C(sp²)–H Borylation of Fluorinated Arenes Using an Air-Stable Cobalt Precatalyst: Electronically Enhanced Site Selectivity Enables Synthetic Opportunities

Abstract

Cobalt catalysts with electronically enhanced site selectivity have been developed, as evidenced by the high ortho-to-fluorine selectivity observed in the C(sp2)–H borylation of fluorinated arenes. Both the air-sensitive cobalt(III) dihydride boryl 4-Me-(iPrPNP)Co(H)2BPin (1) and the air-stable cobalt(II) bis(pivalate) 4-Me-(iPrPNP)Co(O2 CtBu)2 (2) compounds were effective and exhibited broad functional group tolerance across a wide range of fluoroarenes containing electronically diverse functional groups, regardless of the substitution pattern on the arene. The electronically enhanced ortho-to-fluorine selectivity observed with the cobalt catalysts was maintained in the presence of a benzylic dimethylamine and hydrosilanes, overriding the established directing-group effects observed with precious-metal catalysts. The synthetically useful selectivity observed with cobalt was applied to an efficient synthesis of the anti-inflammatory drug flurbiprofen.

Mechanistic Studies of Cobalt-Catalyzed C(sp2)–H Borylation of Five-Membered Heteroarenes with Pinacolborane

“…2-Methylfuran was selected as the substrate because Co-catalyzed borylation of this arene with HBPin occurred at a rate that was conveniently monitored by 31 P NMR spectroscopy. As shown in Figure 1, only trans- ( iPr PNP)Co(H) 2 BPin 5a,8 was detected over the course of the reaction, and neither 4-BPin-( iPr PNP)Co(N 2 )BPin 8a nor 4-BPin-( iPr PNP)Co(H) 2 BPin 8a was observed, demonstrating that the 4-position of the pincer does not undergo competitive borylation with the substrate.…”

“…8a However, under these conditions, borylation of the 4-position of the pincer ligand of the cobalt catalyst occurred prior to turnover, rendering the metal relatively electron poor and slowing the rate of oxidative addition of the arene C−H bond. These findings inspired the synthesis of second-generation catalysts where methyl and pyrrolidinyl groups were installed in the 4-position of the pincer to block unwanted borylation and increase the electron density of the cobalt center (Scheme 1).…”

“…These findings inspired the synthesis of second-generation catalysts where methyl and pyrrolidinyl groups were installed in the 4-position of the pincer to block unwanted borylation and increase the electron density of the cobalt center (Scheme 1). 8a The increased activity of these catalysts was applied to the borylation of fluoroarenes where unprecedented levels of selectivity for sites ortho to fluorine were observed and used in a streamlined synthesis of the anti-inflammatory drug, Flurbiprofen. 8b …”

“…8a The increased activity of these catalysts was applied to the borylation of fluoroarenes where unprecedented levels of selectivity for sites ortho to fluorine were observed and used in a streamlined synthesis of the anti-inflammatory drug, Flurbiprofen. 8b …”

“…9 However, despite the mature understanding of the mechanisms of iridium- 10–16 and cobalt-catalyzed C(sp 2 )−H borylation using B 2 Pin 2 as the boron reagent, 8a open questions remain about the operative pathways in cobalt-catalyzed reactions when HBPin is used as the stoichiometric boron source. With ( iPr PNP) cobalt precatalysts, the success of the catalytic C−H borylation depends on the identity of the boron reagent.…”