Mechanism of Cu-Catalyzed Aryl Boronic Acid Halodeboronation Using Electrophilic Halogen: Development of a Base-Catalyzed Iododeboronation for Radiolabeling Applications.

John J Molloy,Sally L Pimlott,Andrew Sutherland,Kerry M O’Rourke,Nikki L Sloan,Matthew J West,Carolina P Frias,Allan J B Watson

doi:10.1021/acs.orglett.9b00942

Abstract

An investigation into the mechanism of Cu-catalyzed aryl boronic acid halodeboronation using electrophilic halogen reagents is reported. Evidence is provided to show that this takes place via a boronate-driven ipso-substitution pathway and that Cu is not required for these processes to operate: general Lewis base catalysis is operational. This in turn allows the rational development of a general, simple, and effective base-catalyzed halodeboronation that is amenable to the preparation of 125I-labeled products for SPECT applications.

Highlights

In terms of metal-free processes, in 1930, Challenger reported the halodeboronation of PhB(OH)[2] using aqueous X2 as well as with CuX2, with the latter proceeding via a pathway involving X2 produced in situ by the known redox of CuX2 → CuX + X2.3a In the 1950s, Kuivila established kinetic parameters for specific aryl boronic acid halodeboronation using X2 in both acidic and basic buffer, proposing an ipsosubstitution proceeding via a boronate generated in situ as the most likely mechanism (Scheme 1d).[6,7]
Mechanistic proposals have suggested a process via oxidative addition of Cu(I) to a halosuccinimide or derivative, transmetalation of an organoboron to the resulting Cu(III) intermediate, and subsequent reductive elimination.4a,b,e there is little evidence to support this proposed mechanism
We provide a mechanistic investigation of arylboronic acid halodeboronation using X+ reagents, showing that these reactions proceed via a common base-catalyzed ipsosubstitution mechanism, and that specific “Cu-catalyzed” reactions do not require Cu to proceed

Summary

Introduction

In terms of metal-free processes, in 1930, Challenger reported the halodeboronation of PhB(OH)[2] using aqueous X2 as well as with CuX2, with the latter proceeding via a pathway involving X2 produced in situ by the known redox of CuX2 → CuX + X2.3a In the 1950s, Kuivila established kinetic parameters for specific aryl boronic acid halodeboronation using X2 in both acidic and basic buffer, proposing an ipsosubstitution proceeding via a boronate generated in situ as the most likely mechanism (Scheme 1d).[6,7] Boronate-based ipsosubstitution has been proposed in halodeboronation reactions of aryl potassium trifluoroborates (ArBF3K).3f,g,i,j. Halodeboronation of Boronic Acids and Derivatives: (a) General Reaction; (b) Metal-Free Methods; (c) Cu-Catalyzed Approaches; (d) Proposed Mechanismsa

Results

Conclusion