Reaction of diethyl 1-acylamino-2,2-dichloroethenylphosphonates with amino acids esters

Article abstract of DOI:10.1134/S1070363212040056

Reactions of available diethyl 1-acylamino-2,2-dichloroethenylphosphonates with amino acids esters were studied, which in the case of esters of proline, nipecotic and isonipecotic acids resulted in N-substituted derivatives of 5-amino-4-diethoxyphosphoryl

Full text of DOI:10.1134/S1070363212040056

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 4, pp. 643–651. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © K.M. Kondratyuk, E.I. Lukashuk, A.V. Golovchenko, E.B. Rusanov, V.S. Brovarets, 2012, published in Zhurnal Obshchei Khimii,
2012, Vol. 82, No. 4, pp. 556–565.
Reaction of Diethyl 1-Acylamino-2,2-
dichloroethenylphosphonates with Amino Acids Esters
K. M. Kondratyuka, E. I. Lukashuka, A. V. Golovchenkoa,
E. B. Rusanovb, and V. S. Brovaretsa
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received February 8, 2011
Abstract—Reactions of available diethyl 1-acylamino-2,2-dichloroethenylphosphonates with amino acids esters
were studied, which in the case of esters of proline, nipecotic and isonipecotic acids resulted in N-substituted
derivatives of 5-amino-4-diethoxyphosphoryloxazol in high yields. Their behavior in the acidic and alkaline
media was investigated by the example of methyl N-(4-diethoxyphosphoryl-2-R-oxazol-5-yl)isonipecotinate.
DOI: 10.1134/S1070363212040056
The study of reactions of the available 1-acyl-
amino-2,2-dichlorethenylphosphonates I with amines
(Scheme 1), which usually give rise to 4-phos-
phorylated derivatives of 5-aminooxazol [1–3], was
continued. In order to expand the limits of the reaction,
we examined for the first time some amino acids
(glycine, β-alanine, γ-aminobutyric acid, proline,
nipecotic, and isonipecotic acids), as well as their
esters as the amino function.
When reagent Ib was used, the yields of the target
products IIb and IId decreased. We failed to isolate
these compounds in analytically pure state. They are
significantly contaminated by the incidentally formed
p-toluamide that can be due to the nucleophilic attack
of amino esters mainly on the α-carbon atom of
enamide I [4, 5]. This can be avoided, when an amino
acid with a secondary amino group (proline, nipecotic
and isonipecotic acid) are used. Due to the steric
hindrances, they do not give the products of the attack
on the α-carbon atom (even a trace of the cor-
responding amides were not found in the reaction mix-
ture by the mass spectrometry). However, the reaction
proceeds extremely slowly at 20–25°C (over several
months). The heating leads to the formation of a com-
plex mixture of substances, from which the target
oxazols were not isolated.
The use of amino acids in this reaction as the amine
function causes some difficulties. Thus, the reaction of
reagent I with glycine, β-alanine, or γ-aminobutyric
acid in the presence of a base at 20–25°C in a medium
of the polar protic and aprotic solvents (water,
methanol, ethanol, 2-propanol, acetonitrile, acetone)
do not yield oxazols in the amount sufficient to
isolation and identification. The TLC analysis and
mass spectra of the reaction mixture indicates that the
reaction process is complicated. Similar results were
obtained in the reaction of I with glycine methyl ester
in the presence of potassium carbonate or triethylamine.
The use of the esters of these acids in the oxazol
cyclization gave the best results: 5-amino-4-diethoxy-
phosphoryl-1,3-oxazol derivatives III–IV were formed
in high yields (79–93%). It should be noted that the
heating accelerates the formation of oxazol rings
without significantly reducing the yield. The initial
reactants are consumed completely within 3 h in
boiling methanol. The isolation of oxazols III–IV
should be performed very carefully. For example,
washing out the organic extract from the triethylamine
excess and amino acids esters should be done with
In the case of methyl esters of β-alanine and γ-
aminobutyric acid the oxazols are formed, but there are
some differences depending on the structure of the
starting dichloroenamide I. The reaction with the
compound Ia at room temperature over 3 months gives
rise to products IIa and IIc in good yields (71–79%).
643

644
KONDRATYUK et al.
Scheme 1.
