Synthesis of 3-substituted pyrazoles by oxidative dehydrogenation of 4,5-dihydro-3H-pyrazoles

Full text of DOI:10.1134/S1070428009060293

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 950–952. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © K.V. Yakovlev, D.V. Petrov, V.A. Dokichev, Yu.V. Tomilov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 6,
pp. 962–964.
SHORT
COMMUNICATIONS
Synthesis of 3-Substituted Pyrazoles by Oxidative
Dehydrogenation of 4,5-Dihydro-3H-pyrazoles
K. V. Yakovleva, D. V. Petrova, V. A. Dokicheva, and Yu. V. Tomilovb
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: dokichev@anrb.ru
b Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Leninskii pr. 47, Moscow, 119991 Russia
Received November 10, 2008
DOI: 10.1134/S1070428009060293
Nowadays considerable attention is given to the
development of new methods for the preparation of
pyrazole derivatives since the presence of pyrazole
ring in organic molecules gives rise to versatile physio-
logical activity of many compounds of both synthetic
and natural origin [1]. 3-Alkenylpyrazoles and bipyra-
zoles attract specific interest [1–6]. For example,
3-(2-methylprop-1-en-1-yl)-1H-pyrazole was found to
enhance soporific effect of Hexobarbital [1]. Pyrazole
derivatives are also used as building blocks in the
synthesis of practically important indazole derivatives
[2], as well as of a new class of supramolecular com-
plexes, organometallic cage-like structures and self-
assembling metallomacrocycles with bipyrazole li-
gands, that are promising as catalysts, molecular mim-
ics, molecular magnetic devices, sensors, etc. [3–6].
3-Vinyl- and 3-[(Z)-prop-1-en-1-yl]-4,5-dihydro-3H-
pyrazoles Ia and Ib reacted with 20 equiv of MnO2 in
benzene at room temperature to produce 3-vinyl-
and 3-[(Z)-prop-1-en-1-yl]-1H-pyrazoles IIa and IIb
in 36 and 49% yield, respectively (Scheme 1). No
cis–trans isomerization of the propenyl substituent
occurred under these conditions, as followed from the
coupling constant 3J1′,2′ = 11.5 Hz in the 1H NMR spec-
trum of compound IIb.
Scheme 1.
MnO2
N
N
HN
N
R
R
Ia, Ib
IIa, IIb
R = H (a), Me (b).
A convenient synthetic approach to 3-alkenylpyra-
zoles and 3,3′-bipyrazoles is based on 1,3-dipolar
cycloaddition of diazo compounds to 1,3-dienes, fol-
lowed by dehydrogenation of 4,5-dihydro-3H-pyra-
zoles thus obtained [7, 8]. However, we have found no
published data on the synthesis of 3-substituted pyra-
zoles from dihydropyrazoles. The most probable rea-
son is that 3-vinyldihydropyrazoles undergo decom-
position above 120°C with liberation of nitrogen and
formation of vinylcyclopropane and cyclopentene
derivatives [9].
Dehydrogenation of 4,4′,5,5′-tetrahydro-3H,3′H-
3,3′-bipyrazole (III) having two dihydropyrazole rings
was accompanied by elimination of nitrogen molecule
from one dihydropyrazole ring, leading to the forma-
tion of a mixture of bipyrazole IV and 3-cyclopropyl-
1H-pyrazole (V) in 27 and 18% yield, respectively.
Compounds IV and V were isolated as individual sub-
stances by column chromatography. Unlike oxidative
dehydrogenation by the action of manganese dioxide,
the reaction of vinyldihydropyrazole I with 2 equiv of
sulfur in pyridine at 110°C gave a complex mixture of
products. Under analogous conditions, from bicyclic
compound III we obtained a mixture of 1H,1′H-3,3′-
bipyrazole (IV), 4,4′,5,5′-tetrahydro-1H,1′H-3,3′-bi-
pyrazole (VI), and 4,5-dihydro-1H,1′H-3,3′-bipyrazole
We have developed a simple and efficient proce-
dure for the synthesis of 3-alkenyl-1H-pyrazoles and
3,3′-bipyrazoles via oxidative dehydrogenation of
3-vinyl-4,5-dihydro-3H-pyrazoles and 4,4′,5,5′-tetra-
hydro-3H,3′H-3,3′-bipyrazole with manganese dioxide.
950

