J. Am. Chem. Soc. 1999, 121, 3791-3792
3791
Scheme 1
Radical Cyclization of 2-Alkenylthioanilides: A
Novel Synthesis of 2,3-Disubstituted Indoles
Hidetoshi Tokuyama, Tohru Yamashita, Matthew T. Reding,
Yosuke Kaburagi, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo
CREST, Japan Science and Technology Corporation (JST)
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
ReceiVed October 22, 1998
The indole nucleus is present in a wide range of natural
products, and the synthesis of this important structure has been a
steady topic of interest for many years.1 Among the numerous
methods that have been developed for the synthesis of indoles,
few practical and mild procedures are available for the construc-
tion of 2,3-disubstituted indoles.2 Specifically, although the
venerable Fischer indole synthesis still sees frequent use, the
general necessity for acid and heat often produces significant
purification difficulties.3 Furthermore, the more recently developed
Gassman and Fu¨rstner indole syntheses require the frequently
laborious synthesis of R-thiomethyl ketones and o,N-diacyl-
anilines, respectively.4,5 In this communication, we describe a
novel indole synthesis that is carried out under mild radical
cyclization conditions. In addition, we show that the thioanilide
indole precursors may be easily synthesized in a modular fashion,
to make accessible a wide range of 2,3-disubstituted indoles, in
some cases with substituents on the carbocyclic aromatic ring as
well.
Scheme 2
Furthermore, a similar reaction was complete within 5 min at
room temperature using Et3B as the radical initiator,8 to afford 9
in 93% yield.9,10 The rate of the Et3B-initiated reaction proved to
be dependent upon the geometry of the olefin. For example,
cyclization of trans-8 afforded only 39% of 9 along with the
recovered starting material (19%), even after stirring for 90 min
at room temperature.11
As shown in Table 1, a wide range of both base- and acid-
sensitive functional groups such as esters, THP ethers, and
â-lactams could be introduced at the indole 2- and 3-positions.12
In the case of a thioanilide derived from a chiral R-amino acid,
no detectable racemization was observed after the indole forma-
tion.13 In addition, we have found that hypophosphorous acid can
be employed as an alternative radical reducing agent to tin
hydride.14 For example, 2-cyclohexylindole was prepared in 71%
yield after heating a mixture of the substrate, hypophosphorous
acid (10 equiv), triethylamine (15 equiv), and AIBN (1.1 equiv)
in n-PrOH at 100 °C for 20 min.
In an earlier study, we reported that the R-stannoimidoyl radical
2, generated by addition of tri-n-butyltin radical to 2-alkenyl-
phenylisonitrile 1, leads to the formation of 2-stannylindole 3
through radical cyclization and subsequent tautomerization (eq
1).6 This methodology proved to be applicable to the synthesis
The present protocol is also well-suited for the preparation of
2,3-disubstituted indoles bearing substituents on the carbocyclic
aromatic ring. 5- or 6-Methoxyindoles could be synthesized by
our method in about 80% yield (Table 2). Remarkably, a bromo-
substituted carbocyclic ring survived the radical reaction with only
a small amount of radical hydrodebromination to afford the
corresponding 5-bromoindole.
of a variety of 2-substituted and 2,3-disubstituted indoles. It has
recently been reported that tin radicals add to thionoesters or
thioamides to generate stabilized radical species.7 With this in
mind, we reasoned that tin radicals might add to thioamide
derivatives such as 2-alkenylthioanilide 4 to form sp3 (5) or
imidoyl radical species (6), which might then undergo radical
cyclization to furnish 2,3-disubstiuted indoles 7 (Scheme 1).
The 2-alkenylthioanilides cis- and trans-8 were prepared from
2-iodoaniline in several steps (vide infra) and subjected to typical
radical cyclization conditions. Gratifyingly, treatment of cis-8 with
tri-n-butyltin hydride and AIBN in toluene at 80 °C for 5 min
resulted in the clean formation of the expected 2-n-pentyl-3-
(acetoxyethyl)indole (9) in 93% isolated yield (Scheme 2).
(8) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron 1989, 45, 923.
(9) While comparable results were obtained using benzene, acetonitrile,
or THF as solvents, the reaction was sluggish in ethanol and tert-butyl alcohol.
(10) A typical experimental procedure is as follows. To a stirred solution
of 2-alkenylthioanilide (0.025 M in toluene) and n-Bu3SnH (2.0 equiv) was
added Et3B (0.10 equiv, 1.0 M in hexane) at room temperature under an argon
atmosphere. After TLC analysis showed that the starting material had been
consumed, the reaction mixture was diluted with AcOEt, washed with saturated
aqueous KF and brine, and dried over MgSO4. Filtration and concentration
on a rotary evaporator afforded the crude product. The desired indole was
purified by flash column chromatography on silica gel.
(11) Under thermal conditions with AIBN as the radical initiator, however,
cis and trans substrates afforded the corresponding indoles in comparable
yields. For example, the reaction of trans-8 was complete in 45 min at 80 °C
to afford 9 in 75% yield.
(12) The corresponding phenylthioamide and phenylethynylthioamide did
not afford the desired indoles under the reaction conditions. Thioformamides
afforded the corresponding formamide.
(1) (a) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1. (b) Saxton,
J. E. Indoles; Wiley-Interscience: New York, 1983; Part 4.
(2) Sundberg, R. J. Indoles; Academic Press: London, 1996 and references
therein.
(3) Reference 2, Chapter 7.
(4) (a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr.
J. Am. Chem. Soc. 1974, 96, 5495. (b) Gassman, P. G.; Gilbert, D. P.; van
Bergen, T. L. J. Chem. Soc., Chem. Commun. 1974, 201.
(5) (a) Fu¨rstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991. (b)
Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468.
(6) (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116,
3127. (b) Kobayashi, Y.; Fukuyama, T. J. Heterocycl. Chem. 1998, 35, 1043.
(7) (a) Bachi, M. D.; Bosch, E.; Denenmark, D.; Girsh, D. J. Org. Chem.
1992, 57, 6803. (b) Feldman, K. S.; Schildknegt, K. J. Org. Chem. 1994, 59,
1129.
(13) A reduction of enantiomeric excess occurred during the conversion
of the corresponding amide to the starting thioanilide (Lawesson’s reagent (2
equiv) and pyridine (5 equiv) in toluene at 100 °C). Addition of pyridine was
required to prevent further epimerization.
(14) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. J. Org. Chem. 1993,
58, 6838.
10.1021/ja983681v CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/02/1999
Tokuyama, Hidetoshi
