Rapid acid hydrolysis of 5-aryl-3-(β-thiomorpholinoethyl)-1,2,4- oxadiazoles

Article abstract of DOI:10.1007/s10593-010-0597-8

The acid hydrolysis of a series of 5-aryl-3-(β-thiomorpholinoethyl)-1, 2,4-oxadiazoles gave substituted benzoic acids and 2-amino-8-thia-1-aza-5- azoniaspiro[4.5]dec-1-ene chloride hydrate, whose structure was demonstrated by spectral methods and X-ray diffraction structural analysis.

Full text of DOI:10.1007/s10593-010-0597-8

Chemistry of Heterocyclic Compounds, Vol. 46, No. 7, 2010
RAPID ACID HYDROLYSIS OF 5-ARYL-
3-(-THIOMORPHOLINOETHYL)-1,2,4-OXADIAZOLES
L. A. Kayukova1*, M. A. Orazbaeva1, G. I. Gapparova1, K. M. Beketov1,
A. A. Espenbetov1, M. F. Faskhutdinov1, and B. T. Tashkhodjaev2
The acid hydrolysis of a series of 5-aryl-3-(-thiomorpholinoethyl)-1,2,4-oxadiazoles gave substituted
benzoic acids and 2-amino-8-thia-1-aza-5-azoniaspiro[4.5]dec-1-ene chloride hydrate, whose structure
was demonstrated by spectral methods and X-ray diffraction structural analysis.
Keywords: 5-aryl-3-(-thiomorpholinoethyl)-1,2,4-oxadiazoles, 2-amino-8-thia-1-aza-5-azoniaspiro-
[4.5]dec-1-ene chloride hydrate, substituted benzoic acids, acid hydrolysis, X-ray diffraction structural
analysis.
The possibility that -amino-O-aroylpropioamidoximes and 3-(-aminoethyl)-5-aryl-1,2,4-oxadiazoles
exist both as stable bases and hydrochlorides has been demonstrated in our previous work, in which
-piperidine, -morpholine, and -benzimidazole derivatives are described. These compounds do not undergo
structural change upon isolation from the reaction mixture and recrystallization. Physicochemical and spectral
data as well as X-ray diffraction structural data were obtained for these compounds [1-3].
Scheme 1
N
O
N
O
C6H4X
N
S
C6H4X
N
– H2O
NH2
2a–e
O
1a–e
N
XC6H4COCl
S
S
N
OH
HCl
N
OH
N
S
N
·
2HCl
3·2HCl
1,2 a X = p-MeO, b X = p-Me, c X = H, d X = p-Br, e X = m-Cl
NH2
NH2
3
_______
* To whom correspondence should be addressed, e-mail: lkayukova@mail.ru.
1A. B. Bekturov Institute of Chemical Sciences, 050010 Almaty, Republic of Kazakhstan.
2S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of
Uzbekistan, Tashkent 100170, Republic of Uzbekistan; e-mail: cnc@icps.org.uz.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 46, No. 7, pp. 1086-1096, July, 2010.
Original article submitted February 1, 2009. Submitted after revision January 20, 2010.
0009-3122/10/4607-0879©2010 Springer Science+Business Media, Inc.
879

