Aza-Michael addition of pyrazoles to maleic acid

Full text of DOI:10.1134/S1070363215080320

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 8, pp. 1982–1983. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © H.N. Khachatryan, S.S. Hayotsyan, K.S. Badalyan, H.S. Attaryan, G.V. Hasratyan, 2015, published in Zhurnal Obshchei Khimii,
2015, Vol. 85, No. 8, pp. 1395–1396.
LETTERS
TO THE EDITOR
Aza-Michael Addition of Pyrazoles to Maleic Acid
H. N. Khachatryana, S. S. Hayotsyana, K. S. Badalyana, H. S. Attaryana, and G. V. Hasratyanb
a Institute of Organic Chemistry, Scientific and Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia,
ave. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: shayotsyan@gmail.com
b Armenian Institute of Applied Chemistry “Ariak,” CJSC, Artashat hwy., 5/2, Yerevan, 0033 Armenia
Received May 7, 2015
Keywords: pyrazole, maleic acid, addition, aza-Michael reaction
DOI: 10.1134/S1070363215080320
We have previously investigated the reactivity of
pyrazoles I–III in addition reactions to the carbon–
carbon double bond conjugated with electron-
withdrawing groups [1, 2]. In order to verify the
possibility of attaching azoles to conjugated systems
under mild conditions, we performed reactions
of pyrazoles I–III with maleic acid; in the latter
molecule the double bond is not polarized due to a
mismatched action of two electron-withdrawing
groups [3].
of less basic pyrazole I (pKb = 2.53) the reaction
proceeded with yield of 65%. In the case of 3(5)-
methylpyrazole II (pKb = 3.55), the desired product
was obtained in yield of 80% as a mixture of two
isomers Va and Vb in the ratio of 9 : 1. Isomer 5a was
isolated via fractional crystallization from water.
2-(1H-Pyrazol-1-yl)butanedioic acid (IV). A
mixture of 1.5 g (0.022 mol) of pyrazole I and 3.0 g
(0.024 mol) of maleic acid was heated to 110°C. The
reaction temperature spontaneously went up to 130°C.
Heating was continued at 110°C for 2.5 h. The
resulting mixture was recrystallized from water. Yield
2.6 g (65%), mp 170°C. IR spectrum, ν, cm–1: 1520
The experiments showed that pyrazoles I–III react
with maleic acid similarly to the cases of acrylic acid
[4] and methyl vinyl ketone [1]: when heated in bulk in
the absence of any catalyst, they yielded the
corresponding (pyrazol-1-yl)succinic acids IV–VI
(Scheme 1).
1
(ring), 1570 (COOH). H NMR spectrum, δ, ppm (J,
Hz): 2.99 d.d (1H, CH2, J 17.0, 7.6), 3.14 d.d (1H,
CH2, J 17.0, 6.2), 5.27 d.d (1H, CH, J 7.6, 6.2), 6.18
d.d (1H, =CH, J 2.3, 1.8), 7.37 d.d (1H, =CH, J 1.8,
0.8), 7.65 d.d (1H, =CH, J 2.3, 0.8), 12.20 br.s (2H,
COOH). Found, %: C 45.85; H 4.75; N 15.56.
C7H8N2O4. Calculated, %: C 45.66; H 4.38; N 15.21.
Yields of aza-Michael adducts IV–VI depended
strongly on the azoles basicity. When maleic acid
reacted with 3,5-dimethylpyrazole III (pKb = 4.38),
yield of compound VI was of 96%, whereas in the case
Scheme 1.
R
R
CO2H
Δ
N
N
+
R'
R'
N
N
CO2H
H
CO2H
HO2C
IV_VI
I_III
R1 = R2 = H (I, IV); R1 = CH3, R2 = H (IIа, Vа); R1 = H, R2 = CH3 (IIb, Vb); R1 = R2 = CH3 (III, VI).
1982

