Catalytic addition of pyrazoles to but-3-enenitrile

Full text of DOI:10.1134/S1070363215100291

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 10, pp. 2408–2410. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © S.S. Hayotsyan, H.N. Khachatryan, H.S. Attaryan, G.V. Hasratyan, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85,
No. 10, pp. 1737–1739.
LETTERS
TO THE EDITOR
Catalytic Addition of Pyrazoles to But-3-enenitrile
S. S. Hayotsyana, H. N. Khachatryana, 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, but-3-enenitrile, cyclic amines, isomerization, addition
DOI: 10.1134/S1070363215100291
Recently, we have shown that pyrazoles react with
but-3-enenitrile under rigid conditions (200–220°C,
pressure reactor) [1]. It was assumed that at 200–220°C
the presence of basic pyrazoles (pKa = 20.4–22.0 [2])
causes isomerization of but-3-enenitrile into but-2-
enenitrile, which further facilitates the nucleophilic
addition at the β-carbon atom of the conjugated double
bond.
readily at 20–25°C within 24 h to form the correspon-
ding adducts 7–9 (Scheme 2).
The reaction time was reduced approximately 2-fold
with increasing temperature from 20 to 40°C. Further
increase in temperature led to decrease in the yield of
the target compounds due to the occurrence of a by-
processes, in particular, acetone self-condensation [6].
The use of alkali metal alcoholates as catalysts had
no special advantages. Performing the reaction under
phase transfer catalysis using triethylbenzylammonium
chloride led to the predominant formation of by-pro-
ducts due to acetone self-condensation, which caused a
decrease in the yield of the target compounds as well
as made their isolation difficult.
Taking into account the data obtained, we assumed
that the basicity of pyrazole is not sufficient to ensure
non-conjugated double bond isomerization, so the
reaction should be carried out under rigid conditions.
To test our hypotheses, we have carried out a
similar reaction involving cyclic amines of higher
basicity: morpholine (pKa = 8.36), piperidine (pKa =
11.22) and pyrrolidine (pKa = 11.27) [3].
Scheme 1.
We found that the selected amines reacted with but-
3-enenitriles at moderate heating. This fact confirmed
our assumption that the formation of the double bond
adducts includes a two stage process: first isomeriza-
tion and further aza-addition of a nucleophile to the
conjugated system (Scheme 1).
O
N
O
N
CN
CN
H
1, 78%
CN
We concluded that the addition of pyrazoles 4–6 to
but-3-enenitrile can be carried out under conditions
supporting isomerization of but-3-enenitrile into but-2-
enenitrile. For this purpose we have chosen acetone–
water mixture as a solvent and KOH as a catalyst of
the isomerization [4, 5]. Compared with non-catalytic
thermal process (200–220°C), KOH-catalyzed reac-
tions of pyrazoles 4–6 with but-3-enenitrile occurred
N
N
H
2, 68%
N
H
N
CN
3, 65%
2408

