Acylation of amines and pyrazole with [2-isopropyl-4-(o-methoxyphenyl)- tetrahydropyran-4-yl]acetyl chloride

Article abstract of DOI:10.1007/s10593-013-1241-1

[2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic acid has been obtained by the hydrolysis of previously synthesized [2-isopropyl-4-(o- methoxyphenyl)tetrahydropyran-4-yl]acetonitrile. The acyl chloride prepared from this acid gave new amides an

Full text of DOI:10.1007/s10593-013-1241-1

Chemistry of Heterocyclic Compounds, Vol. 49, No. 2, May, 2013 (Russian Original Vol. 49, No. 2, February, 2013)
ACYLATION OF AMINES AND PYRAZOLE WITH
[2-ISOPROPYL-4-(o-METHOXYPHENYL)-
TETRAHYDROPYRAN-4-YL]ACETYL CHLORIDE
N. S. Arutjunyan1, N. Z. Hakobyan1, L. A. Hakobyan1,
G. A. Gevorgyan1*, and G. A. Panosyan2
[2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic acid has been obtained by the hydrolysis
of previously synthesized [2-isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetonitrile. The acyl
chloride prepared from this acid gave new amides and 1-acylpyrazole upon interaction with various
amines and with pyrazole.
Keywords: [2-isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic acid, N-substituted amides,
acylation, hydrolysis.
There are data in the literature on the antimicrobial, analgesic, anxiolytic, antioxidant, and antiarrythmic
activity of amides; certain amides display fairly high antimicrobial activity against strains of staphylococci,
Escherichia coli, aerobic bacilli, and yeast fungi [1-4].
In a continuation of our investigations devoted to the search for new biologically active compounds
among the derivatives of (4-aryl-2-isopropyltetrahydropyran-4-yl)acetonitrile [5], we have engaged in the
synthesis of amides in this series.
[2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic acid (2) was obtained by the hydrolysis
of o-methoxyphenyl derivative 1. Treatment of the acid 2 with thionyl chloride led to the acyl chloride 3, which
upon interaction with various primary and secondary amines (including cyclic amines) gave N-substituted
amides of [2-isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic acid 4a-i and the 1-acylpyrazole 4k.
The composition and structures of the synthesized compounds were confirmed by data of elemental
analysis (Table 1) and 1H NMR spectra (Table 2).
_______
*To whom correspondence should be addressed, e-mail: gyulgev@gmail.com.
1The Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences
of Armenia, A. L. Mnjoyan Institute of Fine Organic Chemistry, 26 Azatutyan Ave., Yerevan 0014, Armenia.
2Molecular Structure Research Center of the Scientific Technological Center for Organic and Pharmaceutical
Chemistry, National Academy of Sciences, 26 Azatutyan Ave., Yerevan 0014, Armenia; e-mail:
henry@msrc.am.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 273-276, February, 2013. Original
article submitted May 4, 2011; revision submitted February 11, 2013.
0009-3122/13/4902-0249©2013 Springer Science+Business Media New York
249

C6H4OMe-o
C6H4OMe-o
SOCl2
C6H6
KOH
O
O
O
Ethylene glycol
, 6 h
CN
, 2 h
OH
i-Pr
i-Pr
2
1
C H OMe-
o
o
C6H4OMe-
O
6
4
O
O
O
RH, Et3N
C6H6
, 3 h
R
Cl
i-Pr
i-Pr
4a–k
3
4 a R = NEt2, b R = NHC6H4OMe-п, c R = 2-furylmethylamino, d R = NH(CH2)3NMe2,
e R = NH(CH2)3NEt2, f R = NH(CH2)3OMe, g R = 1-pyrrolidinyl, h R = 2-thiazolylamino,
i R = 1-piperidinyl, j R = 1-morpholino, k R =1-pyrazolyl
A simple synthesis has therefore been developed for the synthesis of new amides of 4-tetrahydro-
pyranylacetic acid.
EXPERIMENTAL
1
The IR spectra were recorded on a Nicolet Avatar 330 FT-IR spectrometer in nujol. The H NMR
spectra were recorded on a Varian Mercury 300 instrument (300 MHz ) in DMSO-d6, internal standard was
TMS. Melting points were determined on Boetius hot stage apparatus.
[2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetonitrile (1) was obtained as described
previously [5].
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds 4a-k
Found, %
Bp, oC (mm Hg)
or mp, oC
——————
Com-
pound
Empirical
formula
Yield, %
Calculated, %
H
C
N
C21H33NO3
72.63
72.58
72.58
72.52
71.08
71.13
70.25
70.18
71.31
71.25
69.45
69.39
72.97
73.01
64.06
64.14
9.59
9.57
7.79
7.86
7.91
7.87
9.69
9.64
9.92
9.97
9.18
9.15
9.09
9.04
7.08
7.00
4.00
4.03
3.55
3.52
3.70
3.77
7.41
7.44
6.89
6.92
3.81
3.85
4.12
4.05
7.52
7.48
175-178 (1)
125-126
64
72
65
68
70
71
67
70
65
63
58
4a
4b
4c
4d
4e
4f
C24H31NO4
C22H29NO4
C22H36N2O3
C24H40N2O3
C21H33NO4
C21H31NO3
C20H26N2O3S
C22H33NO3
C21H31NO4
C20H26N2O3
208-210 (1)
200-204 (2)
205-208 (2)
190-195 (1.5)
205-210 (1)
112-114
4g
4h
4i
73.46
73.50
69.71
69.78
70.10
70.15
9.30
9.25
8.58
8.64
7.71
7.65
3.94
3.90
3.81
3.87
8.20
8.18
220-223 (1)
225-230 (2)
98-100
4j
4k
250