In the present work, we studied the reaction of hydrogen chloride with 5-aryl-3-(-thiomorpholino-
ethyl)-1,2,4-oxadiazoles 1a-e obtained by the dehydration of O-aroyl--(thiomorpholino)propioamidoximes
2a-e. These amidoximes were prepared by the acylation of -(thiomorpholino)propioamidoxime (3) using acid
chlorides of substituted benzoic acids [4, 5] (Scheme 1).
An ethereal solution of HCl with traces of moisture was added dropwise at room temperature to
ethanolic solutions of 5-aryl-3-(-thiomorpholinoethyl)-1,2,4-oxadiazoles 1a-e to lower the pH to 2. In all cases,
a precipitate of 2-amino-8-thia-1-aza-5-azoniaspiro[4.5]dec-1-ene chloride hydrate (4) formed immediately after
addition of the hydrogen chloride solution. This precipitate has low solubility in ethanol. The filtrates were
evaporated and the corresponding substituted benzoic acids 5a-e were isolated (Tables 1-3).
The formation of compound 4 may be seen as a series of steps involving acid hydrolysis and
intramolecular heterocyclization through intermediates 1·HCl - 1·2HCl·2H2O - 1·HCl·2H2O (Scheme 2) during
the reaction of 1,2,4-oxadiazoles bases 1a-e with undried HCl. We propose that the determining factor is the
formation ammonium compound 1·HCl and the hydrolysis product 1·2HCl·2H2O upon the attack of the oxygen
atom of the hydroxonium chloride on N(2) atom and of the water molecule oxygen on C(5) atom in the
1,2,4-oxadiazole ring of compounds 1a-e. Stabilization of the positive charge on the ammonium nitrogen atom
of the thiomorpholine ring by the unshared electron pair of the oxime nitrogen atom and loss of a water
molecule in 1·HCl·2H2O completes the heterocyclization to give spiro compound 4.
At room temperature, spiroazonium chloride 4 has low solubility in the solution of HCl in aqueous
ethanol serving as the reaction medium and forms a high-melting white precipitate. Evaporation of the filtrate
gives the corresponding substituted benzoic acids 5a-e identified using their spectral characteristics and
TABLE 1. Physicochemical Characteristics of Compounds 3, 3·2HCl,
4, and Benzoic Acids 5a-e
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С*
Rf
Yield, %
С
Н
Hal
—
3
C7H15N3OS
44.20
44.42
32.50
32.06
8.10
7.99
6.46
6.53
170
178
0.54
0.07
92
98
C7H17Cl2N3OS
27.30
27.04
32HCl
4*2
C7H16ClN3OS
a)37.10; a)7.52; a)15.02;
b)37.88; b)7.40; b)15.24;
c)37.23; c)6.56; c)15.41;
d)37.84; d)6.95; d)15.80;
302
0.09
40-47
e)37.74
37.25
e)6.86
7.14
e)16.03
15.71
5a
5b
5c
5d
5e
C8H8O3
63.00
63.15
70.20
70.57
68.93
68.85
42.20
41.83
5.90
5.30
6.33
5.92
5.06
4.95
3.04
2.51
—
—
—
180
0.75
0.76
0.79
0.81
0.82
43
45
41
40
43
(181-186)
C8H8O2
178
(179-182)
112
(121-123)
247
(251-256)
150
(154-157)
C7H6O2
C7H5BrO2
C7H5ClO2
39.55
39.75
23.03
22.64
53.90
53.70
3.70
3.22
_______
*The literature data from the Acros Organics 2004-2005 Catalog are given
in parentheses.
*2The values given for Found in the elemental analysis of compound 4
correspond to the values calculated corresponding to the syntheses of these
compounds from 1a-e.
880

melting point (Tables 1-3). Spiroazonium chloride 4 is an isomer of the amidoxime hydrochloride 3·HCl and the
1
1
IR and H NMR spectral data of 3·HCl and the IR and H NMR spectral data of 4 are in accord with the
structure of 3·HCl.
Scheme 2

Cl
H
H
O
N
+
H
O
N
O
HCl
+ H2O
+ HCl
HCl
+
C6H4X
H
N
C6H4X
1ae
N
O
+
N
+
N
H
H

H

S
S
Cl
Cl
1·HCl
1·2HCl·2H2O
OH H
H
NH2
N
O
 H2O
+ H2O
+
O

Cl
N
N
C6H4X
N
H
+
O
H
. H2O
C6H4X
O
N
+
H

S
5ae
Cl
S
4
1·HCl·2H2O
5 a X = p-OMe, b X = p-Me, c X = H, d X = p-Br, e X = m-Cl
The melting points of compounds 3, 3·2HCl, and 4 are 170, 178, and 303°C, respectively. The
characteristic stretching and deformation bands are given in Table 2. In going from compound 3 to 3·2HCl and
4, the 1H NMR spectra show a shift in the signals of the protons of the -CH2 and -CH2 groups from  2.08 and
2.55 (compounds 3) to 3.04 and 3.45 (3·2HCl) and to 3.14 (C(3)CH2) and 3.88 ppm (C(4)H2) in compound 4.
Furthermore, the signals of the protons of the N(+)CH2)2 and S(CH2)2 groups in the thiomorpholine ring of
compound 4 are downfield relative to the analogous signals for compounds 3 and 3·2HCl and divide into two
groups of multiplets at  3.74, 3.62 and 2.88, 3.14 ppm with two-proton intensity (Table 3).
–
Cl
+
N
N
OH
S
H
NH2
3 · HCl
The sharp difference between the physicochemical and spectral data of compound 4 and the
corresponding data for -(thiomorpholino)propioamidoxime (3) and its dichloride 3·2HCl led us to carry out an
X-ray diffraction structural analysis of this sample.
This structural analysis showed that compound 4 is 2-amino-8-thia-1-aza-5-azoniaspiro[4.5]dec-1-ene
chloride hydrate. Figure 1 shows the structures of the two crystallographically independent cations (A and B),
which are bound to each other by intermolecular hydrogen bonds, with the chloride anions and water molecules.
881

