Synthesis of 4-hetaryl-substituted 5-amino- and 5-sulfanyl-1,3-oxazole derivatives

Article abstract of DOI:10.1134/S1070363211020204

Previously unknown 5-amino- and 5-sulfanyl-1,3-oxazole derivatives containing a 1,3,4-oxadiazole, 1,3,4-thiadiazole, or 1,2,4-triazole fragment at C⁴ were synthesized from accessible 1,3-oxazole-4-carboxylic acid hydrazides.

Full text of DOI:10.1134/S1070363211020204

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 2, pp. 405–410. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.M. Prokopenko, S.G. Pil’o, V.S. Brovarets, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 2, pp. 307–312.
Synthesis of 4-Hetaryl-Substituted 5-Amino-
and 5-Sulfanyl-1,3-oxazole Derivatives
V. M. Prokopenko, S. G. Pil’o, and V. S. Brovarets
Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received March 1, 2010
Abstract—Previously unknown 5-amino- and 5-sulfanyl-1,3-oxazole derivatives containing a 1,3,4-oxadiazole,
1,3,4-thiadiazole, or 1,2,4-triazole fragment at C4 were synthesized from accessible 1,3-oxazole-4-carboxylic
acid hydrazides.
DOI: 10.1134/S1070363211020204
In the early 1950s J.W. Cornforth, who was one of
the most prominent researchers of the chemistry of
oxazoles, noted that oxazole derivatives rarely
occurred in nature and that therefore they were not
promising from the viewpoint of searching for new
biologically active substances [1]. However, recent
studies performed mostly during the past 30 years
showed that various bacteria and marine organisms
produced numerous antibiotics belonging to the oxazole
series [2–5]. Moreover, numerous oxazole-based syn-
thetic bioregulators are known, which exhibit strong
antimicrobial, cytostatic, immune stimulating, neuro-
leptic, analgesic, and other kinds of biological activity
[6–8]. In this connection, the synthesis of oxazole
derivatives containing hetaryl substituents, in particular
1,3,4-oxadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole
fragments which could considerably affect bioregula-
tor properties of oxazole, attracts certain interest, for
the above heterocyclic fragments potentially possess a
broad spectrum of biological properties [7, 10–15].
methyl or ethyl iodide in an alcoholic solution of
potassium hydroxide afforded the corresponding S-
alkyl derivatives VIII (Table 1).
Acylation of hydrazides II with benzoyl and p-
methylbenzoyl chlorides occurred regioselectively at
the primary amino group with the formation of N′-acyl-
2-aryl-5-amino(or arylsulfanyl)-1,3-oxazole-4-carbohyd-
razides IV. The treatment of the latter with phosphoryl
chloride or Lawesson’s reagent resulted in cyclization
to 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives
VI and VII (Table 1). All 4-hetaryl-substituted 1,3-
oxazoles V–VIII are characterized by the presence of
an additional nitrogen- or sulfur-containing substituent
in the 5-position of the oxazole ring, which is
important from the viewpoint of biological activity
[16–19].
The newly synthesized oxazole derivatives
(Scheme 1) were chromatographically pure crystalline
substances whose structure directly followed from the
procedure of their preparation and was confirmed by
As key starting compounds for the synthesis of 4-
hetaryl-substituted 5-amino- and 5-sulfanyl-1,3-oxa-
zoles V–VIII we selected 1,3-oxazole-4-carboxylic
acid hydrazides II that are readily obtainable from the
corresponding esters I as shown in Scheme 1. Hyd-
razides II reacted with methyl and phenyl iso-
thiocyanates to produce thiosemicarbazides III which
readily underwent intramolecular cyclization in aqueous
potassium hydroxide. The acidification with acetic
acid precipitated triazoles V as colorless crystalline
substances. The alkylation of compounds V with
1
1
the IR and H NMR spectra (Table 2). The H NMR
spectra of III and IV lacked singlets at δ 4.32–4.34
and 8.82–8.92 ppm, which are typical of the NH2 and
NH protons, respectively, in initial hydrazides II;
instead, two singlets appeared in the region δ 8.33–
10.43 ppm; the latter disappeared as a result of
formation of triazole, oxadiazole, or thiadiazole ring in
the course of the transformations III→V, IV→VI,
1
and IV→VII. Compounds V displayed in the H
NMR spectra a broadened signal in the region δ 10.90–
405

406
PROKOPENKO et al.
