trost and Marrs have described a [3 + 21 cycloaddition approach to the synthesis of pyrrolidines via reaction of the extremely versatile all carbon 173-dipole synthon 24 with imines under Pd-catalysis.l6 Whereas simple imines fail to react, incorporation of electron-withdrawing groups at either the nitrogen or carbon centres enhance the electrophilicity of the imine sufficiently to make it an excellent acceptor. The results are consistent with a two-step addition process. COpMe 29 Shibuya et al. have described an approach to the trans-2,5-disubstituted pyrrolidine derivatives 31 via radical cyclization involving A4~s-oxazolidin-2-one precursors 30.The high diastereoselectivity is attributable to minimization of A',3 strain in the Harrison: Saturated nitrogen heterocycles 21 1preferred transition state 32.19 Shibuya has used an extension of this methodology in a useful synthesis of ( + )-bulgecinine 36 (Scheme 4).20 Thus, cyclization of the O-stannyl ketyl radical 34 derived from the aldehyde 33 proceeded with high face selectivity, but without diastereoselectivity at the alcohol bearing centre, to provide a 1 : 1 mixture of the alcohols 35. These two alcohols subsequently converged following oxidation - reduction of the unwanted epimer.” 30 32 RO OH 31 s, r 1 Bu,SnH, BnO 0 ::HN * 1 Bno>N7] 33 HO k - * C 0 2 H 36 34 I BnO 35 Scheme 4 An alternative approach to the stereoselective synthesis of trans-2,5-disubstituted pyrrolidines 38 involves cyclization of aminyl radicals generated from unsaturated amines 37.The high stereoselectivity is noteworthy and contrasts with the results obtained when aminyl radicals are generated by other means.*l Rate constants for the cyclization of aminyl radicals have been determined.22 ,i*R3 (ii) (i) BuoSnH NCS.PhH -AIBN. Ri--J!-&il rH R2 PhH, reflux Re A 37 38 Treatment of 1,6-dienes 39 with tributyltin hydride under CO pressure leads to stannyl- formylation with concomitant ring closure, leading to the substituted pyrrolidines 40 in moderate yield.23 A 39 A 40 The samarium(r1) iodide mediated ring closure of N-ally1 and N-propargyl substrates 41 derived from L-serine has been investigated by Baldwin et al., leading to 2,3,4-trisubstituted pyrrolidine derivatives 42.However, in general the reactions are not diastereo~elective.~~ 41 42 Hecht et al. have reported a concise synthesis of ( + )-preussin 44 utilizing a mercury mediated 5-endo-dig cyclization of the ynone 43, prepared in two steps from N-Boc-(S)-phenylalanine. The overall synthesis is complete in five steps.” 43 X = HgCl: H 8 : 1 ( i ) NaBH, Ph Me 44 2.1.3 Pyrrolidines via miscellaneous methods A number of alternative methods for the stereoselective synthesis of 2,5-disubstituted pyrrolidines have appeared during the period covered by this report. Thus, the bicycle 45, which is Ar (i) NaBH,. MeOH (iii) LiDBB, THF (i) Ar’MgX, THF (iii) LiDBB. THF (ii) (PhS),, Et3P THF H A r e H *-Ari 46 47 212 Contemporary Organic Synthesisreadily prepared by addition of Grignard reagents to phenylglycinol-derived imines, functions as a precursor to either (R)-Zaryl 46 or (R,R) 2,5-bis (aryl) pyrrolidines 47.26 Saski et al.have reported a general method for the chirospecific synthesis of any enantiomer of the 2,5-disubstituted pyrrolidine derivatives 50, by appropriate choice of the desired enantiomers of the starting glycidyl triflate 48 and the sulfone 49. The reactioin proceeds via regioselective ( > 92%) attack of the sulfonyl carbanion of 49 at C-1 of the glycidyl triflate, followed by 5-ao cyclization onto the adjacent e ~ o x i d e . ~ ~ ;9”,-c””” OTHP - 2 ~ i + 0 r -! OTH P I Li’ 48 49 L -I I Two reports describing the synthesis of optically active 2,5-trans-disubstituted pyrrolidines by reaction of amines with 1,4-dibromo and 1,4-mesyloxy derivatives have appeared.28729 The synthesis of 3-methylenepyrrolidines by [3 + 21 cycloaddition reactions involving activated imines has already been described. l6 In a conceptually similar approach, the addition of the allyzinc reagent 51 to activated imines 52 bearing a chiral group on nitrogen, followed by Pdo-catalysed cyclization of the adduct 53, allows the one-pot preparation of 3-methylene pyrrolidines with good to excellent diastereosele~tivity.