Synthesis of pyrazoles and pyrazolones from 1,3- and 1,4-diketones of the adamantane series

Article abstract of DOI:10.1134/S1070428009120124

Various pyrazole and dihydropyrazolones containing an adamantane fragment were synthesized from adamantyl-substituted 1,3- and 1,4-diketones, ethyl 4-(1-adamantyl)-2-R-4-oxobutanoates (R = CN, Ac), and ethyl 2-(1-adamantylcarbonyl)-4-oxo-4-phenylbutanoate

Full text of DOI:10.1134/S1070428009120124

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 12, pp. 1824–1828. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © S.A. Kon’kov, I.K. Moiseev, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 12, pp. 1828–1831.
Synthesis of Pyrazoles and Pyrazolones
from 1,3- and 1,4-Diketones of the Adamantane Series
S. A. Kon’kov and I. K. Moiseev
Samara State Technical University, ul. Molodogvardeiskaya 244, Samara, 443100 Russia
e-mail: ikmoiseev@mail.ru
Received February 11, 2009
Abstract—Various pyrazole and dihydropyrazolones containing an adamantane fragment were synthesized
from adamantyl-substituted 1,3- and 1,4-diketones, ethyl 4-(1-adamantyl)-2-R-4-oxobutanoates (R = CN, Ac),
and ethyl 2-(1-adamantylcarbonyl)-4-oxo-4-phenylbutanoate.
DOI: 10.1134/S1070428009120124
Methods of synthesis and chemical properties of
1,2-diazoles and their derivatives have been well docu-
mented [1–5]. Compounds of this series attract interest
as pyrazolone dyes and drugs. Examples of the latter
are Phenazone, Aminophenazone, and Metamizole
sodium. However, there are only a few publications on
the synthesis of 1,2-diazoles and pyrazolones having
an adamantane fragment. N-Phenyl-3-adamantyl- and
N-phenyl-3-adamantylmethylpyrazolones were synthe-
sized for the first time from the corresponding oxo
esters [6, 7]. Later on, reactions of dioxo esters with
hydrazine and phenylhydrazine were reported [8, 9]. It
was found that, depending on the initial ester structure,
either adamantanecarboxylic acid hydrazide or
3-(1-adamantylmethyl)-4,5-dihydro-1H-pyrazol-5-one
and 3-(1-adamantylmethyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-5-one were formed. The reaction of ethyl
3-(1-adamantyl)-2-(1-adamantylcarbonyl)-3-oxopro-
panoate with hydrazine gave ethyl 3,5-bis(1-ada-
mantyl)-1H-pyrazole-4-carboxylate [8].
butanoate. Known procedures for the preparation of
1,3-diketones are based on the Claisen condensation,
i.e., acylation of ketones with esters in the presence of
strong bases such as metallic sodium, sodium hydride,
sodium amide, and others [10], reaction of ketones
with carboxylic acid anhydrides in the presence of
boron trifluoride–ether complex [11, 12], acylation of
ketones (preliminarily treated with lithium diisopropyl-
amide and chlorotrimethylsilane) with carboxylic acid
chlorides in the presence of Lewis acids (TiCl4, SnCl4,
ZnCl2) [13], and acylation of ketones with carboxylic
acid anhydrides in the presence of ZnCl2 and SiCl4
[14]. We synthesized adamantyl-substituted 1,3-di-
ketones I and II by reaction of 1-adamantyl methyl
ketone with carboxylic acid anhydrides catalyzed by
boron trifluoride–ether complex (Scheme 1). However,
we failed to obtain the corresponding 1,3-diketone
from adamantane-1-carboxylic anhydride under analo-
gous conditions. We also tried to perform acylation of
1-adamantyl methyl ketone with carboxylic acid anhy-
drides in the presence of ZnCl2 and SiCl4 in boiling
methylene chloride, but the yields were lower than in
the reactions catalyzed by BF3·Et2O.
In this paper we describe the synthesis of hetero-
cyclic compounds on the basis of 1,3- and 1,4-di-
ketones of the adamantane series, as well as from ethyl
4-(1-adamantyl)-2-R-4-oxobutanoates [R = CN, Ac]
and ethyl 2-(1-adamantylcarbonyl)-4-oxo-4-phenyl-
Ethyl 4-(1-adamantyl)-2-R-4-oxobutanoates III and
IV (R= CN, Ac) were obtained by reactions of (1-ada-
Scheme 1.
