Synthesis of 2,3-dialkylindoles from 2-alkenylphenylisocyanides and imines by silyltelluride- and tin hydride-mediated sequential radical reactions

Article abstract of DOI:10.1055/s-2005-871931

A new method for the synthesis of 2,3-dialkylindoles is described. The silyltelluride-mediated coupling reaction of imines and 2- alkenylphenylisocyanides selectively occurred at the isocyanide moiety to give the corresponding imidoyltelluride. Tin hydrid

Full text of DOI:10.1055/s-2005-871931

LETTER
1893
Synthesis of 2,3-Dialkylindoles from 2-Alkenylphenylisocyanides and Imines
by Silyltelluride- and Tin Hydride-Mediated Sequential Radical Reactions
S
ynthesis of 2,3-Dialky
a
lindoles sashi Kotani,a Shigeru Yamago,*a,c Ayumu Satoh,b Hidetoshi Tokuyama,*b,d Tohru Fukuyamab
a
b
c
d
Division of Molecular Materials Science, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan
Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo 113-0033, Japan
PRESTO, Japan Science and Technology Agency, Osaka City University, Osaka 558-8585, Japan
PRESTO, Japan Science and Technology Agency, The University of Tokyo, Tokyo 113-0033, Japan
E-mail: yamago@sci.osaka-cu.ac.jp; E-mail: tokuyama@mol.f.u-tokyo.ac.jp
Received 28 May 2005
This method, however, still have drawbacks; the synthesis
of carbon-substituted derivatives requires the intermedia-
cy of unstable 2-stannylindoles, and the C-2 carbon sub-
stituent is limited to alkenyl, aryl, and alkynyl groups.
Abstract: A new method for the synthesis of 2,3-dialkylindoles is
described. The silyltelluride-mediated coupling reaction of imines
and 2-alkenylphenylisocyanides selectively occurred at the iso-
cyanide moiety to give the corresponding imidoyltelluride. Tin hy-
dride-mediated intramolecular cyclization of the imidoyltelluride While the use of alkyl radicals instead of the tin radical
affords 2,3-dialkylindoles in good to excellent combined yields.
seems to be an obvious alternative, the most standard
method for the generation of alkyl radicals from alkyl
halides and tin radical could not be applicable. This is
probably because tin radical would possess similar reac-
tivities towards isocyanides and alkyl halides, and, thus,
selective alkyl radical generation would be difficult, as an
analogy of the reactivity of silyl radicals.6
Key words: indoles, radical reactions, cyclization, isocyanides,
tellurium
The invention of new synthetic routes to indoles has
attracted a great deal of attention due to their significant
biological activities.1 While a number of methods have al-
ready been reported to construct indole skeleton under
acid-, base-, and transition metal-catalyzed conditions,2
radical-mediated synthesis, which shows high functional
group compatibility with chemo- and regioselectivity,
would be advantageous in view of the rich functionalities
present in many naturally occurring indole derivatives. In
this respect, one of us has already reported the synthesis
of 2-stannylindole 3 by tributyltin radical promoted in-
tramolecular cyclization of 2-alkenylphenylisocyanide 1
through imidoyl radical 2 (Scheme 1).3,4 Furthermore, the
alkenylstannane functionality in 3 could be further trans-
formed to carbon substituents by the Migita–Stille cou-
pling reactions.3c Therefore, this method represents a rare
example which can be practically applicable to the synthe-
sis of highly functionalized 2,3-disubstituted indoles.5
One of us has recently reported that organotellurium com-
pounds thermally react with isocyanides to give imidoyl-
tellurides without the use of tin radicals.7 Since the
reaction of imines with triethoxysilylphenyltelluride (5)
produces the corresponding a-aminomethyltellurides
(e.g., compound 9), and, subsequently, the corresponding
a-aminomethyl radicals under mild thermal conditions,8
we chose this method for the radical generation and inves-
tigated the reaction with isocyanide 1. We report here a
new protocol to construct 2,3-dialkylindoles based on the
new synthetic strategy.9 While a few examples have been
reported on the intramolecular cyclization of alkyl-substi-
tuted imidoyl radical to give the 2,3-dialkylindole,10,11
their synthetic scope is rather limited due to the difficulty
to synthesize the radical precursors.
