Synthesis of N-vinylpyrazoles

Article abstract of DOI:10.1007/s10593-005-0170-z

A method is proposed for the alkylation of pyrazoles with dichloroethane in water in the presence of the phase-transfer catalyst benzyltriethylammonium chloride (TEBAC). It was shown that dehydrochlorination of the corresponding N-(β-chloroethyl)pyrazoles in water under conditions of phase-transfer catalysis proceeds smoothly with the formation of N-vinylpyrazoles in 80-90% yield. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0170-z

Chemistry of Heterocyclic Compounds, Vol. 41, No. 4, 2005
SYNTHESIS OF N-VINYLPYRAZOLES
O. S. Attarian, S. G. Matsoyan, and S. S. Martirosyan
A method is proposed for the alkylation of pyrazoles with dichloroethane in water in the presence of the
phase-transfer catalyst benzyltriethylammonium chloride (TEBAC). It was shown that
dehydrochlorination of the corresponding N-(β-chloroethyl)pyrazoles in water under conditions of
phase-transfer catalysis proceeds smoothly with the formation of N-vinylpyrazoles in 80-90% yield.
Keywords: N-vinylpyrazoles, alkylation, dehydrochlorination, phase-transfer catalysis.
In the present work the N-alkylation of pyrazole (1), 3(5)-methylpyrazole (2), and 3,5-dimethylpyrazole
(
3) with dichloroethane (DCE) and the dehydrochlorination of the obtained 1-(β-chloroethyl)pyrazoles 4-6 has
been carried out with the aim of synthesizing N-vinylpyrazoles.
R1
R1
R1
PTC
PTC
N
N
N
R
N
H
R
R
ClCH CH Cl
N
– HCl
N
2
2
CH CH Cl
CH CH2
–9
2
2
1
–3
4
–6
7
1
1
1
1
1
, 4, 7 R = R = H; 2, 5, 8 R = H, R = Me, R = Me, R = H; 3, 6, 9 R = R = Me
Attempts to carry out the reaction under standard conditions (water–benzene–NaOH–TEBAC) did not
lead to the desired result. The alkylation of compounds 1-3 occurs slowly with low yields of products (Table 1).
It turned out however that the yields were sharply increased if benzene was excluded from the reaction medium
[
1-5], replacing it with an excess of reagent.
Investigations showed that the ease of alkylation depends strongly on the basicity of the pyrazole. The
introduction of an electron-donating substituent (Me) into the molecule of pyrazole 1 increases the electron
density at the "pyrrole" nitrogen atom, as a result of which deprotonation is hindered and the base is consumed in
the elimination of dichloroethane. Thus on alkylation of pyrazole 1 (pK 2.53) the substitution product is isolated
b
predominantly and in the case of 3(5)-methylpyrazole 2 (pK 3.55) and 3,5-dimethylpyrazole 3 (pK 4.38) vinyl
b
b
chloride is also formed in significant amounts (Table 1). Consequently on alkylation of compound 3 a 7-fold
excess of alkali is necessary, since the main portion of it is consumed by the competing β-elimination of
dichloroethane.
It must also be mentioned that a 5 to 7-fold excess of dichloroethane is necessary to obtain optimal
yields on alkylation of compounds 1-3. Reduction of this amount does not lead to bisalkylation since DCE is
rapidly dehydrochlorinated and the alkylation process stops due to the absence of base.
_
3
_________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of the Republic of Armenia, Erevan
75091; e-mail: MVM@lx2.yerphi.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4,
pp. 533-536, April, 2005. Original article submitted March 14, 2003.
4
52 0009-3122/05/4104-0452©2005 Springer Science+Business Media, Inc.

