Ratio of 1,3- and 1,5-dialkyl-substituted pyrazoles obtained from chlorovinyl alkyl ketones and alkylhydrazines, 3(5)-pyrazoles and alkyl bromides

Article abstract of DOI:10.1134/S1070428014110190

Unsymmetrically substituted 1,3- and 1,5-dialkylpyrazoles and 1,3-dialkyl-5-chloropyrazoles were prepared. 2-Chlorovinyl ketones react with C₁-C₈-alkylhydrazines along two routes giving mixtures of 1-R′-3-R- and 1-R′-5-R-pyrazoles wi

Full text of DOI:10.1134/S1070428014110190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 11, pp. 1650–1662. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.V. Popov, E.V. Rudyakova, L.I. Larina, V.A. Kobelevskaya, G.G. Levkovskaya, 2014, published in Zhurnal Organicheskoi Khimii,
2014, Vol. 50, No. 11, pp. 1663–1675.
Ratio of 1,3- and 1,5-Dialkyl-Substituted Pyrazoles
Obtained from Chlorovinyl Alkyl Ketones and Alkylhydrazines,
3(5)-Pyrazoles and Alkyl Bromides
A. V. Popov, E. V. Rudyakova, L. I. Larina, V. A. Kobelevskaya, and G. G. Levkovskaya
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: ggl@irioch.irk.ru
Received June 26, 2014
Abstract—Unsymmetrically substituted 1,3- and 1,5-dialkylpyrazoles and 1,3-dialkyl-5-chloropyrazoles were
prepared. 2-Chlorovinyl ketones react with С1–С8-alkylhydrazines along two routes giving mixtures of 1-R'-3-
R- and 1-R'-5-R-pyrazoles with the prevalence of 1,3-isomer. The proportion of 3-substituted 1-alkylpyrazole
in the isomers mixture grows from 60 to 94–97% with growing length of the alkyl chain in the hydrazine. The
alkylation of 1-unsubstituted 3(5)-alkylpyrazoles with alkyl bromides afforded predominantly (by 16–50%)
1,3-disubstituted pyrazoles. 1,3-Dialkyl-5-chloropyrazoles form from 2,2-dichlorovinyl alkyl ketones and
functionalized alkylhydrazines. It was suggested to synthesize 1,3-dialkyl-substituted pyrazoles by dechlori-
nation of unsymmetrically substituted 1,3-dialkyl-5-chloropyrazoles in the presence of complex nickel catalyst
and water as the proton source.
DOI: 10.1134/S1070428014110190
Pyrazole and its derivatives attract attention owing
to their versatile pharmacological activity [1, 2]
(antibacterial [1, 3], antidepressant [4], antiphlogistic
[5], antitumor [6], etc.). Besides the specific action of
numerous pyrazole derivatives makes it possible to
apply them as pesticides [7, 8]. Pyrazole derivatives
are widely used as isectoacaricides [8, 9]. The high
interest attracted by this class of heterocyclic
compounds is also due to their vast potential in the
production of modern dyes for cosmetics, photo-
industry, fluorescent substances, stabilizers [2, 10].
Compounds of the pyrazole series are used both in the
large-scale production and in the fine organic synthesis
[1, 2], in supramolecular [11] and polymer chemistry
[12], as liquid crystals [13], ligands for metal complex
catalysts [14], in the preparation of complexes with
uncommon magnetic properties [15]. The practical
application of pyrazole derivatives and the extension
of the fields of their usage requires the solution of a
topical issue: the preparation of individual isomers of
unsymmetrically substituted pyrazoles.
densation reaction of 1,3-dicarbonyl compounds and
their synthetic equivalents, acetylene ketones, with
hydrazines [2, 16–22]. This often results in the forma-
tion of regioisomeric mixtures of unsymmetrically
substituted pyrazoles, and the variation of the synthesis
conditions provides only insignificant increase in the
yield of the target product. Finally, a lot of limitations
exist connected with the availability of the reagents
[17–21]. Quite a number of publications [1, 2, 16–21]
treat the problem of preparation of individual isomers
of unsymmetrically substituted pyrazoles.
The analysis of the known approaches indicates that
the utilization of halogenenones (precursors of 1,3-
dicarbonyl compounds) as initial reagents is promising
for pyrazoles synthesis, in particular, for the
preparation of individual isomers, while the halogen is
a good leaving group in the reactions of nucleophilic
substitution [22–34]. The systematic investigation of
reactivity of diverse halogenenones has shown that the
reactions of 2,2-dichloro(bromo)(fluoro)vinyl ketones
with unsymmetrical dialkylhydrazines, alkyl-, aryl-
hydrazines [23–30] under various conditions leads to
the chemo- and regiospecific formation of 1-alkyl-
One among the most widely spread preparation
methods for substituted pyrazoles is the cyclocon-
1650

RATIO OF 1,3- AND 1,5-DIALKYL-SUBSTITUTED PYRAZOLES
1651
Table 1. Overall yield and fraction of 1,3- and 1,5-disubstituted pyrazoles IIа–IIp and IIIа–IIIp in the mixture obtained by
reaction of alkyl 2-chlorovinyl ketones with alkylhydrazines
R
N
N
R
N
R'
N
R'
IIa-IIp
IIIa-IIIp
Compound
no.
Fraction of 1,3-isomer
Fraction of 1,5-isomer
Run no.
R
R'
Overall yield, %
II, %
III, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
IIа, IIIа
IIb, IIIb
IIc, IIIc
IId, IIId
IIe, IIIe
IIf, IIIf
IIg, IIIg
IIh, IIIh
IIi, IIIi
IIj, IIIj
IIk, IIIk
IIl, IIIl
IIm, IIIm
IIn, IIIn
IIo, IIIo
IIp, IIIp
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Me
Et
Bu
t-Bu
Bn
Amyl
Hex
Ht
Oct
Hex
Oct
Hex
Hex
Bn
89
89
71
61
95
81
89
75
48
83
62
81
28
61
61
66
60
60
71
58
60
95
97
85
95
82
96
91
73
88
79
77
40
40
29
42
40
5
3
15
5
18
4
9
27
12
21
23
Bu
Bu
Amyl
СН3СHBr
CH3CHCl
CH3CCl2
CHCl2
Bn
Bn
(aryl)-3-alkyl(aryl)(chloroalkyl)(perfluoroalkyl)-5-ha-
lopyrazoles. The nature of the hydrazine and the
reaction conditions do not affect the direction of the
process. A general procedure was developed for the
preparation of 5-halo-1,3-disubstituted pyrazoles
consisting in the primary formation of the correspond-
ding hydrazones of halogenenones followed by the
intramolecular attack with the nucleophilic amine
fragment on the β-carbon atom of the vinyl group. The
obtained N-alkyl-substituted pyrazole halides undergo
decomposition with the formation of a haloalkane or
hydrogen halide and a substituted pyrazole [26–29]. In
the reaction of 2,2-difluoro-1-alkylvinyl phenyl(cyclo-
hexyl)ketones with monosubstituted alkyl– and aryl-
hydrazines (2 equiv.) in the presence of 2 equiv. of
BuLi first the fluorine atom is substituted and then
occurs the intramolecular cyclization, dehydration, and
the formation of 1,3-disubstituted 5-fluoropyrazoles [30].
aryl-3-alkylpyrazole, and therewith the second isomer
was not detected [31, 32]. Mixtures of 1,3- and 1,5-
dialkylsubstituted pyrazoles were not obtained in
reactions of 2-chlorovinyl ketones with alkylhydra-
zines with a long alkyl chain [31, 33].
We showed formerly that in the reaction of 2-
chlorovinyl propyl ketone with ethyl-, butyl– and
benzylhydrazine [27] and of 1-chloroethyl 2-chloro-
vinyl ketone with benzylhydrazine [29] formed a
mixture of 1-R'-5-R– and 1-R'-3-R– in the ratio 1 : 2–
2 : 5 and 1 : 7 respectively. In order to find the depen-
dence of the reaction direction on the structure of
chloroenones and hydrazine and to obtain 1,3- and 1,5-
dialkyl-substituted pyrazoles, in particular, pure
isomers, we continued the study of reactions of 2-
chlorovinyl and 2,2-dichlorovinyl ketones with
hydrazine, alkyl-, and 1,1-dialkylhydrazines (Table 1),
and also the N-alkylation reactions with С1–С6-alkyl
halides of 3(5)-alkylpyrazoles unsubstituted in the
position 1 obtained from hydrazine and chloroenones
(Table 2). The main attention in the research was
drown to reveling the factors affecting the isomeric
composition of the obtained pyrazoles: the nature of
The synthesis of 1,3-disubstituted pyrazoles lacking
halogen atom in the ring from 2-chlorovinyl ketones is
limited by the hydrazine structure. The reaction of
arylhydrazines with 2-chlorovinyl alkyl ketones and
dialkoxyketoacetals was used for the preparation of 1-
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POPOV et al.
1652
Table 2. Overall yield and fraction of 1,3- and 1,5-disubstituted pyrazoles in the mixture obtained by alkylation of tautomers
mixture of 3(5)-alkylpyrazoles with bromoalkanes in DMSO
R
N
N
R
N
R'
II
N
R'
III
Run
no.
1
2
3
4
5
6
7
Overall
yield, %
72
Fraction of 1,3-
disubstituted pyrazole, %
Fraction of 1,5-disubstituted
Compound no.
R
R'
pyrazole, %
IIq, IIIq
IIr, IIIr
IIа, IIIа
IIf, IIIf
IIg, IIIg
IIh, IIIh
IIs, IIIs
IIt, IIIt
IIu, IIIu
IIv, IIIv
IIg, IIIg
Et
Et
Pr
Pr
Pr
Pr
Bu
Ме
Amyl
Hex
Ht
Ме
Et
Pr
60
62
60
61
59
58
47
58
60
60
75
40
38
40
39
41
42
53
42
40
40
25
73
89
90
92
75
76
80
84
Pr
Bu
Bu
Bu
Bu
Pr
8
9
10
Bu
Hex
84
92
11а
а
Obtained in the presence of NaN(SiMe3)2.
substituents in the acyl fragment of monochloro-
enones, the length of the alkyl chain in ketones and
alkylhydrazines, reaction conditions.