O
S
O
O
N
H
NHR
N
H
OMe
NHNH2
N
N
N
H2NNH2 H2O
RNCS
Ar
Ar
Ar
X
X
O
IIa_IIf
Δ
X
Δ
O
O
Ia_If
IIIa_IIIc
(1) KOH, Δ
Ar'C(O)Cl,
Et3N
(2) H+
O
O
N N
N
H
N
H
Ar'
SH
N
N
N
R
POCl3
Ar
Ar
X
X
Δ
O
O
IVa_IVj
Va_Vc
AlkI,
KOH
Δ
Δ
RL
N N
S
N
N
N
N
Ar'
Ar'
SAlk
N
N
N
O
N
R
Ar
Ar
Ar
X
X
X
O
O
O
VIIa_VIIi
VIa_VIg
VIIIa_VIIIe
S
S
RL = MeO
P
P
S
OMe
S
I, II, Ar = Ph (a, c, e, f), 4-MeC6H4 (b, d); X = piperidino (a, b), morpholino (c, d), 4-MeC6H4S (e), 4-ClC6H4S (f); III, IV,
Ar = Ph (a–d, g–j), 4-MeC6H4 (e, f); Ar′ = Ph (a, c, e, g, i), 4-MeC6H4 (b, d, f, h, j); X = piperidino (a, b), morpholino (c–f),
4-MeC6H4S (g, h), 4-ClC6H4S (i, j); V, Ar = Ph (a), 4-MeC6H4 (b, c); R = Ph (a, b), Me (c); X = piperidino (a), morpholino
(b, c); VI, Ar = Ph (a, b, d–g), 4-MeC6H4 (c); Ar′ = 4-MeC6H4 (a, b, e, g), Ph (c, d, f); X = piperidino (a), morpholino (b, c),
4-MeC6H4S (d, e), 4-ClC6H4S (f, g); VII, Ar = Ph (a–c, f–i), 4-MeC6H4 (d, e); Ar′ = 4-MeC6H4 (a, c, e, g, i), Ph (b, d, f, h);
X = piperidino (a), morpholino (b–e), 4-MeC6H4S (f, g), 4-ClC6H4S (h, i); VIII, Ar = Ph (a, b), 4-MeC6H4 (c–e); R = Ph
(a–d), Me (e); Alk = Me (a, c), Et (b, d, e); X = piperidino (a, b), morpholino (c–e).
11.36 ppm, which was assigned to the SH proton; no
such proton was present in alkylation products VIII.
No absorption was observed in the regions 1640–1700
and 3000–3600 cm–1 of the IR spectra of VI and VII,
EXPERIMENTAL
The IR spectra were recorded in KBr on a Vertex 70
1
spectrometer. The H NMR spectra were measured
1
from solutions in DMSO-d6 on a Varian VXR-300
spectrometer using tetramethylsilane as internal
reference. The melting points were determined on a
Fisher–Johns melting point apparatus.
and their H NMR spectra contained no signal at δ
9.60–10.43 ppm, which is typical of the NH proton in
acylated hydrazides IV. The above findings suggest
participation of the –C(O)NHNHC(O)– fragment in
the intramolecular cyclization with the formation of
Methyl 2-aryl-5-piperidino(or morpholino)-1,3-
oxazole-4-carboxylates Ia–Id were synthesized as des-
cribed in [20]. Methyl 2-aryl-5-arylsulfanyl-1,3-
oxazole-4-carboxylates Ie and If were prepared
according to the procedure described in [21].
1
oxadiazole or thiadiazole ring. In the H NMR spectra
of all compounds V–VIII, signals from aromatic and
aliphatic protons with intensity ratios corresponding to
the assumed structures were also observed.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

SYNTHESIS OF 4-HETARYL-SUBSTITUTED 5-AMINO-...
Table 1. Yields, melting points, and elemental analyses of compounds I–VIII
407
Found, %
S (Cl)
Calculated, %
N S (Cl)
Comp.
no.