~~ ‘C02Bn I 52 51 t r 1 L J Enantiomerically pure 3- and 3,3-disubstituted pyrrolidines 55 can be prepared by alkylation of the phenyl-glycinol derived bicyclic lactam 54, followed by reduction (Scheme 5).31 An alternative approach to 3,3- and 3,4-disubstituted pyrrolidines, reported by Denmark et al., involves the Lewis-acid promoted [4 + 21 cycloaddition of nitroalkenes with vinyl ethers to afford cyclic nitronates 56 in good yield, followed by reduction (Scheme 5).32 H H 54 55 \ [4 + 21 56 Scheme 5 N-Tosyl aziridines can be ring-opened with the dianion derived from a P-keto ester to provide pyrrolidine derivatives 57 after acid-mediated cyclization.In general the less-hindered (E)-isomers of 57 are formed.33 L C 0 2 M e + p - &co2Me NHTs - - amberlyst 15 PhMe, reflux I @C02Me 57 An interesting annulation reaction of N-Cbz- a-amino aldehydes with allyltrimethylsilane has been reported by Kiyooka et al., leading to all-cis 2,3,5-trisubstituted pyrrolidines 58. It is interesting that the si-face selection with F3B-OEt2 results in r 1 I 53 a x P h H Me C02Bn t C b z N y SiMe3 58 Hawison: Saturated nitrogen heterocycles 213the ‘chelation controlled’ stereochemistry; cyclization of the resulting silicon cationic intermediate then provides the pr~duct.’~ Taguchi et al.35 have described a highly stereoselective zirconium-mediated ring contraction reaction of vinyl morpholine derivatives 59 (readily prepared from amino acids) leading to 2,3,4-trisubstituted pyrrolidines 60.The stereochemistry of the final product is independent of diastereoisomers generated at any step in the synthesis of the starting vinyl morpholines 59, and depends only on the absolute configuration of the starting amino acid (Scheme 6).35 R2 r 2.2 Pyrrolidinones The use of radical chemistry for the preparation of lactams is currently undergoing a resurgence.In studies directed toward synthesis of the kainoids, Taylor et al. have investigated the radical cyclization of the serine-derived a-chloroamides 63. In general, radicals substituted at the a-position (R’, R2 = Me, H; Ph, H; Clz) were found to cyclize more efficiently than the unsubstituted derivative^.^^ Zard et al. have reported the remarkable reagent system of nickel powder and acetic acid for effecting a similar cyclization. This particularly mild and selective method extends the scope of radical cyclizations of a-halo amides by allowing atom transfer cyclizations and intermolecular trapping of the cyclized radicals with radical traps, i.e. cyanide, TEMPO, 02.39 r R2 63 6 2 60 Scheme 6 Panek et al.have described an asymmetric synthesis of the highly functionalized pyrrolidines 62 by low temperature condensation of chiral (E)-crotyl silanes 61 with in situ generated achiral N-acyl imines derived from aromatic aldehyde^.^' This study represents the first asymmetric addition of a chiral ally1 silane to in situ generated imines. F3B-, +,C02Me ?( + w C 0 2 M e th&iPh 61 X = H, OMe Ar x, A CH2C12 -78 “C \ MewsiMe2Ph CH2C12 -100-+-78°C OMe ‘ 0 Ar ArAOMe +H2N KOMe C02Me 62 Finally, a review detailing the hetero Diels-Alder reaction with nitroso dienophiles has been published.37 The adducts can be easily transformed into pyrrolidines via stereospecific reactions. Magnesium-methanol is a simple, yet selective, reagent for the reduction of a, P-unsaturated esters.This method has been used in a one-pot synthesis of 5-substituted 2-pyrrolidinones 65 from the N- alkoxycarbonyl y-amino a, P-unsaturated carboxylates 64 without ra~emization.