(Scheme 1, Table 1). The course of the reaction is not
affected by the order of reagents mixing, solvent
character, and the process temperature (see EXPERI-
MENTAL, method а). In all cases we obtained
mixtures of isomers of 1,3- and 1,5-dialkyl-substituted
pyrazoles (Table 1).
Under the conditions of chemo– and regioselective
synthsesis of 1,3-dialkyl-substituted 5-chloropyrazoles
from 2,2-dichlorovinyl ketones and 1,3-dialkyl-
pyrazoles [26–29] alkyl(1-haloalkyl) 2-chlorovinyl
ketones Iа–Ig reacted with hydrazines in the presence
of triethylamine affording a mixture of 1,3- and 1,5-
dialkyl-substituted pyrazoles IIа–IIp and IIIа–IIIp
The ratio of 1,3- and 1,5-substituted pyrazoles is
not essentially affected by the nature of solvent and the
conditions of reaction between chlorovinyl ketone and
alkylhydrazines. Propyl-2-chlorovinyl ketone reacts
Scheme 1.
O
R
HO
O
N
H
N
_
.
Et3N HCl
_H2O
NHNHR'
R
R
Cl
R'
Ia-Ig
+
R
NH2NHR'
NNHR'
+
_
+
.
_H2O
R
Cl
N
N
Et3N HCl
Et3N
R
N
N
R'
IIa-IIp, 58-97%
R'
IIIa-IIIp, 3-42%
I, R = Pr (a), Bu (b), Amyl (c), СН3СHBr (d), CH3CHCl (e), CH3CCl2 (f), CHCl2 (g); II, III, R = Pr, R' = Me (a), Et (b),
Bu (c), t-Bu (d), PhCH2 (e), Amyl (f), Hex (g), Ht (h), Okt (i); R = Bu, R' = Hex (j), Okt (k); R = Amyl, R' = Hex (l);
R = СН3СHBr, R' = Hex (m); R = CH3CHCl, R' = Bn (n); R = CH3CCl2, R' = Bn (o); R = CHCl2, R' = Bn (p).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

RATIO OF 1,3- AND 1,5-DIALKYL-SUBSTITUTED PYRAZOLES
1653
with methylhydrazine in ether, acetic acid, in alcohol,
also in a fluorinated alcohol (perfluoro-6,1,1-trihydro-
hexan-1-ol), in the presence of bases (triethylamine) or
acids (НCl) with predominant formation of 1,3-
substituted pyrazoles, whereas the condensation of 1,3-
diketones with methyl- and phenylhydrazine in 2,2,2-
trifluoroethanol or 1,1,1,3,3,3-hexafluoropropan-2-ol
results in the prevailing formation (75–99%) of one
among two isomers of substituted pyrazole [20].
Taking into account that 2-chlorovinyl ketones are
precursors of 1,3-dicarbonyl compounds [32], classical
source of pyrazoles preparation, we have hoped to
obtain similar result but have failed to observe the
desired prevailing formation of one of isomers.
individual isomer also in the reaction of propyl 2-
chlorovinyl ketone with tert-butylhydrazine, although
1-(tert-butyl)-5-propylpyrazole was obviously more
sterically hindered and thermodynamically less favo-
rable than the 1,3-substituted analog. The maximum
amount of 1,5-disubstituted pyrazoles III formed in the
reaction of propyl 2-chlorovinyl ketone with С1–С4
alkylhydrazines (Table 1, runs nos. 1–4).
As known [22, 26, 34], the reactions of R-2-chloro-
vinyl ketones with unsymmetrical dialkylhydrazines
lead to the selective formation of 1-alkyl-3-R-
pyrazoles. We succeeded to extend this procedure to
the preparation in the 33% yield of 3-(1-bromoethyl)-
1-methyl-1H-pyrazole (IV), an important precursor in
the synthesis of 3-alkenylpyrazole [29] and functiona-
lized derivatives of 3-alkylpyrazole [35] (Scheme 2).
We have not found a correlation between the
quantitative composition of the arising mixture of 1,3-
and 1,5-dialkyl-substituted pyrazoles (Table 1) and the
structure of 2-chlorovinyl ketone. Still some rules were
observed. In reactions of ketone Ia with С1–С4-
alkylhydrazines and benzylhydrazine (Table 1, runs
nos. 1–5) the ratio of 1,3- (58–60%) and 1,5-isomers
(40–42%) changed insignificantly.
Scheme 2.
Br
O
Et3N, Et2O,
1.5 h, 20oC
NH2NMe2
+
Cl
N
_
.
Et3N HCl
N
Br
Introduction of one or two halogen atoms in the
alkyl fragment of alkyl 2-chlorovinyl ketones Id–Ig
(Table 1, runs nos. 13–16) led to the formation of a
mixture enriched with 1,3-isomer by 17–28% compa-
red with the yield of 1-benzyl-5-(haloalkyl)pyrazoles
(12–23%). The ratio of isomeric 1,3- and 1,5-
disubstituted unsymmetrical pyrazoles depends on the
structure of alkylhydrazine. In reactions of С4–С8-
alkylhydrazines with propyl, butyl, amyl 2-chlorovinyl
ketones Ia–Ic (Table 1, runs nos. 6–12) the fraction of
1,5-isomer in the mixture considerably decreases (to
3–18%, Table 1). The least amount of 1,5-dialkyl-
substituted isomers formed in reactions of propyl 2-
chlorovinyl ketone with hexyl– and octylhydrazine and
of butyl 2-chlorovinyl ketone with octylhydrazine
(Table 1, runs nos. 7, 9, 11).
Me
Ic
IV
In continuation of the research in the chosen
direction we synthesized NH-unsubstituted pyrazoles
Va–Vc and explored their alkylation with various alkyl
bromides and methyl iodide. It was formerly reported
that the alkylation with higher alkyl halides of 1-
unsubstituted 3(5)-alkylpyrazoles results in the forma-
tion of exclusively 1,3-disubstituted pyrazoles [33].
The alkylation of 4-amyl-3(5)-hexylpyrazole with
haloalkanes afforded 1,4,5-trisubstituted pyrazoles [33]
in 70–82% yields. It was presumed that the reaction
mixture contained also 1,3,4-trisubstituted pyrazoles
[33], but the quantity of isomeric pyrazoles was not
determined.
At the introduction of a bulky bromine atom into
the alkyl fragment of 2-chlorovinyl ketone Id the ratio
of 1,3- and 1,5-isomers obtained in the reaction of
butyl 2-chlorovinyl ketone with hexylhydrazine (Table
1, run no. 13) virtually unchanged. The overall yield of
the mixture of isomeric 1,3- and 1,5-pyrazoles did not
exceed 28%. In all other reactions the mixture of
pyrazole isomers was obtained in 39 to 95% yields.
The mixture of two tautomers obtained by the
reaction of 2,2-difluoro-1-butylvinyl phenyl ketone
with unsubstituted hydrazine reacted with iodo– and
bromoalkanes, 4-nitrofluorobenzene in the presence of
sodium hydride giving 3-fluoro-5-phenyl-1-alkyl
(nitrophenyl)pyrazoles (68–97%) with an admixture of
5-fluoro-substituted pyrazoles (3–36%) whose quantity
depended on the bulk of the substituent at the nitrogen
atom [30] (at the alkylation with methyl iodide 3% of
5-fluoroisomer was obtained, in the reaction with
isopropyl iodide, 36%).
Note that in no experiments on reactions with С4–С8-
alkylhydrazines, in contrast to [33], we obtained
individual 1,3-isomers. We failed to prepare an
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POPOV et al.
1654
Scheme 3.
O
R
R
Cl
DMSO, NaOH, 2 h, 20oC,
R'Br, 2_24 h
R
Ia, Ib, Ih
+
N
Et2O, 1.5 h, 34oC
_Et3N . HCl
N
N
N
H
R
+
N
N
NH2NH2
R'
R'
+
Et3N
IIa, IIf, IIg, IIh, IIq-IIv IIIa, IIIf, IIIg, IIIh, IIIq-IIIv
Va-Vc
R = Pr (Ia, Vb), Bu (Ib, Vc), Et (Ih, Va); II, III, R = Et, R' = Pr (q), Bu (r); R = Pr, R' = Me (a), Amyl (f, g, h); R = Bu, R' = Me (s),
Et (t), Pr (u), Bu (v).
We demonstrated that the alkylation of
unsubstituted in the position 1 3(5)-alkylpyrazoles
obtained from 2-chlorovinyl ketones and hydrazine
afforded prevailingly 1-alkyl-3-R-pyrazoles (Table 2,
Scheme 3).
1,3-dialkylpyrazoles appears upfield with respect to
the Н3 signal in the 1,5-disubstituted pyrazoles.
In the 15N NMR spectra of 1-ethyl-3- (IIb) and -5-
propylpyrazole (IIIb) the signal of the pyridine
nitrogen appears in the region of –76.5 ppm, and the
corresponding signal of the pyrrole nitrogen, in the
region –164.5 and –166.5 ppm respectively.
3(5)-Ethyl-, propyl-, and butylpyrazoles Va–Vc at
the alkylation with С2–С4–alkyl bromides in dimethyl
sulfoxide in the presence of alkali furnished a mixture
of isomeric 1,3- and 1,5-disubstituted pyrazoles in a
ratio ~3 : 2. Only at the alkylation of 3(5)-butyl-
pyrazole with methyl iodide under similar conditions
the formed mixture of 1,3- and 1,5-isomers contained a
small excess (by 6%) of 5-butyl-1-methyl-pyrazole
(IIIs) (Scheme 3) (Table 2, run no. 7). N-Alkylation in
THF in the presence of a strong base (Me3Si)2NNa
(Table 2, run no. 11) analogously to the N-alkylation
of 4-butyl-3(5)-phenyl-5(3)-fluoropyrazole [30] also
did not afford a single isomer.
