Heterocyclization reaction of chloroacetylenephosphonates with 2-acylamidomalonates into 5-(dialkoxyphosphorylmethylidene)oxazolines

Full text of DOI:10.1134/S1070363212040299

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 4, pp. 776–778. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.A. Khramchikhin, A.V. Dogadina, A.V. Khramchikhin, B.I. Ionin, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82,
No. 4, pp. 694–696.
LETTERS
TO THE EDITOR
Heterocyclization Reaction of Chloroacetylenephosphonates
with 2-Acylamidomalonates into
5-(Dialkoxyphosphorylmethylidene)oxazolines
V. A. Khramchikhin, A. V. Dogadina, A. V. Khramchikhin, and B. I. Ionin
St. Petersburg State Technological Institute, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: borisionin@mail.ru
Received January 23, 2012
DOI: 10.1134/S1070363212040299
Oxazoline structure and its pharmacophore proper-
ties are well known [1]. Generally, oxazoline ring is
formed in the reaction of carbonyl compounds with
iminomalonates [2, 3] and nitriles [4]. Literature and
patent data exist on the synthesis of oxazoline ring
through the heterocyclization of acetylene amides in
the presence of various catalysts [5, 6].
acetamidomalonate residue has two nucleophilic sites,
carbonyl and amine groups of the amide fragment. The
interaction of these sites with an acetylene bond can
lead to the formation of oxazoline or aziridine
structure, respectively. The reaction was shown to give
rise to 2-substituted 4,4-bis(ethoxycarbonyl)-5-(dimeth-
oxyphosphorylidene)-1,3-oxazolines I–V in 80–90%
yields.
There is no information up to date on obtaining
phosphorylated oxazolines, although it can be assumed
that the introduction of the phosphorus-containing
moiety into the oxazoline ring can expand the range of
biological activity of these compounds.
The reaction proceeds quite stereoselectively to
form oxazolines I–V as a mixture of Z,E-isomers in a
ratio of 10:1. In the 1H NMR spectra of the compounds
there are the characteristic doublets of the olefinic
protons: a strong doublet at ~ δ 5.4–5.5 ppm (2ЈHP 7.6 Hz)
of the Z-isomer and a doublet of low intensity in a
weaker field at ~ δ 5.6–5.7 ppm (2ЈHP ~ 5 Hz) of the E-
isomer. The 31P NMR spectra also contain two signals
with an intensity ratio of 10:1 at 15–17 ppm. The
major Z-isomers of oxazolines I–V were isolated by
the recrystallization from a petroleum ether–methylene
chloride mixture. Their configuration (the cis-
arrangement of dimetoxyphosphoryl group and the
oxazoline oxygen atom relative to the exocyclic double
We found that the reaction of dimethyl chloro-
acetylenephosphonate with amidomalonates in anhyd-
rous acetonitrile in the presence of potassium car-
bonate at room temperature results in the new class of
compounds, namely, phosphorylated oxazolines. The
reaction proceeds as a 2-C-alkynylation of amido-
malonates further involving the triple bond of the
assumed intermediate A into the heterocyclization. The
intermediate A formed by the replacement of the
chlorine atom in chloroacetylenephosphonate with
Me
O
Me
O
Me
O
P
O
P
O
P
K2CO3
CO2Et
CO2Et
+
RC(O)NHCH(CO2Et)2
Cl
O
C
(CO2Et)2
CH3CN
O
O
O
NH
O
Me
Me
O
N
Me
R
R
I_V (Z:E 10:1)
A
R = Me (I); Ph (II), p-MePh (III), p-ClPh (IV), p-NO2Ph (V).
