Reaction of phenylmalonyl dichloride with 3-phenylpropynamide and transformations of the product by the action of some nucleophiles

Article abstract of DOI:10.1007/s11176-005-0316-9

Phenylmalonyl dichloride reacted with 3-phenylpropynamide to give 4-hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one. Treatment of the latter with hydrazine afforded 3,5-disubstituted 1,2,4-triazole. Reactions of 4-hydroxy-5-phenyl-2-phenylethynyl-6H-

Full text of DOI:10.1007/s11176-005-0316-9

Russian Journal of General Chemistry, Vol. 75, No. 5, 2005, pp. 770 773. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 5, 2005,
pp. 815 819.
Original Russian Text Copyright
2005 by Komarov, Yakovlev, Zakhs, Prep’yalov.
Reaction of Phenylmalonyl Dichloride
with 3-Phenylpropynamide and Transformations of the Product
by the Action of Some Nucleophiles
A. V. Komarov, I. P. Yakovlev, V. E. Zakhs, and A. V. Prep’yalov
St. Petersburg State Chemical and Pharmaceutical Academy, St. Petersburg, Russia
Received November 4, 2003
Abstract Phenylmalonyl dichloride reacted with 3-phenylpropynamide to give 4-hydroxy-5-phenyl-2-
phenylethynyl-6H-1,3-oxazin-6-one. Treatment of the latter with hydrazine afforded 3,5-disubstituted 1,2,4-tri-
azole. Reactions of 4-hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one with methanol and ethanol led
to formation of the corresponding malonamic acid esters. The structure of the products was proved by the
1H and 13C NMR and IR spectra, quantum-chemical calculations (PM3, MNDO, MINDO3), and some
chemical transformations.
Monosubstituted malonyl dichlorides are known to
react with aromatic amides to give 5-substituted 2-
aryl-4-hydroxy-6H-1,3-oxazin-6-ones in good yield
[1 4]. We thought it reasonable to examine reactions
of monosubstituted malonyl dichlorides with unsat-
urated carboxamides with a view to elucidate their
(Scheme 1) and transformations of the product in re-
actions with some nucleophiles (Schemes 2, 3).
3-Phenylpropynamide (I) reacted with phenyl-
malonyl dichloride (II) in refluxing dichloroethane (re-
action time 1 h) to afford 4-hydroxy-5-phenyl-2-
direction and scope. Here we report on the reaction of phenylethynyl-6H-1,3-oxazin-6-one (III) in 73% yield
phenyl malonyl dichloride with 3-phenylpropynamide (Scheme 1, Table 1).
Scheme 1.
O
Cl
OH
O
C
N
O
C C C
+
CH
C
C C
O
NH2
Cl
O
I
II
III
Compound III can exist as four tautomers A D.
Semiempirical quantum-chemical calculations (PM3,
MNDO, MINDO3; HyperChem 3.0 for Windows) of
the electronic structure of possible tautomeric forms
showed that the most energetically favorable tautomer
of oxazine III is structure A. Below are given the
1
energies of formation (kcal mol ) of tautomers A D,
calculated by the PM3, MNDO, and MINDO3 methods.
OH
O
O
O
H
O
O
+
N
N
N
N
H
C C
C C
C C
C C
O
O
O
O
O
OH
A
B
C
D
1070-3632/05/7505-0770 2005 Pleiades Publishing, Inc.

