Open AccessNickel-Catalyzed Three-Component Cycloadditions of Enoates, Alkynes, and Aldehydes
Author(s) -
Aireal D. Jenkins,
Michael T. Robo,
Paul M. Zimmerman,
John Montgomery
Publication year - 2020
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.9b02446
Subject(s) - chemistry , cycloaddition , ketene , isomerization , substituent , alkylation , aldol reaction , metallacycle , medicinal chemistry , catalysis , stereoselectivity , stereochemistry , organic chemistry , physics , x ray crystallography , diffraction , optics
A method for the three-component cycloaddition of enoates, alkynes, and aldehydes has been developed. Building upon previous work by this group in which stoichiometrically generated metallacycles undergo alkylation, we report a catalytic, alkylative [3 + 2] cycloaddition. From simple starting materials, structurally complex cyclopentenones may be rapidly assembled. Computational investigation of the mechanism (ωB97X-D3/cc-pVTZ//ωB97X/6-31G(d)) identified three energetically feasible pathways. Based on the relative rates of ketene formation compared to isomerization to a seven-membered metallacycle, the most likely mechanism has been determined to occur "ketene-first", with carbocyclization prior to aldol addition. Deuterium labeling studies suggest that formation of the seven-membered metallacycle becomes possible when an α-substituted enoate is used. This observed change in selectivity is due to the increased difficulty of phenoxide elimination with the inclusion of additional steric bulk of the α-substituent. The net transformation results in a [3 + 2] cycloaddition accompanied by an alkylation of the enoate substituent.