Scheme 2 Synthesis of 1-hydroxy-5- and -6-nitroindole-3-carbaldehydes, and analogs

As a second route, we have tried the ether cleavage of the 1-methoxy group in 1-methoxy-6-nitroindole-3-carbaldehyde (10b), which is obtained from 8a through 1-methoxy-6-nitroindole (9) [13]. Although the treatment of 10b with trimethylsilyl iodide is unsuccessful, BBr3 is found to generate 5a. The yield is, however, not improved to more than 40% under various examined reaction conditions. With this point in mind, we have decided to change the alkyl group on the 1-hydroxy oxygen from a methyl to a benzyl group. Ben-zylation of 8a with benzyl bromide/K2CO3 affords 1-benzyloxy-6-nitroindole (8b, 95%). Subsequent Vilsmeier-Haack reaction of 8b affords 1-benzyloxy-6-nitroindole-3-carbaldehyde (11, 96%). Benzyl ether cleavage of 11 with BBr3 proceeds successfully as expected, culminating in the formation of 5a (97%).

As a third route, we conceived the idea to attack the methyl carbon of the 1-methoxy group in 10b with a base relying on the acidic nature of 1-hydroxyindole compounds [14]. The idea has actually been realized by employing 1,4-diazabicyclo[2.2.2]octane (DABCO) as explained in detail in Sect. 3.3.2.

This new reaction is successfully applied for the preparation of 1-hydroxy-5-nitroindole-3-carbaldehyde (6a, 96%) from 6b that is obtained in 97% yield by the Vilsmeier-Haack reaction of readily available 1-methoxy-5-nitroindole (12) [5-7,9].

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