Reaction of 3-[(alkylsulfanyl)methyl]pentane-2,4-diones with nicotinic hydrazide

Article abstract of DOI:10.1007/s10593-020-02698-1

The reaction of 3-[(alkylsulfanyl)methyl]pentane-2,4-diones with nicotinic hydrazide in ethanol as solvent produces 4-[(alkylsulfanyl)- methyl]-substituted 1-(pyridin-3-yl)carbonyl-1H-pyrazoles, whereas 1-acyl-1H-pyrazoles are formed in acetic, propanoic,

Full text of DOI:10.1007/s10593-020-02698-1

DOI 10.1007/s10593-020-02698-1
Chemistry of Heterocyclic Compounds 2020, 56(5), 548–554
Reaction of 3-[(alkylsulfanyl)methyl]pentane-2,4-diones
with nicotinic hydrazide
Larisa A. Baeva1*, Radik M. Nugumanov1,
Rail R. Gataullin1, Akhnef А. Fatykhov1
1 Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences,
69 Oktyabrya Ave., Ufa 450054, Russia; е-mail:sulfur@anrb.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(5), 548–554
Submitted December 5, 2019
Accepted after revision March 16, 2020
The reaction of 3-[(alkylsulfanyl)methyl]pentane-2,4-diones with nicotinic hydrazide in ethanol as solvent produces 4-[(alkylsulfanyl)-
methyl]-substituted 1-(pyridin-3-yl)carbonyl-1H-pyrazoles, whereas 1-acyl-1H-pyrazoles are formed in acetic, propanoic, or pentanoic
acid solution. The reaction in methanol in the presence of ZnCl2 is accompanied by elimination of nicotinic acid and the formation of
(alkylsulfanyl)methyl-substituted 1H-pyrazoles.
Keywords: 1-acyl-1H-pyrazole, 3-[(alkylsulfanyl)methyl]pentane-2,4-dione, nicotinic hydrazide, 1-(pyridin-3-yl)carbonyl-1H-pyrazole,
heterocyclization.
Derivatives of (pyridin-3(4)-yl)carbonyl-1H-pyrazoles1
and acyl-1H-pyrazoles,1a,b,2 together with their hydro-
genated analogs pyrazolines, exhibit a wide spectrum of
biological activity, including antitumor,1a–c,2a–d anti-inflam-
matory,2d,e antimalarial,1d antibacterial,1e,2d,f,g analgesic,1f,2d
and neuropsychotropic.1g–i,2h–j Among 4(2)-[alkyl(aryl)-
sulfanyl(sulfonyl)methyl]-1H-pyrazoles, compounds possess-
ing fungicidal3 activity, properties of progesterone receptor
antagonists,4 N-myristoyltransferase inhibitors,5 and also
selective extractants and ligands in the preparation of sulfur-
containing Pt(II) and Pd(II) complexes6 were found. The
variety of useful properties of 1H-pyrazoles with alkyl-
(aryl)sulfanyl(sulfonyl)methyl, (pyridin-3(4)-yl)carbonyl,
or acyl moieties maintains the interest in developing
convenient methods for the preparation of new molecules
combining such structural units.
halogen derivatives of 1H-pyrazoles with an alkyl(aryl)-
sulfanyl group.4–6c Cyclization of alkenyl ketones with the
corresponding hydrazides1d,e,2e or hydrazine hydrate in the
presence of AcOH2b,c,f,h,i is used for the synthesis of
hydrogenated derivatives of 1-(pyridin-3(4)-yl)carbonyl-
1H-pyrazoles and 1 acyl-1H-pyrazoles. 1-(Pyridin-3(4)-yl)-
carbonyl-1H-pyrazoles and 1-acyl-1H-pyrazoles are
prepared via the reaction of 1,3-dicarbonyl compounds
with hydrazides;1a,f reactions of 1H-pyrazoles with acyl-
(nicotinoyl) chlorides2a,g,7a–c as well as acids in the presence
7a,d
of SOCl2 are most often used, however. An example of
multistep synthesis of 4-phenylsulfanyl-1-(pyridin-3-yl)-
carbonyl-1H-pyrazoles, agonists of G-protein-coupled
GPR109A receptors, via the reaction of nicotinoyl
chlorides with 4-phenylsulfanyl-1H-pyrazoles, which, in
turn, are obtained in the reaction of 3-chloropentane-2,4-
diones with thiophenols and subsequent heterocyclization
of the resulting 3-(phenylsulfanyl)pentane-2,4-diones with
hydrazine hydrate is known.8
The existing synthesis methods of 4(2)-[alkyl(aryl)-
sulfanyl(sulfonyl)methyl]-1H-pyrazoles are based on the
substitution of the halogen atom in the corresponding
0009-3122/20/56(5)-0548©2020 Springer Science+Business Media, LLC
548

Chemistry of Heterocyclic Compounds 2020, 56(5), 548–554
Scheme 1
Table 1. Condensation of 3-[(hexylsulfanyl)methyl]pentane-
In this work, an alternative approach to access new
2,4-dione 1c with nicotinic hydrazide (1:1 molar ratio, reflux)
4-(alkylsulfanyl)methyl-substituted 1-(pyridin-3-yl)carbonyl-
1H-pyrazoles and 1-acyl-1H-pyrazoles is explored that
avoids the use of halogen derivatives. The proposed
method is based on the cyclization of 3-[(alkylsulfanyl)-
methyl]pentane-2,4-diones with nicotinic hydrazide. The
starting (sulfanyl)methyl-substituted 2,4-diones are easily
formed as a result of the three-component condensation of
acetylacetone with aldehydes and thiols, which meets the
requirements of green chemistry.3,9
Yield of compound, %
Solvent
Time, h
2с
3с
MeCN
5
13
18
9
43
11
MeCN
15
56
72
68
66
27
14
12
12
10
EtOH (method II)
EtOH, EtCOOH (1.5 equiv) (method I)
EtOH, AcOH (1.5 equiv) (method I)
EtOH, AcOH (1 equiv) (method I)
9
3-[(Alkylsulfanyl)methyl]pentane-2,4-diones 1a–с are
reacted with an equimolar amount of nicotinic hydrazide in
EtOH in the presence of AcOH (EtCO2H) or without acid
to form the corresponding 1-(pyridin-3-yl)carbonyl-1H-
pyrazoles 2a–c in up to 72% yields (Scheme 1). When
carrying out the reaction in MeCN medium (Table 1), the
selectivity of the reaction decreases due to the formation of
more than five byproducts.
