Amidation activation using thionyl chloride

Preparation of acid chlorides is one of the easiest methods to activate an acid. Thionyl chloride (SOCh) [12, 13] is used widely to generate acid chlorides. The reaction of SOCb with water or other nucleophiles is extremely exothermic, and generates large quantities of sulfur dioxide and HCI. Nevertheless, acid chlorides (via SOCI2) and mixed anhydrides (via acid chlorides or chloroformates), are the most common reagents used for amide formation in the pharmaceutical industry, with N,N -carbonyldiiniidazole (CDl) growing in popularity[8]. 

Acyl or acid chlorides are used frequently in amide formation as activated forms of the corresponding carboxylic acid. A wide selection of acyl chlorides is available commercially. Otherwise, they can be prepared readily from the corresponding carboxylic acid in the presence of reagents such as thionyl chloride (9), oxalyl chloride 5 (10), phosphorus trichloride (11), and phosphorus pentachloride (12). Reactions that use oxalyl chloride or thionyl chloride are promoted by the addition of a catalytic amount of DMF (13) (see Fig. 3). 

The most frequently used approaches for derivatizing carboxylic acids are esterification with a variety of single-enantiomer alcohols, or formation of amides with single-enantiomer amines [234,252]. The formation of amide derivatives requires activation of the carboxylic acid by formation of the acid chloride with thionyl chloride, mixed anhydrides with chloroformates, N-acylimidazoles with 1,1 -carbonyldiimidazole or N-acylureas with dicyclohexylcarbodiimide. Esterification reactions generally re-... 

Eligh yields of esters are obtained from both acid-sensitive (cyanoacetic acid) and base-sensitive carboxylic acids (3-phenyl-propionic acid and trichloroacetic acid) and, in these latter cases, use of 4-(dimethylamino)pyridinium chlorosulfite chloride is much more effective than use of thionyl chloride alone. The esterification process has been claimed to be independent of the steric environment of the carboxyl function, though this reagent may be of more limited value with heavily substituted benzoic acids. Carboxyl activation, in the presence of a primary amine, leads to the corresponding amide in excellent yield (eq 2). In both the esterification and amidation processes and the oxime dehydration reaction discussed below, recovery of DMAP is straightforward. 

An alternative to this route involves 4-vinylaniline or 4-vinylbenzoic acid, relatively easily coupled to various acid counterparts to produce amide linkages. A multitude of amide coupling protocols may in this case in principle be used, for example, by initial activation of the acid by thionyl- or oxalyl chloride and subsequent addition of the corresponding amine in the presence of base (pyridine, triethylamine, etc.) [5,6], or by use of coupling reagents such as dicyclohexylcarbodii-mide (DCC). 

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