Addition of azoles to methyl vinyl ketone by the Aza-Michael reaction

Full text of DOI:10.1134/S1070363215040398

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 4, pp. 993–995. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © S.S. Hayotsyan, A.N. Khachatryan, A.O. Baltayan, H.S. Attaryan, G.V. Hasratyan, 2015, published in Zhurnal Obshchei Khimii,
2015, Vol. 85, No. 4, pp. 692–694.
LETTERS
TO THE EDITOR
Addition of Azoles to Methyl Vinyl Ketone
by the Aza-Michael Reaction
S. S. Hayotsyan, A. N. Khachatryan, A. O. Baltayan, H. S. Attaryan, and G. V. Hasratyan
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia, Institute of Organic Chemistry,
Azatutyan ave. 26, Yerevan, 0014 Armenia
e-mail: shayotsyan@gmail.com
Received December 15, 2014
Keywords: pyrazole, 1,2,4-triazole, imidazole, tetrazole, methyl vinyl ketone, Michael reaction
DOI: 10.1134/S1070363215040398
The capability of azoles to react with compounds
containing activated double bond allows to prepare a
variety of their derivatives [1–7]. The conjugate
addition of azoles to methyl vinyl ketone in most cases
occurs in the presence of acidic catalysts [8–11] or any
other agents (ethylamine [12], molecular iodine on
alumina [13], imidazolium salts [14]). There are some
examples of the addition in dimethyl sulfoxide [15].
Only two papers described the addition of imidazole
and pyrazole to methyl vinyl ketone in the absence of
any catalysts and solvents; the target adducts were
isolated in 63–74% yields [16, 17].
In the case of tetrazole VI (pKa 4.89 [21]), the reaction
was completed in 15 min.
Addition of 1,2,4-triazole IV (pKa 15.4 [22]) and
imidazole V (pKa 14.52 [22]) to methyl vinyl ketone
took place analogously to pyrazole I. Hence, in a series
of pyrazoles I–III the presence of electron-donor
substituents in the positions 3 and 5 of the the pyrazole
ring affects the rate of the reaction, and an increase in
the number of N atoms in the azole ring accelerates the
reaction.
In the case of addition of 3-methylpyrazole II the
final product represents a mixture of two isomers
VIIIa and VIIb in a ratio of 3 : 1.
In the present work, we studied the interaction of
pyrazole I, 3(5)-methylpyrazole II, 3,5-dimethyl-
pyrazole III, 1,2,4-triazole IV, imidazole V and
tetrazole VI with methyl vinyl ketone in the absence of
a catalyst and a solvent (Scheme 1).
The reaction of 1,2,4-triazole IV with methyl vinyl
ketone proceeded stereoselectively to afford only isomer
Xa [23].
The introduction of hetero atoms in the azole ring
enhances the reactivity of the corresponding hetero-
cycles in nucleophilic addition reactions [18, 19].
The interaction of tetrazole VI with methyl vinyl
ketone took place with the formation of 1- and 2-
substituted isomers XIIa and XIIb in a ratio of 1 : 2.
After the removal of the excess of the methyl vinyl
ketone, the product of ~96% purity was obtained
(according to NMR data). Despite the high yields the
separation and characterisation of individual isomers
was impossible due to their high instability at higher
temperatures. The identification of isomers was done
according to the position of signals of ring hydrogens
in NMR spectra. In the isomer (XIIb) the signal of the
ring proton is revealed in the stronger field compared
to the proton of isomer (XIIa) [24].
We found that the addition of pyrazoles I–III to
methyl vinyl ketone proceeded in 0.5–3 h. The reaction
rate depends on the acidity of pyrazoles. By the
reaction rate, the studied pyrazoles can be arranged in
the following sequence: pyrazole I ) (pKa 20.4 [20]) >
3(5)-methylpyrazole II pKa 21.0 [20]) > 3,5-dimethyl-
pyrazole III (pKa 22.0 [20]).
The introduction of an electron-donor methyl
substituents into the pyrazole ring affects the
deprotonation, thus decreasing the rate of the reaction.
993