882

TABLE 4. Some Torsion Angles () in the Structure of Compound 4
Angle
, deg
Angle
, deg
Imidazolidine ring
Thiomorpholine ring
N(10A)–N(1A)–C(2A)–C(3A)
N(1A)–C(2A)–C(3A)–C(4A)
C(2A)–C(3A)–C(4A)–N(10A)
C(3A)–C(4A)–N(10A)–N(1A)
C(2A)–N(1A)–N(10A)–C(4A)
N(10B)–N(1B)–C(2B)–C(3B)
N(1B)–C(2B)–C(3B)–C(4B)
C(2B)–C(3B)–C(4B)–N(10B)
C(8B)–C(9B)–N(10B)–N(1B)
C(2B)–N(1B)–N(10B)–C(4B)
-5(2)
N(10A)–C(5A)–C(6A)–S(7A)
C(5A)–C(6A)–S(7A)–C(8A)
C(6A)–S(7A)–C(8A)–C(9A)
S(7A)–C(8A)–C(9A)–N(10A)
C(8A)–C(9A)–N(10A)–C(5A)
C(6A)–C(5A)–N(10A)–C(9A)
N(10B)–C(5B)–C(6B)–S(7B)
C(5B)–C(6B)–S(7B)–C(8B)
C(6B)–S(7B)–C(8B)–C(9B)
S(7B)–C(8B)–C(9B)–N(10B)
C(8B)–C(9B)–N(10B)–C(4B)
C(6B)–C(5B)–N(10B)–C(9B)
60.7(17)
-55.8(13)
58.1(14)
-63.9(16)
58.7(18)
-57.9(19)
64.6(16)
-55.3(14)
56.9(15)
-65.1(17)
-67.2(18)
-63.9(18)
-8(2)
15.2(17)
-18.4(17)
14.7(17)
-0.4(18)
16(2)
-24.3(17)
174.0(13)
-16.4(16)
TABLE 5. Intermolecular Interactions in the Structure of Compound 4
Angle
Distance, Å
…
Bond*
…
…
А
DН А, deg
DН
Н
А
D
…
3.12 (1)
3.08(1)
3.12(1)
3.12(1)
3.37(2)
3.31(2)
3.26(1)
3.30(1)
O(1W) Cl(1)i
…
O(1W) Cl(2)i
…
O(2W) Cl(1)i
…
O(2W) Cl(2)i
…
0.97
0.97
0.86
0.86
1.99
94.9
90.5
C(3A)–H(3AD) O(1W)i
…
2.01
2.41
2.44
С(3В)–H(3BD) O(2W)i
…
170.6
174.3
N(3B)–H(3BC) Cl(1)ii
…
N(3A)–H(3AC) Cl(2)iii
_______
* Symmetry codes: (i) x, y, x; (ii) 1-x, 0.5+y, 0.5-z; (iii) -x, -0.5+y, 0.5-z.
The thiomorpholine rings in ammonium chloride hydrates A and B are isostructural within experimental
error and have chair conformation, while the imidazolidines rings have envelope conformation and are mirror
images of each other (Table 4).
Layers parallel to the ab plane are formed in crystals of compound 4 by means of a system of hydrogen
bonds (Fig. 2). The geometry of the intermolecular interactions is given in Table 5.
Fig. 1. Association of molecules of 4 (independent part) with numbering of the non-hydrogen atoms.
883

Fig. 2. Crystal structure of compound 4.
TABLE 6. Crystallographic Parameters and Unit Cell Data for Compound 4
Empirical formula
C7H14ClN3OS
Unit cell parameters
a, Å
10.166(2)
b, Å
11.060(2)
c, Å
19.610(4)
Space group
P212121
Unit cell volume, V, Å3
Z (two independent formula units in a cell)
Crystal density, calc, g/cm3
Absorption coefficient, , mm-1 F(000)
F(000)
2204.9(8)
8
1.348
4.598
944
Number of reflections measured
Number of reflections for the calculation
GOOF
1885
1221
1.008
Final R-factor [I > 2I)]
Residual electron density, e/Å3
R1 = 0.0666, wR2 = 0.1992
0.658 and -0.325
Thus, 1,2,4-oxadiazoles with a 3-(-thiomorpholino)ethyl substituent 1a-e are chemically unstable
compounds and undergo acid hydrolysis to give 2-amino-8-thia-1-aza-5-azoniaspiro[4.5]dec-1-ene chloride
hydrate (4).
884