The assignment of the carbon signals was carried
out using 2D spectra HMBC 1H–13C and HSQC 1H–13C.
It follows from [22, 26, 34] that individual 1,3-
dialkylpyrazoles are obtained by the reaction of alkyl
2-chlorovinyl ketones with 1,1-dialkylhydrazines.
Since the only available unsymmetrical dialkylhyd-
razine is 1,1-dimethylhydrazine whose salts are
exclusively unstable and explosive, this procedure for
the regiodirectional synthesis of 1,3-dialkyl-substituted
pyrazoles cannot be recommended for industrial
application.
It should be stressed that in none of the reactions
with RBr, where R is an alkyl of a long chain, in
contrast to the data of [33], individual 1,3-isomers
have not formed.
The analysis of published data and our own results
show that the most appropriate way of synthesis of
individual isomers of 1,3-substituted pyrazoles,
promising ligands for the preparation of complex
compounds with uncommon magnetic properties [15],
is the dechlorination of available 5-chloro-1,3-
disubstituted pyrazoles [2, 24, 26–29, 36, 37]. The
reduction of 1,3-dimethyl-4Н- and -4-phenyl-5-chlo-
ropyrazoles with hydrogen on Raney nickel was
previously suggested for elucidating the proton
chemical shifts in the positions 3 and 5 of the 1,3- and
1,5-disubstituted pyrazoles [37].
The structure of synthesized 1,3- and 1,5-dialkyl-
substituted pyrazoles II and III was established by
means of 1H, 13C, 15N NMR spectroscopy. The analysis
of 2D 1Н and 13С NMR spectra of mixtures of 1-alkyl-
3-propylpyrazoles II and 1-alkyl-5-propylpyrazoles III
made it possible to elucidate the structure and assign
the proton signals in the positions 4, 3 and 4, 5. In the
NOESY spectra of the mixture of 1-ethyl-3- (IIb) and
-5-propylpyrazole (IIIb) a cross peak was observed of
the protons of CH2 groups belonging to ethyl and
propyl substituents in the positions 1 and 5 of the
pyrazole ring.
We have found that the reductive dechlorination of
1-methyl-3-propyl-5-chloropyrazole [24, 28] can be
performed applying a metal complex catalyst based on
nickel with 2,2'-bipyridyl as ligand utilizing as the
hydrogen source a system of water–zinc or magnesium
similarly to the dehalogenation of fluorochloroarenes
The chemical shifts of atoms Н4 virtually coincide
in the spectra of 3- and 5-alkylpyrazoles II and III,
and the chemical shift of proton Н5 in the spectra of
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RATIO OF 1,3- AND 1,5-DIALKYL-SUBSTITUTED PYRAZOLES
1655
Scheme 4.
O
Cl
R
R
R
Cl
N
VIa, VIb
o
N
,
NEt3 Et2O, 1.5 h, 34 C
Cl
O
N
N
+
_
.
Et3N HCl
OH
H
OH
N
H2N
VIIa, VIIb
R = Me (a), Pr (b).
[38]. Nonoptimized yield of 1-methyl-3-propyl-
pyrazole reached 21%. This method is especially
attractive since 1,3-dialkyl-substituted 5-chloropy-
razoles are now available and can be regioselectively
prepared in good yields both from 1,3-dicarbonyl
compounds and hydrazines in two stages and by a one-
step reaction of hydrazines with 2,2-dichlorovinyl
ketones [2, 24, 26–29].
succeed to obtain individual 1,3- and 1,5-dialkyl-
substituted pyrazoles from available highly reactive
alkyl-2-chlorovinyl ketones. The reactions of nitrogen-
unsubstituted pyrazoles obtained from 2-chlorovinyl
ketones with haloalkanes also resulted in mixtures of
1,3- and 1,5-isomers. Only in reactions of higher
specimens of alkyl 2-chlorovinyl ketones and alkyl-
hydrazines the fraction of sterically hindered 1,5-
dialkylpyrazoles decreased to 3%.
We confirmed that reactions of 2,2-dihalovinyl
ketones with versatile hydrazines, among them with
hydroxyalkylhydrazines, were chemoselective and
afforded exclusively 1,3-disubstituted 5-chloropyra-
zoles. The reactions of dichlorovinyl ketones with
hydroxyalkylhydrazines were not studied prior to our
research, and their direction could not be predicted
because of the possibility of side processes involving
the hydroxy group. Under the standard conditions of
the synthesis of 5-halopyrazoles [24, 26–29] from 2,2-
dihalovinyl ketones VIа and VIb and 2-hydroxy-
alkylhydrazines we obtained in good yields 5-chloro-
pyrazoles VIIа and VIIb (Scheme 4). Evidently the
stage of hydrazone formation is the decisive factor for
the selective synthesis of 1,3-dialkyl-5-chloro-
pyrazoles from 2,2-dichlorovinyl ketones and
hydrazines. No side products from reactions involving
the hydroxy group of the hydrazine and condensed
bisheterocyclic compounds, the corresponding pyra-
zolo[5,1-b][1,3]oxazoles etc., were not detected.
EXPERIMENTAL
1Н, 13С, 15N NMR spectra were registered on a
spectrometer Bruker DPX-400 (400.61, 100.13, and
40.56 МHz respectively) from 3–5% solutions in
СDCl3. IR spectra were recorded on a spectro-
photometer Bruker IFS-25 from thin films of samples.
1
Chemical shifts in Н and 13С NMR spectra were
measured with respect to TMS with an accuracy of
0.01 and 0.02 ppm respectively. Spin-spin coupling
constants JCН were determined with an accuracy of
0.1 Hz. The assignment of signals was performed
applying 2D NMR spectra HSQC-GP 1H–13C [39] and
HMBC-GP 1H–13C [40].
Chemical shifts in 15N NMR spectra were measured
with an accuracy of 0.1 ppm (with respect to external
reference CH315NO2) utilizing 2D NMR spectra
HMBC-GP 1H–15N.
Therefore the individual 1,3-dialkyl-5-chloro-
pyrazoles are readily and selectively formed by
reactions of versatile aryl, alkyl, haloalkyl-2,2-dichloro
(bromo)(fluoro)vinyl ketones with aryl-, alkylhydra-
zines, and also with hydroxyalkyl- and unsymmetrical
dialkylhydrazines.
Mass spectra of electron impact (70 eV) of
compounds II–VI were taken on an instrument
GCMS-QP5050A of Shimadzu (quadrupole mass
analyzer, the range of detected masses 34–650 Da).
Chromatographic separation of compounds under
study was carried out on a capillary column SPB–5
(60 m × 0.25 mm × 0.25 µm), carrier gas helium, flow
rate 0.7 mL/min. The temperatures of vaporizer and
ion source 220°С, pressure 100 kPa; ramp from 60 to
The individual 1,3-dialkylpyrazoles may be
prepared by the reaction of alkyl 2-chlorovinyl ketones
and 1,1-dialkylhydrazines [22, 25, 26, 34]. We did not
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

POPOV et al.
1656
220°С at a rate 8 deg/min. The samples of the volume
1 µL were introduces at split ratio 1 : 2.
maintaining the temperature below 25ºС, was added
dropwise 0.12 mol of alkyl halide. The reaction
mixture was stirred at 21–23ºС for 6 h. On completion
of the reaction the mixture was poured into water, the
reaction product was extracted into diethyl ether
(3 × 50 mL). The extract was dried with MgSO4, eva-
porated, the residue was distilled in a vacuum.
Initial 2-chlorovinyl ketones Iа–Ic and Ie were
obtained by reacting the corresponding acyl chlorides
with acetylene (anhydrous aluminum chloride
catalyst), their constants were in agreement with the
data published in [29, 31, 32, 41]. 1-Bromoethyl 2-
chlorovinyl ketone (Id) was obtained with admixture
of ketone Ie by the reaction of 2-bromopropionyl
chloride with 1,1-dichloroethylene catalyzed with
aluminum chloride [29]. Dichloroalkyl 2-chlorovinyl
ketones If and Ig were prepared by reacting 1-
chloropropionic acid and chloroacetyl chloride with
1,2-dichloroethylene respectively [42, 43]. Physico-
chemical constants of ketones Iа–If were consistent
with the published data.
A mixture of 1-methyl-3-propylpyrazole (IIа)
and 1-methyl-5-propylpyrazole (IIIа) was obtained
by procedure а from 1.30 g (0.01 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 1.01 g (0.01 mol) of tri-
ethylamine, and 0.46 g (0.01 mol) of methylhydrazine,
yield 1.10 g (89%); by procedure b from 11.01 g (0.1 mol)
of 3(5)-propyl-1Н-pyrazole (Vb), 17.03 g (0.12 mol)
methyl iodide, and 12 g (0.3 mol) of KOH, yield 11.05 g
(89%). 1H NMR spectrum, δ, ppm (J, Hz), (IIа): 0.92 t
(3H, CH3, J 7.2), 1.61 m (2H, CH2СH3), 2.54 t (2H,
CH2C2H5), 3.79 s (3H, NCH3), 5.96 d (1H, H4, J 2.0),
7.18 d (1H, H5); (IIIа): 0.95 t (3H, CH3, J 7.2), 1.62
d.d (2H, CH2CH3), 2.52 t (2H, CH2C2H5), 3.73 s (3H,
NCH3), 5.96 d (1H, H4, J 1.6), 7.32 d (1H, H3). Found,
%: С 67.67; H 9.57; N 22.05. C7H12N2. Calculated, %:
С 67.70; H 9.74; N 22.56.
Initial 2,2-dichlorovinyl ketones VIa and VIb were
synthesized from the corresponding acyl chlorides and
1,1-dichloroethylene by known procedures, the phy-
sicochemical constants of ketones VIa and VIb were
consistent with the published data [44].
