.
Angewandte
Communications
DOI: 10.1002/anie.201304443
BN Heterocycles
Rhodium-Catalyzed Boron Arylation of 1,2-Azaborines**
Gabriel E. Rudebusch, Lev N. Zakharov, and Shih-Yuan Liu*
The biphenyl scaffold can be considered a privileged struc-
tural motif in medicinal chemistry.[1] Biaryl compounds have
shown a wide range of therapeutic activities, including
antifungal, antiinfective, antihypercholesteremic, antirheu-
matic, analgesic, antiinflammatory, and antiarrhythmic activ-
ities.[1] In addition, a statistical analysis of binding data on
Scheme 1. Biphenyl motif and its BN isostere. FG=functional group.
a variety of protein targets showed that compounds featuring
a biphenyl substructure bind to a wide range of proteins with
high levels of specificity.[2]
Herein, we present a general functional-group-tolerant
synthesis of BN biphenyls through a rhodium-catalyzed cross-
coupling reaction of B-Cl-substituted 1,2-azaborines with
arylstannanes. To demonstrate the scope of our method, we
prepared BN felbinac, the BN isostere of the nonsteroidal
anti-inflammatory drug felbinac. Furthermore, we present
mechanistic studies that support a consecutive transmetala-
tion pathway for the catalytic coupling reaction.
We chose N-ethyl-2-chloro-1,2-azaborine (1a) and
trimethyl(phenyl)tin as model reactants to optimize the
coupling conditions. No background reaction occurred
between 1a and trimethyl(phenyl)tin at 1008C after 24 h
(Table 1, entry 1). Because of the resemblance of our model
reaction to the Stille cross-coupling, we surveyed a series of
Pd catalysts that are typically used in a Stille reaction,[10] but
An objective of synthetic chemistry is to create new
chemical space that enables novel structure–activity relation-
ship investigations. BN/CC isosterism is emerging as a viable
strategy to expand the structural diversity of compounds
relevant to biomedical research and materials science.[3,4] In
particular, 1,2-dihydro-1,2-azaborines (abbreviated as 1,2-
azaborines from hereon) have attracted growing attention as
BN isosteres of the biologically important family of aromatic
compounds.[5] As an example, we recently demonstrated that
BN isosteres of ethylbenzene serve as inhibitors of ethyl-
benzene dehydrogenase rather than as substrates.[6,7]
In order to expand the chemical space of biaryl structures
through BN/CC isosterism, new synthetic tools for the
preparation of BN isosteres of biphenyls (BN biphenyls)
need to be developed (Scheme 1). While the synthesis of
biphenyls (including the use of various cross-coupling meth-
ods)[8] is well established, a general method to access BN
biphenyls has not been explored. The boron position in the
1,2-azaborine heterocycle appears to be a straightforward
point of attachment for their synthesis. However, the scope
with respect to the boron position is currently limited to aryl
substituents with functional groups that are compatible with
organomagnesium and organolithium reagents.[9]
Table 1: Survey of catalysts for the coupling of 1a with trimethyl-
(phenyl)tin.
Entry
Catalyst
Yield [%][a]
1
2
–
0
0
0
[Pd(PPh3)4]
[Pd2dba3]/PCy3
[Pd2dba3]/rac-BINAP
[{Ir(cod)Cl}2]
[Rh(PPh3)3Cl]
[{Rh(cod)Cl}2]
[Rh(cod)2]BF4
[{Rh(nbd)Cl}2]
[Rh(nbd)2]BF4
[Rh(cod)(dppb)]BF4
[{Rh(C2H4)2Cl}2]/rac-BINAP
[{Rh(C2H4)2Cl}2]/(S)-p-tol-BINAP
[{Rh(C2H4)2Cl}2]/BIPHEP
[{Rh(C2H4)2Cl}2]/BIPHEP
3[b]
4
[*] G. E. Rudebusch, Prof. Dr. S.-Y. Liu
Department of Chemistry and Biochemistry
University of Oregon
0
5
6
7
8
<5
18
43
42
71
67
22
83
91
95
89
Eugene, OR 97403-1253 (USA)
E-mail: lsy@uoregon.edu
9
Dr. L. N. Zakharov
Center for Advanced Materials Characterization in Oregon
University of Oregon
10
11
12
13
14
15[c]
Eugene, OR 97403-1253 (USA)
[**] Correspondence concerning X-ray crystallography should be
directed to Lev Zakharov (lev@uoregon.edu). This research was
supported by the National Institutes of Health (National Institute of
General Medical Sciences, R01-GM094541 and R41-GM099181).
Funding for the University of Oregon Chemistry Research and
Instrumentation Services has been provided in part by the NSF
(CHE-0923589). We thank Dr. Adam Marwitz for performing the
stability assessment of BN felbinac.
[a] Yields determined by GC analysis using hexadecane as a calibrated
internal standard, average of two runs. [b] 10 mol% PCy3. [c] 2 mol% Rh/
BIPHEP. BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl,
BIPHEP=2,2’-bis(diphenylphosphino)-1,1’-biphenyl, cod=1,5-cyclo-
octadiene, Cy=cyclohexyl, dba=trans,trans-dibenzylideneacetone,
dppb=1,1’-bis(diphenylphosphino)butane, nbd=2,5-norbornadiene,
p-tol-BINAP=2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl.
Supporting information for this article is available on the WWW
9316
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 9316 –9319