Cyclization of O-benzoyl-β-piperidinopropionamidoximes to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles

Article abstract of DOI:10.1023/A:1021628430346

The reactions of β-piperidinopropionamidoxime with substituted benzoyl chlorides afforded O-benzoylation products, which underwent cyclization to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles upon heating in dimethylformamide in the presence of molecular sieves at 60°C for 1 - 2.5 h. Heating of O-benzoyl-β-piperidinopropionamidoxime in dimethylformamide in the presence of K₂CO₃ at 85°C for 4 h afforded a mixture of 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazole, benzoic acid, and N-(β-piperidino)ethylurea.

Full text of DOI:10.1023/A:1021628430346

2100
Russian Chemical Bulletin, International Edition, Vol. 51, No. 11, pp. 2100—2105, November, 2002
Cyclization of Oꢀbenzoylꢀβꢀpiperidinopropionamidoximes
to form 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazoles
L. A. Kayukova,ꢀ I. S. Zhumadildaeva, and K. D. Praliyev
A. B. Bekturov Institute of Chemical Sciences, Ministry of Education and Science of the Republic of Kazakhstan,
106 Shokan Ualikhanov Str., 480100 Almaty, Republic of Kazakhstan.
Fax: +7 (327 2) 91 2471. Eꢀmail: ICS_RK@hotmail.com, lkayukova@mail.ru
The reactions of βꢀpiperidinopropionamidoxime with substituted benzoyl chlorides afforded
Oꢀbenzoylation products, which underwent cyclization to form 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ
1,2,4ꢀoxadiazoles upon heating in dimethylformamide in the presence of molecular sieves at
60 °C for 1—2.5 h. Heating of Oꢀbenzoylꢀβꢀpiperidinopropionamidoxime in dimethylformamide
in the presence of K2CO3 at 85 °C for 4 h afforded a mixture of 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ
1,2,4ꢀoxadiazole, benzoic acid, and Nꢀ(βꢀpiperidino)ethylurea.
Key words: Oꢀbenzoylꢀβꢀpiperidinopropionamidoximes, dimethylformamide, 5ꢀphenylꢀ
3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazoles, Beckmann rearrangement, Nꢀ(βꢀpiperidino)ethylurea.
Amino acids and their derivatives play an important
Oꢀacylamidoximes giving rise to 1,2,4ꢀoxadiazoles has
been carried out in solutions of acetic acid or acetic anꢀ
hydride in water, dilute sodium hydroxide, sulfuric acid,9
diphenyl ether,7 or toluene.10 Spontaneous cyclodeꢀ
hydration of amidoxime Oꢀethers (without their isolaꢀ
tion) proceeds in pyridine.11
We prepared βꢀpiperidinopropionamidoxime (2) startꢀ
ing from βꢀpiperidinopropionitrile (1). Compound 2 was
used for the synthesis of Oꢀaroylꢀβꢀpiperidinopropionꢀ
amidoximes (3a—f) by either acylation with substituted
benzoyl chlorides in benzene in the presence of triethyꢀ
lamine (compounds 3a—c) or upon treatment of hydroꢀ
chlorides of acylation products with K2CO3 (compounds
3d—f) (Scheme 1). The results of elemental analysis,
physicochemical characteristics, and spectroscopic data
for compounds 3a—f are given in Tables 1—4.
role in all life processes. The synthesis, isolation, physiꢀ
cochemical characteristics, and biological properties of
amino acids and their derivatives are topical fields of
research. Thus, hydrolysis of natural antibiotics tuberꢀ
actinomycins A and N afforded derivatives of amino acꢀ
ids, viz., threoꢀγꢀhydroxyꢀβꢀlysine and the erythro isomer
of a βꢀalanine derivative.1 In the present study, we examꢀ
ined derivatives of primary amidoximes of βꢀaminoꢀ
propionic acids and used the piperidine group as the
βꢀamino fragment. It is known that many compounds
containing piperidine fragments are pharmaceuticals exꢀ
hibiting various therapeutic effects.2 Due to the presence
of the primary amidoxime group, these compounds can
be widely used as synthons possessing the ambident reacꢀ
tivity.