~’ An alternative approach to pyrrolidinones starting from y-amino a, P-unsaturated carboxylates 66, involves Michael addition of nitromethane followed by reduction of the nitro group with Raney nickel. Reasonable diastereoselectivity is observed in the addition leading to 3-aminoethyl substituted pyrrolidines 67 after spontaneous ring closure (Scheme 7).41(a) Mg in MeOH - 0 H 64 65 66 Scheme 7 67 Finally, pyrrolidines can be prepared in good yield by cyclization of p, y-unsaturated amides using trifluoromethanesulfonic a ~ i d . ~ ’ ( ~ ) 3 Six-membered rings 3.1.1 Piperidines via [4 + 21 cycloaddition reactions The asymmetric hetero Diels-Alder reaction has recently been reviewed.42 For the construction of 214 Contemporary Organic Synthesispiperidine rings, either hetero-dienes or hetero- dienophiles (imines) can be employed.A number of papers have appeared describing chiral aldimines derived from amino acids, e.g. 68,43 from ethyl lactate, e.g. 69,44 and from chiral iron-tricarbonyl complexes, e.g. 70.45 These chiral dienophiles react with electron rich dienes, e.g. Danishefsky's diene, under Lewis acid catalysis to afford 4-piperidinone derivatives with good selectivity. 68 X = 0, H2 69 70 2-Amino-1,3-butadienes such as 71 react with non-activated achiral aldimines derived from aromatic aldehydes under the aegis of ZnClz to afford 4-piperidinone derivatives 72 after hydrolysis.The stereoselectivity of the reaction is very high but strongly dependent on the nature of the imine.46 Amino-dienes, such as 71 but bearing a proline- derived chiral amine, have been shown to undergo stereoselective aza-Diels-Alder cycloaddition with N-silyl aldimines to provide 4-piperidinone derivatives with high enantiomeric excess.47 (OR ,OR2 71 72 Unactivated imines, such as 73, derived from alkyl aldehydes and bearing a-hydrogens, react smoothly with 2-siloxy-l,3-butadienes using TMSOTf as catalyst.48 Gilchrist et al. have reported that the 2-azadiene 74 undergoes [4 + 21 cycloaddition with both electron rich (e.g. enamines) and electron poor dienophiles (eg. methyl vinyl ketone).In general yields are moderate to poor, and in all cases the cycloadditions were highly regioselective but not stereo~elective.~~ Y O z M e 'f " Ar 74 73 R', R2 = alkyl, H In an extension of his earlier work, Ghosez has reported that chiral aza-dienes 75 derived from a, /?-unsaturated aldehydes and Enders' hydrazines cycloadd to cyclic dienophiles with high facial selectivities. The adducts can be readily converted into enantiopure piperidine derivative^.^' To date, efforts to employ less reactive dienophiles, such as methyl acrylate or dimethyl fumarate, have proved unsuccessful. 4 0 3.1.2 Piperidines via intramolecular cyclization Cyclization of the homochiral urethane 76 under palladium catalysis occurs with efficient chirality transfer, affording the homochiral piperidine 77 in good yield." A Pdo-catalysed intramolecular N- alkylation forms the key step in a synthesis of piperidine alkaloids described by Tadano et al.Thus, treatment of the allylic chloride 78 with NaH in the presence of catalytic Pdo led to the piperidine derivative 79 with high dia~tereoselectivity.