Yield,
%
mp, °C (solvent)
Formula
N
85
86
75
101–103 (hexane)
105–109 (EtOH)
111–114 (cyclohexane)
9.36
9.33
19.41
–
–
–
C17H20N2O3
C16H18N2O4
C15H18N4O2
9.33
9.27
19.57
–
–
–
Ib
Id
IIа
79
79
80
85
92–94 (cyclohexane)
163–166 (EtOH)
135–138 (EtOH)
153–156 (EtOH)
18.59
19.33
18.48
12.20
–
C16H20N4O2
C14H16N4O3
C15H18N4O3
C16H12ClN3O2S
18.65
19.43
18.53
12.15
–
–
–
IIb
IIc
IId
IIf
–
–
9.25 (10.33)
9.27 (10.25)
75
76
74
80
82
84
82
89
85
90
88
78
82
80
71
70
68
72
69
70
72
86
83
151–153 (EtOH)
180–184 (EtOH)
16.72
14.25
13.95
14.35
13.74
13.68
13.25
9.85
7.55
C22H23N5O2S
C22H22N4O3
C23H24N4O3
C21H20N4O4
16.61
14.35
13.85
14.28
13.78
13.78
13.32
9.78
7.61
IIIа
IVа
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
–
–
166–170 (EtOH)
–
–
185–188 (МеCN)
–
–
235–239 (МеCN–DMF, 3:1)
194–196 (EtOH)
–
C22H22N4O4
–
–
–
C22H22N4O4
C23H24N4O4
C24H19N3O3S
C25H21N3O3S
C23H16ClN3O3S
C24H18ClN3O3S
C22H21N5OS
C22H21N5O2S
C17H19N5O2S
C23H22N4O2
–
–
202–205 (EtOH)
192–196 (МеCN)
7.44
7.47
175–179 (МеCN)
9.35
7.19
9.47
7.23
186–189 (МеCN)
9.41
7.14 (7.95)
6.93 (7.72)
7.91
9.34
7.13 (7.88)
6.91 (7.64)
7.95
177–181 (МеCN)
9.09
9.06
IVj
Vа
234–236 (EtOH)
17.39
16.79
19.62
14.45
14.28
14.30
10.26
9.93
17.36
16.69
19.59
14.50
14.42
14.42
10.21
9.88
258–262 (EtOH)
7.62
7.64
Vb
226–229 (EtOH)
8.95
8.97
Vc
173–175 (МеCN)
–
–
VIа
VIb
VIc
VId
VIe
VIf
VIg
VIIа
VIIb
199–203 (МеCN–DMF, 3:1)
234–237 (EtOH–DMF, 1:1)
151–153 (МеCN)
–
C22H20N4O3
–
–
C22H20N4O3
–
7.75
C24H17N3O2S
C25H19N3O2S
C23H14ClN3O2S
C24H16ClN3O2S
C23H22N4OS
C21H18N4O2S
7.79
152–154 (МеCN)
7.51
7.54
180–182 (МеCN)
9.61
7.45 (8.52)
7.14 (8.05)
7.90
9.73
7.42 (8.21)
7.19 (7.95)
7.97
191–193 (МеCN)
9.41
9.42
200–203 (МеCN–DMF, 3:1)
184–185 (МеCN–DMF, 3:1)
13.81
14.20
13.92
14.35
8.23
8.21
81
79
85
197–200 (МеCN–DMF, 3:1)
214–216 (EtOH–DMF, 1:1)
216–218 (МеCN–DMF, 3:1)
13.65
13.75
13.42
8.07
8.08
7.64
C22H20N4O2S
C22H20N4O2S
C23H22N4O2S
13.85
13.85
13.39
7.93
7.93
7.66
VIIc
VIId
VIIe
90
158–162 (МеCN)
9.75
15.05
C24H17N3OS2
9.83
15.00
VIIf
89
83
85
71
182–184 (МеCN)
189–192 (МеCN)
208–210 (МеCN)
9.41
9.20
8.92
14.49
14.30 (8.12)
13.80 (7.75)
7.55
C25H19N3OS2
C23H14ClN3OS2
C24H16ClN3OS2
C23H23N5OS
9.52
9.38
9.10
14.52
14.32 (7.91)
13.88 (7.67)
7.68
VIIg
VIIh
VIIi
152–155 (cyclohexane)
16.85
16.77
VIIIа
79
76
83
74
170–173 (EtOH)
158–162 (cyclohexane)
178–182 (EtOH)
16.25
16.03
15.55
18.26
7.48
7.42
7.06
8.38
C24H25N5OS
C23H23N5O2S
C24H25N5O2S
C19H23N5O2S
16.23
16.15
15.65
18.17
7.43
7.40
7.16
8.32
VIIIb
VIIIc
VIIId
VIIIe
150–182 (cyclohexane)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

408
PROKOPENKO et al.
