Synthesis and properties of ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates

Article abstract of DOI:10.1134/S1070428017010110

Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates reacted with phenylhydrazine to give the corresponding hydrazones, ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates, which were converted to ethyl 1′-aryl-4-formy

Full text of DOI:10.1134/S1070428017010110

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 1, pp. 62–65. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.A. Potopnyk, V.S. Matiichuk, M.D. Obushak, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 1, pp. 67–70.
Synthesis and Properties of Ethyl 1-Aryl-5-methyl-
4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates
M. A. Potopnyk, V. S. Matiichuk, and M. D. Obushak*
Ivan Franko National University of Lviv, ul. Kyrylla i Mefodiya 6, Lviv, 79005 Ukraine
*e-mail: obushak@in.lviv.ua
Received August 31, 2016
Abstract—Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates reacted with phenylhydrazine to give
the corresponding hydrazones, ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-car-
boxylates, which were converted to ethyl 1′-aryl-4-formyl-5′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazole-3′-car-
boxylates by treatment with the Vilsmeier–Haack reagent. No indole derivatives were formed from the same
hydrazones under the Fischer reaction conditions, but cyclization to 2-aryl-3,4-dimethyl-6-phenyl-2,6-dihydro-
7H-pyrazolo[3,4-d]pyridazin-7-ones was observed.
DOI: 10.1134/S1070428017010110
Arylhydrazones derived from aromatic and hetero-
aromatic ketones are convenient starting compounds
for the synthesis of various nitrogen heterocycles.
Their treatment with mineral protic or Lewis acids
leads to the formation of indole derivatives (Fischer
indole synthesis) [1–4]. This reaction also provides the
most convenient method for the preparation of 2-aryl
(hetaryl)indoles. Pyridinyl- [5], pyrimidinyl- [6], in-
dolyl- [7], and quinazolinyl-substituted indoles [8], as
well as other indole derivatives, have been synthesized
in this way. Arylhydrazones are known to react with
the Vilsmeier‒Haack reagent to give 4-formyl-
pyrazoles [9].
Phenylhydrazones 2a–2e were synthesized by
reaction of phenylhydrazine with ethyl 1-aryl-4-acetyl-
5-methyl-1H-pyrazole-3-carboxylates 1a–1e in ethanol
(Scheme 1), and initial ketones 1a–1e were prepared
from the corresponding ethyl chloro(arylhydrazinyli-
dene)acetates and acetylacetone [10–12]. No expected
indole derivatives 3a–3e were formed when hydra-
zones 2a–2e were heated in boiling acetic acid
(method a). By heating compounds 2a–2e in THF in
the presence of a mineral acid (HCl) or in dimethyl-
formamide in the presence of a Lewis acid (ZnCl2)
(methods b and c, respectively) we obtained 2-aryl-3,4-
dimethyl-6-phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]-
pyridazin-7-ones 4a–4e in 71–82% yields (Scheme 2).
We have studied the behavior of ethyl 1-aryl-4-
acetyl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-
1H-pyrazole-3-carboxylates 2a–2e in the Fischer and
Vilsmeier‒Haack reactions. No such reactions have
been reported previously for 4-acetylpyrazole phenyl-
hydrazones.
Treatment of hydrazones 2a and 2b with the
Vilsmeier–Haack reagent (POCl3/DMF) afforded bi-
pyrazoles 5a and 5b that are promising as building
1
blocks for organic synthesis. In the H NMR spectra
of 5a and 5b, the aldehyde proton resonated at
Scheme 1.
HN
Ph
HN
O
O
O
N
O
EtO
Me
EtO
Me
EtO
i–iii
PhNHNH2, EtOH
N
N
N
Me
Me
Me
N
N
N
C6H4R
1a–1e
C6H4R
2a–2e
C6H4R
3a–3e
i: AcOH, reflux; ii: HCl, THF, reflux; iii: ZnCl2, DMF, 100°C; 1, 2, R = H (a), 4-Cl (b), 3-Cl (c), 2-Cl (d), 4-Br (e).
62

SYNTHESIS AND PROPERTIES OF ETHYL 1-ARYL-5-METHYL-...
