Synthesis and properties of 2-substituted 5-chloro-1,3-oxazole-4- carboxamides

Article abstract of DOI:10.1134/S1070363214060206

Chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitrile in aqueous acetic acid at 50-60°C afforded new 2-aryl-5-chloro-1,3-oxazole-4- carboxamides. The reactivity of the chlorine atom with respect to the N-, O-, and S-nucleophiles was investiga

Full text of DOI:10.1134/S1070363214060206

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 6, pp. 1186–1189. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.N. Kornienko, S.G. Pil’o, V.M. Prokopenko, V.S. Brovarets, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 6,
pp. 1007–1010.
Synthesis and Properties
of 2-Substituted 5-Chloro-1,3-oxazole-4-carboxamides
A. N. Kornienko, S. G. Pil’o, V. M. Prokopenko, and V. S. Brovarets
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kyiv, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received August 26, 2013
Abstract—Chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitrile in aqueous acetic acid at 50–60°C
afforded new 2-aryl-5-chloro-1,3-oxazole-4-carboxamides. The reactivity of the chlorine atom with respect to
the N-, O-, and S-nucleophiles was investigated.
Keywords: 1,3-oxazole-4-carboxamides, functionalization, reactivity, nucleophiles
DOI: 10.1134/S1070363214060206
In recent decades a significant amount of natural
(Dendroamide A, Nostocyclamide, Madumycin II,
Thiangazole, Tantazol) [1–3] and synthetic [4–7] com-
pounds containing 1,3-oxazole-4-carboxamide moiety
and possessing diverse biological activity were found.
of oxazoles IIa and IIb was performed in aqueous
acetic acid at 50–60°C for 0.5 h. Under these optimal
conditions the chlorination occurred at the position 5
of the oxazole moiety. In addition, the hydrolysis of
the nitrile group into an amide proceeded to form 2-aryl-
5-chloro-1,3-oxazole-4-carboxamides IIIa and IIIb
with 60–64% yields. Product IIIa has been obtained
previously in [15] by a multistage synthesis. The study
of its chemical properties consisted only in the
functionalization of the oxazole ring at the position 4.
We found that the chlorine atom in oxazoles IIIa and
IIIb is labile and could be replaced by a variety of
nucleophiles. Reaction of compounds IIIa and IIIb
with amines or thiophenols in the presence of triethyl-
amine in dioxane under reflux afforded substituted 2-
aryl-5-amino-1,3-oxazole-4-carboxamides IVa–IVd or 2-
aryl-5-arylsulfanyl-1,3-oxazole-4-carboxamides Va–
Vc with 75–80 and 74–85% yields, respectively.
Oxazoles IIIa and IIIb reacted with sodium phenolate
to form 2-aryl-5-aryloxy-1,3-oxazole-4-carboxamides
VIa–VId with 68–72% yields. Compounds IV–VI
were prepared by us for the first time (Scheme 2).
The functionalization of the oxazole fragment is
one of the most efficient approaches to obtain
potentially bioactive substances [8–13]. It has been
shown previously [13] that oxidative chlorination of 2-
aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitriles II,
obtained from available 1-acylamino-2,2-dichloro-
acrylonitriles I [14] afforded target 2-aryl-4-cyano-1,3-
oxazole-5-sulfonyl chlorides along with small amounts
of their 5-chloro derivatives. It was also observed that
the content of the chlorinated product increased as the
reaction temperature increased or when crystallization
of sulfonyl chlorides was performed (Scheme 1).
The present work was aimed to develop a
preparative method for the synthesis of 5-chloro-1,3-
oxazole derivatives in order to use them for obtaining
new representatives of oxazole series. The chlorination
Scheme 1.
H
N
(1) NaSH (excess)
(2) HCl
(3) BnCl/Et3N
CN
CN
N
Ar
Cl
Ar
SBn
O
O
Cl
Ia, Ib
IIa, IIb
1186

