Synthesis of 1-(2-aminoethyl)pyrazoles under phase-transfer catalysis

Article abstract of DOI:10.1134/s1070363208010234

Alkylation of pyrazoles with 2-chloroethylamine was performed under conditions of phasetransfer catalysis. Depending on the substrate acidity, the electrophilic substitution process may be accompanied by dehydrochlorination of the alkylating agent, so that 6 equiv of 2-chloroethylamine should be used in the alkylation of 3,5-dimethylpyrazole.

Full text of DOI:10.1134/s1070363208010234

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 1, pp. 136 138.
Pleiades Publishing, Ltd., 2008.
Original Russian Text
No. 1, pp. 144 146.
O.S. Attaryan, A.O. Baltayan, R.E. Sagatelyan, K.Ts. Takmazyan, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78,
Synthesis of 1-(2-Aminoethyl)pyrazoles
under Phase-Transfer Catalysis
O. S. Attaryana, A. O. Baltayana, R. E. Sagatelyanb, and K. Ts. Takmazyanb
a Institute of Organic Chemistry, National Academy of Sciences of Armenia,
ul. Zakariya Sarkavaga 167a, Erevan, 375091 Armenia
e-mail: angelabaltayan@mail.ru
b State University of Engineering of Armenian Republic, Erevan, Armenia
Received May 3, 2007
Abstract Alkylation of pyrazoles with 2-chloroethylamine was performed under conditions of phase-
transfer catalysis. Depending on the substrate acidity, the electrophilic substitution process may be accom-
panied by dehydrochlorination of the alkylating agent, so that 6 equiv of 2-chloroethylamine should be used
in the alkylation of 3,5-dimethylpyrazole.
DOI: 10.1134/S1070363208010234
1-(2-Aminoethyl)pyrazoles are prepared by alkyla-
tion of pyrazoles with 2-chloroethylamine hydrochlo-
ride at elevated temperature (110 C), and the reaction
requires 20 25 h [1]. While continuing our studies on
the synthesis of azoles having functional substituents
on the nitrogen atom [2 9], we examined reactions
of pyrazoles I III with 2-chloroethylamine under
conditions of phase-transfer catalysis.
dehydrochlorination of 2-chloroethylamine, and the
yield considerably decreased in going from pyrazole
(I) to 3,5-dimethylpyrazole (III). Analogous relation
was observed previously in the alkylation of pyrazoles
with dichloroethane and dibromoethane [5, 6]. The
maximal yields of amines IV VI (70 80%) were ob-
tained using the following reactant ratios: pyrazole (I)
NaOH 2-chloroethylamine 1:2:2; 3(5)-methylpyrazole
(II) NaOH 2-chloroethylamine 1:3:3; 3,5-dimethyl-
pyrazole (III) NaOH 2-chloroethylamine 1:5:5.
Scheme 1.
R
The reactions with 3(5)-methylpyrazole and 3,5-
dimethylpyrazole, especially in the presence of excess
alkylating agent, were accompanied by further alkyla-
tion at the amino nitrogen atom with formation of
compounds VII and VIII (Scheme 2).
+ ClCH2CH2NH2
N
R
N
H
I III
R
phase-transfer
catalyst
Scheme 2.
N
N
R
R
70 C
+ ClCH2CH2NH2
N
CH2CH2NH2
R
N
IV VI
CH2CH2NH2
V, VI
I, IV, R = R = H; II, V, R = CH3, R = H (a); R = H, R =
CH3 (b); III, VI, R = R = CH3.
R
N
R
The reactions were carried out in a system liquid
solid using benzene as organic solvent and benzyltri-
ethylammonium chloride (BTEAC) as catalyst
(Scheme 1). The alkylation with equimolar amounts
of the reactants was characterized by poor yields (20
40%) of alkylated products IV VI due to concurrent
N
CH2CH2NHCH2CH2NH2
VII, VIII
V, VII, R = CH3, R = H (a); R = H, R = CH3 (b);
VI, VIII, R = R = CH3.
136

