Halogenation and Acylation

Electrophilic substitution reactions of 1-methoxyindoles proceed in a quite different way from that of the corresponding N(1) - H indoles [25]. For example, bromination of Nb-methoxycarbonyltryptamine (55) with 1.2-mol eq. of Br2/NaOAc/AcOH affords 2-oxindole (56, 44%), 36 (3%), 5,7-dibromo-(57, 3%), and 2,5-dibromotryptamines (58, 4%) (Table 1).

Under similar reaction conditions, 35 generates many products such as 7-bromo- (59), 2,7-dibromotryptamines (60), 57, 7-bromo- (61), 5-bromo-2-oxindoles (62), 56,2-bromotryptamine (63), and 58, depending on the bromination conditions (entries 1-3). 1-Hydroxy-Nb-methoxycarbonyltryptamine (52) shows almost the same results as 35. It should be noted that the ratio of all of the 7-brominated indoles to the total products, observed in the bromination of 1-hydroxyindole derivatives (35 and 52), is much higher than that of the N(1)-H compound (55).

Melatonin (64) shows characteristic positional selectivity upon bromination depending on the quantity of Br2 (Table 2) [26]. With an increase in the quantity of Br2 from 1 to 2-mol eq., the product distribution changes from 4-bromo- (65), 2-bromo- (66), and 2,4-dibromomelatonins (68) to 65, 2,6-dibromo- (67), and 68 (entries 1 and 2). When 3-mol eq. of Br2 is employed, 2,4,6-tribromomelatonin (69) is obtained as a sole product in 94% yield (entry 3).

Once a methoxy group is introduced onto the N(1) of melatonin, namely in the case of 1-methoxymelatonin (70), remarkable differences in the po-

Table 1 Bromination of Nb-methoxycarbonyltryptamine and its 1-hydroxy analogs


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