H
HN
C(O)OAlk, Et3N (excess)
HCl H2N
C(O)OMe, Et3N (excess)
R
N
P(O)(OEt)2
n
MeOH, 20_25oC, 3 months
O
MeOH, Δ, 3 h
Cl
Ia, Ib
Cl
C(O)OMe
HCl
HN
, Et3N (excess)
MeOH, Δ, 3 h
P(O)(OEt)2
P(O)(OEt)2
H
P(O)(OEt)2
C(O)OMe
N
N
N
C(O)OAlk
R
N
R
O
R
N
C(O)OMe
n
N
O
O
IVa_IVd
IIa_IId
IIIa, IIIb
R = Me (a, c), 4-MeC6H4 (b, d); n = 2 (IIa, IIb), 3 (IIc, IId);
HN
HN
C(O)OAlk =
HN
C(O)OMe (IVa, IVb),
C(O)OEt (IVc, IVd).
diluted acetic acid, but not hydrochloric acid, as in the
latter case a partial splitting of the oxazol ring occurs.
In addition, it is important to remove acetic acid
completely, since its traces also lead to the destruction
of the oxazol ring at purifying the reaction products.
The 31P NMR spectra of compounds II–IV contain
the signal at 12.14–13.69 ppm. In the 1H NMR spectra
there are all the signals of aromatic and aliphatic
protons with the appropriate ratios of integrated
intensities (Table 2). The IR spectra contain the
absorption bands of C=O group in the range of 1727–
1745 cm–1, as well as the bands of moderate or high
intensity at ν 1603–1680 and 1576–1646 cm–1, which
correspond to the 4-phosphorylated 5-aminooxazol
derivatives [2]. The band of moderate intensity of the
P=O bond lies in the region of 1195–1250 cm–1. The
characteristic absorption bands of the P–O–C fragment
are manifested at ν 1024–1026 and 967–977 cm–1.
From the foregoing it can be concluded that a key
role in the direction of the oxazol ring formation is the
nature of the amino substrate. For example, amino
acids and their esters containing the primary amino
groups form oxazols in low yields or do not lead at all
to their formation, except for oxazols containing alkyl
substituents in a 2 position. However, the amino acids
esters containing a secondary amino group give good
results in the cyclization regardless of the starting
dichloroenamine I structure that can be used for the
preparative production of the N-(4-diethoxyphosphoryl-
2-R-oxazol-5-yl)-substituted amino acids derivatives
and the search among them the for biologically active
compounds [6, 7].
The mass spectra of compounds II–IV are not
always informative, as they contain an additional peak
with m/z [M + 19]+ corresponding to the product of the
oxazol ring cleavage.
Further transformations of the oxazol derivatives
were studied by the example of compounds IVa and
IVb. Owing to the stability of the oxazol ring in an
alkaline medium, the stepwise hydrolysis of the ester
and diethoxyphosphoryl groups was carried out under
the action of sodium hydroxide. Thus, the use of
1 equivalent of NaOH followed by the acidification
with acetic acid leads only to the ester group
Compounds II–IV are stable oily substances
soluble in almost all organic solvents and partially
soluble in water. They are stored at room temperature
for a long time without changing.
The yields, physicochemical constants, and elemental
analysis data are given in Table 1.
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REACTION OF DIETHYL 1-ACYLAMINO-2,2-DICHLOROETHENYLPHOSPHONATES
645
Table 1. Yields, physicochemical constants, and elemental analysis data of compounds II–X
Found, %
Calculated, %
Yield,
%
mp, °С
(solvent for purification)
Comp. no
Formula
N
P
N
P
79
71
88
87
88
79
85
93
38
46
50
95
66
93
92
79
Oil (hexane)
8.54
8.09
7.89
6.46
7.59
6.30
7.29
5.98
8.01
6.55
6.97
7.51
6.18
7.21
5.89
7.05
9.86
9.44
9.17
7.55
8.81
7.33
8.43
7.02
9.14
7.60
8.12
8.72
7.21
8.33
7.03
8.24
C12H21N2O6P
C13H23N2O6P
C14H23N2O6P
C20H27N2O6P
C15H25N2O6P
C21H29N2O6P
C16H27N2O6P
C22H31N2O6P
C14H23N2O6P
C20H27N2O6P
C18H23N2O6P
C14H25N2O7P
C20H29N2O7P
C15H27N2O7P
C21H31N2O7P
C16H21N2O7P
8.75
8.38
8.09
6.63
7.77
6.42
7.48
6.22
8.09
6.63
7.10
7.69
6.36
7.40
6.16
7.29
9.67
9.27
8.94
7.33
8.60
7.10
8.27
6.88
8.94
7.33
7.85
8.50
7.03
8.19
6.82
8.06
IIа
Oil (hexane)
IIc
Oil (petroleum ether)
Oil (petroleum ether)
Oil (hexane)
IIIа
IIIb
IVа
IVb
IVc
IVd
Vа
Oil (hexane)
Oil (hexane)
Oil (hexane)
62–70а
162–163а
Vb
133–134 (2-propanol)
131–132b
137–138b
VIb
VIIа
VIIb
VIIIа
VIIIb
Xb
99–100 (petroleum ether)
45–60 (petroleum ether)
106–107b
a Without additional purification. b After washing with acetone.
