1,1-Bis(3,5-dimethyl-1-pyrazolyl)- and 1-amino-1-(3,5-dimethyl-1-pyrazolyl) -4,4-dichloro-1-buten-3-ones

Article abstract of DOI:10.1007/s11178-005-0051-z

Reaction of 1,1,4,4-tetrachloro-3-buten-2-one with 3,5-dimethylpyrazole gave 1,1-dichloro- 4,4-bis-(3,5-dimethyl-1-pyrazolyl)-3-buten-2-one. Treatment of the latter with amines resulted in replacement of one pyrazole ring by the amine residue with formati

Full text of DOI:10.1007/s11178-005-0051-z

Russian Journal of Organic Chemistry, Vol. 40, No. 10, 2004, pp. 1508–1511. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004,
pp. 1557–1560.
Original Russian Text Copyright © 2004 by Potkin, Petkevich, Kaberdin, Kurman.
1,1-Bis(3,5-dimethyl-1-pyrazolyl)- and 1-Amino-1-(3,5-dimethyl-
1-pyrazolyl)-4,4-dichloro-1-buten-3-ones
V. I. Potkin, S. K. Petkevich, R. V. Kaberdin, and P. V. Kurman
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: potkin@ifoch.bas-net.by
Received February 4, 2004
Abstract—Reaction of 1,1,4,4-tetrachloro-3-buten-2-one with 3,5-dimethylpyrazole gave 1,1-dichloro-4,4-bis-
(3,5-dimethyl-1-pyrazolyl)-3-buten-2-one. Treatment of the latter with amines resulted in replacement of one
pyrazole ring by the amine residue with formation of the corresponding 4-amino-1,1-dichloro-4-(3,5-dimethyl-
1-pyrazolyl)-3-buten-2-ones.
Functionalized pyrazole derivatives are widely used
in industry, agriculture, and medicine, specifically in
the synthesis of dyes, chemical bleaching agents,
luminescent and fluorescent components for various
materials, fuel antioxidants [1], chemical means for
plant protection [2], and effective drugs with versatile
activity [3]. Synthesis of pyrazoles containing
a chlorinated ketone moiety attracts interest, for
chlorinated aliphatic ketones of the C4 series have been
successfully used for the preparation of various
biologically active compounds [4]. In addition, it is
known that introduction of chlorine atoms usually
enhances biological effect of a chemical compounds
[5]. An accessible and reactive chlorinated ketone is
1,1,4,4-tetrachloro-3-buten-2-one (I) which is obtained
by oxidation of 1,1,3,4-tetrachloro-1,3-butadiene (II)
with concentrated nitric acid (Scheme 1); compound II
is readily available via dechlorination of trichloro-
ethylene dimer [6].
redistribution in the molecule thus creating a strongly
electrophilic center on C4. In the present work we
examined alkylation with ketone I of a weakly reactive
N-nucleophile, 3,5-dimethylpyrazole, with a view to
obtain functionally substituted pyrazole derivatives.
Ketone I failed to react with 3,5-dimethylpyrazole at
room temperature, but heating of the reactants in
boiling benzene over a period of 30 h gave 1,1-di-
chloro-4,4-bis(3,5-dimethyl-1-pyrazolyl)-1-buten-3-
one (III) as a result of alkylation of two 3,5-dimethyl-
pyrazole molecules. By the action of primary and
secondary amines on compound III, one pyrazole frag-
ment in the latter was replaced by the amine residue
to afford the corresponding 4-amino-1,1-dichloro-4-
(3,5-dimethyl-1-pyrazolyl)-1-buten-3-ones IV–XII.
The following amines were used: 4-bromoaniline,
4-toluidine, anisidine, 2-methoxyaniline, phenetidine,
ethyl 4-aminobenzoate, 1-naphthylamine, diethyl-
amine, and morpholine. The carbonyl group in mole-
cule III remained intact in these reactions.
As shown in [6], ketone I readily reacts with
primary and secondary amines to give the correspond-
ing amino ketones as a result of replacement of the
terminal chlorine atoms in the vinyl group. The high
reactivity of ketone I in nucleophilic substitution
processes originates from activating effect of the con-
jugated carbonyl group, which induces electron density
The structure of products III–XII was confirmed
1
by their elemental compositions and IR, H NMR, and
mass spectra. The IR spectra contain absorption bands
at 1629–1694 cm–1 due to stretching vibrations of the
carbonyl group. The carbonyl vibration frequency in
the spectra of compounds IV–X having a secondary
amino group is considerably lower (1629–1649 cm–1)
than the corresponding frequency for compounds XI
and XII with a tertiary amino group (1655–1694 cm–1).