1983
AZA-MICHAEL ADDITION OF PYRAZOLES TO MALEIC ACID
2-[3(5)-Methyl-1H-pyrazol-1-yl]butanedioic acid
(Va, Vb) was obtained similarly from 8.2 g (0.1 mol)
of 3(5)-methylpyrazole II and 7.7 g (0.11 mol) of
maleic acid. Yield 15.8 g (80%), mp 200°C. IR spec-
IR spectra were obtained using a Nexus instrument
(Thermo Nicolet Corporation, USA). H NMR spectra
of the solutions in DMSO–CCl4 (1 : 3) were recorded
with a Varian Mercury spectrometer (300 MHz).
Elemental analysis was performed using a Korshun–
Klimova apparatus.
1
1
trum, ν, cm–1: 1530 (ring), 1680 (COOH). H NMR
spectrum, δ, ppm (J, Hz): 2.19 s (3H, CH3), 2.20 s (3H,
CH3), 2.93 m (1H, CH2), 3.11 m (1H, CH2), 5.14 m
(2H, NCH2), 5.94 d (1H, =CH, J 2.2), 7.21 d (1H,
=CH, J 2.4), 7.49 d (1H, =CH, J 2.2), 12.20 br.s (2H,
COOH). Found, %: C 48.80; H 5.49; N 14.38.
C8H10N2O4. Calculated, %: C 48.49; H 5.09; N 14.14.
ACKNOWLEDGMENTS
This work was supprted by State Committee
Science MES RA, in frame of the research project
no. SCS 13Ar_2e031.
After fractional recrystallization of a mixture of
isomers Va and Vb from water, isomer Va (50%) was
isolated, mp. 215–218°C. H NMR spectrum, δ, ppm
REFERENCES
1
(J, Hz): 2.19 s (3H, CH3), 2.93 d.d (1H, CH2, J 16.9,
7.2), 3.11 d.d (1H, CH2, J 16.9, 6.7), 5.14 d.d (1H, CH,
J 7.2,6.7), 5.93 d (1H, =CH, J 2.2), 7.48 d (1H, =CH,
J 2.2), 12.4 br.s (2H, COOH).
1. Hayotsyan, S.S., Khachatryan, A.N., Baltayan, A.O.,
Attaryan, H.S., and Hasratyan, G.V., Russ. J. Gen.
Chem., 2015, vol. 85, no. 4, p. 993. DOI: 10.1134/
S1070363215040398.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)butanedioic acid
(VI) was obtained similarly from 9.6 g (0.1 mol) of
3,5-dimethylpyrazole III and 7.7 g (0.11 mol) of
maleic acid. Yield 20.4 g (96%), mp 220°C [5]. IR
2. Khachatryan, A.N., Hayotsyan, S.S., Attaryan, H.S., and
Hasratyan, G.V., Russ. J. Gen. Chem., 2015, vol. 85,
no. 4, p. 996. DOI: 10.1134/S1070363215040404.
3. Nesmeyanov, A.N., Rybinskaya, M.I., and Rybin, L.V.,
1
spectrum, ν, cm–1: 1540 (ring), 1690 (COOH). H
Russ. Chem. Rev., 1967, vol. 36, no. 7, p. 453.
NMR spectrum, δ, ppm (J, Hz): 2.12 s (3H, CH3), 2.28
s (3H, CH3), 3.00 d.d (1H, CH2, J 17.1, 8.0), 3.15 d.d
(1H, CH2, J 17.1, 5.8), 5.03 d.d (1H, CH, J 8.0, 5.8),
5.7 q (1H, =CH, J 0.7), 12.30 br.s (2H, COOH).
Found, %: C 50.45; H 5.38; N 13.56. C9H12N2O4.
Calculated, %: C 50.94; H 5.70; N 13.20.
4. Darbinyan, E.G., Matsoyan, M.G., Oganesyan, K.G.,
Mitardzyan, Yu.B., Saakyan, A.A., and Matsoyan, S.G.,
USSR Inventors Certificate 688499, 1979.
5. Grandbeg, I.I. and Kost, A.N., Zh. Obshch. Khim., 1959,
vol. 29, no. 4, p. 1099.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 8 2015