Carboxylic acids coupling

Imidazole-2-carboxylic acid, 4-methylr ethyl ester synthesis, 5, 474 Imidazole-4-carboxylic acid coupling, 5, 403 iodination, 5, 400 reactions... 

Attempts to prepare fluorothiophenes from diazonium salts (the fluoro-borate and hexafluorophosphate salts) have met only variable success. Methyl 3-fluorothiophene-2-carboxylate (32) was obtained in 89% yield by this method (Scheme 12), but the 3-diazonium salt of the corresponding 4-ester could not be isolated. Furthermore, the methyl ester of 2-diazothiophene-3-carboxylic acid coupled before decomposition could be attempted [85H(23) 1431]. 

Scheme 4. Functional dienes from alkyne/carboxylic acid coupling.

Scheme 5. Alkenylidenecyclobutenes from alkynol/carboxylic acid coupling.

It is possible to extend the middle phase region by increasing the concentration of carboxylic acid, coupled with an increase in alcohol concentration. The phase behavior of a mixed microemulsion system containing 5 gm/dl TRS 10—410, 1.5 gm/dl octanoic acid and 8 gm/dl IBA at 22°C is shown in Figure 17. Between 1.5 and 4 gm/dl NaCl, if only NaOH concentration is varied then upper - middle - lower phase transitions occur, apparently due to an increase in the ionization of the surfactant. Extension of salinity and NaOH concentrations in Figure 17 is expected to show upper - middle - lower + middle, and other phase transitions as observed in the oleic acid system (4). 

The carboxylic acid coupling partner is initially deprotonated by triethylamine typically, forming the carboxylate ion which then reacts with the acid chloride to give a mixed anhydride. This forms the first part of the two-step procedure. The acylating agent dimethyiaminopyridine (DMAP) is then added, which reacts with the mixed anhydride to form an acyl pyridinium salt with the elimination of an aromatic carboxylate anion. The second coupling partner, the alcohol, then reacts with the acyl pyridinium salt to give the desired ester. 

An exception to the expected ester formation of a phenol and a carboxylic acid is found in the case of salicylaldehydes. Girard et al. found that salicylaldehydes (91) preferentially form hydrazones like 92 when DEAD or related azadicarboxylates are employed in the Mitsunobu reaction. The hydrazone formation occurs with or without a carboxylic acid coupling partner. If DEAD is used during the reaction, the neighboring alcohol is protected as the boc ester during the reaction. This presiunably occurs through Boc transfer from DEAD via a tetrahedral intermediate. The subsequent hydrazone formation can then proceed via a concerted or nonconcerted reaetion with the reactive triphenylphosphonium boc hydrazide species that is formed after the collapse of the tetrahedral intermediate. 

---