Acylating agents from carboxylic acids

Scheme 3.4 gives some typical examples of preparation and use of active acylating agents from carboxylic acids. 

The main applications of oxalyl chloride, as described in Chapter 4, are the formation of aryl isocyanates and chloroformates (by reactions with amines and hydroxylic substrates, respectively), and the formation of acyl chlorides from carboxylic acids under very mild conditions. Oxalyl chloride reacts with amides to give acyl isocyanates, and it is used with dimethyl sulfoxide as a mild reagent for the oxidation of alcohols (Swern-type oxidation). It is also used with N,N-dimethylformamide as a mild reagent for chlorination and formylation. Oxalyl chloride is widely used in commercial formulations of speciality polymers, antioxidants, photographic chemicals, X-ray contrasting agents, and chemiluminescent materials. Other physical properties are presented in Chapter 3. 

In addition to acyl halides and acid anhydrides, there are a number of milder and more selective acylating agents that can be readily prepared from carboxylic acids. Imidazolides, the (V-acyl derivatives of imidazole, are examples.115 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with carbonyldiimidazole. 

Benzotriazoles are neutral acylating agents, successfully used for the preparation of amides, oxamides and hydrazides The acylbenzotriazoles 95a-d are prepared from carboxylic acids 94a-d by reaction with l-methanesulfonyl-l//-benzotriazole (Scheme 51). Reaction of 1-benzoyl-l//-benzotriazole with hydroxylamine hydrochloride in the... 

The highly acidic conditions required to generate peracids in situ from carboxylic acids and hydrogen peroxide are usually not conducive to efficient amine oxidation. In situ generation from anhydrides in neutral solution or other acylated agents in alkali can be employed. In situ perphthalic or permaleic have been reported for pyrimidine oxidation.332... 

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). 

Acylations with carboxylic acids and anhydrides have been carried out with sulfuric acid as both solvent and catalyst, the reactive acylating agents from acyl halides probably being haloacyloxonium ions. Trifluoroacetic anhydride offers a rather milder reagent for reactions of carboxylic acids, with mixed anhydrides being likely intermediates. However, polyphosphoric acid remains the most widely used dehydrating agent for acylations by carboxylic acids. 

Addition compounds from carboxylic acid chlorides and pyridine are powerful acylating agents. They react with water to give anhydrides and with H2S to give acyl sulfides at temp, below 0 . 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

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