63
Scheme 2.
EtO
O
O
CHO
Ph
N
i–iii
POCl3, DMF
N
N
N
2a–2e
RC6H4
N
N
N
RC6H4
N
Me
4a–4e
Ph
Me
Me
5a, 5b
i: AcOH, reflux; ii: HCl, THF, reflux; iii: ZnCl2, DMF, 100°C;
4, R = H (a), 4-Cl (b), 3-Cl (c), 2-Cl (d), 4-Br (e); 5, R = H (a), 4-Cl (b).
δ 9.82 ppm, and the 5-H proton signal appeared at
δ 8.57–8.58 ppm. Pyrazolopyridazines 4a–4e dis-
played in the H NMR spectra signals from methyl
groups on the pyrazole and pyridazine rings at δ 2.53–
2.58 and 2.62–2.68 ppm, respectively.
112.9 (2C), 120.1, 123.7, 126.4, 126.9 (2C), 129.1
(2C), 129.3 (2C), 129.5, 134.6, 137.2, 139.4,
145.0, 162.2. Found, %: C 63.73; H 5.20; N 13.97.
C21H21ClN4O2. Calculated, %: C 63.55; H 5.33;
N 14.12.
1
Ethyl 1-(3-chlorophenyl)-5-methyl-4-[1-(phenyl-
hydrazinylidene)ethyl]-1H-pyrazol-3-carboxylate
(2c). Yield 3.4 g (85%), mp 121°C. 1H NMR spectrum,
δ, ppm: 1.39 t (3H, CH3, J = 7.2 Hz), 2.25 s (3H, CH3),
2.43 s (3H, CH3), 4.41 q (2H, CH2, J = 7.2 Hz), 6.80–
7.65 m (10H, NH, Harom). 13C NMR spectrum, δC, ppm:
11.8, 14.3, 17.1, 61.2, 113.0 (2C), 120.1, 123.7, 126.0,
128.9, 129.2 (2C), 130.1, 134.9, 137.3, 138.8, 139.5,
140.0, 141.6, 145.0, 162.2. Found, %: C 63.69; H 5.43;
N 14.02. C21H21ClN4O2. Calculated, %: C 63.55;
H 5.33; N 14.12.
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
a Varian Gemini spectrometer at 200 and 50 MHz,
respectively, using CDCl3 as solvent and tetramethyl-
silane as internal standard. The elemental analyses
were obtained on a Carlo Erba 1106 analyzer. The
melting points were measured on a Boetius melting
point apparatus.
Compounds 2a–2e (general procedure). Phenylhy-
drazine, 1 mL (10 mmol), was added to a solution of
10 mmol of compound 1a–1e in 20 mL of ethanol, and
the mixture was refluxed for 2 h. After cooling, the
mixture was poured into 50 mL of water, and the
precipitate was filtered off, dried, and recrystallized
from ethanol–DMF.
Ethyl 1-(2-chlorophenyl)-5-methyl-4-[1-(phenyl-
hydrazinylidene)ethyl]-1H-pyrazole-3-carboxylate
1
(2d). Yield 3.2 g (82%), mp 123°C. H NMR spec-
trum, δ, ppm: 1.38 t (3H, CH3, J = 7.2 Hz), 2.27 s (3H,
CH3), 2.29 s (3H, CH3), 4.41 q (2H, CH2, J = 7.2 Hz),
6.85 t (1H, Harom, J = 7.2 Hz), 7.10 d (2H, Harom, J =
7.2 Hz), 7.25 t (2H, Harom, J = 7.2 Hz), 7.30 d (2H,
Ethyl 5-methyl-1-phenyl-4-[1-(phenylhydra-
zinylidene)ethyl]-1H-pyrazole-3-carboxylate (2a).
H
arom, J = 7.2 Hz), 7.37–7.58 m (3H, NH, Harom).
1
Yield 2.6 g (73%), mp 113°C. H NMR spectrum, δ,
Found, %: C 63.32; H 5.41; N 14.27. C21H21ClN4O2.