This difference indicates formation in molecules IV–X
of intramolecular hydrogen bond –N–H···O=C–
which closes a six-membered H-chelate ring typical of
Scheme 1.
Cl
Cl
Cl
O
HNO3 (d = 1.5)
Cl
Cl
Cl
Cl
Cl
II
I
1070-4280/04/4010-1508 © 2004 MAIK “Nauka/Interperiodica”

1,1-BIS(3,5-DIMETHYL-1-PYRAZOLYL)- AND 1-AMINO-...
1509
Scheme 2.
Me
N
Me
O
Me
Cl
O
N
Cl
Cl
N
+
Cl
N
N
Me
Me
N
Cl
Cl
H
Me
I
III
NRR' O
NHCOMe
RR'NH
∆, AcOH
R = H
Cl
N
N
Me
R' = 4-MeOC6H4
MeO
Cl
Me
IV–XII
XIII
IV, R = H, R' = 4-BrC6H4; V, R = H, R' = 4-MeC6H4; VI, R = H, R' = 4-MeOC6H4; VII, R = H, R' = 2-MeOC6H4; VIII, R = H,
R' = 4-EtOC6H4; IX, R = H, R' = 4-EtOC(O)C6H4; X, R = H, R' = 1-naphthyl; XI, R = R' = Et; XII, RR'N = morpholino.
conjugated β-enaminovinyl ketones [7]. In the 1H NMR
Compound VI remained unchanged on heating in
boiling methanol, while heating of VI in glacial acetic
acid resulted in its decomposition to form a complex
mixture of tarry products. Among the products, we
succeeded in isolating and identifying by gas chroma-
tography–mass spectrometry N-(4-methoxyphenyl)-
acetamide (XIII). Obviously, amide XIII is formed via
cleavage of the HN–Cketone bond, and its yield does not
exceed 20%.
spectra of III–XII we observed a singlet at δ 5.63–
6.06 ppm due to proton of the dichloromethyl group.
This finding confirms that the CHCl2 group is not
involved in the nucleophilic substitution process. The
1H NMR spectra also contained signals from the =CH–
proton in the ketone fragment and protons in the pyra-
zole ring and amine residue. The NH signals appear in
the spectra of IV–X as broadened singlets at δ 8.4–
12.3 ppm. Compounds III–XII showed in the mass
spectra the molecular ion peaks with an isotope ratio of
100:65:1.1 which corresponds to the presence of two
chlorine atoms [8, 9]. The fragment ions arise from
elimination of chlorine atoms, methyl groups, and
amine residues from the molecular ion.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Protégé-
1
460 Fourier spectrometer. The H NMR spectra were
measured on a Tesla-567A instrument (100 MHz) from
solutions in CDCl3 using tetramethylsilane as refer-
ence. The mass spectra (electron impact, 50 eV) were
run on an MKh-1320 mass spectrometer. GC–MS anal-
ysis was performed on a Hewlett–Packard HP 5972
mass-selective detector coupled with an HP 5890 gas
chromatograph.
We previously revealed an unusual transformation
of 3,4,4-trichloro-1-azolyl-1-arylamino-2-nitro-1,3-
butadienes on heating in proton-donor solvents (such
as methanol or acetic acid). This transformation
includes elimination of the azole fragment and subse-
quent intramolecular cyclization to give benzazetine
structures with trichloronitropropenyl group in position
2 [10]. This reaction opens a new synthetic route to
difficultly accessible and poorly studied benzazetines.
We tried to effect an analogous transformation of
1,1-dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-(4-
methoxyphenylamino)-1-buten-3-one (VI) which can
be regarded as somewhat related to 3,4,4-trichloro-
1-azolyl-1-arylamino-2-nitro-1,3-butadienes; like the
latter, compound VI contains a chlorinated C4-aliphatic
chain with a conjugated vinyl group which is activated
by electron-acceptor effect of the carbonyl group.