Table 2. IR and 1H NMR spectra of compounds I–VIII
Comp.
no.
IR spectrum (KBr),a ν, cm–1
1H NMR spectrum (DMSO-d6), δ, ppm
1693 (CO)
1.63 br.s and 3.73 br.s [10H, (CH2)5N], 2.35 s (3H, CH3), 3.60 s (3H, OCH3), 7.31–7.73 m
(4H, C6H4)
Ib
1703 (CO)
2.36 s (3H, CH3), 3.67–3.74 m [11H, OCH3, O(CH2)4N], 7.32–7.75 m (4H, C6H4)
Id
1645 (CO), 3215–3420 (NH as.,
NH2 as.)
1.61 br.s and 3.65 br.s [10H, (CH2)5N], 4.34 br.s (2H, NH2), 7.47–7.86 m (5H, C6H5), 8.82
s (1H, NH)
IIa
1628 (CO), 3280–3400 (NH as.,
NH2 as.)
3.72 m [8H, O(CH2)4N], 4.34 br.s (2H, NH2), 7.48–7.88 m (5H, C6H5), 8.92 s (1H, NH)
IIc
1653 (CO), 3270–3350 (NH as.,
NH2 as.)
2.35 s (3H, CH3), 3.71 m [8H, O(CH2)4N], 4.32 br.s (2H, NH2), 7.32–7.77 m (4H, C6H4),
8.88 s (1H, NH)
IId
IIf
1680 (CO), 3314–3415 (NH as.,
NH2 as.)
4.33 br.s (2H, NH2), 7.40–7.91 m (9H, C6H4, C6H5), 8.85 s (1H, NH)
1672 (CO), 3130–3320 (NH as.)
1.72 br.s and 3.79 br.s [10H, (CH2)5N], 7.25–7.92 m (10H, C6H5), 8.33 br.s (2H, NH), 9.04
br.s (1H, NH)
IIIa
IVb
IVc
IVd
IVe
IVf
1654 (CO), 1680 (CO), 3100–3340 1.62 br.s and 3.70 br.s [10H, (CH2)5N], 2.38 s (3H, CH3), 7.30–7.94 m (9H, C6H4, C6H5),
(NH as.) 9.60 s (1H, NH), 10.24 s (1H, NH)
1649 (CO), 1685 (CO), 3150–3340 3.74 br.s [8H, O(CH2)4N], 7.48–7.95 m (10H, C6H5), 9.73 s (1H, NH), 10.33 s (1H, NH)
(NH as.)
1643 (CO), 1682 (CO), 3200–3360 2.38 s (3H, CH3), 3.73 br.s [8H, O(CH2)4N], 7.27–7.93 m (9H, C6H4, C6H5), 9.69 s (1H,
(NH as.)
NH), 10.25 s (1H, NH)
1673 (CO), 1695 (CO), 3100–3350 2.36 s (3H, CH3), 3.72 br.s [8H, O(CH2)4N], 7.29–7.90 m (9H, C6H4, C6H5), 9.63 s (1H,
(NH as.) NH), 10.24 s (1H, NH)
1654 (CO), 1689 (CO), 3180–3320 2.37 s (6H, CH3), 3.72 br. s [8H, O(CH2)4N], 7.30–7.81 m (8H, C6H4), 9.61 s (1H, NH),
(NH as.)
10.22 s (1H, NH)
1693 (CO),b 3100–3250 (NH as.)
1671 (CO),b 3150–3280 (NH as.)
1675 (CO),b 3100–3250 (NH as.)
1673 (CO),b 3100–3280 (NH as.)
