One-Pot Synthesis of Amide, Dipeptide, Ester and Hydroxamate Using Oxyma and Thionyl Chloride (SOCl2)

An improved, one-pot two-step process is described to convert carboxylic acid to amides, dipeptides, esters, and hydroxamates using Oxyma and thionyl chloride. The addition of Oxyma to thionyl chloride in the presence of Hunig's base results in a mixture of probably Oxyma-sulfinyl chloride and sulfinyl diOxyma, two new intermediates, which successfully converts the carboxylic acid into its Oxyma ester. Adding a nucleophile to the generated Oxyma ester leads to corresponding amide, ester, or hydroxamic acid formation at room temperature. The procedure is mild and well tolerant to various carboxylic acids, including N-protected amino acids and different nucleophiles such as methyl esters of amino acids and alcohols. 32 examples with moderate to good yield (67-86 %) are reported. A rigorous mechanism investigation is performed using H-1 and C-13-NMR. By-product Oxyma can be recovered and recycled. Thionyl chloride has been used for such coupling reactions in industries and academia for a few hundred years to date. Nevertheless, minimum racemization, side reaction, and waste generation make the addition of Oxyma (this methodology) a valuable improvement.