Regioselective Palladium-Catalyzed Heterocyclization–Sonogashira Coupling Cascades from 2-Alkynylbenzamides and Terminal Alkynes: Experimental and DFT Studies

Abstract

A regioselective heterocyclization–Sonogashira coupling cascade between 2-alkynylbenzamides and terminal alkynes is described. The reaction proceeds under Pd­(II) catalysis, with air used as a terminal oxidant to regenerate the catalyst from the Pd(0) produced in the C–C coupling. The cascade process provides alkynyl-substituted isobenzofuranimine products in a single operation. These products are the result of a 5-exo O-cyclization, while products derived from the alternative 6-endo cyclization mode are observed in minor amounts. Two competing mechanisms have been considered to account for the observed results. Both involve heterocyclization, alkyne C–H activation, and reductive elimination steps but differ in the relative order of the first two. Control experiments using a preformed alkynylpalladium complex have shown that a mechanism starting with alkyne C–H activation is viable. On the other hand, DFT calculations indicate that the alternative cyclization-first mechanism is also competitive, particularly when PPh3 is used as ligand. Calculations also suggest that the exo cyclization is favored over the endo mode by the presence of PPh3 and σ-C Pd ligands in the activated complex undergoing cyclization.

Palladium‐Catalyzed Cascade Cyclization/Alkynylation Reactions

“…Recently, Aurrecoechea and Álvarez successfully accomplished a palladium‐catalyzed heterocyclization‐Sonogashira coupling from 2‐alkynylbenzamides ( 12 ) with terminal alkynes for the synthesis of alkynylisobenzofuranimines ( 13 ) (Scheme ) . The main products are the result of a 5‐ exo O ‐cyclization, while the products derived from the alternative 6‐ endo cyclization mode are observed in minor amounts.…”

“…[20] Recently,A urrecoechea and lvarez successfully accomplished ap alladium-catalyzed heterocyclization-Sonogashira couplingf rom 2-alkynylbenzamides (12)w ith terminal alkynes for the synthesis of alkynylisobenzofuranimines (13) (Scheme6). [23] The main products are the result of a5 -exo Ocyclization,w hile the products derived from the alternative 6endo cyclization mode are observed in minor amounts. Two competing mechanismsh ave been consideredt oa ccount for the observed results.B oth involve heterocyclization, alkyne CÀ Ha ctivation,a nd reductive elimination steps, but differ in the relative order of the first two.…”

Assembly of Functionalized 4‐Alkynylisoxazoles by Palladium‐Catalyzed Three‐Component Cascade Cyclization/Alkynylation

“…Finally, the resulting palladium(0) is additionally oxidized to the palladium(II) active catalyst species by air to complete this catalytic cycle . Despite all these results, we still cannot absolutely rule out the alkyne C−H activation process, which has been demonstrated by Aurrecoechea, Álvarez, and co‐workers …”

“…[24] Despite all these results, we still cannot absolutely rule out the alkyneC ÀHa ctivation process, which has been demonstrated by Aurrecoechea, lvarez,a nd co-workers. [25]…”

Catalytic Enantioselective Aminopalladation–Heck Cascade

“…[1] In parallel, the nucleopalladation of alkynes followed by trapping of the resulting achiral vinylpalladium intermediates has also been developed into a powerful synthetic tool (Scheme 1 b-i). [2] For example, the Pd II -catalyzed 5-endo cyclization of 2-alkynylanilines [3] has been successfully combined with Heck reaction, [4] Sonogashira reaction, [5] carbocyclization, [6] Suzuki reaction, [7] amination, [8] carboesterification, [9] alkoxycarbonylation, [10] imidoylation [11] and nucleophilic addition to aldehydes [12] for the synthesis of 2,3-difunctionalized indoles (Scheme 1 b-i). However, applying this strategy to the synthesis of chiral molecules remains scarce (Scheme 1 b-ii).…”