Synthesis of new pyrazole and triazole derivatives containing a saturated γ-lactone ring

Full text of DOI:10.1134/S1070428011060236

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 6, pp. 954–957. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © G.G. Tokmadzhyan, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 6, pp. 935–938.
SHORT
COMMUNICATIONS
Synthesis of New Pyrazole and Triazole Derivatives
Containing a Saturated γ-Lactone Ring
G. G. Tokmadzhyan
Erevan State University, ul. Aleka Manukyana 1, Erevan, 375025 Armenia
e-mail: tokmajyang@yahoo.com
Received August 9, 2010
DOI: 10.1134/S1070428011060236
Pyrazole ring is a structural fragment of molecules
of many medicines, including such common drugs as
phenazone and aminophenazone [1]. Some pyrazoles,
e.g., tartrazine (yellow dye), are also used in food
industry [2]. Triazole derivatives also exhibit a broad
spectrum of biological activity [3]. Therefore, synthe-
sis of compounds whose molecules contain both γ-lac-
tone and pyrazole or triazole rings attracts some
interest, for such compounds are expected to possess
important properties.
intermediate formation of the corresponding hydrazone
which underwent intramolecular cyclization to substi-
tuted pyrazole III (Scheme 2). Pyrazolone IV was
synthesized by reaction of hydrazide II with ethyl
acetoacetate (Scheme 3).
It is known that intermediate products formed by
cyanoacetylation of hydrazines with ethyl cyanoacetate
and its α-alkyl and α,α-dialkyl derivatives undergo
isomerization into aminopyrazolones on heating or in
the presence of base catalyst [5]. The product isolated
in the reaction of hydrazide II with ethyl cyanoacetate
was identified as aminopyrazolone V (Scheme 4) on
the basis of the IR and 1H NMR data.
5,5-Dimethyl-2-oxotetrahydrofuran-4-ylacetohy-
drazide (II) was selected as starting compound; it was
synthesized from the corresponding acid [4] through
ester I according to Scheme 1. Pyrazole derivatives
were prepared using acetylacetone and ethyl acetoace-
tate as 1,3-dicarbonyl compounds. Presumably, the
reaction of hydrazide II with acetylacetone involved
Taking into account published data on reactions of
carboxylic acid hydrazides with triethyl orthoformate
[6], an attempt was made to perform an analogous
reaction with hydrazide II. The reaction smoothly af-
Scheme 1.
COOH
COOEt
CONHNH2
EtOH, H+
N2H4 ·H2O
Me
Me
Me
Me
Me
Me
II
O
O
O
O
O
O
I
Scheme 2.
O
OH
Me
Me
O
O
HN
Me
N
II +
N
N
Me
–H2O
Me
Me
Me
Me
O
O
O
O
O
Me
Me
O
O
Me
Ac
Me
O
Ac
O
Me
Me
HN
Me
N
N
N
Me
O
III
954

SYNTHESIS OF NEW PYRAZOLE AND TRIAZOLE DERIVATIVES
955
Scheme 3.
O
O
OH
O
O
O
HN
N
N
II +
N
Me
Me
–EtOH
Me
OEt
H
H
Me
Me
O
O
O
O
Me
Me
O
O
Ac
O
O
–H2O
O
Me
N
N
Me
H
IV
Scheme 4.
HN
O
O
O
O
N
O
HN
Me
II +
NC
N
N
–EtOH
O
OEt
H
H
CN
Me
O
O
O
Me
Me
H2N
O
N
O
N
O
H
Me
O
Me
V
dure described in [7, 8]. 1,2,4-Triazoles VIIa–VIIc
were thus obtained (Scheme 6).
Ethyl 2-(2,2-dimethyl-5-oxotetrahydrofuran-
3-yl)acetate (I). A mixture of 40 g (0.22 mol) of
5,5-dimethyltetrahydro-2-oxofuran-4-ylacetic acid,
forded oxadiazole VI in a high yield (92%; Scheme 5).
With a view to synthesize triazole derivatives contain-
ing a γ-lactone ring, hydrazide II was brought into
reaction with carboxylic acid amides at 180–200°C
under solvent-free conditions according to the proce-
Scheme 5.
O
OH
OEt
OEt
HN
Me
N
II + HC(OEt)3
N
N
Me
–2EtOH
O
O
O
O
Me
Me
N
O
N
O
Me
Me
VI
O
–EtOH
Scheme 6.
O
R
H
N
O
O
N
R
NH2
HN
N
II +
N
Me
Me
VIIa–VIIc
O
Me
R
NH2
O
O
Me
R = H (a), Me (b), Ph (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