In the present study, we carried out acylation of
βꢀpiperidinopropionamidoxime with substituted benzoyl
chlorides and subjected the resulting Oꢀacyl derivatives to
dehydration with the aim of preparing 1,2,4ꢀoxadiazoles.
Previously, it has been demonstrated that some amidꢀ
oximes, their Oꢀacyl derivatives, and products of dehyꢀ
dration of the latter, viz., 1,2,4ꢀoxadiazoles, exhibit psyꢀ
chotropic properties.3 βꢀAminopropionamidoximes show
cytostatic activity.4 We revealed local anesthetic, antiꢀ
arythmic, and tuberculostatic properties of Oꢀacylꢀβꢀamiꢀ
nopropionamidoximes.5
Xꢀray diffraction analysis of Oꢀaroylꢀβꢀpiperidinoꢀ
propionamidoxime hydrochlorides (3a•HCl and
3c•HCl)12 confirmed that the reaction proceeded at the
O atom of the amidoxime group. It was also found that
the C—NH2 and O—C(O) bonds are in the syn orientaꢀ
tion with respect to the C=N bond and that the C=N.
The IR spectra of compounds 3a—f have characterꢀ
istic stretching absorption bands of the C(=O)O esꢀ
ter group (1728—1736 cm–1) and the amino group
(3110—3500 cm–1) as well as intense bands of the C=C
double bond at 1564—1638 cm–1 (see Table 2).
The 1H NMR spectra of Oꢀaroylꢀβꢀpiperidinopropionꢀ
amidoximes 3a—f show signals for the aroyl groups
(δ 7.00—8.29). The spectra of compounds 3a,b have sigꢀ
nals of the pꢀMe and pꢀMeO groups at δ 2.37 and 2.50,
respectively. The signals for the protons of the NH2 groups
are observed at δ 6.57—6.77, and the signals for the proꢀ
Results and Discussion
The synthesis of Oꢀacylated amidoximes attracts the
attention of researchers primarily as an approach to
1,2,4ꢀoxadiazoles.6—8 Previously, cyclodehydration of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1945—1950, November, 2002.
1066ꢀ5285/02/5111ꢀ2100 $27.00 © 2002 Plenum Publishing Corporation

Synthesis of 1,2,4ꢀoxadiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2101
Scheme 1
which is more convenient for the preparative use. The
function of bipolar aprotic DMF in the dehydration reacꢀ
tion of Oꢀaroylꢀβꢀaminopropionamidoximes 3a—f is to
stabilize the transition states A and B via intermolecular
hydrogen bonding (Scheme 2).
Scheme 2
X = pꢀMe (a), pꢀMeO (b), H (c), pꢀBr (d), mꢀCl (e), pꢀNO2 (f)
tons of three methylene groups of the piperidine ring are
observed as two multiplets at δ ∼1.40 and 1.55. The proꢀ
tons of the αꢀ and βꢀmethylene groups give triplets at
δ 2.27—2.38 and 2.36—3.10, respectively. The methylene
groups of the piperidine ring bound to the N atom give a
multiplet with the intensity of four protons (δ 2.37—2.56)
(see Table 3).
It was found that heterocyclization of compounds 3d—f
containing electronꢀwithdrawing substituents proceeded
faster (TLC control) and was completed in 1 h, whereas
heterocyclization of compounds 3a,b bearing electronꢀ
releasing substituents as well as of Oꢀbenzoylꢀβꢀpipeꢀ
ridinopropionamidoxime (3c) was completed in 2.5 h.
Apparently, the activation barriers of the formation of the
transition state A stabilized by the Nδ ...Cδ interaction
are lower for compounds 3d—f containing the electronꢀ
withdrawing substituents in the C6H4Х fragment, which
increase the fractional positive charge on the carbonyl
C atom.
In the IR spectra of compounds 4a—f, stretching bands
of the C(=O)O ester groups and the amino group are
absent. These spectra show intense stretching absorption
bands of the C=C double bonds (1584—1600 cm–1) and
powerful stretching absorption bands of the C=N bonds
(1652—1660 cm–1) (see Table 2).