9
The mechanism of the formation of 1-acyl-1H-pyrazoles
4a–f under the studied reaction conditions probably
involves nucleophilic addition of the amino group of
nicotinic hydrazide to the enol form of pentane-2,4-dione
1a,c, similar to that described in the literature,12 and
subsequent acylation of the amino group of intermediate
pyrazolidine-3,5-diols A with carboxylic acids (Scheme 2,
path a). The initial acylation of nicotinic hydrazide with
carboxylic acids is also possible with the formation of 1,2-
diacyl hydrazines 5a–c, which then participate in the
reaction with pentane-2,4-diones 1a,c (Scheme 2, path b).
Aromatization of pyrazolidine-3,5-diols C is accompanied
by elimination of hydroxyl and (pyridin-3-yl)carbonyl
groups followed by the loss of proton leading to target
compounds 4a–f. In this case, the eliminated nicotinic acid
has weaker basic properties. The physicochemical proper-
ties of the isolated nicotinic acid are consistent with
published data.13
When heating 1H-pyrazoles 3a,c with an excess of
AcOH under reflux, the formation of 1-acyl-1H-pyrazoles
4a,d is not observed. At the same time, nicotinic hydrazide
under these conditions forms N'-acetylnicotinic hydrazide
(5a) in a 43% yield. We also obtained 1,2-diacyl hydrazine
5a following a published method.14 The possibility of using
1,2-disubstituted hydrazines in the synthesis of 1H-pyrazole
derivatives is shown in the literature.15 It was found that the
reaction of acetylnicotinic hydrazide 5a with pentane-
2,4-diones 1a,с in AcOH leads to 1-acyl-1H-pyrazoles 4a,d
in less than 10% yields. The obtained results suggest that
the formation of 1-acyl-1H-pyrazoles can proceed via both
path a and path b (Scheme 2).
The main byproducts are 4-[(alkylsulfanyl)methyl]-3,5-
dimethyl-1H-pyrazoles 3a–c, the yields of which in EtOH
reach 14% (Table 1). In the reaction of pentane-2,4-diones
1a–c with nicotinic hydrazide in MeOH in the presence of
ZnCl2, the formation of 1H-pyrazoles 3a–c is predominant
(91–96% yields). In this case, nicotinic acid methyl ester is
formed as a byproduct, the IR spectra, as well as the 1H and
13C NMR spectra of which are identical to those published.10
The ZnCl2-catalyzed reaction of pentane-2,4-dione 1a–c
with nicotinic hydrazide in MeOH apparently proceeds
according to the mechanism described in the literature,3
with the difference that heterocyclization is accompanied
by elimination of nicotinic acid and the formation of its
methyl ester. The obtained results are consistent with the
data of studies describing the possible thermolysis of
1-acyl-1H-pyrazoles in the presence of catalytic amounts of
11
H2SO4 and their alcoholysis by the action of benzyl
alcohol, accelerated in the presence of NaH or BF3·OEt2.7a
Heterocyclization of pentane-2,4-diones 1a,c with
nicotinic hydrazide in acetic, propanoic, or pentanoic acids
is accompanied by reacylation and the formation of 1-acyl-
3-[(alkylsulfanyl)methyl]-1H-pyrazoles 4a–f in 50–81%
yields (Scheme 1). The yield of 1-acyl-1H-pyrazole 4b
decreases from 77 to 40% with increasing reaction
temperature from 116 to 144 °C.
549

Chemistry of Heterocyclic Compounds 2020, 56(5), 548–554
Scheme 2
O
OH
Me
SR
Me
Me
N
Me
RS
Me
SR
OH
HO
O
··
1a,c
N
N
HN NH2
N
N
··
R1
Me
Path a
N
O
O
H
4a–f
A
O
OH
Me
R1CO2H
O O
R1CO2H
Me
Me
RS
R1
SR
S
OH
Me
N
Me
N
Me
SR
OH
SR
OH
H
HO
O
1a,c
Path b
R1
+
··
N
N
+
N
N:
O
··
Me
Me
N
N
N
HN
NH
Me
Me
N
N
··
··
O
5a–c
R1
R1
R1
R1
O
O
C
O
The structure of 1-(pyridin-3-yl)carbonyl-1H-pyrazoles
2a–c was characterized by spectroscopic techniques. Their
IR spectra contain intense absorption bands of stretching
vibrations of the carbonyl group at 1699 cm–1, C=C and
C=N bonds of the pyrazole and pyridine rings in the 1583–
1586 cm–1 range.
10.6 ppm. The signal of the C-4 carbon atom of the
pyrazole ring in the 13C NMR spectrum of compound 3b is
located upfield (111.9 ppm) compared to the corresponding
signals in the spectra of 1-(pyridin-3-yl)carbonyl-1H-
pyrazoles 2a–c (119.3–120.1 ppm).
