Catalytic Enantioselective Boryl and Silyl Substitution with Trifluoromethyl Alkenes: Scope, Utility, and Mechanistic Nuances of Cu–F β-Elimination

Abstract

Catalytic enantioselective methods are introduced that allow access to a variety of allyl boronates and silanes that contain a difluoroalkene unit; the resulting products may be used for the preparation of organofluorine compounds in high enantiomeric purity. Furthermore, a number of key mechanistic aspects of the transformations have been investigated and analyzed. Thus, first, an NHC–Cu-catalyzed method for boryl substitution with F3C-substituted alkenes is introduced. These processes, unlike the previously reported strategies, are applicable to alkyl as well as aryl substituted substrates, afford allyl boronates bearing a difluoroalkene moiety (up to 98% yield and 95:5 er). Second, the corresponding silyl substitutions, the first reported cases of their kind, are presented (up to 94% yield and 97:3 er). Third, experimental and computational (DFT) investigations are described that shed light on key mechanistic aspects of the catalytic processes. Evidence (X-ray structures of Cu–alkyl intermediates and kinetic studies) is put forth illustrating that the initial Cu–boryl and Cu–silyl addition is significantly faster than the ensuing Cu–F elimination, and that the latter step can be facilitated by either a mild Lewis acid (e.g., a Li or Na cation) or a nucleophilic promoter (e.g., an alkoxide). These findings together with DFT studies demonstrate that Cu–F β-elimination probably proceeds with anti-stereochemistry. Representative cases of ways through which the new mechanistic understanding may be used to rationalize previously disclosed findings, significantly improve a transformation, or develop new diastereo- and enantioselective catalytic methods are provided. For example, an explanation is provided regarding why bisphosphine–Cu complexes do not efficiently promote boryl substitutions with aryl-substituted substrates, but the corresponding silyl substitutions are facile, and how the size of a ligand can impact regioselectivity and efficiency.

Activation of the Si–B interelement bond related to catalysis

“…Later, the Hoveyda group presented an enantioselective silyl substitution by using NHC-copper catalysis, allowing for a practical and general entry into the synthesis of chiral allylic silanes with r94% ee (99g-j -(R)-100g-j, Scheme 31). 50 The mechanism was probed experimentally. For this, the NHC-Cu-Si complex 102 was prepared and characterised under N 2 atmosphere.…”

Sulfonate N‐Heterocyclic Carbene–Copper Complexes: Uniquely Effective Catalysts for Enantioselective Synthesis of C−C, C−B, C−H, and C−Si Bonds

“…Catalytic silyl substitutions that afford γ,γ‐ gem ‐difluoroallylsilanes were recently introduced (Scheme 79 a). [51] In line with the C−B bond forming reactions, processes involving sulfonate NHC‐Cu catalysts, while efficient, were less enantioselective. Nonetheless, reaction with a PMB‐protected alcohol starting material was most efficient with the catalyst derived from imid(S)‐3 a (80 % conv., 60 % yield, 93:7 e.r.…”

“… [50] The Cu complex derived from imid(S)‐2 c was the most effective. Inclusion of PhB(neo) (neo=neopentyl glycolate) improved yield and e.r., likely because the borate is the alkylating agent [51] …”

Beyond Carbon: Enantioselective and Enantiospecific Reactions with Catalytically Generated Boryl- and Silylcopper Intermediates

“…Later, Hoveyda and Torker reported another process, employing CuCl as precatalyst and a chiral N-heterocyclic carbene ligand ( S , S )- L3 ; both aryl- and alkyl-substituted alkenes are compatible with this catalytic system. 84 By replacing that ligand with ( S , S )- L4 , the method was also applicable to the silicon pronucleophile, i.e., Me 2 PhSiBpin ( 2 ), thereby allowing for the enantioselective formation of the C–Si bond. Just recently, Ito and Hoveyda extended this strategy to allylic difluorides by modification of the reaction setup ( Scheme 4 b).…”