1,6-Stannatropic strategy: Effective generation and cyclization of 1,5-dipoles from o-stannylmethylated thioanilides or phenyl isothiocyanates

Article abstract of DOI:10.1021/ol0612758

A new method for the generation of 1,5-dipoles from o-stannylmethylated thioanilides via 1,6-stannatropy under neutral conditions was developed. Cyclization of the 1,5-dipoles afforded indole derivatives effectively. The strategy has potential for application to the generation of alternative 1,5-dipoles from o-stannylmethylated aryl isothiocyanates leading to indole derivatives having a stannylthio group that was readily converted to other functional groups.

Full text of DOI:10.1021/ol0612758

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3693-3695
1,6-Stannatropic Strategy: Effective
Generation and Cyclization of
1,5-Dipoles from o-Stannylmethylated
Thioanilides or Phenyl Isothiocyanates
Satoshi Minakata,* Yukihiro Kasano, Hirofumi Ota, Yoji Oderaotoshi, and
Mitsuo Komatsu*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
minakata@chem.eng.osaka-u.ac.jp
Received May 25, 2006
ABSTRACT
A new method for the generation of 1,5-dipoles from o-stannylmethylated thioanilides via 1,6-stannatropy under neutral conditions was developed.
Cyclization of the 1,5-dipoles afforded indole derivatives effectively. The strategy has potential for application to the generation of alternative
1,5-dipoles from o-stannylmethylated aryl isothiocyanates leading to indole derivatives having a stannylthio group that was readily converted
to other functional groups.
Cyclization1 and cycloaddition2 of 1,5-dipoles, which are 1,3-
dipoles directly bound to an unsaturated moiety, are promi-
nent methods for construction of heterocyclic rings. While
only a few examples of [5+2] cycloadditions of 1,5-dipoles
leading to seven-membered heterocycles are known, cycliza-
tion of 1,5-dipoles via 1,5-electrocyclic ring closure for the
synthesis of five-membered heterocycles was studied ac-
tively. 2-Vinylpyridinium ylides, which are representative
vinyl-substituted azomethine ylides, serve as useful precur-
sors of indolizine derivatives via 1,5-dipolar cyclization.3 On
the other hand, we have created a potential strategy for the
generation of azomethine ylides from N-silyl- or N-stannyl-
methylated amide derivatives via thermal 1,4-sila/stannat-
ropy.4
ropy leading to a 1,5-dipole, which is a kind of vinylogous
azomethine ylide (Scheme 1A). The dipoles would furnish
Scheme 1
If a vinyl group, here a benzene ring, is introduced between
a silyl or stannyl group substituted carbon and amide
nitrogen, the reactive molecule would induce 1,6-metallat-
10.1021/ol0612758 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

