Abstract
We have recently reported a novel multicomponent reaction between arylacetic acids and isocyanides, affording α-acyloxyacrylamides through an unusual mechanism. The products of this novel multicomponent reaction can rearrange to five membered heterocyclic compounds when exposed to an alkaline environment. Depending on the reaction conditions and on the substitution pattern on the substrates, various pyrrolidine derivatives can be selectively obtained. We now wish to report that libraries endowed with skeletal diversity, thus responding to the requirements of Diversity Oriented Synthesis (DOS), can be efficiently prepared in this manner, and phenotypic biological assays have shown interesting properties of some representative compounds.
Highlights
Isocyanide-based multicomponent reactions (I-MCRs) have received much attention during the last decades, for their ability to assemble in one step three or more building blocks in a single molecule and because many heterocycles, relevant from a biological point of view, can be Molecules 2011, 16 synthesised in a combinatorial fashion combining the multicomponent step with a post-condensation transformation [1,2]
Interaction of one molecule of acid with one of isocyanide forms an activated carboxylic acid ester 5 that reacts with one additional molecule of isocyanide to generate intermediate 6 that tautomerises to more stable 7 and is attacked by a second molecule of acid to form 8, rearranging to 3 in a way similar to the one occurring in the classic Passerini reaction
2-acyl-5-aminooxazoles [5]; according to the postulated mechanism the ketene generated in situ from the acyl chloride in the presence of triethylamine reacts first with the isocyanide to form an acylnitrilium ion similar to 6, that is subsequently trapped intramolecularly by the amidic oxigen to form the final oxazole. In principle this reaction could be extended to any carboxylic acid, in practice we found that only arylacetic acids furnished compounds 3, while other acids, like those reported in Figure 1, reacted with isocyanides under the same conditions to give mainly, via 1,3 O→N acyl shift of adduct 5, N-formylamides as recently reported by Danishefsky [6]
Summary
In preliminary form, an unexpected reaction between arylacetic acids 1 and isocyanides 2, leading to α-acyloxyacrylamides 3 (Scheme 1, top), and their rearrangement to give 5-membered heterocycles [3]. Compounds 3 incorporate two molecules of the same carboxylic acid 1, the reaction still falls under the definition of multicomponent condensation. In this full paper we report a more thorough discussion on this new methodology, as well as its application in the combinatorial synthesis of a library endowed with both scaffold and decoration diversity. (a) The novel reaction between two molecules of arylacetic acid and two molecules of isocyanide, leading to α-acyloxyacrylamide 3 and formamide 4; (b) Below, the postulated mechanism. Ugi early reported the reaction of diphenylketene with cyclohexylisocyanide in the presence of benzoic acid and the Passerini-like α-benzoyloxy- , -diphenylacrylamide was obtained as a consequence of the electrophilic addition of the ketene to the isocyanide, the former behaving as a carbonyl derivative [4]
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