5346
H. Lin, X.-W. Sun / Tetrahedron Letters 49 (2008) 5343–5346
H
N
COOH
1a
N
H
N
H
4a
OH
O
O
OH2
O
H+
O
OH
N
H
O
O
8
2a
7
O
O
O
O
-H2O
-H+
H
N
H
N
3a
H
9
Scheme 2. Possible reaction mechanism for the generation of 3-indolyl-phthalides.
As shown in Table 2, the process was found to be general with
Acknowledgements
indoles bearing different substituents. A number of substituted
indoles 1a–l, containing either electron-donating or electron-with-
drawing groups, even N-hetero-indole, have been tested in the
reaction with 2-formylbenzoic acid 2a to give the corresponding
products in good to excellent yields. To our delight, even the in-
doles with strong electron-withdrawing group, NO2, can react with
2-formylbenzoic acids smoothly in high yield (Table 2, entry 9).
Subsequently, we examined substituted 2-formylbenzoic acids.
For the substrates with either electron-donating group such as
2b (Table 2, entry 12) or electron-withdrawing group such as 2c,
2d, and 2e (Table 2, entries 13–15), the reactions went smoothly,
affording the corresponding 3-indolyl-phthalides in high yields.
For elucidation of the reaction mechanism, a comparison reac-
tion between indole 1a and methyl 2-formylbenzoate 5 was car-
ried out. The results are summarized in Table 3. Not surprisingly,
we did not detect the corresponding adduct 3a or bisindole prod-
uct 6 (Table 3, entry 1). However, the reaction of 1a and 5 led to
6 in 88% isolated yield in the presence of 1.5 equiv of benzoic acid
(Table 3, entry 2). The 2-formylbenzoic acid is known to exist par-
tially in the 3-hydroxy phthalide form 7.7 These indicated that the
generation of 3-indolyl-phthalides may proceed through the O,O-
acetals pathway catalyzed by 2a itself via Friedel–Crafts reaction
of indoles with 7 as shown in Scheme 2. The reaction of indole
and protonated 3-hydroxy phthalide 8 could afford intermediate
9. The product 3a was obtained as a result of re-aromatization of
9 subsequently. As for bisindol product 4a, it could be formed by
second Friedel–Crafts reaction of another equivalent of 1a with
3a catalyzed by 2-formylbenzoic acid.
Financial support from the National Natural Science Foundation
of China (20772017), Fudan University (EYH1615026) is gratefully
acknowledged. We thank Professor Guo-Qiang Lin for helpful
discussions.
References and notes
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Atta-ur-Rahman; Basha, A. Indole Alkaloids; Harwood Academic: Chichester, UK,
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Natural Products; ApSimon, J., Ed.; Wiley-Interscience: New York, 1977; Vol. 3, p
273; (d) Faulkner, D. J. Nat. Prod. Rep. 2002, 1; (e) Amat, M.; Llor, N.; Bosch, J.;
Solans, X. Tetrahedron 1997, 53, 719; (f) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875. and references therein.
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references therein.
3. (a) Devon, T. K.; Scott, A. I. In In Handbook of Naturally Occurring Compounds;
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Wiley: New York, 1997; (b) Grieco, P. A. Organic Synthesis in Water; Blackie:
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2001; (d) Lindström, U. M. Chem. Rev. 2002, 102, 2751; (e) Li, C.-J. Chem. Rev.
2005, 105, 3095; (f) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68; (g) Herrerias, C.
I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546. For selected recent
examples, see: (h) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10,
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4047.
6. General procedure for the preparation of 3-indolyl-phthalide 3a–o: A mixture of
indole (0.3 mmol) and 2-formylbenzoic acid (0.45 mmol) in pure water (1 mL)
was stirred at the indicated temperature. When the reaction is complete, 200 mL
of dichloromethane was added. The organic layer was separated, washed with
saturated aqueous NaHCO3 (15 mL ꢀ 2), dried over anhydrous Na2SO4, and
evaporated in vacuo. The crude product was purified by column
chromatography on silica gel to give 3-indolyl-phthalide.
7. (a) Nagarajan, K.; Shenoy, S. J. Indian J. Chem. 1992, 31B, 73; (b) Lee, D. Y.; Cho, C.
S.; Jiang, L. H.; Wu, X.; Shim, D. C.; Oh, D. H. Synth. Commun. 1997, 27, 3449; (c)
Donati, C.; Prager, R. H.; Weber, B. Aust. J. Chem. 1989, 42, 787; (d) Pahari, P.;
Senapati, B.; Mal, D. Tetrahedron Lett. 2004, 45, 5109; (e) Khattab, S. N.; Hassan,
S. Y.; El-Faham, A.; EI Massry, A. M.; Amer, A. J. Heterocycl. Chem. 2007, 44,
617.
In summary, we have developed an efficient and simple method
for the synthesis of 3-indolyl-substituted phthalides by Friedel–
Crafts reaction of indoles with 2-formylbenzoic acids in pure
water. This reaction is attractive because of its high efficiency,
environmental friendliness, and no need of any other catalyst. Var-
ious substituted indoles and substituted 2-formylbenzoic acids can
react smoothly to give corresponding phthalides in a green way.
Attempts toward the asymmetric version of the reaction as well
as the application of this method are underway in our laboratory
currently.