2-Amino-4-nitroindole

Similar heterocyclizations were shown to proceed between wta-nitroanilines and carbanions of alkanenitriles to produce 2-amino-4-(and -6-)nitroindoles. For example, the reaction of weta-nitroaniline with acetonitrile leads to 2-amino-4-nitroindole, while 6-nitroindole derivative is formed in the reaction with phenylace-tonitrile (Scheme 58) [171]. 

Filter, wash toluene with water, NaHC03, water and dry, evaporate in vacuum to get 100 g gamma-Cl-butyraldehyde (I) (can distill 28/2). 10 g (I), 20 g 3-nitro-phenylhydrazine dissolve in the minimum volume of hot ethanol containing 10% glacial acetic acid. Heat on steam bath one hour cool and add water until dark oil separates. Evaporate in vacuum the ethanol and decant the water to get the oily gamma-Cl-butyraldehyde-3-intro-phenylhydrazone(II). 29 g (11), 300 ml concentrated HC1, ZOO ml benzene stir three hours, replace benzene with fresh benzene and stir four hours. Combine the two benzene portions, wash with water and dry, evaporate in vacuum to get 4 g 3-(beta-Cl-ethyl)-4 and 6-nitroindole (m). 3.56 g (III), 200 ml ethanol, 200 ml 34% aqueous DMA (or other amine) and let stand at room temperature for one week. Evaporate in vacuum the ethanol, filter, dissolve the precipitate in dilute HC1 and filter. Basify the filtrate with dilute NaOH to precipitate 3 g 4 and 6-nitro-DMT (IV). 5.2 g (IV), 350 ml ethanol, 100 ml IN NaOH heat to 50° and add a solution of 3 g Na dithionite in 15 ml 0.2N NaOH. filter hot and evaporate in vacuum to get 2 g 4 and 6 amino-DMT (can purity by dissolving in HC1, filter, basify, extract with ether and dry and evaporate in vacuum the extract). 

In Figure 4.70, in the overall process, 5-nitroindole is reduced to amino-indole the chloride ion is present in the form of HG1 and the 5-nitroindole is protonated under these acid conditions. 

Nitroindole-2-carboxylic acid (0.86 g), l-[3-(N-isopropyl)amino-2-pyridinyl]piperazine (0.43 g), l-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.45 g) and THF (4 ml), were stirred at 20-25°C for 3 hr then the reaction mixture was dissolved in chloroform (50 ml) and extracted with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (200 g silica) eluting with ethyl acetate/hexane (50/50), the appropriate fractions were pooled and concentrated to give l-[5-nitroindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2-pyridinyl]piperazine, mp 153°-154°C. 

NTII was prepared by reacting naltrexone with (4-nitrophenyl)hydrazine to form 5 -nitroindole (142) which was reduced by catalytic hydrogenation over Raney nickel to the 5 -amino derivative (143). Treatment with thio-phosgene yielded NTII [203]. 

Some more recent examples of nucleophilic displacement of halide involve activation by nitro groups for example, 2-iodo-3-nitro-l-(phenylsulfonyl)indole 71 yields 2-amino-3-nitroindoles 72 in good yields when treated with secondary amines, but fails to undergo SnAt with sodium azide, phenol, and ammonia [36]. 

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... 

In the first route (Scheme 4), indoUne (5) is nitrated to 6-nitro-2,3-dUiydroindole (22, 92%). Apphcation of the tungstate method to 22 and subsequent methylation provide l-methoxy-6-nitroindole (9, 77%) via 8a. A Vilsmeier-Haack reaction (94%), followed by nitroaldol reaction (85%), leads 9 to l-methoxy-6-nitro-3-(2-nitrovinyl)indole (23) through 1-methoxy-6-nitroindole-3-carbaldehyde (10b). After selective reduction of the nitro-vinyl part of 23 with NaBH4, the resultant l-methoxy-6-nitro-3-(2-nitro-ethyl)indole (24,84%) is treated with Zn/HCl and then AC2O to give 21 (81%). Reduction of 24 with Zn/AcOH produces 6-amino-l-methoxytryptamine (25, 30%). 

Use of oxygen, the most common oxidant, for oxidation of the a"-adducts is limited to the adducts of primaiy and secondary carbanions. Since the oxidation of these a"-adducts by oxygen proceeds efficiently only in the presence of an excess of base, we suppose that the dianions produced via further deprotonation of the a"-adducts are oxidized by oxygen [17]. This process is illustrated by direct ONSH in nitroarenes with enolates of ketones that proceeds selectively para to the nitro group [18, 19]. On the other hand, reaction of such enolates with m-nitroanilines—an efficient synthesis of nitroindoles proceeds mostly ortho to the amino and nitro groups [18]. Both of these reactions proceed in the presence of atmospheric oxygen and do not require another oxidant (Scheme 11.9). 

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