1,1-Dichloro-4,4-bis(3,5-dimethyl-1-pyrazolyl)-3-
buten-2-one (III). Ketone I, 2.16 g (10.4 mmol), was
added under stirring to a solution of 4 g (41.6 mmol) of
3,5-dimethylpyrazole in 20 ml of benzene. The mix-
ture was heated for 30 h under reflux, the solvent was
distilled off, the residue was diluted with 20 ml of
diethyl ether, the precipitate of 3,5-dimethylpyrazole
hydrochloride was filtered off, the filtrate was
evaporated under reduced pressure, and the residue
was recrystallized from hexane. Yield 2.44 g (72%),
mp 71°C. IR spectrum, ν, cm–1: 776 (C–Cl); 1566,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

POTKIN et al.
1510
1
1601, 1663 (C=C, C=N); 1694 (C=O). H NMR spec-
trum, δ, ppm: 1.70 s (3H, CH3), 2.03 s (3H, CH3),
2.26 s (6H, 2CH3), 5.76 s (1H, CHCl2), 5.99 s and
6.06 s (2H, 4-H, pyrazole), 6.84 s (1H, =CHCO).
Found, %: C 51.17; H 4.99; Cl 21.78; N 17.41.
[M]+ 326. C14H16Cl2N4O. Calculated, %: C 51.39;
H 4.93; Cl 21.67; N 17.12. M 327.21.
1,1-Dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-
(2-methoxyphenyl)-3-buten-2-one (VII). Yield 55%,
mp 104–105°C. IR spectrum, ν, cm–1: 785 (C–Cl);
1512, 1559, 1575, 1607 (C=C, C=N); 1643 (C=O);
1
3280 (NH). H NMR spectrum, δ, ppm: 1.97 s (3H,
CH3), 2.24 s (3H, CH3), 3.90 s (3H, CH3O), 5.82 s
(1H, CHCl2), 5.87 s (1H, 4-H, pyrazole), 5.97 s
(1H, =CHCO), 5.92 d (1H, Harom), 6.54–7.10 m (3H,
Harom), 11.70 br.s (1H, NH). Found, %: C 54.31;
H 4.92; Cl 19.97; N 11.98. [M]+ 353. C16H17Cl2N3O2.
Calculated, %: C 54.25; H 4.84; Cl 20.02; N 11.86.
M 354.24.
Reactions of 1,1-dichloro-4,4-bis(3,5-dimethyl-1-
pyrazolyl)-3-buten-2-one (III) with amines (general
procedure). Appropriate amine, 3.2 mmol, was added
under stirring to a mixture of 1.05 g (3.2 mmol) of
bispyrazole derivative III and 15 ml of diethyl ether,
and the mixture was heated for 4 h under reflux. The
sol-vent was distilled off under reduced pressure to 2/3
of the initial volume, 10 ml of hexane was added to the
residue, and the precipitate was filtered off and recrys-
tallized from hexane.
1,1-Dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-
(4-ethoxyphenyl)-3-buten-2-one (VIII). Yield 58%,
mp 62–64°C. IR spectrum, ν, cm–1: 779 (C–Cl); 1509,
1563, 1596 (C=C, C=N); 1629 (C=O); 3255 (NH).
1H NMR spectrum, δ, ppm: 1.35 t (3H, CH2CH3),
1.98 s (3H, CH3), 2.25 s (3H, CH3), 3.94 q (2H,
CH2O), 5.77 s (1H, CHCl2), 5.86 s (1H, 4-H, pyra-
zole), 5.97 s (1H, =CHCO), 6.45–6.85 m (4H, Harom),
8.40 br.s (1H, NH). Found, %: C 55.76; H 5.12;
Cl 19.50; N 11.71. [M]+ 367. C17H19Cl2N3O2. Cal-
culated, %: C 55.45; H 5.20; Cl 19.25; N 11.41.
M 368.26.
