Synthesis of 2,4,5-substituted oxazoles from 2-hydroxyaromatic aldehydes

Full text of DOI:10.1134/S1070428010050350

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 779−780. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.A. Gavrilova, T.A. Frolenko, E.S. Semichenko, G.A. Suboch, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 5, pp. 783−784.
SHORT
COMMUNICATIONS
Synthesis of 2,4,5-substituted Oxazoles
from 2-Hydroxyaromatic Aldehydes
N. A. Gavrilova, O. S. Pozhil’tsova, E. S. Semichenko, and G.A. Suboch
Siberian State Technological University, Krasnoyarsk, 660049 Russia
e-mail: organic@scn.ru
Received June 30, 2009
DOI: 10.1134/S1070428010050350
1
The oxazole ring is contained in the natural alkaloids,
and oxazole derivatives are present in the composition of
pharmaceuticals [1]. The most common method of
2-aryloxazoles synthesis is the cyclocondensation of
2-hydroxyimino-1,3-diketones with aromatic aldehydes
[2]. No oxazole formation from salicylaldehydes is known
up till now; it however would permit the preparation of
oxazoles with a chelate node.
In the H NMR spectra of compounds IVa–IVd
singlets belonging to the methyl group at the oxazole ring
appear at δ 2.33–2.72 ppm. The hydroxy group protons
give rise to broadened singlets at 10.63–12.53 ppm. The
aromatic protons are observed as multiplets in the region
δ 6.94–8.79 ppm. Besided the spectra of compounds IVa
and IVc contain singlet signals of the acetyl group protons
at 2.54 and 2.57 ppm respectively. In the spectra of
compounds IVb and IVd the ethoxy group protons appear
as a triplet (1.42 and 0.92 ppm) and a quartet (4.35 and
3.86 ppm).
We performed a cyclocondensation of 5-bromo-2-
hydroxybenzaldehyde (Ia) with 3-hydroxyiminopentane-
2,4-dione (IIa) and ethyl 2-hydroxyimino-3-oxobutanoate
(IIb) in acetic acid in a flow of gaseous HCl. The obtained
hydrochlorides IIIa and IIIb were reduced with zinc
powder to obtain previously unknown 2-(2-hydroxyaryl)-
5-methyloxazoles IVa and IVb in 60 and 25% yield
respectively. The similar cyclocondensation of compounds
IIa, IIb with 2-hydroxynaphthaldehyde (Ib) in acetic acid
afforded previously unknown 2-(2-hydroxy-1-naphthyl)-
5-methyloxazoles IVc and IVd in 19 and 70% yields
respectively.
The 13C NMR spectra of compounds IVa and IVc
contain the signals of aromatic carbon atoms in the region
δ 111.25–158.87 ppm, and of carbonyl carbons from the
acetyl groups (δ 193.19–193.20 ppm). The signals of the
carbon atoms of the the methyl groups attached to the
oxazole ring are observed at δ 11.92 and 12.03 ppm
respectively. The signals of the carbon atoms of the
oxazole ring appear in the region 133.74–160.03 ppm.
Mass spectra of compounds IVa–IVd contain the
peaks of molecular ions. In the mass spectrum of
compounds IVa and IVb a characteristic distribution is
observed in the peak clusters corresponding to the
The composition and structure of compounds IVa–
IVd were confirmed by the data of mass spectrometry,
1H and 13C NMR spectra.
Cl_
R'
O
O
O
R
Me
R'
R
Me
R'
R
HCl
AcOH
Zn
AcOH
+
NOH
N
+
N
HO
O
H
Me
O
O
O
IIIa_IIId
Ia, Ib
IVa_IVd
IIa, IIb
R = 5-Br-2-OHC6H3 (Ia, IIIa, IIIb, IVa, IVb), 2-hydroxy-1-naphthyl (Ib, IIIc, IIId, IVc, IVd); R' = Me (IIa, IIIa, IIIc, IVa, IVc),
OEt(IIb, IIIb, IIId, IVb, IVd)
779