Calculated, %: C 63.55; H 5.33; N 14.12.
ppm: 1.38 t (3H, CH3, J = 7.1 Hz), 2.27 s (3H, CH3),
2.40 s (3H, CH3), 4.41 q (2H, CH2, J = 7.1 Hz), 6.86 t
(1H, Harom, J = 7.3 Hz), 6.97–7.54 m (10H, NH, Harom).
13C NMR spectrum, δC, ppm: 11.8, 14.3, 17.2, 61.0,
113.0 (2C), 120.0, 123.3, 125.7 (2C), 128.7, 129.09
(2C), 129.13 (2C), 129.3, 137.9, 139.0, 139.5, 145.0,
162.4. Found, %: C 69.41; H 6.27; N 15.24.
C21H22N4O2. Calculated, %: C 69.59; H 6.12; N 15.46.
Ethyl 1-(4-bromophenyl)-5-methyl-4-[1-(phenyl-
hydrazinylidene)ethyl]-1H-pyrazole-3-carboxylate
(2e). Yield 3.3 g (74%), mp 131°C. 1H NMR spectrum,
δ, ppm: 1.39 t (3H, CH3, J = 7.2 Hz), 2.25 s (3H, CH3),
2.41 s (3H, CH3), 4.41 q (2H, CH2, J = 7.2 Hz), 6.78–
7.69 m (10H, NH, Harom). 13C NMR spectrum, δC, ppm:
11.8, 14.3, 17.1, 61.2, 112.7, 113.0 (2C), 120.1, 127.2
(2C), 127.4, 129.2 (2C), 132.3 (2C), 132.5, 137.3,
138.0, 139.4, 145.0, 162.2. Found, %: C 57.03; H 4.69;
N 12.78. C21H21BrN4O2. Calculated, %: C 57.15;
H 4.80; N 12.69.
Ethyl 1-(4-chlorophenyl)-5-methyl-4-[1-(phenyl-
hydrazinylidene)ethyl]-1H-pyrazole-3-carboxylate
(2b). Yield 3.1 g (77%), mp 119°C. 1H NMR spectrum,
δ, ppm: 1.38 t (3H, CH3, J = 7.1 Hz), 2.25 s (3H, CH3),
2.40 s (3H, CH3), 4.41 q (2H, CH2, J = 7.1 Hz), 6.86 t
(1H, Harom, J = 7.0 Hz), 6.96–7.54 m (9H, NH, Harom).
13C NMR spectrum, δC, ppm: 12.1, 14.3, 17.1, 61.1,
Compounds 4a–4e (general procedures). a. A solu-
tion of 2 mmol of compound 2a–2e in 10 mL of acetic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 1 2017

POTOPNYK et al.
64
1
acid was refluxed for 4 h. After cooling, the mixture
was poured into 30 mL of water, and the precipitate
was filtered off, dried, and recrystallized from ethanol–
dimethylformamide.
Yield 0.51 g (72%), mp 201°C. H NMR spectrum, δ,
ppm: 2.53 s (3H, CH3), 2.62 s (3H, CH3), 7.29–7.67 m
(9H, Harom). 13C NMR spectrum, δC, ppm: 11.5, 19.9,
117.0, 126.1 (2C), 127.4, 127.9, 128.7 (2C), 129.5,
130.3, 131.6, 131.7, 136.0, 138.3, 141.3, 141.7,
142.9, 155.7. Found, %: C 64.89; H 4.24; N 15.86.
C19H15ClN4O. Calculated, %: C 65.05; H 4.31;
N 15.97.
b. Concentrated aqueous HCl, 1 mL, was added to
a solution of 0.72 g (2 mmol) of compound 2a in
10 mL of THF. The mixture was refluxed for 3 h,
cooled, poured into 30 mL of water, and neutralized
with 10 mL of a saturated aqueous solution of sodium
hydrogen carbonate. The product was extracted with
methylene chloride (3×40 mL), the extract was dried
over sodium sulfate and concentrated, and the residue
was recrystallized from ethanol–DMF.
2-(4-Bromophenyl)-3,4-dimethyl-6-phenyl-2,6-
dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (4e).
