make the sp-hybridized carbon center of the allenyl moiety
slightly electron-deficient due to the inductive effect of the
electron-deficient N-acyl moiety through the benzene ring.
The activated sp-hybridized center would hopefully be
attacked by the nitrogen functionality in a formal endo-mode
manner8 with aid of the palladium catalyst and/or weak bases
leading to the indole frameworks (Scheme 1). On the basis
Table 1. Palladium(0)-Catalyzed Coupling Reaction of 1a with
2a
Scheme 1
entry additive (3 equiv) solvent time (h) 3a (%) 4a (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2
0.5
1
1
7
2
2.5
1
96
18
52
64
53
12
LiCl
LiBr
LiI
KCl
Et4NCl
Bu4NCl
BnEt3NCl
56
46
84
24
29
of these considerations, we investigated the coupling reaction
of the N-acyl-2-iodoanilines with the allenylstannanes. This
letter describes the preliminary results of (i) a novel and
efficient protocol for preparing 2,3-disubstituted indoles by
taking advantage of the Stille coupling reaction,9 followed
by the formal endo-mode ring-closing reaction8 in a one-
pot process, and (ii) its application to the synthesis of
indomethacin.
20
b
K2CO3
9
a Reactions were carried out with aniline 1a, allene 2, Pd2(dba)3 (3 mol
%), TFP (24 mol %), CuI (10 mol %), and additive (3 equiv). b 1.2 equiv
of K2CO3 was used.
reaction was performed in the presence of LiCl (3 equiv),
the distribution of the products drastically changed and the
desired indole derivative 3a could be isolated in 56% yield
along with 4a in 18% yield (entry 2).13 Interestingly, other
lithium halides such as LiBr and LiI exclusively produced
4a instead of 3a (entries 3 and 4). These results suggested
that the chloride anion might be the most favorable additive
for the efficient construction of 3a. Thus, we evaluated four
additional chloride species (entries 5-8). As a result, three
chlorides provided 3a as the major product (entries 6-8).
In particular, tetra-n-butylammonium chloride (TBAC) was
found to be the most effective for our purpose and led to
the exclusive formation of 3a in 84% yield (conditions B)
(entry 7).14 Thus, it turned out that the allene derivative 4a
and 1-(tert-butoxycarbonyl)-3-(tert-butyldimethylsiloxy)-
methyl-2-methylindole (3a) can be selectively prepared by
the reaction of 1a with 2 by proper choice of conditions (with
or without TBAC). TFP was found to be superior to the other
ligands examined, although Ph3As worked as well as TFP
(72%).
The Stille coupling reaction9 of N-(tert-butoxycarbonyl)-
2-iodoaniline (1a) under standard conditions was first
investigated. Treatment of 1a with 210,11 in DMF in the
presence of 3 mol % of Pd2(dba)3,12 tri-2-furylphosphine
(TFP, 24 mol %), and CuI (10 mol %) at room temperature
for 2 h afforded the normal Stille coupling product 4a in
96% yield (conditions A) (Table 1, entry 1). When the
(7) For selected references, see: (a) Sakamoto, T.; Kondo, Y.; Iwashita,
S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1305-1308.
(b) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689-6690.
(c) Wensbo, D.; Eriksson, A.; Jeschke, T.; Annby, U.; Gronowitz, S.; Cohen,
L. A. Tetrahedron Lett. 1993, 34, 2823-2826. (d) Jeschke, T.; Wensbo,
D.; Annby, U.; Gronowitz, S.; Cohen, L. A. Tetrahedron Lett. 1993, 34,
6471-6474. (e) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
1998, 63, 7652-7662. (f) Chaplin, J. H.; Flynn, B. L. Chem. Commun.
2001, 1594-1595. (g) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron
2001, 57, 8017-8028. (h) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med.
Chem. 2002, 45, 2670-2673. (i) Liu, X.; Deschamp, J. R.; Cook, J. M.
Org. Lett. 2002, 4, 3339-3342. (j) Hiroya, K.; Matsumoto, S.; Sakamoto,
T. Org. Lett. 2004, 6, 2953-2956. (k) Shen, M.; Li, G.; Lu, B. Z.; Hossain,
A.; Roschangar, F.; Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129-
4132. (l) Konno, T.; Chae, J.; Ishihara, T.; Yamanaka, H. J. Org. Chem.
2004, 69, 8258-8265. (m) Ackermann, L. Org. Lett. 2005, 7, 439-442
and references therein.
Our next step was to determine the electronic effect of
the substituent on the benzene ring in the above procedures
(Table 2). A mixture of 1b, having a methoxy group, and 2
was used along with the palladium-catalyzed coupling
conditions in the absence of TBAC (conditions A) to afford
the allene 4b in 90% yield, while the indole derivative 3b
was obtained in 65% yield when exposed to the palladium
catalyst in the presence of TBAC (conditions B). The nitro
compound 1c unexpectedly gave the indole derivative 3c in
(8) Upon treatment with NaH at room temperature, N-(tert-butoxycar-
bonyl)-2-(1-phenylsulfonylpropa-1,2-dien-1-yl)aniline underwent the endo-
mode ring-closing reaction to furnish the corresponding indole derivative
in a high yield. Mukai, C.; Kobayashi, M.; Kubota, S.; Takahashi, Y.;
Kitagaki, S. J. Org. Chem. 2004, 69, 2128-2136.
(9) For leading references, see: (a) Stille, J. K. Angew. Chem., Int. Ed.
Engl. 1986, 25, 508-524. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J.
Org. React. 1997, 50, 1.
(10) We chose 1-(tert-butyldimethylsiloxy)-2-(tributylstannyl)-2,3-buta-
diene (2) as the first allene for this investigation, because the expected indole
derivatives would possess a hydroxymethyl functionality at the C3-position,
which must be useful for further elaborations such as the carbon homolo-
gation reaction, if the reaction proceeded as planned.
(11) All allenes used in this study were prepared by the method of
Marshall, see: (a) Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1992, 57,
1242-1252. (b) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64,
8214-8219. (c) Williams, D. R.; Mi, L.; Mullins, R. J.; Stites, R. E.
Tetrahedron Lett. 2002, 43, 4841-4844.
(13) When 10 equiv of LiCl was added to the reaction mixture (3.5 h at
room temperature), 3a was obtained in 67% yield as the sole product.
(14) When N-acetyl-2-iodoaniline was exposed to conditions A or B,
the corresponding allenyl derivative or indole derivative was selectively
formed in the respective yields of 80% and 70%, although a higher reaction
temperature (50 °C) was necessary under conditions A.
(12) Several other palladium catalysts were screened, but no catalysts
could exceed the result of Pd2(dba)3.
5794
Org. Lett., Vol. 7, No. 26, 2005