(EtO)3SiTePh
R1
R1
R1
(5)
NBn
Bu3Sn
+
R2
CH3CN, 60 °C
NC
NC
N
SnBu3
8–15 h
1
4
1
2
R1
A: R1 = CO2Me, B: R1 = Ph, C: R1 = n-Bu
a: R2 = Ph, b: R2 = C6H4OMe-p, c: R2 = C6H4CF3-p,
d: R2 = t-Bu, e: R2 = i-Pr
SnBu3
R1
R1
N
H
AIBN
Bu3SnH
NHBn
R2
3
N
TePh
benzene, 80 °C
1–3 h
Scheme 1
N
H
R2
NRBn
7
6
i: R = Si(OEt)3
silica gel
ii: R = H
SYNLETT 2005, No. 12, pp 1893–1896
Advanced online publication: 07.07.2005
0
1
.0
8
.2
0
0
5
Scheme 2
DOI: 10.1055/s-2005-871931; Art ID: U16705ST
© Georg Thieme Verlag Stuttgart · New York

1894
M. Kotani et al.
LETTER
The coupling reaction was carried out by heating a solu- steric bulkiness of the alkyl substituents (entry 4 vs. 5),
tion of 1A (R1 = CO2Me), imine 4a (R2 = Ph, 2.0 equiv), but the desired imidoyltellurides were formed in good to
and 5 (2.0 equiv) in acetonitrile at 60 °C for 10 hours excellent yields in all cases. The R1 group of 1 did not af-
(Scheme 2). We surprisingly found that the reaction ex- fect the coupling efficiency of the first step, and the de-
clusively afforded imidoyltelluride 6Aa–i [R1 = CO2Me, sired products were formed in good to excellent yields
R2 = Ph, R = Si(OEt)3], which was hydrolyzed during sil- (entries 6–9). The second step, namely the intramolecular
ica gel chromatography to give 6Aa–ii (R1 = CO2Me, cyclization also proceeded in good to excellent yields in
R2 = Ph, R = H) in 96% isolated yield (Table 1, entry 1). all cases irrespective of the R1 and R2 substituents of 6ii.
We could not observe the formation of cyclized product at
Table 1 Synthesis of 2,3-Disubstituted Indoles
all. Several attempts to obtain cyclized product directly
from 1A and 4a in a selective manner were unsuccessful
so far by changing solvents, reaction temperatures, and
concentration of the substrates. For example, the reaction
at 100 °C afforded 6Aa and cyclized product 7Aa in 20%
and 12% yields, respectively, together with oligomers of
1A as judged by gel permeation chromatography analy-
ses.12
Entry
1
4
Yield (%)a
R1
R2
6ii
96
96
68
80
65
95
79
83
82
7
1
CO2Me (A)
CO2Me (A)
CO2Me (A)
CO2Me (A)
CO2Me (A)
Ph (B)
Ph (a)
87
88
70
81
78
80
66
78
81
2
4-CH3OC6H4 (b)
4-CF3C6H4 (c)
t-Bu (d)
3
It has been reported that the first-order rate constants of
intramolecular cyclization of acyl radicals, which possess
isoelectronic structure with imidoyl radicals, are 103–105
s–1.13 On the other hand, the phenyltellanyl group transfer
with alkyl radicals is reported to proceed at the second-
order rate constant of 107 M–1 s–1.14 Therefore, the failure
of intramolecular cyclization of the imidoyl radical 8 can
be primarily attributed to the faster phenyltellanyl group
transfer with 9 to give 6 rather than the intramolecular
cyclization (Scheme 3).15 In contrast to organotellurium
intermediate 9 which possesses thermally labile sp3-
carbon–tellurium bond, the sp2-carbon–tellurium bond in
imidoyltelluride 6 is thermally stable. Therefore, once
imidoyltelluride 6 forms, regeneration of imidoyl radical
8 from 6 does not occur under the reaction conditions.
4b
5b
6
i-Pr (e)
4-CH3OC6H4 (b)
t-Bu (d)
7b
8
Ph (B)
n-Bu (C)
n-Bu (C)
4-CH3OC6H4 (b)
t-Bu (d)
9b
a Isolated yield after purification by silica gel column chromato-
graphy.
b Since the hydrolysis of silicon–nitrogen bond of 6i did not complete
during the column chromatography, the reaction mixture was stirred
with silica gel in CH2Cl2 for 1 h at r.t. before purification.
We next examined one-pot synthesis, but it turned out to
be unsuccessful. For example, the reaction mixture con-
taining 6Aa–i prepared from 1A and 4a in the same man-
ner was treated with tributyltin hydride (1.2–2.0 equiv) in
the presence of AIBN at 80 °C, but we isolated indole 7Aa
in only 22% yield from complex reaction mixtures. Con-
trol experiments suggested that the low cyclization effi-
ciency was attributed to the existence of triethoxysilyl
group in 6i. Thus, while the tributyltin hydride-mediated
cyclizations of 6Ad–ii (R1 = CO2Me, R2 = t-Bu, R = H)
afforded cyclized 7Ad in 81% yield (Table 1, entry 4),
that of isolated 6Ad–i [R1 = CO2Me, R2 = t-Bu,
R = Si(OEt)3] resulted in 42% yield of 7Ad after hydroly-
sis of silicon–nitrogen bond. This is probably because
bulky triethoxysilyl group hindered to take suitable con-
formation(s) for the cyclization in the imidoyl radical
intermediate.