2.34 s (3H, CH3), 7.31–7.95 m (14H, C6H4, C6H5), 10.40 br. s (2H, NH)
2.33 s and 2.39 s (3H each, CH3), 7.29–7.89 m (13H, C6H4, C6H5), 10.42 d (2H, NH)
7.30–7.88 m (14H, C6H4, C6H5), 10.41 br.s (2H, NH)
IVg
IVh
IVi
IVj
Va
2.39 s (3H, CH3), 7.32–7.93 m (13H, C6H4, C6H5), 10.43 br.s (2H, NH)
1.66 br.s and 3.30 br.s [10H, (CH2)5N], 7.28–7.66 m (10H, C6H5), 11.36 s (1H, SH)
–
–
2.38 s (3H, CH3), 3.35 br. s, 3.83 br. s [8H, O(CH2)4N], 7.17–7.55 m (9H, C6H4, C6H5),
11.07 br. s (1H, SH)
Vb
–
2.43 s (3H, CH3), 3.46 m and 3.88 m [11H, CH3, O(CH2)4N], 7.29–7.84 m (4H, C6H4),
10.90 s (1H, SH)
Vc
–
–
1.67 br.s and 3.67 br.s [10H, (CH2)5N], 2.41 s (3H, CH3), 7.42–7.94 m (9H, C6H4, C6H5)
2.41 s (3H, CH3), 3.71 br.s and 3.81 br.s [8H, O(CH2)4N], 7.40–7.94 m (9H, C6H4, C6H5)
VIa
VIb
–
–
–
2.38 s (3H, CH3), 3.71 m and 3.81 m [8H, O(CH2)4N], 7.34–8.04 m (9H, C6H4, C6H5)
2.32 s (3H, CH3), 7.21–8.09 m (14H, C6H4, C6H5)
2.31 s (3H, CH3), 2.43 s (3H, CH3), 7.21–8.03 m (13H, C6H4, C6H5)
VIc
VId
VIe
–
–
–
7.41–8.06 m (14H, C6H4, C6H5)
VIf
2.43 s (3H, CH3), 7.40–8.04 m (13H, C6H4, C6H5)
VIg
VIIa
1.68 br.s and 3.74 br.s [10H, (CH2)5N], 2.38 s (3H, CH3), 7.37–7.89 m (9H, C6H4, C6H5)
–
–
3.81 br.s [8H, O(CH2)4N], 7.56–8.03 m (10H, C6H5)
VIIb
VIIc
2.38 s (3H, CH3), 3.80 m [8H, O(CH2)4N], 7.35–7.90 m (9H, C6H4, C6H5)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

SYNTHESIS OF 4-HETARYL-SUBSTITUTED 5-AMINO-...
409
Table 2. (Contd.)
Comp.
no.
IR spectrum (KBr),a ν, cm–1
1H NMR spectrum (DMSO-d6), δ, ppm
–
2.38 s (3H, CH3), 3.80 m [8H, O(CH2)4N], 7.33–7.98 m (9H, C6H4, C6H5)
VIId
–
–
–
2.37 s (6H, CH3), 3.78 m [8H, O(CH2)4N], 7.32–7.85 m (8H, C6H4)
2.32 s (3H, CH3), 7.19–8.02 m (14H, C6H4, C6H5)
VIIe
VIIf
VIIg
2.31 s (3H, CH3), 2.41 s (3H, CH3), 7.21–7.98 m (13H, C6H4, C6H5)
–
–
7.40–8.03 m (14H, C6H4, C6H5)
VIIh
VIIi
2.41 s (3H, CH3), 7.38–8.05 m (13H, C6H4, C6H5)
–
–
1.69 br.s and 3.38 br.s [10H, (CH2)5N], 2.75 s (3H, SCH3), 7.34–7.66 m (10H, C6H5)
VIIIa
VIIIb
1.45 m (3H, CH3), 1.66 br.s and 3.37 br. s [10H, (CH2)5N], 3.31 m (2H, SCH2), 7.34–7.66
m (10H, C6H5)
–
–
–
2.37 s (3H, CH3), 2.74 s (3H, SCH3), 3.49 m and 3.87 m [8H, O(CH2)4N], 7.15–7.52 m
(9H, C6H4, C6H5)
VIIIc
VIIId
1.45 t (3H, CH3), 2.37 s (3H, CH3), 3.30 m (2H, SCH2), 3.49 m and 3.86 m [8H, O(CH2)4N],
7.15–7.52 m (9H, C6H4, C6H5)
1.48 t (3H, CH3), 2.42 s (3H, CH3), 3.30 m (2H, SCH2), 3.56 m and 3.86 m [11H, O(CH2)4N,
CH3], 7.29–7.84 m (4H, C6H4)
VIIIe
The IR spectra of V–VIII lack absorption bands in the regions 1640–1700 and 3000–3600 cm–1. b Weak band with a shoulder.
a
2-Aryl-5-piperidino(or morpholino)-1,3-oxazole-
4-carbohydrazides IIa–IId (general procedure).