The 1H NMR spectroscopic data for compounds 4a—f
are given in Table 3. The spectra of these compounds
differ radically from those of compounds 3a—f in that
they have no signals of the NH2 group, whereas the signals
for the protons of three methylene groups C—(CH2)3—C
of the piperidine ring are observed as multiplets with the
The 13C NMR spectra of compounds 3a—f show
signals for the carbonyl carbon atom of the ester
group at δ 161.9—170.0 and a signal for the C atom
of the amidoxime group (C(=NOCOC6H4X)NH2) at
δ 157.3—169.2. Six signals for the aromatic C atoms of
the substituted benzene ring are observed at δ 125.1—144.4
(see Table 4).
–
+
1
Previously,13 when recording the H NMR spectrum
of compound 3c in DMSOꢀd6 at ∼20 °C, we have found
that the base of Oꢀbenzoylꢀβꢀpiperidinopropionamidꢀ
oxime (3c) was readily transformed into 5ꢀphenylꢀ3ꢀ(βꢀpiꢀ
peridino)ethylꢀ1,2,4ꢀoxadiazole (4c). In the present study,
we performed dehydration leading to heterocyclization of
Oꢀaroylamidoximes 3a—f with the formation of oxaꢀ
diazoles 4a—f by heating in DMF in the presence of
molecular sieves (4 Å) for 1—2.5 h (see Scheme 1). Alꢀ
though DMSO and DMF have close dielectric perꢀ
meabilities, the latter solvent has the lower boiling point,

2102
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Kayukova et al.
Table 1. Yields, retention factors, melting points, and data from elemental analysis of Oꢀaroylꢀβꢀpiperidinoꢀ
propionamidoximes 3a—f, 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazoles 4a—f, and Nꢀ(βꢀpiperidino)ethylurea
hydrochloride (5•HCl)
Comꢀ Yield
pound (%)
Rf
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
С
Н
Hal
N
3a
3b
3c
3d
3e
3f
93
83
93
84
86
89
67
70
72
73
70
68
0.76
0.76
0.74
0.75
0.66
0.69
0.84
0.82
0.76
0.89
0.75
0.79
—
78
(PriOH)
96
(ЕtOH)
61
(EtOH)
92
(PriOH)
74
65.80
65.43
62.87
62.93
65.52
65.43
50.64
50.86
58.23
58.16
56.35
56.24
70.76
70.82
66.92
66.87
70.09
70.01
53.72
53.58
61.81
61.75
60.07
59.59
43.51
43.33
7.63
7.68
7.54
7.59
7.49
7.68
5.72
5.69
6.47
6.51
6.24
6.29
7.84
7.80
7.44
7.37
7.52
7.44
5.44
5.39
6.27
6.21
6.28
6.00
8.35
8.18
—
—
—
14.89
15.26
13.62
13.76
15.11
15.26
11.75
11.86
13.68
13.56
17.33
17.49
15.62
15.48
14.84
14.62
16.25
16.33
12.56
12.50
14.61
14.40
18.83
18.53
25.07
25.27
С16H23N3O2
С16H23N3O3
C15H21N3O2
C15H20BrN3O2
C15H20ClN3O2
C15H20N4O4
C16H21N3O
22.43
22.56
11.39
11.44
—
(EtOH)
87
(PriOH)
108
4a
4b
4c
4d
4e
4f
—
—
—
(PriOH)
102
C16H21N3O2
C15H19N3O
(EtOH)
83
(EtOH)
114
23.84
23.76
14.53
12.15
—
C15H18BrN3O
C15H18ClN3O
C15H18N4O3
C8H18ClN3O
(PriOH)
96
(PriOH)
109
(EtOH)
208
(EtOH)
5•HCl 23
16.35
15.99
Table 2. IR spectra of Oꢀaroylꢀβꢀpiperidinopropionamidoximes 3a—f and 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazoles 4a—f
Comꢀ
pound
X
ν(C(=O)O) ν(C=N), δ(N—H)
ν(C=C)
ν(C—N)
ν(N—O), ν(C—O)
ν(NH2)
cm–1
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
pꢀMe
pꢀMeO
H
1732
1732
1736
1732
1736
1728
—
—
—
—
—
1684
1636
1632
1632
1632
1632
1652
1656
1652
1656
1656
1660
1636
1588
1608
1598
1576
1564
1596
1590
1584
1588
1594
1600
1268
1268
1272
1268
1248
1276
1264
1276
1272
1276
1276
1274
1120, 1092
1112, 1096
1072, 1096
1104, 1064
1120, 1068
1124, 1096
1016, 1072
1112, 1072
1116, 1068
1068, 1120
1080, 1120
1068, 1120
3120, 3376, 3496
3200, 3328, 3472
2936, 3120, 3264
3104, 3376, 3496
3200, 3376, 3496
3112, 3304, 3480
pꢀBr
mꢀCl
pꢀNO2
pꢀMe
pꢀMeO
H
pꢀBr
mꢀCl
pꢀNO2
—
—
—
—
—
—
—
average values at δ 1.50, 1.70, and 1.80. The signals of the
αꢀ and βꢀmethylene groups of 1,2,4ꢀoxadiazoles 4a—f are
shifted downfield as compared to those of Oꢀaroyl derivaꢀ
tives 3a—f (δ 3.05—3.12 and 3.77—3.80, respectively).