O
O
BF3 ·Et2O
Me
R
+
R
O
R
O
O
O
I, II
I, R = Me; II, R = Et.
1824

SYNTHESIS OF PYRAZOLES AND PYRAZOLONES
1825
Scheme 2.
O
O
Na
Na+
R
R
OEt
OEt
RCHNaCOOEt
O
CH2Br
OEt
O
O
R
III, IV
O
O
Ph
O
Na+
+
OEt
OEt
Ph
CH2Br
O
O
O
V
III, R = CN; IV, R = MeCO.
adamantyl) bromomethyl ketone with ethyl cyano-
acetate and ethyl acetoacetate, respectively, and ethyl
2-(1-adamantylcarbonyl)-4-oxo-4-phenylbutanoate (V)
was synthesized from ethyl 3-(1-adamantyl)-3-oxopro-
panoate and bromoacetophenone (Scheme 2).
dihydro-1H-pyrazol-5-ones XIV and XV, respectively
(Scheme 4).
Presumably, the observed difference in the chem-
ical behaviors of compounds III and IV is related to
stronger electron-withdrawing effect of the cyano
group in III as compared to the acetyl group in IV.
With a view to synthesize heterocyclic compounds,
diketones I–IV were brought into reactions with di-
functional nucleophiles, such as hydrazine, phenyl-
hydrazine, semicarbazide, and thiosemicarbazide.
From diketones I and II we obtained the corresponding
pyrazoles VI–XIII (Scheme 3), while compound III
was converted into carboxylic acid hydrazides. Com-
pound IV reacted with hydrazine and phenylhydrazine
to give 4-[2-(1-adamantyl)-2-oxoethyl]-3-methyl-4,5-
EXPERIMENTAL
The IR spectra were measured in KBr on
a Shimadzu FTIR-8400S spectrometer. The 1H NMR
spectra were recorded on a Bruker AM-300 instrument
at 300 MHz using DMSO-d6 as solvent and tetra-
methylsilane as internal reference. The purity of the
Scheme 3.
R1
R2
R2NHNH2
R1
N
N
O
O
I, II
VI–XIII
VI–IX, R1 = Me; X–XIII, R1 = Et; VI, X, R2 = H; VII, XI, R2 = Ph; VIII, XII, R2 = C(O)NH2; IX, XIII, R2 = C(S)NH2.
Scheme 4.
Me
O
RNHNH2
N
OEt
O
N
O
O
O
Me
R
IV
XIV, XV
XIV, R = H; XV, R = Ph.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

KON’KOV, MOISEEV
1826
isolated compounds was checked by TLC (using
Silufol plates) and GLC.
(25 mmol) of ethyl acetoacetate and 6.40 g (25 mmol)
of 1-adamantyl bromomethyl ketone. Yield 2.40 g
(31%), colorless crystals, mp 45–46°C (from ethanol).
IR spectrum, ν, cm–1: 2905, 2848 (C−HAd); 1735
1-(1-Adamantyl)butane-1,3-dione (I). Boron tri-
fluoride–ether complex, 10 ml, was quickly added to
a mixture of 10 g (56 mmol) of 1-adamantyl methyl
ketone and 11.42 g (112 mmol) of acetic anhydride.
The mixture was heated for 8.5 h under reflux and was
then kept for 1 h in a refrigerator. The precipitate was
filtered off, washed with water, dried, and recrystal-
lized from ethanol. Yield 9.64 g (78%), yellow crys-
tals, mp 55–57°C; published data [13]: mp 53–56°C.
IR spectrum, ν, cm–1: 2912, 2852 (C−HAd); 1646
1
(C=O, ester); 1679, 1697 (C=O, ketone). H NMR
spectrum, δ, ppm: 1.15 t (3H, CH3), 1.21 t (3H, CH3),
1.68 s (5H, Ad), 1.77 m (6H, Ad), 2.00 s (4H, Ad),
3.00 s (1H, CH), 3.96 q (2H, CH2), 4.10 q (2H, CH2).
Found, %: C 70.07; H 8.88. C18H28O4. Calculated, %:
C 70.13; H 9.09.
Ethyl 2-(1-adamantylcarbonyl)-4-oxo-4-phenyl-
butanoate (V) was synthesized in a similar way from
6 g (24 mmol) of ethyl 3-(1-adamantyl)-3-oxopropan-
oate and 4.80 g (24 mmol) of bromacetophenone.