REACTION OF PHENYLMALONYL DICHLORIDE
Table 1. Yields, melting points, Rf values, and elemental analyses of compounds III VII
Found, %
771
Calculated, %
Comp.
no.
Yield,
%
mp,
C
Rfa
Formula
C
H
N
C
H
N
III
IV
V
VI
VII
73
92
84
88
81
222 224
154 156
168 170
162 164
148 150
0.15
0.43
0.72
0.72
0.73
74.8
78.8
71.1
71.7
75.2
3.7
4.9
4.7
5.2
4.3
4.9
16.3
4.3
4.3
4.7
C18H11NO3
C17H13N3
C19H15NO4
C20H17NO4
C19H13NO3
74.8
78.8
71.0
71.7
75.3
3.8
4.8
5.0
4.7
5.1
4.3
16.2
4.4
4.2
4.6
a
Eluent ethyl acetate.
1
Tautomer
PM3
MNDO
MINDO3
In the H NMR spectrum we observed signals from
aromatic protons ( 7.36 7.73 ppm) and proton of the
hydroxy group on C4 ( 13.40 ppm). Crystalline
oxazine III displayed in the IR spectrum absorption
bands at 1750 [ (C=O)], 1600 [ (C=C)], 1540
A
B
C
D
13.1
13.6
20.7
23.1
7.2
3.9
2.1
15.0
54.6
54.1
50.0
48.4
1
[ (C=N)], and 2210 cm [ (C C)].
The results of quantum-chemical calculations are
confirmed by the spectral data. The 13C NMR spec-
trum of 4-hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-
oxazin-6-one (III) in DMSO-d6 contains signals
corresponding to sp2-hybridized carbon atoms in the
benzene ( 118.1 132.7 ppm) and oxazine rings (
The reaction of oxazine III with hydrazine in
methanol at 20 22 C (24 h) gave 92% of 5-benzyl-3-
phenylethynyl-1,2,4-triazole (IV) (Scheme 2, Table 1)
as a result of cleavage of the C2 O bond in the initial
oxazine. Presumably, unstable intermediate triazole
IVa undergoes decarboxylation to final product IV.
C
C
1
97.2, 147.8, 160.0, 164.7 ppm) and sp-hybridized car-
The structure of triazole IV was confirmed by H
bon atoms at the triple bond ( 80.8 and 91.7 ppm).
NMR and IR spectroscopy.
C
Scheme 2.
COOH
CH
CH2
N
N
NH2NH2
NH
C C
IV
III
C C
IVa
NH
CO2
N
N
1
The H NMR spectrum of IV in DMSO-d6 con-
tained signals from protons in the benzene rings (
7.30 7.49 ppm) and methylene protons ( 3.80 ppm).
In the IR spectrum of crystalline triazole IV absorp-
tion bands at 1570 1645 [ (C=C)], 1600 [ (C=N)],
of compounds V and VI in DMSO-d6 contained
signals from sp3-hybridized carbon atoms in the alkyl
groups and PhCH group ( C 13.8 61.2 ppm), aromatic
carbon atoms ( 118.8 132.9 ppm), carbonyl carbon
C
atoms ( 151.6 168.5 ppm), and sp-hybridized carbon
C
1
3310 [ (NH)], and 2220 cm [ (C C)] were present.
atoms at the triple bond ( 82.8 89.3 ppm). In the
C
1H NMR spectra of V and VI, aromatic proton signals
appeared at 7.35 7.65 ppm, signal from the PhCH
proton was located at 5.20 5.21 ppm, alkyl proton
Treatment of 4-hydroxy-5-phenyl-2-phenylethynyl-
6H-1,3-oxazin-6-one (III) with boiling methanol or
ethanol in 0.5 1.0 h resulted in cleavage of the C6 O
bond in the oxazine ring with formation of the cor-
responding esters V and VI (yield 84 and 88%, re-
spectively; Scheme 3, Table 1). The 13C NMR spectra
signals were present at
1.16 4.13 ppm, and the
amide proton signal was observed at
11.89 ppm.
11.86
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

772
KOMAROV et al.
OH
+0.33N
C
C
+0.42
O
O
LUMO: 1.45
0.07
HOMO: 9.02
NH2NH2
0.31
0.31
HOMO 11.14
CH3OH (C2H5OH)
Scheme of interaction between 4-hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one (III) with nucleophiles. Shaded
circles denote contributions of the corresponding AOs to the LUMO of oxazine III and HOMO of hydrazine, methanol, and
ethanol; and the numbers above the circles denote the charges of the corresponding atoms.
Scheme 3.
The direction of the reactions of oxazine III with
hydrazine and alcohols conforms to the results of
calculations of the electronic structure of the reagents,
according to which the reaction of oxazine III with
hydrazine is orbital-controlled while the reaction with
methanol or ethanol is charge-controlled (see figure,
Table 2). Scheme 4 illustrates the mechanisms of re-
actions of oxazine III with nucleophiles.
O
O
O
ROH
C C CNHCCHCOR
C6H5
V, VI
OCH3
N
III
CH2N2
C C
O
EXPERIMENTAL
O
VII
The IR spectra were recorded on a Specord IR-75
spectrometer from samples dispersed in mineral oil.
1
R = CH3, C2H5.
The H and 13C NMR spectra were obtained on a
Bruker AM-500 instrument from solutions in DMSO-
d6. The progress of reactions was monitored by thin-
layer chromatography on Sorbfil plates using ethyl
acetate as eluent.
By reaction of oxazine III with excess diazome-
thane in diethyl ether at 20 22 C (1 h) we obtained
4-methoxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-
6-one (VII) in 81% yield (Scheme 3, Table 1). Com-
pound VII can be regarded as a model of tautomer A.
4-Hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-
oxazin-6-one (III). A mixture of 2.90 g of 3-phenyl-
propynamide (I) and 4.77 g of phenylmalonyl dichlo-
ride (II) in 30 ml of dry 1,2-dichloroethane was
heated for 1 h under reflux. The precipitate was fil-
1
The H and 13C NMR and IR spectra of VII were
fully consistent with the corresponding data for initial
oxazine III, except for signals belonging to the
4-methoxy group ( 3.94 ppm,
55.8 ppm).
C
Table 2. HOMO and LUMO energies, total charges (q) on the carbon atoms in the heteroring, and their orbital coef-
ficients (w) in the LUMO of oxazine III and HOMO and LUMO energies, total charges of atoms (q), and their orbital
coefficients (w) in the HOMO of nucleophiles, calculated by the PM3 method
E, eV
q
w
Compound
HOMO LUMO
C2
C4
C6
Nu
C2
C4
C6
Nu
Oxazine III
Hydrazine
Methanol
Ethanol
8.77
9.02
11.14
11.13
1.45
2.76
3.51
3.36
0.33
0.20
0.42
0.49
0.32
0.05
0.07
0.31
0.31
0.26
0.19
0.10
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005