The methylene groups bound to the N atom of the piperiꢀ
dine ring each give two signals with the intensities of two
protons for the axial and equatorial protons. The halfꢀ
width of the signals for Heq (δ ∼3.30) is smaller (22 Hz)

Synthesis of 1,2,4ꢀoxadiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2103
Table 3. 1H NMR spectra of Oꢀaroylꢀβꢀpiperidinopropionamidoximes 3a—f and 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazoles
4a—f (in DMSOꢀd6)
Comꢀ
pound
δ (J/Hz)
X
(CH2)3 (m)
1.39, 1.52
N(CH2)2 (m)
αꢀCH2 (t)
βꢀCH2 (t)
NH2
6.62
COC6H4X
3a
pꢀMe
2.54
(4 H)
2.50
(4 H)
2.37
(4 H)
2.37
(4 H)
2.56
2.30
(J = 7.2)
2.33
(J = 7.0)
2.26
(J = 7.0)
2.27
(J = 7.0)
2.38
(J = 7.0)
2.27
(J = 7.2)
3.12
(J = 7.0)
3.12
(J = 7.0)
3.15
(J = 7.0)
3.07
(J = 7.8)
3.07
(J = 8.1)
3.05
(J = 7.5)
2.36
(J = 7.2)
2.60
(J = 7.0)
2.54
(J = 7.0)
2.54
(J = 7.0)
2.72
(J = 7.0)
3.10
(J = 7.2)
3.80
(J = 7.0)
3.80
(J = 7.0)
3.83
(J = 7.0)
3.77
(J = 7.8)
3.77
(J = 8.1)
3.77
(J = 7.5)
2.37 (pꢀMe); 7.30, 8.04
(both d, 2 H each, J = 8.7)
2.50 (pꢀMeO); 7.00, 8.05
(both d, 2 H each, J = 8.3)
7.40—8.10 (m, 5 H)
3b
3c
3d
3e
3f
pꢀMeO
H
1.40, 1.51
1.37, 1.50
1.37, 1.49
1.41, 1.56
1.40, 1.60
6.61
6.58
6.57
6.77
6.60
—
pꢀBr
7.50, 8.09
(both d, 2 H each, J = 8.3)
7.54—8.06 (m, 4 H)
mꢀCl
pꢀNO2
pꢀMe
pꢀMeO
H
(4 H)
2.53
8.22, 8.29
(4 H)
3.33 (2 Heq);
(both d, 2 H each, J = 8.4)
2.16 (pꢀMe); 7.01, 7.69
(both d, 2 H each, J = 8.0)
2.26 (pꢀMeO); 7.75, 8.76
(both d, 2 H each, J = 8.7)
7.25—7.86 (m, 5 H)
4a
4b
4c
4d
4e
4f
1.53, 1.70,
1.86
1.54, 1.75,
1.84
1.52, 1.72,
1.83
1.50, 1.70,
1.85
1.50, 1.70,
1.82
1.50, 1.71,
1.81
3.50 (2 Hax
3.33 (2 Heq);
3.44 (2 Hax
3.33 (2 Heq);
3.46 (2 Hax
3.30 (2 Heq);
3.40 (2 Hax
3.28 (2 Нeq);
3.41 (2 Нax
3.29 (2 Heq);
3.40 (2 Hax
)
—
)
—
)
pꢀBr
—
7.43, 7.74
(both d, 2 H each, J = 8.1)
7.23—7.77 (m, 4 H)
)
mꢀCl
pꢀNO2
—
)
—
8.07, 8.20
(both d, 2 H each, J = 9.0)
)
Table 4. 13C NMR spectra of Oꢀaroylꢀβꢀpiperidinopropionamidoximes 3a—f and 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiꢀ
azoles 4a—f
Comꢀ
pound
δ
X
C=O (3) or
C=N (3) or αꢀCH2 βꢀCH2 N(CH2)2 (CH2)3
C arom.