Table 2. Spectral data of compounds II–X
31P NMR
spectrum,
δP, ppmb
13.19
Comp.
no
Mass spectrum,
IR spectrum, ν, cm–1 а
1Н and 13С NMR spectra, δ, ppm b
m/z, [M + 1]+
3406 (N–H), 1736 (C=O), 1678, 1.32 t (6H, CH3CH2O), 2.34 s (3H, CH3), 2.62 m (2Н,
1641, 1599 (oxazol), 1249 (Р=О), СН2), 3.57 m (2Н, СН2), 3.71 s (3Н, СН3О), 3.98–4.17 m
321
ІІа
1026 (Р–О–С), 977 (Р–О–С–С)
(4Н, CH3CH2O), 6.09 br.m (1Н, NH)
ІІbc
–
1.34 t (6H, CH3CH2O), 2.38 s (3H, CH3), 2.68 m (2Н,
13.01
397
СН2), 3.65–3.74
m (5Н, СН2, СН3О), 4.12 (4Н,
CH3CH2O), 6.29 br.t (1Н, NH), 7.23 d, 7.79 d (4Н, С6Н4,
3JHH 8.0 Hz )
3356 (N–H), 1734 (C=O), 1678, 1.32 t (6H, CH3CH2O), 1.92 m (2Н, СН2), 2.34 s (3H,
1628, 1588 (oxazol), 1195 (Р=О), CH3), 2.41 m (2Н, СН2), 3.33 m (2Н, СН2), 3.69 s (3Н,
13.52
13.69
335
411
ІІc
1025 (Р–О–С), 972 (Р–О–С–С)
СН3О), 4.10 m (4Н, CH3CH2O), 6.18 br.s (1Н, NH)
ІІdc
–
1.35 t (6H, CH3CH2O), 1.99 m (2Н, СН2), 2.39 s (3H,
CH3), 2.46 m (2Н, СН2), 3.46 m (2Н, СН2), 3.69 s (3Н,
СН3О), 4.13 m (4Н, CH3CH2O), 6.15 br.t (1Н, NH), 7.22
d and 7.79 d (4Н, С6Н4, 3JHH 8.0 Hz)
1745 (C=O), 1633, 1588 (oxazol), 1.32 m (6H, CH3CH2O), 1.97 m (2Н, СН2), 2.06–2.31 m
1214 (Р=О), 1026 (P–O–C), 967 (5H, CH3, СН2), 3.68–3.83 m (5Н, СН2, СН3О), 4.12 m
12.89
12.80
347
423
IIIa
(Р–О–С–С)
(4Н, 2CH3CH2O), 4.86 m (1Н, СН)
1744 (C=O), 1607, 1583 (oxazol), 1.36 m (6H, 2CH3CH2O), 2.05 m (2Н, СН2), 2.15–2.41 m
1214 (Р=О), 1025 (P–O–C), 969 (5H, CH2, СН3), 3.75 s (3Н, СН3О), 3.80–3.95 m (2Н,
IIIb
(Р–О–С–С)
СН2), 4.20 m (4Н, CH3CH2O), 4.92 m (1Н, CН), 7.25 d
and 7.74 d (4Н, С6Н4, 3JHH 7.6 Hz)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

646
KONDRATYUK et al.
Table 2. (Contd.)