To conclude, either 4-(alkylsulfanyl)methyl-substituted
1
The H NMR spectra of compounds 2a–c exhibit the
1-(pyridin-3-yl)carbonyl-1H-pyrazoles
or
1-acyl-1H-
characteristic signals of protons of the pyridine ring,
methylsulfanylalkyl fragment, and two methyl substituents
3-CH3 (2.27–2.30 ppm) and 5-CH3 (2.62–2.64 ppm) of the
pyrazole ring. In the 13C NMR spectrum of compounds
2a–c, the signals in the 152.9–153.0, 141.7–141.9, and
119.3–120.1 ppm regions correspond to the C-3, C-5, and
C-4 carbon atoms of the 1H-pyrazole ring, and signals at
166.4 ppm can be assigned to the carbon atom of the
carbonyl group.
pyrazoles, promising in the synthesis of biologically active
compounds, depending on the conditions, can be obtained
by reacting 4-[(alkylsulfanyl)methyl]pentane-2,4-diones
with nicotinic hydrazide.
Experimental
IR spectra were registered on a Shimadzu IR Prestige-21
spectrometer using a thin film of the sample in petroleum
1
jelly. H, 13C, and 15N NMR spectra were acquired on a
The IR spectra of 1-acyl-1H-pyrazoles 4a–f contain
intense absorption bands of stretching vibrations of the
carbonyl group in the region of 1726–1729 cm–1 and of the
C=C and C=N bonds of the pyrazole ring at 1601 cm–1.
In contrast to the spectra of 1-(pyridin-3-yl)carbonyl-1H-
pyrazoles 2a–c, the proton signals of the pyridine fragment
Bruker Avance III 500 MHz spectrometer (500, 125, and
50 MHz, respectively) in DMSO-d6 (compound 5а) or
СDСl3 (remaining compounds), using residual solvent
signals as internal standard (СDСl3: 7.27 ppm for 1Н nuclei,
1
77.1 ppm for 13С nuclei; DMSO-d6: 2.50 ppm for Н nuclei,
1
1
39.5 ppm for 13С nuclei). COSY, Н–13С HSQC, Н–13С
HMBC spectra for compound 2b were acquired on a
Bruker Avance III 500 MHz spectrometer. Mass spectra
were recorded on a Shimadzu LCMS-2010 EV system with
one quadrupole in positive ion registration mode at a
capillary potential of 4.5 kV, electrospray ionization, eluent
MeCN–H2O, 95:5. Elemental analysis was performed on a
HEKAtech Euro EA 3000 CHNS-analyzer. Melting points
were determined on a Boetius heating bench. GC analysis
of the obtained compounds and monitoring of the reaction
progress were done on a Khromos 1000 chromatograph,
1 m × 3 mm column, SE-30 (5%) stationary phase, on
chromaton N-AW-DMCS (0.16–0.20 mm), at 50–300°С,
flame ionization detector, helium carrier gas.
Chromatographic separation of compounds was carried out
on MN Kieselgel 60 (0.063–0.2 μm) silica gel.
1
are absent in the H NMR spectra of 1-acyl-1H-pyrazoles
1
4a–f. In the H NMR spectra of 1-acetyl-1H-pyrazoles
4a,d, an additional singlet signal of the methyl protons of
the acetyl group is detected at 2.60 ppm, and in the spectra
of 1-propionyl- and 1-pentanoyl-1H-pyrazoles 4b,c,e,f,
signals of the protons of methyl (0.92–1.22 ppm) and
methylene groups (1.39–1.70, 3.06–3.10 ppm) of the acyl
fragments can be observed.
In the 13C NMR spectra of compounds 4a–f, the
characteristic signals of the carbon atom of the carbonyl
group (171.4–174.8 ppm) predictably appear downfield
relative to the signals of a similar carbon atom in the
spectra of 1-(pyridin-3-yl)carbonyl-1H-pyrazoles 2a–c
(166.4 ppm).
The structure of 1H-pyrazoles 3a,c was confirmed by
comparing the spectral characteristics with published
data.16 A characteristic feature of the 1H NMR spectrum of
1H-pyrazole 3b is the presence of the singlet signal of the
equivalent 3-CH3, 5-CH3 groups at 2.26 ppm and the
broadened singlet signal of the amino group proton at
Compounds 1a–c9a and N-acetylnicotinohydrazide14
were synthesized by published methods.
Synthesis of {4-[(alkylsulfanyl)methyl]-3,5-dimethyl-
1H-pyrazol-1-yl}(pyridin-3-yl)methanones 2a–с (General
procedure). Method I. Nicotinic hydrazide (0.28 g, 2 mmol)
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Chemistry of Heterocyclic Compounds 2020, 56(5), 548–554
in EtOH (5 ml) and AcOH (or EtCO2H) (3 mmol) were
C=N), 1455, 1417, 1378, 1347, 1292, 1243, 1193, 994,
1
added with stirring to a solution of compound 1a–с
(2 mmol) in EtOH (5 ml). The reaction mixture was heated
under reflux for 9 h; it was then diluted with H2O (in 1:4
ratio), and the resulting mixture as extracted with CHCl3.
The extracts were successively washed with 4% aqueous
NaHCO3, H2O, and dried over MgSO4. The solvent was
evaporated under reduced pressure, the residue was
purified by column chromatography on silica gel, eluent
EtOAc–hexane, 1:4 to 1:2 gradient.
936. H NMR spectrum, δ, ppm (J, Hz): 0.87 (3H, t,
3J = 7.1, 8'-CH3); 1.22–1.32 (4H, m, 7',6'-СН2); 1.32–1.41
3
(2H, m, 5'-CH2); 1.58 (2H, quint, J = 7.4, 4'-СН2); 2.27
3
(3H, s, 3-CH3); 2.46 (2H, t, J = 7.4, 3'-CH2); 2.62 (3H, s,
3
5-CH3); 3.52 (2H, s, 1'-CH2); 7.40 (1H, dd, J = 7.9,
3J = 4.8, H-5"); 8.29 (1H, dt, 3J = 7.9, 4J = 1.6, H-4"); 8.74
3
4
(1H, dd, J = 4.8, J = 1.6, H-6"); 9.18 (1H, s, H-2").