~~ 76 77 Alkaloids containing a 2,6-disubstituted piperidine system are ubiquitous in nature: in general the trans-isomers are less available than the corresponding cis-isomers. Asymmetric dihydroxylation of the N-alkenyl urethane 80 derived from D-alanine provides a mixture of (i) TBDMSCVimid (iii) H$Pd(OH), (ii) MSCIEt3N 1 82 Harrison: Saturated nitrogen heterocycles 215diastereoisomeric alcohols 81 which, after protection of the primary alcohol and activation of the secondary alcohol, undergo ring closure to afford the trans-2,6-disubstituted piperidine 82 as the major (3 : 1) isomer.53 4-Hydroxy-5hexenylamines such as 83 have hitherto proved fairly unreactive toward electrophilic cyclization.However, carbamates, sulfonamides, and amides of these precursors undergo efficient selenium-induced cyclization in the presence of silica gel and anhydrous KzCO3 to give predominantly tran~-2-(phenylselenomethyl)- 3-hydroxypiperidines 84 in moderate yield. The selenium moiety can be replaced by a hydroxyl group, following oxidation to the selenone and nucleophilic displacement with NaOH.54 83 84 major (3421) (I) MCPBA (ii) NaOH I U Y O H R An extremely versatile approach to either cis- or trans-2,6-disubstituted piperidines involves the stereoselective cyclization of an a-cyanoarnine containing a vinyl group induced by TiCI4.When the vinyl group is unsubstituted, the cis- diastereoisomer 85 is formed whereas when the vinyl group contains a silyl substituent the trans- isomer 86 is the exclusive 85 1 I Pr R = H, SiMe (R = SiMed 1 87 , I 88 PhsP, DEAD I K 8Q 3.1.3 Piperidines via miscellaneous methods Homes et al. have utilized an intramolecular nitrone cycloaddition to assemble the key piperidine ring in an enantioselective synthesis of the azasugar deoxynojirimycin 90." The aza-sugar skeleton is secured by the kinetic preference for a six- membered ring over a seven-membered ring during the initial carbon-carbon bond formation. ,OSiBu'Me, B d P h & i i R OBn OSiMe,Bu' OBn 2 - O The use of pyroglutamic acid as a starting material for natural product synthesis is well established.Thus, N-Boc pyroglutamate ethyl ester 91 can be ring-opened with the lithiated sulfoxide 92 91 - TFAAIPy i 1 Amino-alcohol derivatives such as 88 (obtained by sequential addition of the bis-metallic reagent 87 to an imine, then an aldehyde under Lewis acid catalysis) can be cyclized under Mitsunobu conditions to provide piperidines, e.g. 89 although diastereoselectivity is Scheme 8 TdS O n p;' C02Et Boc 94 2 16 Contemporary Organic Synthesisto first provide the adduct 93. This material then undergoes Pummerer rearrangement with concomitant intramolecular cyclization leading to the 5-0x0 pipecolic acid derivative 94 in near quantitative yield (Scheme 8).This route provides a new synthetic approach to this important class of natural products.58 homochiral piperidines such as 97 starting from the optically active enaminoester 95. The route involves conjugate addition of 95 to an a,p-enone, followed by reductive cyclization-fragmentation to octahydroimidazopyridines 96, and finally further reduction to remove the auxiliary atoms.59 In this sequence 95 functions as a homochiral 'ethanol enamine' equivalent. Jones et al. have reported a new route to (ii) BH3. THF then Ph" 50% aq. H2S0, Ph" [ H$ I; 96 \** Q H 97 3.2 Piperidones In a series of publications, Stille et al. have described a synthetic approach to the 2-piperidone derivatives 98 utilizing the aza-annulation of enamines with acryloyl chloride (Scheme 9).This strategy provides a convergent route for the construction of six-membered nitrogen heterocycles, and has been illustrated by the total synthesis of a range of alkaloid^.^'-^^ '0 *.