Multicomponent Cascade Reactions: A Novel and Expedient Approach to Functionalized Indoles by an Unprecedented Nucleophilic Addition‐Heterocyclization‐Oxidative Alkoxycarbonylation Sequence

Abstract

A novel multicomponent cascade process is reported, based on the sequential combination between an initial nucleophilic attack step to an imine moiety and a palladium-catalyzed oxidative heterocyclization-alkoxycarbonylation process. By this new process, five simple molecules [2-alkynylaniline imines, alcohol (ROH), carbon monoxide (CO), alcohol (ROH), and oxygen (O 2 )] are sequentially activated, selectively leading to high value-added functionalized indole derivatives in a single operation.

Oxidative Carbonylation as a Powerful Tool for the Direct Synthesis of Carbonylated Heterocycles

“…[8] The heterocyclization/alkoxycarbonylation pathway was also followed by 2-alkynyl anilines 5 (Scheme 8), each containing an internal triple bond and a secondary amino group. [12] Scheme 9. [9] The presence of a secondary amino group and of an internal triple bond in the starting material was essential for the selectivity of the Scheme 8.…”

A General Synthesis of Indole‐3‐carboxylic Esters by Palladium‐Catalyzed Direct Oxidative Carbonylation of 2‐Alkynylaniline Derivatives

“…[22] Scheme 2. Multicomponent cascade reaction leading to 1-(alkoxyarylmethyl)indole-3-carboxylic esters 4 from 2-alkynylaniline imines 3 through the intermediate formation of [(alkoxymethyl)(2alkynylaryl)]amines I.…”

“…were prepared by reductive amination of the corresponding primary 2-alkynylanilines [prepared in their turn by Sonogashira coupling between the appropriate 2-haloaniline and 1-alkynes, as we previously described [22] and as described below for 4-methyl-2-(phenylethynyl)aniline]. All other materials were commercially available and were used without further purification.…”

“…[19] An attractive alternative method for the synthesis of indole-3-carboxylic esters 2 would consist in the direct oxidative carbonylation of 2-alkynylanilines 1, according to Equation (1). [22] Reactions were carried out at 80°C in a 3:1 HC(OMe) 3 /MeOH mixture as the solvent, in the presence of 2 mol-% of PdI 2 in conjunction with an excess of KI (KI/ PdI 2 molar ratio 10:1), and under a total pressure of 40 atm of a 4:1 mixture CO/air. [20] The general applicability of this method, however, was not demonstrated; moreover, an excess of a metallic reoxidant (CuCl 2 , 3 equiv.…”

“…

A general synthesis of indole-3-carboxylic esters by direct Pd-catalyzed oxidative carbonylation of readily available 2alkynylaniline derivatives is reported. [22] Scheme 2. On the other

PdI 2 /KI system as the catalyst, [21] in the presence of only oxygen as the oxidizing agent; see Equation (1), catalyst: PdI 2 /KI, [OX] = (1/2)O 2 , [OXH 2 ] = H 2 O.

Results and Discussion

We have recently reported an innovative approach to 1-(alkoxyarylmethyl)indole-3-carboxylic esters 4, based on an unprecedented multicomponent cascade reaction, involving ROH addition to the imino group of 2-alkynylaniline imines 3 to give [(alkoxymethyl)(2-alkynylaryl)]amines I as intermediates, followed by the PdI 2 -catalyzed reaction of the latter with CO, ROH, and O 2 to give the final products Scheme 1.

…”