4-(4-Bromophenyl)-1,1-dichloro-4-(3,5-dimethyl-
1-pyrazolyl)-3-buten-2-one (IV). Yield 71%, mp 113–
115°C. IR spectrum, ν, cm–1: 787 (C–Cl); 1509, 1567,
1
1605 (C=C, C=N); 1636 (C=O); 3265 (NH). H NMR
spectrum, δ, ppm: 2.04 s (3H, CH3), 2.22 s (3H, CH3),
5.85 s (1H, CHCl2), 5.92 s (1H, 4-H, pyrazole),
5.96 s (1H, =CHCO), 6.42 d.d (2H, Harom), 7.29 d.d
(2H, Harom), 11.50 br.s (1H, NH). Found, %: C 44.50;
H 3.32; Hlg 37.53; N 10.48. [M]+ 401. C15H14Br-
Cl2N3O. Calculated, %: C 44.69; H 3.50; Hlg 37.41;
N 10.42. M 403.10.
Ethyl 4-[4,4-dichloro-1-(3,5-dimethyl-1-pyra-
zolyl)-3-oxo-1-butenylamino]benzoate (IX). Yield
24%, mp 117–119°C. IR spectrum, ν, cm–1: 767
(C–Cl); 1510, 1566, 1571, 1593 (C=C, C=N); 1649,
1
1698 (C=O); 3290 (NH). H NMR spectrum, δ, ppm:
1,1-Dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-
(4-methylphenyl)-3-buten-2-one (V). Yield 35%,
mp 85–87°C. IR spectrum, ν, cm–1: 784 (C–Cl); 1519,
1572, 1607 (C=C, C=N); 1638 (C=O); 3260 (NH).
1H NMR spectrum, δ, ppm: 1.98 s (3H, CH3), 2.24 s
(6H, 2CH3), 5.82 s (1H, CHCl2), 5.88 s (1H, 4-H,
pyrazole), 5.97 s (1H, =CHCO), 6.48 d.d (2H, Harom),
6.98 d.d (2H, Harom), 11.70 br.s (1H, NH). Found, %:
C 56.60; H 4.88; Cl 20.70; N 12.50. [M]+ 337.
C16H17Cl2N3O. Calculated, %: C 56.82; H 5.07;
Cl 20.96; N 12.42. M 338.24.
1.37 t (3H, CH2CH3), 2.07 s (3H, CH3), 2.26 s (3H,
CH3), 4.34 q (2H, CH2O), 5.93 s (1H, CHCl2), 5.97 s
(1H, =CHCO), 6.00 s (1H, 4-H, pyrazole), 6.56 d.d
(2H, Harom), 7.91 d.d (2H, Harom), 11.60 br.s (1H, NH).
Found, %: C 54.72; H 4.71; Cl 17.49; N 10.82.
[M]+ 395. C18H19Cl2N3O3. Calculated, %: C 54.56;
H 4.83; Cl 17.89; N 10.60. M 396.27.
1,1-Dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-
(1-naphthyl)-3-buten-2-one (X). Yield 59%, mp 144–
145°C. IR spectrum, ν, cm–1: 766 (C–Cl); 1513, 1564,
1572, 1609 (C=C, C=N); 1633 (C=O); 3255 (NH).
1H NMR spectrum, δ, ppm: 1.80 s (3H, CH3), 2.21 s
(3H, CH3), 5.84 s (1H, CHCl2), 6.01 s (1H, 4-H, pyra-
zole), 6.04 s (1H, =CHCO), 6.43 d (1H, Harom), 7.07–
8.30 m (6H, Harom), 12.30 br.s (1H, NH). Found, %:
C 60.78; H 4.73; Cl 18.59; N 11.09. [M]+ 373.
C19H17Cl2N3O. Calculated, %: C 60.97; H 4.58;
Cl 18.94; N 11.23. M 374.27.
1,1-Dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-
(4-methoxyphenyl)-3-buten-2-one (VI). Yield 80%,
mp 130–131°C. IR spectrum, ν, cm–1: 776 (C–Cl);
1511, 1565, 1598, 1606 (C=C, C=N); 1630 (C=O);
1
3250 (NH). H NMR spectrum, δ, ppm: 1.98 s (3H,
CH3), 2.22 s (3H, CH3), 3.73 s (3H, CH3O), 5.79 s
(1H, CHCl2), 5.86 s (1H, 4-H, pyrazole), 5.96 s (1H,
=CHCO), 6.40–6.90 m (4H, Harom), 11.70 br.s (1H,
NH). Found, %: C 54.52; H 4.99; Cl 19.73; N 11.81.
[M]+ 353. C16H17Cl2N3O2. Calculated, %: C 54.25;
H 4.84; Cl 20.02; N 11.86. M 354.24.