SYNTHESIS AND PROPERTIES
1187
Scheme 2.
IIа, IIb
50_60oC
Cl2, MeCOOH, H2O
O
NH2
N
Ar2ONa
R2NH, Et3N
Ar
Cl
IIIa, IIIb
Δ
Δ
O
O
O
Ar1SH, Et3N
Δ
O
NH2
NH2
N
N
Ar
Ar
OAr2
VIa_VId
NH2
SAr1
NR2
IVa_IVd
N
O
O
Ar
O
Va_Vc
Ar = Ph (Ia, IIa, IIIa, IVa, IVc, Va, VIa, VIc), 4-MeC6H4 (Ib, IIb, IIIb, IVb, IVd, Vb, Vc, VIb, VId); Ar1 = 4-MeC6H4
(Va, Vb), 4-ClC6H4 (Vc); Ar2 = Ph (VIa, VIb), 4-MeC6H4 (VIc, VId); R2NH = (CH2)5NH (IVa, IVb), O(CH2)4NH (IVc, IVc).
Composition and structure of derivatives III–VI
were confirmed by elemental analysis, IR, Н NMR
spectroscopy, and chromatography-mass spectrometry
data (Tables 1, 2). The formation of 5-chloro-1,3-
oxazole-4-carboxamides IIIа and IIIb was indicated
by the disappearance of the absorption band of nitrile
group at 2232–2241 cm–1 in the IR spectra [13] and by
the appearance of the absorption bands at 1688–1691
and 3129–3475 cm–1 belonging to C=O and N–Н
1
1
groups, respectively. The Н NMR spectra of the
Table 1. Yields, melting points, and elemental analysis data of compounds III–VI
Found, %
Calculated, %
Comp. Yield,
mp, °С
Formula
no.
%
C
H
N
Cl(S)
15.99
C
H
N
Cl(S)
IIIа
60
187–188 (МеCN) 54.10 3.28 12.30
C10H7ClN2O2
53.95
3.17 12.58 15.92
183 [15]
IIIb 64
181–182 (МеCN) 56.75 3.71 11.65
15.09
C11H9ClN2O2
C15H17N3O2
C16H19N3O2
C14H15N3O3
C15H17N3O3
55.83
66.40
67.35
61.53
62.71
65.79
66.65
3.83 11.84 14.98
IVа
IVb
IVc
IVd
Vа
75
79
79
80
74
85
85
175–176 (EtOH)
174–175 (EtOH)
156–157 (EtOH)
169–170 (EtOH)
165–166 (EtOH)
172–174 (EtOH)
202–203 (EtOH)
66.55 6.57 15.28
67.53 6.93 14.57
61.78 5.67 15.26
63.50 6.03 14.41
–
–
–
–
6.32 15.49
6.71 14.73
5.53 15.38
5.96 14.62
–
–
–
–
65.94 4.71 8.87 (10.37) C17H14N2O2S
4.55
4.97
3.80
9.03 (10.33)
8.64 (9.88)
Vb
66.83 5.14 8.43
59.43 4.00 7.96
(9.81)
C18H16N2O2S
Vc
10.19
(9.35)
C17H13ClN2O2S 59.22
8.12 10.28
(9.30)
VIа
VIb
VIc
VId
70
72
68
72
210–211 (МеCN) 68.65 4.43 9.72
211–212 (МеCN) 69.57 4.81 9.31
211–212 (МеCN) 69.55 4.98 9.33
216–218 (МеCN) 70.28 5.57 8.89
–
–
–
–
C16H12N2O3
C17H14N2O3
C17H14N2O3
C18H16N2O3
68.57
69.38
69.38
70.12
4.32
4.79
4.79
5.23
9.99
9.52
9.52
9.09
–
–
–
–
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1188
KORNIENKO et al.
Table 2. Spectral data of compounds III–VI
Comp.
no.
Mass
spectrum, m/z
IR spectrum, ν, cm–1
1Н NMR spectrum (DMSO-d6), δ, ppm
IIIа
IIIb
IVа
1405, 1605; 1691 (С=О);
3129, 3456 (NН2)
7.59 m, 8.00 m (5НAr), 7.72 s, 7.77 s (2Н, NH2)
223 [M + 1]+
1408, 1498, 1600; 1688
(С=О); 3146, 3467 (NН2)
2.38 s (3Н, СН3), 7.37 d and 7.85 d (4НAr, J 8.0 Hz), 7.70 br.s (2Н, 237 [M + 1]+
NH2)
1.62 br.s (6Н, СН2, piperidine), 3.70 br.s (4Н, СН2, piperidine), 6.98 272 [M + 1]+
s, 7.12 s (2Н, NH2), 7.49 m and 7.88 m (5НAr)
1275, 1448, 1578; 1661
(С=О); 2859, 2942; 3149,
3460 (NН2)
IVb
IVc
IVd
1267, 1450, 1577; 1661
(С=О); 2856, 2940; 3144,
3465 (NН2)
1.60 br.s (6Н, СН2, piperidine), 2.36 s (3Н, СН3), 3.65 br.s (4Н, 286 [M + 1]+
СН2, piperidine), 6.98 s and 7.13 s (2Н, NH2), 7.32 d and 7.76 d
(4НAr, J 7.6 Hz)
3.73 br.s (8Н, 4СН2, morpholine), 7.09 s and 7.20 s (2Н, NH2), 7.50 274 [M + 1]+
m and 7.90 m (5НAr)
1257, 1445, 1580; 1692
(С=О); 2864, 2953; 3150,
3467 (NН2)
1257, 1448, 1579; 1646
(С=О); 2840, 2966; 3165,
3432 (NН2)