31P NMR
spectrum,
δP, ppmb
Comp.
no
Mass spectrum,
IR spectrum, ν, cm–1 а
1Н and 13С NMR spectra, δ, ppm b
m/z, [M + 1]+
1732 (C=O), 1627, 1580 (oxazol), 1.33 t (6H, CH3CH2O), 1.78 m (2Н, СН2), 1.94 m (2Н,
1231 (Р=О), 1026 (P–O–C), 969 СН2), 2.30 s (3H, CH3), 2.48 m (1Н, CН), 3.10 m (2Н,
12.47
12.57
12.37
12.14
361
437
375
451
IVа
(Р–О–С–С)
СН2), 3.68 s (3Н, СН3О), 3.96 m (2Н, СН2), 4.10 m (4Н,
CH3CH2O)
1732 (C=O), 1604, 1576 (oxazol), 1.36 t (6H, CH3CH2O), 1.88 m (2Н, СН2), 2.03 m (2Н,
1235 (Р=О), 1025 (P–O–C), 970 СН2), 2.37 s (3H, CH3), 2.54 m (1Н, CН), 3.22 m (2Н,
IVb
IVc
IVd
(Р–О–С–С)
СН2), 3.70 s (3Н, СН3О), 4.11 m (2Н, СН2), 4.18 m (4Н,
CH3CH2O), 7.20 d, 7.78 d (4Н, С6Н4, 3JHH 8.0 Hz)
1727 (C=O), 1680, 1646 (oxazol), 1.25 t (3H, CH3CH2O), 1.34 t (6H, CH3CH2O), 1.65 m
1250 (Р=О), 1024 (P–O–C), 977 (2Н, СН2), 1.78 m and 2.08 m (2Н, СН2), 2.32 s (3H,
(Р–О–С–С)
CH3), 2.62 m (1Н, CН), 3.08 m and 3.21 m (2Н, СН2),
3.88 m and 4.01 m (2Н, СН2), 4.13 m (6Н, CH3CH2O)
1727 (C=O), 1603, 1577 (oxazol), 1.27 t (3H, CH3CH2O), 1.38 t (6H, CH3CH2O), 1.72 m
1242 (Р=О), 1026 (P–O–C), 968 (2Н, СН2), 1.84 m and 2.13 m (2Н, СН2), 2.39 s (3H,
(Р–О–С–С)
CH3), 2.70 m (1Н, CН), 3.20 m and 3.34 m (2Н, СН2),
4.02 m and 4.18 m (8Н, CH3CH2O, СН2), 7.21 d and 7.80
d (4Н, С6Н4, 3JHH 8.0 Hz)
1712 (C=O), 1630, 1582 (oxazol), 1.34 t (6H, CH3CH2O), 1.84 m (2Н, СН2), 1.98 m (2Н,
1174 (Р=О), 1026 (P–O–C), 972 СН2), 2.32 s (3H, CH3), 2.50 m (1Н, CН), 3.11 m (2Н,
(Р–О–С–С)
12.34
12.47
347
423
Vа
СН2), 3.93 m (2Н, СН2), 4.13 m (4Н, CH3CH2O)d
1715 (C=O), 1609, 1584 (oxazol), 1.37 t (6H, CH3CH2O), 1.92 m (2Н, СН2), 2.06 m (2Н,
1194 (Р=О), 1014 (P–O–C), 961 СН2), 2.38 s (3H, CH3), 2.55 m (1Н, CН), 3.23 m (2Н,
Vb
(Р–О–С–С)
СН2), 4.07 m (2Н, СН2), 4.20 m (4Н, CH3CH2O), 7.21 d
and 7.78 d (4Н, С6Н4)d; δС: 14.9 (СН2СН3), 19.9 (CH3),
26.3 [(CH2)2CH], 38.6 (CH), 46.5 [N(CH2)2], 60.9
1
(OCH2), 101.0 d (СР, JCP 252 Hz), 123.3, 124.6, 129.1,
139.2 (C6H4), 150.6, 160.4 (oxazol), 175.3 (СООН)
1720 (C=O), 1613e (oxazol), 1239 1.23 t (3H, CH3CH2O), 1.63 m (2Н, СН2), 1.90 m (2Н,
(Р=О), 1040 (P–O–C), 957 СН2), 2.35 s (3H, CH3), 3.15 m (2Н, СН2), 3.78 m (1Н,
8.50
395
VIb
(Р–О–С–С)
CН), 3.95 m (2Н, CH3CH2O), 4.03 m (2Н, СН2), 7.29 d,
7.73 d (4Н, С6Н4)d
3411 (N–H), 1713 (C=O), 1681 1.22 m (6H, CH3CH2O), 1.31–1.70 m (2Н, СН2), 1.83 m 17.71, 17.74
(C=O), 1646 (C=O), 1206 (Р=О), (2Н, СН2), 1.91 s (3H, CH3); 2.80 m, 3.15 m, 3.44 m,
VIIа
1024 (Р–О–С), 957 (Р–О–С–С)
3.88 m, 4.21 m (5H, CH2, CH), 4.04 m (4Н, CH3CH2O),
5.46 m (1Н, CНP), 8.45 m (1Н, NН)d; δС: 14.6 (СН2СН3),