TABLE 7. Bond Lengths (d) in Compound 4
Bond
d, Å
Bond
d, Å
Bond
d, Å
N(1A)–C(2A)
N(1A)–N(10A)
C(2A)–N(3A)
C(2A)–C(3A)
C(3A)–C(4A)
C(4A)–N(10A)
C(5A)–N(10A)
C(5A)–C(6A)
1.272(19)
1.463(18)
1.312(19)
1.50(2)
C(6A)–S(7A)
S(7A)–C(8A)
C(8A)–C(9A)
C(9A)–N(10A)
N(1B)–C(2B)
N(1B)–N(10B)
C(2B)–N(3B)
C(2B)–C(3B)
1.790(16)
1.79(2)
C(3B)–C(4B)
1.51(2)
C(4B)–N(10B) 1.48(2)
C(5B)–C(6B) 1.50(2)
C(5B)–N(10B) 1.525(16)
C(6B)–S(7B)
S(7B)–C(8B)
C(8B)–C(9B)
1.56(2)
1.49(2)
1.50(2)
1.320(19)
1.490(18)
1.345(18)
1.46(2)
1.813(15)
1.800(17)
1.50(3)
1.559(18)
1.457(17)
1.53(2)
C(9B)–N(10B) 1.541(18)
TABLE 8. Valence Angles () in Compound 4
Angle
ω, deg
Angle
ω, deg
C(2A)–N(1A)–N(10A)
N(1A)–C(2A)–N(3A)
N(1A)–C(2A)–C(3A)
N(3A)–C(2A)–C(3A)
C(2A)–C(3A)–C(4A)
C(3A)–C(4A)–N(10A)
N(10A)–C(5A)–C(6A)
C(5A)–C(6A)–S(7A)
C(6A)–S(7A)–C(8A)
C(9A)–C(8A)–S(7A)
N(10A)–C(9A)–C(8A)
C(5A)–N(10A)–N(1A)
C(5A)–N(10A)–C(9A)
N(1A)–N(10A)–C(9A)
C(5A)–N(10A)–C(4A)
N(1A)–N(10A)–C(4A)
C(9A)–N(10A)–C(4A)
108.7(12)
124.1(15)
115.4(15)
120.5(13)
103.5(14)
102.5(12)
115.3(12)
111.9(11)
95.9(8)
C(2B)–N(1B)–N(10B)
N(1B)–C(2B)–N(3B)
N(1B)–C(2B)–C(3B)
N(3B)–C(2B)–C(3B)
C(2B)–C(3B)–C(4B)
N(10B)–C(4B)–C(3B)
C(6B)–C(5B)–N(10B)
C(5B)–C(6B)–S(7B)
C(8B)–S(7B)–C(6B)
C(9B)–C(8B)–S(7B)
C(8B)–C(9B)–N(10B)
C(4B)–N(10B)–N(1B)
C(4B)–N(10B)–C(5B)
N(1B)–N(10B)–C(5B)
C(4B)–N(10B)–C(9B)
N(1B)–N(10B)–C(9B)
C(5B)–N(10B)–C(9B)
104.1(12)
119.9(15)
117.2(14)
122.9(13)
100.5(13)
103.8(12)
112.4(14)
112.0(11)
95.8(9)
111.2(13)
111.8(16)
108.5(11)
112.9(12)
106.9(13)
110.6(13)
106.5(10)
111.0(13)
113.7(13)
110.2(14)
107.4(12)
112.8(14)
103.9(12)
116.7(12)
105.1(12)
109.9(13)
EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer in KBr pellets. The 1H NMR spectra were taken on
a Mercury-300 spectrometer at 300 MHz with HMDS as the internal standard ( 0.05 ppm). The reaction course
was monitored using thin-layer chromatography on Fluka silica gel plates with 3:1 ethanol–benzene as the
eluent. The solvents used in these experiments were prepared in accord with standard procedures [6]. The yields,
elemental analysis results, and spectral data of the products are given in Tables 1-3, while the X-ray diffraction
structural data for compound 4 are given in Tables 4-8.
Synthesis of -(Thiomorpholino)propioamidoxime (3) was given in our previous work [4].
Preparation of the Solution of Hydrogen Chloride in Diethyl Ether Containing Traces of Water
Used for the Acid Hydrolysis of 1,2,4-Oxadiazoles 1a-e. Absolute diethyl ether was saturated with gaseous
HCl formed upon the addition of concentrated sulfuric acid to commercial dry sodium chloride. Drying of the
gaseous HCl in a trap filled with concentrated sulfuric acid was not carried out.
-(Thiomorpholino)propioamidoxime Dichloride (3·2HCl). -(Thiomorpholino)propioamidoxime (3)
(0.2 g, 1.0 mmol) was dissolved in anhydrous chloroform (20 ml) and brought to pH 2 by the addition of
ethereal HCl (the hydrogen chloride used for saturating the solution in absolute diethyl ether was passed
885

