Rearrangement Reaction of 1-Ethoxy- and 1-Hydroxy-2-phenylindole

Abstract

Photoirradiation of 1-ethoxy-2-phenylindole in methanol and the reaction of 1-hydroxy-2-phenylindole with tosyl chloride produced 6-ethoxyand 6-tosyloxy-2-phenylindoles, respectively, as minor products. The latter was derived to 6-ethoxy-2-phenylindole. The structure is determined by direct comparison of the spectral data with those of the authentic 4-, 5-, 6-, and 7ethoxy-2-phenylindoles whose syntheses are reported in detail. We speculated that indole natural products having 3-, 4-, and/or 6-methoxy (or hydroxy) substituent could be produced in plant leaves by the sun light from the corresponding 1-alkoxyor 1hydroxyindoles. In order to examine this 1-hydroxyindole hypotheses, we attempted the photochemical reaction of 1-ethoxy-2-phenylindole (2), derived from 1-hydroxy-2-phenylindole (1). Upon irradiation of 2 with Hannovia UV lamp in MeOH, we characterized 2-phenylindole (3) and 3ethoxy-2-phenylindole (4) in 35 and 12% yields, respectively, from the closely overlapped eight products monitored on tlc (Scheme 1). At the same time, we isolated a 3% yield of product X (5), which was a 2phenylindole carrying an ethoxy group in the benzene ring. On the other hand, upon reaction of 1 with tosyl chloride, we isolated a 6% yield of product Y (6), which has a tosyloxy group on the benzene ring, in addition to 2-phenyl-3-tosyloxyindole (7), 2,2’-diphenyl-3,3’-bisindolyl (8), and 3 in 53, 2, and 5% † Dedicated to Prof. Dr. Albert Padwa. ‡ Professor Emeritus of Kanazawa University. Present address: 56-7 Matsuhidai, Matsudo-shi, Chiba 270-2214, Japan. yields, respectively. At that time, we employed H-NMR spectrum in order to determine the position of substituent on the indole ring utilizing the anisotropy effect of 1-acyl group (Scheme 2). Thus, the unknown indole having R-group (9) is led to the corresponding 1-acyl derivative (10), where the C(7)-proton shifts to lower magnetic field and becomes clearly discernible from other aromatic protons. Based on its coupling pattern, we can determine the position of the R-group unequivocally. In cases of product X (5) and product Y (6) the above structural determination method was impossible because the phenyl group at the 2position blocked the introduction of an acyl group into the 1-position under various reaction conditions (Ac2O reflux or NaH, AcCl). Moreover, the low resolving power of 60 MHz H-NMR apparatus at that time was of no use for analyzing the coupling pattern of aromatic protons. Although we could later utilize a 270 and a 500 MHz H-NMR instruments, they have still not enough resolving power to judge the coupling pattern of the indole benzenoid protons due to the overlapping protons of 2-phenyl group. The left course for the structure determination of product X (5) and product Y (6) was the only one, direct comparison with the authentic 4(11), 5(12), 6(13), and 7-ethoxy-2-phenylindoles (14). Their syntheses required new reactions such as regioselective thallation-palladation method for the preparation of 4-substituted, and 7-substituted indoles, general preparation method for 1-hydroxyindoles, and selective 2-lithiation method of 1-methoxyindoles. After discovering these essential new methods, we succeeded at last in the syntheses of authentic 11, 12, 13, and 14 in 1998. Consequently, structures of N