Carboxylic esters, from acyl chloroformates

The so-called acylanthranils played an important role in the discussion on the structure of anthranils. Heller regarded the possibility of obtaining them by acylation of anthranils as evidence for structure 164, and for the lactam structure for anthranils in general. However, he was soon forced to reconsider this view. In particular, it was realized that the product from ethyl chloroformate and anthranil was not anthranil carboxylic ester,243 but rather the known compound isatoic anhydride (165).1I7,121,289, 291-293 jsatoic anhydride and benzoyl chloride formed benzoylanthranil, 291,294 and the structural connection between the two compounds was recognized. Nevertheless, structure 163, (R = Ph), first suggested by Angeli,295 and undoubtedly correct, has been too often overlooked, and some later authors, even up to the present day, have persisted with the lactam formula.296-301... 

Other acylating agents are similarly effective in the formation of ketones by reaction with homocuprates. Kim has demonstrated that activated esters such as the 2-pyridyl carboxylates are satisfactory cuprate traps.These esters can be prepared from carboxylic acids and 2-pyridyl chloroformate, provided a catalytic amount of DMAP is utilized (Scheme 35). 

More recently, a similar synthetic strategy was utilized to prepare the Dolastatin 15 via acylation of Meldrum s ester (156). In this work, isopropenyl chloroformate was found to give the best results of several mixed carbonic anhydrides derived from the required starting carboxylic acid when used in the presence of 5 molar equivalents of DMAP. Dolastatin proved to exhibit promising remarkable anticancer properties. 

Carboxylic, and arylsulfonic acid halides react rapidly with pyridines generating 1-acyl- and 1-arylsulfonylpyridinium salts in solution, and in suitable cases some of these can even be isolated as crystalline solids. The solutions, generally in excess pyridine, are commonly used for the preparation of esters and sulfonates from alcohols and of amides and sulfonamides from amines. 4-Dimethylaminopyridine (DMAP) is widely used (in catalytic quantities) to activate anhydrides in a similar manner. The salt derived from DMAP and t-butyl chloroformate is stable even in aqueous solution at room temperature. " ... 

Acylating agents that have been employed are carbon dioxide, alkyl chloroformates, alkyl formates, add chlorides, esters, benzonitrile and dimethylformamide the expected acylation products from reaction with the above reagents were formed in each case. However, the N,N-dimethyl-amide derivatives of higher carboxylic acids did not yield acylated product as in the case of dimethylformamide . When R = H (equation 63), it was necessary to employ two equivalents of the lithiodithiane due to product enolate formation. 

In addition to the general usefulness of this class of compounds, the popularity of this chemistry is largely due to the facile preparation of the starting materials (Scheme 7). The most straightforward method of preparation of Barton esters of types I to IV is acylation by activation of the corresponding carboxylic acid (paths A and B). Accordingly, the hydroxamic acid sodium salt can be O-acylated with the acyl chlorides or, alternatively, the free hydroxamic acid can be condensed with primary carboxylic acids in the presence of N,W -dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP). Likewise, condensation of the free thiohydroxamic acid or the corresponding sodium salt with the mixed anhydride formed from the acid and isobutyl chloroformate in the presence of N-methylmorpholine has proven to... 

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