Hydrazines (methyl-, ethyl-, butyl-, tert-butyl-,
pentyl-, benzyl-, 2-hydroxyethyl-, and 2-hydroxy-
propylhydrazine) and bromoalkanes were commercial
reagents. Hexyl-, heptyl-, octylhydrazines were
prepared by hydrazine alkylation [33].
c. Reduction of 1-methyl-3-propyl-5-chloropyra-
zole. Synthesis of 1-methyl-3-propylpyrazole. A mix-
.
ture of 0.26 g (0.0011 mol) of NiCl2 6H2O, 0.21 g
(0.0011 mol) of 2,2'-bipyridyl, 0.26 g (0.0108 mol) of
Mg, 0.19 g (0.0108 mol) of H2O in 3 mL of DMF was
stirred for 10 min till the appearance of black color.
Then 0.57 g (0.0036 mol) of 5-chloro-1-methyl-3-
propyl-1H-pyrazole was added, and the stirring was
continued for 7 h. The reaction mixture was diluted
with 10 mL of H2O, the reaction product was extracted
into ethyl acetate (3 × 15 mL). The organic phase was
dried with MgSO4, the solvent was evaporated, the
residue was purified by column chromatography.
Eluent CHCl3–MeOH, 95 : 5. We obtained compound
IIa. Yield 0.10 g (21%).
3(5)-Dialkylpyrazoles Vа–Vc unsubstituted in the
position 1 were obtained from 0.1 mol of mono-
chlorovinyl ketones and 0.2 mol of hydrazine hydrate
[31]. Physicochemical constants of pyrazoles Vа–Vc
were consistent with the published data [31, 33].
Mixtures of pyrazoles II and III. а. Reaction of 2-
chlorovinyl ketones with alkylhydrazines. To a
solution of 0.01 mol of 2-chlorovinyl ketone in 10 mL
of diethyl ether cooled to –10°С was added dropwise a
solution of 0.01 mol of triethylamine in 5 mL of
diethyl ether and after that a solution of 0.01 mol of
alkylhydrazine in 5 mL of diethyl ether within 30 min
was added. Then the reaction mixture was refluxed for
30 min. The precipitate was filtered off. The filtrate
was evaporated. After distilling off diethyl ether a
mixture of 1,3- and 1,5-disubstituted pyrazoles was
obtained that was distilled in a vacuum.
A mixture of 1-ethyl-3-propylpyrazole (IIb) and
1-ethyl-5-propylpyrazole (IIIb) was obtained by
procedure а from 1.30 g (0.01 mol) of (1E)-1-chloro-
hex-1-en-3-one (Iа), 1.01 g (0.01 mol) of triethyl-
amine, and 0.60 g (0.01 mol) of ethylhydrazine, yield
1
1.25 g (89%). H NMR spectrum, δ, ppm (J, Hz),
(IIb): 0.92 t (3H, CH3, J 7.2), 1.61 d.d (2H, CH2СH3),
2.54 t (2H, CH2C2H5), 3.79 q (2H, NCH2), 5.96 d (1H,
H4, J 2.0), 7.18 d (1H, H5); (IIIb): 0.95 t (3H, CH3),
1.62 d.d (2H, CH2CH3), 2.52 t (2H, CH2C2H5), 3.73 m
(2H, NCH2), 5.96 br.s (1H, H4), 7.32 br.s (1H, H3).
b. Alkylation of 3(5)-alkylpyrazoles with alkyl
halides. In 20 mL of DMSO was charged 0.3 mol of
KOH, the mixture was stirred for 10 min, 0.1 mol of 3-
alkyl-1H-pyrazole was added, and the reaction mixture
was stirred for another 15 min. Then slowly,
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RATIO OF 1,3- AND 1,5-DIALKYL-SUBSTITUTED PYRAZOLES
1657
Found, %: С 69.30; H 10.05; N 20.18. C8H14N2.
Calculated, %: С 69.52; H 10.21; N 20.27.
5.27 s (2H, СН2N), 6.09 d (H, H4, J 2.2), 7.03 m (6H,
H5, Ph), 7.23 d (1Н, H3, J 2.2). Found, %: С 77.90; H
8.00; N 14.01. C13H16N2. Calculated, %: С 77.96; H
8.05; N 13.99.
A mixture of 1-butyl-3-propylpyrazole (IIc) and
1-butyl-5-propylpyrazole (IIIc) was obtained by
procedure а from 1.33 g (0.01 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 1.01 g (0.01 mol) of
triethylamine, and 0.88 g (0.01 mol) of butylhydrazine.
Yield 1.01 g (71%), bp 83–85°С (12 mmHg). IR
spectrum, ν, cm–1: 3080 (=CH); 2960, 2930, 2875
A mixture of 1-pentyl-3-propylpyrazole (IIf) and
1-pentyl-5-propylpyrazole (IIIf) was obtained by
procedure а from 1.30 g (0.01 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 1.01 g (0.01 mol) of tri-
ethylamine, and 1.02 g (0.01 mol) of pentylhydrazine,
yield 1.46 g (81%); by procedure b from 11.01 g (0.1 mol)
of 3-propyl-1Н-pyrazole (Vb), 18.12 g (0.12 mol) of
amyl bromide, and 12 g (0.3 mol) of KOH, yield
16.23 g (90%). 1H NMR spectrum, δ, ppm, (IIf): 0.87 t
(3H, CH3 pentyl), 0.94 t (3H, СH3 propylа), 1.31 m
[4Н, (СН2)2СН3 pentyl], 1.64 m (2H, CH2СН3 propyl),
1.82 m (2Н, СН2 pentyl), 2.59 t (2Н, СН2 propyl), 4.02
t (2Н, NCH2), 5.99 d (1H, H4, J 2.0 Hz), 7.23 d (1H,
H5); (IIIf): 0.87 t (3H, CH3 pentyl), 0.96 t (3H, СH3
propyl), 1.31 m [4Н, (СН2)2СН3 pentyl], 1.67 m (2H,
CH2СН3 propyl), 1.82 m (2Н, СН2 pentyl), 2.64 t (2Н,
СН2 propyl), 4.02 t (2Н, NCH2), 5.99 s (1H, H4), 7.39
s (1H, H3). Found, %: С 73.20; H 11.09; N 15.50.
C11H20N2. Calculated, %: С 73.28; H 11.18; N 15.54.
1
(Alk); 1680, 1580 (C=N, C=C). H NMR spectrum, δ,
ppm (J, Hz), (IIc): 0.92 m (6H, 2CH3), 1.61 d.d (2H,
CH2СH3), 2.58 t (2H, CH2C2H5), 3.79 t (2H, NCH2),
6.04 d (1H, H4, J 2.0), 7.18 d (1H, H5); (IIIc): 0.93 m
(6Н, 2CH3, J 7.2), 1.62 d.d (2H, CH2CH3), 1.29 m
(8Н, 4СН2, J 7.2), 2.56 t (2H, CH2C2H5), 3.73 m (2H,
CH2), 4.09 m (2Н, СН2N, J 7.2), 5.96 d (1H, H4, J
1.6), 7.32 d (1H, H3). Found, %: С 72.28; H 10.35; N
16.62. C10H18N2. Calculated, %: С 72.24; H 10.91; N
16.85.
A mixture of 1-(tert-butyl)-3-propylpyrazole
(IId) and 1-(tert-butyl)-5-propylpyrazole (IIId) was
obtained by procedure а from 2.01 g (0.015 mol) of
(1E)-1-chlorohex-1-en-3-one (Iа) in 10 mL of
methanol, 1.9 g (0.015 mol) of tert-butylhydrazine
hydrochloride dissolved in 3 mL of water, and 3 g
(0.045 mol) of triethylamine. The reaction product was
extracted into diethyl ether (3 × 25 mL). Yield 1.52 g
(61%). IR spectrum, ν, cm–1: 3126, 3100 (=CH); 2963,
2934, 2873 (Alk); 1519 (C=C, C=N).
A mixture of 1-hexyl-3-propylpyrazole (IIg) and
1-hexyl-5-propylpyrazole (IIIg) was obtained by
procedure a from 1.30 g (0.01 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 1.01 g (0.01 mol) of tri-
ethylamine, and 1.17 g (0.01 mol) of hexylhydrazine,
yield 1.7 g (89%), bp 92°С (2 mmHg); by procedure b
from 11.01 g (0.1 mol) of 3(5)-propyl-1Н-pyrazole
(Vb), 19.81 g (0.12 mol) of hexyl bromide, and 12 g
1
Compound IId. H NMR spectrum, δ, ppm: 1.54 s
(9Н, 3СН3), 5.99 d (1Н, H4, J 2.2 Hz), 7.38 d (1Н, H5).
13С NMR spectrum, δ, ppm: 29.87, 102.88, 125.84,
150.25. 15N NMR spectrum, δ, ppm: –78.6, –152.6.
1
(0.3 mol) of KOH, yield 18.15 g (92%). H NMR
spectrum, δ, ppm (J, Hz), (IIg): 0.83 t (3H, CH3
hexyl), 0.92 t (3H, СH3 propyl), 1.25 br.s [6Н,
(СН2)3СН3 hexyl], 1.62 m (2H, CH2СН3 propyl), 1.79
m (2Н, СН2 hexyl), 2.57 t (2Н, СН2 propyl), 4.01 t
(2Н, NCH2), 5.96 d (1H, H4, J 2.1), 7.21 d (1H, H5);
Compound IIId. 1H NMR spectrum, δ, ppm: 1.61 s
(9Н, 3СН3), 6.07 d (1Н, H4, J 1.6 Hz), 7.34 d (1Н, H3).
13С NMR spectrum, δ, ppm: 30.34, 106.02, 136.22,
140.26. 15N NMR spectrum, δ, ppm: –82.6, –151.3.
Found, %: C 72.21; H 9.72; N 16.51. C10H18N2.
Calculated, % C 72.24; H 10.91; N 16.85.