CX
C(5)=N (4) C(3)=N (4)
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
pꢀMe
pꢀMeO
H
166.8
164.4
163.0
163.0
161.9
170.0
168.1
168.1
168.0
168.7
163.0
170.0
166.3
157.3
158.2
158.2
157.9
169.2
167.8
159.6
167.8
158.5
156.3
169.2
29.0
26.4
27.5
27.5
26.9
32.9
30.5
30.6
30.5
26.5
26.9
25.5
58.3
53.7
55.6
53.2
54.8
62.1
59.8
59.8
59.8
54.6
63.1
57.8
61.8
53.0
53.2
55.6
52.8
65.6
63.4
63.3
63.3
52.2
55.2
53.2
18.5, 19.4
22.2, 23.4
23.6, 25.2
23.6, 27.5
23.0, 24.4
22.4, 23.3
20.1, 20.4
20.1, 21.0
20.1, 21.0
22.7, 26.5
22.3, 24.2
22.1, 22.7
125.1, 126.5, 127.0, 138.7 19.5 (pꢀMe)
127.4, 130.2, 130.5, 144.4 22.3 (pꢀMeO)
128.1, 128.9, 129.2, 132.4
128.1, 128.9, 129.3, 132.4
127.3, 127.7, 128.5, 131.1
130.4, 131.1, 132.7, 134.8
—
—
—
—
pꢀBr
mꢀCl
pꢀNO2
pꢀMe
pꢀMeO
H
pꢀBr
mꢀCl
pꢀNO2
127.1, 128.6, 136.7, 138.4 20.9 (pꢀMe)
127.2, 127.5, 128.7, 129.0 24.9 (pꢀMeO)
126.4, 127.6, 128.5, 141.2
127.8, 130.5, 131.2, 133.4
127.4, 130.0, 133.5, 137.2
128.5, 134.8, 138.0, 151.8
—
—
—
—
Note. The 13C NMR spectra of compounds 3a—f, 4a,b, and 4c—f were recorded in DMSO, CHCl3, and a 1 : 1 CHCl3—MeOH
mixture, respectively.
than that of the signals for Hax (δ ∼3.45, 27 Hz). The
signals for the aromatic protons of 1,2,4ꢀoxadiazoles 4a—f
are observed at δ 7.01—8.76.
Based on the H NMR spectra, it can be concluded
that the transformation of Oꢀaroylꢀβꢀpiperidinopropionꢀ
amidoximes 3a—f to 5ꢀaroylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀ
oxadiazoles 4a—f under the conditions in which the NMR
spectra were recorded leads to deceleration of the piꢀ
peridineꢀring inversion because the system becomes
more rigid.
1

2104
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002
Kayukova et al.
In the 13C NMR spectra of compounds 4a—f, the
signals for the C(3) and C(5) atoms of the 1,2,4ꢀoxadiazole
ring are observed at δ 156.3—169.2 and 163.0—170.0,
respectively. The assignments of the signals for the C
atoms of the C(3)=N and C(5)=N bonds were made based
on the comparison of the electronegativities of the O and
N atoms in the 1,2,4ꢀoxadiazole ring. Thus, the set of
signals observed at lower field was assigned to the C atoms
of the C(5)=N bond because the C(5) atom is bound to
the more electronegative O atom. The signals for the
αꢀ and βꢀmethylene C atoms are observed at δ 25.5—30.6
and 54.6—63.1, respectively. The C atoms of the benzene
ring give signals at δ 126.4—151.8 (see Table 4).
