Indolizine nitration

Indolizine, hydroxy-conformations, 4, 451 GLC retention times, 4, 451 synthesis, 4, 121 tautomerism, 4, 198, 452 Indolizine, 2-hydroxy-synthesis, 4, 463 Indolizine, 8-hydroxy-conformation, 4, 452 Indolizine, 2-hydroxymethyl-synthesis, 4, 461 Indolizine, 3-hydroxymethyl-synthesis, 4, 461 Indolizine, 6-hydroxymethyl-synthesis, 4, 461 Indolizine, methyl-mass spectra, 4, 187, 450 NM 4, 448 Indolizine, 2-methyl-diazo coupling, 4, 454 mass spectra, 2, 529, 4, 450 nitration, 4, 50, 454 nitrosation, 4, 454 reaction with diaryl disulfide, 4, 460 reaction with nitroethane, 4, 460 Indolizine, 3-methyl-basicity, 4, 454 Indolizine, 5-methyl-acidity, 4, 461 synthesis, 4, 466 Indolizine, 6-methyl-mass spectra, 4, 450 Indolizine, l-methyl-2-phenyl-nitration, 4, 454 nitrosation, 4, 454, 455 Indolizine, 3-methyl-2-phenyl-reaction... 

Indolizine is much more basic than indole (p Ta = 3.9 vs. —3.5), and the stability of the cation makes it less reactive and resistant to acid-catalyzed polymerization. Protonation occurs at C-3, although 3-methylindolizine protonates also at C-l. Introduction of methyl groups raises the basicity of indolizines. Electrophilic substitutions such as acylation, Vilsmeyer formylation, and diazo-coupling all take place at C-3. Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-l, presumably via attack on the indolizinium cation. However, the nitration of indolizines often can provoke oxidation processes. 

The monosubstitution products of the Friedel-Crafts reaction and of the nitration reaction have been interrelated to show that the substituent group is introduced at the same position in each case. A further correlation with the adduct (Id) from indolizine and methyl propiolate provides evidence that this is the 1-position as predicted.56 Acylation of 2-methoxycarbonyl-3-phenylcycl[3,2,2]azine (Is) takes place in the pyrrole part of the molecule.51... 

Nitration of benzof/jjthiophene (HN03/AcOH) yields mainly the 3-nitro derivative. Under these conditions the p to a ratio of substitution is approximately 5 1, which is significantly less than for indole itself which undergoes almost exclusive (3 substitution. Indolizines are readily nitrated, e.g. brief treatment of 2-methylindolizine with a mixture of concentrated nitric and sulfuric acids gives 2-methyl-l-nitroindolizine (66). 

Nitration of indolizines often runs the risk of oxidation. The orientation of the substitution appears to depend on the experimental conditions nitration of 2-methylindolizine in a mixture of nitric acid and sulfuric acid occurs at the 1 -position (46JCS1075) in acetic anhydride at -70 °C, on the other hand, 2-methyl-3-nitroindolizine is formed (72JCS(P1)2954). The nitration of 2-phenylindolizine with nitric acid in aqueous sulfuric acid gave 2-(4-nitro-phenyl)indolizine (32a) and l-nitro-2-(4-nitrophenyl) indolizine (32b) together with 20% of an unidentified dinitro compound, possibly 3-nitro-2-(4-nitrophenyl)indolizine (32c) <79JCS(P2)312>. 

A kinetic study of the nitration and nitrosation of l-methyl-2-phenylindolizine revealed that substitutions at the 3-position derive from an attack on the indolizine base while substitutions elsewhere involve attack on the conjugate acid (79JCS(P2)312>. 

Nitration of indolizines is seldom attempted in view of accompanying oxidation reactions. Thus the synthesis of 6- and 8-nitro-2-phenyl-indolizine has been achieved by the cyclization of appropriately substituted 2-methyl-1-phenacylpyridinium bromide.179 However, 1-nitro and 1,3-dinitro compounds have been prepared.4 From the behavior of the indolizine nucleus toward other electrophiles, 3-nitroindolizine might be expected to be the primary product. This compound has been synthesized using a dilute solution of nitric acid in acetic acid at - 70°C where the substrate could well be the base and not the 3-protonated cation as in a nitric acid-sulfuric acid mixture.180... 

The nitration of 2-phenylindolizine seems to be critically dependent on the reagents and the reaction conditions. The addition of one equivalent of nitric acid at 0°C gives 2-(4-nitrophenyl)indolizine (41%) and a small... 

Nitration of l-methyl-2-phenylindolizine gives 90% of the l-methyl-2-(4-nitrophenyl) product under these conditions, and the results indicate that nitration occurs on the conjugate acid of the indolizine resulting from protonation at C-3 [69JCS(C)1279] (Fig. 3). 

Nitration of 3-acetyl-2-phenylindolizine using nitric acid in sulfuric acid gives a mixture of 3-acetyl-2-(4-nitrophenyl), 3-acetyl-l-nitro-2-(4-nitrophenyl), 3-nitro-2-(4-nitrophenyl), and l,3-dinitro-2-(4-nitrophenyl) indolizine (Fig. 4) (46JCS1077). 

Pyrrolo[l,2-ci]quinoline is a benzo derivative of indolizine and its 2,7-dimethyl derivative (8.65) is nitrosated, acetylated. diazo coupled, and formylated in the expected 1-position in 90, 40, 90, and 70% yields, respectively (79JHC393). Nitration also goes in the 1-position if the conditions are not strongly acidic, in which case it goes in the 6-position. This... 

Nitration of 2-methyl-6-nitroindolizine gave the tetrasubstituted indolizine (18), from the 8-nitroisomer only the monosubstitution product (19) was obtained <89MI 809-01 >. 

A kinetic study of the nitrosation, at C-3, of the indolizine (764) and of its nitration, which occurs at C-4, has been presented.The reaction of diethyl azodicarboxylate with 2-methylindolizine yields a mixture of the mono-adduct (765 R = H) and the di-adduct [765 R = N(C02Et)NHC02Et]. "" The novel zwitterion (767 Ar = P-CIC6H4) is formed by the action of chlorobenzene-p-sulphonyl azide on the cyclohexenoindolizine (766). A stable carbo-selenaldehyde (768) has been obtained by treatment of 2,7-dimethylindolizine with the dimethylformamide-phosphorus oxychloride complex followed by sodium hydrogen selenide. ... 

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