3
(IIIg): 7.37 d (1H, H3, J 1.6). 13C NMR spectrum, δ,
ppm, (IIg): 13.80, 23.00, 30.14 (propyl), 13.73, 22.34,
26,16, 30.35, 31.18, 51.75 (hexyl), 103.39 (С4), 129.17
(С5), 152.80 (С3). Found, %: С 74.02; H 11.29; N
14.37. C12H22N2. Calculated, %: С 74.17; H 11.41; N
14.42.
A mixture of 1-benzyl-3-propylpyrazole (IIe)
and 1-benzyl-5-propylpyrazole (IIIe) was obtained
by procedure а from 1.33 g (0.01 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 1.01 g (0.01 mol) of tri-
ethylamine, and 1.22 g (0.01 mol) of benzylhydrazine.
Yield 1.30 g (95%). IR spectrum, ν, cm–1: 3080 (=CH);
A mixture of 1-hexyl-3-propylpyrazole (IIg) and
1-hexyl-5-propylpyrazole (IIIg). To a solution of
0.55 g (0.005 mol) of 3-propyl-1Н-pyrazole (Vb) in
3 mL of anhydrous THF cooled to –10°С was added
dropwise a solution of 0.50 g (0.005 mol) of sodium
hexamethyldisilazide in THF, then 0.83 g (0.005 mol)
1
2960, 2930, 2875 (Alk); 1680, 1580 (C=N, C=C). H
NMR spectrum, δ, ppm (J, Hz): 0.92 m (3Н, CH3, J
7.2), 1.53 m (2Н, CH2, J 7.2), 2.61 m (2Н, СН2, J 7.2),
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POPOV et al.
1658
of hexyl bromide, and the mixture was stirred at room
temperature for 6 h. The precipitate was filtered off,
the solvent was distilled off. Yield 0.70 g (72%).
butyl), 4.02 t (2Н, NCH2), 5.99 d (1H, H4, J 1.8 Hz),
7.23 d (1H, H5); (IIIj): 0.86 t (3H, CH3 hexyl), 0.95 t
(3H, СH3 butyl), 1.28 br.s [6Н, (СН2)3СН3 hexyl], 1.38
m (2Н, СН2СН2СН3 butyl), 1.61 m (2H, CH2СН3
butyl), 1.81 m (2Н, СН2 hexyl), 2.57 t (2Н, СН2
butyl), 4.01 t (2Н, NCH2), 5.99 s (1H, H4), 7.38 s (1H,
H3). Found, %: С 74.87; H 11.35; N 13.40. C13H24N2.
Calculated, %: С 74.94; H 11.61; N 13.45.
A mixture of 1-heptyl-3-propylpyrazole (IIh)
and 1-heptyl-5-propylpyrazole (IIIh) was obtained
by procedure а from 0.66 g (0.005 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 0.5 g (0.005 mol) of
triethylamine, and 0.65 g (0.005 mol) of heptyl-
hydrazine, yield 0.78 g (75%); by procedure b from
11.01 g (0.1 mol) of 3-propyl-1Н-pyrazole (Vb),
21.49 g (0.12 mol) of heptyl bromide, and 12 g (0.3 mol)
A mixture of 1-octyl-3-butylpyrazole (IIk) and 1-
octyl-5-butylpyrazole (IIIk) was obtained by
procedure a from 0.36 g (0.0025 mol) of (1E)-1-
chlorohept-1-en-3-one (Ib), 0.25 g (0.0025 mol) of
1
of KOH, yield 15.6 g (75%). H NMR spectrum, δ,
ppm, (IIh): 0.86 t (3H, CH3 heptyl), 0.94 t (3H, СH3
propyl), 1.27 br.s [8Н, (СН2)4СН3 heptyl], 1.64 m (2H,
CH2СН3 propyl), 1.81 m (2Н, СН2 heptyl), 2.58 t (2Н,
СН2 propyl), 4.02 t (2Н, NCH2), 5.98 s (1H, H4), 7.23
s (1H, H5); (IIIh): 0.87 t (3H, CH3 heptyl), 0.99 t (3H,
СH3 propyl), 1.27 br.s[8Н,(СН2)4СН3 heptyl], 1.64 m
(2H, CH2СН3 propyl), 1.81 m (2Н, СН2 heptyl), 2.54 t
(2Н, СН2 propyl), 4.00 t (2Н, NCH2), 5.98 s (1H, H4),
7.38 s (1H, H3). Found, %: С 74.87; H 11.57; N 13.38.
C13H24N2. Calculated, %: С 74.94; H 11.61; N 13.45.
triethylamine, and 0.36
g
(0.0025 mol) of
octylhydrazine. Yield 0.36 g (62%). 1H NMR
spectrum, δ, ppm, (IIk): 0.87 t (3H, CH3 octyl), 0.92 t
(3H, СH3 butyl), 1.28 br.s [10Н, (СН2)5СН3 octyl],
1.37 m (2Н, СН2СН2СН3 butyl), 1.62 m (2H, CH2СН3
butyl), 1.82 m (2Н, СН2 octyl), 2.62 t (2Н, СН2 butyl),
4.03 t (2Н, NCH2), 5.99 d (1H, H4, J 2.2 Hz), 7.24 d
(1H, H5); (IIIk): 0.87 t (3H, CH3 octyl), 0.93 t (3H,
СH3 butyl), 1.28 br.s [10Н,(СН2)5 СН3 octyl], 1.37 m
(2Н, СН2СН2СН3 butyl), 1.61 m (2H, CH2СН3 butyl),
1.82 m (2Н, СН2 octyl), 2.62 t (2Н, СН2 butyl), 4.03 t
(2Н, NCH2), 5.99 d (1H, H4), 7.39 d (1H, H3, J 1.7 Hz).
Found, %: С 76.18; H 11.76; N 11.79. C15H28N2.
Calculated, %: С 76.21; H 11.94; N 11.85.
A mixture of 1-octyl-3-propylpyrazole (IIi) and
1-octyl-5-propylpyrazole (IIIi) was obtained by
procedure a from 0.33 g (0.0025 mol) of (1E)-1-
chlorohex-1-en-3-one (Iа), 0.25 g (0.0025 mol) of
triethylamine, and 0.36
g
(0.0025 mol) of
A mixture of 1-hexyl-3-pentylpyrazole (IIl) and
1-hexyl-5-pentylpyrazole (IIIl) was obtained by
procedure a from 0.40 g (0.0025 mol) of (1E)-1-
chlorooct-1-en-3-one (Ic), 0.25 g (0.0025 mol) of
triethylamine, and 0.29 g (0.0025 mol) of hexyl-
octylhydrazine. Yield 0.27 g (48%). 1H NMR
spectrum, δ, ppm (J, Hz), (IIi): 0.86 t (3H, CH3 octyl),
0.94 t (3H, СH3 propyl), 1.27 br.s [10Н, (СН2)5СН3
octyl], 1.64 m (2H, CH2СН3 propyl), 1.81 m (2Н, СН2
octyl), 2.58 t (2Н, СН2 propyl), 4.02 t (2Н, NCH2),
5.98 d (1H, H4, J 2.2), 7.23 d (1H, H5); (IIIi): 0.86 t
(3H, CH3 octyl), 0.94 t (3H, СH3 propyl), 1.27 br.s
[10Н, (СН2)5СН3 octyl], 1.64 m (2H, CH2СН3 propyl),
1.81 m (2Н, СН2 octyl), 2.58 t (2Н, СН2 propyl), 4.02 t
(2Н, NCH2), 5.98 d (1H, H4), 7.38 d (1H, H3, J 1.7).
Found, %: С 75.48; H 11.68; N 12.56. C14H26N2.
Calculated, %: С 75.62; H 11.79; N 12.60.
1
hydrazine. Yield 0.45 g (81%). H NMR spectrum,
δ, ppm, (IIl): 0.86 t (3H, CH3 hexyl), 0.89 t (3H, СH3
amyl), 1.30 m [10Н, (СН2)3СН3 hexyl, (СН2)2СН3
amyl], 1.63 m (2H, CH2СН2 amyl), 1.80 m (2Н,
СН2 hexyl), 2.60 t (2Н, СН2 amyl), 4.04 t (2Н, NCH2),
5.99 d (1H, H4, J 2.2 Hz), 7.23 d (1H, H5); (IIIl):
0.86 t (3H, CH3 hexyl), 0.89 t (3H, СH3 amyl), 1.30
m [10Н, (СН2)3СН3 hexyl, (СН2)2СН3 amyl], 1.63
m (2H, CH2СН2 amyl), 1.80 m (2Н, СН2 hexyl),
2.60 t (2Н, СН2 amyla), 4.04 t (2Н, NCH2), 5.99 s (1H,
H4), 7.30 s (1H, H3). Found, %: С 74.82; H 11.60; N
13.25. C14H26N2. Calculated, %: С 75.62; H 11.79; N
12.60.
A mixture of 1-hexyl-3-butylpyrazole (IIj) and 1-
hexyl-5-butylpyrazole (IIIj) was obtained by
procedure a from 0.36 g (0.0025 mol) of (1E)-1-
chlorohept-1-en-3-one (Ib), 0.25 g (0.0025 mol) of
triethylamine, and 0.29
g
(0.0025 mol) of
hexylhydrazine. Yield 0.43 g (83%). 1H NMR
spectrum, δ, ppm, (IIj): 0.86 t (3H, CH3 hexyl), 0.92 t
(3H, СH3 butyl), 1.28 br.s [6Н, (СН2)3СН3 hexyl], 1.38
m (2Н, СН2СН2СН3 butyl), 1.61 m (2H, CH2СН3
butyl), 1.81 m (2Н, СН2 hexyl), 2.61 t (2Н, СН2
A mixture of 1-hexyl-3-(1-bromoethyl)pyrazole
(IIm) and 1-hexyl-5-(1-bromoethyl)pyrazole (IIIm)
was obtained by procedure a from 3.95 g (0.02 mol) of
(1E)-4-bromo-1-chloropent-1-en-3-one (Id), 2.02 g
(0.02 mol) of triethylamine, and 2.32 g (0.02 mol) of
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RATIO OF 1,3- AND 1,5-DIALKYL-SUBSTITUTED PYRAZOLES
1659
hexylhydrazine. Yield 1.45 g (28%). 1H NMR
spectrum, δ, ppm, (IIm): 0.85 t (3H, CH3), 1.26 br.s
[6Н, (СН2)3СН3], 1.81 m (2Н, СН2), 1.84 d (3H, СН3),
4.04 t (2Н, NCH2), 5.17 q (1Н, СНBr), 6.26 d (1H, H4,
J 2.2 Hz), 7.28 d (1H, H5); (IIIm): 0.85 t (3H, CH3),
1.26 br.s [6Н, (СН2)3СН3], 1.81 m (2Н, СН2), 1.90 d
(3H, СН3), 4.12 t (2Н, NCH2), 5.10 q (1Н, СНBr),
6.26 d (1H, H4), 7.41 d (1H, H3, J 2.0 Hz). Found, %:
С 50.86; H 7.28; Br 30.78; N 10.74. C11H19BrN2.
