Enamides

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

N O Y O R I Chiral homogeneous hydrogenation Homogeneous chiral hydrogenation ol unsaluraled alcohols, or cartMxyNc acids, enamides, ketones in the presence ol BINAP Ru or Rh complex 8 as catalyst. 

The allyl group was used to protect the nitrogen in a /3-lactam synthesis, but was removed in a four-step sequence. Whether a transition-metal-catalyzed isomerization to the enamide followed by hydrolysis is an effective cleavage procedure remains to be tested and warrants further study. ... 

Fluorocylatwn of enarnines and enamides has been intensively studied by different groups [78, 79, 80 SI] The effectiveness of this particular electrophilic substitution reaction becomes obvious when the nitrogen atom of the enamine moiety is engaged in an aromatic system [82 S3] or when the olefinic system is part of an aromatic nucleus [84] (equations 37 and 38) A further extension of this reaction is demonstrated by the tnfluoracetylation of aldehyde dialkyl hydrazones [S5 86] (equation 39)... 

Halogen-free A/-acyl aldimines and N-acyl ketiimnes tautomenze readily to give enamides [J6] In contrast, perfluonnatedyV-acylimines are stable compounds These electron-deficient itnmes not only exhibit high thermal stability but also show umque properties both as electrophiles and as strongly polanzed hetero-1,3-dienes... 

N-acyl enaminc (104, R = CHjCHj) gave an unstable enamine (106) which decomposed readily to 3-cholestanone. The steroidal N-acetyl enamines (107 and 108, R = C HjCHj) can be reduced by lithium aluminum hydride in tctrahydrofuran to the corresponding enamines (109, R = CJH5CH2) in 90 and 68% yield, respectively 100). Attempts to reduce the enamide (107, R = CH3) led to the formation of the impure enamine (109, R = CHj), which decomposed to the hydroxy ketone (110). 

The simpler enamide, l-styryT2-pyrrolidone (111), is reduced by lithium aluminum hydride in refluxing ether to 1-styrylpyrrolidine (112) in 52% yield 101). 

The reduction of enamides (62-73) has been applied primarily to the synthesis of cyclic enamines (74-76), but also to acyclic enamines (77). 

An enamine was obtained in the synthesis of coronaridine (648) by aluminum hydride reduction of a bridged lactam, followed by dehydration on alumina. Additional examples of enamine formation by reduction of enamides (649) and thioenamides (650) were reported. 

The photochemical rearrangement of enamides to vinylogous amides was described (65],652). Rearrangement of cyclopropyl ketimines to enamines with acid was applied to syntheses of myosamine, apoferrosamine, mesembrine, and desmethoxymesembrine (653-656). 

Reactions of benzoylperoxide with morpholinocyclohexene and morpho-linocyclopentene furnished the corresponding a-benzoyloxyketones in modest yields (480,481). This oxidation has also been applied to some vinylogous amides (482), and the expected faster rate of reaction of the enamine system as compared with enamides has been noted in derivatives of 20-ketosteroids, in reactions with perbenzoic acid (59,483). 

The most extensive use of enamine halogenations has, hctwever, been in the attachment of fluorine to the steroid skeleton (499-503). The formation of a ]6-fluoro-17-ketosteroid by the reaction of perchlorofluoride with a 17-enamide has also been reported (504). 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

A new selective reduction of nitroalkenes into enamides has been carried out by a combina-m of iron powder, a carboxylic acid, and the corresponding anhydnde fEq 6 64)... 

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

A possible side reaction in A-acyliminium chemistry is caused by deprotonation, giving rise to the formation of an enamide. Though this tautomerization is in principle reversible in acid media, this is not always the case. The enamide may react as a nucleophile with the /V-acyliminium ion still present, to produce dimers14. 

Formation of A-acyliminium ions via protonation of enamides or enecarbamatcs is occasionally utilized. 

A representative example is the cyclic enamide 1, containing an optically active A-camphanoyl substituent as a chiral auxiliary82. Treatment of 1 at — 78 C with hydrogen chloride and then a Lewis acid leads to the chiral A -acyliminium intermediate that is alkylated with high stereoselectivity to provide optically active piperidine derivatives. 

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