Yield 5.30 g (60%), colorless crystals, mp 88–92°C
(from ethanol). IR spectrum, ν, cm–1: 2935, 2850
(C−HAd); 1758 (C=O, ester); 1713, 1685 (C=O,
1
(C=O). H NMR spectrum, δ, ppm: 1.42 m (6H, Ad),
1.75 s (6H, Ad), 1.92 s (3H, Ad), 2.02 s (3H, CH3),
5.45 s (1H, CH=C), 15.45 br.s (1H, OH, enol). Found,
%: C 76.26; H 9.06. C14H20O2. Calculated, %: C 76.36;
H 9.09.
1-(1-Adamantyl)pentane-1,3-dione (II) was syn-
thesized in a similar way from 10 g (56 mmol) of
1-adamantyl methyl ketone and 17.92 g (112 mmol) of
propionic anhydride. Yield 8.02 g (61%), colorless
crystals, mp 104–106°C (from ethanol). IR spectrum,
1
ketone). H NMR spectrum, δ, ppm: 1.18 t (3H, CH3),
1.62 s (5H, Ad), 1.79 m (6H, Ad), 2.10 s (4H, Ad),
3.09 s (1H, CH), 3.94 q (2H, CH2), 4.18 q (2H, CH2),
7.37 m (1H, C6H5), 7.49 m (2H, C6H5), 7.55 m (2H,
C6H5). Found, %: C 77.89; H 8.58. C22H28O3. Calculat-
ed, %: C 77.65; H 8.24.
1
ν, cm–1: 2908, 2854 (C−HAd); 1646 (C=O). H NMR
spectrum, δ, ppm: 1.21 t (3H, CH3), 1.62 s (6H, Ad),
1.78 s (7H, Ad), 1.99 s (2H, Ad), 2.63 q (2H, CH2),
6.38 s (2H, CH2). Found, %: C 77.09; H 9.67.
C15H22O2. Calculated, %: C 76.92; H 9.40.
3-(1-Adamantyl)-5-methyl-1H-pyrazole (VI).
Hydrazine, 0.23 g (4 mmol), was added dropwise on
cooling to a solution of 0.5 g (4 mmol) of diketone I in
8–10 ml of ethanol. The mixture was heated for 3 h
under reflux and cooled, and the precipitate was
filtered off and recrystallized from ethanol. Yield
0.62 g (63%), colorless crystals, mp 193–195.5°C. IR
spectrum, ν, cm–1: 3163 (N−H); 2905, 2849 (C−HAd);
Ethyl 4-(1-adamantyl)-2-cyano-4-oxobutanoate
(III). A three-necked round-bottom flask equipped
with a stirrer (with a glycerol seal), dropping funnel,
and reflux condenser capped with a drying tube was
charged with 1.58 g (14 mmol) of ethyl cyanoacetate
and 0.32 g (14 mmol) of metallic sodium in 40 ml of
anhydrous diethyl ether. The mixture was stirred for
24 h at room temperature, 3.60 g (14 mmol) of 1-ada-
mantyl bromomethyl ketone was added over a period
of 2 h, and the mixture was heated for 2 h under reflux,
cooled, poured into water, and acidified with 2% sul-
furic acid (according to Congo Red). The organic layer
was separated and dried over sodium sulfate. The sol-
vent was distilled off, and the residue was recrystal-
lized from ethanol. Yield 2.58 g (55%), colorless crys-
tals, mp 108–110°C. IR spectrum, ν, cm–1: 2904, 2849
(C−HAd); 2251 (C≡N); 1744 (C=O, ester); 1697 (C=O,
1
1569 (C=N). H NMR spectrum, δ, ppm: 1.85 s (6H,
Ad), 2.02 s (3H, Ad), 2.10 s (6H, Ad), 2.16 t (3H,
CH3), 5.75 s (1H, CH), 11.90 br.s (1H, NH). Found, %:
C 77.77; H 9.06; N 12.80. C14H20N2. Calculated, %:
C 77.78; H 9.26; N 12.96.
Compounds VII–XV were synthesized in a simi-
lar way.
3-(1-Adamantyl)-5-methyl-1-phenyl-1H-pyra-
zole (VII) was obtained from 0.5 g (2.3 mmol) of com-
pound I and 0.25 g (2.3 mmol) of phenylhydrazine.