13C NMR spectrum, δ, ppm: 12.3 (3-CH3); 12.7 (5-СH3);
14.0 (C-8'); 22.5 (С-7'); 24.1 (C-1'); 28.6 (C-4'); 29.4 (C-5');
31.4 (C-3'(C-6')); 32.0 (C-6'(C-3')); 119.3 (С-4); 122.7 (C-
5"); 129.6 (C-3"); 138.7 (C-4"); 141.7 (C-5); 151.9 (C-2");
152.3 (C-6"); 152.9 (C-3); 166.4 (C=O). Mass spectrum, m/
z (Irel, %): 332 [M+H]+ (68), 373 [M+H+MeCN]+ (100).
Found, %: С 65.29; Н 7.67; N 12.76; S 9.72. С18Н25N3ОS.
Calculated, %: С 65.22; Н 7.60; N 12.68; S 9.67.
Method II. Nicotinic hydrazide (0.28 g, 2 mmol) in
EtOH (5 ml) was added with stirring to a solution of
compound 1a–с (2 mmol) in EtOH (5 ml). The reaction
mixture was heated under reflux for 18 h; it was then
diluted with H2O (in 1:4 ratio), and the resulting mixture
was extracted with CHCl3. The extracts were washed with
H2O and dried over MgSO4. They were then processed as
in method I.
Synthesis of 4-[(alkylsulfanyl)methyl]-3,5-dimethyl-
1H-pyrazoles 3a–c (General method). Nicotinic hydrazide
(0.28 g, 2 mmol) in MeOH (5 ml) and ZnCl2 (0.11 g,
0.8 mmol) were added with stirring to a solution of
compound 1a–с (2 mmol) in MeOH (5 ml). The reaction
mixture was heated under reflux for 16 h; it was then
diluted with H2O (in 1:4 ratio), and the resulting mixture
was extracted with CHCl3. The extracts were washed with
H2O and dried over MgSO4. The solvent was evaporated
under reduced pressure to afford a mixture of compounds
3а–c with methyl nicotinate in a 1:0.7 ratio (0.66, 0.70,
0.73 g, respectively). The mixture was purified by column
chromatography on silica gel, eluent EtOAc–hexane, 1:4 to
1:2 gradient to give analytical samples of methyl nicotinate
and compounds 3а–c.
{4-[(Butylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}(pyridin-3-yl)methanone (2a). Yield 0.37 g (61%,
method I), colorless oil. IR spectrum (thin film), ν, cm–1:
1699 (C=O), 1583 (С=С, C=N), 1455, 1417, 1378, 1347,
1
1292, 1245, 1193, 994, 936. H NMR spectrum, δ, ppm
3
(J, Hz): 0.92 (3H, t, J = 7.4, 6'-CH3); 1.41 (2H, sext,
3
3J = 7.4, 5'-СH2); 1.60 (2H, quint, J = 7.4, 4'-СH2); 2.30
3
(3H, s, 3-CH3); 2.49 (2H, t, J = 7.4, 3'-СH2); 2.64 (3H, s,
5-CH3); 3.53 (2H, s, 1'-CH2); 7.34–7.44 (1H, m, H-5"); 8.29
3
(1H, d, J = 7.9, H-4"); 8.75 (1H, br. s, H-6"); 9.18 (1H, s,
H-2"). 13C NMR spectrum, δ, ppm: 12.4 (3-CH3); 12.7
(5-СH3); 13.7 (C-6'); 22.0 (С-5'); 24.0 (С-1'); 31.4
(C-3'(C-4')); 31.7 (C-4'(C-3')); 120.1 (С-4); 123.0 (C-5");
129.8 (C-3"); 139.0 (C-4"); 141.9 (C-5); 151.8 (C-2");
152.1 (C-6"); 152.9 (C-3); 166.4 (C=O). Mass spectrum,
m/z (Irel, %): 304 [M+H]+ (65), 345 [M+H+MeCN]+ (100).
Found, %: С 63.49; Н 7.01; N 13.90; S 10.62. С16Н21N3ОS.
Calculated, %: С 63.33; Н 6.98; N 13.85; S 10.57.
