Theoretical Study of the Addition of Cu–Carbenes to Acetylenes to Form Chiral Allenes

Abstract

Terminal alkynes have become one of the most versatile building blocks for C–C bond construction in the past few decades, and they are usually considered to convert to acetylides before further transformations. In this study, a novel direct nucleophilic addition mode for Cu­(I)-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones to synthesize chiral allenes is proposed, and it was investigated by density functional theory with the M11-L density functional. Three different reaction pathways were considered and investigated. The computational results show that the proposed reaction pathway, which includes direct nucleophilic attack of protonated acetylene, deprotonation of the vinyl cation, and catalyst regeneration, is the most favorable pathway. Another possible deprotonation–carbenation–insertion pathway is shown to be unfavorable. The direct nucleophilic addition step is the rate- and enantioselectivity-determining step in the catalytic cycle. Noncovalent interaction analysis shows that the steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand is important to control the enantioselectivity. In addition, calculation of a series of chiral bisoxazoline ligands shows that a bulky group on the oxazoline ring is favorable for high enantioselectivity, which agrees with experimental observations. Moreover, copper acetylides are stable, and their generation is a favorable pathway in the absence of chiral bisoxazoline ligands.

Recent Advances in Theoretical Studies on Transition-Metal-Catalyzed Carbene Transformations

“…In our computational study, several different mechanistic scenarios were taken into account (Figure 5). 1 The Cu(I)catalyzed deprotonation of phenylacetylene could occur through transition state TS-10 with an activation free energy of 16.7 kcal/mol, reversibly generating copper acetylide intermediate 23. However, the followed carbenation step through the denitrogenation transition state TS-11 has an activation free energy of 40.8 kcal/mol, which indicates that this mechanism is less likely.…”

“…The electrostatic potential (ESP) and the frontier molecular orbitals (FMOs) of Cu-carbene intermediate 26 were analyzed to investigate the reactivity of this metal carbene. 1 The ESP map (Figure 6a) showed that carbene carbon C1 exhibits electropositive character. Meanwhile, the FMO analyses (Figure 6b) demonstrated that the LUMO of Cu-carbene 26 is mainly located at the p orbital of carbene carbon C1.…”

“…57−61 The intermolecular nucleophilic addition toward metal carbene is displayed in model B. 1,62 In model C, a novel outer-sphere nucleophilic addition mechanism in which the metal acts as a Lewis acid is proposed. 2 Here the outer sphere refers to the feature where the carbene carbon is not coordinated with the metal center and the nucleophile can attack the naked carbene carbon without coordinating to the metal center (Scheme 1).…”

Transition-Metal-Catalyzed Cross-Coupling with Ketones or Aldehydes via N-Tosylhydrazones

“…The generated propargyl copper species would undergo a regioselective protonation to deliver the corresponding allene products (Scheme a). Recently, DFT calculations have suggested that a nucleo­philic attack of the alkyne to the copper carbene species followed by deprotonation of the generated vinyl cation is involved in the reaction mechanism, rather than the carbene migratory insertion process …”

“…Recently, DFT calculations have suggested that a nucleophilic attack of the alkyne to the copper carbene species followed by deprotonation of the generated vinyl cation is involved in the reaction mechanism, rather than the carbene migratory insertion process. 75 Following this work, the substrate scope is then substantially expanded for the synthesis of allenes with various substitution patterns. Simple copper iodide is an efficient catalyst to catalyze the coupling of aldehyde derived N-tosylhydrazones with terminal alkynes under ligand-free conditions, providing 1,3disubstituted allenes in good yields (Scheme 15b).…”