A Metal‐Free Approach Toward Saturated N‐Propargyl Heterocycles via an Annulation/Decarboxylative Coupling Sequence

Abstract

A three‐component reaction of a 1,2‐amino alcohol or 1,3‐amino alcohol with a formaldehyde solution and a propiolic acid was developed and studied. This new strategy provided an efficient access to biologically and synthetically important N‐propargyl oxazolidines, 1,3‐oxazinanes and thiazolidine bearing a diverse range of substituents in good yields. The transformation involves a cascade process that begins with an annulation and is followed by the metal‐free decarboxylative coupling.magnified image

Mechanistic studies on the metal-free decarboxylative coupling reaction for synthesis of propargylamines by NMR

“…4,5 Since then, several related methods have been independently developed by us and other groups. [6][7][8][9][10][11][12][13][14][15][16] The decarboxylative coupling of alkynylcarboxylic acids showed a similar reaction pattern to the Sonogashira reaction of terminal alkynes. Therefore, alkynylcarboxylic acids have been used as the surrogates of terminal alkynes in the coupling reactions and three-component reactions.…”

Decarboxylative A3‐coupling reactions: An overview

“…Drawing inspiration from these works, an elegant domino procedure for the synthesis of N ‐propargyl oxazolidines 48 through a three‐component reaction between alkynyl carboxylic acids 46 , 1,2‐amino alcohols 47 , and formaldehyde 18 , in which two new CN, one CO, and one CC bonds are formed, was developed by Sun et al (Scheme 21). [ 37 ] The reactions were carried out under catalyst‐free conditions in refluxing DCM and afforded moderate to excellent yields of the target products, ranging from 26 to 96%, through an annulation/decarboxylative coupling sequence. Some important information of this metal‐free tandem approach to N ‐propargyl oxazolidines are listed below: (a) aromatic alkynyl carboxylic acids afforded better yields compared to aliphatic ones; (b) electron‐donating aryl alkynyl carboxylic acids showed more effectiveness than electron‐withdrawing ones; (c) the protocol for 1,2‐amino alcohols bearing electron‐withdrawing groups and unsubstituted 1,2‐amino alcohol was considerably less efficient; and (d) 2‐aminophenol and propiolic acid failed to enter into this reaction.…”

The Applications of (Para)formaldehyde in Metal‐Catalyzed Organic Synthesis

“…More recently, Sun and co‐workers reported an interesting three‐component reaction of 1,2‐ or 1,3‐amino alcohols with formaldehyde and propiolic acids to prepare biologically and synthetically important N ‐propargyloxazolidines, 1,3‐oxazinanes and thiazolidines (Scheme ) 28. In this cascade process, condensation between an amino alcohol and a first molecule of formaldehyde led to oxazolidine intermediate A , which condensed with a second molecule of formaldehyde to afford iminium B .…”