through a concentrated sulfuric acid trap). The white precipitate of the dichloride 3·2HCl was filtered off. A
precipitate of the dichloride 3·2HCl formed upon evaporation of the filtrate in vacuum. All the portions of
3·2HCl were collected and recrystallized from 2-propanol.
Acid Hydrolysis of 5-(m-Chlorophenyl)-3-(thiomorpholinoethyl)-1,2,4-oxadiazole (1e). 1,2,4-Oxa-
diazole 1e (0.25 g, 0.81 mmol) was dissolved in 5 ml absolute ethanol and then brought to pH 2 by adding
ethereal hydrogen chloride containing traces of water. The precipitate formed was filtered off and recrystallized
from ethanol to give 0.073 g (0.32 mmol, 40%) 2-amino-8-thia-1-aza-5-azoniaspiro[4.5]dec-1-ene chloride
hydrate (4), mp 302°C. The filtrate was evaporated to dryness to give a white precipitate. Recrystallization of
the precipitate from ethanol gave 0.051 g (43%) m-chlorobenzoic acid (5e), mp 150°C.
The hydrolyses of the other 1,2,4-oxadiazoles 1a-d were carried out analogously.
X-ray Diffraction Structural Analysis of 4 was carried out on a STOE STADI-4 diffractometer at
room temperature using CuK radiation, graphite monochromator, and /2-scanning. Orthorhombic crystals of
4 were grown from solution in 2-propanol, calc = 1.357 g/cm3. The structure was solved using the direct method.
The hydrogen atoms at the nitrogen and carbon atoms were placed in geometrically calculated positions. The
hydrogen atoms in the water molecules were not revealed. The structure was refined anisotropically for the
non-hydrogen atoms (the hydrogen atoms were refined with fixed positional and temperature parameters) by the
method of least squares using the SHELX-97 programs [7]. The final R-factor was 0.0666 related to
1221 reflections with I > 2(I).
The X-ray diffraction structural data were deposited in the Cambridge Crystallographic Data Center
(CCDC 711438).
REFERENCES
1.
2.
3.
4.
K. M. Beketov, J. T. Welch, P. J. Toscano, L. A. Kayukova, A. L. Akhelova, and K. D. Praliev, Zh.
Strukt. Khim., 45, 540 (2004).
L. A. Kayukova, K. D. Praliev, and I. S. Zhumadil'daeva, Khim. Geterotsikl. Soed., 253 (2003). [Chem.
Heterocycl. Comp., 39, 223 (2003)].
L. A. Kayukova, K. M. Beketov, A. L. Akhelova, and K. D. Praliev, Khim. Geterotsikl. Soedin., 1057
(2006). [Chem. Heterocycl. Comp., 42, 914 (2006)].
L. A. Kayukova and M. A. Orazbaeva, Izv. Ministerstv. Obraz. Nauki Resp. Kazakhstan, Nats. Akad.
Nauk Resp. Kazakhstan, Ser. Khim., No. 5, 37 (2007).
5.
6.
7.
L. A. Kayukova and M. A. Orazbaeva, Khim. Zh. Kazakhstan, No. 1, 99 (2008).
A. Gordon and R. Ford, The Chemist's Companion, Wiley, New York, London, Sidney, Toronto (1972).
G. M. Sheldrick, SHELXS97 and SHELXL97, Univ. Göttingen, Göttingen, Germany (1997).
886