4-[(Butylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazole
1
(3a). Yield 0.38 g (96%). IR, H, and 13C NMR spectra of
compound 3a match those published earlier.16
3,5-Dimethyl-4-[(pentylsulfanyl)methyl]-1H-pyrazole
(3b). Yield 0.40 g (95%), colorless oil. IR spectrum (thin
film), ν, cm–1: 3201 (N–H), 3144 (N–H), 3091 (N–H), 1590
(C=N), 1514 (C=C), 1465, 1437, 1420, 1378, 1303, 1248,
1203, 1152 (N–H), 1033, 1001. 1H NMR spectrum, δ, ppm
{3,5-Dimethyl-4-[(pentylsulfanyl)methyl]-1H-pyrazol-
1-yl}(pyridin-3-yl)methanone (2b). Yield 0.41 g (64%,
method I), colorless oil. IR spectrum (thin film), ν, cm–1:
1699 (C=O), 1586 (С=С, C=N), 1456, 1418, 1377, 1348,
3
(J, Hz): 0.88 (3H, t, J = 7.1, 7'-CH3); 1.24–1.36 (4H, m,
1
3
1292, 1242, 1193, 995, 935. H NMR spectrum, δ, ppm
6',5'-СН2); 1.57 (2H, quint, J = 7.1, 4'-CH2); 2.26 (6H, s,
3
3
(J, Hz): 0.90 (3H, t, J = 7.3, 7'-CH3); 1.28–1.40 (4H, m,
3,5-CH3); 2.42 (2H, t, J = 7.4, 3'-CH3); 3.53 (2H, s,
6',5'-СН2); 1.61 (2H, quint, J = 7.3, 4'-CH2); 2.29 (3H, s,
1'-CH2); 10.60 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
10.8 (3,5-СH3); 14.0 (C-7'); 22.3 (С-6'); 24.7 (C-1'); 29.2
(C-5'); 31.5 (C-3'(C-4')); 31.7 (C-4'(C-3')); 111.9 (С-4);
142.8 (C-3,5). Found, %: С 62.28; Н 9.53; N 13.24;
3
3-CH3); 2.48 (2H, t, 3J = 7.3, 3'-CH3); 2.63 (3H, s, 5-CH3);
3.54 (2H, s, 1'-CH2); 7.44 (1H, dd, 3J = 7.8, 3J = 4.8, H-5");
3
3
8.32 (1H, d, J = 7.8, H-4"); 8.77 (1H, d, J = 4.8, H-6");
9.21 (1H, br. s, H-2"). 13C NMR spectrum, δ, ppm: 12.4
3-СH3); 12.7 (5-CH3); 14.0 (C-7'); 22.3 (С-6'); 24.2 (C-1');
29.2 (C-4'); 31.2 (C-5'); 32.0 (C-3'); 119.3 (С-4); 122.9
(C-5"); 129.8 (C-3"); 139.0 (C-4"); 141.8 (C-5); 151.8
(C-2"); 152.1 (C-6"); 153.0 (C-3); 166.4 (C=O). 15N NMR
spectrum, δ, ppm: 227.2; 299.6. Mass spectrum, m/z
(Irel, %): 318 [M+H]+ (63), 359 [M+H+MeCN]+ (100).
Found, %: С 64.36; Н 7.35; N 13.31; S 10.18. С17Н23N3ОS.
Calculated, %: С 64.32; Н 7.30; N 13.24; S 10.10.
S
15.16. С11Н20N2S. Calculated, %:
С
62.22;
Н 9.49; 13.19; S 15.10.
4-[(Hexylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazole
(3c). Yield 0.41 g (91%). IR, H, and 13C NMR spectra of
1
compound 3c match those published earlier.16
Methyl nicotinate. Yield 0.24–0.26 g (88–95%), mp 38–
39°С (EtOAc–hexane, 1:4) (mp 38–39°С10a). IR, H, and
1
13C NMR spectra of methyl nicotinate match those
published earlier.10
{4-[(Hexylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}(pyridin-3-yl)methanone (2c). Yield 0.45 g (68%,
method I), 0.37 g (56%, method II), colorless oil.
IR spectrum (thin film), ν, cm–1: 1699 (C=O), 1586 (С=С,
Synthesis of 1-{4-[(alkylsulfanyl)methyl]-3,5-dimethyl-
1H-pyrazol-1-yl}alkanones 4a–f (General method).
Nicotinic hydrazide (0.28 g, 2 mmol) in carboxylic acid
(acetic, propanoic, pentanoic) (3 ml) was added with
551

Chemistry of Heterocyclic Compounds 2020, 56(5), 548–554
stirring to a solution of compound 1a,с (2 mmol) in
S 11.45. С15Н26N2OS. Calculated, %: С 63.79; Н 9.28;
carboxylic acid (3 ml). The reaction mixture was stirred at
112–116°С for 2–3 h. After the completion of the reaction,
the formed precipitate of nicotinic acid was separated by
filtration. The filtrate was diluted with H2O (in 1:8 ratio),
and the resulting mixture was extracted with CHCl3
(3×15 ml). The extracts were successively washed with 4%
aqueous NaHCO3 (3×15 ml), H2O (2×15 ml), and dried
over MgSO4. The solvent was evaporated under reduced
pressure, and the residue was purified by column chromato-
graphy on silica gel, eluent EtOAc–hexane, 1:7.
N 9.92; S 11.35.
1-{4-[(Hexylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}ethanone (4d). Yield 0.34 g (63%), colorless oil.
IR spectrum (thin film), ν, cm–1: 1727 (С=О), 1601 (С=С,
C=N), 1457, 1429, 1377, 1368, 1334, 1291, 1241. 1H NMR
3
spectrum, δ, ppm (J, Hz): 0.88 (3H, t, J = 7.1, 8'-CH3);
1.21–1.31 (4H, m, 7',6'-СН2); 1.31–1.36 (2H, m, 5'-СH2);
1.56 (2H, quint, 3J = 7.4, 4'-СН2); 2.28 (3H, s, 3-CH3); 2.42
3
(2H, t, J = 7.4, 3'-CH2); 2.51 (3H, s, 5-СH3); 2.65 (3H, s,
CH3CO); 3.47 (2H, s, 1'-CH2). 13C NMR spectrum, δ, ppm:
12.3 (3-CH3); 12.9 (5-СH3); 14.0 (C-8'); 22.5 (С-7'); 23.6
(CH3CO); 24.1 (C-1'); 28.6 (С-4'); 29.4 (C-5'); 31.4
(C-3'(C-6')); 31.8 (C-6'(C-3')); 118.6 (С-4); 140.6 (C-5);
151.9 (C-3); 171.5 (CO). Mass spectrum, m/z (Irel, %): 269
[M+H]+ (100), 310 [M+H+MeCN]+ (7). Found, %:
С 62.74; Н 9.10; N 10.36; S 12.02. С14Н24N2OS.
Calculated, %: С 62.64; Н 9.01; N 10.44; S 11.95.
1-{4-[(Butylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}ethanone (4a). Yield 0.39 g (81%), colorless oil.