21.1 (СН3); 26.0, 26.5, 38.7, 40.6, 44.5 (СН2, СНСО),
1
46.0 d (CHP, JCP 150 Hz), 62.5 (OCH2CH3); 163.5,
169.2, 176.0 (CON, CONH, COO)
3337 (N–H), 1722 (C=O), 1631e 1.30 m (6H, CH3CH2O), 1.73 m and 2.00 m (4Н, СН2), 16.48, 16.92
(2C=O), 1232 (Р=О), 1022 2.40 s (3H, CH3); 2.57 m, 3.03 m, 3.32 m (3H, CH2, CH),
441
379
VIIb
(Р–О–С), 978 (Р–О–С–С)
3.99–4.36 m (6Н, CH3CH2O, CH2), 4.77 br.m (1Н, NН),
5.80 m (1Н, CНP), 7.21–7.79 m (4Н, С6Н4)d; δС: 14.7
(СН2СН3); 19.9 (СН3); 25.9, 26.5, 38.7, 40.6, 44.4 (СН2,
1
СНСО), 46.7 d (CHP, JCP 150 Hz), 62.6 (OCH2CH3);
126.4, 128.3, 129.5, 141.7 (C6H4); 163.3, 165.9, 176.3
(CON, CONH, COO)
3310 (N–H), 1734 (C=O), 1677 1.31 m (6H, CH3CH2O), 1.68 m (2Н, СН2), 1.97 m (2Н, 16.73, 16.74
(C=O), 1631 (C=O), 1255 (Р=О), СН2), 1.82–2.06 m (5H, CH3, СН2), 2.50–3.31 m (3H,
VIIIа
1026 (Р–О–С), 980 (Р–О–С–С)
CH2, CH), 3.68 s (3Н, CH3O), 3.95–4.42 m (6Н,
CH3CH2O, CH2), 5.53 m (1Н, CНP), 6.68 m (1Н, NН);
δС: 14.7 (СН2СН3), 21.4 (СН3); 26.0, 26.5, 39.0, 40.5,
1
44.4 (СН2, СНСО), 46.2 d (CHP, JCP 148 Hz), 50.4
(OCH3), 62.2 (OCH2CH3); 163.2, 168.4, 173.6 (CON,
CONH, COO)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

REACTION OF DIETHYL 1-ACYLAMINO-2,2-DICHLOROETHENYLPHOSPHONATES
Table 2. (Contd.)
647
31P NMR
spectrum,
δP, ppmb
Comp.
no
Mass spectrum,
IR spectrum, ν, cm–1 а
1Н and 13С NMR spectra, δ, ppm b
m/z, [M + 1]+
3413 (N–H), 1732 (C=O), 1645e 1.31 m (6H, CH3CH2O); 1.72 m, 2.02 m (4Н, СН2), 2.40 s
(2C=O), 1247 (Р=О), 1022 (3H, CH3), 2.50–4.45 m (9Н, CH3CH2O, CH2, CH), 3.69
16.62
455
VIIIb
(Р–О–С), 978 (Р–О–С–С)
s (3Н, CH3O), 5.74 m (1Н, CНP), 7.24 d and 7.73 d (4Н,
С6Н4, 3JHH 7.1 Hz), 7.31 m (1Н, NН); δС: 14.7 (СН2СН3),
19.9 (СН3); 26.0, 26.5, 39.0, 40.6, 44.4 (СН2, СНСО),
1
46.6
d
(CHP, JCP 148 Hz), 50.4 (OCH3), 62.3
(OCH2CH3); 126.3, 128.3, 129.6, 141.6 (C6H4); 163.4,
165.6, 173.6 (CON, CONH, COO)
2500–3500 (N–H), (О–H), 1716 1.71 m (2Н, СН2), 2.07 m (2Н, СН2), 2.31 s (3H, CH3),
(C=O), 1613 (2C=O), 1190 (Р=О) 2.65 m (1Н, CН), 2.98 m (2Н, СН2), 3.33 m (2Н, СН2),
9.29
385
Хb
2
4.81 d (1Н, CНP, JHP 21.3 Hz), 7.28 d and 7.67 d (4Н,
С6Н4, 3JHH 8.1 Hz)
a
IR spectra of compounds IIа, IIc, ІІІа, IIIb, IVа–IVd, Vа, VIIа, VIIIb were recorded in CH2Cl2, of compounds Vb, VIb, VIIb, VIIIа,
from KBr pellets. b CDCl3 (IIа–IId, IIIа, IIIb, IVа–IVd, Va, Vb, VIIb, VIIIa, VIIIb); DMSО-d6 (VIb, VIIa); D2O (Хb). c The spectra
of compounds IIb and IId are extracted from a spectrum of the mixture. d In the 1Н NMR spectrum the ОН proton was not observed. e
A
broad band with a shoulder.