Calculated, %: С 50.97; H 7.39; Br 30.83; N 10.81.
was obtained by procedure a from 1.73 g (0.01 mol) of
(3E)-1,1,4-trichlorobut-3-en-2-one (If), 1.01 g (0.01 mol)
of triethylamine, and 1.22 g (0.01 mol) of benzyl-
hydrazine. Yield 1.59 g (66%). IR spectrum, ν, cm–1:
3130, 3080 (=CH); 3000, 2970 (Alk); 1585, 1524
1
(C=C, C=N). H NMR spectrum, δ, ppm, (IIp): 5.50 s
(2H, NCH2), 6.50 d (1H, H4, J 2.3 Hz), 6.53 s (1H,
CHСl2), 7.14–7.29 m (5H, C6H5), 7.31 d (1H, H5).
Mass spectrum, m/z (Irel, %): 240 (20) [M]+, 205 (80),
169 (35), 91 (100), 65 (50), 51 (30), 39 (28). 1H NMR
spectrum, δ, ppm, (IIIp): 5.45 s (2H, NCH2), 6.50 s
(1H, H4), 6.57 s (1H, CHCl2), 7.16 s (1H, H3), 7.15–
7.30 m (5H, C6H5). Mass spectrum of pyrazole, m/z
(Irel, %): 240 (13) [M]+, 205 (12), 169 (30), 91 (100),
65 (23), 51 (18), 39 (17). Found, %: C 55.00; H 4.17;
Cl 29.29; N 11.66. C11H10Cl2N2. Calculated, %: C
54.79; H 4.18; Cl 29.41; N 11.62.
A mixture of 1-benzyl-3-(1-chloroethyl)pyrazole
(IIn) and 1-benzyl-5-(1-chloroethyl)pyrazole (IIIn)
was obtained by procedure a from 7.65 g (0.05 mol) of
(1Е)-1,4-dichloropent-1-en-3-one (Ie), 5.06 g (0.05 mol)
of triethylamine, and 6.11 g (0.05 mol) of benzylhyd-
razine. Yield 6.72 g (61%). 1H NMR spectrum, δ, ppm
(J, Hz), (IIn): 1.91 d (3H, CH3, J 6.8), 5.24 q (1H,
CHCl, J 6.8), 5.26 s (2H, NCH2), 6.36 d (1H, H4, J
2.2), 7.29 d (1H, H5, J 2.2), 7.21–7.37 m (5H, C6H5);
(IIIn): 1.80 d (3H, CH3, J 6.8), 4.93 q (1H, CHCl, J
6.8), 5.25 s (2H, NCH2), 6.33 d (1H, H4, J 1.8), 7.30–
7.17 m (6H, C6H5, H3). 13C NMR spectrum, δ, ppm,
(IIn): 25.05 (CH3), 52.22 (CHCl), 55.89 (NCH2),
103.73 (C4), 127.63 (C2,6phenyl), 128.03 (C4phenyl), 128.76
(C3,5phenyl), 130.33 (C5), 136.24 (С1phenyl), 153.91 (С3);
(IIIn): 25.05 (CH3), 47.49 (CHCl), 53.54 (NCH2),
104.76 (C4), 126.95 (C2,6phenyl), 127.93 (C4phenyl), 128.90
(C3,5phenyl), 136.75 (С1phenyl), 138.62 (C3), 143.08 (С5).
Found, %: С 65.57; H 5.95; Cl 15.97; N 12.73. C12H13ClN2.
Calculated, %: С 65.31; H 5.94; Cl 16.06; N 12.69.
A mixture of 1-propyl-3-ethylpyrazole (IIq) and
1-propyl-5-ethylpyrazole (IIIq) was obtained by
procedure b from 9.61 g (0.1 mol) of 3-ethyl-1Н-
pyrazole (Vа), 14.76 g (0.12 mol) of propyl bromide,
and 12 g (0.3 mol) of KOH. Yield 9.93 g (72%), bp
94–100ºС (30–35 mmHg). 1H NMR spectrum, δ, ppm,
(IIq): 0.88 m (3H, CH3 propyl), 1.24 m (3H, CH3
ethyl), 1.84 m (2H, CH2), 2.62 m (2H, CH2), 3.98 m
(2H, NCH2), 5.99 d (1H, H4, J 1.83 Hz), 7.24 d (1H,
H5, J 1.83 Hz); (IIIq): 6.00 s (1H, H4), 7.38 s (1H, H3).
Found, %: C 69.79; H 10.19; N 20.02. C8H14N2.
Calculated, %: C 69.52; H 10.21; N 20.27.
A mixture of 1-butyl-3-ethylpyrazole (IIr) and 1-
butyl-5-ethylpyrazole (IIIr) was obtained by
procedure b from 9.61 g (0.1 mol) of 3-ethyl-1Н-
pyrazole (Vа), 16.44 g (0.12 mol) of butyl bromide,
and 12 g (0.3 mol) of KOH. Yield 11.10 g (73%), bp
A mixture of 1-benzyl-3-(1,1-dichloroethyl)pyra-
zole (IIo) and 1-benzyl-5-(1,1-dichloroethyl)-pyra-
zole (IIIo) was obtained by procedure a from 1.87 g
(0.01 mol) of (1Е)-1,4,4-trichloropent-1-en-3-one (If),
1.01 g (0.01 mol) of triethylamine, and 1.22 g (0.01 mol)
of benzylhydrazine. Yield 1.56 g (61%). IR spectrum,
ν, cm–1: 3131, 3085 (=CH); 2995, 2975, (Alk); 1585,
1
102–105ºС (30– 35 mmHg). H NMR spectrum, δ,
ppm, (IIr): 0.91 m (3H, CH3 butyl), 1.22 m (3H, CH3
ethyl), 1.29 m (2H, CH2), 1.80 m (2H, CH2), 2.64 m
(2H, CH2), 4.01 m (2H, NCH2), 5.99 d (1H, H4, J 2.2 Hz),
7.23 d (1H, H5, J 2.2 Hz); (IIIr): 6.01 s (1H, H4), 7.37
s (1H, H3). Found, %: C 70.67; H 10.55; N 18.78.
C9H16N2. Calculated, %: C 71.01; H 10.59; N 18.40.
1
1524 (C=C, C=N). H NMR spectrum, δ, ppm, (IIo):
2.66 s (3H, CH3), 5.24 s (2H, NCH2), 6.52 d (1H, H4, J
2.2 Hz), 7.14–7.28 m (5H, C6H5), 7.30 d (1H, H5 J
2.2 Hz). Mass spectrum, m/z (Irel, %): 240 (20) [M]+.
1H NMR spectrum, δ, ppm, (IIIo): 2.65 s (3H, CH3),
5.25 s (2H, NCH2), 6.53 s (1H, H4), 7.15–7.26 m (5H,
C6H5), 7.28 d (1H, H3). Mass spectrum, m/z (Irel, %):
240 (13) [M]+. Found, %: C 56.72; H 4.73; Cl 27.67; N
10.93. C12H12Cl2N2. Calculated, %: C 56.49; H 4.74;
Cl 27.79; N 10.98.
A mixture of 1-methyl-3-butylpyrazole (IIs) and
1-methyl-5-butylpyrazole (IIIs) was obtained by
procedure b from 12.42 g (0.1 mol) of 3-butyl-1Н-
pyrazole (Vc), 17.03 g (0.12 mol) of methyl iodide,
and 12 g (0.3 mol) of KOH. Yield 10.49 g (76%), bp
1
93–98ºС (8–10 mmHg). H NMR spectrum, δ, ppm,
A mixture of 1-benzyl-3-dichloromethylpyrazole
(IIp) and 1-benzyl-5-dichloromethylpyrazole (IIIp)
(IIs): 0.91 m (3H, CH3), 1.38 m (2H, CH2), 1.60 m
(2H, CH2), 2.58 m (2H, CH2), 3.76 s (3H, NCH3), 5.98
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

POPOV et al.
1660
d (1H, H4, J 1.87 Hz), 7.20 d (1H, H5, J 1.87 Hz);
(IIIs): 3.81 s (3H, NCH3), 5.99 s (1H, H4), 7.34 s (1H,
H3). Found, %: C 69.86; H 10.18; N 19.96. C8H14N2.
Calculated, %: C 69.52; H 10.21; N 20.27.
30 min, and then the reaction mixture was kept at room
temperature for 3 h. The precipitate was filtered off,
the filtrate was evaporated. Yield 0.16 g(33%). H
NMR spectrum, δ, ppm (J, Hz): 1.88 d (3H, CH3, J
6.9), 3.88 s (3H, NCH3), 5.19 q (1H, СHBr, J 6.9),
6.29 d (1H, H4, J 2.2), 7.30 d (1H, H5). Found, %: C
38.19; H 4.81; Br 42.18; N 14.74. C6H9BrN2.
Calculated, %: C 38.12; H 4.80; Br 42.27; N 14.82.