SYNTHESIS OF 3-SUBSTITUTED PYRAZOLES
951
Scheme 2.
MnO2
+
HN
NH
HN
N
N
N
IV
V
N
N
N
N
S8, pyridine
III
IV
+
+
HN
NH
HN
NH
N
N
N
N
VI
VII
(VII) at a ratio of 2.2 : 2.8 : 1 (overall yield 63%;
Scheme 2).
NH). 13C NMR spectrum (CDCl3), δC, ppm: 15.92
(Me), 104.76 (C4), 119.52 (C2′), 127.84 (C1′), 134.83
(C5), 143.80 (C3). Mass spectrum: m/z 109 [M + H]+.
Found, %: C 66.66; H 7.42; N 25.92. C6H8N2. Calcu-
lated, %: C 66.64; H 7.46; N 25.90. M 108.14.
The structure of compounds IIa, IIb, and IV–VII
1
was determined on the basis of the H and 13C NMR
and IR data. The 1H NMR spectrum of pyrazole IIa in
CDCl3 contained signals from protons in the vinyl
group and two doublets from protons in the pyrazole
ring at δ 6.25 (4-H) and 7.40 ppm (5-H) with a cou-
pling constant J of 1.8 Hz. Compounds IIa, IIb, and V
displayed in the 13C NMR spectra three downfield
signals with equal intensities from one quaternary and
two CH carbon atoms in the pyrazole ring [10].
Oxidative dehydrogenation of 4,4′,5,5′-tetrahy-
dro-3H,3′H-3,3′-bipyrazole (III) with manganese di-
oxide. Compound III, 0.5 g (3.62 mmol), was dis-
solved in 100 ml of benzene, 12.0 g (138 mmol) of
MnO2 was added, and the mixture was stirred for 10 h
at room temperature. The precipitate was filtered off,
the solvent was removed from the filtrate under re-
duced pressure, and the residue was purified by chro-
matography on silica gel using petroleum ether–ethyl
acetate (2:1) as eluent to isolate 0.131 g (27%) of
bipyrazole IV {colorless crystals, mp 255–256°C;
published data [11]: mp 258°C} and 0.07 g (18%) of
cyclopropylpyrazole V (colorless crystals).
Thus we have developed a convenient method for
the synthesis of 3-alkenyl-1H-pyrazoles and 3,3′-bipyr-
azoles.
Initial dihydropyrazoles Ia, Ib, and III were syn-
thesized as described in [9, 11].
3-Vinyl-1H-pyrazole (IIa). Compound Ia, 0.6 g
(6.24 mmol), was dissolved in 100 ml of benzene,
12.0 g (138 mmol) of MnO2 was added, and the mix-
ture was stirred for 5 h at room temperature. The pre-
cipitate was filtered off, the solvent was removed from
the filtrate under reduced pressure, and the residue was
purified by chromatography on silica gel. Yield 0.21 g
(36%), oily substance, Rf 0.55 (hexane–ethyl acetate,
2:1). Compound IIa was identified by comparing with
an authentic sample [12].
3-Cyclopropyl-1H-pyrazole (V). IR spectrum, ν,
cm–1: 3196, 2926–3003, 1450–1550, 1100, 1043, 763
1
(NH). H NMR spectrum (CDCl3), δ, ppm: 0.74 m
(2H, trans-2′-H, trans-3′-H), 0.96 m (2H, cis-2′-H, cis-
3′-H), 1.95 m (1H, 1′-H), 5.96 br.s (1H, 4-H), 7.45 br.s
(1H, 5-H), 10.06 br.s (1H, NH). 13C NMR spectrum
(CDCl3), δC, ppm: 7.78 (C2′, C3′), 13.86 (C1′), 98.70
(C4), 130.36 (C5), 146.66 (C3). Mass spectrum:
m/z 109 [M + H]+. Found, %: C 66.58; H 7.52;
N 25.83. C6H8N2. Calculated, %: C 66.64; H 7.46;
N 25.90. M 108.14
3-[(Z)-Prop-1-en-1-yl)-1H-pyrazole (IIb). Com-
pound Ib, 0.66 g (6 mmol), was dissolved in 100 ml of
benzene, 9.94 g (0.114 mol) of MnO2 was added, and
the mixture was stirred for 5 h at room temperature.
The precipitate was filtered off, the solvent was
removed from the filtrate under reduced pressure, and
the residue was purified by chromatography on silica
gel. Yield 0.32 g (49%), oily substance, Rf 0.45 (hex-
ane–ethyl acetate, 2:1). IR spectrum, ν, cm–1: 3157,
Dehydrogenation of 4,4′,5,5′-tetrahydro-3H,3′H-
3,3′-bipyrazole (III) with sulfur in pyridine. Elemen-
tal sulfur, 0.46 g (0.014 mol), was added to a solution
of 1 g (7.24 mmol) of compound III in 5 ml of pyri-
dine, and the mixture was stirred for 5 h at 110°C. The
precipitate was filtered off, and the solvent was
removed from the filtrate under reduced pressure to
isolate 0.63 g (63%) of a mixture of compounds IV,
VI, and VII at a ratio of 2.2:2.8:1.
1
2924–2958, 1400–1572, 1093, 781 (NH). H NMR
spectrum (CDCl3), δ, ppm: 1.98 d.d (3H, Me, J = 1.7,
7.1 Hz), 5.86 d.t (1H, 2′-H, J = 7.1, 11.5 Hz), 6.34 d
(1H, 4-H, J = 2.1 Hz), 6.43 d.t (1H, 1′-H, J = 1.7,
11.5 Hz), 7.58 d (1H, 5-H, J = 2.1 Hz), 11.75 br.s (1H,
4,4′,5,5′-Tetrahydro-1H,1′H-3,3′-bipyrazole (VI).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.71 t (4H,
4-H, 4′-H, J = 9.9 Hz), 3.27 t (4H, 5-H, 5′-H′, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

YAKOVLEV et al.
952
9.9 Hz), 6.99 br.s (2H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 31.63 (C4, C4′), 47.69 (C5, C5′),
148.33 (C3, C3′). Mass spectrum: m/z 139 [M + H]+.
2. Diaz-Ortiz, A., de la Hoz, A., and Langa, F., Green
Chem., 2000, vol. 2, p. 165.
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4,5-Dihydro-1H,1′H-3,3′-bipyrazole (VII).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.86 t (2H,
4-H, J = 9.8 Hz), 3.27 t (2H, 5-H, J = 9.8 Hz), 6.46 br.s
(1H, 4′-H), 6.99 br.s (1H, NH), 7.66 br.s (1H, 5′-H),
12.89 br.s (1H, NH). Mass spectrum: m/z 137 [M + H]+.
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UR-20 and Specord M-80 spectrometers from samples
dispersed in mineral oil or neat substances. The mass
spectra (electron impact, 70 eV) were obtained on
a Thermo Finnigan MAT 95-XP high-resolution mass
spectrometer (ion source temperature 250°C, direct
inlet probe temperature programming from 50 to
270°C at a rate of 10 deg/min). The products were
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