1
Yield 0.60 g (76%), mp 247°C. H NMR spectrum, δ,
ppm: 2.53 s (3H, CH3), 2.62 s (3H, CH3), 7.29–7.67 m
(9H, Harom). 13C NMR spectrum, δC, ppm: 11.5, 19.9,
117.0, 126.1 (2C), 127.4, 127.9, 128.7 (2C), 129.5,
130.3, 131.6, 131.7, 136.0, 138.3, 141.3, 141.7,
142.9, 155.7. Found, %: C 57.51; H 3.93; N 14.02.
C19H15BrN4O. Calculated, %: C 57.74; H 3.83;
N 14.17.
c. A solution of 0.72 g (2 mmol) of compound 2a
and 0.27 g (2 mmol) of ZnCl2 in 5 mL of DMF was
stirred for 5 h at 100°C. The mixture was cooled and
poured into 30 mL of water, and the precipitate was
filtered off and recrystallized from ethanol–DMF.
3,4-Dimethyl-2,6-diphenyl-2,6-dihydro-7H-pyra-
zolo[3,4-d]pyridazin-7-one (4a). Yield 0.51 g (81%,
a), 0.48 g (76%, b), 0.52 g (82%, c); mp 239°C.
1H NMR spectrum, δ, ppm: 2.53 s (3H, CH3), 2.62 s
(3H, CH3), 7.29–7.67 m (10H, Harom). 13C NMR spec-
trum, δC, ppm: 11.5, 19.9, 117.0, 126.1 (2C), 127.4,
127.9, 128.7 (2C), 129.5, 130.3, 131.6, 131.7, 136.0,
138.3, 141.3, 141.7, 142.9, 155.7. Found, %: C 72.35;
H 5.19; N 17.53. C19H16N4O. Calculated, %: C 72.14;
H 5.10; N 17.71.
Compounds 5a and 5b (general procedure).
Phosphoryl chloride, 0.56 mL (6 mmol), was added
dropwise with stirring to 5 mL of dimethylformamide
cooled to 0°C, maintaining the temperature below
10°C. The mixture was stirred for 30 min, a solution of
2 mmol of compound 2a or 2b in 2 mL of DMF was
added, and the mixture was stirred for 1 h at a tem-
perature not exceeding 10°C, heated to 65°C, and
stirred for 2 h at 65°C. The mixture was cooled, poured
onto 30 g of ice, and neutralized with solid potassium
carbonate to pH ~8. The precipitate was filtered off,
washed with water, and recrystallized from ethanol.
2-(4-Chlorophenyl)-3,4-dimethyl-6-phenyl-2,6-
dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (4b).
1
Yield 0.57g (81%), mp 224°C. H NMR spectrum, δ,
Ethyl 4-formyl-5′-methyl-1,1′-diphenyl-1H,1'H-
3,4′-bipyrazole-3′-carboxylate (5a). Yield 0.61 g
ppm: 2.58 s (3H, CH3), 2.66 s (3H, CH3), 7.29–7.54 m
3
4
(7H, Harom), 7.65 d.t (2H, Harom, J = 7.2, J = 1.6 Hz).
13C NMR spectrum, δC, ppm: 12.3, 20.0, 117.7, 125.9
(2C), 127.2 (2C), 127.4, 128.7 (2C), 129.5 (2C), 135.6,
136.6, 136.8, 141.3, 141.6, 142.6, 155.7. Found, %:
C 65.30; H 4.16; N 15.79. C19H15ClN4O. Calculated,
%: C 65.05; H 4.31; N 15.97.
1
(76%). H NMR spectrum, δ, ppm: 1.30 t (3H, CH3,
J = 7.1 Hz), 2.39 s (3H, CH3), 4.34 q (2H, CH2, J =
7.1 Hz), 7.34–7.58 m (8H, Harom), 7.78 d (2H, Harom
,
J = 7.9 Hz), 8.58 s (5-H), 9.82 s (1H, CHO). 13C NMR
spectrum, δC, ppm: 11.5, 14.2, 61.2, 113.3, 119.5 (2C),
124.1, 125.7 (2C), 127.8, 129.0, 129.2 (2C), 129.6
(2C), 136.8, 138.8, 139.0, 141.2, 142.1, 146.9, 162.0,
185.1. Found, %: C 69.14; H 4.87; N 13.78.
C23H20N4O3. Calculated, %: C 68.99; H 5.03; N 13.99.
