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

Full text of DOI:10.1007/s11172-010-0078-3

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 300—301, January, 2010
300
Synthesis of regioisomeric 3ꢀ(Nꢀphenylpyrazolyl)indoles
from comanic acid and phenylhydrazine
B. I. Usachev, D. L. Obydennov, and V. Ya. Sosnovskikh
A. M. Gorky Ural State University,
51 prosp. Lenina, 620083 Ekaterinburg, Russian Federation.
Fax: +7 (343) 261 5978. Eꢀmail: Boris.Usachev@mail.ru
Scheme 1
Synthesis of new indole derivatives receives much atꢀ
tention because the indole ring is an important structural
unit of many natural alkaloids and biologically active comꢀ
pounds.1 It is known that γꢀpyrone reacts with phenylꢀ
hydrazine to give 1ꢀphenylpyrazolꢀ5ꢀylacetaldehyde pheꢀ
nylhydrazone.2 Recently,3 we have demonstrated that
a reaction of 6ꢀ(trifluoromethyl)comanic acid4 with pheꢀ
nylhydrazine can yield phenylhydrazones of 1ꢀphenylꢀ5ꢀ
trifluoroacetonylpyrazoleꢀ3ꢀcarboxylic acid or 1ꢀphenylꢀ
3ꢀtrifluoroacetonylpyrazoleꢀ5ꢀcarboxylic 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
3ꢀ(1ꢀphenylpyrazolꢀ3ꢀyl)pyruvic acid phenylhydrazone 2,
which was not isolated) to indole 3 in 35% yield. Interestꢀ
ingly, heating of acid 1 with phenylhydrazine hydrochloꢀ
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
1
by data from elemental analysis, H and 13C NMR specꢀ
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 3ꢀ(Nꢀphenylpyrazolꢀ5ꢀyl)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, conꢀ
firms the proposed structure.
To sum up, comanic acid and phenylhydrazine can be
used as starting reagents for the synthesis of regioisomeric
3ꢀ(Nꢀphenylpyrazolyl)indoleꢀ2ꢀcarboxylic acids. The latꢀ
ter are of interest for medicinal chemistry because the
presence of hydrophilic substituents in drug molecules
i. Dioxane, Δ. ii. H2O, 20 °C. iii. AcOH, H2O, HCl.
makes them more soluble in aqueous media, which usualꢀ
ly enhances their pharmacological properties.
3ꢀ(1ꢀPhenylꢀ1Hꢀpyrazolꢀ3ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxylic 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, DMSOꢀd6), 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);
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 291—292, January, 2010.
1066ꢀ5285/10/5901ꢀ0300 © 2010 Springer Science+Business Media, Inc.