indole derivatives through 1,5-dipolar cyclization or 6π
electrocyclization.
Scheme 2
Moreover, our strategy can be expanded to the generation
of 1,5-dipoles from o-metallomethylated phenyl isothiocy-
anates (Scheme 1B).
Herein we report on the generation of 1,5-dipoles from
o-metallomethylated anilide and isothiocyanate derivatives
via 1,6-metallatropy and cyclization of the 1,5-dipoles leading
to indole derivatives. Various biologically active compounds
having indole rings are found in nature, and the indole
derivatives are important key compounds for the synthesis
of a variety of natural products, pharmacologically interesting
compounds,5 and various functional materials.5a
Our first investigation was to observe the behavior of
o-metallomethylated anilides under thermal conditions.
When benzene solutions of o-silylmethylated anilides or
o-silylmethylated thioanilides were heated in sealed tubes,
the reactions did not proceed at all even at 200 °C. Our
preliminary experiments clarified the tendency toward the
migration of the metallo groups as Sn > Si, where a larger
affinity between tin and sulfur was observed. These facts
encouraged us to study the thermal reaction of o-stannyl-
methylated thioanilides. Thus, we successfully found that
heating a benzene solution of thioanilide 1a at 110 °C
for 30 h gave 2,3-diphenylindole 2a in high yield
(Scheme 2).
clization of the 1,5-dipole, and (3) elimination of tributyl-
stannanethiol causing aromatization.6
With an acceptable result for the formation of an indole
from o-stannylmethylated thioanilide 1a in hand, the versatile
method was extended to the synthesis of a variety of
thioanilides 1b-h (Table 1).
Table 1. Synthesis of Indole Derivatives from
o-Stannylmethylated Thioanilides via 1,6-Stannatropy
Indole 2a might be formed via (1) the generation of a 1,5-
dipolar intermediate from thioanilide 1a by thermal 1,6-
migration of the tin atom (1,6-stannatropy), (2) electrocy-
(1) (a) Taylor, E. C.; Turchi, I. J. Chem. ReV. 1979, 79, 181-231. (b)
Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947-1034. (c) Grigg,
R.; Gunaratne, H. Q. N.; Henderson, D.; Sridharan, V. Tetrahedron 1990,
46, 1599-1610. (d) Ohno, M.; Miyata, H.; Komatsu, M.; Ohshiro, Y.
Tetrahedron Lett. 1991, 32, 5093-5096. (e) Grigg, R.; Myers, P.;
Somasunderan, A.; Sridharan, V. Tetrahedron 1992, 48, 9735-9744. (f)
Grigg, R.; Kennewell, P.; Savic, V.; Sridharan, V. Tetrahedron 1992, 48,
10423-10430. (g) Gupton, J. T.; Petrich, S. A.; Smith, L. L.; Bruce, M.
A.; Vu, P.; Du, K. X.; Dueno, E. E.; Jones, C. R.; Sikorski, J. A. Tetrahedron
1996, 52, 6879-6892. (h) Gupton, J. T.; Krumpe, K. E.; Bumham, B. S.;
Dwornik, K. A.; Petrich, S. A.; Du, K. X.; Bruce, M. A; Vu, P.; Vargas,
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5075-5088. (i) Butler, R. N.; Farrell, D. M. J. Chem. Res., Synop. 1998,
82-83. (j) Friebolin, W.; Eberbach, W. Tetrahedron 2001, 57, 4349-4358.
(k) Friebolin, W.; Eberbach, W. HelV. Chim. Acta 2001, 84, 3822-3836.
(l) Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41, 1778-
1780. (m) McNab, H.; Morrow, M. ARKIVOC 2002, VIII, 125-133. (n)
Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. J. Am. Chem. Soc. 2003,
125, 4692-4693. (o) Noguchi, M.; Shirai, M.; Nakashima, K.; Arai, I.;
Nishida, A.; Yamamoto, H.; Kakehi, A. Tetrahedron 2003, 59, 4581-4590.
(p) Nyerges, M.; Pinte´r, AÄ .; Vira´nyi, A.; Blasko´, G.; To¨ke, L. Tetrahedron
2005, 61, 8199-8205. (q) Nyerges, M.; To¨ke, L. Tetrahedron Lett. 2005,
46, 7531-7534.
temp time
yield
entry substr.
R1
R2
(°C)
(h) product (%)
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
1g
1h
4-MeOC6H4 Ph
4-CF3C6H4 Ph
styryl
Ph
110
110
110
45
15
5
12
9
12
96
2b
2c
2d
2e
2f
2g
2h
84
70
48
82
50
55
58
Ph
4-ClC6H4 110
H
Me
Ph
Ph
Ph
H
200
200
200
The reaction of thioanilide 1b, having an electron-donating
group on the thiocarbonyl aromatic ring, afforded indole
derivative 2b in high yield (entry 1). In contrast, the
introduction of an electron-withdrawing group at the same
position accelerated the reaction extensively (entry 2). In the
case of thioanilide 1d, having a styryl group, the reaction
also proceeded smoothly to give the corresponding indole
2d (entry 3). A chloro-substituted phenyl group as R2 might
have contributed to the stabilization of the dipolar intermedi-
ate, leading to indole 2e (entry 4). As shown in entries 5-7,
the generation of less-stabilized 1,5-dipoles from 1f-h (R1
) H, Me or R2 ) H) could be realized to cyclize to the
(2) (a) Ried, W.; Dietrich, R. Liebigs Ann. Chem. 1964, 666, 113-135.
(b) Rothenberger, O. S.; Taylor, R. T.; Dalrymple, D. L.; Moore, J. A. J.
Org. Chem. 1972, 37, 2640-2642. (c) Hiyama, T.; Taguchi, H.; Nozaki,
H. Bull. Chem. Soc. Jpn. 1974, 47, 2909-2910. (d) Crabb, J. N.; Storr, R.
C. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley
and Sons: New York, 1984; Vol. 2, pp 554-558.
(3) Pohjala, E. Tetrahedron Lett. 1972, 13, 2585-2588.
(4) (a) Ohno, M.; Komatsu, M.; Miyata, H.; Ohshiro, Y. Tetrahedron
Lett. 1991, 32, 5813-5816. (b) Iyoda, M.; Sultana, F.; Komatsu, M. Chem.
Lett. 1995, 1133-1134. (c) Komatsu, M.; Kasano, Y.; Yonemori, J.-I.;
Oderaotoshi, Y.; Minakata, S. Chem. Commun. 2006, 5, 526-528.
(5) (a) Gribble, G. G. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Bird, C. W., Eds.; Elsevier
Science: Oxford, 1996; Vol. 2, pp 207-257. (b) Gossauer, A. In Progress
in the Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby,
G. W., Eds.; Springer: Wien; 2003, Vol. 86, pp 1-188. (c) Somei, M.;
Yamada, F. Nat. Prod. Rep. 2005, 22, 73-103.
(6) Because initial reaction rates of the reactions at different initial
concentrations are the same, the migration of the stannyl group of
thioanilides 1 should occur intramolecularly. See Supporting Information
data.
3694
Org. Lett., Vol. 8, No. 17, 2006