Heating of Oꢀbenzoylꢀβꢀpiperidinopropionamidoxime
(3c) in DMF at 85 °C for 4 h afforded 5ꢀphenylꢀ
3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazole (4c) (Rf 0.76),
Nꢀ(βꢀpiperidino)ethylurea (5) (Rf 0.29), and benzoic acid
(Rf 0.80) (Scheme 3). Compound 5 was characterized as
hydrochloride 5•HCl (see Table 1). The formation of
urea 5 occurred through the Beckmann rearrangement,
which was described for Oꢀacylamidoximes.14 However,
elimination of the acylꢀcontaining residue has not previꢀ
ously been observed.
the presence of potassium carbonate at 85 °C for 4 h gave
Nꢀ(βꢀpiperidino)ethylurea (5), benzoic acid, and 5ꢀpheꢀ
nylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazole (4c).
Experimental
The 1H and 13C NMR spectra were recorded on Mercuryꢀ300
(300 MHz) and Bruker (20.13 MHz) instruments, respectively,
with HMDS as the internal standard. The IR spectra were meaꢀ
sured on a URꢀ20 instrument in KBr pellets. The course of the
reactions was monitored by TLC on Sorbfil plates (benꢀ
zene—MeOH, 1 : 3, as the eluent).
Nitrile 1 was synthesized according to a procedure described
previously.15 The procedure for the preparation of amidoxime 2
has been developed by us earlier.16
The solvents used for acylation (CHCl3 and benzene), deꢀ
hydration (DMF), precipitation, recrystallization (hexane,
EtOH, PriOH, and AcOEt), and TLC (MeOH and benzene)
were purified according to standard procedures.17
OꢀBenzoylꢀβꢀpiperidinopropionamidoxime (3a). A solution of
benzoyl chloride (0.41 g, 2.9 mmol) in dry CHCl3 (5 mL) was
added dropwise with stirring to a mixture of βꢀpiperidinoꢀ
propionamidoxime (2) (0.5 g, 2.9 mmol), dry CHCl3 (25 mL),
and Et3N (0.4 mL, 2.9 mmol) at ∼20 °C. The reaction mixture
was stirred at ∼20 °C for 8 h. The solvent was distilled off on a
rotary evaporator and then water (5 mL) was added to the resiꢀ
due. The precipitate that formed was filtered off, dried, and
recrystallized from PriOH. Compound 3a was obtained in a
yield of 0.74 g (93%).
Scheme 3
Compounds 3b,c were prepared analogously.
Oꢀ(pꢀNitrobenzoyl)ꢀβꢀpiperidinopropionamidoxime (3f). A soꢀ
lution of pꢀnitrobenzoyl chloride (1.09 g, 5.9 mmol) in dry benꢀ
zene (5 mL) was added with stirring to a mixture of amidoxime 2
(1.02 g, 5.9 mmol) and dry benzene (35 mL) at ∼20 °C. After
10 h, Oꢀ(pꢀnitrobenzoyl)ꢀβꢀpiperidinopropionamidoxime hydroꢀ
chloride (3f•HCl) was filtered off in a yield of 1.76 g (5.2 mmol),
which was dissolved in distilled water (5 mL). Then K2CO3
(0.36 g, 2.6 mmol) was added. The precipitate that formed was
filtered off and recrystallized from EtOH. Compound 3f was
obtained in a yield of 1.40 g (89%).
OꢀAroylꢀβꢀpiperidinopropionamidoximes 3d,e were prepared
analogously.
The yields, retention factors, physicochemical characterisꢀ
tics, spectroscopic data, and results of elemental analysis of
Oꢀacylamidoximes 3a—f are given in Tables 1—4.
