Synthesis of regioisomeric 3-(N-phenylpyrazolyl)indoles from comanic acid and phenylhydrazine

Abstract

Synthesis of new indole derivatives receives much at tention because the indole ring is an important structural unit of many natural alkaloids and biologically active com pounds.1 It is known that γ pyrone reacts with phenyl hydrazine to give 1 phenylpyrazol 5 ylacetaldehyde phe nylhydrazone.2 Recently,3 we have demonstrated that a reaction of 6 (trifluoromethyl)comanic acid4 with phe nylhydrazine can yield phenylhydrazones of 1 phenyl 5 trifluoroacetonylpyrazole 3 carboxylic acid or 1 phenyl 3 trifluoroacetonylpyrazole 5 carboxylic acid, depending on the solvent nature. In the present work, we found that the reaction of comanic acid 1 with phenylhydrazine hydrochloride in boiling dioxane leads (probably through the expected 3 (1 phenylpyrazol 3 yl)pyruvic acid phenylhydrazone 2, which was not isolated) to indole 3 in 35% yield. Interest ingly, heating of acid 1 with phenylhydrazine hydrochlo ride in AcOH–H2O (2 : 1) gives isomeric indole 4 in 50% yield. In this case, intermediate pyrazole 5 was isolated in low yield (18%) when the reaction was carried out in water at ~20 °C. Reflux of compound 5 in AcOH—H2O (2 : 1) in the presence of HCl for 1 h affords indole 4 in 67% yield (Scheme 1). The structures of the products obtained were confirmed by data from elemental analysis, 1H and 13C NMR spec troscopy, and IR spectroscopy. The 1H NMR spectrum of indole 4 shows doublets for the pyrazole H(3) and H(4) protons at δ 7.80 and 6.56 (J = 1.6 Hz), respectively. These chemical shifts agree well with the literature data5 for its closest analog 3 (N phenylpyrazol 5 yl)indole (δ: 7.75 (H(3)), 6.60 (H(4)), J = 2.0 Hz). In the spectrum of isomer 3, the doublets for the H(5) and H(4) protons are shifted downfield to δ 8.61 and 7.24 (J = 2.5 Hz), respectively. This results from the planar conformation of the molecule and, along with the coupling constant, con firms the proposed structure. To sum up, comanic acid and phenylhydrazine can be used as starting reagents for the synthesis of regioisomeric 3 (N phenylpyrazolyl)indole 2 carboxylic acids. The lat ter are of interest for medicinal chemistry because the presence of hydrophilic substituents in drug molecules makes them more soluble in aqueous media, which usual ly enhances their pharmacological properties. 3 (1 Phenyl 1H pyrazol 3 yl) 1H indole 2 carboxylic acid (3). Freshly distilled phenylhydrazine (0.25 g, 2.3 mmol), acid 1 (0.14 g, 1.0 mmol), and three drops of conc. HCl were added to anhydrous dioxane (6 mL). The reaction mixture was refluxed for 3 h, whereupon water (6 mL) was added. The resulting oily phase slowly crystallized with time. The crystalline precipitate was filtered off and recrystallized from AcOH—H2O (2 : 1). The yield was 0.08 g (35%), m.p. 270 °C. Found (%): C, 71.10; H, 4.42; N, 14.01. C18H13N3O2. Calculated (%): C, 71.28; H, 4.32; N, 13.85. IR, ν/cm–1: 3330, 3281, 1667, 1598. 1H NMR (400 MHz, DMSO d6), δ: 7.18 (t, 1 H, H(5) J = 7.6 Hz); 7.24 (d, 1 H, H(4 ), J = 2.5 Hz); 7.33 (t, 1 H, H(4 ), J = 8.2 Hz); 7.35 (t, 1 H, H(6), J = 7.8 Hz); 7.51 (d, 1 H, H(7), J = 8.3 Hz); Scheme 1