Convenient synthetic approach to (2-aryl-5-phenyl-1,3-oxazol-4-yl) phosphonic acids and their functional derivatives

Article abstract of DOI:10.1007/s11176-005-0265-3

Successive treatment of available amidophenacylating agents of the general formula PhCOCH?ClNHCOAr with trimethyl phosphite and phosphorus pentachloride gave previously unknown (2-aryl-5-phenyl-1,3-oxazol-4-yl) phosphonic dichlorides which are suitable dt

Full text of DOI:10.1007/s11176-005-0265-3

Russian Journal of General Chemistry, Vol. 75, No. 4, 2005, pp. 523 526. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 4, 2005,
pp. 561 564.
Original Russian Text Copyright
2005 by Belyuga, Brovarets, Drach.
Convenient Synthetic Approach
to (2-Aryl-5-phenyl-1,3-oxazol-4-yl)phosphonic Acids
and Their Functional Derivatives
A. G. Belyuga, V. S. Brovarets, and B. S. Drach
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received November 11, 2003
Abstract Successive treatment of available amidophenacylating agents of the general formula PhCOCH
ClNHCOAr with trimethyl phosphite and phosphorus pentachloride gave previously unknown (2-aryl-5-phe-
nyl-1,3-oxazol-4-yl)phosphonic dichlorides which are suitable dtarting materials for preparing other phospho-
rylated oxazoles containing P(O)(OH)2, P(O)(NHAlk)2, P(O)(OMe)NHAlk, P(O)(OMe)NAlk2, and other
groups in the 4 position of the heteroring.
It was previously shown [1 4] that phenylglyoxal
(I) is easily converted to amidophenacylating agents
II and III that found use in the synthesis of various
functionally substituted azoles and azines [4 7]. In the
present work we studied the reaction of reagents III
with trimethyl phosphite, that gave corresponding
Arbuzov rearrangement products IV and synthesized
on their basis a series of novel 4-phosphorylated
oxazoles V XII (see scheme). The most important
proved to be the cyclocondensation of compounds IV
with excess phosphorus pentachloride, resulting in the
synthesis of previously unknown (2-aryl-5-phenyl-1,3-
oxazol-4-yl)phosphonic dichlorides VI in high yields.
The latter exhibited a high reactivity toward various
nucleophilic agents, which allowed us to prepare (2-
aryl-5-phenyl-1,3-oxazol-4-yl)phosphonic acid hydra-
tes VII and other derivatives of these acids VIII XII.
The structures of all the compounds presented in the
scheme were confirmed by their chemical transforma-
tions and IR and 1H NMR spectra (Tables 1 and 2).
phosphorus atom takes up only one methoxy group
that gives a doublet at 3.62 ppm.
Thus, we obtained unambiguous evidence for the
structures of phosphorylated oxazoles V XII.
It is evident that the scope of application of this
synthetic approach to 4-phosphorylated oxazoles is
significantly wider than it is presented in the scheme,
since, apart from phenylglyoxal, some other aryl- and
heterylglyoxals can be involved in such syntheses.
From the other side, amidophenacylating agents can
be prepared from various aliphatic, aromatic, and
heterocyclic carboxamides.
Finally, note that the convenient approach for
introducing variously substituted phosphoryl groups
in the 4 position of the oxazole ring, developed in the
present work, much extends the range of the methods
