Keto amides, hydrolysis preparation

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

A completely different approach to Y-keto-esters proceeds via Michael additions of carboxylic acid dianions to an a-anilino-acrylonitrile followed by alkylation of the resulting anion and finally acidic hydrolysis (Scheme 13). Overall yields are in the range 47-79% the method is also useful in the synthesis of r-keto-amides. An alternative anion-based route to y-keto-esters utilizes the homoenolate (166) as the interroediate which undergoes smooth acylation by a wide variety of acid chlorides.The homoenolate is obtained from the corresponding iodoester using Zn-Cu couple, and it seems likely that the method can be used to prepare more highly substituted keto-esters although such reactions have not yet been reported. 

The a-keto amides are less susceptible to hydrolysis and preparation of a-keto esters and acids are preferable for synthesizing various derivatives thereof. Various aryl iodides and bromides can be converted into a-keto esters on reactions with alcohols and carbon monoxide in the presence of a base such as tertiary amines or potassium acetate with catalytic amounts of tertiary phosphine-coordinated palladium complexes (Eq. 11).[42]-[46] jjjgjj yields of a-keto esters can be achieved only when iodide substrates are used. Double carbonylation of aryl bromides to a-keto esters can be accomplished with difficulty at much slower rates. Alkyl and benzyl iodides give no double carbonylation products. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Although the selfcondensation of amide chlorides proceeds well to give amide chlorides derived from 3-keto acids (56 equation 35) this reaction has only been used to synthesize 3-keto acid amides, which result after hydrolysis of the condensation products (56), and not to prepare the salts (56) in the pure state. The condensation reaction of aromatic aldehydes with the //A -dimethylacetamide-POCb adduct... 

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