White solid, yield: 89%, mp. 213.4˚C - 215.1˚C. 1H NMR (DMSO-d6, 400 MHz) δ:5.07 (s, OH), 6.56 (d, J = 8.0 Hz, 1 H), 6.78 (s, 1 H), 6.88 - 6.90 (m, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.80 (t, J = 7.2 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 10.18 (s, NH); 13C NMR (DMSO-d6, 100 MHz) δ: 171.2, 154.6, 150.2, 135.9, 132.3, 131.5, 129.8, 129.3, 128.0, 127.5, 124.5, 120.2, 114.3, 112.9, 105.5, 78.5; C16H11NO3 (265.07): calcd. C 72.45, H 4.18, N 5.28; found C 72.70, H 3.99, N 5.16.
2.2.2. 3-(6-(Benzyloxy)-1H-indol-3-Yl)isobenzofuran- 1(3H)-One (3k)
White solid, yield: 89%, mp. 194.5˚C - 195.7˚C. 1H NMR (CDCl3, 400 MHz), δ:5.19 (d, J = 3.2 Hz, 2H, CH2), 6.60 - 6.68 (m, 2 H), 6.84 (s, 1 H), 6.92 (d, J = 2.8 Hz, 1 H), 7.26 - 7.98 (m, 9 H), 8.00 (d, J = 8.8 Hz, 1 H), 10.24 (b, NH). 13C NMR (CDCl3, 100 MHz), δ:170.6, 154.3, 149.4, 137.7, 135.0, 132.3, 129.5, 128.6, 127.9, 127.6, 126.6, 126.1, 125.8, 125.3, 123.3, 122.9, 119.0, 113.0, 108.6, 82.5, 70.4; C23H17NO3 (355.12): calcd. C 77.73, H 4.82, N 3.94; found C 77.57, H 4.99, N 3.98.
2.2.3. 3-(6-Chloro-1H-indol-3-Yl)isobenzofuran- 1(3H)-One (3m)
White solid, yield: 88%, mp. 139.1˚C - 140.6˚C. 1H NMR (DMSO-d6, 400 MHz), δ:6.77 (d, J = 3.6 Hz, 1 H), 6.91 (s, 1H), 7.04 (dd, J = 2.8 Hz, 9.2 Hz, 1 H), 7.52-7.68 (m, 5H), 7.96 (d, J = 9.6 Hz, 1H), 8.83 (s, 1 H); 13C NMR (DMSO-d6, 100 MHz) δ:170.9, 150.7, 137.7, 135.6, 130.3, 128.7, 128.2, 127.4, 125.9, 124.4, 123.6, 119.4, 114.5, 111.9, 78.6; C16H10ClNO2 (283.04): calcd. C 67.74, H 3.55, N 4.94; found C 67.84, H 3.56, N 4.86.
3. Results and Discussion
In our initial studies, all kinds of experimental parameters, such as solvents, molar ratios of the two substrates and catalyst loadings, were thoroughly investigated in the model Friedel-Crafts alkylation of indole (2a) with 3-hydroxyisobenzofuran-1(3H)-one (1) employing the TsOH·H2O as the catalyst. And the results are listed in Table 1.
Solvent evaluation revealed that chloroalkanes (CH2Cl2 and CHCl3) favored this transformation in terms of high yield (Table 1, Entries 1 and 2), and CH2Cl2 is
Table 1. Optimization of the reaction conditionsa.
the optimal solvent providing the corresponding FriedelCrafts alkylation product with the highest yield of 95% (Table 1, Entry 2, 95%). Marked decrease in yields was observed in this reaction when using other solvents, such as THF, methanol, ethanol and ethyl acetate (Table 1, Entries 3-6). Moreover, it was found that a ring-opened product was obtained in the case of the methanol or ethanol as the solvent. In addition, the adjustment of the catalyst loading also brought out some influence both on the reaction rate and chemical yield. For example, using the great amount of catalyst, we could obtain the alkylation product 3a in quite shorter time with almost the same high level yield (Table 1, Entry 8). Reducing the catalyst loading from 2 mol-% to 1 mol-% led to an obvious decrease both on reaction rate and yield. Furthermore, the molar ratio of the two reactants was found to be an essential factor to the yield of the reaction. As shown in Table 1, the yield of 3a was enhanced with the decrease in the molar ratio of 1 to 2a, and the maximal yield of 95% was obtained when the molar ratio reached 1:1.2 (Table 1, Entry 2). Further decreased the molar ratio to 1:1.5 resulted in a lower yield of 3a (Table 1, Entry 10).
On the basis of the optimal reaction conditions of indole 2a (2 mol-% TsOH·H2O as the catalyst, substrates molar ratio (1:2a = 1:1.2), 0.5 M 3-hydroxyisobenzofuran-1(3H)-one 1, at 20℃ in CH2Cl2), a plethora of indoles 2 were evaluated for the reaction with 3-hydroxyisobenzofuran-1(3H)-one 1, and the results are summarized in Table 2.