-* ' 0 98 Scheme 9 Homochiral3-substituted-2-piperidinone derivatives such as 100 are obtained by alkylation of the corresponding hydroxy lactam 99; the excellent diastereoselection observed can be rationalized via the chelated amide enolate intermediate 101.64 An interesting approach to 2-piperidinone derivatives utilizes an intramolecular hetero Diels-Alder reaction from the chiral acylnitroso compound 102. The diastereoselectivity of the process is significantly enhanced when the reaction is carried out in a aqueous solvent system, producing the major trans-isomer 103 in a 4.5 : 1 ratio.The lactam 103 was subsequently converted into ( -)-pumiliotoxin C.65 99 L 100 101 L 102 I BnO H p o 103 Two reports detailing novel approaches to 3-piperidinones have appeared. In the first of these, West et al. have utilized the Stevens rearrangement of ammonium ylides 105 to generate 2-substituted- 3-piperidinones 106. The ylides 105 can be generated by rhodium(I1)-catalysed decomposition of amino-bearing diazo-carbonyl compounds 104. In all the cases studied the carbon with the best radical stabilizing substituent was found to undergo migrat ion.66 L 105 104 R' = CH2Ar2, CH2C02Me R2 = Me, Et 106 Alternatively, a-silylamino-enones and ynones 107, which are readily prepared from amino acids, undergo photoinduced radical cyclization under SET conditions to provide 3-piperidinone derivatives 108.This 6-endo cyclization has been shown to proceed with high levels of diastereoselectivity .67 108 Harrison: Saturated nitrogen heterocycles 217A particularly facile synthesis of 2,6-disubstituted 4-piperidinones 109 has been described by Edwards et al. where the condensation between an a, P-unsaturated ketone, an aldehyde, and an amine gives the products 109 with generally high cis- selectivity.68 The yields are poor (20-35%), but the operational simplicity of a one-pot reaction should make this a useful synthetic method. 109 Thermolyses of amino ethylalkynyl ether derivatives 110 at 150°C produce the corresponding ketenes which can be trapped intramolecularly, leading to the lactams 111. This methodology can be used to produce 6-15 membered lactams in good to excellent yield.69 NHBn Brl 111 110 (n= 1-10) 4 General methods for the construction of nitrogen heterocycles of varying ring sizes 4.1 Monocyclic heterocycles A review detailing the synthesis of medium-sized rings by ring expansion reactions has been p~blished.~' The use of iminophosphoranes as useful building blocks for the preparation of nitrogen heterocycles (ma-Wittig reaction) has also been reviewed.71 Beak et al.have reported a general approach to nitrogen heterocycles via a lithiation/ intramolecular cyclization sequence. Using this methodology a variety of easily prepared acyclic N- Boc amines 112 are transformed to the cyclic products 113.72 Epoxides as well as halides have been used as the leaving group X.112 113 Kim et al. have reported novel cyclizations involving alkyl azides leading to nitrogen heterocycle^.^' In this approach, the heterocycle is generated by direct carbon-nitrogen bond formation via addition of an alkyl radical to an azide (Scheme 10). Of key importance to the success of this approach was the finding that azides are relatively inert to tris(trimethylsily1)silyl radical, thus allowing chemoselective alkyl radical generation from an iodo a i d e 114 without concomitant azide reduction. 114 Scheme 10 The intramolecular cyclization of alkenes onto iminium ions provides a versatile method for the construction of nitrogen heterocycles. Mariano et al. have described the oxidation of a-silyl amines 115 as a mild, regioselective method of iminium ion generation.Both photoinduced single-electron transfer and metal-based oxidants can be used.74 In related work, Pandey et al. have demonstrated that a-silyl amines such as 116 undergo efficient cyclization upon photoinduced electron transfer leading to pyrrolidines and piperidines. These authors invoke a delocalizaed a-silylmethylamine radical cation as an intermediate (Scheme ll).75 I Ph I Ph 115 Scheme 11 Buchwald et al. have reported that cyclic amines 118 can be produced with very high e.e.3 by catalytic asymmetric hydrogenation of the corresponding cyclic imines 117 using a chiral titanocene catalyst. The reaction is general for cyclic imines of ring size 5-7 and exhibits a high degree of functional group ~ompatibility.