994
HAYOTSYAN et al.
Scheme 1.
N
N
O
VII
+
N
N N
N
N
N
+
N
N
N
N
N
O
N
O
N
H
N
O
N
O
N
I
H
II
N
VIIIa
VIIIb
XIIa
XIIb
N
N
O
N
+
H
N
VI
N
N
H
H
N
III
N
N
N
N
N
H
N
N
O
O
N
V
H
IV
IX
XI
N N
N
N
N
O
N
O
Xb
Xa
In summary, aza-addition of azoles can be
performed in the absence of a catalyst and a solvent at
heating with 10% excess of methyl vinyl ketone.
(2H, CH2C=O), 4.15–4.22 m (2H, NCH2), 6.20 d (1H,
H4, J 2.3), 7.30 d (a) (1H, H5, J 2.3), 7.19 d (b) (1H,
H3, J 2.3). Found, %: C 63.55; H 7.35; N 18.85.
C8H12N2O. Calculated, %: C 63.13; H 7.95; N 18.41.
4-(1H-Pyrazol-1-yl)butan-2-one (VII). A mixture
of 3.4 g (0.05 mol) of pyrazole I and 3.85 g
(0.055 mol) of methyl vinyl ketone was heated in an
oil bath at 110°C for 0.5 h. After cooling, the reaction
mixture was distilled in a vacuum. Yield 5.70 g (83%),
mp 79°C (3 mmHg), nD20 1.4841. IR spectrum, ν, cm–1:
4-(3,5-Dimethyl-1H-pyrazol-1-yl)butan-2-one (IX)
was prepared similarly from 4.8 g (0.05 mol) of 3,5-
dimethylpyrazole III by heating for 3 h. Yield 6.97 g
(84%), bp 112°C (5 mmHg), nD20 1.4831. IR spectrum,
1
ν, cm–1: 1540 (ring), 1720 (C=O). Н NMR spectrum,
1
1520 (ring), 1720 (C=O). Н NMR spectrum, δ, ppm
δ, ppm (J, Hz): 2.22 s (3H, 3-CH3), 2.26 s (3H,
5-CH3), 2.96 t (2H, CH2C=O, J 6.6), 4.15 t (2H,
NCH2, J 6.6), 6.25 s (1H, 4H). Found, %: C 65.48; H
8.79; N 16.34. C9H14N2O. Calculated, %: C 65.03; H
8.49; N 16.85.
(J, Hz): 2.21 s (3H, 3-CH3), 2.93 t (2H, CH2C=O, J
6.6), 4.11 t (2H, NCH2, J 6.6), 6.15 d.d (1H, 4H, J
2.3), 7.34 d.d (1H, 3H, J 1.8), 7.54 d.d (1H, 5H, J 2.3).
Found, %: C 60.35; H 7.80; N 20.56. C7H9N3.
Calculated, %: C 60.85; H 7.30; N 20.28.
4-(1H-1,2,4-Triazol-1-yl)butan-2-one (Xa) was
prepared similarly from 3.45 g (0.05 mol) of 1,2,4-
triazole IV. Yield 6.26 g (90%), bp 120°C (2 mmHg),
nD20 1.4701. IR spectrum, ν, cm–1: 1510 (ring), 1720
(C=O). 1Н NMR spectrum, δ, ppm (J, Hz): 2.13 s (3H,
CH3), 3.03 t (2H, 2H, CH2C=O, J 6.6), 4.36 t (2H, NCH2,
J 6.6), 7.71 s (1H, CH). Found, %: C 51.48; H 6.85;
N 30.49. C6H9N3O. Calculated, %: C 51.79; H 6.52; N 30.20.
4-(3-Methyl-1H-pyrazol-1-yl)butan-2-one (VIIIa,
VIIIb) (mixture of isomers) was prepared similarly
from 4.75 g (0.05 mol) of 3(5)-methylpyrazole II by
heating for 1.5 h. Yield 6.69 g (88%), bp 103°C
(5 mmHg), nD20 1.4760. IR spectrum, ν, cm–1: 1530
(ring), 1720 (C=O). 1Н NMR spectrum, δ, ppm (J, Hz):
2.21 s (a) and 2.22 s (b) [3H, 3(5)-CH3], 2.94–3.5 m
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 4 2015

ADDITION OF AZOLES TO METHYL VINYL KETONE
995
6. Attaryan, O.S., Baltayan, A.O., and Matsoyan, S.G.,
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4-(1H-Imidazol-1-yl)butan-2-one (XI) was pre-
pared similarly from 3.4 g (0.05 mol) of imidazole V.
Yield 5.87 g (85%), bp 146°C (7 mmHg), nD20 1.4838.
1
IR spectrum, ν, cm–1: 1540 (ring), 1720 (C=O). Н
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NMR spectrum, δ, ppm (J, Hz): 2.11 s (3H, CH3), 2.94
t (2H, CH2C=O, J 6.6), 4.16 t (2H, NCH2, J 6.6), 6.78
m (1H, CH), 6.94 m (1H, CH), 7.42 m (1H, CH).
Found, %: C 60.39; H 7.85; N 20.54. C6H7N2O.
Calculated, %: C 60.85; H 7.30; N 20.28
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4-(1H-Tetrazol-1-yl)butan-2-one (XIIa, XIIb) (mix-
ture of isomers, 1 : 2) was prepared similarly from 3.5 g
(0.05 mol) of tetrazole VI and 3.85 g (0.055 mol) of
methyl vinyl ketone by heating under the conditions
for preparation of compound (VII) within 15 min.
After cooling, an excess of methyl vinyl ketone was
removed under reduced pressure to give 6.8 g of a
1
mixture of isomers XIIa,b in a ratio of 1 : 2 (by H
NMR). Yield 6.8 g (97%). IR spectrum, ν, cm–1: 1500
1
(ring), 1720 (C=O). Н NMR spectrum (300 MHz), δ,
ppm (J, Hz): isomer XIIа, 2.19 s (3H, CH3), 3.25 t
(2H, CH2C, J 6.7), 4.83 t (2H, NCH2, J 6.7), 8.57 s
(1H, CH); isomer XIIb, 2.15 s (3H, CH3), 3.17 t (2H,
CH2C, J 6.5), 4.62 t (2H, NCH2, J 6.5), 9.09 s (1H,
CH).
IR spectra were obtained on a Nexus spectrometer
(Thermo Nicolet Corporation, USA). H NMR spectra
were recorded on Varian Mercury instrument (300 MHz)
in DMSO–CCl4, 1 : 3. Elemental analysis was per-
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