5ꢀ(pꢀBromophenyl)ꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazole
(4d). A solution of Oꢀ(pꢀbromobenzoyl)ꢀβꢀpiperidinopropionꢀ
amidoxime (3d) (0.52 g, 1.5 mmol) was heated with stirring in
DMF in the presence of molecular sieves (4 Å) at 60 °C for 1 h.
Then the molecular sieves were filtered off and washed on the
filter with benzene. The solvents were evaporated in vacuo with
the successive use of a waterꢀjet and an oil pump. Hexane was
added to the residue. The precipitate that formed was filtered off
and recrystallized from EtOH. Oxadiazole 4d was obtained in a
yield of 0.36 g (73%).
Benzoic acid and urea 5 can be generated by the reacꢀ
tion of the intermediate rearrangement product C with
the water molecule liberated upon dehydration of 3c
to form 5ꢀphenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiꢀ
azole (4c).
Therefore, acylation of βꢀpiperidinopropionamidꢀ
oxime (2) with substituted benzoyl chlorides proceeds at
the O atom of the amidoxime group. Dehydration of
Oꢀaroylamidoximes 3 on heating in DMF (60 °C) in the
presence of molecular sieves (4 Å) for 1—2.5 h afforded
5ꢀarylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazoles 4. Heatꢀ
ing of Oꢀbenzoylꢀβꢀpiperidinopropionamidoxime (3c) in
1,2,4ꢀOxadiazoles 4a—c,e,f were prepared analogously. Deꢀ
hydration of the compounds containing electronꢀwithdrawing
substituents in the benzene ring (3d—f) was completed in 1 h.
Dehydration of the compounds bearing electronꢀreleasing subꢀ

Synthesis of 1,2,4ꢀoxadiazoles
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 11, November, 2002 2105
stituents (3a,b) and the compound with the unsubstituted benꢀ
zene ring (3c) was completed in 2.5 h.
The yields, retention factors, physicochemical characterisꢀ
tics, spectroscopic data, and results of elemental analysis of
1,2,4ꢀoxadiazoles 4a—f are given in Tables 1—4.
Pat. 126439; Ref. Zh. Khim., 1974, No. 15, N4O1P; Denꢀ
mark Pat. 160097; Ref. Zh. Khim., 1991, No. 23, O79P.
4. K. P. Flora, B. van’t Reit, and G. L. Wampler, Cancer Res.,
1978, 38, 1291.
5. Kazakhstan PreꢀPat., 8391; Byul. Izobr. of the Kazakhstan
Republic, 2000, 1 (in Russian); Kazakhstan PreꢀPat., 9969;
Byul. Izobr. of the Kazakhstan Republic, 2001, 3 (in Russian).
6. O. M. Glozman, T. A. Voronina, E. K. Orlova, L. M.
Meshcheryakova, I. Kh. Rakhmankulova, A. A. Kazanskaya,
L. D. Smirnov, A. Rostok, and Kh. Zigel´mund, Khim.ꢀfarm.
Zh., 1989, 9, 1147 [Pharm. Chem. J., 1989, 9 (Engl. Transl.)];
V. G. Chizh, Ph. D. (Chem.) Thesis, Perm State University,
Perm, 1997, 128 pp. (in Russian).
7. N. S. Ooi and W. S. Wilson, J. Chem. Soc., Perkin Trans. 1,
1980, 1792.
8. J. GuiꢀYu, X. MinꢀYu, Zh. GuoꢀFeng, and L. ZhongꢀFa,
Chem. J. Chin. Univ., 1994, 15, 1009.
9. F. Eloy and R. Lenaers, Chem. Rev., 1962, 62, 155; F. Eloy,
Fortschr. Chem. Forsch., 1965, 4, 807.
