.
Angewandte
Communications
Table 3: IMesCuCl-catalyzed cyanoborylation of vinylarenes.[a]
84% yield upon isolation, and with only trace amounts of 3
(entry 11). This optimized protocol was used in the remainder
of our studies.
The efficiency of the cyanoborylation was explored across
a range of substituted styrenes. With styrene itself, exclusive
ortho cyanation was observed, and no evidence for the meta
or para isomers was obtained (Table 2, entry 1). Similarly,
Table 2: IMesCuCl-catalyzed cyanoborylation of substituted styrenes.
Entry
X
Y
Z
Yield [%][a]
1
2
3
4
5
6
7
8
H
F
Cl
Me
tBu
Ph
CH2OTBS
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
84
81
45
81
84
79
72
[a] Regioisomers shown were obtained with >97:3 selectivity. Yields are
those of the isolated products. [b] The BPin derivative shown was
oxidized to the corresponding alcohol with NaOH and H2O2. The overall
yield for the cyanoborylation and oxidation is shown. [c] The BPin
oxidation process was accompanied by an N to O Boc migration.
examined in the transformation. A dihydroindene derivative
and the N-Boc derivative of 2-vinylpyrrole both underwent
highly regioselective cyanation at the least-hindered ortho-
position (Table 3; 5 and 6). However, 2-vinylnaphthalene
underwent highly regioselective cyanation at the more
hindered C1-position (7) and an N-Boc indole bearing a 5-
vinyl group similarly underwent highly regioselective cyana-
tion at the 4-position (8). These observed regioselectivities
with substrates that possess extended conjugation are con-
sistent with the related transformations reported by Yang and
Buchwald,[5] where exclusive cyanation in naphthalenes
occurred at the C1-position, and were explained through
computational studies from Yang and Liu.[6] Carbazoles were
also effective substrates, with cyanation of the N-Boc
derivative of 3-vinylcarbazole selectively occurring at the
C4-position (9). Similarly, a dibenzofuran substrate under-
went regioselective cyanation at the C1-position (10). Finally,
regioselective derivatization of an estrone-derived substrate
bearing a vinyl group at the C3-position was accomplished,
with installation of the cyano group occurring exclusively at
the C2-position (11). Thus, a broad range of substrates,
including simple substituted styrenes, napthalenes, and mono-
and polycyclic heteroaromatics may be regioselectively
derivatized in efficient catalytic processes at room temper-
ature.
While significant insights have been provided into the
mechanism of the borylation/ortho-cyanation of vinylnaph-
thalenes,[5,6] we sought to gain evidence for the reactive
intermediate involved in the functionalization of simple
styrenes. Authentic samples of either the bis(borylated)
derivative 12 or alkylborane 3, when subjected to the
optimized reaction conditions for styrene derivatization,
failed to produce 2 (Scheme 1). However, subjecting inde-
pendently synthesized benzylic copper species 13[10] to the
reaction conditions produced 2 in 61% yield upon isolation.
The conversion of 13 into 2 proceeded similarly in either the
presence or absence of IMesCuCl. These observations, in
combination with previously obtained insights, provide strong
evidence for the intermediacy of benzyl copper intermediates
in the borylation/ortho-cyanation process.
CH(OEt)2
81
9
1-propenyl[b]
H
Me
CH2OTBS
Br
OMe
H
65[c]
10
11
12
13
14
H
H
H
H
H
65 (10:1)
67 (10:1)
78 (>20:1)
71 (5:1)[c]
67%
[a] Yield of the isolated product is reported. For entries 10–13, the major
isomer is isomer 4 and the minor isomer corresponds to cyanation at the
more hindered position ortho to both the boroalkyl group and the Y
substituent. [b] A 1:1 E/Z mixture of the 1-propenyl substituent was
used. [c] The BPin derivative was oxidized to the corresponding alcohol
with NaOH and H2O2. The overall yield for the cyanoborylation and
oxidation is shown. M.S.=molecular sieves, TBS=tert-butyldimethyl-
silyl.
with para-substituted styrenes, cyanation ortho to the vinyl
group was exclusively observed, and the procedure cleanly
tolerated fluoro, chloro, methyl, tert-butyl, phenyl, silyloxy-
methyl, and acetal-containing substituents (entries 2–8).
Yields were uniformly high aside from the chlorostyrene
substrate, which proceeded in modest yield (entry 3). Notably,
a 1-propenyl substituent was tolerated, with the procedure
being highly chemoselective for addition to the vinyl sub-
stituent (entry 9). To examine meta-substitution patterns on
the styrene, examples were conducted with methyl, silylox-
ymethyl, bromo, and methoxy substituents meta to the vinyl
group (entries 10–13). In these cases, cyanation at the least
hindered position ortho to the vinyl functionality was favored,
with a minor isomer being derived from cyanation of the more
hindered site ortho to the two substituents. Finally, a styrene
bearing an ortho-methyl substituent was exclusively cyanated
ortho to the vinyl functionality (entry 14). Notably, despite
the higher activation barriers predicted for isolated styrenes
compared with the corresponding vinylnaphthalenes,[6]
a broad range of borylation/ortho-cyanations of simple
styrenes are available at room temperature by using the
IMesCuCl catalyst system.
To further elucuidate the scope and regioselectivity,
a number of heteroaromatic and polycyclic substrates were
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12683 –12686