~' 117 (if 2Bu"Li (ii) 2.5 - 3 PhSiH3 H2* chirai catalyst (1 -5 n?d%) R =Q" H 118 71 - 86% yield 95 - 99% e.e.n = 1-3. Cyclic imines such as 117 are conveniently prepared by the tandem addition-cyclization of Grignard reagents to co-bromonitriles 119. The use of hydrocarbodether solvent mixtures to suppress enolization of the nitrile is critical to the success of this reaction.77 218 Contemporary Organic Synthesis119 117 Cyclic imines bearing both C-2 and C-3 substituents such as 120 are useful precursors for the generation of cis-2,3-disubstituted pyrrolidines and piperidines 121. These imines undergo stereoselective reduction (NaCNBH3, AcOH, EtOH, OOC) from the less-hindered face of the heterocycle, leading to the cis-products 121 with high ~electivity.~’ Terminal alkenes containing a remote carbonyl group, e.g.122, react with iodobenzene diacetate, diphenyl diselenide, and sodium azide to afford the products of anti-Markovnikov azido- phenylselenenylation of the double bond, e.g. 123. Addition of triphenylphosphine to these products produces the corresponding imines 125 bearing a pendant phenylselenyl moiety via the iminophosphorane intermediate 124 (Scheme 12).79 122 123 Php, PhH 1 R = alkyl, aryl,OMe #= 1,2. L 125 124 Scheme 12 Nitrohydroxylated pyrrolidines and piperidines 127 are conveniently prepared through a one-pot procedure involving initial Michael addition of a nitrogen nucleophile bearing a latent aldehyde to nitroethylene. The latent aldehyde is directly trapped in a subsequent nitroaldolization step. Both the amino alcohols 126 and the amino esters 128 can function as the nitrogen nucleophile.’’ The products can be transformed into a range of useful products, including amino alcohols. Ph I (ii) Swern Ph/ C02Me ‘+iH Ph I 126n=1.2 127 128 Naito et al.have reported an alternative route to amino alcohols which involves intramolecular radical cyclization of oxime ethers which are tethered to an aldehyde or ketone 129. The reaction is mediated by tributyltin hydride, and in general the trans-isomers predominate. Yields are moderate.’l 0 NOMe OH NHOMe OH NHoMe 129m= 1,2,3 n= 1.2 In a useful extension to earlier work, Larock and Weinreb have described a versatile synthesis of the 2-( 1-alkeny1)pyrrolidine sulfonamides 130 starting from simple vinylic halides and unactivated olefinic sulfonamides.” The sequence proceeds via vinyl palladium addition to the olefin, followed by regioselective rearrangement to a .n-allylpalladium intermediate, and subsequent intramolecular nucleophilic displacement of palladium.NHTS R b X n - 1.2 X = Br, I, OTf Pdo i Ts 130 4.2 Bicyclic and polycyclic heterocycles trans-Fused bicyclic pyrrolidines and piperidines such as 132 can be prepared from a-halogenoalkyldichloroboranes 131, following amination with benzylazide and intramolecular nucleophilic substitution; the precursors 131 are readily prepared either by hydroboration or Diels-Alder reaction.g3 131 LPh 132 Viehe et al. have described a general, diastereoselective synthesis of the fused heterocycles 135 based on the ‘a-cyclization of tertiary arnine~.”