SYNTHESIS OF 1-(2-AMINOETHYL)PYRAZOLES UNDER PHASE-TRANSFER CATALYSIS
137
1
1
The structure of 1-(2-aminoethyl)pyrazoles IV VI
was confirmed by spectral data (IR, H NMR). The
cm : 1540 (ring), 3300 3370 (NH2). H NMR spec-
trum (DMSO-d6), , ppm (J, Hz): 1.40 br.s (2H, NH2),
2.18 s (3H, 5-CH3), 2.18 s (3H, 3-CH3), 2.96 br.s (2H,
CH2NH2), 3.98 br.s (2H, NCH2), 5.88 d (1H, 4-H, J =
1.8), 7.18 d (1H, 3-H, J = 1.8), 7.34 d (1H, 5-H, J =
2.2). Found, %: C 57.38; H 8.51; N 33.28. C6H11N3.
Calculated, %: C 57.60; H 8.80; N 33.60.
1
IR spectra of IV VI contained absorption bands at
1
1520 1550 cm , typical of pyrazole ring vibrations,
and two absorption bands in the region 3300
1
3370 cm , belonging to stretching vibrations of the
primary amino group.
From the reaction mixture we also isolated 3.0 g
As might be expected, the alkylation of 3(5)-me-
thyl-1H-pyrazole (II) gave rise to a mixture of iso-
meric pyrazoles V at a ratio of 3:2 (according to the
1H NMR data) with an overall yield of 75%. We
succeeded in separating and identifying the isomeric
products. In the H NMR spectrum of Va, protons in
the methyl group resonated at 2.18 ppm, while the
of N-{2-[3(5)-methyl-1H-pyrazol-1-yl]ethyl}ethane-
1,2-diamine (VII), bp 135 139 C (1 mm), nD20
=
1
1.4940. H NMR spectrum (DMSO-d6), , ppm (J,
Hz): 1.44 br.s (3H, NH2, NH), 2.21 s (3H, 3-CH3),
2.22 s (3H, 5-CH3), 2.61 m and 2.72 m (4H, CH2CH2
NH2), 3.0 m (2H, HNCH2), 4.15 m (2H, NCH2),
5.96 d (1H, 4-H, J = 1.8), 7.21 d (1H, 3-H, J = 1.8),
7.32 d (1H, 5-H, J = 2.2). Found, %: C 57.44; H 9.27;
N 33.61. C8H16N4. Calculated, %: C 57.14; H 9.52;
N 33.33.
1
corresponding signal from methyl protons in Vb
appeared at 2.29 ppm, i.e., the difference in their
1
chemical shifts was
0.11 ppm. The H NMR
spectra of IV VI also contained upfield signals from
the amino group at 1.4 ppm.
The isomer mixture was separated by fractional
distillation using a 30 4-cm column packed with a
metal filling. The head of the column was maintained
at 85 88 C, the still temperature was 120 C, the re-
sidual pressure was 3 mm, and the reflux number R
was 20. The still was charged with 120 g of isomer
mixture Va/Vb, and distillation gave 40 g of 2-(3-
methyl-1H-pyrazol-1-yl)ethanamine (Va), bp 60 C
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spectro-
1
meter from thin films (neat). The H NMR spectra
were measured on a Varian Mercury-300 instrument
at 300 MHz. The products were analyzed by GLC on
an LKhM8MD chromatograph using a 1-m column
packed with 10% of Carbowax-20M on Inerton AW-
(1 mm), n2D0 = 1.5030, d240 = 1.0320, and 25 g of
2-(5-methyl-1H-pyrazol-1-yl)ethanamine (Vb), bp
1
HMDS; carrier gas helium (40 m /min ); detector
68 C (1 mm), n2D0 = 1.5100, d240 = 1.0470. H NMR
1
temperature 220 C.
spectrum (DMSO-d6), , ppm (J, Hz): Va: 1.40 br.s
(2H, NH2), 2.18 s (3H, 3-CH3), 2.95 t (2H, CH2NH2,
J = 5.9), 3.98 t (2H, NCH2, J = 5.9), 5.88 d (1H, 4-H,
J = 2.2), 7.34 d (1H, 5-H, J = 2.2); Vb: 1.40 br.s (2H,
NH2), 2.29 s (3H, 5-CH3), 2.96 t (2H, CH2NH2, J =
6.1), 3.98 t (2H, NCH2, J = 6.1), 5.88 d (1H, 4-H, J =
1.8), 7.18 d (1H, 3-H, J = 1.8).
2-(1H-Pyrazol-1-yl)ethanamine (IV). A solution
of 0.2 mol of 2-chloroethylamine in 80 ml of benzene
was added dropwise over a period of 2.0 h to a mix-
ture of 6.8 g of pyrazole (I), 8.0 g of sodium hydr-
oxide, 50 ml of benzene, and 1.2 g of benzyltriethyl-
ammonium chloride under stirring at 75 80 C. The
mixture was heated for 2 h under reflux with stirring,
cooled, and filtered. The solvent was distilled off, and
the residue was distilled under reduced pressure. Yield
2-[3,5-Dimethyl-1H-pyrazol-1-yl]ethanamine
(VI) was synthesized in a similar way from 9.6 g of
3,5-dimethylpyrazole (III), but 0.6 mol of 2-chloro-
ethylamine and 0.6 mol of the base were added in
three portions in 1.5-h intervals. Yield 9.7 g (70%),
bp 78 C (1 mm), nD20 = 1.5030, d240 = 1.0096. IR spec-
8.8 g (80%), bp 49 50 C (1 mm), n2D0 = 1.5150, d420
=
1
1.0629. IR spectrum, , cm : 1520 (ring), 3300 3370
(NH2). 1HNMR spectrum (DMSO-d6), , ppm (J, Hz):
1.66 br.s (2H, NH2), 2.99 t (2H, CH2NH2, J = 6.0),
4.09 t (2H, NCH2, J = 6.0), 6.14 d. d (1H, 4-H, J =
2.4, 1.8), 7.33 d (1H, 3-H, J = 1.8), 7.50 d (1H, 5-H,
J = 2.4). Found, %: C 54.10; H 8.48; N 37.57.
C5H9N3. Calculated, %: C 54.05; H 8.10; N 37.83.
1
1
trum, , cm : 1550 (ring), 3300 3370 (NH2). H
NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.25 br.s
(2H, NH2), 2.11 s (3H, 3-CH3), 2.23 s (3H, 5-CH3),
2.94 t (2H, CH2NH2, J = 6.1), 3.88 t (2H, NCH2, J =
6.1), 5.65 s (1H, 4-H). Found, %: C 60.81; H 9.54;
N 30.42. C7H13N3. Calculated, %: C 60.43; H 9.35;
N 30.21.
2-[3(5)-Methyl-1H-pyrazol-1-yl]ethanamine (V)
was synthesized in a similar way from 8.2 g of com-
pound II, but 0.4 mol of 2-chloroethylamine and
0.4 mol of the base were added in two portions with
an interval of 2 h. Yield 9.3 g (75%), bp 60 65 C
(1 mm), n2D0 = 1.5065, d240 = 1.0390. IR spectrum, ,
N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]etha-
ne-1,2-diamine (VIII). Yield 4.2 g, bp 142 145 C
1
(1 mm). H NMR spectrum (DMSO-d6), , ppm (J,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 1 2008

