Nickel-Catalyzed Cross Couplings of Benzylic Ammonium Salts and Boronic Acids: Stereospecific Formation of Diarylethanes via C–N Bond Activation

Abstract

We have developed a nickel-catalyzed cross coupling of benzylic ammonium triflates with aryl boronic acids to afford diarylmethanes and diarylethanes. This reaction proceeds under mild reaction conditions and with exceptional functional group tolerance. Further, it transforms branched benzylic ammonium salts to diarylethanes with excellent chirality transfer, offering a new strategy for the synthesis of highly enantioenriched diarylethanes from readily available chiral benzylic amines.

Transition-Metal-Catalyzed Cleavage of C–N Single Bonds

“…258 It is noted that chiral diarylethanes could be efficiently generated with high enantioselectivity via the Nicatalyzed Suzuki coupling reaction. In this process, an oxidative addition of the Ni catalyst to the C−N bond cleaves the C sp 3 − N bond of benzylic ammonium salts.…”

At the Forefront of the Suzuki–Miyaura Reaction: Advances in Stereoselective Cross-Couplings

“…Based on the precedent of using aryl ammonium salts as cross-coupling partners in nickel-catalysed Suzuki-Miyaura cross-couplings [87], Watson and co-workers developed a mild and effective variant involving benzylic trimethyl ammonium salts 79 [88]. Careful optimization of reaction conditions led to a stereospecific preparation of diarylethane compounds 80 from optically enriched secondary benzylic amines as stable precursors (Scheme 20a).…”

A general, simple catalyst for enantiospecific cross couplings of benzylic ammonium triflates and boronic acids: no phosphine ligand required

“…To overcome this restriction, we developed an enantiospecific, nickel-catalyzed cross coupling of benzylic ammonium triflates with aryl boronic acids (Scheme 1A). 8 This method not only allows the use of commercially available, functional group tolerant boronic acid coupling partners, but also enables the use of amine-derived substrates. In our view, amines are ideal starting materials for enantiospecific reactions due to their wide availability in excellent enantiopurity via a variety of methods.…”

“…In particular, our previous investigations of the cross couplings of benzylic ammonium triflates focused largely on the use of carbocyclic aryl boronic acids with only one example of a vinyl boronic acid. 8 Our attempts to use heteroaromatic boronic acids resulted in modest yields and ee's. In addition, substituents other than methyl were not demonstrated at the benzylic stereocenter (R 1 ) in the enantiospecific cross couplings of ammonium triflates.…”

“…12,5b, c, 6, 13 For example, under our previously reported conditions, the cross couplings of benzylic ammonium salts 1 with naphthyl substituents (Ar 1 = 2-Np) occurs with an average yield of 72%. 8 However, the cross coupling of benzylic ammonium triflates with substituted phenyl substituents occurs with an average yield of only 45%. Given the importance of heteroaromatic and substituted phenyl groups in pharmaceutical agents and other biologically active compounds, 14 we sought to develop conditions for the enantiospecific cross coupling of benzylic ammonium triflates that would overcome these limitations.…”