~ The reaction is thought to proceed via initial [2+2] cycloaddition of DEAD to the enamine 133, followed by ring-opening and hydrogen shift to generate the cyclization precursor 134 (Scheme 13).Harrison: Saturated nitrogen heterocycles 219133 n = 1 - 4 El& c--- R 135 Scheme 13 134 The intramolecular cyclization of a tethered nucleophile onto an iminium ion provides one of the most useful methods for the synthesis of nitrogen heterocycles. By careful choice of the group on nitrogen, Overman et al. were able to selectively prepare either stereoisomer of the 1-substituted octahydroisoquinoline 137 by reaction of the allylsilane 136 with an aldehyde.” The reversal of selectivity is attributed to non-bonded interactions between R’ and R2 in the cyclization transition state when R’ is large. + eCH0 R’HN 136 I 137 favoured with favoured with large R’ small R’ Rigby et al.have utilized a relatively uncommon 7-endo radical cyclization process for construction of the hydroapoerysopine ring system 138. None of the corresponding product derived from a 6-ex0 pathway was detected, and the formation of the trans-fused product is noteworthy.86 The cyclization was unsuccessful under palladium-mediated cyclization conditions. Bu”3SnH AIBN (65%) J$ / Me0 \ MeO Finally, Padwa et al. have described a powerful approach to polyheterocyclic ring synthesis based on a tandem cyclization-(dipolar cyc1oaddition)- cationic cyclization sequence.87 Thus the a-diazoimides 139 undergo cyclization-cycloaddition under the aegis of Rh2+ to provide oxabicyclic amides 140.These useful cycloadducts contain a ‘masked’ N-acyliminium ion which is able to further react with an internal tethered nucleophile leading to more-complex heterocyclic systems (141). The approach is specifically illustrated by conversion of the a-diazoimide 142 into the tricycle 143 (Scheme 14). 1 39 1 40 141 Bn 142 143 Scheme 14 5 Pyrrolizidine, indolizidine, and quinolizidine ring systems 5.1 Pyrrolizidines Aminyl radicals generated from sulfenamide precursors, e.g. 144, undergo tandem radical cyclization in the presence of low concentrations of C02Me GN+ OMe R h 2 ( 0 A ~ ) 2 ~ PhMe,A e0 (73%) 0 0 146 147 OMe 138 148 220 Contemporary Organic SynthesisBu3SnH to provide the pyrrolizidine skeleton 145.88 Kim et al. have utilized a diazoketo ester-thioimide cyclization of the precursor 146 to generate the bicyclic lactam 147, which was readily converted into ( & )-supinidine 14tLs9 An unusual approach to the pyrrolizidine skeleton involves the photocatalysed addition of N- substituted pyrrolidines to the butenolide 149.The adduct 150 undergoes cyclization in the presence of KOBu' to provide the lactam 151, which has the ring skeleton and stereochemistry of the pyrrolizidine alkaloid lindel~fidine.'~ I SiMe3 bnzophenone MeCN 149 p (N) TBDMSO "OH 150 KOBd THF I 151 5.2 Indolizidines Shibasaki et al. have used a catalytic asymmetric Heck reaction for the synthesis of the indolizidine derivative 153 starting from the prochiral alkenyl iodide 152. Enantiomeric efficiencies of up to 86% have been obtained." An alternative approach to homochiral indolizidine derivatives involves thermal rearrangement of isoxazolines, e.g. 155, which are H 0 152 0 153 L N 0 2 Ph PhNCO, EtaN, Et& 154 155 1 A 156 prepared from homochiral (R)-( - )-2-chloro- Snitropentane 154, via nitrile oxide cy~loaddition.~~ The diastereoisomeric indolizidines 156 are obtained with 96% e.e.The enantioselectivity of the thermal rearrangement is dependent on the experimental conditions and on the structures of the chiral isoxazolines. indolizidine skeleton involve substituted pyrroles as precursors. Thus, diethyl-L-glutamate. HCl (157) undergoes reaction with 2,5-dimethoxy tetrahydrofuran to provide the pyrrole 158 without racemization. Following Friedel-Crafts acylation (BBr,), the homochiral keto-pyrrole 159 can be reduced to either the indolizidine 160 or the hydroxy derivative 161 depending on the catalyst used (Scheme 15).93 A similar approach using L- glutamic acid and HCl/MeOH for the Friedel- Crafts step has previously been described by Taylor et aZ.94 A number of synthetic approaches to the 157 Me0 158 161 160 159 Scheme 15 Pipecolic acid derivatives contain useful functionality for further elaboration to the indolizidine skeleton.As the key step in a total synthesis of ( + )-monomorine (164) Angle et al. have used the conformationally restricted Claisen rearrangement of the lactone 162 to produce the pipecolic acid derivative 163. This intermediate was transformed into the natural product in just three operation^.