As shown in Table 2, the reaction has broad applicability with respect to the indoles. A wide range of indoles bearing either an electron-withdrawing or electrondonating substituent at various positions on the indole ring were included as the reaction partners, leading to the formation of the desired products in good to excellent yields (Table 2, Entries 2-14, in most cases, over 90% yields were obtained). Generally, electron-rich indoles exhibited a higher reactivity than those of electron-poor ones. It is worth noting that the most electron-deficient nitro-substituted indole 2n also worked well to affording the corresponding alkylation product 3n with satisfactory yield (Table 2, Entry 14). Subsequently, the reaction between indole (2a) and 3-ethyl-3-hydroxyisobenzofuran- 1(3H)-one [23,27], an interesting reaction partner, since an oxygen-containing quaternary carbon will be created in the Friedel-Crafts alkylation reaction, was also investigated. Unfortunately, no reaction occurred even at elevated reaction temperature (60˚C).
In summary, we have developed an efficient and facile method for the synthesis of 3-indolyl-substituted phthalides by Friedel-Crafts alkylation of indoles with
Table 2. The synthesis of 3-indolyl-substituted phthalides between 3-hydroxyisobenzofuran-1(3H)-one and indoles catalyzed by TsOH·H2Oa.
3-hydroxyisobenzofuran-1(3H)-one. Compared to the limited literature reports, this method is more attractive because of its high efficiency, mild reaction conditions, readily available starting materials as well as the cheap catalyst. Various substituted indoles can react smoothly to give the corresponding phthalides in good to excellent yield. Attempts toward the asymmetric version of this alkylation reaction are underway in our laboratory at present.
This work is supported by the Research Fund for Young Scientist (No.52LX29), Tianjin.
- T. K. Devon and A. I. Scott, “Handbook of Naturally Occurring Compounds,” Vol. 1, Academic Press, New York, 1975.
- J. B. John and S. C. Chou, “The Structural Diversity of Phthalides from the Apiaceae,” Journal of Natural Products, Vol. 70, No. 5, 2007, pp. 891-900. doi:10.1021/np0605586
- R. Bentley, “Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant,” Chemical Reviews, Vol. 100, No. 10, 2000, pp. 3801-3826.
- J. G. Lei, R. Hong, S. G. Yuan and G. Q. Lin, “Nickel-
- Catalyzed Tandem. Reaction to Asymmetric Synthesis of Chiral Phthalides,” Synlett, Vol. 2002, No. 6, 2002, pp. 927-930. doi:10.1055/s-2002-31932
- W. W. Chen, M. H. Xu and G. Q. Lin, “Unusual Heterochiral Crystallization Tendency of 3-Arylphthalide Compounds in Non-Racemic Solution: Reinvestigation on Asymmetric Ni-catalyzed Tandem Reaction of Substituted o-Halobenzaldehydes,” Tetrahedron Letters, Vol. 48, No. 42, 2007, pp. 7508-7511. doi:10.1016/j.tetlet.2007.08.060
- B. Witulski, A. Zimmermann and N. D. Gowans, “First total Synthesis of the Marine Illudalane Sesquiterpenoid Alcyopterosin E,” Chemical Communications, No. 24, 2002, pp. 2984-2985. doi:10.1039/b209573d
- K. A. Dekker, T. Inagaki, T. D. Gootz, K. Kanede, E. Nomura, T. Sakakibara, S. Sakemi, Y. Sugie, Y. Yamauchi, N. Yoshikawa and N. Kojima, “CJ-12,954 and Its Congeners, New Anti-Helicobacter Pylori Compounds Produced by Phanerochaete Velutina: Fermentation, Isolation, Structural Elucidation and Biological Activities,” Journal of Antibiotics, Vol. 50, 1997, pp. 833-839. doi:10.7164/antibiotics.50.833
- X. W. Wang, “3-n-Butylphthalide. Cerebral Antiischemic,” Drugs of the Future, Vol. 25, No. 1, 2000, pp. 16-29. doi:10.1358/dof.2000.025.01.562281
- K. Yoganathan, C. Rossant, S. Ng, Y. Huang, M. S.Butler and A. D. Buss, “10-Methoxydihydrofuscin, Fuscinarin, and Fuscin, Novel Antagonists of the Human CCR5 Receptor from Oidiodendron griseum,” Journal of Natural Products, Vol. 66, No. 8, 2003, pp. 1116-1117. doi:10.1021/np030146m
- D. J. Faulkner, “Marine Natural Products,” Natural Product Reports, Vol. 19, No. 1, 2002, pp. 1-49. doi:10.1039/b009029h
- A. Kleeman, J. Engel, B. Kutscher and D. Reichert, “Pharmaceutical Substances,” 4th Edition, Thieme, New York, 2001.