5ꢀPhenylꢀ3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazole (4c) and
Nꢀ(βꢀpiperidino)ethylurea (5). A solution of Oꢀbenzoylꢀβꢀpiꢀ
peridinopropionamidoxime (3c) (0.28 g, 1 mmol) in dried DMF
(5 mL) was heated with K2CO3 (0.1 g, 0.7 mmol) at 85 °C for 4 h
(TLC control). The solvent was evaporated in vacuo using a
waterꢀjet pump and then distilled water (2 mL) was added to the
residue. After trituration of the residue, benzoic acid was obꢀ
tained in a yield of 0.03 g (24%), m.p. 120 °C, Rf 0.80. The
aqueous filtrate was extracted with benzene. The benzene layer
was separated, dried over calcined K2CO3, and evaporated in
vacuo. The residue was triturated in hexane to obtain 5ꢀphenylꢀ
3ꢀ(βꢀpiperidino)ethylꢀ1,2,4ꢀoxadiazole (4c) in a yield of 0.08 g
(32%), Rf 0.76. Found (%): C, 70.12; H, 7.64; N, 16.43.
C
15H19N3O. Calculated (%): C, 70.01; H 7.44; N, 16.33. The
aqueous filtrate was concentrated. The organic residue was dried
by the addition of benzene (2×5 mL) and vacuum distillation
using a waterꢀjet pump. The residue was dissolved in anhydrous
EtOH (0.5 mL). Then a solution of HCl in EtOH was added to
pH 3. Nꢀ(βꢀPiperidino)ethylurea hydrochloride (5•HCl) was
precipitated with ethyl acetate in a yield of 0.05 g (23%). IR,
10. M. J. Crimmen, P. J. O’Hanlon, N. H. Roger, and
G. Walker, J. Chem Soc., Perkin Trans. 1, 1989, 2047.
11. L. B. Clapp, Adv. Heterocycl. Chem., 1976, 20, 65; Sh. Choiou
and H. J. Shine, J. Heterocycl. Chem., 1989, 26, 125; V. V.
Sosnina and E. R. Kofanov, Tez. dokl. I Vseros. konf. po
khimii geterotsiklov pamyati A. N. Kosta [Abstrs. of Papers,
I AllꢀRussian Conf. on Chemistry of Heterocycles Dedicated to
the Memory of A. N. Kosta] (September 19—23, 2000, Suzdal´),
Suzdal´, 2000, 489 (in Russian).
12. L. A. Kayukova, K. D. Praliyev, M. H. Cynamon, J. T.
Welch, P. Toskano, V. L. Bismildina, and R. A. Agzamova,
Abstrs. of Papers, Intern. Conf. on Natural Products and
Physiologically Active Substances (ICNPASꢀ98) (Novemꢀ
ber 30—December 6, 1998, Novosibirsk), Novosibirsk,
1998, 87.
ν/cm–1: 1604 (δ(N—H)), 1664 (ν(C=O)), 3048 (ν (NH2)), 3264
s
(ν (NH2)). 1H NMR (DMSOꢀd6), δ: 1.55, 1.76, and 1.86 (all m,
as
6 H, —N(CH2)2(CH2)3); 3.11 (t, 2 H, CH2N(CH2)2, J =
7.0 Hz); 3.33 (m, 2 H, NCH2 (Heq)); 3.49 (m, 2 H, NCH2 (Hax));
3.84 (t, 2 H, (CH2CH2N(CH2)2, J = 7.0 Hz); 7.37 (s, 2 H,
NH2). 13C NMR (DMSO), δ: 20.1 (1 C, N(CH2)2(CH2)2CH2);
21.0 (2 C, —N(CH2)2(CH2)2CH2); 30.6 (1 C, NHCH2CH2N);
59.8 (1 C, NHCH2CH2N); 63.4 (2 C, N(CH2)2(CH2)2CH2);
167.6 (1 H, C=O).
13. L. A. Kayukova, K. D. Praliyev, I. S. Zhumadildaeva, and
S. P. Klepikova, Khim. Geterotsikl. Soedin., 1999, 701 [Chem.
Heterocycl. Compd., 1999, 35, 629 (Engl. Transl.)].
14. V. H. Brachwitz, J. Pract. Chem., 1969, 311, 661.
15. F. S. Whitemore, H. S. Mosher, R. R. Adams, R. B. Taylor,
E. C. Chapin, C. Weisel, and W. Yanko, J. Am. Chem. Soc.,
1944, 66, 725.
This study was in part financially supported by the US
Civilian Research and Development Foundation (CRDF,
Grant KB2ꢀ2314ꢀALꢀ02).
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Received October 8, 2001;
in revised form March 25, 2002