Angewandte
Chemie
DOI: 10.1002/anie.201308855
Zinc-Catalyzed Borylation
Hot Paper
Zinc-Catalyzed Borylation of Primary, Secondary and Tertiary Alkyl
Halides with Alkoxy Diboron Reagents at Room Temperature**
Shubhankar Kumar Bose, Katharina Fucke, Lei Liu, Patrick G. Steel, and Todd B. Marder*
Abstract: A new catalytic system based on a ZnII NHC
precursor has been developed for the cross-coupling reaction
of alkyl halides with diboron reagents, which represents a novel
b) classical or transition-metal-catalyzed hydroboration of
olefins;[5] c) transition-metal-catalyzed C H activation/bory-
À
lation of alkanes;[6] and d) metal-catalyzed b-borylation of
a,b-unsaturated carbonyl compounds.[7] However, these
methods have significant limitations, such as functional-
group incompatibility in the generation of reactive organo-
lithium/organomagnesium reagents, and regioselectivity in
the hydroboration of internal olefins. To address this chal-
lenge recent attention has been given to the development of
transition-metal-catalyzed borylation of unactivated alkyl
À
use of a Group XII catalyst for C X borylation. This approach
gives borylations of unactivated primary, secondary, and
tertiary alkyl halides at room temperature to furnish alkyl
boronates, with good functional-group compatibility, under
mild conditions. Preliminary mechanistic investigations dem-
onstrated that this borylation reaction seems to involve one-
electron processes.
[8–11]
À
electrophiles for the formation of C B bonds.
Thus,
A
lkyl boronic acid derivatives have emerged as versatile
a versatile and powerful approach for the synthesis of alkyl
boronate esters by copper-catalyzed borylation of alkyl
halides and pseudohalides was established by our groups,[8]
and expanded upon by others using Cu, Ni, and Pd
catalysts.[9–11] Being less toxic than Pd or Ni, inexpensive,
abundant and environmentally more acceptable, zinc is an
attractive alternative to the commonly used expensive noble
metals in a number of catalytic reactions.[12] However, the
potential for zinc catalysis of borylation or other reactions
typically involving oxidation state changes (e.g. oxidative
addition/reductive elimination processes) remained to be
examined.[13]
intermediates for transition-metal-catalyzed cross-coupling
reactions[1,2] and have a wide range of applications in
medicinal chemistry.[3] Current approaches for the synthesis
of alkyl boronic acid derivatives can be classified into four
categories (Scheme 1): a) reaction of alkyl lithium or alkyl
magnesium reagents with suitable boron compounds;[4]
À
The only example of zinc-mediated C B bond formation
is a stoichiometric reaction reported by Yamashita and
Nozaki using a zinc boryl complex.[14] Knochel et al. devel-
oped boron zinc transmetalation reactions resulting in the
formation of stereochemically pure organozinc species, which
can react with several classes of electrophiles with retention
of configuration.[15] Recently, zinc-mediated and zinc-cata-
lyzed propargylation of ketones using propargylboronates has
also been reported.[16] Given the low cost and low toxicity of
zinc, we were interested to explore its use in the borylation of
alkyl halides and now report the first efficient zinc-catalyzed
borylation of primary, secondary, and tertiary alkyl halides
with alkoxy diboron reagents at room temperature.
Using cyclohexyl bromide 9a as the model substrate in
reactions with the diboron compound B2pin2 to produce the
corresponding cyclohexyl boronate 9b, we screened a range
of conditions, solvents, ligands, zinc sources, and bases to
assess the scope and limitations of this reaction (Table 1). The
desired alkyl boronic ester 9b was obtained in 61% yield at
room temperature in 18 h using IMes (L1) as the ligand
(IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)
and ZnCl2 as zinc source in THF (entry 1). We screened
a range of solvents, from benzene to polar solvents (Table 1,
entries 2–7), with methyl-tert-butylether (MTBE) proving to
be optimal giving a yield of 91% in 1 h (entry 5). The limited
solubility of KOtBu or the initially formed B2pin2/KOtBu
adduct[17,18] may account for the low yield of product in some
Scheme 1. General approaches for the construction of alkyl boronic
acid derivatives.
[*] Dr. S. K. Bose, Dr. K. Fucke, Prof. Dr. T. B. Marder
Institut fꢀr Anorganische Chemie
Julius-Maximilians-Universitꢁt Wꢀrzburg
Am Hubland, 97074 Wꢀrzburg (Germany)
E-mail: todd.marder@uni-wuerzburg.de
Prof. Dr. L. Liu
Department of Chemistry, Tsinghua University
Beijing 100084 (China)
Prof. Dr. P. G. Steel
Department of Chemistry, Durham University
South Road, Durham DH1 3LE (UK)
[**] S.K.B. thanks the Alexander von Humboldt Foundation (AvH) for
a postdoctoral fellowship. T.B.M. thanks AllylChem Co. Ltd. for
a generous gift of B2pin2 and B2neop2. L.L. thanks NSFC (No.
21221062) for research support. We thank Prof. K. Mꢀller-Busch-
baum, T. Wehner, L. Meyer, and F. Schçnfeld for powder X-ray
diffraction analysis.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1799 –1803
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1799