A novel C-C bond formation reaction with 1-methoxymethylindolylborate

Article abstract of DOI:10.1039/b109880b

The reaction of 1-methoxymethylindolylborates 2 with electrophiles in the presence of benzaldehyde enabled the novel construction of tri-substituted indoles in a 'one-pot' procedure.

Full text of DOI:10.1039/b109880b

A novel C–C bond formation reaction with
1-methoxymethylindolylborate†
Minoru Ishikura,* Hiromi Kato and Nobuyuki Ohnuki
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido
061-0293, Japan. E-mail: ishikura@hoku-iryo-u.ac.jp
Received (in Cambridge, UK) 30th October 2001, Accepted 6th December 2001
First published as an Advance Article on the web 17th January 2002
Table 1 Reaction of 2 with MeOH and benzaldehyde
The reaction of 1-methoxymethylindolylborates 2 with
electrophiles in the presence of benzaldehyde enabled the
novel construction of tri-substituted indoles in a ‘one-pot’
procedure.
Yield (%)a
MeOH
(equiv.)
PhCHO
(equiv.)
R
4
5
The intramolecular migration reaction of an alkyl group from
boron to carbon is a familiar characteristic of organoboron
chemistry,1 with the intramolecular alkyl migration reaction in
1-methyltrialkylindolylborates leading to 2-alkyl-1-methylin-
doles being a prime example.2 Another unique feature is boron
isomerisation in organoboron compounds under thermal condi-
tions,3 which has been recently applied to the stereoselective
construction of three adjacent carbon stereocenters.4 During our
continuing studies of indolylborate chemistry,5 we have
previously reported the formation of 2-alkyl-1-methylindoles 5
from the reaction of 1-methoxymethylindolylborates 2 with
MeOH, in which the intermediary formation of alkylboranes 3
through a novel cascade of alkyl–boryl migration steps was
taken as the key reaction feature.6 To our knowledge, such a
cascade of alkylboryl migration processes has hitherto been
unknown. Thus, we were intrigued by the idea as to whether
operation of 3 in ordinary organoboron chemistry might enable
the construction of more elaborate indole derivatives in a novel
‘one-pot’ procedure from 1.
Et
1.5
1.5
2.0
2.0
1.5
1.5
2.0
2.0
3.0
2.0
49
58
52
49
15
10
10
5
8
40
sec-Bu
a All yields are based on 1.
Therefore, we undertook the reaction of in situ generated 3
with benzaldehyde as an initial experiment. Methanol and
benzaldehyde were added to a THF solution of 2, generated
from 1 in situ, at 0 °C, and the mixture was then gradually
warmed to room temperature and stirred for 20 h (Scheme 1).
This was found to provide alcohol 4 along with the formation of
a small amount of 2-alkyl-1-methylindole 5 from 1 in a ‘one-
pot’ manner (Table 1). The reaction outcome could be
rationalized by the steps in a queuing cascade as shown in
Scheme 1; (1) initial protonation at the C3 of the indole ring in
2 promotes alkyl migration from the boron to the C2 of the
indole ring, (2) boron migration leads to 3, and (3) subsequent
C–C bond formation between the C–B bond of 3 and
benzaldehyde provides 4.
Table 2 Reaction of 2 with electrophiles and substituted benzaldehydes
R
ArCHO
Conditiona Yield (%) of 6b
Et
PhCHO
PhCHO
A
B
65% (6a) E = –CH2CHNCH2
65% (6a) E = –CH2CHNCH2
B
30% (6b) E = –CH2CHNCH2
B
B
50% (6c) E = –CH2CHNCH2
60% (6d) E = –CH2CHNCH2
c
sec-Bu PhCHO
B
C
D
D
53% (6e) E = –CH2CHNCH2
20% (6f) E =
Et
Et
PhCHO
PhCHO
27% (6g) E = c
sec-Bu PhCHO
45% (6h) E =
Scheme 1
a Condition; A: allyl bromide, B: PdCl2(Ph3P)2 (0.05 equiv.)–allyl acetate,
C: PdCl2(Ph3P)2 (0.05 equiv.)–butadiene monoxide, D: Pd2(dba)3·CHCl3
(0.05 equiv.) + Ph3P (0.2 equiv.)–methyl 4-bromocrotonate. b Yields are
based on 1. c Two diastereoisomers in a 1+1 ratio.
† Electronic supplementary information (ESI) available: selected spectral
data for compounds 4a, 6a, 6e (a pair of diastereoisomers) and 6g. See http:
//www.rsc.org/suppdata/cc/b1/b109880b/
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CHEM. COMMUN., 2002, 220–221
This journal is © The Royal Society of Chemistry 2002

Simply heating a mixture of 2a with allyl bromide and
benzaldehyde in THF under an argon atmosphere at 60 °C for
0.5 h provided 6a in 65% yield.
mediates, and we are currently exploring this chemistry for the
preparation of more elaborate indoles in a ‘one-pot’ manner.
This work was supported in part by a Grant-in-Aid for
Scientific Research (No. 1367226), and a Grant-in-Aid for High
Technology Research Programs from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
This initial success led to the examination of the further
reaction of 2 with p–allyl palladium complexes, as electro-
philes, in the presence of substituted benzaldehydes (Table 2).
First, allyl acetate (2 equiv.) in the presence of a catalytic
amount of PdCl2(Ph3P)2 was subjected to reaction with 2 in the
presence of substituted benzaldehydes (2 equiv.) to produce 6a–
e, in which the reaction of 2a using 3,4-dimethoxybenzaldehyde
produced 6b in lower yield. Also, the palladium catalyzed
reaction of 2 with butadiene monoxide and methyl 4-bromocro-
tonate in the presence of benzaldehyde at 60 °C for 30 min
afforded 6f–h, respectively. The reaction of 2b with p–allyl
palladium complexes and benzaldehyde afforded 6e and 6h, as
a pair of diastereoisomers in a 1+1 ratio.
We have demonstrated, though preliminary experiments, the
first examples of a ‘one-pot’ procedure for the formation of
substituted indoles 4 and 6 based on the reaction of in-
dolylborates 2, generated in situ from 1, with electrophiles and
benzaldehydes. The alkylborane intermediates 3, stemming
from the novel cascade of intramolecular alkyl–boryl migration
steps in 2, can be considered to be useful synthetic inter-
Notes and references
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London, 1988, pp. 281.
2 A. B. Levy, Tetrahedron Lett., 1979, 4021.
3 B. M. Mikhailov and Yu. N. Bubnov, Organoboron Compounds in
Organic Synthesis, Harwood Academic Publisher GmbH, London, 1984,
pp. 211; H. C. Brown and B. C. S. Rao, J. Am. Chem. Soc., 1959, 81,
6434; H. C. Brown and G. Zweifel, J. Am. Chem. Soc., 1960, 82, 1504;
L. D. Field and S. P. Gallagher, Tetrahedron Lett., 1985, 26, 6125; S.
Pereira and M. Srebnik, J. Org. Chem., 1995, 60, 4316.
4 L. O. Bromm, H. Laaziri, F. Lhermitte, K. Harms and P. Knochel, J. Am.
Chem. Soc., 2000, 122, 10218.
5 M. Ishikura and I. Agata, Recent Res. Dev. Org. Chem., 1997, 1, 145.
6 M. Ishikura, I. Agata and N. Katagiri, J. Heterocyclic Chem., 1999, 36,
873.
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