138
ATTARYAN et al.
Hz): 1.64 br.s (2H, NH2), 2.14 s (3H, 3-CH3), 2.15
s (3H, 5-CH3), 2.55 br.s and 2.64 br.s (4H, CH2CH2
NH2), 2.89 t (2H, NHCH2, J = 6.3), 3.95 t (2H, NCH2,
J = 6.3), 5.64 s (1H, 4-H). Found, %: C 59.68; H 9.37;
N 30.26. C9H18N4. Calculated, %: C 59.34; H 9.89;
N 30.77.
4. Attaryan, O.S., Asratyan, G.V., Eliazyan, G.A., and
Darbinyan, E.G., Khim. Geterotsikl. Soedin., 1989,
no. 4, p. 497.
5. Attaryan, O.S., Martirosyan, S.S., Panosyan, G.A., and
Matsoyan, S.G., Russ. J. Gen. Chem., 2004, vol. 74,
no. 8, p. 1264.
6. Attaryan, O.S., Martirosyan, S.S., Grigoryan, R.T.,
Panosyan, G.A., Kinoyan, F.S., Asratyan, G.V., and
Matsoyan, S.G., Khim. Zh. Arm., 2004, vol. 57, no. 3,
p. 95.
REFERENCES
1. Brzovowski, Z., Pac-Pomarnacka, P., Dekarz, B., An-
gielski, S., and Woycikowski, C., Acta Pol. Pharm.,
1976, vol. 33, p. 461.
7. Attaryan, O.S., Martirosyan, S.S., and Matsoyan, S.G.,
Khim. Geterotsikl. Soedin., 2005, no. 4, p. 533.
2. Darbinyan, E.G., Attaryan, O.S., Eliazyan, G.A., As-
ratyan, G.V., and Matsoyan, S.G., USSR Inventor’s
Certificate no. 688 499, 1983; Byull. Izobret., 1984,
no. 3.
8. Khachatryan, S.F., Attaryan, O.S., Matsoyan, M.S.,
Kinoyan, F.S., and Asratyan, G.V., Khim. Zh. Arm.,
2005, vol. 58, no. 1, p. 134.
3. Attaryan, O.S., Asratyan, G.V., Eliazyan, G.A., Dar-
binyan, E.G., and Matsoyan, S.G., Arm. Khim. Zh.,
1986, vol. 39, no. 10, p. 630.
9. Khachatryan, S.F., Attaryan, O.S., Matsoyan, M.S.,
Kinoyan, F.S., and Asratyan, G.V., Khim. Zh. Arm.,
2005, vol. 58, no. 4, p. 115.
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