TOKMADZHYAN
956
80 ml of ethanol, and 2.6 ml of concentrated sulfuric
acid was heated for 6 h under reflux (on a water bath).
Ethanol was distilled off, 50 ml of water was added to
the residue, and the mixture was extracted with diethyl
ether. The extract was dried over magnesium sulfate
and evaporated, and the residue was distilled under
reduced pressure. Yield 33 g (75%), bp 145°C (3 mm),
mp 39–40°C, Rf 0.90 (acetone–hexane, 5:1). IR spec-
1H NMR spectrum, δ, ppm: 1.30 s and 1.50 s (3H each,
2′-CH3), 2.10 s (1H, 4-H), 2.40 s (3H, Ac), 2.45–
2.80 m (5H, 3′-H, 4′-H, 3′-CH2), 5.80–5.95 br.s (1H,
NH). Found, %: C 57.15; H 6.95; N 11.35. C12H17N2O4.
Calculated, %: C 56.92; H 6.72; N 11.11.
5-Amino-1-[2-(2,2-dimethyl-5-oxotetrahydro-
furan-3-yl)-2-oxoethyl]-2,5-dihydro-1H-pyrazol-3-
one (V). A mixture of 1 g (5.3 mmol) of hydrazide II
and 0.6 g (5.3 mmol) of ethyl cyanoacetate was heated
for 10 h at 120–130°C. After cooling, the precipitate
was filtered off and recrystallized. Yield 0.47 g (35%),
mp 154°C (from ethanol), Rf 0.46 (acetone–benzene,
3:1). IR spectrum, ν, cm–1: 3340, 3280 (NH, NH2);
1775 (C=O, lactone); 1660 (C=O, amide); 1640
1
trum: ν 1770 cm–1 (C=O, ester). H NMR spectrum, δ,
ppm: 1.00–1.40 m (9H, CH3, CH2CH3), 2.00–2.80 m
(5H), 4.10 q (2H, OCH2). Found, %: C 60.25; H 7.80.
C10H15O4. Calculated, %: C 60.30; H 7.54.
2-(2,2-Dimethyl-5-oxotetrahydrofuran-3-yl)-
acetohydrazide (II). A solution of 10 g (0.05 mol) of
ester I in 15 ml of ethanol was heated to the boiling
point, 2.95 g (0.05 mol) of 85% hydrazine hydrate in
5 ml of ethanol was slowly added dropwise, and the
mixture was heated for 2 h more under reflux. After
cooling, the precipitate was filtered off and recrystal-
lized. Yield 9 g (96%), mp 130–131°C (from ethanol),
Rf 0.85 (acetone–hexane, 5:1). IR spectrum, ν, cm–1:
3360, 3220 (NH); 1770 (C=O, lactone); 1680 (C=O,
1
(C=C). H NMR spectrum, δ, ppm: 1.25 s and 1.40 s
(3H each, 2′-CH3), 2.10–2.65 m (5H, 3′-H, 4′-H,
3′-CH2), 4.10–4.50 br.s (1H, 4-H). Found, %: C 52.36;
H 6.00; N 17.03. C11H15N3O4. Calculated, %: C 52.17;
H 5.93; N 16.60.
5,5-Dimethyl-4-(1,3,4-oxadiazol-2-ylmethyl)-
tetrahydrofuran-2-one (VI). A mixture of 0.93 g
(5 mmol) of hydrazide II and 2.25 g (0.02 mol) of
triethyl orthoformate was heated for 6 h on a boiling
water bath. After cooling, the precipitate was filtered
off and recrystallized. Yield 0.9 g (92%), mp 128°C
(from ethanol), Rf 0.60 (acetone–benzene, 3:1). IR
spectrum, ν, cm–1: 1770 (C=O, lactone); 1650, 1630
1
amide). H NMR spectrum, δ, ppm: 1.27 s and 1.42 s
(3H each, CH3), 1.90 d (2H, CH2, J = 4.5 Hz), 1.95 d
(2H, CH2, J = 4.5 Hz), 2.50 m (1H), 2.65 br.s (3H).
Found, %: C 51.50; H 7.40; N 14.78. C8H13N3O3. Cal-
culated, %: C 51.90; H 7.03; N 15.14.
1
4-(4-Acetyl-3-methyl-1H-pyrazol-5-ylmethyl)-
5,5-dimethyltetrahydrofuran-2-one (III). A mixture
of 0.93 g (5 mmol) of hydrazide II and 1.5 g
(15 mmol) of acetylacetone was heated for 10 h at
