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).

4. Conclusion

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.

5. Acknowledgements

This work is supported by the Research Fund for Young Scientist (No.52LX29), Tianjin.


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