Hydrazine hydrate, 0.015 mol, was added to a solution
of 0.005 mol of compound Ia–Id in 20 ml of
methanol. The mixture was heated for 3 h under reflux
and was left to stand for 12 h at 20–25°C. The
precipitate was filtered off, washed with water, dried,
and purified by recrystallization.
procedure). Compound IIa–IId, 0.005 mol, was
dissolved in 30 ml of anhydrous acetonitrile, 0.005 mol
of triethylamine and 0.005 mol of benzoyl or 4-
methylbenzoyl chloride were added, and the mixture
was heated for 3 h under reflux and left to stand for
12 h at 20–25°C. The mixture was diluted with 80 ml
of water, and the precipitate was filtered off, dried, and
purified by recrystallization.
2-Aryl-5-arylsulfanyl-1,3-oxazole-4-carbohydrazides
IIe and IIf (general procedure). Hydrazine hydrate,
0.015 mol, was added to a solution of 0.005 mol of com-
pound Ie or If in 20 ml of methanol. The mixture was
heated for 3 h under reflux and was left to stand for 12 h
at 20–25°C. The precipitate was filtered off, washed
with water, dried, and purified by recrystallization.
N′-Aroyl-2-aryl-5-arylsulfanyl-1,3-oxazole-4-carbo-
hydrazides IVg–IVj (general procedure). Compound
IIe or IIf, 0.005 mol, was dissolved in 30 ml of
anhydrous acetonitrile, 0.005 mol of triethylamine and
0.005 mol of benzoyl or 4-methylbenzoyl chloride
were added, and the mixture was heated for 3 h under
reflux and left to stand for 12 h at 20–25°C. The mixture
was diluted with 80 ml of water, and the precipitate was
filtered off, dried, and purified by recrystallization.
1-{[2-Aryl-5-piperidino(or morpholino)-1,3-oxazol-
4-yl]carbonyl}-4-methyl(or phenyl)thiosemicarbazides
IIIa–IIIc (general procedure). A mixture of 0.005 mol
of compound IIa or IId and 0.005 mol of methyl or
phenyl isothiocyanate in 10 ml of anhydrous dioxane
was heated for 3 h under reflux. The mixture was then
left to stand for 12 h at 20–25°C, the solvent was
removed under reduced pressure, and the residue was
treated with water and used in further syntheses
without additional purification. An analytical sample
of compound IIIa was obtained by recrystallization
from ethanol.
3-[2-Aryl-5-piperidino(or morpholino)-1,3-oxazol-
4-yl]-4-methyl(or phenyl)-1,2,4-triazole-5-thiols Va–
Vc (general proocedure). A mixture of 0.004 mol of
compound IIIa–IIIc and 0.008 mol of potassium
hydroxide in 20 ml of water was heated for 3 h at the
boiling point. The mixture was left to stand for 12 h at
20–25°C and acidified with acetic acid to pH ~4–5,
and the precipitate was filtered off, washed with water,
dried, and purified by recrystallization.
5-Aryl-2-[2-aryl-5-piperidino(or morpholino)-
1,3-oxazol-4-yl]-1,3,4-oxadiazoles VIa–VIc (general
procedure). A solution of 0.002 mol of compound
N′-Aroyl-2-aryl-5-piperidino(or
morpholino)-
1,3-oxazole-4-carbohydrazides IVa–IVf (general
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

410
PROKOPENKO et al.
2. Chamberlin, J.W. and Chen, S.J., J. Antibiot., 1977,
IVb–IVe in 5 ml of POCl3 was heated for 6 h under
reflux. The mixture was cooled to 20–25°C and poured
onto ice, and the precipitate was filtered off, dried, and
purified by recrystallization.
vol. 30, no. 3, p. 197.
3. Jansen, R., Kunze, B., Reichenbach, H., Jurkiewicz, E.,
Hunsmann, G., and Höfle, G., Liebigs Ann. Chem.,
1992, no. 4, p. 357.