IR spectrum (thin film), ν, cm–1: 1726 (С=О), 1601 (С=С,
C=N), 1457, 1429, 1377, 1368, 1334, 1291, 1241. 1H NMR
3
spectrum, δ, ppm (J, Hz): 0.89 (3H, t, J = 7.3, 6'-CH3);
3
3
1.38 (2H, sex, J = 7.3, 5'-CH2); 1.55 (2H, quint, J = 7.3,
4'-CH2); 2.27 (3H, s, 3-CH3); 2.42 (2H, t, 3J = 7.3, 3'-CH2);
2.50 (3H, s, 5-CH3); 2.64 (3H, s, CH3CO); 3.46 (2H, s,
1'-CH2). 13C NMR spectrum, δ, ppm: 12.3 (3-CH3); 12.8
(5-CH3); 13.7 (C-6'); 22.1 (C-5'); 23.6 (CH3CO); 24.1
(C-1'); 31.4 (C-3'(C-4')), 31.5 (C-4'(C-3')); 118.6 (C-4);
140.6 (C-5); 151.9 (C-3); 171.4 (CO). Mass spectrum, m/z
(Irel, %): 241 [M+H]+ (100), 282 [M+H+MeCN]+ (8).
Found, %: С 60.07; Н 8.34; N 11.61; S 13.45. С12Н20N2ОS.
Calculated, %: С 59.96; Н 8.39; N 11.65; S 13.34.
1-{4-[(Hexylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}propan-1-one (4e). Yield 0.34 g (60%), colorless oil.
IR spectrum (thin film), ν, cm–1: 1729 (С=О), 1601 (С=С,
1
C=N), 1461, 1428, 1377, 1362, 1317, 1278, 1234. H NMR
3
spectrum, δ, ppm (J, Hz): 0.86 (3H, t, J = 7.3, 8'-CH3);
3
1.21 (3H, t, J = 7.4, СH3CH2CO); 1.21–1.30 (4H, m,
7',6'-СH2); 1.30–1.42 (2H, m, 5'-CH2); 1.57 (2H, quint,
3J = 7.3, 4'-СН2); 2.26 (3H, s, 3-CH3); 2.41 (2H, t, 3J = 7.3,
1'-CH2); 2.50 (3H, s, 5-CH3); 3.10 (2H, q, 3J = 7.4,
CH3СH2CO); 3.46 (2H, s, 1'-CH2). 13C NMR spectrum,
δ, ppm: 8.4 (СH3CH2CO); 12.3 (3-CH3); 12.8 (5-CH3);
14.0 (C-8'); 22.5 (С-7'); 24.1 (C-1'); 28.6, 28.7 (С-4',
CH3CH2CO); 29.4 (C-5'); 31.4 (С-3'(C-6')); 31.7
(С-6'(C-3')); 118.3 (С-4); 140.6 (C-5); 151.6 (C-3); 174.8
(CO). Mass spectrum, m/z (Irel, %): 283 [M+H]+ (100), 324
[M+H+MeCN]+ (5). Found, %: С 63.84; Н 9.30; N 9.99;
S 11.42. С15Н26N2OS. Calculated, %: С 63.79; Н 9.28;
N 9.92; S 11.35.
1-{4-[(Butylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}propan-1-one (4b). Yield 0.39 g (77%), colorless oil.
IR spectrum (thin film), ν, cm–1: 1729 (С=О), 1601 (С=С,
1
C=N), 1459, 1429, 1377, 1363, 1317, 1277, 1237. H NMR
3
spectrum, δ, ppm (J, Hz): 0.90 (3H, t, J = 7.3, 6'-CH3);
1.22 (3H, t, 3J = 7.4, CH3CH2CO); 1.40 (2H, sex, 3J = 7.3,
3
5'-СH2); 1.55 (2H, quint, J = 7.3, 4'-СН2); 2.27 (3H, s,
3-CH3); 2.43 (2H, t, 3J = 7.3, 3'-CH2); 2.51 (3H, s, 5-CH3);
3
3.10 (2H, q, J = 7.4, CH3СH2CO); 3.47 (2H, s, 1'-CH2).
13C NMR spectrum, δ, ppm: 8.4 (СH3CH2CO); 12.3
(3-CH3); 12.8 (5-CH3); 13.7 (C-6'); 22.1 (C-5'); 24.1 (C-1');
28.7 (CH3CH2CO); 31.4 (C-3'(C-4')); 31.5 (C-4'(C-3'));
118.2 (С-4); 140.6 (C-5); 151.6 (C-3); 174.8 (CO). Mass
spectrum, m/z (Irel, %): 255 [M+H]+ (100), 296
[M+H+MeCN]+ (8). Found, %: С 61.49; Н 8.84; N 11.08;
S 12.68. С13Н22N2OS. Calculated, %: С 61.38; Н 8.72;
N 11.01; S 12.60.
1-{4-[(Hexylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}pentan-1-one (4f). Yield 0.31 g (50%), colorless oil.
IR spectrum (thin film), ν, cm–1: 1728 (С=О), 1601 (С=С,
C=N), 1456, 1428, 1378, 1353, 1321, 1281, 1231. 1H NMR
3
spectrum, δ, ppm (J, Hz): 0.86 (3H, t, J = 7.1, 8'-CH3);
0.94 (3H, t, 3J = 7.4, 5''-CH3); 1.20–1.32 (4H, m,
7',6'-СН2); 1.30–1.36 (2H, m, 5'-СH2); 1.39 (2H, sex,
3
1-{[4-(Butylsulfanyl)methyl]-3,5-dimethyl-1H-pyrazol-
1-yl}pentan-1-one (4c). Yield 0.42 g (74%), colorless oil.
