Facile Direct Synthesis of Acetylenedicarboxamides

Abstract

A convenient, rapid and widely applicable one-pot procedure has been developed for the synthesis of acetylenedicarboxamides from various primary and secondary amines, including amino acid derivatives, protected carbohydrates, and fluorescent labels. By using DMTMM for amide coupling, acetylenedicarboxylic acid was directly converted into acetylenedicarboxamides in highly competitive overall yields (52-80%).Acetylenedicarboxylic acid (ADA, 1) and its derivatives are widely used compounds in the synthesis of carbo-and heterocycles. In the case of acetylenedicarboxylic acid diesters the electron-deficient triple bond readily reacts as a dipolarophile or dienophile in thermal cycloadditions, and as a conjugate acceptor in Michael additions. 1 Often, both types of reaction pathways are involved in the synthesis of heterocyclic systems when using ADA derivatives. 2 As part of our ongoing research on the multidecoration of nanoscaffolds by 'click'-type conjugation reactions, 3 in particular by using ADA diesters as both functionalizing and branching elements, 3a we were interested in acetylenedicarboxylic diamides (ADCAs) as chemically more stable analogues of diesters. However, the formation of amides of ADA 1 suffers from competing and/or subsequent Michael additions of the amine component because of the highly electrophilic nature of the conjugated triple bond. Only a few general protocols for the preparation of ADCAs have been described (Scheme 1) that are based on acid halides such as dibromofumaroyl dichloride (2) 4 or acetylenedicarbonyl difluoride (3). 5 Reports on the use of acetylenedicarbonyl dichloride (4) remain controversial, 6 with only few applications for the synthesis of ADCAs; 7 mixed anhydrides of 1 tend to polymerize. 8 All these protocols require several steps and involve sensitive reagents or intermediates. The widely applied standard technique for direct amide coupling using carbodiimides seems to be generally inefficient in the case of 1, 9 and our attempts to prepare ADCAs via carbonyldiimidazole activation 10 also resulted in no product formation.On the assumption that ADA deprotonation should render the triple bond more electron rich 11 and hence more stable to conjugate nucleophilic attack by amines, we, therefore, searched for a coupling reagent that involves the incipient formation of an ionic ammoniumcarboxylate intermediate in the reaction mechanism.Scheme 1 Common strategies for the synthesis of acetylenedicarboxamides: Reagents and conditions: (i) Br 2 ; (ii) PCl 5 ; (iii) R 1 NHR 2 ; (iv) Zn; (v) SF 4 (X = F) or SOCl 2 (X = Cl).From the broad range of peptide-coupling reagents 12 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 5), 13 which is commercially available or can be readily prepared from cyanuric chloride in two steps, 14,15 seemed to be a reagent that could fulfill this condition. Indeed, when using a slightly modified Kunishima protocol 15 for a test reaction of 1 with 2-phenylethylamine (6a) in tetrahydrofuran the desired N 1 ,N 4 -diphenethylbut...