N(Si(OEt)3)Bn
R1
R2
TePh
R1
R2
9
NHBn
R2
6
//
NHBn
N
N
8
Scheme 3
The imidoyltelluride could be reactivated upon the reac-
tion with tin radical, and subsequent cyclization of imi-
doyl radical 8 afforded the cyclized product. Thus, 6Aa
was converted to indole 7Aa in 87% yield by treatment
with tributyltin hydride (1.2 equiv) in the presence of
AIBN (0.2 equiv) in benzene at 80 °C for one hour.7e,8
The stepwise synthesis of indole 7 from 1 and 4 was gen-
erally applicable to a variety of substituents R1 and R2 of
1 and 4, respectively, as summarized in Table 1.16 For the
imine part, both aromatic and aliphatic imines (4a–e)
were coupled with 1A to give 6ii after hydrolysis of sili-
con–nitrogen bond (entries 1–5). The coupling efficien-
cies were slightly affected by the electron-withdrawing
group on the phenyl group (entries 1 and 2 vs. 3) and the
The virtue of the current method is the ease of further in-
corporation of substituents to form more structurally
elaborated indoles. For example, treatment of 6Aa–ii with
ethyl 2-(tributylstannylmethyl)acrylate (1.2 equiv) in the
presence of AIBN (0.2 equiv) resulted in the formation of
allylated product 8 in 59% yield (Scheme 4).
Synlett 2005, No. 12, 1893–1896 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3-Dialkylindoles
1895
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AIBN (0.2 equiv)
CO2Et
CO2Et
CO2Me
TePh
SnBu3
CO2Me
(1.2 equiv)
NHBn
N
Benzene, 80 °C
48 h
N
Ph
Ph
6Aa
NHBn
H
59%
8
Scheme 4
In summary, we have developed the new synthetic route
to 2,3-dialkylindoles from 2-alkenylphenylisocyanide and
imines by silyltelluride- and tin hydride-mediated sequen-
tial radical reactions. This method would be useful for the
combinatorial synthesis of indoles by modular approach,
because the reaction is insensitive to the R1 and R2 groups
in 1 and 4 as well as the reagents used for the cyclization
reaction. In addition, the both reactions proceed under
mild thermal conditions to give desired products in high
combined yields. Therefore, this method would find
various synthetic applications especially for the synthesis
of highly functionalized indoles.
(10) Fujiwara, S.; Matsuya, T.; Maeda, H.; Shinike, T.; Kambe,
N.; Sonoda, N. J. Org. Chem. 2001, 66, 2183.
(11) Bowman, W. R.; Fletcher, A. J.; Lovell, P. J.; Pedersen, J. M.
Synlett 2004, 1904.
Acknowledgment
This work was partly supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science and
from the Ministry of Education, Culture and Sports, and PRESTO
program from the Japan Science and Technology Agency.
(12) Attempts to obtain well-defined oligomers by the living
radical oligomerization were also unsuccessful. See:
(a) Yamago, S. Proc. Japan Acad. Ser. B 2005, 81, 117.
(b) Yamago, S.; Iida, K.; Yoshida, J. J. Am. Chem. Soc.
2002, 124, 2874. (c) Yamago, S.; Iida, K.; Yoshida, J. J. Am.
Chem. Soc. 2002, 124, 13666. (d) Yamago, S.; Iida, K.;
Nakajima, M.; Yoshida, J. Macromolecules 2003, 36, 3793.
(e) Goto, A.; Kwak, Y.; Fukuda, T.; Yamago, S.; Iida, K.;
Nakajima, M.; Yoshida, J. J. Am. Chem. Soc. 2003, 125,
8720.
(13) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem.
Rev. 1999, 99, 1991.
(14) (a) Curran, D. P.; Martin-Esker, A. A.; Ko, S.-B.; Newcomb,
M. J. Org. Chem. 1993, 58, 4691. (b) Newcomb, M.
Tetrahedron 1993, 49, 1151.
(15) For group-transfer cyclization of organotellurium
compounds, see: (a) Engman, L.; Gupta, V. J. Chem. Soc.,
Chem. Commun. 1995, 2515. (b) Engman, L.; Gupta, V. J.
Org. Chem. 1997, 62, 157. (c) Berlin, S.; Ericsson, C.;
Engman, L. Org. Lett. 2002, 4, 3. (d) Berlin, S.; Ericsson,
C.; Engman, L. J. Org. Chem. 2003, 68, 8386. (e) Ericsson,
C.; Engman, L. J. Org. Chem. 2004, 69, 5143.