for preparing 4-phosphorylated oxazoles, based on the
application of chlorine-containing enamides [8 10].
Compounds IV are actually formed by the Arbuzov
rearrangement, because they contain a characteristic
PCHNH fragment, which follows from the observa-
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80
1
1
spectrometer in KBr pellets. The H and 31P NMR
tion in the H NMR spectra of a doubled doublet
methine proton signal at 6.3 6.4 ppm. At the same
time, the involvement of the benzoyl group and amide
residue in the cyclizations of IV into V and VI is
confirmed by the disappearance of two strong bands
at 1690 and 1950 cm 1 from the IR spectra. Moreover,
the transformation V VI is consistent with the dis-
appearance of of the methoxyl proton signal at 3.3
spectra were recorded on a Varian VXR-400 spec-
trometer (300 and 121.42 MHz, respectively) in
(CD3)2SO and CDCl3 solutions against TMS.
Dimethyl (1-acylamino-2-oxo-2-phenylethyl)-
phosphonates IVa and IVb. To a solution of
0.01 mol of compound IIIa or IIIb in 50 ml of
benzene, 0.011 mol of trimethyl phosphite was added.
The resulting mixture was refluxed for 4 h, cooled,
1
3.4 ppm in the H NMR spectrum, whereas in the
course of the transformation of VI XI the
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524
BELYUGA et al.
O
OH
NH
Ar
Cl
H2NC(O)Ar
SOCl2
Ph
Ph
Ph
H
NH
Ar
O
O
O
O
O
I
IIa, IIb
IIIa, IIIb
OMe
OMe
H2O
O=P OMe
N
O=P OMe 1) SOCl2;
2) NaHCO3/H2O
Ph
Ar
Ph
NH
Ar
IVa, IVb
O
O
O
Va, Vb
PCl5 (excess)
PCl5 (excess)
+
Cl
O
H3NCH2Ph
OH
+
H2O
Ar
H3NCH2Ph
O=P Cl
N
O=P O
H2O (excess)
SOCl2 (excess)
O=P OH
N
2H2NCH2Ph
N
Ar
Ph
Ar
Ph
Ph
O
O
O
VIa, VIb
VIIa, VIIb
VIIIa, VIIIb
;
O
1) 2HN
2) H2O
1) 2H2NCH2Ph;
2) MeONa
O
N
AlkNH2 (excess)
NHAlk
NHCH2Ph
O=P NHAlk
N
O=P OMe
O=P OH
N
N
C6H4Me-4
C6H4Me-4
C6H4Me-4
Ph
Ph
Ph
O
IX, X
O
XI
O
XII
Table 1. 1H and 31P NMR spectra of synthesized compounds
, ppm [(CD3)2SO]
3
3
IVa
IVb
3.67 d (3H, CH3O), 3.69 d (3H, CH3O), 6.35 d.d (1H, CH, JHH 9.9, JHP 23.1 Hz), 7.42 8.02 m (10H, 2C6H5),
9.09 (1H, NH, JHH 9.9 Hz)
3
2.37 s (3H, CH3), 3.67 d (3H, CH3O), 3.69 d (3H, CH3O), 6.34 d.d (1H, CH, 3JHH 9.2, 3JHP 21.5 Hz), 7.25 7.99
3
(9H, C6H4, C6H5), 8.93 d (1H, NH, JHH 9.2 Hz);
22.11
Va
3.35 d (3H, CH3O), 7.36 8.41 m (11H, 2C6H5, OH); P 10.20
P
Vb
2.39 s (3H, CH3), 3.35 d (3H, CH3O), 7.33 8.41 m (10H, C6H4, C6H5, OH)
7.53 8.15 m (10H, 2C6H5)
2.43 s (3H, CH3), 7.30 8.09 m (9H, C6H4, C6H5)
VIaa
VIba
VIIb
2.42 s (3H, CH3), 3.64 d (2H, 2HO), 7.34 8.15 (9H, C6H4, C6H5);
6.60
P
VIIIb 2.38 s (3H, CH3), 3.84 s (4H, 2CH2), 7.23 7.38 m (10H, 2C6H5), 7.89 d, 8.28 d (4H, C6H4)
IX
X
2.56 t (6H, 2CH3), 2.40 s (3H, CH3), 2.90 m (4H, 2CH2), 4.51 m (2H, 2NH), 7.38 7.52 m (5H, C6H5), 8.07 d,
8.31 d (4H, C6H4);
13.70
0.83 t (6H, 2CH3), 1.44Pq (4H, 2CH2), 2.42 (3H, CH3), 2.78 m (4H, 2CH2), 4.34 m (2H, 2NH), 7.31 7.47 m (5H,
C6H5), 7.97 d, 8.24 d (4H, C6H4)
XI
2.42 s (3H, CH3), 3.62 d (3H, CH3O), 4.10 m (2H, CH2), 5.85 m (1H, NH), 7.15 7.50 m (10H, 2C6H5), 7.95 d,
8.17 d (4H, C6H4)
XII
2.40 s (3H, CH3), 3.89 br.s [8H, N(CH2)4O], 7.30 7.44 m (5H, C6H5), 7.92 d, 8.13 d (4H, C6H4)
a
In CDCl .
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005

