Synthesis of DBpin using Earth-abundant metal catalysis

Abstract

The synthesis of DBpin was achieved using (^EtBIP)CoCl₂ or (^tBuPNN)FeCl₂ as pre-catalysts activated with NaO^tBu. (^EtBIP)CoCl₂ was used as a pre-catalyst for the hydrogen isotope exchange of HBpin with D₂, and (^tBuPNN)FeCl₂ for deuterogenolysis of B₂pin₂. The one-pot, tandem hydrogenolysis-hydroboration/deuterogenolysis-deuteroboration reaction of terminal alkenes could be catalysed by (^tBuPNN)FeCl₂ to give alkyl boronic esters.

Introduction

Deuterated compounds have found use across a wide range of applications from mechanistic analysis to pharmacokinetic studies. The strength of the C-D bond slows metabolism and can therefore facilitate lower pharmaceutical doses and numerous deuterated active pharmaceutical ingredients are currently undergoing clinical trials, with Deutetrabenazine having been fully approved by the FDA [1].

Boronic esters are ubiquitous in modern organic chemistry due to their functional group tolerance and broad applications [[2], [3], [4]]. Boronic esters are commonly prepared by the metal-catalysed hydroboration of alkenes and alkynes, with a wide range of transition metal and main group catalysts having been developed [5,6]. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (HBpin) has become a common reagent in organic synthesis, due to its stability and that of alkyl and aryl pincacolboronic esters [7]. The deutero-isotopologue, DBpin offers a simple means of deuterium-incorporation and has been commonly used for in situ reaction monitoring of reactive species, and allows for a B–H kinetic isotope effect to be determined [[8], [9], [10], [11], [12], [13], [14], [15], [16]].

The synthesis of HBpin was first reported by Knochel by reaction of Me₂S·BH₃ with pinacol and distillation to give a high yield of HBpin [17]. A similar synthetic route has been commonly used to prepare DBpin, but requires the prior synthesis of B₂D₆ gas, which is toxic, pyrophoric, and requires a complex reaction setup [18]. DBpin has also been prepared by hydrogen isotope exchange of HBpin, however low deuterium incorporation is common, and forcing conditions can be needed. The first example of hydrogen isotope exchange of HBpin was reported by Perutz and co-workers using a rhodium catalyst, however the DBpin was not isolated from the reaction [19]. Further examples of hydrogen isotope exchange have been shown with iridium and ruthenium complexes [13,20], but only a single example has been reported using an Earth-abundant metal, a methyl-cobalt complex, which gave good deuterium incorporation at room temperature [8].

The deuterogenolysis of bis-(pincolato)borane (B₂pin₂) provides a synthetically simple route to DBpin, with high deuterium incorporation. The deuterogenolysis of B₂pin₂ was first demonstrated by Hartwig and Hall using an iridium catalyst, however due to low reactivity the reaction required multiple charges of D₂ over the period of 24 h [9]. Marder and Braunschweig demonstrated the hydrogenolysis of B₂pin₂ using a heterogenous catalyst [21]. Huang demonstrated the use of a PNN-ligated cobalt catalyst for the deuterogenolysis of B₂pin₂, with high reactivity and the generated DBpin could be used in situ for the deuteroboration of alkenes and alkynes using the same catalyst. NaHBEt₃ was required to activate the cobalt pre-catalyst (Scheme 1) [22].

We have previously demonstrated NaO^tBu as an alternative to organometallic activators in Earth-abundant metal catalysis, thus we sought to extend this to the synthesis of DBpin [23]. Herein we report the use of Earth-abundant metal catalysts for the hydrogen isotope exchange of HBpin and deuterogenolysis of B₂pin₂ using bench stable pre-catalysts and NaO^tBu as the activator to give DBpin with high deuterium incorporation and simple purification.