TABLE 1. Alkylation of Pyrazoles 1-3 by Dichloroethane in Water*
Yield
Com-
pound
Dichloroethane
(mol)
Yield of vinyl
chloride (mol)
pK
b
NaOH (mol)
of compounds
-6, %
4
1
2.53
3.55
0.3
0.15
0.15
70.0
80.0
45.0*
—
0.02
—
0
0
0
.5
.5
.5
2
0.15
3
0.15
4.15*
60.0
—
2
0.3
0.2 + 0.2
0.25
—
0
0
0
0
.5
.5
.5
.5
40.0
68.0
80.0
45.0*
25.0
50.0
78.0
40.0*
0.10
—
0.2 + 0.1
0.2 + 0.2
0.2 + 0.2
0.25
—
2
—
3
4.38
0.5
0.16
—
0
0
0
.5
.5
.5
0.2 + 0.2
0.2 + 0.25 + 0.25
0.2 + 0.25 + 0.25
—
2
—
_
*
*
*
______
Pyrazole 0.1 mol, TEBAC catalyst 0.0052 mol, 70°C, 2-4 h.
2
H O + benzene.
Without catalyst.
2
3
In the presence of DCE the rates of bisalkylation and HCl elimination from the obtained
β-chloroethylpyrazoles 4-6 are superseded by the rate of alkylation of the pyrazoles (Fig. 1), consequently the
1
products of monoalkylation may be isolated in yields of 75-80%. The IR and H NMR spectra of the
β-chloroethylpyrazoles 4-6 are given in Table 2.
Elimination of HCl from β-chloroethylpyrazoles 4-6 under the action of 50% aqueous solutions of KOH
or NaOH [6-10] on using TEBAC as catalyst at 80°C is complete after 1.5 h. Yields of N-vinylpyrazoles 7-9
under the same conditions but without using catalyst were only 10%.
The rate of dehydrochlorination falls in the series 4 > 5 > 6 (Fig. 2). Such a difference may be explained
by the difficulty of detaching the proton under the influence of electron-donating substituents.
TABLE 2. Characteristics of the Synthesized Compounds 4-6
1
Com-
pound
IR spectrum,
ν, cm (ring)
H NMR spectrum (DMSO-d
300 MHz), δ, ppm (J, Hz)
6
,
Lite-
rature
2
0
n
D
bp/mm Hg
43-48/3
-1
4
1.5021
1.5030
1530
1544
3.81 (2H, t, J = 6.0, NCH
.42 (2H, t, J = 6.0, CH Cl); 6.26 (1H,
t, J = 2.2, H-4); 7.50 (1H, d, J = 2.4,
H–3); 7.58 (1H, d, J = 2.0, H-5)
2
);
[11]
4
2
5
55-60/1
60-65/1
2.16 (3H, s, CH
s, CH -5); 3.70 (2H, m, NCH
.38 (2H, m, CH Cl); 5.85 (1H, d,
J = 2.0, H-5); 7.22 (1H, d, J = 2.0,
H-3); 7.42 (1H, d, J = 2.3, H-5)
3
-3); 2.18 (3H,
[11]
3
2
);
4
2
6
1.5010
1560
2.11 (3H, s, CH
3
-3); 2.23 (3H, s,
[11]
CH -5); 3.93 (2H, t, J = 6.0, NCH );
3
2
4
5
2
.10 (2H, t, J = 6.0, CH Cl);
.67 (1H, s, H-4)
4
53