- K. A. Jrgensen, “Asymmetric Friedel-Crafts Reactions: Catalytic Enantioselective Addition of Aromatic and Heteroaromatic C-H Bonds to Activated Alkenes, Carbonyl Compounds and Imines,” Synthesis, No. 7, 2003, pp. 1117-1125. doi:10.1055/s-2003-39176
- M. Bandini, A. Melloni and A. Umani-Ronchi, “Neue Katalytische Methoden in der Stereoselektiven FriedelCrafts-Alkylierung, ”Angewandte Chemie International Edition, Vol. 43, No. 5, 2004, pp. 550-556. doi:10.1002/anie.200301679
- M. Bandini, A. Melloni, S.Tommasi and A. UmaniRonchi, “A Journey across Recent Advances in Catalytic and Stereoselective Alkylation of Indoles,” Synlett, Vol. 2005, No. 8, 2005, pp. 1199-1122. doi:10.1055/s-2005-865210
- S. B. Tsogoeva, “Recent Advances in Asymmetric Organocatalytic 1,4-Conjugate Additions,” European Journal of Organic Chemistry, Vol. 2007, No. 11, 2007, pp. 1701-1716. doi:10.1002/ejoc.200600653
- W. E. Noland and J. E. Johnson, “3-(3-Indolyl)phthalides and 3-(2-Carboxy-benzyl)indoles,” Journal of the American Chemical Society, Vol. 82, No. 19, 1960, pp. 5143- 5147. doi:10.1021/ja01504a031
- C. W. Rees and C. R. Sabet, “Mechanism of the Reaction of Phthalaldehydic Acid with Indoles. Intramolecular Catalysis in Aldehyde Reactions,” Journal of the Chemical Society, 1965, pp. 680-687. doi:10.1039/jr9650000680
- H. Lin and X. W. Sun, “Highly Efficient Synthesis of 3-Indolyl-Substituted Phthalides via Friedel-Crafts Reactions in Water,” Tetrahedron Letters, Vol. 49, No. 36, 2008, pp. 5343-5346. doi:10.1016/j.tetlet.2008.06.055
- H. Lin, K. S. Han, X. W. Sun and G. Q. Lin, “Synthesis of 3-Indolyl-Substituted Phthalides Catalyzed by Acidic Cation Exchange Resin Amberlyst 15,” Chinese Journal of Organic Chemistry, Vol. 28, No. 8, 2008, pp. 1479- 1482.
- J. N. Freskos, G. W. Morrow and G. S. Swenton, “Synthesis of Functionalized Hydroxyphthalides and Their Conversion to 3-Cyano-1(3M-isobenzofuranones. The Diels-Alder Reaction of Methyl 4,4-Diethoxybutynoate and Cyclohexadienes,” Journal of Organic Chemistry, Vol. 50, No. 6, 1985, pp. 805-810. doi:10.1021/jo00206a016
- D. L. Comins and J. D. Brown, “Directed Lithiation of Tertiary Beta-Amino Benzamides,” Journal of Organic Chemistry, Vol. 51, No. 19, 1986, pp. 3566-3572. doi:10.1021/jo00369a002
- K. Shinji, N. Nobuaki, T. Koji and M. Toshiaki, “NonCryogenic Metallation of Aryl Bromides Bearing Proton Donating Groups: Formation of a Stable MagnesioIntermediate,” Tetrahedron Letters, Vol. 43, No. 41, 2002, pp. 7315-7317. doi:10.1016/S0040-4039(02)01747-1
- H. Yang, G. Y. Hu, J. Chen, Y. Wang and Z. H. Wang, “Sythesis, Resolution, and Antiplatelet Activity of 3-Substituted 1(3H)-Isobenzofuranone,” Bioorganic & Medicinal Chemistry Letters, Vol. 17, No. 18, 2007, pp. 5210-5213. doi:10.1016/j.bmcl.2007.06.082
- W. Wang, X. X. Cha, J. Reiner, Y. Gao, H. L. Qiao, J. X. Shen and J. B. Chang, “Synthesis and Biological Activity of n-Butylphthalide Derivatives,” European Journal of Medicinal Chemistry, Vol. 45, No. 5, 2010, pp. 1941- 1946. doi:10.1016/j.ejmech.2010.01.036
- H. Baba and H. Togo, “Sulfonylamidation of Alkylbenzenes at Benzylic Position with p-Toluenesulfonamide and 1,3-Diiodo-5,5-dimethylhydantoin,” Tetrahedron Letters, Vol. 51, No. 15, 2010, pp. 2063-2066. doi:10.1016/j.tetlet.2010.02.060
- S. L. Zhang, Y. F. Zhao, Y. J. Liu, D. Chen, W. H. Lan, Q. L. Zhao, C. C. Dong, L. Xia and P. Gong, “Synthesis and Antitumor Activities of Novel 1,4-Disubstituted Phthalazine Derivatives,” European Journal of Medicinal Chemistry, Vol. 45, No. 8, 2010, pp. 3504-3510. doi:10.1016/j.ejmech.2010.05.016
- K. Q. Ling, G. Ji, H. Cai and J. H. Xu, “Dye-Sensitized Photooxygenations Of 1,3-Isoquinolinediones,” Tetrahedron Letters, Vol. 39, No. 16, 1998, pp. 2381-2384. doi:10.1016/S0040-4039(98)00344-X