SCHEME 1a
A Non -cr yogen ic Meth od for th e
P r ep a r a tion of 2-(In d olyl) Bor a tes, Sila n es,
a n d Sila n ols
Enrique Vazquez,* Ian W. Davies, and J oseph F. Payack
Department of Process Research, Merck & Co. Inc.,
P.O. Box 2000, Rahway, New J ersey 07065-0900
a
Key: (a) (i) N-Boc indole, 1.0 M in THF, 0-5 °C, 1.2 equiv of
LDA (2.0 M), (ii) 2N HCl.
enrique_vazquez@merck.com
Received J une 21, 2002
TABLE 1. P r ep a r a tion of N-Boc-2-in d oyl Bor a tes
entry
R )
yield (%)
entry
R )
yield (%)
1
2
3
4
2a , 4-Cl
2b, 5-Cl
2c, H
99
5
6
7
8
2e, 5-OMe
2f, 5-Me
2g, 5-CN
2h , 5-F
89
Abstr a ct: 2-Indolyl borates are prepared via addition of
LDA to a mixture of N-Boc-indole and triisopropyl borate
at 0-5 °C. Following acidic hydrolysis, the boronic acids are
isolated by crystallization in good to excellent yield (73-
99%). The method is quite general, tolerating a wide range
of functional groups, and also provides access to 2-silyl
derivatives (80-91%).
94
85
96a
92a
81a
73a
2d , 5-Br
a
Assay yield by HPLC using an analytically pure standard.
1.2 equiv) to a solution of N-Boc indole (1 M in THF) and
triisopropyl borate (1.5 equiv) at 0-5 °C also produces
the boronic acid in near-quantitative yield (Scheme 1).
With this observation in hand, we set out to demon-
strate the broad generality of this metalation strategy.
A number of commercially available indoles were N-Boc
protected under standard conditions (Table 1). The
resulting N-Boc indoles were taken forward without
further purification to yield the desired boronic acids after
isopropyl borate ester hydrolysis. A number of features
are noteworthy. All reactions were unoptimized but the
yields were uniformly good to excellent. In the cases
where lower yields were observed, the deprotected indole
was typically observed and accounted for the mass
balance. The reaction tolerates a wide variety of func-
tional groups and substitution patterns in the indole. The
metalation of N-Boc-5-cyanoindole (entry 7) is significant
since reaction at -78 °C followed by addition of the
electrophile led to 65% assay yield. However, metalation
with in situ trapping at higher temperature increased
the yield to 81%.
Encouraged by the successful synthesis of the boronic
acids, we moved to the more ambitious goal of expanding
the methodology to silicon electrophiles. The palladium-
catalyzed, cross-coupling reactions of organosilicon com-
pounds to organic halides has emerged as a viable
alternative to the well-established and versatile
Stille-Migita-Kosugi coupling of organostannanes and
Suzuki-Miyaura coupling of organoboranes. Pioneering
studies by Kumada and Hiyama have shown that activa-
tion of organofunctional silicon compounds is possible by
addition of a fluoride source to promote the palladium-
catalyzed, cross-coupling reactions to various organic
halides.8 Chloro- and fluoro-organosilanes and orthosili-
conates9 have been successfully employed in cross-
coupling reactions. Most noteworthy is the demonstrated
synthetic potential of silacyclobutanes,10 silanols,11 silyl
The 2-aryl-substituted indoles, e.g., 2-aryltryptanes,
are important privileged structures1 and are present in
a wide range of pharmacophores, e.g., GnRH antago-
nists.2 Palladium-catalyzed cross coupling has emerged
as a general route to these compounds.3 This cross-
coupling methodology relies on the accessibility of the
appropriately functionalized partners that enter the
reaction.4 Very often, the 2-indolylboronic acid is a
partner in the Suzuki-Miyaura reaction, and these
boronic acids are prepared by lithiation at <-70 °C.5,6
In this paper, we describe a simple non-cryogenic ap-
proach for the metalation of N-Boc indoles with an in situ
electrophilic quench leading to the isolation of the cor-
responding boron or silicon derivatives.
Recently, we required an elaborated 2-substituted
indole. We initially chose to investigate the use of a
Suzuki-Miyaura cross-coupling of an N-Boc-protected
indole. The indole was metalated in the 2-position and
quenched with triisopropyl borate at -78 °C. Although
the boronic acid was obtained in high yield following
hydrolysis (>90%), the cryogenic conditions were not
ideal for operation on a larger scale. To overcome this
liability, we investigated the metalation of N-Boc with
an in situ electrophilic quench.7 We have discovered that
addition of LDA (2.0 M in n-heptane/ethylbenzene/THF,
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10.1021/jo026087j CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/18/2002
J . Org. Chem. 2002, 67, 7551-7552
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