776

HETEROCYCLIZATION REACTION OF CHLOROACETYLENEPHOSPHONATES
777
bond) was confirmed by the X-ray analysis of
oxazoline IV (CCDC 847497).
spectrum, δC, ppm: 13.70 (CH3), 52.36 br.s (CH3O),
3
63.23 (OCH2), 84.33 d (C3, JСP 6.5 Hz), 91.36 d (С1,
1JСP 190.9 Hz), 124.63 (ipso-Ph), 126.63 (m-Ph),
128.98 (о-Ph), 133.16 (p-Ph), 161.81 (С2), 164.62
(С=O), 165.26 (C4). 31P NMR spectrum, δP, ppm: 15.1
(Z-isomer), 17.8 (E-isomer).
The 13C NMR spectra of Z-oxazolines I–V contain
the characteristic signals of ethylene carbon atoms: an
intensive doublet at δC 90 ppm with a characteristic
1
large spin-spin coupling constant JCP 180–190 Hz, a
slightly split doublet signal of low intensity of the
second carbon atom at δC 160 ppm, and a signal of the
malonate tetrasubstituted carbon atom in oxazoline
ring at δC 80 ppm with a characteristic constant 3JCP 7–
13 Hz. The signal of the carbon atom of the C=N
fragment in the oxazoline ring is shifted downfield and
appears as a singlet at δC 164 ppm. The spectra of
oxazoline IV taken in a 13C–1H coupling mode and a
DEPT experiment confirm this assignment. The ESI
mass spectrum of oxazoline IV contains a single signal
with m/z 445.37 [M]+.
2-(p-Methylphenyl)-4,4-bis(ethoxycarbonyl)-5-di-
methoxyphosphorylmethylidene-1,3-oxazoline (III)
was obtained similarly from 0.5 g (3 mmol) of di-
methyl chloroacetylenephosphonate, 0.81 g (6 mmol)
of powdered anhydrous potassium carbonate, and 0.61 g
(3 mmol) of diethyl 2-(3-methylbenzamido)malonate.
1
Yield 0.7 g (82%). H NMR spectrum, δ, ppm: Z-
3
isomer, 1.25 t (6H, CH3, JHH 7.0 Hz), 2.3 (3H, CH3),
3
3.74 d (6H, OCH3, JHP 11.0 Hz), 4.26 q (4H, OCH2,
3JHH 7.0 Hz), 5.46 d (1H, CH, 2JHP 7.2 Hz), 7.21 d (2H,
3
3
4
m-Ph, JHH 7.6 Hz), 7.93 d (2H, o-Ph, JHH 7.6, JHH
2.8 Hz); E-isomer, 5.61 d (1H, CH, JHP 5.2 Hz). 13С
2
2-Methyl-4,4-bis(ethoxycarbonyl)-5-dimethoxy-
phosphorylmethylidene-1,3-oxazoline (I). To a mix-
ture of 0.5 g (3 mmol) of dimethyl chloroacetylene-
phosphonate and 0.81 g (6 mmol) of powdered
anhydrous potassium carbonate in 10 ml of anhydrous
acetonitrile was added 0.66 g (3 mmol) of diethyl 2-
acetamidomalonate. The reaction was carried out at
room temperature with vigorous stirring for 16 h. Then
the inorganic precipitate was centrifuged off, and the
solvent was removed in a vacuum. Yield 1.01 g (85%),
viscous dark red liquid. 1H NMR spectrum, δ, ppm: Z-
isomer, 1.1 t (6H, CH3, 3JHH 6.8 Hz), 2.09 s (3H, CH3),
3.56 d (6H, OCH3, 3JHP 11.2 Hz), 4.27 d.q (4H, OCH2,
NMR spectrum, δC, ppm: 13.68 (CH3), 21.49 (CH3),
2
52.32 d (OCH3, JСP 5.4 Hz), 63.16 (OCH2), 84.25 d
3
1
(C3, JСP 9.1 Hz), 92.05 d (С1, JСP 192.3 Hz), 121.82
(ipso-Ph), 128.95 (o-Ph), 129.31 (m-Ph), 144.04 (ipso-
CH3-Ph), 161.95 (С2), 164.69 (C=O), 165.31 (С4). 31P
NMR spectrum, δP, ppm: 14.9 (Z-isomer), 18.1 (E-
isomer).
