Acyl-enamino acids

For the construction of peptides with an N-methyldehydroamino acid unit, use can be made of the observation by Rich (328) that selective N-methylation of N-acyl enamino acid units can be carried out with methyl iodide/potassium carbonate in dimethylformamide. 

Acylation with aromatic acid chlorides was believed to occur on carbon 91). The dibenzoylation of the enamine (113) with benzoyl chloride in the presence of triethylamine has, however, been shown to give a mixture of three products (92). The major components are the cis and Irons isomers of the O-acylated enamino ketone (Ola and b) and the minor isomer is the 2,6-diacylated enamine (132). 

The enamino ketone 49 has also been found to react with o-nitrobenzene-sulfenyl chloride to give the derivative 156, having the o-nitrophenylthio group substituted in the 2 position (93), i.e., the same position at which normal acylation with acid chlorides takes place. 

The syntheses of simple 1,3-oxazines (74AG596 86G361) from acylated amino acids (86G361) by treatment with dihalotriphenylphosphorane and of heterocondensed l,3-oxazin-4-ones from several N-acylated heterocyclic /3-enamino esters (81CB3188) have been implemented by aza-Wittig reactions of heterocyclic 2-(triphenylphosphoranylidenamino)esters with acid halides. 

Only a few esters of dehydroamino acids are stable and these only as hydrochlorides, so that all the reactions at the amino group studied to date are electrophilic. As the enamino group is less nucleophilic than an amino group, enamino acid esters can only be acylated by the most reactive acid derivatives, such as acid chlorides (368, 373) and mixed anhydrides (69, 257, 313). Attempted peptide formation from acylamino acids and enamino acid esters by the DCCD or DCCD/hydroxysuccini-mide methods is unsuccessful. The formation of Schiff bases at the enamino group proceeds rather slowly, but can be achieved in the case of the stable dehydrovaline methyl ester by direct condensation with aromatic aldehydes (287, 352). 

There is some spectral evidence that acylation of enamines of cyclic ketones with acid chlorides having an a-hydrogen in the presence of triethylamine proceeds via the ketene and subsequent cycloaddition (84). The intermediate cyclobutanone is then opened to give the enamino ketone which is hydrolyzed to the 2-acyl cyclohexanone. In the case of enamines of larger cyclic ketones the alternate mode of the cyclobutanone opening predominates, with the formation of ring-expanded 1,3-diketones upon... 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

It would thus appear that O acylation is the normal course of the acylation of enamino ketones. Surprisingly the enamino ketones 49 and 50 undergo reaction with acid chlorides not having an a-hydrogen (e.g., benzoyl and pivalyl chlorides) to give the products of C acylation (133). 

The first representative of this group, a /3-acylamino-a,/8-unsaturated ester, yielded 67 through pyrolysis in diphenyl ether205-207 [Eq. (53)]. A modification of this method used a Schiff s base instead of die TV-acyl derivative of a j8-amino-a,j8-unsaturated acid.208 Similarly, enamino esters react with benzoyl chloride to yield 6//-l,3-oxazines.209... 

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). 

A-Acyl-jS-enamino ketones (306), prepared from A-substituted dithiocarbonimidates and the potassium enolates of methyl ketones, on treatment with perchloric acid or methanesulfonic acid, yield 1,3-oxazinium salts (307) (Equation (30)) <83JOC623>. 

Acetic acid (s. a. under HgBOg) 2-(a-Enamino)- from 2-acyl-furans... 

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