Enamine alkylation

Primary alkyl enamines undergo spontaneous trimerization to form 1,3,5-hexahy-drotriazines via the imino derivatives (148 equation 77) (80T2497). 

Bach and coworkers investigated the photocycloaddition of 7V-acyl, 7V-alkyl enamines 125 with benzaldehyde [125]. The 3-amido oxetanes 126 were formed with excellent regioselectivity (analogous to reactions with enolethers—vide supra) and good diastereoselectivity (Sch. 41). Enamines, not deactivated by acylation at the nitrogen atom are poor substrates for Paterno-Buchi reactions due to preferred electron transfer reactivity (formation of the corresponding enamine radical cation and subsequent reactions). 

Evidence for the two-step nature of the dihydropyran formation follows from the observation that both cis- and fraws-dibenzoylethene gave the same dihydropyran96, under conditions where cis-trans isomerism of the electrophilic alkene did not occur. On heating, the dihydropyrans rearrange into a mixture of the corresponding alkylated enamines (44 and 45) (Scheme 29). This is kinetically rather than thermodynamically controlled, since the equilibrium composition was obtained only after treatment with acid96, and can therefore be regarded as irreversible in an aprotic solvent (benzene) at 80°C. 

Considerable work has been carried out by Risaliti and coworkers on the re-gioselectivity and stereoselectivity of the alkylation of enamines with vinyl sul-phones100-105 and nitro alkenes106-116. A surprising result was observed in the reaction of phenyl vinyl sulphone with 1-iV-morpholinocyclohexene in that the more substituted mono-alkylated enamine (51) was the main product. Its isomer 52 was formed only in 25% yield (Scheme 35). 

Kuehne and Foley117 have shown that nitroethene reacts exothermically with 1-N-morpholinocyclohexene in acetonitrile to give the less substituted alkylated enamine (54), whereas the cyclobutane (53) is produced in hydrocarbon solvent. This is attributed to the increased lifetime and selectivity of the intermediate zwitterion in polar solvents, which is expressed in the proton transfer, via a six-membered transition state, to the enamine product (54, Scheme 38). 

Similar results were obtained with enamines of acyclic ketones such as desoxybenzoin. Nitrostyrene gave only the less substituted mono-alkylated enamine and hence the / -nitro-a-phenylethyl ketone on hydrolysis117. Surprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine106. A hexahydrobenzo-l,2-oxazine-7V-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isomers107 (Scheme 39). 

The reaction of enamines and imines with acrylamide results in aza-annulation120,121. Other electrophilic alkenes which have been used to alkylate enamines and the products used in hetero- or carbocyclic synthesis include ethyl / -nitroacrylate122, where reaction occurs beta to the nitro not the ester group, 2-(phenylseleno)prop-2-enenitrile [CH2 = C(SePh)CN]123,124, phenyl a-phenylselenovinyl sulphone [CH2 = C(SePh)-S02Ph]124 and phenyl a-bromovinyl sulphone124. An electrophilic allene, phenylsulpho-nylpropadiene, has also been used to alkylate enamines125 (Scheme 44). 

A new diastereoselective and enantioselective synthesis of a-amino-y-oxo acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80 de > 96%)174 (Scheme 71). The use of a chiral ester [R = ( + )- or ( —)-menthyl or (—)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 24-67%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH2), obtained in 80% yield, was shown to have the (l S, 2R)-configuration174. 

Non-concerted rearrangements of 7V-alkylated enamines have also been observed These rearrangements have been shown to take place through a reversal of a primary Af-alkylation, followed by subsequent C-alkylation. This was observed for methyl, ethyl and benzyl groups . But allylic groups rearrange intra-molecularly in a concerted way . ... 

A -Silylated enaminesv43 can undergo similar acid-catalyzed hydrolysis under the conditions outlined in Scheme 3 to A -alkyl enamines 44, while 45 fail to hydrolyze, presumably due to their sensitivity to the conditions employed. However, by using tetrabutylammonium fluoride as a catalyst enamines 46 are formed". ... 

The entropic assistance provided by the intramolecular cycloaddition, the inability of the dienes to tautomerize, and the relative stability of the product (acyl versus alkyl enamine) contribute to the success of this process. A total synthesis of (-)-deoxynupharidine based on the implementation of the in situ generation and subsequent intramolecular Diels-Alder reaction of an A-acyl-l-aza-l,3-butadiene has been detailed [Eq. (13)].32c... 

Because of the predominance of the less substituted enamine, alkylations occur primarily at the less substituted a-carbon. Synthetic advantage can be taken of this selectivity. Hydrolysis of the alkylated enamine produces the alkylated ketone. Some typical reactions are shown in Scheme 1.9. 

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