CONVENIENT SYNTHETIC APPROACH
525
Table 2. Constants, yields, and elemental analyses of compounds IV XII
Found, %
Calculated, %
mp, C (solvent for
Formula
crystallization)
N (Cl)
P
N (Cl)
P
IVa
IVb
Vaa
Vbb
VIa
VIb
VIIad
VIIbe
VIIIa
VIIIb
IX
76
82
108 110(methanol)
141 143(methanol)
4.11
4.04
4.03
8.63
8.41
9.17
8.82
9.23
9.00
9.61
9.02
5.87
5.72
8.21
7.57
7.13
8.38
C17H18NO5P
C18H20NO5P
4.03
3.88
4.20
8.92
8.57
9.29
8.92
9.16
8.80
9.70
9.29
6.01
5.84
8.38
7.79
7.20
8.46
73 >340(benzene)
69 >340(benzene)
C16H14NO4P H2O
C17H16NO4P H2O
C15H10Cl2NO2P
C16H12Cl2NO2P
C15H12NO4P H2O
C16H14NO4P H2O
C29H30N3O4P
C30H32N3O4P
C20H24N3O2P
C22H28N3O2P
C25H23N2O3P
3.95
4.03
72c
65c
82
75
79
78
63
76
64
57
94 96(acetonitrile)
(20.05)
(19.55)
4.28
4.05
8.06
(20.97)
(20.13)
4.39
4.20
8.15
97 99(acetonitrile)
268 270(acetonitrile)
180 182(acetonitrile)
171 173f
189 191f
7.88
7.93
151 153(acetonitrile)
144 146(acetonitrile)
140 142(acetonitrile)
201 203(acetonitrile)
10.98
10.71
6.38
11.38
10.57
6.51
X
XI
XII
7.54
C20H24N2O4P
7.65
a
b
Found, %: C 57.45; H 4.82. Calculated, %: C 57.66; H 4.84. Found, %: C 65.56; H 5.15. Calculated, %: C 65.71; H 5.22.
c
d
e
By method a. Found, %: C 56.26; H 4.32. Calculated, %: C 56.43; H 4.42. Found, %: C 57.39; H 4.59. Calculated, %: C 57.66;
f
H 4.84. After washing with THF.
and treated with 10 ml of hexane. The precipitate was
filtered off and recrystallized from methanol.
oxychloride was added. The resulting mixture was
heated for 2 h at 80 C, cooled, and treated with sulfur
dioxide. Volatile compounds were removed in a
vacuum. The residue was treated with 10 ml of an-
hydrous acetonitrile, and the precipitate was filtered
off. The yields of compounds VIa and VIb were
80 90%.
Hydrogen methyl (2-aryl-5-phenyl-1,3-oxazol-
4-yl)phosphonate hydrates Va and Vb. A mixture
of 0.005 mol of compound IVa or IVb and 5 ml of
thionyl chloride was refluxed for 2 h. Excess thionyl
chloride was removed in a vacuum to leave a viscous
oil that was treated with saturated aqueous sodium
bicarbonate for crystallization and then recrystallized
from benzene.
c. A suspension of 0.002 mol of compound VIIa
(see below) and 0.008 mol of thionyl chloride in 5 ml
of benzene was refluxed on an oil bath for 2 h. Vo-
latile compounds were removed in a vacuum, and
compound VIa was isolated as described above, yield
92%.
(2-Aryl-5-phenyl-1,3-oxazol-4-yl)phosphonic
dichlorides VIa and VIb. a. To a suspension of
0.002 mol of compound IVa or IVb in 2 ml of phos-
phorus oxychloride, 0.008 mol of phosphorus penta-
chloride was added. The resulting mixture was heated
for 3 h until gas no longer evolved, and cooled.
Excess phosphorus pentachloride was removed by
treatment with sulfur dioxide, and volatile compounds
were distilled off in a vacuum. The residue was
treated with 10 ml of anhydrous acetonitrile for crys-
tallization. The precipitate was filtered off, and
compounds VIa and VIb were used in further
transformations without additional purification.
Analytically pure samples of compounds VIa and VIb
were obtained by recrystallization from acetonitrile.
(2-Aryl-5-phenyl-1,3-oxazol-4-yl)phosphonic
acid hydrates VIIa and VIIb. Compound VIa or
VIb, 0.002 mol, was added in portions with stirring
over the course of 1 h to 20 ml of water cooled with
ice water. The resulting mixture was left to stand for
24 h at 20 25 C. The precipitate was filtered off and
recrystallized from acetonitrile.
Bis(benzylammonium) (2-aryl-5-phenyl-1,3-
oxazol-4-yl)phosphonates VIIIa and VIIIb. To a
solution of 0.001 mol of acid VIIa or VIIb in 5 ml of
THF, 0.0025 mol of benzylamine was added. The
precipitate was filtered off, washed with THF, and
dried in a vacuum.
b. To a suspension of 0.002 mol of compound Va
or Vb in 15 ml of benzene, 0.005 mol of phosphorus
(5-Phenyl-2-p-tolyl-1,3-oxazol-4-yl)phosphonic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005

526
BELYUGA et al.
dialkylamides IX and X. To a solution of 0.002 mol
of compound VIb in 20 ml of anhydrous dioxane, a
solution of 0.005 mol of ethyl- or propylamine in
10 ml of dioxane was added dropwise with stirring
and cooling with ice water. The resulting mixture was
left to stand for 5 h at 20 25 C. The precipitate was
filtered off and recrystallized.
removed in a vacuum, and compound XII was re-
crystallized.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005