IR spectrum (thin film), ν, cm–1: 1729 (С=О), 1601 (С=С,
C=N), 1456, 1429, 1377, 1353, 1321, 1280, 1233. 1H NMR
3J = 7.4, 4''-CH2); 1.55 (2H, quint, J = 7.4, 4'-CH2); 1.70
3
(2H, quint, J = 7.4, 3''-CH2); 2.27 (3H, s, 3-CH3); 2.41
3
(2H, t, J = 7.4, 3'-CH2); 2.50 (3H, s, 5-CH3); 3.07 (2H, t,
3J = 7.4, 2''-CH2); 3.46 (2H, s, 1'-CH2). 13C NMR spectrum,
δ, ppm: 12.3 (3-CH3); 12.8 (5-СH3); 13.9, 14.0 (C-5'',
C-8'); 22.2 (C-7'(С-4'')); 22.5 (C-4''(С-7')); 24.1 (C-1');
26.4 (C-3''); 28.6 (C-4'); 29.5 (C-5'); 31.4, 31.7 (C-6', С-3');
34.9 (C-2''); 118.3 (С-4); 140.6 (C-5); 151.6 (C-3); 174.1
(CO). Mass spectrum, m/z (Irel, %): 311 [M+H]+ (100), 352
[M+H+MeCN]+ (5). Found, %: С 65.84; Н 9.80; N 9.16;
S 10.46. С17Н30N2ОS. Calculated, %: С 65.76; Н 9.74;
N 9.02; S 10.33.
3
spectrum, δ, ppm (J, Hz): 0.87 (3H, t, J = 7.4, 6'-CH3);
0.92 (3H, t, 3J = 7.4, 5''-CH3); 1.31−1.43 (4H, m,
3
5',4''-CH2); 1.53 (2H, quint, J = 7.4, 4'-CH2); 1.68 (2H,
3
quint, J = 7.4, 3''-CH2); 2.25 (2H, s, 3-CH3); 2.40 (2H, t,
3J = 7.4, 3'-CH2); 2.49 (3H, s, 5-CH3); 3.06 (2H, t, 3J= 7.4,
2''-CH2); 3.45 (2H, s, 1'-CH2). 13C NMR spectrum, δ, ppm:
12.3 (3-CH3); 12.8 (5-СH3); 13.6, 13.9 (C-6',5''); 22.0
(C-5'(C-4'')); 22.2 (C-4''(C-5')); 24.0 (C-1'); 26.4 (3''-CH2);
31.4 (C-3'(C-4')); 31.5 (C-4'(C-3')); 34.8 (2''-CH2); 118.2
(С-4); 140.6 (C-5); 151.5 (C-3); 174.1 (CO). Mass
spectrum, m/z (Irel, %): 283 [M+H]+ (100), 324
[M+H+MeCN]+ (8). Found, %: С 63.89; Н 9.34; N 10.01;
Nicotinic acid. Yield 0.24–0.25 g (98–99%), mp 236–
237°С (EtOH) (mp 237.7–239.1°С (EtOAc–EtOH, 4:1)13a).
IR, 1H, and 13C NMR spectra of nicotinic acid match those
published earlier.13
552

Chemistry of Heterocyclic Compounds 2020, 56(5), 548–554
N'-Acetylpyridine-3-carbohydrazide (5a). Method I.14
Ac2O (0.4 ml, 4 mmol) was added to a solution of nicotinic
hydrazide (0.41 g, 3 mmol) in H2O (4.5 ml). The reaction
mixture was stirred at room temperature for 30 min. Then
the solvent was evaporated under reduced pressure, and the
residue was recrystallized from PhH. Yield 0.51 g (95%),
mp 139–140°C (PhH). IR spectrum (petroleum jelly), ν, cm–1:
3282 (NH), 3206 (NH), 1651 (С=О), 1645 (C=O), 1509,
1486, 1420, 1358 (С–N), 1336, 1275 (C–N).
1H NMR spectrum, δ, ppm (J, Hz): 1.92 (3H, s, CH3СO);
(e) Shaharyar, M.; Siddiqui, A. A.; Ali, M. A.; Sriram, D.;
Yogeeswari, P. Bioorg. Med. Chem. Lett. 2006, 16, 3947.
(f) Nigade, G.; Chavan, P.; Deodhar, M. Med. Chem. Res.
2012, 21, 27. (g) Kawazura, H.; Takahashi, Y.; Shiga, Y.;
Shimada, F.; Ohto, N.; Tamura, A. Jpn. J. Pharmacol. 1997,
73, 317. (h) Li, X.B.; Inouei, T.; Abekawai, T.; YiRui, F.;
Koyama, T. Eur. J. Pharmacol. 2004, 505, 145. (i) Gallagher, M.;
Lund, P. K.; Selcher, J. C.; Melcher, T. US Patent
20060014801.
2. (a) Pippione, A. C.; Sainas, S.; Federico, A.; Lupino, E.;
Piccinini, M.; Kubbutat, M.; Contreras, J.-M.; Morice, C.;
Barge, A.; Ducime, A.; Boschi, D.; Al-Karadaghi, S; Lolli, M. L.
Med. Chem. Commun. 2018, 9, 963. (b) Cox, C. D.; Breslin, M. J.;
Mariano, B. J.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.;
Hamilton, K.; Huber, H. E.; Kohl, N. E.; Torrent, M.; Yan, Y.;
Kuo, L. C.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2005,
15, 2041. (c) Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.;
Secci, D.; Chimenti, P.; Ferlini, C.; Scambia, G. Bioorg. Med.
Chem. Lett. 2005, 15, 4632. (d) Karrouchi, K.; Radi, S.;
Ramli, Y.; Taoufik, J.; Mabkhot, Y. N; Al-aizari, F. A.;
Ansar, M. Molecules 2018, 23, 134. (e) Ghareb, N.;
Elshihawy, H. A.; Abdel-Daim, M. M.; Helal, M. A. Bioorg.
Med. Chem. Lett. 2017, 27, 2377. (f) Lv, P. C.; Sun, J.; Luo, Y.;
Yang, Y.; Zhu, H. L. Bioorg. Med. Chem. Lett. 2010, 20, 4657.