1,1-Dichloro-4-diethylamino-4-(3,5-dimethyl-1-
pyrazolyl)-3-buten-2-one (XI). Yield 61%, mp 88–
90°C. IR spectrum, ν, cm–1: 777 (C–Cl); 1550, 1570
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

1,1-BIS(3,5-DIMETHYL-1-PYRAZOLYL)- AND 1-AMINO-...
1511
(C=C, C=N); 1665 (C=O). 1H NMR spectrum, δ, ppm:
REFERENCES
1.25 t (6H, NCH2CH3), 2.26 s (6H, CH3), 3.25 q (4H,
CH2N), 5.63 s (1H, CHCl2), 5.83 s (1H, 4-H, pyra-
zole), 5.95 s (1H, =CHCO). Found, %: C 51.42; H 6.01;
Cl 23.09; N 13.91. [M]+ 303. C13H19Cl2N3O. Calculat-
ed, %: C 51.33; H 6.30; Cl 23.31; N 13.81. M 304.22.
1. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 4.
Translated under the title Obshchaya organicheskaya
khimiya, Moscow: Khimiya, 1985, vol. 8, p. 430.
2. Granov, A.F., Usp. Khim., 1999, vol. 68, p. 773.
4,4-Dichloro-4-(3,5-dimethyl-1-pyrazolyl)-4-mor-
pholino-3-buten-2-one (XII). Yield 90%, mp 109–
111°C. IR spectrum, ν, cm–1: 774 (C–Cl); 1575, 1594
(C=C, C=N); 1668 (C=O). 1H NMR spectrum, δ, ppm:
2.24 s (6H, CH3), 3.05–3.35 m (4H, CH2N), 3.65–
3.97 m (4H, CH2O), 5.63 s (1H, CHCl2), 5.81 s (1H,
4-H, pyrazole), 5.98 s (1H, =CHCO). Found, %: C 49.38;
H 5.09; Cl 22.01; N 13.52. [M]+ 317. C13H17Cl2N3O2.
Calculated, %: C 49.07; H 5.38; Cl 22.28; N 13.21.
M 318.20.
3. JPN Patent Appl. no. 58-24522, 1992; Ref. Zh., Khim.,
1993, no. 7Zh108.
4. Pilgram, K. and Kendall, H.D., J. Med. Chem., 1975,
vol. 18, p. 1204.
5. Mel’nikov, N.N., Khimiya i tekhnologiya pestitsidov
(Chemistry and Technology of Pesticides), Moscow:
Khimiya, 1974, p. 50.
6. Ol’dekop, Yu.A., Kaberdin, R.V., and Buslov-
skaya, E.E., Zh. Org. Khim., 1982, vol. 18, p. 1835.
7. Freimanis, Ya.F., Khimiya enaminoketonov, enamino-
iminov, enaminotionov (Chemistry of Enamino Ketones,
Enamino Imines, and Enamino Thiones), Riga: Zinatne,
1974, p. 111.
Decomposition of 1,1-dichloro-4-(3,5-dimethyl-1-
pyrazolyl)-4-(4-methoxyphenyl)-3-buten-2-one (VI)
in acetic acid. A mixture of 0.4 g (1.1 mmol) of
1,1-dichloro-4,4-bis(3,5-dimethyl-1-pyrazolyl)-3-
buten-2-one (VI) and 15 ml of glacial acetic acid was
stirred for 15 h at 60°C. The mixture was poured into
an ice–water mixture and treated with methylene
chloride. The extract was dried over magnesium
sulfate, and the solvent was distilled off. Analysis of
the residue by gas chromatography–mass spectrometry
showed the presence of N-(4-methoxyphenyl)acet-
amide (XIII).
8. Takhistov, V.V., Prakticheskaya mass spektrometriya
organicheskikh soedinenii (Practical Mass Spectrometry
of Organic Compounds), Leningrad: Leningr. Gos.
Univ., 1977, p. 265.
9. Takhistov, V.V., Rodin, A.A., and Maksimov, B.N., Usp.
Khim., 1991, vol. 60, p. 2143.
10. Potkin, V.I., Zapol’skii, V.A., Knizhnikov, V.A., Kaber-
din, R.V., Yanuchok, A.A., and Petkevich, S.K., Russ. J.
Org. Chem., 2001, vol. 37, p. 689.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004