2409
CATALYTIC ADDITION OF PYRAZOLES TO BUT-3-ENENITRILE
Scheme 2.
R1
R1
H2O_acetone
KOH
CN
N
N
+
R2
R2
N
H
N
CN
7_9, 47_74%
4_6
R1 = R2 = H (4, 7); R1 = H, R2 = CH3 (5а, 8а); R1 = CH3, R2 = H (5b, 8b); R1 = R2 = CH3 (6, 9).
Unlike thermal process [1], in the case of the
catalytic addition of pyrazoles 4–6 to but-3-enenitrile
the adduct yield decreased when passing from pyrazole
4 to 3,5-dimethylpyrazole 6. Probably, the base promotes
the isomerization of but-3-enenitrile as well as pyrazole
anion generation. Introduction of donor methyl substi-
tuents into the pyrazole ring complicates deprotonation
[7, 8], thereby slowing down the addition reaction.
16.6, 7.7), 2.56–2.61 m [5H, N(CH2)2, CH2CN], 2.65–
2.75 m (1H, CH). Found, %: C 64.42; H 10.52; N
20.55. C8H16N2. Calculated, %: C 64.52; H 10.21; N 20.27.
3-(1H-Pyrazol-1-yl)butanenitrile (7). To a solu-
tion of 2.8 g (0.05 mol) KOH in 7 mL of water and
25 mL of acetone was added with stirring at 40°C
3.4 g (0.05 mol) of pyrazole 4 and 5.4 g (0.08 mol) of
but-3-enenitrile. The reaction mixture was stirred for
12 h, then cooled. Acetone was removed under a
reduced pressure; the residue was extracted with
benzene. The extract was dried with MgSO4 and
evaporated. The residue was distilled under a reduced
pressure. Yield 4.9 g (74%), bp 93°C (1 mmHg), nD20
1.4852, d420 1.0462 [1].
3-(Morpholin-4-yl)butanenitrile (1). A mixture of
4.3 g (0.05 mol) of morpholine and 5.0 g (0.075 mol)
of but-3-enenitrile was heated on a water bath for 6 h.
After cooling, the reaction mixture was distilled under
a reduced pressure. Yield 6 g (78%), bp 129°C
(4 mmHg), nD20 1.4690, d420 1.0291. IR spectrum, ν,
1
cm–1: 2200 (CN). H NMR spectrum, δ, ppm (J, Hz):
1.16 d (3H, CH3, J 6.7), 2.45 d.d (1H, CH2, J 16.8,
7.0), 2.46–2.51 m [4H, N(CH2)2], 2.55 d.d (1H, CH2, J
16.8, 5.9), 2.83–2.94 m (1H, CHCH2), 3.56–3.62 m
[4H, O(CH2)2]. Found, %: C 62.85; H 9.80; N 18.56.
C8H14N2. Calculated, %: C 62.31; H 9.15; N 18.17.
3-[3(5)-Methyl-1H-pyrazol-1-yl]butanenitrile (8a,
8b) was prepared similarly from 8.2 g (0.1 mol) of
3(5)-methylpyrazole 5 and 10.1 g (0.15 mol) of but-3-
enenitrile. Yield 9 g (61%), bp 102°C (2 mmHg), nD20
1.4812, d420 1.0109 [1].
3-(Piperidin-1-yl)butanenitrile (2) was prepared
similarly from 8.5 g (0.1 mol) of piperidine and 10.1 g
(0.15 mol) of but-3-enenitrile. Yield 10.4 g (68%), bp
95°C (4 mmHg), nD20 1.4660, d420 0.9375. IR spectrum,
ν, cm–1: 2220 (CN). 1H NMR spectrum, δ, ppm
(J, Hz): 1.13 d (3H, CH3, J 6.7), 1.39 m (2H, CH2),
1.50–1.59 m (4H,CH2), 2.38 d.d (1H, NCH2, J 16.6,
7.3), 2.42–2.46 m [4H, N(CH2)2], 2.50 d.d (1H, NCH2,
J 16.6, 6.0), 2.87–2.98 m (1H, CH). Found, %: C
71.75; H 10.29; N 18.55. C9H16N2. Calculated, %: C
71.01; H 10.59; N 18.40.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)butanenitrile (9)
was prepared similarly from 9.6 g (0.1 mol) of 3,5-
dimethylpyrazole 6 and 10.1 g (0.15 mol) of but-3-
enenitrile. Yield 7.7 g (47%), bp 123°C (1 mmHg), nD20
1.4802, d420 0.9765 [1].
IR spectra were recorded on a Nexus instrument
1
(Thermo Nicolet Corporation, USA). H NMR spectra
were obtained on a Varian Mercury spectrometer
(300 MHz) in DMSO–CCl4 (1 : 3). Elemental analysis
was performed on a Korshun–Klimova instrument.
But-3-enenitrile was produced in “Ariak.”
3-(Pyrrolidin-1-yl)butanenitrile (3) was prepared
similarly from 2.1 g (0.03 mol) of pyrrolidine and
3.4 g (0.05 mol) of but-3-enenitrile. Yield 2.7 g (65%),
bp 84°C (2 mmHg), nD20 1.4645, d420 0.9419. IR spec-
ACKNOWLEDGMENTS
1
trum, ν, cm–1: 1500 (ring), 2250 (CN). H NMR
This work was financially supported by the Ministry
of Education and Science of the Republic of Armenia
(project no. SCS 13Ap_2e031).
spectrum, δ, ppm (J, Hz): 1.29 d (3H, CH3, J 6.4),
1.75–1.84 m (4H, NCH2CH2), 2.41 d.d (1H, CH2CN, J
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HAYOTSYAN et al.
5. Attaryan, H.S., Asratyan, G.V., Darbinyan, E.G., and
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