1
A mixture of 1-ethyl-3-butylpyrazole (IIt) and 1-
ethyl-5-butylpyrazole (IIIt) was obtained by proce-
dure b from 12.42 g (0.1 mol) of 3-butyl-1Н-pyrazole
(Vc), 13.07 g (0.12 mol) of ethyl bromide, and 12 g
(0.3 mol) of KOH. Yield 12.16 g (80%), bp 95–103ºС
3(5)-Butylpyrazole (Vc). To a solution of 5.84 g
(0.04 mol) of (1E)-1-chloropent-1-en-3-one (Ib) in 10 mL
of diethyl ether at stirring and cooling with water was
added 4 g (0.08 mol) of hydrazine hydrate. The
mixture was stirred at 20–22ºС for 24 h, then it was
heated for 1 h, cooled, and diluted with 20 mL of 40%
NaOH solution. The reaction product was extracted
with ether, the extract was dried with MgSO4. Yield
3.87 g (78%), bp 151–152ºС (33–35 mmHg). 1H NMR
spectrum, δ, ppm (J, Hz): 0.90 t (3H, CH3, J 7.4), 1.36
m (2H, CH2, J 7.4), 1.63 m (2H, CH2, J 7.4), 2.67 t
1
(8–10 mmHg). H NMR spectrum, δ, ppm, (IIt): 0.93
m (3H, CH3 butyl), 1.38 m (3H, CH3 ethyl), 1.44 m
(2H, CH2), 1.61 m (2H, CH2), 2.59 m (2H, CH2), 4.07
m (2H, NCH2), 5.99 d (1H, H4, J 1.53 Hz), 7.25 d (1H,
H5, J 1.53 Hz); (IIIt): 6.00 s (1H, H4), 7.38 s (1H, H3).
Found, %: C 71.37; H 10.63; N 18.00. C9H16N2. Calcu-
lated, %: C 71.01; H 10.59; N 18.40.
A mixture of 1-propyl-3-butylpyrazole (IIu) and
1-propyl-5-butylpyrazole (IIIu) was obtained by
procedure b from 12.42 g (0.1 mol) of 3-butyl-1Н-
pyrazole (Vc), 14.72 g (0.12 mol) of propyl bromide,
and 12 g (0.3 mol) of KOH. Yield 13.94 g (84%), bp
(2H, CH2, J 7.4), 6.05 d (1H, H4, J 1.8), 7.47 d (1H, H3(5)
,
J 1.8). 13C NMR spectrum, δ, ppm: 13.90 (CH3), 22.50
(CH2), 26.48 (CH2), 31.74 (NCH2), 103.29 (C4),
135.10 (C5), 147.83 (C3).
1
108–110ºС (30–35 mmHg). H NMR spectrum, δ,
ppm, (IIu): 0.90 m (3H, CH3 butyl), 0.93 m (3H, CH3
propyl), 1.37 m (2H, CH2 butyl), 1.60 m (2H, CH2
propyl), 1.82 m (2H, CH2 butyl), 2.58 m (2H, CH2
butyl), 3.98 m (2H, NCH2), 5.98 d (1H, H4, J 2.08 Hz),
7.23 d (1H, H5, J 2.08 Hz); (IIIu): 5.99 d (1H, H4, J
1.59 Hz), 7.37 d (1H, H3, J 1.59 Hz). Found, %: C
71.88; H 10.93; N 17.19. C10H18N2. Calculated, %: C
72.24; H 10.91; N 16.85.
Pyrazoles VII from alkyl 2,2-dichlorovinyl
ketones and hydroxyalkylhydrazines. General
procedure. To a solution of 0.02 mol of alkyl 2,2-
dichlorovinyl ketone in 20 mL of ether was added
dropwise a mixture of 0.02 mol of hydroxyalkyl-
hydrazine and 0.02 mol of triethylamine. On comple-
tion of the exothermic reaction the reaction mixture
was boiled for 1.5 h and afterwards poured in water.
The organic layer was separated, the reaction product
was extracted from water layer with diethyl ether (3 ×
25 mL), organic solutions were combined, dried with
MgSO4, evaporated, the residue was distilled in a
vacuum.
A mixture of 1,3-dibutylpyrazole (IIv) and 1,5-
dibutylpyrazole (IIIv) was obtained by procedure b
from 12.42 g (0.1 mol) of 3-butyl-1Н-pyrazole (Vc),
16.44 g (0.12 mol) of butyl bromide, and 12 g (0.3 mol)
of KOH. Yield 15.12 g (84%), bp 110–115ºС
(30–35 mmHg). 1H NMR spectrum, δ, ppm, (IIv): 0.91
m (6H, 2CH3), 1.35 m (4H, 2CH2), 1.60 m (2H, CH2),
1.79 m (2H, CH2), 2.58 m (2H, CH2), 4.02 m (2H,
NCH2), 5.97 d (1H, H4, J 2.08 Hz), 7.23 d (1H, H5, J
2.08 Hz); (IIIv): 5.98 d (1H, H4, J 1.59 Hz), 7.37 d (1H,
H3, J 1.59 Hz). Found, %: C 72.98; H 11.12; N 15.90.
C11H20N2. Calculated, %: C 73.28; H 11.18; N 15.54.
1-(3-Methyl-5-chloro-1H-pyrazol-1-yl)propan-2-
ol (VIIa) was obtained from 2.78 g (0.02 mol) of 4,4-
dichlorobut-3-en-2-one (VIa), 1.80 g (0.02 mol) of 1-
hydrazinopropan-2-ol, and 2.02 g (0.02 mol) of tri-
ethylamine. Yield 2.83 g (81%), bp 76–78ºС (5 mmHg).
1Н NMR spectrum, δ, ppm: 1.19 d (3Н, СНСН3), 2.21
s (3Н, СН3), 3.90 m (1Н, СН), 4.16 m (2Н, NСН2),
5.99 s (1Н, H4). Found, %: С 47.90; Н 6.37; Cl 20.10;
N 16.12. C7H11ClN2О. Calculated, %: С 48.15; Н 6.35;
Cl 20.30; N 16.04.
3-(1-Bromoethyl)-1-methyl-1H-pyrazole (IV). To
a solution of 0.5 g (0.0026 mol) of (1E)-4-bromo-1-
chloropent-1-en-3-one (Ic) in 20 mL of diethyl ether
cooled to –10°С was added dropwise a solution of 0.26 g
(0.0026 mol) of triethylamine in 5 mL of diethyl ether,
and later a solution of 0.16 g (0.0026 mol) of 1,1-
dimethylhydrazine in 10 mL of diethyl ether within
1-(3-Propyl-5-chloro-1H-pyrazol-1-yl)propan-2-
ol (VIIb) was obtained from 3.34 g (0.02 mol) of 1,1-
dichlorohex-1-en-3-one (VIb), 1.8 g (0.02 mol) 1-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

RATIO OF 1,3- AND 1,5-DIALKYL-SUBSTITUTED PYRAZOLES
1661
10. Yang, L., Okuda, F., Kobayashi, K., Nozaki, K.,
Tanabe, Y., Ishii, Y., and Haga, M., Inorg. Chem., 2008,
vol. 47, p. 7154.
hydrazinopropan-2-ol, and 2.02 g (0.02 mol) of tri-
ethylamine. Yield 3.20 g (79%), bp 99–103ºС (6 mmHg).
1Н NMR spectrum, δ, ppm (J, Hz): 0.92 t (3Н, СН3, J
7.3), 1.17 d (3Н, СН3, J 6.1), 1.60 m (2Н, СН2, J 7.3),
2.50 t (2Н, СН2, J 7.3), 3.90 m (1H, CHОН, J 10.5, J
6.1), 4.05 d (2Н, NСН2, J 10.5), 6.01 s (1Н, H4).
Found, %: С 53.69; Н 7.49; Cl 17.19; N 13.65.
C9H15ClN2О. Calculated, %: С 53.33; Н 7.46; Cl
17.49; N 13.82.
11. Chang, E.-M., Lee, C.-T., Chen, C.-Y., Wong, F.F., and
Yeh, M.-Y., Aust. J. Chem., 2008, vol. 61, p. 342.
12. Han, L.M. and Timmons, R.B., Chem. Mater., 1998,
vol. 10, p. 1422; Shatalov, G.V., Preobrazhenskii, S.A.,
and Kuznetsov, V.A., Izv. Vuzov. Ser. Khim. i Khim.
Tekhnol., 1999, vol. 42, p. 62.
13. Cavero, E., Uriel, S., Romero, P., Serrano, J.L., and
Main results were obtained using the materials and
equipment of the Baikal analytic center of joint use of
Siberian Branch of the Russian Academy of Sciences.
Giménez, R., J. Am. Chem. Soc., 2007, vol. 129, p. 11608.
14. Ye, C., Gard, G.L., Winter, R.W., Syvret, R.G.,
Twamley, B., and Shreeve, J.M., Org. Lett., 2007, vol. 9,
p. 3841; Ojwach, S.O. and Darkwa, G.L., J. Inorg.
Chim. Acta, 2011, vol. 363, p. 1947; Potapov, A.S.,
Domnina, G.A., Petrenko, T.V., and Khlebnikov, A.I.,
Polyhedron, 2012, vol. 33, p. 150.
15. Ovcharenko, V.I., Maryunina, K.Yu., Fokin, S.V.,
Tretyakov, E.V., Romanenko, G.V., and Ikorskii, V.N.,
Russ. Chem. Bull., 2004, vol. 53, p. 2406; Fokin, S.,
Ovcharenko, V., Romanenko, G., and Ikorskii, V.,
Inorg. Chem., 2004, vol. 43, p. 969.
The study was carried out under the financial
support of the Siberian Branch of the Russian
Academy of Sciences (grant no. 21) and Belarus
Republic Foundation for Basic Research (grant no.
Х12СО-012).
REFERENCES
16. Elguero, J., Compr. Heterocycl. Chem. II, 1996, vol. 3,
p. 1; Kost, A.N. and Grandberg, I.I., Adv. Heterocycl.