Yield 0.5 g (76%), yellow crystals, mp 73–76°C (from
ethanol). IR spectrum, ν, cm–1: 2903, 2847 (C−HAd);
1
ketone). H NMR spectrum, δ, ppm: 1.20 t (3H, CH3),
1
1.63 s (6H, Ad), 1.72 m (6H, Ad), 2.00 s (3H, Ad),
3.31 s (1H, CH), 4.20 q (2H, CH2), 4.33 q (2H, CH2).
Found, %: C 70.35; H 7.68; N 4.57. C17H23NO3. Cal-
culated, %: C 70.59; H 7.96; N 4.84.
1569 (C=N); 779, 767, 700 (δC−Harom). H NMR spec-
trum, δ, ppm: 1.76 s (6H, Ad), 1.85 s (3H, Ad), 2.12 s
(6H, Ad), 2.18 t (3H, CH3), 6.01 s (1H, CH), 7.31 m
(1H, C6H5), 7.48 m (2H, C6H5), 7.51 m (2H, C6H5).
Found, %: C 83.08; H 6.67; N 8.23. C20H20N2. Calcu-
lated, %: C 83.33; H 6.94; N 8.33.
Ethyl 2-acetyl-4-(1-adamantyl)-4-oxobutanoate
(IV) was synthesized in a similar way from 3.25 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

SYNTHESIS OF PYRAZOLES AND PYRAZOLONES
1827
3-(1-Adamantyl)-5-methyl-1H-pyrazole-1-car-
boxamide (VIII) was obtained from 0.5 g (2.3 mol) of
compound I and 0.25 g (2.3 mol) of semicarbazide
hydrochloride. Yield 0.24 g (40%), colorless crystals,
mp 180–182°C (from propan-2-ol). IR spectrum, ν,
cm–1: 3214 (N−H); 2908, 2847 (C−HAd); 1686 (C=O);
1H NMR spectrum, δ, ppm: 1.11 t (3H, CH3), 1.65 s
(6H, Ad), 1.78 s (7H, Ad), 1.93 s (2H, Ad), 2.63 q (2H,
CH2), 5.71 s (1H, CH), 11.95 br.s (2H, NH2). Found,
%: C 70.56; H 8.65; N 15.40. C16H23N3O. Calculated,
%: C 70.33; H 8.42; N 15.38.
3-(1-Adamantyl)-5-ethyl-1H-pyrazole-1-carbo-
thioamide (XIII) was obtained from 0.5 g (2.1 mmol)
of compound II and 0.36 g (4 mmol) of thiosemicar-
bazide. Yield 0.39 g (64%), colorless crystals, mp 184–
186°C (from ethanol). IR spectrum, ν, cm–1: 3159,
3082 (N−H); 2905, 2847 (C−HAd); 1693 (S=CNH2);
1
1662 (C=N). H NMR spectrum, δ, ppm: 1.66 s (6H,
Ad), 1.78 s (7H, Ad), 1.94 s (2H, Ad), 2.11 s (3H,
CH3), 5.80 s (1H, CH), 7.49 s (2H, NH2). Found, %:
C 74.22; H 8.67; N 17.29. C15H21N3. Calculated, %:
C 74.07; H 8.64; N 17.28.
1
3-(1-Adamantyl)-5-methyl-1H-pyrazole-1-carbo-
thioamide (IX) was obtained from 0.5 g (2.3 mmol) of
compound I and 0.41 g (4.5 mmol) of thiosemicar-
bazide. Yield 0.39 g (62%), colorless crystals, mp 148–
151°C (from ethanol). IR spectrum, ν, cm–1: 3244
(N−H); 2905, 2851 (C−HAd); 1693 (S=CNH2); 1601
1601 (C=N). H NMR spectrum, δ, ppm: 1.26 t (3H,
CH3), 1.32 t (3H, CH3), 1.56 s (6H, Ad), 1.89 s (7H,
Ad), 2.00 s (2H, Ad), 2.79 q (2H, CH2), 5.85 d (2H,
NH2), 7.78 s (1H, CH). Found, %: C 66.40; H 7.91;
N 14.30. C16H23N3S. Calculated, %: C 66.44; H 7.96;
N 14.53.