100°C. After cooling, the precipitate was filtered off
and recrystallized. Yield 0.9 g (75%), mp 108°C (from
ethanol), Rf 0.76 (acetone–benzene, 3:1). IR spectrum,
ν, cm–1: 3200 (NH), 1775 (C=O, lactone), 1730 (C=O,
ketone), 1600 (C=N). 1H NMR spectrum, δ, ppm: 1.60 s
and 1.70 s (3H each, 5-CH3), 2.50 s (3H, NCH3),
2.90 s (3H, Ac), 3.00–3.60 m (5H, 3-H, 4-H, 4-CH2),
6.20 s (1H, NH). Found, %: C 62.67; H 7.43; N 11.70.
C13H18N2O3. Calculated, %: C 62.40; H 7.20; N 11.20.
(C=N). H NMR spectrum, δ, ppm: 1.30 s and 1.50 s
(3H each, 5-CH3), 2.50–2.75 m (5H, 3-H, 4-H, 4-CH2),
4.10 br.s (1H, 5′-H). Found, %: C 55,29; H 6,37;
N 14.70. C9H12N2O3. Calculated, %: C 55.10; H 6.12;
N 14.28.
Substituted 1,2,4-triazoles VIIa–VIIc (general
procedure). A mixture of 1 g (5.3 mmol) of hydrazide
II and 5.3 mmol of formamide, acetamide, or benz-
amide was heated for 4–5 h at 180–200°C. The crys-
talline material was purified by recrystallization.
5,5-Dimethyl-4-(1H-1,2,4-triazol-5-ylmethyl)-
tetrahydrofuran-2-one (VIIa). Yield 0.6 g (63%),
mp 130°C (from ethanol), Rf 0.50 (acetone–benzene,
3:1). IR spectrum, ν, cm–1: 3240 (NH), 1775 (C=O,
4-Acetyl-3-(2,2-dimethyl-5-oxotetrahydrofuran-
3-ylmethyl)-4,5-dihydro-1H-pyrazol-5-one (IV).
A mixture of 0.5 g (2.6 mmol) of hydrazide II and
0.4 g (3 mmol) of ethyl acetoacetate was heated for 6 h
at 120–130°C. After cooling, the precipitate was fil-
tered off and recrystallized. Yield 0.45 g (75%),
mp 110°C (from ethanol), Rf 0.63 (acetone–benzene,
3:1). IR spectrum, ν, cm–1: 3240 (NH), 1770 (C=O,
lactone), 1710 (C=O, ketone), 1620 (C=O, amide).
1
lactone), 1615 (C=N). H NMR spectrum, δ, ppm:
1.15 s and 1.25 s (3H each, 5-CH3), 2.10–2.60 m (5H,
3-H, 4-H, 4-CH2), 3.60 s (1H, 3′-H). Found, %:
C 55.58; H 6.60; N 21.30. C9H13N3O2. Calculated, %:
C 55.38; H 6.67; N 21.54.
5,5-Dimethyl-4-(3-methyl-1H-1,2,4-triazol-5-
ylmethyl)tetrahydrofuran-2-one (VIIb). Yield 0.8 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

SYNTHESIS OF NEW PYRAZOLE AND TRIAZOLE DERIVATIVES
957
(72%), mp 160°C (from ethanol), Rf 0.25 (acetone–
benzene, 3:1). IR spectrum, ν, cm–1: 3230 (NH), 1770
(C=O, lactone), 1610 (C=N). H NMR spectrum, δ,
isolated compounds was checked by TLC on Silufol
UV-254 plates; spots were visualized by treatment with
iodine vapor and by UV irradiation.
1
ppm: 1.30 s and 1.50 s (3H each, 5-CH3), 2.00 s (3H,
3′-CH3), 2.30–2.75 m (5H, 3-H, 4-H, 4-CH2). Found,
%: C 58.00; H 7.35; N 21.00. C10H15N3O2. Calculated,
%: C 57.42; H 7.18; N 20.09.
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benzene, 3:1). IR spectrum, ν, cm–1: 3200, 3070
(C–Harom); 1770 (C=O, lactone); 1615 (C=N); 1590
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(C=Carom). H NMR spectrum, δ, ppm: 1.20 s and
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N 15.76. C15H17N3O2. Calculated, %: C 66.42; H 6.27;
N 15.50.
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