^' 162 1 63 1 64 Both K e ~ k ~ ~ and Kibaya~hi~~ have described a new chiral route to (-)-swainsonine (168) and related compounds based on an intramolecular acylnitroso cycloaddition.The Kibayashi approach is summarized in Scheme 16. In both cases the diastereomeric ratio of the product 1,2-oxazines 166 and 167 was low when CH2C12 or CHC13 was used as solvent. However, some improvement in diastereoselectivity and yield was achieved when the reaction was conducted under aqueous condition^.^^ Harrison: Saturated nitrogen heterocycles 2210 0 0 165 168 Scheme 16 CHCI,; 1.3 : 1 H20 4.1 : 1 + BnO Q-3 u 167 Wasserman et al. have further extended the use of vicinal tricarbonyls to the synthesis of the indolizidine alkaloid ( f )-slaframine. The key step in the synthesis is the intramolecular alkylation of the N-substituted 3-hydroxypyrrole derivative 171 to provide the indolizidine skeleton 172.The hydroxy pyrrole 171 was itself prepared in a single step by reaction of the primary amine 169 with the vicinal tricarbonyl 170.98 OH silica gel &OBn OTBS 0 0 1 70 5-40.. Y OTBS 172 Finally, Pearson et al. have developed an intramolecular variant of the Schmidt reaction of azides with carbocations for the construction of nitrogen heterocycles. Thus, upon treatment with triflic acid the alcohol 173 undergoes ionization and the resulting carbocation is captured intramolecularly to produce an aminodiazonium ion intermediate. Carbon-to-nitrogen bond rearrangement then occurs providing the indolizidine 174 in 47% yield.99 By appropriate choice of starting material a range of interesting bridged or fused nitrogen heterocycles (e.g.quinuclidines) can be prepared with reasonable efficiency. HO '' Q N3 b f 2 173 1 74 5.3 Quinolizidines Beckwith et al. have described the highly diastereoselective formation of substituted indolizidines and quinolizidines 176 by intramolecular radical cyclization starting from the bromides 175. In all cases studied the radical intermediate approaches the side of the double bond anti-to the substituent at C-2 with high selectivity.lW 175 1 76 In an extension of earlier work. West et al. have utilized the Stevens [l, 21-shift of cyclic ammonium ylides in an enantioselective route to the quinolizidine ( - )-epilupinine. Thus, treatment of the diazo ketone 177 with Cu(acac)2 provided the bicyclic ketone 179 with high diastereoselectivity (178: 179 = 5 : 95) and 65-75% e.e.(Scheme 17). Much lower diastereoselectivity (178 : 179 = 1 : 3) was obtained using Rh2(OAc)4 as the catalyst.'" 177 1-0 0 L J Bn02C H 0 (35 Bno& 178 179 Scheme 17 Finally, Martin et al. have disclosed a novel technique for the efficient synthesis of fused nitrogen heterocycles based on the molybdenum alkylidene-catalysed 'metathesis of the a, cu-dienes 180. These precursors are readily prepared from succinimide and glutarimide in three steps, and they undergo efficient ring-closing methathesis in the presence of the catalyst 182 to provide the corresponding bicycles 181 in 65-90% yields.lo2 222 Contemporary Organic Synthesis1 8 0 ~ = 1,2 n=0-3 20 Y. Yuasa, J.Ando, and S. Shibuya, J. Chem. SOC., 21 M. Tokuda, H. Fujita, and H. Suginome, J. Chem. 22 M. Newcomb, J.H. Horner, and H. Shahin, 23 I. Ryu, A. Kurihara, H. Muraoka, S. Tsunoi, N. 24 (a) J.E. Baldwin, S.C. MacKenzie Turner, and M.G. Chem. Commun., 1994,1383. SOC., Perkin Trans. 1, 1994, 777. Tetrahedron Lett., 1993,34, 5523. Kambe, and N. 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