1
(C=N). H NMR spectrum, δ, ppm: 1.69 s (6H, Ad),
4-(1-Adamantylcarbonyl)-3-methyl-4,5-dihydro-
1H-pyrazol-5-one (XIV) was synthesized from 0.5 g
(1.6 mmol) of ester IV and 0.08 g (1.6 mmol) of
hydrazine. Yield 0.23 g (40%), colorless crystals,
mp 244–247°C (from propan-2-ol). IR spectrum, ν,
cm–1: 3348 (N−H); 2901, 2847 (C−HAd); 1605 (C5=O).
1H NMR spectrum, δ, ppm: 1.10 s (3H, CH3), 1.57 s
(5H, Ad), 1.95 m (5H, Ad), 2.09 s (5H, Ad), 4.12 q
(2H, CH2), 6.02 s (1H, CH), 11.78 br.s (1H, NH).
Found, %: C 70.12; H 8.20; N 10.23. C16H22N2O2. Cal-
culated, %: C 70.07; H 8.03; N 10.22.
1.87 s (7H, Ad), 1.99 s (2H, Ad), 2.10 s (3H, CH3),
5.85 s (1H, CH), 7.78 s (2H, NH2). Found, %: C 65.67;
H 7.98; N 15.34. C15H21N3S. Calculated, %: C 65.45;
H 7.64; N 15.27.
3-(1-Adamantyl)-5-ethyl-1H-pyrazole (X) was
obtained from 0.5 g (2.1 mmol) of diketone II and
0.21 g (4.2 mmol) of hydrazine. Yield 0.31 g (63%),
colorless crystals, mp 174–178°C (from ethanol). IR
spectrum, ν, cm–1: 3159 (N−H); 2905, 2847 (C−HAd);
1
1562 (C=N); 1450 (C=C). H NMR spectrum, δ, ppm:
1.10 t (3H, CH3), 1.60 s (6H, Ad), 1.78 s (7H, Ad),
1.92 s (2H, Ad), 2.45 q (2H, CH2), 5.71 s (1H, CH),
11.94 br.s (1H, NH). Found, %: C 78.46; H 9.78;
N 12.39. C15H22N2. Calculated, %: C 78.26; H 9.57;
N 12.17.
4-[2-(1-Adamantyl)-2-oxoethyl]-3-methyl-1-
phenyl-4,5-dihydro-1H-pyrazol-5-one (XV) was
obtained from 0.5 g (1.6 mmol) of compound IV and
0.18 g (1.6 mmol) of phenylhydrazine. Yield 0.30 g
(60%), colorless crystals, mp 183–185°C (from
propan-2-ol). IR spectrum, ν, cm–1: 2908, 2851
(C−HAd); 1670 (C=O, ketone); 1605 (C5=O); 775, 756,
3-(1-Adamantyl)-5-ethyl-1-phenyl-1H-pyrazole
(XI) was obtained from 0.5 g (2.1 mmol) of compound
II and 0.23 g (2.1 mmol) of phenylhydrazine. Yield
0.31 g (48%), colorless crystals, mp 113–115°C (from
ethanol). IR spectrum, ν, cm–1: 2900, 2851 (C−HAd);
1
694 (δC−Harom). H NMR spectrum, δ, ppm: 1.19 s
(3H, CH3), 1.58 s (5H, Ad), 1.92 m (5H, Ad), 2.06 s
(5H, Ad), 4.09 q (2H, CH2), 6.02 s (1H, CH), 6.89 m
(1H, C6H5), 7.00 m (2H, C6H5), 7.12 m (2H, C6H5).
Found, %: C 75.45; H 7.49; N 8.10. C22H26N2O2. Cal-
culated, %: C 75.43; H 7.43; N 8.00.
1
1597 (C=N); 798, 764, 694 (δC−Harom). H NMR spec-
trum, δ, ppm: 1.11 t (3H, CH3), 1.53 q (2H, CH2),
1.69 s (12H, Ad), 1.79 s (3H, Ad), 5.98 s (1H, CH),
7.26 m (1H, C6H5), 7.30 m (2H, C6H5), 7.44 m (2H,
C6H5). Found, %: C 82.12; H 8.35; N 9.04. C21H26N2.
Calculated, %: C 82.35; H 8.50; N 9.15.
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mp 170–173°C (from ethanol). IR spectrum, ν, cm–1:
2901, 2847 (C−HAd); 1686 (C=O); 1662 (C=N).
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