Regioisomeric 3ꢀ(Nꢀphenylpyrazolyl)indoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
301
7.57 (t, 2 H, H(3´´), H(5´´), J = 7.8 Hz); 7.94 (d, 2 H, H(2´´),
H(6´´), J = 7.9 Hz); 8.30 (d, 1 H, H(4), J = 8.2 Hz); 8.61 (d, 1 H,
H(5´), J = 2.5 Hz); 11.93 (s, 1 H, NH); 13.6—13.9 (br.s,
1 H, CO2H).
3ꢀ(1ꢀPhenylꢀ1Hꢀpyrazolꢀ5ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxylic acid
(4). Method A. Three drops of conc. HCl and phenylhydrazone 5
(0.1 g, 0.31 mmol) were added to a 2 : 1 mixture (4 mL) of AcOH
and water. The resulting suspension was refluxed for 1 h to comꢀ
plete homogenization and cooled. The crystals that formed were
filtered off, washed with water, and dried. The yield was 0.05 g
(67%), m.p. 275 °C.
Method B. Acid 1 (0.15 g, 1.1 mmol) and phenylhydrazine
hydrochloride (0.34 g, 2.4 mmol) were added to a 2 : 1 mixture
(4 mL) of AcOH and water. The reaction mixture was refluxed
for 4 h and then cooled to ~20 °C. The crystalline product that
formed was filtered off, washed with water, dried, and recrystalꢀ
lized from AcOH—H2O (1 : 1). The yield was 0.16 g (50%).
Found (%): C, 71.05; H, 4.39; N, 13.77. C18H13N3O2. Calculatꢀ
ed (%): C, 71.28; H, 4.32; N, 13.85. IR, ν/cm–1: 3310, 3280,
1666, 1597, 1498. 1H NMR (400 MHz, DMSOꢀd6), δ: 6.56 (d, 1 H,
H(4´), J = 1.6 Hz); 7.07 (t, 1 H, H(5), J = 7.6 Hz); 7.13—7.30
(m, 6 H, H(6), Ph); 7.32 (d, 1 H, H(4), J = 8.2 Hz); 7.47 (d, 1 H,
H(7), J = 8.2 Hz); 7.80 (d, 1 H, H(3´), J = 1.6 Hz); 12.02 (s, 1 H,
NH); 12.6—13.2 (br.s, 1 H, CO2H). 13C NMR (100 MHz,
DMSOꢀd6), δ: 110.0 (C(4´)), 110.3 (C(3)), 113.2 (C(7)), 120.6
(C(6)), 121.3 (C(5)), 123.7 (C(2″)), 125.4 (C(4)), 126.4 (C(5´)),
127.1 (C(4″)), 127.7 (C(2)), 129.0 (C(3″)), 135.5 (C(3a)), 136.3
(C(1″)), 140.2 (C(7a)), 140.8 (C(3´)), 162.2 (CO2H).
precipitate that formed was filtered off, washed with water, dried,
and recrystallized from AcOH–H2O (1 : 1, 12 mL). The yield
was 0.06 g (18%), m.p. 215 °C. Found (%): C, 67.30; H, 5.12;
N, 17.27. C12H10N2O3. Calculated (%): C, 67.49; H, 5.03;
1
N, 17.49. IR, ν/cm–1: 3024, 1664, 1601, 1580, 1497. H NMR
(400 MHz, DMSOꢀd6), δ: 4.01 (s, 2 H, CH2); 5.94 (d, 1 H,
H(4), J = 1.6 Hz); 6.87 (t, 1 H, H(4´), J = 7.4 Hz); 7.23 (t, 2 H,
H(3´), H(5´), J = 7.8 Hz); 7.32 (d, 2 H, H(2´), H(6´), J = 8.1 Hz);
7.42 (t, 1 H, H(4″), J = 7.8 Hz); 7.46 (d, 1 H, H(3), J = 1.6 Hz);
7.54 (t, 2 H, H(3″), H(5″), J = 7.8 Hz); 7.65 (d, 2 H, H(2″),
H(6″), J = 7.9 Hz); 10.15 (s, 1 H, NH); 11.6—12.2 (br.s,
1 H, CO2H).
References
1. R. J. Sundberg, The Chemistry of Indoles, Academic Press,
New York, 1996, 113.
2. C. Ainsworth, R. G. Jones, J. Am. Chem. Soc., 1954, 76, 3172.
3. B. I. Usachev, D. L. Obydennov, M. I. Kodess, V. Ya. Sosꢀ
novskikh, Tetrahedron Lett., 2009, 50, 4446.
4. B. I. Usachev, I. A. Bizenkov, V. Ya. Sosnovskikh, Izv. Akad.
Nauk, Ser. Khim., 2007, 537 [Russ. Chem. Bull., Int. Ed.,
2007, 56, 558].
5. V. P. Gorbunov, K. F. Turchin, N. N. Suvorov, Khim.
Geterotsikl. Soedin., 1970, 1508 [Chem. Heterocycl. Compd.
(Engl. Transl.), 1970, 6].
2ꢀ(Phenylhydrazono)ꢀ3ꢀ(1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀyl)propionic
acid (5). Freshly distilled phenylhydrazine (0.25 g, 2.3 mmol)
and acid 1 (0.15 g, 1.1 mmol) were added to water (3 mL). The
reaction mixture was stirred and kept at 20 °C for 18 h. The
Received July 20, 2009,
in revised form November 3, 2009