Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

Abstract

Alkenes are ubiquitous in organic chemistry, yet many classes of alkenes remain challenging to access by current synthetic methodology. Herein, we report a copper hydride-catalyzed approach for the synthesis of Z-configured trisubstituted alkenes with high stereo- and regioselectivity via alkyne hydroalkylation. A DTBM-dppf-supported Cu catalyst was found to be optimal, providing a substantial increase in product yield compared to reactions conducted with dppf as the ligand. DFT calculations show that the DTBM substitution leads to the acceleration of alkyne hydrocupration through combined ground and transition state effects related to preventing catalyst dimerization and enhancing catalyst–substrate dispersion interactions, respectively. Alkyne hydroalkylation was successfully demonstrated with methyl and larger alkyl tosylate electrophiles to produce a variety of (hetero)aryl-substituted alkenes in moderate to high yields with complete selectivity for the Z stereochemically configured products. In the formation of the key C–C bond, computational studies revealed a direct SN2 pathway for alkylation of the vinylcopper intermediate with in situ-formed alkyl iodides.

Enantioselective Synthesis of Cyclopropanes via CuH-Catalyzed Intramolecular Hydroalkylation

“…A ΔΔ G ‡ = 3.7 kcal/mol between these two structures accounts for the experimentally observed high diastereoselectivity in favor of the trans-product ( S , S )- 3b over ( R , S )- 3b . It should be noted that these TSs resemble the structures previously computed by Ito and co-workers and are in line with recent work by Buchwald and Liu et al showing that Cu-mediated alkylations can occur through direct nucleophilic substitution via donation from the Cu-alkyl σ-bond into the C–Br σ* orbital even though competing with oxidative addition–reductive elimination sequences. , However, in our case, the ring closure step remains a key point that needs to be clarified. Indeed, this could occur also by an alternative mechanism as depicted in Figure B.…”

Asymmetric Synthesis of SCF3‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes

“…We also calculated the relative Gibbs free energies of each intermediate and transition state, giving ( S )‐ or ( R )‐enantiomer, respectively, in the asymmetric hydroboration of 1‐trifluoromethylthioalkene 1 o with the ( R )‐DTBM‐SEGPHOS ligand (Scheme 5A). The dimeric CuH species is generally thermodynamically stable than monomeric CuH 6 , [23d,24] expecting that the reaction was initiated by the coordination of substrate 1 o to the active 6 in equilibrium. Actually, a clear linear effect of enantiomer excess (ee) between ligand and product was observed (Figure S4), supporting the identification of monomeric CuH as the real active species.…”

CuH-Catalyzed Regio- and Enantioselective Formal Hydroformylation of Vinyl Arenes

“…However, given the high electrophilicity of oxocarbenium ions, we anticipated that the strongly reducing conditions required for copper hydride catalysis might be problematic. Based our prior work on hydroalkylation we considered the use of a protocol in which the slow in situ generation of an active electrophile might mitigate unproductive side reactions between the oxocarbenium and a silane. We envisioned that this could be accomplished through exposure of the commercially available ortho ester, diethoxy methyl acetate, to a suitable Lewis acid catalyst.…”