(g) Wang, D. J.; Liu, H., Kang, Y. F.; Hu, Y. J.; Wei, X. H. J.
Chil. Chem. Soc. 2015, 60, 2857. (h) Chimenti, F.; Bolasco, A.;
Manna, F.; Secci, D.; Chimenti, P.; Granese, A.; Befani, O.;
Turini, P.; Cirilli, R.; La Torre, F.; Alcaro, S.; Ortuso, F.;
Langer, T. Curr. Med. Chem. 2006, 13, 1411. (i) Manna, F.;
Chimenti, F.; Bolasco, A.; Secci, D.; Bizzarri, B.; Befani, O.;
Turini, P.; Mondovì, B.; Alcaro, S.; Tafi, A. Bioorg. Med.
Chem. Lett. 2002, 12, 3629. (j) Secci, D.; Bolasco, A.;
Chimenti, P.; Carradori, S. Curr. Med. Chem. 2011, 18, 5114.
3. Akhmadiev, N. S.; Akhmetova, V. R.; Boyko, T. F.;
Ibragimov, A. G. Chem. Heterocycl. Compd. 2018, 54, 344.
[Khimiya geterotsikl. soedinenii 2018, 54, 344.]
3
7.50–7.53 (1H, m, H-5'); 8.18 (1H, d, J = 8.0, H-4'); 8.71
3
4
(1H, dd, J = 4.7, J = 1.5, H-6'); 8.98 (1H, br. s, H-2');
9.99 (1H, br. s, NHCO); 10.52 (1H, br. s, NHCOCH3)
13C NMR spectrum, δ, ppm: 20.9 (СH3CO); 124.1 (C-5');
128.6 (C-3'); 135.7 (C-4'); 148.7 (C-2'); 152.8 (C-6'); 164.7
(CO); 169.3 (COCH3). Mass spectrum, m/z (Irel, %): 178
[M–H]+ (100). Found, %: С 53.71; Н 5.15; N 23.52.
С8Н9N3О2. Calculated, %: С 53.63; Н 5.06; N 23.45.
Method II. A solution of nicotinic hydrazide (0.28 g,
2 mmol) in AcOH (6 ml) was stirred at 112−116°С for 2.5 h.
AcOH was then evaporated under reduced pressure, the
residue was washed with CHCl3 and dried. A mixture
(0.32 g) was obtained, which contains the starting
compound and N'-acetylpyridine-3-carbohydrazide (5a) in
a 1:1 ratio according to 1H NMR.
Reaction of 3-[(butylsulfanyl)methyl]pentane-2,4-
dione (1a) with N'-acetylpyridine-3-carbohydrazide
(5a). A mixture of compound 1a (0.20 g, 1 mmol) and
N'-acetylpyridine-3-carbohydrazide (5a) (0.18 g, 1 mmol)
in AcOH (3 ml) was stirred at 112−116°С for 2.5 h. AcOH
was then evaporated, and the residue was mixed with H2O
in 1:8 ratio. The resulting mixture was extracted with
CHCl3 (3×10 ml). The extracts were successively washed
with 4% aqueous NaHCO3 (3×10 ml), H2O (2×10 ml) and
dried over MgSO4. The solvent was evaporated under
reduced pressure; the residue (0.23 g) was subjected to
chromatography on silica gel, eluent EtOAc–hexane, 1:7.
Starting compound 1a (0.16 g, 80%) and 1-{4-[(hexyl-
sulfanyl)methyl]-3,5-dimethylpyrazol-1-yl]ethanone (4d)
(0.021 g, 8%) were obtained from N'-acetylpyridine-
3-carbohydrazide (5a) (0.18 g, 1 mmol) and compound 1c
(0.23 g, 1 mmol).
4. Bradley, P. A.; Dack, K. N.; Johnson, P. S.; Skerratt, S. E.
US Patent 7425569.
5. Brand, S.; Cleghorn, L. A. T.; McElroy, S. P.; Robinson, D. A.;
Smith, V. C.; Hallyburton, I.; Harrison, J. R.; Norcross, N. R.;
Spinks, D.; Bayliss, T.; Norval, S.; Stojanovski, L.; Torrie, L. S.;
Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A. J.;
Read, K. D.; Wyatt, P. G.; Gilbert, I. H. J. Med. Chem. 2012,
55, 140.
6. (a) Anpilogova, G. R.; Baeva, L. A.; Nugumanov, R. M.;
Fatykhov, A. A.; Murinov, Yu. I. Russ. J. Inorg. Chem. 2018,
63, 1100. [Zh. Neorg. Khim. 2018, 1065.] (b) Akhmetova, V. R.;
Akhmadiev, N. S.; Tulyabaev, А. R.; Khisamutdinov, R. А.;
Ibragimov, А. G.; Dzhemilev, U. М. RF patent 2672265.
(c) Grotjahn, D. B.; Van, S.; Combs, D.; Lev, D. A.;
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Rheingold, A. L.; Rideout, M.; Meyer, C.; Hernandez, G.;
Mejorado, L. Inorg. Chem. 2003, 42, 3347.
7. (a) Kashima, C.; Harada, H.; Kita, I.; Fukuchi, I.; Hosomi, A.
Synthesis 1994, 61. (b) Schütznerová, E.; Popa, I.; Kryštof, V.;
Koshino, H.; Trávníček, Z.; Hradil, P.; Cankař, P.
Tetrahedron 2012, 68, 3996. (c) Tang, M.; Zhang, F. M.
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The study was carried out on the subject of state
assignment (No. AAAA-A19-119011790021-4).
Spectral and analytical results were obtained using the
equipment of the Center for Collective Use ''Chemistry'' of
Ufa Institute of Chemistry of the Ufa Federal Research
Center of the Russian Academy of Sciences.
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