2.35 s (3Н, СН3), 3.70 br.s (8Н, 4СН2, morpholine), 7.08 s and 7.20 288 [M + 1]+
s (2Н, NH2), 7.32 d and 7.79 d (4НAr, J 7.6 Hz)
Vа
1384, 1488, 1609; 1684
(С=О); 3108, 3462 (NН2)
2.33 s (3Н, СН3), 7.27 d and 7.46 d (4НAr, J 8 Hz), 7.49 m and 7.88 311 [M + 1]+
m (5НAr), 7.65 s, 7.71 s (2Н, NH2)
Vb
1382, 1495, 1612; 1686
(С=О); 3118, 3463 (NН2)
2.31 s (3Н, СН3), 2.34 s (3Н, СН3), 7.25 d and 7.44 d (4НAr, J 8 Hz), 325 [M + 1]+
7.33 d and 7.73 d (4НAr, J 8 Hz), 7.64 s and 7.67 s (2Н, NH2)
Vc
1386, 1475; 1686 (С=О);
3142, 3446 (NН2)
2.36 s (3Н, СН3), 7.35–7.80 m (10Н, 8НAr, NH2)
346 [M + 1]+
281 [M + 1]+
295 [M + 1]+
VIа
VIb
VIc
VId
1231, 1490, 1644; 1691
(С=О); 3139, 3466 (NН2)
7.24–7.94 m (12Н, 10НAr, NH2)
1441, 1629; 1715 (С=О);
3254, 3465 (NН2)
2.37 s (3Н, СН3), 7.22–7.75 m (11Н, 9НAr, NH2)
1218, 1439, 1627; 1718
(С=О); 3184, 3444 (NН2)
2.33 s (3Н, СН3), 7.10 d, 7.23 d (4НAr, J 8 Hz), 7.53 m and 7.85 m 295 [M + 1]+
(5НAr), 7.76 br.s (2Н, NH2)
2.33 s (3Н, СН3), 2.37 s (3Н, СН3), 7.08 d and 7.23 d (4НAr, J 8 Hz), 309 [M + 1]+
7.33 d and 7.74 d (4НAr, J 8 Hz), 7.68 br.s (2Н, NH2)
1218, 1442, 1630; 1712
(С=О); 3247, 3475 (NН2)
obtained compounds contained two signals (IIIа, IVа–
IVd, Vа, Vb) or one broadened signal (IIIb, VIc,
VId) of the NH2 protons at 6.64–7.77 ppm. In the
spectra of Vc, VIа, VIb these signals overlapped with
the signals of aromatic protons. Mass spectra of com-
pounds III–VI contained the peaks of molecular ions
[M + 1]+.
labile, which was used for preparation of new 5-
amino-, 5-aryloxy- and 5-arylsulfanyl derived 1,3-oxa-
zole-4-carboxamides.
EXPERIMENTAL
IR spectra were recorded on a Vertex 70 spectro-
1
meter from KBr pellets. The H NMR spectra were
taken on a Bruker AVANCE DRX-500 spectrometer
(500 MHz), internal reference TMS. GC-MS spectra
were registered on a HPLC Agilent 1100 Series liquid
chromatography-mass spectrometry system equipped
with a diode array with a mass selective detector
In summary, a new method for the synthesis of 2-
aryl-5-chloro-1,3-oxazole-4-carboxamides based on
chlorination of the available 2-aryl-5-benzylsulfanyl-
1,3-oxazole-4-carbonitriles was developed. It was
found that the chlorine atom in the resulting product is
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

SYNTHESIS AND PROPERTIES
Agilent LC\MSD SL [Zorbax SB-C18 column, 1.18 µm
1189
REFERENCES
4.6Ч15 mm (PN 821975-932); eluent acetonitrile–
water (95 : 5), 0.1% aqueous trifluoroacetic acid;
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atmospheric pressure (APCI), scan range of m/z 80–
1000]. Melting points were measured on a Fisher-
Johns instrument. The reaction progress and
individuality of the obtained compounds were moni-
tored by TLC on Silufol UV-254 plates, eluting with a
chloroform–methanol mixture (9 : 1) and detecting
with UV irradiation. Elemental analysis was performed
in the Institute of Bioorganic Chemistry and Petro-
chemistry, National Academy of Sciences of Ukraine.
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and 0.01 mol of the corresponding sodium phenolate in
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vacuum. The residue was treated with water, filtered
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