On the Two-Component Microwave-Mediated Reaction of Isonitriles with Carboxylic Acids: Regarding Alleged Formimidate Carboxylate Mixed Anhydrides

Abstract

Microwave induced two component coupling (2CC) reaction of carboxylic acids with isonitriles gives rise to various N-formylamides. The formimidate carboxylate mixed anhydride (FCMA) is proposed as the reactive intermediate, which undergoes 1,3-O → N acyl transfer to give the observed product. The formation and survival of the labile FCMA system has been evaluated.Recently we reported on the microwave induced coupling of carboxylic acids with isonitriles, giving rise to various N-formylamides (cf. 4, Scheme 1). 1 We suggested the term two component coupling (2CC) to differentiate this work from earlier studies. 2 As we discussed previously, one likely mechanistic interpretation of the 2CC reaction is that 4 arises from a 1,3-O→N acyl transfer within 3. 3,4 The latter comes about from a protonation-addition sequence in the joining of 1 and 2. To the best of our knowledge, no structure corresponding to a formimidate-carboxylate mixed anhydride 3 (hereafter referred to in this paper as a FCMA), had been documented in a convincing way, let alone fully characterized. 5-7 Our thoughts and experiences in this area led us to suppose that a generic FCMA, 3, would be a highly reactive acyl donor. Accordingly, a recent report 5a to the effect that FCMA 7 is produced at room temperature as a crystalline product from the reaction of acid 5 and isonitrile 6 in water, provoked our curiosity. Moreover we noted that the spectroscopic properties of the alleged 7 (particularly its reported IR spectrum), 8 do not correspond to what would be expected from such a structure. 9In our hands, reaction of 5 and 6 in water did indeed produce, as reported by the authors, 5a a crystalline product, mp 69-71 ºC. Surprisingly at the time, microwave heating of this solid in chloroform failed to produce any discernible amounts of what would have been the expected product, 8, given the claimed structure 7. 1 Adding to the puzzle, it was found that the crystalline product could not be retrieved after it had been dissolved in chloroform, even without E-mail: s-danishefsky@ski.mskcc.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript thermolysis (i.e. at room temperature). Instead, evaporation of the solvent leaves a residue which does not have the properties of its precursor, allegedly 7. The residue from chloroform could be separated into components 5 and 9 by exploiting their differing acidic and neutral solubility properties, respectively.Fortunately, it proved possible to obtain some diffraction-worthy crystals from the product of the reaction of 5 and 6. Crystallographic analysis of the sample revealed the structure to be 10, a stable complex (fascinating in its own right!) between N-formylcyclohexylamine 9 and m-nitrobenzoic acid 5 (see Figure 1). 10 Apparently, the fragile molecular association between 5 and 9 unravels upon dissolution in chloroform. Thus, the claim that the reaction of 5 and 6 produces FCMA 7 is not correct Also noteworthy was a report, in the same paper, describing a high...

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