corresponding indoles, respectively, although a higher reac-
tion temperature was required. Therefore, the present 1,6-
stannatropic strategy was found to be highly effective for
the synthesis of substituted indole derivatives.
-donating, chloro, or methoxy group, at the position of R1
were employed, the reactions afforded disulfides 5b,c in
excellent yields, albeit with a longer reaction time than that
for 3a (entries 2 and 3). The reaction of isothiocyanate 3d,
bearing a chloro group on the Ph group (R2), also gave
disulfide 5d in high yield (entry 4).
Because it was difficult to isolate 2-indolyl sulfides 4 under
ordinary workup conditions, in situ transformation of the
stannylthio group of 4 in one pot was attempted. Thus, the
stannylthio group of 2-indolyl sulfide 4a was readily
transformed to alkylthio (6), 2-pyridylthio (7), and acylthio
groups (8) in good yields (Scheme 3).8
The 1,6-stannatropic protocol for the generation of 1,5-
dipoles from o-stannylmethylated thioanilides was expected
to be applicable to an alternative sulfur-containing conjugated
system. If a molecule having an isothiocyanate moiety such
as 3a is employed, a 1,6-shift of the stannyl group onto sulfur
atom might generate the corresponding 1,5-dipole, including
a carbon-nitrogen triple bond (Scheme 1B). When a benzene
solution of o-stannylmethylated phenyl isothiocyanate 3a was
heated in a sealed tube at 150 °C for 15 h, the expected
reaction occurred to give tributyltin 2-indolyl sulfide 4a in
an excellent yield (Table 2, entry 1). Because some examples
Scheme 3. Transformation of the Tributylthio Group of Indole
Derivative 4a
Table 2. Synthesis of Disulfides 5 from o-Stannylmethylated
Isothiocyanates 3 via 1,6-Stannatropy
time
(h)
yield
(%)
entry substrate
R1
R2
product
In summary, we have achieved effective and unprec-
edented generation of 1,5-dipoles from o-stannylmethylated
thioanilides via 1,6-stannatropy and their cyclization to afford
indole derivatives in high yields. Based on this concept, the
method was extended to the novel synthesis of tributyltin
2-indolyl sulfide derivatives from aryl isothiocyanates.
1
2
3
4
3a
3b
3c
3d
H
Cl
Ph
Ph
15
96
60
72
5a
5b
5c
5d
88 (91)a
96
94
OMe Ph
4-ClC6H4
H
85
a Isolated yield of 4a under dry nitrogen atmosphere.
Acknowledgment. The work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
One of the authors (Y. K.) expresses his special thanks for
the 21st century center of excellence (21COE) program,
“Creation of Integrated EcoChemistry of Osaka University”.
of biologically active indole derivatives bearing sulfur
functional groups at the 2-position have been reported,7 the
method would be useful for the synthesis of such compounds.
The cyclization of o-stannylmethylated phenyl isothiocy-
anates 3a-d is listed in Table 2. In these cases, disulfides
5a-d were obtained after purification by silica gel column
chromatography because of high susceptibility of 2-indolyl
sulfides 4 toward hydrolysis and spontaneous oxidation.
When isothiocyanates 3b,c having electron-withdrawing or
Supporting Information Available: Experimental pro-
cedures and product characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0612758
(7) (a) Tanaka, J.; Higa, T.; Bernardinelli, G.; Jefford, C. W. Tetrahedron
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M. Phytochemistry 1991, 30, 2915-2917. (c) Rewcastle, G. W.; Palmer,
B. D.; Dobrusin, E. M.; Fry, D. W.; Kraker, A. J.; Denny, W. A. J. Med.
Chem. 1994, 37, 2033-2042.
(8) (a) Harpp, D. N.; Aida, T.; Chan, T. H. Tetrahedron Lett. 1979, 20,
2853-2856. (b) Gingras, M.; Chan, T. H.; Harpp, D. N. J. Org. Chem.
1990, 55, 2078-2090. (c) Chen, J. X.; Crisp, G. T. Synth. Commun. 1992,
22, 683-686.
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