2-(3-Chlorophenyl)-3,4-dimethyl-6-phenyl-2,6-
dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (4c).
1
Yield 0.50 g (71%), mp 192°C. H NMR spectrum, δ,
ppm: 2.58 s (3H, CH3), 2.68 s (3H, CH3), 7.29–7.69 m
(9H, Harom). 13C NMR spectrum, δC, ppm: 12.3, 20.0,
117.7, 124.1, 125.9 (2C), 126.3, 127.4, 128.7 (2C),
129.7, 130.2, 135.0, 136.7, 139.2, 141.3, 141.6,
142.7, 155.7. Found, %: C 65.26; H 4.21; N 15.90.
C19H15ClN4O. Calculated, %: C 65.05; H 4.31;
N 15.97.
Ethyl 1′-(4-chlorophenyl)-4-formyl-5′-methyl-1-
phenyl-1H,1′H-3,4′-bipyrazole-3′-carboxylate (5b).
Yield 0.73 g (84%). 1H NMR spectrum, δ, ppm: 1.29 t
(3H, CH3, J = 7.2 Hz), 2.39 s (3H, CH3), 4.34 q (2H,
CH2, J = 7.2 Hz), 7.32–7.57 m (7H, Harom), 7.77 d (2H,
Harom, J = 8.0 Hz), 8.57 s (5-H), 9.82 s (1H, CHO).
13C NMR spectrum, δC, ppm: 11.6, 14.1, 61.3, 113.6,
119.5 (2C), 124.1, 126.8 (2C), 127.8, 129.4 (2C),
2-(2-Chlorophenyl)-3,4-dimethyl-6-phenyl-2,6-
dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one (4d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 1 2017

SYNTHESIS AND PROPERTIES OF ETHYL 1-ARYL-5-METHYL-...
65
6. Franco, L.H. and Palermo, J.A., Chem. Pharm. Bull.,
2003, vol. 51, p. 975.
7. Alford, P.E., Fu, L., Kubert, J.K., Wang, L., and
129.6 (2C), 129.9, 134.9, 137.3, 138.9, 141.2, 142.4,
146.5, 161.9, 184.8. Found, %: C 63.33; H 4.65;
N 12.69. C23H19ClN4O3. Calculated, %: C 63.52;
H 4.40; N 12.88.
Gribble, G.W., Tetrahedron Lett., 2011, vol. 52, p. 2642.
8. Bubenyák, M., Pálfi, M., Takács, M., Béni, S.,
Szökő, E., Noszál, B., and Kökösi, J., Tetrahedron Lett.,
2008, vol. 49, p. 4937.
REFERENCES
9. Abdel-Wahab, B.F., Khidre, R.E., and Farahat, A.A.,
Arkivoc, 2011, part (i), p. 196.
10. Matiichuk, V.S., Potopnyk, M.A., and Obushak, N.D.,
Russ. J. Org. Chem., 2008, vol. 44, p. 1352.
1. Robinson, B., Chem. Rev., 1963, vol. 63, p. 373.
2. Robinson, B., Chem. Rev., 1969, vol. 69, p. 227.
3. Ishii, H., Acc. Chem. Res., 1981, vol. 14, p. 275.
4. Robinson, B., The Fischer Indole Synthesis, New York:
11. Matiichuk, V.S., Potopnyk, M.A., and Obushak, N.D.,
Russ. J. Org. Chem., 2009, vol. 45, p. 712.
Wiley, 1982.
5. Bobko, M.A., Evans, K.A., Kaura, A.C., Shuster, L.E.,
12. Matiichuk, V.S., Potopnyk, M.A., and Obushak, N.D.,
and Su, D.-S., Tetrahedron Lett., 2012, vol. 53, p. 200.
Russ. J. Org. Chem., 2010, vol. 46, p. 1550.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 1 2017