2-(p-Chlorophenyl)-4,4-bis(ethoxycarbonyl)-5-di-
methoxyphosphorylmethylidene-1,3-oxazoline (II)
was obtained similarly from 0.5 g (3 mmol) of di-
methyl chloroacetylenephosphonate, 0.81 g (6 mmol)
of powdered anhydrous potassium carbonate, and 0.9 g
(3 mmol) of diethyl 2-(4-chlorobenzamido)malonate.
The products were isolated by the recrystallization
2
3JHH 6.8 Hz), 5.22 d (1H, CH, JHP 7.6 Hz); E-isomer,
2
5.32 d (1H, CH, JHP 5.2 Hz). 13С NMR spectrum, δC,
1
ppm: 13.16 (CH3), 13.28 (CH2CH3), 51.89 d (OCH3,
from water. Yield 1.1 g (82%), mp 120°C (water). H
2JСP 5.8 Hz), 62.87 (OCH2), 83.91 d (C3, 3JСP 11.9 Hz),
NMR spectrum, δ, ppm: Z-isomer, 1.31 t (6H, CH3,
1
3
90.73 d (С1, JСP 189.8 Hz), 164.54 (С=O), 166.76
3JHH 7.5 Hz), 3.79 d (6H, OCH3, JHP 11.2 Hz), 4.32 q
(C4). 31P NMR spectrum, δP, ppm: 13.95 (Z-isomer),
17.84 (E-isomer).
and 4.34 q (4H, OCH2), 5.54 d (1H, CH, JHP 6.4 Hz),
2
7.45 d (2H, о-Ph, 3JHH 8.0 Hz), 8.04 d (2H, m-Ph, 3JHH
8.0 Hz). 13С NMR spectrum, δC, ppm: 13.64 (CH3),
2-Phenyl-4,4-bis(ethoxycarbonyl)-5-dimethoxy-
phosphorylmethylidene-1,3-oxazoline (II) was ob-
tained similarly from 0.5 g (3 mmol) of dimethyl chloro-
acetylenephosphonate, 0.81 g (6 mmol) of powdered
anhydrous potassium carbonate, and 0.54 g (3 mmol)
of diethyl 2-benzamidomalonate. Yield 1.1 g (89%).
1H NMR spectrum, δ, ppm: Z-isomer, 1.28 t (6H, CH3,
2
52.33 d (OCH3, JСP 5.5 Hz), 63.22 (OCH2), 84.15 d
3
1
(C3, JСP 13 Hz), 91.67 d (С1, JСP 188.1 Hz), 123.09
(ipso-Ph), 128.97 (m-Ph), 130.66 (o-Ph), 139.66 (ipso-
Cl-Ph), 161.71 d (С2, 2JСP 3.0 Hz), 164.39 (С4), 164.39
(С=O). 31P NMR spectrum, δP, ppm: 14.5 (Z-isomer),
17.9 (E-isomer).
3
3JHH 7.6 Hz), 3.78 d (6H, OCH3, JHP 11.2 Hz), 4.28 q
2-(p-Nitrophenyl)-4,4-bis(ethoxycarbonyl)-5-di-
methoxyphosphorylmethylidene-1,3-oxazoline (II)
was obtained similarly from 0.5 g (3 mmol) of di-
methyl chloroacetylenephosphonate, 0.81 g (6 mmol)
of powdered anhydrous potassium carbonate, and
3
and 4.29 q (4H, OCH2, JHH 7.6 Hz), 5.52 d (1H, CH,
3
2JHP 7.2 Hz), 7.45 t (2H, m-Ph, JHH 7.8 Hz), 7.56 t
(1H, p-Ph, 3JHH 7.8 Hz), 8.08 d (2H, о-Ph, 3JHH 7.8 Hz);
2
E-isomer, 5.67 d (1H, CH, JHP 5.2 Hz). 13С NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

778
KHRAMCHIKHIN et al.
0.64 g (3 mmol) of diethyl 2-(3-nitrobenzamido)malo-
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012