2.3- Dimethyl-4-nitroindole

Despite simplicity and versatility of this new way of indole synthesis, there have been only few reports on application of this reaction to the synthesis of compounds of biological interest [168-170]. Thus, 2,3-dimethyl-4-nitroindole, obtained according to [167], was oxidized to nitroacetophenone derivative, which was used as a starting material for the synthesis of homocamptothecin derivatives, tested as potential inhibitors of DNA topoisomerase I (Scheme 57) [170]. 

Substitution for PABA in a FA analogue by an indole ring has been accomplished by a Russian group Scheme 3.159) [290], Thus, acylation of dimethyl glutamate with 5-nitroindole-2-carbonyl chloride followed by catalytic hydrogenation furnished (701) which was condensed with (11) to yield imine (702). This was reduced with sodium borohydride to give (703) uneventfully. 

Nitration of indole by benzoyl nitrate gives 3-nitroindole (35%) [68JCS(C)2145]. Nitration of some alkyl-substituted indoles by nitric acid/ sulfuric acid (63JOC2262 79JOU528) takes place upon the protonated species, and in such cases the rates pass through a maximum at 90% sulfuric acid in the usual way. 2-Methyl-, 1,2-dimethyl-, 2-f-butyl-, and 2,3-dimethylindole are each nitrated at the 5-position, the former two compounds in 84 and 82% yield, respectively, the latter two compounds at similar rates. This rate similarity suggests that in the protonated species the 5-position is much the most reactive of the benzenoid ring positions. In the protonated species it is probably the 3-position that has become... 

While the 2-nitroindole 85 reacted with dimethyl cuprate in a maimer analogous to 84, the yield was rather low [41], Addition of other nucleophiles, such as enolates, to 2-nitroindole 85 results in the isolation of 3-substituted-2-nitroindoles (91 and 92) in much higher yields. Moreover, if indole is treated with sodium hydride followed by 2-nitroindole 85, a mixture of bis-indoles (93 and 94) is isolated. 

Some final examples of the Makosza indole synthesis are tabulated in Table 2. Volovenko and colleague report a simple synthesis of 3-substituted-2-amino-5-nitroindoles (entry 1), which were transformed into pyrimido[l,2-fl] indoles upon reaction with p-dicarbonyl compounds [26]. A conventional VNS method was used by Lerman and colleagues to craft 6- and 7-hydroxyindoles via sacrificial chlorine atoms that serve to increase the electrophilicity of the benzene ring toward cyanomethylation. Subsequent transfer hydrogenation (Pd/C/HCO NH ) gives the respective hydroxyindoles (entries 2, 3) [27], The preparation of 3,6-dimethyl-5-methoxyindole by Skibo and coworkers (entry 4) was the starting point in a synthesis... 

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