Environmentally benign, microwave-assisted chemoselective N-hydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal

Abstract

Dedicated to Prof. Kenneth Laali on the occasion of his 65 th birthday and life-long contributions to chemistryReceived 07-31-2017 Accepted 10-27-2017 Published on line 11-05-2017 AbstractThe chemoselective microwave-activated N-hydroxyalkylation of indoles using trifluoroacetaldehyde methylhemiacetal as the alkylating agent under mild conditions is described. The chemoselectivity of this reaction is determined by the solvent used. In dimethyl sulfoxide, the reaction occurs without the use of a strong base or a metal catalyst. This approach can be applied to a variety of different substituted indoles to obtain the corresponding N-alkylated products with high selectivity. The product 2,2,2-trifluoro-1-(1-H-indol-1-yl)ethanols combine two moieties of frequent pharmacological interest: the indole core and a CF 3 -group containing a hydroxyalkyl substituent.

Revolutionizing Indole Synthesis: A Microwave‐Powered Approach

“…Notably, despite moderate yields, the reaction exclusively yielded the hydroxyalkylation product, with no observed formation of byproducts, and the unreacted starting indole was recoverable and reusable (Scheme 41). [58] Kwon, et al presented an uncomplicated and efficient copper(I) oxide (Cu2O) catalyst system for the N-arylation reaction involving diverse indole derivatives and various aryl halides (ArÀ X) through microwave irradiation. The optimization process included variations in copper salts, bases, and solvents.…”

“…Interestingly, the use of DMSO as the solvent leads to almost exclusive N‐alkylation, as illustrated in Scheme 53. Although the product can be obtained under entirely base‐free conditions, the introduction of a catalytic amount of triethylamine results in a twofold increase in yield [58] …”

“…Although the product can be obtained under entirely base-free conditions, the introduction of a catalytic amount of triethylamine results in a twofold increase in yield. [58] Azeredo et al documented a Microwave-enhanced synthesis of 3-selenyl-and 3-sulfenyl-indole derivatives. In this procedure, indoles reacted with diselenide or disulphide derivatives, resulting in the ideal products within a concise timeframe in the absence of metal and solvent.…”

“…Notably, despite moderate yields, the reaction exclusively yielded the hydroxyalkylation product, with no observed formation of byproducts, and the unreacted starting indole was recoverable and reusable (Scheme 41). [58] …”