Nickel-Catalyzed Three-Component Cycloadditions of Enoates, Alkynes, and Aldehydes

Abstract

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.

Dehydrogenative Coupling of Alcohols with Internal Alkynes under Nickel Catalysis: An Access to β-Deuterated Branched Ketones

“…This implies that benzaldehyde 1d either, in the presence of NaEt 3 BH, generates benzyl alcohol, which then proceeds the dehydrogenative coupling of alcohol with alkynes, or undergoes a cycloaddition with alkynes using a nickel catalyst to form a β,γ-unsaturated ketone via a metallacycle intermediate as proposed by the research group of Montgomery and Jamison. 73,74 Subsequently, the selective hydrogenation of the β,γ-unsaturated ketone would yield the desired product 1 in the presence of a nickel catalyst. Consequently, benzyl alcohol reacted with alkyne 1a, forming acylated product 1.…”

Intermolecular Pauson–Khand-Type Reaction of Vinyl Iodides with Alkynes and a CO Surrogate

“…24 Other transition-metal-catalyzed approaches which form these important cyclopentenones take mechanistically distinct pathways. 62,63 Examples of this include the transition-metalcatalyzed cyclization of α,β-unsaturated carbonyls with alkynes by Ogoshi, 64 Montgomery, 65,66 Barluenga,67,68 and others. 69−73 Previously, our group has also reported a distinct entry into this class of compounds.…”

“…Other transition-metal-catalyzed approaches which form these important cyclopentenones take mechanistically distinct pathways. , Examples of this include the transition-metal-catalyzed cyclization of α,β-unsaturated carbonyls with alkynes by Ogoshi, Montgomery, , Barluenga, , and others. − Previously, our group has also reported a distinct entry into this class of compounds. We used palladium catalysis to engage α,β-unsaturated acid chlorides and internal alkynes in the presence of a hydrosilane, as a hydride source, to form cyclopentenones through a molecular shuffling approach (Scheme B) .…”

Synthesis of Cyclopentenones through Rhodium-Catalyzed C–H Annulation of Acrylic Acids with Formaldehyde and Malonates

“…However, challenges, including the excess use of toxic carbon monoxide and low reactivity as well as poor selectivity of alkenes associated with the intermolecular PKR, make the development of a novel strategy for cyclopentenones highly attractive. In this respect, important advancements from the groups of Chung, Montgomery, Ogoshi, Ready, Morandi, and others have been documented (Scheme c). Notably, most of these works focused on the development of three-carbon components without alkene and carbon monoxide in the PKR.…”