Pd-catalyzed C3-selective allylation of indoles with allyl alcohols promoted by triethylborane

Article abstract of DOI:10.1021/ja0501161

Under palladium catalysis, Et₃B nicely promotes allyl alcohols to undergo C3-selective allylation of indoles and tryptophan; the yields range 75-95%. Copyright

Full text of DOI:10.1021/ja0501161

Published on Web 03/11/2005
Pd-Catalyzed C3-Selective Allylation of Indoles with Allyl Alcohols Promoted
by Triethylborane
†
Masanari Kimura, Makoto Futamata, Ryutaro Mukai, and Yoshinao Tamaru*
Department of Applied Chemistry, Faculty of Engineering, Nagasaki UniVersity,
-14 Bunkyo, Nagasaki 852-8521, Japan, and Graduate School of Science and Technology,
1
Nagasaki UniVersity, 1-14 Bunkyo, Japan
Received January 8, 2005; E-mail: tamaru@net.nagasaki-u.ac.jp
Table 1. Allylation of Indole (1a, R′ ) H) with Allyl Alcoholsa
Indole is a versatile and useful heterocycle for the synthesis of
a wide range of physiologically important molecules. Indole serves
1
as an ambient nucleophile, and some sophisticated conditions are
required to achieve selective alkylation either at the 1-(N-) or
1
3
-position. Regioselective allylic alkylation at the 3-position of
2
indoles lends itself to an efficient and straightforward method for
the synthesis of many naturally occurring indole alkaloids, e.g.,
the plant growth-promoting acidic materials, auxins, and of
unnatural potent HIV inhibitors, BMS-378806.5
3
4
Taking into consideration versatile reactivities of indoles as a
nucleophile and π-allylpalladiums as an electrophile, it is rather
surprising that only a few articles have appeared on the palladium-
based allylation of indoles, which describe formation of either a
mixture of N- and 3-allylindoles together with N,3-diallylindole,
6
7
albeit in poor yields, or N-allylindoles selectively in modest yield.
Nickel chemistry, on the other hand, seems to be more promising
in view of selectivity; 3-allylindole forms selectively in 59% yield
by the reaction of indole, allyl alcohol in an excess, and a Grignard
reagent in a stoichiometric quantity to indole and allyl alcohol.8
Regrettably, however, the scope has not been clarified yet.
Recently, we have disclosed that a Pd(0) species in the presence
3
of Et B catalytically promotes allyl alcohols to undergo both
9
N-allylation of amines and C-allylation of active methylene
compounds.10 Herein, we report for the first time that the Pd-
Et
3
B system works nicely for the C3 selective allylation of indoles
a Reaction conditions: 1a (1.0 mmol), an allyl alcohol (1.0 mmol in
and provides 3-allylindoles 2 in excellent yields (eq 1). The reaction
can be performed very easily as exemplified by the following
procedure (Table 1, run 1): a homogeneous mixture of 1a (R′ )
runs 1-5, 3.0 mmol in runs 6-8), Pd(PPh3)4 (5 mol %), and Et3B (1 M
solution in hexane; 0.3 mmol in runs 1-5, 2.4 mmol in runs 6-8) in THF
(
2.5 mL) at 50 °C under N2. b cis/trans ) 1:10.
H, 1.0 mmol), allyl alcohol (1.0 mmol), Pd(PPh
Et B (30 mol %) in THF (2.5 mL) was stirred at 50 °C for 12 h
under N . The product 2a was isolated in 80-85% yields after usual
extractive workup and purification by column chromatography.
3 4
) (5 mol %), and
are reluctant (runs 6-8), and the use of excess amounts of both
alcohols (300 mol %) and Et B (240 mol %) is required to obtain
2 in reasonable yields. Remarkably, no N-allylation products were
detected at all.12
3
3
2
11
Each of the three pairs of unsymmetrical allyl alcohols (runs 2
and 3, 4 and 5, and 7 and 8) showed almost the same regioselec-
tivities, suggesting that reactions proceed via common intermediates,
most likely π-allylpalladium species. At this moment, however, it
is premature to give a rationale for the contrasting regioselectivities
providing either a straight-chain isomer 2c or a branched-chain
isomer R-2e almost exclusively.
Table 2 compiles the allylation of a variety of indoles 1b-h
with allyl alcohol. As compared with others, 2- (1c) and 3-meth-
ylindoles (1d) showed a marked difference in reactivity (runs 2
and 3). The former was unreactive and required 3 equiv of allyl
alcohol and long heating, while the latter was so reactive that the
reaction was even complete at room temperature within 2 h.
Interestingly, N-methylindole did not undergo allylation under the
conditions and was recovered quantitatively. It should be noted that
the reaction tolerates both the electron-rich and electron-deficient
The reaction shows a wide scope for the structural variation of
both allyl alcohols and indoles. Table 1 summarizes the allylation
of 1a with a variety of allyl alcohols. As one can see in runs 1-5
(cf., footnote a), the parent allyl alcohol, R-, γ-methyl, and R-,
γ-phenyl-substituted allyl alcohols are all reactive; reactions are
complete within 20 h at 50 °C in the presence of 30 mol % of
Et B and 100 mol % of an allyl alcohol and provide 2 in almost
3
quantitative yields. â-Methyl, R,R-, and γ,γ-dimethylallyl alcohols
†
Graduate School of Science and Technology.
4592
9
J. AM. CHEM. SOC. 2005, 127, 4592-4593
10.1021/ja0501161 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Allylation of Indoles 1 with Allyl Alcohola
In conclusion, this communication demonstrates that under
3
palladium catalysis, Et B nicely promotes the C3-selective allylation
of indoles and tryptophans using a wide structural variety of allyl
alcohols as allylation agents. The yields of allylation are excellent
and in most cases exceed 80%. Mechanistic details that account
for the contrasting regioselectivity (providing either straight-chain
isomer 2c or branched-chain isomer R-2e) and diastereoselectivity
(providing an endo-isomer of 2m) are a subject to be addressed,
and the results together with synthetic applications will be reported
soon.
Acknowledgment. Financial support by the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japanese Govern-
ment, is gratefully acknowledged. We thank Mr. Takashi Utoh, Mrs.
Ayako Kiyonaga for their technical help and Mr. Ohhama, NMR
Facility, for his splendid technical assistance.
Supporting Information Available: Experimental procedure,
characterization data of 2a-m, and complete ref 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(
(
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3 4
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3
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(
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3,14
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