251

[2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic Acid (2). KOH (33.6 g, 0.60 mol)
was dissolved with heating in ethylene glycol (120 ml). The obtained solution was added to nitrile 1 (41.0 g,
0.15 mol). The mixture was refluxed for 6 h, cooled, water (120 ml) was added, and the obtained suspension
was extracted with diethyl ether. The aqueous layer was acidified with concentrated HCl solution (60 ml) and
extracted with benzene (3100 ml). The benzene extract was washed with water, dried, and after distilling off
the benzene, the residue was distilled in vacuum. Yield 26.3 g (60%). Bp 205-208oC (1.5 mm Hg). IR spectrum,
, cm-1: 3400-3200 (OH), 1710 (C=O), 1610, 1590 (C=C arom.). 1H NMR spectrum, δ, ppm (J, Hz): 0.94 (6H,
3
d, J = 6.8, (CH3)2CH); 1.39 (1H, dd, 2J = 13.0, 3J = 11.6, (3-CHAHB); 1.54-1.68 (1H, m, (CH3)2CH); 1.73 (1H, td,
3
2J = 3J = 12.9, J = 5.1, 5-CHAHB); 2.39-2.53 (2H, m, 3-CHAHB, 5-CHAHB); 3.00 (2H, s, CH2CO); 3.32 (1H, ddd,
3
3
3J = 11.6, J = 5.8, J = 1.5, 2-CH); 3.69-3.89 (2H, m, 6-CH2); 3.85 (3H, s, OCH3); 6.83-6.90 (2H, m, H Ar);
7.11-7.18 (2H, m, H Ar); 11.21 (1H, br. s, COOH). Found, %: C 69.75; H 8.33. C17H24O4. Calculated, %:
C 69.84; H 8.27.
[2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetyl Chloride (3). A mixture of acid 2
(29.2 g, 0.1 mol) and SOCl2 (13.1 g, 0.11 mol) in dry benzene (30-35 ml) was boiled at reflux for 2 h, the
benzene was removed by distillation, and the residual viscous mass, 27.7 g (yield of crude product 3 ~90%),
was used for acylation without isolation.
N-Substituted Amides of [2-Isopropyl-4-(o-methoxyphenyl)tetrahydropyran-4-yl]acetic Acid 4a-k.
Acyl chloride 3 (3.1 g, 0.01 mol) was added dropwise with stirring to a solution of the corresponding amine or
pyrazole (0.01 mol) and Et3N (1.0 g, 0.01 mol) in dry benzene (20 ml). The reaction mixture was refluxed for
3 h, then cooled, acidified with concentrated HCl solution to a weakly acidic reaction, and extracted with
benzene. The extract was washed with water, dried, and benzene was distilled off. Compounds 4a-k were
isolated from the residue by distillation in vacuum, or by recrystallization from ethanol.
REFERENCES
1.
R. V. Shutov, E. V. Kuklina, N. A. Anisimova, E. P. Anan'ev, N. I. Kotova, and V. N. Kuklin, Khim.-
Farm. Zh., 46, No. 1, 12 (2012).
2.
3
B. D. Grishchuk, V. S. Baranovskii, and S. I. Klimnyuk, Khim.- Farm. Zh., 45, No. 9, 18 (2011).
V. L. Gein, I. V. Kholkin, T. M. Zamaraeva, E. V. Voronina, and M. I. Vakhrin, Khim.-Farm. Zh., 46,
No. 2, 49 (2012).
4.
5.
N. S. Arutyunyan, R. L. Nazaryan, L. A. Akopyan, R. V. Paronikyan, G. A. Panosyan, and
G. A. Gevorgyan, Khim. Zh. Armenii, 105 (2012).
N. S. Arutjunyan, L. A. Hakobyan, N. Z. Hakobyan, G. A. Gevorgyan, and G. A. Panosyan, Khim.
Geterotsikl. Soedin., 838 (2010). [Chem. Heterocycl. Compd., 46, 670 (2010).].
252