Acylation using enamine intermediate

Mteto esters can be obtained by acylation of enamines of acyclic and cyclic ketones with ethyl chloroformate3. Surprisingly no /J-keto ester was obtained when the reaction was carried out in the presence of triethylamine and an extra mole of enamine or a tertiary aromatic amine must therefore be used to neutralize the acid liberated The intermediate enamino ester can be isolated and reduced by hydride donors225 (Scheme 92). 

The first iyn-selective organocatalytic aldol reaction was disclosed by Barbas III et al. [98]. Based on previous studies on antibody-mediated aldol reactions, they envisaged that the aldol reaction of unmodified hydroxyacetone with an aldehyde should proceed through the (Z)-enamine intermediate in the transition state and thus produce a yn-aldol. Indeed, the reaction catalyzed by O-tBu-L-thyrosine proceeds with high yn-stereoselectivity. Subsequently, the catalyst loading was decreased to 5 mol% by replacing the tyrosine derivative with the O-acylated cysteine (80) [99,90e]. Importantly, donors and acceptors can be used in stoichiometric amounts (Chart 3.10). 

Dehydroprotoberberinium salts may be used as intermediates for the introduction of substituents at the C-5 position of tetrahydroprotoberberine bases. Two-step reduction of dehydronorcoralydine leads to the enamine 51 which can be C-acylated as in 52, or hydroborated and oxidized to give a separable mixture of diastereomeric C-5 hydroxylated tetrahydroprotoberbines ... 

ALKYLATING AND ACYLATING THE a-CARBON USING AN ENAMINE INTERMEDIATE... 

Enamine acylations have been extended to include the Vilsmeier reaction (409) and thus provide a method for the generation of formyl ketones without the use of strong base. By this method an unsaturated potential trialdehyde could be formed as an intermediate in a pyridine-3-carboxaldehyde synthesis (410). 

Enamines 1 are useful intermediates in organic synthesis. Their use for the synthesis of a-substituted aldehydes or ketones 3 by reaction with an electrophilic reactant—e.g. an alkyl halide 2, an acyl halide or an acceptor-substituted alkene—is named after Gilbert Stork. 

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

This time another cyclic amine, pyrrolidine was used to make the enamine 107 and acylation occurred cleanly at carbon in spite of the formation of a quaternary centre. The wide ranging yields are for different Ar groups.21 The intermediate is an iminium salt 108 that can be isolated. The equilibrium methods used earlier for 1,3-dicarbonyl compounds would not work here as the product 104 cannot form a stable enolate. 

The following sequence shows the acylation of an enamine to synthesize a /3-diketone. The initial acylation gives an acyl iminium salt, which hydrolyzes to the /3-diketone product. As we will see in Section 22-15, /3-dicarbonyl compounds are easily alkylated, and they serve as useful intermediates in the synthesis of more complicated molecules. 

As noted earlier, the development of new alkylation and acylation methods for compounds bearing carbonyl groups has fostered the use of enamines as reaction intermediates. 

Enamines also act as useful intermediates for the acylation of aldehydes or ketones at a-position (Scheme 3.21). 

Another approach to cephalotaxine intermediate 43 was reported by Weinstein and Craig (65) in 1976 (Scheme 33). The reaction of 3,4-(methy-lenedioxy)-iS-phenethyl tosylate (191), a derivative of the previously used nosylate 117, and sodium 2-carboethoxypyrrole (192), followed by hydrolysis, produced the carboxylic add 193. Intramolecular Friedel-Crafts acylation of 193 with stannic chloride and trifluoroacetic anhydride yielded the benzazepine 194, which was reduced, hydrogenated, and finally oxidized to produce the tricyclic Dolby-Weinreb enamine 43. 

Scheme 193). On heating the mixture, preferably in the absence of triethylamine, the hexahydro-a-quinolone 185 was obtained directly, together with the enamide 184 and amide 186. Since the enamide could not be cyclized to the hexahydro-a-quinalone under thermal or acid-catalysed conditions, then clearly the enamide is not an intermediate in the formation of the heterocycle which must therefore arise by. /V-acylation of the enamine tautomer, followed by a [3,3]sigmatropic rearrangement and cyclization of the ketene intermediate (Scheme 194). Significantly vide infra), when the imine of 2-methylcyclohexanone was used, the rearrangement to the ketene occurred at the more substituted Cj position. 

An alternative approach to aza-annulation again utilizes condensation to form an enamine, which is subsequently. V-acylated (Scheme 2). The resultant acrylenamide is a stable, isolable intermediate which can be efficiently converted to the corresponding dihydropyridone through photochemical processes. However, application of this photochemical methodology has been the subject of previous reviews, and will not be discussed here.1 Alternative routes for conversion of the acrylenamide to the dihydropyridone, through the use of Lewis acids, protic acids, and heat,... 

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