REACTION OF PHENYLMALONYL DICHLORIDE
773
Scheme 4.
O
H
OH
O
OH
+0.33N
N
N
0.07
R1
R1
Ph + NH2NH2
R1
Ph
Ph
+
O
NH
NH2
O
COOH
CH Ph
O
OH
O
O
NH2
NH2
N
+
R1
NH2
NH
COOH
COOH
CH2 Ph
CH2 Ph
NH
CH Ph
CH Ph
OH
NH
NH
N
N
N
N
N
NH
R1
R1
R1
R1
N
CO2
H2O
N
NH
O
OH
OH
O
O
O
H
N
N
N
0.31
R1
R1
R1
Ph
Ph + R2OH
Ph
R1
C
NH C CH
Ph
C
OR2
+0.42
O
O
OH
+
O
O
R2O
O
O
H
R2
tered off, washed with dichloroethane, and dried.
Yield 4.22 g.
4-Methoxy-5-phenyl-2-phenylethynyl-6H-1,3-
oxazin-6-one (VII). A mixture of 0.29 g of 4-hy-
droxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one
(III) and excess diazomethane in 20 ml of diethyl
ether was stirred for 1 h at room temperature using a
magnetic stirrer. The precipitate was filtered off,
washed with methanol, and dried. Yield 0.25 g.
5-Benzyl-3-phenylethynyl-1,2,4-triazole (IV). A
mixture of 0.29 g of 4-hydroxy-5-phenyl-2-phenyl-
ethynyl-6H-1,3-oxazin-6-one (III) and 0.03 g of hyd-
razine in 20 ml of methanol was stirred for 24 h at
room temperature using a magnetic stirrer. The pre-
cipitate was filtered off, washed with methanol, and
dried. Yield 0.24 g.
REFERENCES
Methyl 3-oxo-2-phenyl-3-(phenylpropynoyl-
amino)propionate (V). A mixture of 0.29 g of 4-hy-
droxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one
(III) in 20 ml of methanol was heated for 0.5 h under
reflux. The precipitate was filtered off, washed with
methanol, and dried. Yield 0.27 g.
1. Ziegler, E. and Meindl, H., Monatsh. Chem., 1964,
vol. 95, nos. 4 5, p. 1318.
2. Yakovlev, I.P., Zakhs, V.E., Prepyalov, A.V., and
Ivin, B.A., Zh. Obshch. Khim., 1994, vol. 64, no. 11,
p. 1825.
Ethyl 3-oxo-2-phenyl-3-(phenylpropynoylami-
no)propionate (VI). A mixture of 0.29 g of 4-hy-
droxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one
(III) in 20 ml of anhydrous ethanol was heated for 1 h
under reflux. The precipitate was filtered off, washed
with methanol, and dried. Yield 0.29 g.
3. Zakhs, V.E., Yakovlev, I.P., and Ivin, B.A., Khim.
Geterotsikl. Soedin., 1987, no. 3, p. 382.
4. Yakovlev, I.P., Zakhs, V.E., Prep’yalov, A.V., and
Rebrov, A.G., Zh. Obshch. Khim., 1996, vol. 66, no. 4,
p. 668.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 5 2005