t, min
t, min
Fig. 1. Kinetic curves for the relationship of
conversion and reaction time for alkylation
with dichloroethane at 60°C: 1) pyrazole;
Fig. 2. Kinetic curves for the relationship of
conversion
and
reaction
time
for
dehydrochlorination at 60°C: 1) 1-(β-chloro-
ethyl)pyrazole; 2) 1-(β-chloroethyl-3(5)-
methylpyrazole; 3) 1-(β-chloroethyl)-3,5-
dimethylpyrazole; 4) dehydrochlorination of
1-(β-chloroethyl)-3(5)-methylpyrazole in the
presence of dichloroethane.
2
4
) methylpyrazole; 3) 3,5-dimethylpyrazole;
) bisalkylation of 3(5)-methylpyrazole (in the
presence of dichloroethane reaction does not
occur).
EXPERIMENTAL
-(β-Chloroethyl)pyrazole (4). A mixture of pyrazole (1) (6.8 g, 0.1 mol), dichloroethane (49.5 g,
1
0
7
.5 mole), sodium hydroxide (6.0 g, 0.15 mol), water (10 ml), and TEBAC (1.2 g, 0.0052 mol) was heated at
0-75°C for 2 h with vigorous stirring. After cooling to 20°C, water (50 ml) was added, the mixture was
extracted with ether (100 ml), and the extract dried over MgSO . After removing the ether, the residue was
4
distilled in vacuum. Compound 4 (10.5 g, 80%) was obtained.
1
-(β-Chloroethyl)-3(5)-methylpyrazole (5). A mixture of 3(5)-methylpyrazole (2) (8.2 g, 0.1 mol),
dichloroethane (49.5 g, 0.5 mol), sodium hydroxide (8.0 g, 0.2 mol), water (10 ml), and TEBAC (1.2 g,
.0052 mol) was heated at 70-75°C for 2 h with vigorous stirring. After cooling to 20°C, further sodium
0
hydroxide (8.0 g, 0.2 mol) and water (10 ml) were added and the mixture heated for a further 2 h (70-75°C).
After cooling to 20°C, water (50 ml) was added, the mixture was extracted with ether (100 ml), and the extract
dried over MgSO . After removing the ether, the residue was distilled in vacuum. A mixture (11.9 g, 82%) of the
4
isomeric 1-(β-chloroethyl)-3-methylpyrazole and 1-(β-chloroethyl)-5-methylpyrazole was obtained (ratio of
isomers was 60:40 according to GLC).
1
-(β-Chloroethyl)-3,5-dimethylpyrazole (6). A mixture of 3,5-dimethylpyrazole (3) (9.6 g, 0.1 mol),
dichloroethane (69.3 g, 0.7 mol), sodium hydroxide (8.0 g, 0.2 mol), water (10 ml), and TEBAC (1.2 g,
.0052 mol) was heated at 70-75°C for 1 h with vigorous stirring. After cooling to 20°C, further sodium
0
hydroxide (10.0 g, 0.25 mol) and water (10 ml) were added and heating continued for a further 2 h (70-75°C).
Then sodium hydroxide (10.0 g, 0.25 mol) and water (10 ml) were added once again and the mixture was heated
a further 2 h (70-75°C). After cooling to 20°C, water (100 ml) was added, the mixture was extracted with ether
(
100 ml), and the extract was dried over MgSO . After removing the ether, the residue was distilled in vacuum.
4
1
-(β-Chloroethyl)-3,5-dimethylpyrazole (12.2 g, 77%) was obtained.
-Vinylpyrazoles 7-9. A mixture of the appropriate 1-(β-chloroethyl)-pyrazole 4-6 (0.1 mol), base
NaOH or KOH) (0.2 mol), water (10 ml), TEBAC (1.2 g, 0.0052 mol), and hydroquinone was stirred
vigorously at 80°C for 1.5 h. After cooling, water (50 ml) was added, the mixture was extracted with ether
1
(
4
54

(
100 ml), and the extract dried over MgSO
give the following.
-Vinylpyrazole (7). Yield 7.5 g (80%); bp 63°C/50 mm Hg, nD 1.5163 [12]. H NMR spectrum
CCl ), δ, ppm (J, Hz): 5.00 (1H, dd, J = 9.0 and J = 1.5, =CH ); 5.52 (1H, dd, J = 15.8 and J = 1.5, =CH ); 6.26
4
. After removing the solvent, the residue was distilled in vacuum to
2
0
1
1
(
(
4
2
2
1H, t, J = 2.2, H-4); 7.12 (1H, dd, J = 15.8 and J = 9.0, N–CH=); 7.50 (1H, d, J = 2.4, H-3); 7.58 (1H, d,
J = 2.0, H-5).
(5)-Methyl-1-vinylpyrazole (8). Yield 9.7 g (90%); bp 55-60°C/10 mm Hg, nD 1.5160 [13]. H NMR
spectrum (CCl ), δ, ppm (J, Hz): 2.16 (3H, s, CH -3); 2.18 (3H, s, CH -5); 4.76 (1H, dd, J = 9.3 and J = 1.5,
2
0
1
3
4
3
3
=
CH ); 5.42 (1H, dd, J = 15.7 and J = 1.5, =CH ); 5.85 (1H, d, J = 2.0, H-4); 6.92 (1H, dd, J = 15.7 and J = 9.3,
2
2
N–CH=); 7.22 (1H, d, J = 2.0, H-3); 7.42 (1H, d, J = 2.3, H-5).
,5-Dimethyl-1-vinylpyrazole (9). Yield 9.2 g (75%); bp 70°C/10 mm Hg, nD 1.5180 [14]. H NMR
spectrum (CCl ), δ, ppm (J, Hz): 2.11 (3H, s, CH -3); 2.23 (3H, s, CH -5); 4.42 (1H, dd, J = 9.5 and J = 1.5,
2
0
1
3
4
3
3
=
CH ); 5.22 (1H, dd, J = 15.3 and J = 1.5, =CH ); 5.67 (1H, s, H-4); 6.33 (1H, dd, J = 15.3 and J = 9.5,
2
2
N–CH=).
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