References
(1) Reviews, see: (a) Joule, J. A. Indole and its Derivatives, In
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Transformations), Category 2, Vol. 10; Thomas, E. J., Ed.;
Georg Thieme Verlag: Stuttgart, 2000, Chap. 10.13.
(b) Sundberg, R. J. Indoles, Best Synthetic Methods;
Katritzky, A. R.; Meth-Cohn, E.; Rees, C. W., Eds.;
Academic Press: London, 1996. (c) Pyrroles and their
Benzo Derivatives, In Comprehensive Heterocyclic
Chemistry II, Vol. 2; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996, Chap. 2.01–2.04.
(d) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045.
(2) Recent representative examples: (a) Hiyora, K.; Itoh, S.;
Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (b) Kessler,
A.; Coleman, C. M.; Charoenying, P.; O’Shea, D. F. J. Org.
Chem. 2004, 69, 7836. (c) Siu, J.; Baxendale, I. R.; Ley, S.
V. Org. Biomol. Chem. 2004, 2, 160. (d) Kamijo, S.;
Yamamoto, Y. J. Org. Chem. 2003, 68, 4764. (e)Katritzky,
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(16) Typical Experimental Procedures.
To a solution of isocyanide 1A (188 mg, 1.0 mmol) and
imine 4a (389 mg, 2.0 mmol) in MeCN (1 mL) was added
silyltelluride 5 (739 mg, 2.0 mmol) under nitrogen
atmosphere, and the resulting solution was stirred at 60 °C
for 10 h. Solvent was removed under reduced pressure
followed by purification by silica gel column
chromatography to give imidoyltelluride 6Aa–ii in 96%
yield (562 mg, 0.96 mmol). 1H NMR (600 MHz, CDCl3):
d = 2.68 (br s, 1 H), 3.77 (s, 3 H), 3.96 (d, J = 13.2 Hz, 1 H),
4.06 (d, J = 13.2 Hz, 1 H), 4.59 (s, 1 H), 6.33 (d, J = 16.1 Hz,
1 H), 6.82 (d, J = 7.8 Hz, 2 H), 6.95 (t, J = 7.5 Hz, 2 H), 7.09
(t, J = 7.4 Hz, 1 H), 7.17–7.20 (m, 3 H), 7.27–7.31 (m, 4 H),
7.34–7.37 (m, 4 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.44 (d, J = 8.0
Hz, 2 H), 7.79 (d, J = 16.0 Hz, 1 H). 13C NMR (150 MHz,
CDCl3): d = 51.61, 52.15, 70.15, 112.84, 118.58, 118.76,
(3) (a) Tokuyama, H.; Fukuyama, T. Chem. Rec. 2002, 2, 37.
(b) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc.
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Fukuyama, T. Synthesis 2000, 429. (d) Tokuyama, H.;
Watanabe, M.; Hayashi, Y.; Kurokawa, T.; Peng, G.;
Fukuyama, T. Synlett 2001, 1403.
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1999, 40, 6325.
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M. Kotani et al.
LETTER
124.42, 125.29, 127.11, 127.71 (two peaks), 128.01, 128.38
(two peaks), 128.47, 128.59, 129.05, 130.82, 138.84,
139.72, 140.70, 141.37, 151.46, 167.26. HRMS (FAB):
m/z calcd for C31H29O2N2130Te (M)+: 591.1247; found:
591.1294. A solution of imidoyltelluride 6Aa–ii (59 mg,
0.10 mmol) and AIBN (3.3 mg, 0.02 mmol) tributyltin
hydride (32 mg, 0.12 mmol) in benzene (2 mL) was heated
to 80 °C with stirring under nitrogen atmosphere for 1 h.
Solvent was removed under reduced pressure followed by
purification by silica gel column chromatography and GPC
to give indole 7Aa in 87% yield (23 mg, 0.060 mmol). 1H
NMR (600 MHz, CDCl3): d = 1.72 (br s, 1 H), 3.55 (s, 3 H),
3.68 (s, 2 H), 3.79 (s, 2 H), 5.22 (s, 1 H), 7.09 (t, J = 7.5 Hz,
1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.24–7.35 (m, 9 H), 7.49 (d,
J = 7.6 Hz, 2 H), 7.56 (d, J = 7.9 Hz, 1 H), 8.58 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 30.09, 51.78, 52.01, 58.21,
105.06, 110.95, 118.55, 119.63, 121.91, 127.22, 127.30,
127.67, 128.17, 128.53, 128.57, 128.78, 134.93, 136.89,
139.75, 141.52, 172.13. HRMS (FAB): m/z calcd for
C25H24O2N2 [M]+: 384.1838; found: 384.1832.
Synlett 2005, No. 12, 1893–1896 © Thieme Stuttgart · New York