Chem., 1966, vol. 6, p. 347.
17. Lee, K.Y., Kim, J.M., and Kim, J.N., Tetrahedron Lett.,
2003, vol. 44, p. 6737; Tang, M. and Zhang, F.-M.,
Tetrahedron, 2013, vol. 69, p. 1427; Sun, A., Ye, J-H.,
Yu, H., Zhang, W., and Wang, X., Tetrahedron Lett.,
2014, vol. 55, p. 889.
1. Elguero, J., Goya, P., Jagerovic, N., and Silva, A.M.S.,
Italian Soc. Chem., 2002, vol. 6, p. 53; Pérez-
Fernández, R., Goya, P., and Elguero, J., Arkivoc, 2014,
vol. ii, p. 233.
2. Fustero, S., Sanchez-Rosello, M., Barrio, P., and Simon-
Fuentes, A., Chem. Rev., 2011, vol. 111, p. 6984; Ja-
nin, Y.L., Chem. Rev., 2012, vol. 112, p. 3924.
3. Genin, M.J., Biles, C., Keiser, B.J., Poppe, S.M.,
Swaney, S.M., Tarpley, W.G., Yagi, Y., and Romeo, D.L.,
J. Med. Chem., 2000, vol. 43, p. 1034.
18. Sakya, S.M. and Rast, B., Tetrahedron Lett., 2003, vol. 44,
p. 7629.
19. Grimmett, M.R., Lim, K.H.R., and Weavers, R.T.,
4. Bailey, D.M., Hansen, P.E., Hlavac, A.G., Baizman, E.R.,
Pearl, J., Defelice, A.F., and Feigenson, M.E., J. Med.
Chem., 1985, vol. 20, p. 256.
Australian J. Chem., 1979, vol. 32, p. 2203.
20. Fustero, S., Roman, R., Sanz-Cereva, J.F., Simon, A.,
Cunat, A.C., Villanova, S., and Murguia, M., J. Org.
Chem., 2008, vol. 73, p. 3523.
5. Szabo, G., Fischer, J., Kis-Varga, A., and Gyires, K.,
J. Med. Chem., 2008, vol. 51, p. 142.
21. Huang, Y.R. and Katzenellenbogen, J.A., Org. Lett.,
2000, vol. 2, p. 2833; Nakamichi, N., Kawashita, Y.,
and Hayashi, M., Org. Lett., 2002, vol. 4, p. 3955;
Peruncheralathan, S., Yadav, A.K., Ila, H., and
Junjappa, H., J. Org. Chem., 2005, vol. 70, p. 9644;
Bamoniria, A., Mirjalili, B.F., Jafarib, A.A., and
Abasaltianb, F., Iran. J. Catal., 2012, vol. 2, p. 75.
6. Farag, A.M., Mayhoub, A.S., Barakat, S.E., and
Bayomi, A.H., Bioorg. Med. Chem., 2008, vol. 16, p. 32.
7. Vicentini, C.B., Romagnoli, C., Andreotti, E., and
Mares, D., J. Agric. Food Chem., 2007, vol. 55,
p. 10331; Li, Y., Zhang, H.-Q., Liu, J., Yang, X.-P., and
Liu, Z.-J.J., J. Agric. Food Chem., 2006, vol. 54, p. 3636;
Shiga, Y., Okada, I., and Fukuchi, T., J. Pesticide Sci.,
2003, vol. 28, p. 313.
22. Ioffe, B.V. and Zelenina, N.L., Chem. Heterocycl.
Comp., 1970, vol. 6, p. 1321.
8. Grapov, A.F., Russ. Chem. Rev., 1999, vol. 68, p. 697.
23. Beltrán-Rodil, S., Edwards, M.G., Pugh, D.S., Reid, M.,
9. Nikitin, A.Ya., Kozlova, Yu.A., Shashina, N.I.,
Germant, O.M., Levkovskaya, G.G., Kondrashov, E.V.,
and Rudyakova, E.V., Dezinfektsionnoe delo, 2010,
vol. 3, p. 26; Aajoud, A., Ravanel, P., and Tissut, M.,
J. Agric. Food Chem., 2003, vol. 5, p. 1347; Hiroshi, V.,
Takekura, K., and Kasei, M., JP Patent no. 41180,
2005.
and Taylor, R.K., Synlett., 2010, p. 602.
24. Pohland, A.E. and Benson, W.R., Chem. Rev., 1966,
vol. 66, p. 161; Kochetkov, N.K., Usp. Khim., 1955,
vol. 24, p. 32; Levkovskaya, G.G., Bozhenkov, G.V.,
and Mirskova, A.N., Izbrannye metody sinteza i
modifikatsii geterotsiklov (Selected Methods of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 11 2014

POPOV et al.
1662
Synthesis and Modification of Heterocycles), Kartsev, V.G.,
33. Grandberg, I.I., Chem. Heterocycl. Comp., 1965, vol. 1,
Ed., Moscow: IBS Press, 2003, vol. 2, p. 284; Kaber-
din, R.V., Potkin, V.I., and Petkevich, S.K., Izv. Natio-
nal Akad. Nauk Belarusi, Ser. Khim. Nauk, 2006, p. 100.
p. 184.
34. Bozhenkov, G.G., Levkovskaya, G.G., Mirskova, A.N.,
and Larina, L.I., Chem. Heterocycl. Comp., 2005, vol. 41,
p. 854; Levkovskaya, G.G., Bozhenkov, G.V., Malyu-
shenko, R.N., and Mirskova, A.N., Russ. J. Org. Chem.,
2001, vol. 37, p. 1795.
25. Moiseev, I.K., Makarova, N.V., and Zemtzova, M.N., Izv.
Vuzov, Ser. Khim. i Khim. Tekhnol., 2007, vol. 50, p. 3.
26. Bozhenkov, G.V., Savosik, V.A., Klyba, L.V., Zhan-
chipova, E.R., Mirskova, A.N., and Levkovskaya, G.G.,
Russ. J. Org. Chem., 2008, vol. 44, p. 1194.
35. Samultsev, D.O., Rudyakova, E.V., and Levkovs-
kaya, G.G., Russ. J. Org. Chem., 2012, vol. 48, p. 1388;
Rudyakova, E.V., Samultsev, D.O., Levanova, E.P., and
Levkovskaya, G.G., Russ. J. Org. Chem., 2013, vol. 49,
p. 734.
27. Bozhenkov, G.V., Savosik, V.A., Larina, L.I., Klyba, L.V.,
Zhanchipova, E.R., Mirskova, A.N., and Levkovs-
kaya, G.G., Russ. J. Org. Chem., 2008, vol. 44, p. 1014.
28. Bozhenkov, G.V., Levkovskaya, G.G., Mirskova, A.N.,
Dolgushin, G.V., Larina, L.N., and Ushakov, P.E.,
Russ. J. Org. Chem., 2003, vol. 39, p. 1069; Levkovs-
kaya, G.G., Bozhenkov, G.V., Larina, L.I., and Mirsko-
va, A.N., Russ. J. Org. Chem., 2002, vol. 38, p. 1501;
Kalikhman, I.D., Lavlinskaya, L.I., Levkovskaya, G.G.,
Mirskova, A.N., Atavin, A.S., and Pestunovich, V.A.,
Bull. Acad. Sci. USSR, Div. Chem. Sci., 1974, vol. 23,
p. 1322; Mirskova, A.N., Levkovskaya, G.G., and
Voronkov, M.G., Bull. Acad. Sci. USSR, Div. Chem.
Sci., 1981, vol. 30, p. 1077; Levkovskaya, G.G.,
Bozhenkov, G.V., Mirskova, A.N., and Tantsyrev, A.P.,
RF Patent 2186772, 2002; Byull. Izobret., 2002, no. 22.
29. Levkovskaya, G.G., Kobelevskaya, V.A., Rudyakova, E.V.,
Ha, Q.Kh., Samultsev, D.O., and Rozentsveig, I.B.,
Tetrahedron, 2011, vol. 67, p. 1844.
36. Habraken, C.L. and Moore, J.A., J. Org. Chem., 1965,
vol. 30, p. 1892.
37. Butler, D.E. and DeWard, H.А., J. Org. Chem., 1971,
vol. 36, p. 2542.
38. Trukhin, D.V., Adonin, N.Yu., and Starichenko, V.F.,
RF Patent 2152921, 2000.
39. Bax, A. and Subramanian, S., J. Magn. Reson., 1986,
vol. 67, p. 565.
40. Bax, A. and Subramanian, S., J. Am. Chem. Soc., 1986,
vol. 108, p. 2093.
41. Klimko, V.G., Mikhalev, V.A., and Skoldinov, A.P., Zh.
Obshch. Khim., 1957, vol. 27, p. 370.
42. Savosik, V.A., Rudyakova, E.V., Albanov, A.I.,
Bozhenkov, G.V., and Levkovskaya, G.G., Russ. J. Org.
Chem., 2009, vol. 45, p. 617.
30. Ichikava, J., Kobayashi, M., Noda, Y., Yokota, N., Ama-
no, K., and Minami, T., J. Org. Chem., 1996, vol. 61, p. 2763.
31. Nesmeyanov, A.N., Kochetkov, N.K., and Rybins-
kaya, M.I., Izv. Akad. Nauk USSR, Ser. Khim., 1950, p. 350.
43. Bozhenkov, G.V., Savosik, V.A., Rudyakova, E.V., Kha
Kuok Khan’, Albanov, A.I., Klyba, L.V., Mirskova, A.N.,
and Levkovskaya, G.G., Russ. J. Org. Chem., 2008, vol. 44,
p. 1745.
32. Nesmeyanov, A.N., Kochetkov, N.K., and Rybins
44. Atavin, A.S., Levkovskaya, G.G., and Mirskova, A.N.,
kaya, M.I., Izv. Akad. Nauk USSR, Ser. Khim., 1951, p. 395.
Zh. Org. Khim., 1973, vol. 9, p. 318.
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