Alkene Borylation-Hydrogenation Enables Highly Active, Site-Selective Cobalt-Catalyzed Borylation

Abstract

A method for promoting highly active and site-selective cobalt-catalyzed C(sp²)-H arene borylation is described. Addition of tert-butyl ethylene (TBE) increased the activity of the cobalt-catalyzed borylation of electron-rich arenes. With monosubstituted anisoles and anilines, synthetically useful site-selectivities favoring the meta-position of the ring were observed. Monitoring the catalytic reaction in situ by ¹H NMR spectroscopy established a borylation-hydrogenation sequence of tert-butyl ethylene as being responsible for the increased catalytic activity where borylation of the alkene preceded functionalization of the arene. Added or in situ generated trans-^tBuCH═CHBPin served as the active H₂ acceptor to overcome the inhibitory effect of HBPin and enabled both HBPin and B₂Pin₂ to be effective reagents for generating the active cobalt catalyst. Normal primary deuterium isotope effects of 5.0(1.2) and 6.0(2.0) in parallel and 3.1(1) and 3.7(3) in competition for meta and para borylation, respectively, were measured at 23 °C for the catalytic borylation of N-phenylmorpholine, supporting irreversible and rate-determining oxidative addition of the C(sp²)-H bond during the catalytic reaction. The combination of the kinetic isotope effects, in situ reaction monitoring, DFT studies, and stoichiometric experiments support the origin of meta selectivity as arising from irreversible oxidative addition of the meta-C(sp²)-H bond to cobalt(I).

Figure 1.

Reaction time course for the cobalt-catalyzed borylation of N-phenyl morpholine. A parallel kinetic isotope effect was measured using N-phenyl-d₅ morpholine.

Figure 2.

Proposed mechanism for active catalyst regeneration by TBE.

Scheme 1.

Representation of 1,3- and 1,3,5-substituted arenes in active pharmaceutical ingredients.

Scheme 2.

Electronically-controlled, site-selective cobalt-catalyzed C(sp²)–H borylation of fluorinated arenes.

Scheme 3.

(a) Site-selective C(sp²)–H borylation with (^iPrACNC)CoMe and B₂Pin₂. (b) Formation of (^iPrACNC)CoH₂BPin resulted in catalyst deactivation. (c) Cobalt-catalyzed borylation of electron-rich arenes suffers from poor activity.

Scheme 4.

Effect of HBPin and TBE on the yield of the cobalt-catalyzed borylation of veratrole with B₂Pin₂. NMR yields using 1,3,5-trimethoxybenzene internal standard are reported and the major product is shown.

Scheme 5.

Scope of the cobalt-catalyzed borylation of mono-substituted arenes in the presence of TBE. Yields determined by NMR spectroscopy using 1,3,5-trimethoxybenzene internal standard.

Scheme 6.

Synthesis of (^iPrACNC)CoPh-d₅ from (^iPrACNC)CoH₂BPin and TBE.

Scheme 7.

Stoichiometric regeneration of (^iPrACNC)CoBPin from (^iPrACNC)CoD₂BPin and trans-^tBuCH=CHBPin.

Scheme 8.

Scope of borylation using trans-^tBuCH=CHBPin and HBPin. NMR yields using 1,3,5-trimethoxybenzene internal standard are reported and the major product is shown. No borylation products were observed in the absence of added alkene.

Scheme 9.

Selectivity of stoichiometric borylation of N-Phenylmorpholine by putative (^iPrACNC)CoBPin. Assay yields were determined by NMR spectrosopy using a 1,3,5-trimethoxybenzene internal standard and the major product is shown.