GAVRILOVA et al.
780
respective bromine-containing ions.
2-(2-Hydroxy-1-naphthyl)-4-carboxy-5-
methyloxazole (IVd). Through a mixture of 3.0 mmol
of ester IIb and 3.3 mmol of aldehyde Ib in 20 ml of
acetic acid cooled to 10°C was bubbled HCl for 2 h. The
mixture was maintained for 24 h at 10°C, and 30 ml of
water was added at this temperature. The product was
extracted into ether (2 × 30 ml). The extract was dried
with Na2SO4 and evaporated. The oily residue of
oxazolium salt IIId was dissolved in 40 ml of acetic acid,
and at stirring 9 mmol of zinc powder was added to the
solution. The reaction mixture was heated at 40°C for 2
h and filtered from impurities. The filtrate was diluted
with 40 ml of water, the separated precipitate was filtered
off and washed with water and ethanol. Yield 0.62 g
(70%). Colorless crystals, mp 244°C (ethanol). 1H NMR
spectrum (CCl4 + TMS), δ, ppm: 0.92 t (3H, CH3,
J 7.5 Hz), 2.33 s (3H, CH3), 3.86 q (2H, CH2, J 6.0 Hz),
6.77 m (2Harom), 6.97 m (1Harom), 7.21 m (2Harom), 8.16
m (1Harom), 11.93 s (1H, OH). Mass spectrum, m/z (Irel,
%): 297 (100) [M] +, 251 (72), 209 (10), 171 (30), 153
(14), 126 (12). Found, %: C 68.60; H 5.00; N 4.73.
C17H15NO4. Calculated, %: C 68.68; H 5.09; N 4.71.
M 297.31.
1H NMR spectra were registered on a spectrometer
Bruker Avance DRX-200 (200 MHz) in the Center of
Collective Use of the Siberian Division of the Russian
Academy of Sciences. The GC-MS analysis was
performed on a gas chromatographAgilent Technologies
6890N equipped with a mass-selective detector Agilent
Technologies 5973, quartz capillary column HP-5MC
(30 m × 0.25 mm, stationary phase 0.33 μm thick);
injector temperature 230°C, detector temperature 270°C;
oven ramp from 70 to 280°C at a rate 15 deg/min; carrier
gas helium, volume of injected sample 1 μl. The detector
operated in the electron impact mode (70 eV) with the
registration of the separated components in extracts with
respect to the total ion current. The reaction progress
was monitored and the purity of compounds obtained was
checked by TLC on Sorbfil plates PTLC-AF-V with UV
indicator, eluent toluene, spots visualized under UV
irradiation.
Oxazoles IVa–IVc. Through a mixture of 3 mmol of
compound IIa, IIb and 3.3 mmol of aldehyde Ia, Ib in
20 ml of acetic acid was bubbled HCl for 2 h at 10°C.
The mixture was maintained for 24 h at 10°C, and 30 ml
of water was added. The precipitated salt of oxazolium
IIIa–IIIc was filtered off and washed with water (30 ml).
The salt was dissolved in 40 ml of acetic acid, and at
stirring 9 mmol of zinc powder was added to the solution.
The reaction mixture was heated at 40°C for 2 h and
filtered from impurities. The filtrate was diluted with 40 ml
of water, the separated precipitate was filtered off and
washed with water and ethanol.
4-Acetyl-2-(5-bromo-2-hydroxyphenyl)-5-
methyloxazole (IVa). Yield 0.53 g (60%). Light-brown
1
crystals, mp 180°C (ethanol). H NMR spectrum
(CD2Cl2), δ, ppm: 2.54 s (3H, CH3), 2.69 s (3H, CH3),
6.95 m (1Harom), 7.45 m (1Harom), 7.91 m (1Harom),
10.70 s (1H, OH). 13C (CD2Cl2), δ, ppm: 11.92, 27.81,
111.25, 112.02, 119.08, 128.34, 133.78, 135.24, 153.87,
156.10, 157.08, 193.20. Mass spectrum, m/z (Irel, %): 297
(97), 295 (100) [M]+, 280 (25), 199 (22), 43 (41). Found,
%: C 48.59; H 3.38; Br 27.50; N 4.65. C12H10BrNO3.
Calculated, %: C 48.67; H 3.40; Br 26.98; N 4.73.
M 296.12
2-(5-Bromo-2-hydroxyphenyl)-4-carboxy-5-
methyloxazole (IVb). Yield 0.25 g (25%). Colorless
1
crystals, mp 170°C (ethanol). H NMR spectrum (CCl4 +
TMS), δ, ppm: 1.42 t (3H, CH3, J 6.3 Hz), 2.72 s (3H,
CH3), 4.35 q (2H, CH2, J 6.9 Hz), 6.94 m (1Harom), 7.84 m
(1Harom), 7.40 m (1Harom), 10.63 s (1H, OH). Mass
spectrum, m/z (Irel, %): 327 (97), 325(100) [M] +, 279
(100), 199 (30), 43 (36). Found, %: C 48.67; H 3.40;
Br 24.98; N 4.73. C13H12BrNO4. Calculated, %: C 47.87;
H 3.71; Br 24.50; N 4.29. M 326.14.
4-Acetyl-2-(2-hydroxy-1-naphthyl)-5-methyl-
oxazole (IVc). Yield 0.15 g (19%). Light-brown crystals,
1
mp 155°C (ethanol). H NMR spectrum (CD2Cl2), δ,
ppm: 2.57 s (3H, CH3), 2.76 s (3H, CH3), 7.25 m (1Harom),
7.43 m (1Harom), 7.60 m (1Harom), 7.83 m (2Harom), 8.79 m
(1Harom), 12.53 s (1H, OH). 13C NMR spectrum
(CD2Cl2), δ, ppm: 12.03, 27.91, 53.44, 102.27, 119.03,
123.81, 128.37, 129.04, 130.28, 132.26, 133.74, 152.78,
158.87, 160.03, 193.19. Mass spectrum, m/z (Irel, %): 267
(100) [M] +, 224 (20), 209 (12), 171 (42), 127 (30), 114
(12), 43 (38). Found, %: C 71.96; H 4.97; N 5.31.
C16H13NO3. Calculated, %: C 71.90; H 4.90; N 5.24.
M 267.28.
REFERENCES
1. Turchi, I.J. and Dewar, J.S., Chem. Rew., 1975, vol. 75, p. 389.
2. Cai, X.-H. and Yang, H.-J., and Zhang, G.-l., Synthesis, 2005,
vol. 10, p. 1569.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010