5-Aryl-2-[2-aryl-5-arylsulfanyl-1,3-oxazol-4-yl]-
1,3,4-oxadiazoles VId–VIg (general procedure). A
solution of 0.002 mol of compound IVg–IVj in 5 ml of
POCl3 was heated for 6 h under reflux. The mixture
was cooled to 20–25°C and poured onto ice, and the
precipitate was filtered off, dried, and purified by
recrystallization.
4. Moody, C.J. and Bagley, M.C., J. Chem. Soc., Perkin
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5. Bertram, A. and Pattenden, G., Synlett, 2001, no. 12,
p. 1873.
6. Oxazoles, Turchi, I.J., Ed., New York: Wiley, 1986.
7. Negwer, M., Organic-Chemical Drugs and Their
Synonyms (An International Survey). Berlin: Akademie,
1994, 7th ed., vols. 1–4.
5-Aryl-2-[2-Aryl-5-piperidino(or morpholino)-
1,3-oxazol-4-yl]-1,3,4-thiadiazoles VIIa–VIIe (general
procedure). A mixture of 0.002 mol of compound
IVb–IVf and 0.003 mol of Lawesson’s reagent in 10 ml
of anhydrous dioxane was heated for 8 h under reflux.
The mixture was kept for 12 h at 20–25°C, the solvent
was removed under reduced pressure, the residue was
treated with a 5% aqueous solution of sodium hyd-
roxide, and the precipitate was filtered off, washed
with water, dried, and purified by recrystallization.
8. Oxazoles: Synthesis, Reactions, and Spectroscopy,
Palmer, D.C., Ed., Hoboken: Wiley, 2003, part A,
p. 255.
9. Shablikin, O.V., Kukharenko, O.P., Jakovenko, I.N.,
Jarmolyuk, S.M., and Brovaretc, V.S., Ukr. Bioorg.
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11. Ilies, M.A., Masereel, B., Rolin, S., Scozzafava, A.,
Campeanu, G., Cimpeanu, V., and Supuran, C.T.,
Bioorg. Med. Chem., 2004, vol. 12, p. 2717.
5-Aryl-2-[2-aryl-5-arylsulfanyl-1,3-oxazol-4-yl]-
1,3,4-thiadiazoles VIIf–VIIi (general procedure). A
mixture of 0.002 mol of compound IVg–IVj and
0.002 mol of Lawesson’s reagent in 10 ml of anhydrous
dioxane was heated for 8 h under reflux. The mixture
was kept for 12 h at 20–25°C, the solvent was removed
under reduced pressure, the residue was treated with a
5% aqueous solution of sodium hydroxide, and the
residue was filtered off, washed with water, dried, and
purified by recrystallization.
12. Matysiak, J. and Opolski, A., Bioorg. Med. Chem.,
2006, vol. 14, p. 4483.
13. Shaban, M.A.E., Nasr, A.Z., and El-Badry, S.M.,
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14. Kaldrikyan,
M.A.,
Grigoryan,
L.A.,
Melik-
Ochandzhanyan, R.G., and Arsenyan, F.G., Khim.-
Farm. Zh., 2009, vol. 43, no. 5, p. 11.
15. Yagisawa, M., Jpn. J. Med. Mycol., 2004, vol. 45, p. 77.
16. Brovarets, V.S., Doctoral (Chem.) Dissertation, Kiev,
3-[2-Aryl-5-piperidino(or morpholino)-1,3-oxazol-
4-yl]-4-methyl(or phenyl)-5-methyl(or ethyl)sulfanyl-
1,2,4-triazoles VIIIa–VIIIe (general procedure). Methyl
or ethyl iodide, 0.002 mol, was added to a solution of
0.002 mol of compound Va–Vc and 0.002 mol of
potassium hydroxide in 10 ml of ethanol. The mixture
was heated for 1 h under reflux and cooled, the solvent
was removed under reduced pressure, the residue was
treated with 80 ml of water, the mixture was kept for
12 h at 20–25°C, and the precipitate was filtered off,
dried, and purified by recrystallization.
1999.
17. Sugihara, I., Uchibayashi, N., Matsuma, K., Nozaki, Y.,
and Ichimori, Y., JPN Patent Appl. no. 341441, 1995;
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