General and Scalable Amide Bond Formation with Epimerization-Prone Substrates Using T3P and Pyridine

Abstract

The mild combination of T3P (n-propanephosphonic acid anhydride) and pyridine has been developed for low-epimerization amide bond formation and implemented for the synthesis of a key intermediate to a glucokinase activator. This robust method is general for the coupling of various racemization-prone acid substrates and amines, including relatively non-nucleophilic anilines, and provides amides in high yields with very low epimerization. With easy reaction setup and product isolation, this protocol offers several practical and experimental benefits.

An Efficient and Epimerization Free Synthesis of C-Terminal Arylamides Derived from α-Amino Acids and Peptide Acids via T3P Activation

“…The literature precedence for the preparation of arylamides using T3P illustrated only condensation of Z-Phg-OH and ZAla-OH with aniline and pyridine for about 18 h (Dunetz et al 2011). With our promising results on T3P mediated reactions, we set forth to synthesize arylamides of N-protected a-amino/ peptide acids in detail.…”

“…Evidently, each of the known methods suffer from some drawbacks, in-terms of low yield, racemization, some of the coupling reagents are hazardous, expensive and consumed in stoichiometric amounts, thus leading to significant amount of wastes. Dunetz et al developed an efficient protocol for amide bond formation using T3P and pyridine for about 12-24 h (Dunetz et al 2011). Hu et al developed a novel protocol for the preparation of amino/ peptide acid arylamides by the ligation of selenocarboxylate with an azide (Wu and Hu 2007).…”

6,7-Diphenyl-5-thia-7-azaspiro[2.6]nonan-8-one

“…As part of our studies of cyclic 1,3-thiaza-4-one compounds, we report the synthesis and structure of the novel title compound. The title molecule was synthesized by condensation of N- [phenylmethylidene]aniline with [1-(sulfanylmethyl)cyclopropyl]acetic acid in the presence of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) and pyridine (Dunetz et al, 2011;Unsworth et al, 2013). We report here the crystal structure of the title compound which crystallizes with two independent molecules, A & B, in the asymmetric unit.…”

“…For amide bond formation using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), see: Dunetz et al (2011). For preparation of various heterocycles using imines and T3P, see: Unsworth et al (2013).…”

Synthesis and Spectroscopic Properties of 2,3-Diphenyl-1,3-thiaza-4-one Heterocycles

“…Reasoning that the amide formation would likely be the rate-determining step, we looked to a paper published by Dunetz et al (2011), which used two equivalents 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) and four equivalents pyridine for amide formation. When applied to the reaction of 2 with 5, successful cyclization was achieved at room temperature to give 6.…”