hydrolysis to form compounds Va and Vb, which is
of compounds IV and V under similar conditions
1
clearly seen in the H and 31P NMR spectra (Table 2).
results not only in the oxazol ring opening, but in the
partial hydrolysis of phosphoryl group to form a
mixture of phosphonic acids IX and X, which was
proved by the mass spectrometry. For example, in the
case of the ring opening of oxazol VIa there are two
signals with m/z 337 and 309 corresponding to the
acids IXa and Xa, respectively. For compound VIb we
also examined the hydrolysis dynamics at 75°C in an
acetic acid–water mixture (5:1). The experimental
results are presented in Table 4. The oxazol ring
opening occurs rapidly enough, the resulting dia-
stereomers mixture of compound IXb (δР 9.76 and
9.96 ppm, 3:2) is gradually transformed into product
Xb (δР 9.29 ppm). The diastereomers ratio of IXb in
the reaction mixture does not change, and the complete
conversion IXb → Xb occurs within 30 h. Note that
the attempts to isolate compound IXb in a pure form
were unsuccessful. When changing the reaction
conditions (time, temperature, solvent), the oxazol ring
opening does not occur or a mixture of compounds
IXb and Xb is formed, which we failed to separate by
the conventional methods. The ease of the oxazol ring
opening and hydrolysis of phosphoryl ethyl fragment of
VI indicates the effect of a strong acidic P(OH) group
(pKa ~ 1.67 in H2O [10]) on the process. Thus, in a
DMSO solution at 75°C, even in the absence of acetic
acid, the transformation of the oxazol ring of compound
VI is completed in ~ 1.5 h. Under the same conditions
compounds IV and V are stable.
The treatment of compounds IVa and IVb with a four-
fold excess of an alcoholic solution of sodium
hydroxide over 10 days at room temperature causes
deeper saponification to give sodium salts VI. Only
acid VIb was isolated in a free state by the gentle
acidification with 10% hydrochloric acid. The isolation
of acid VIa is difficult, since the acidifying even with
a very dilute (1%) hydrochloric acid causes the
opening of the oxazol ring to form compound IXa [8,
9] and the products of deeper hydrolysis. The cleavage
of amino oxazols with an alcoholic solution of
hydrogen chloride leads to the formation of a complex
mixture of substances. One of the identified com-
pounds is the isonipecotinate hydrochloride. A similar
pattern was observed when using glacial acetic acid.
This prompted us to investigate the behavior of
oxazols IV–VI under milder conditions. Thus,
compounds IV and V were easily decomposed by the
heating in an aqueous acetic acid to form the
phosphorylated pseudopeptides VІI and VІІI. We
monitored the dynamics of the cyclic products
transformation into acyclic compounds at 75°C in an
acetic acid–water mixture (5:1) by the example of VIb
using the 31P NMR spectroscopy. The results presented
in Table 3 show that after 7 h under the experimental
conditions a complete transformation occurs of the
oxazol rings into the acyclic product VІІIb.
A more complicated picture is observed under the
action of acetic acid on oxazols VI. Thus, the reaction
The structure of compounds shown in scheme 2 is
proved by the spectral data (Table 2). Thus, the
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648
KONDRATYUK et al.
Scheme 2.
P(O)(OEt)2
N
1 eq NaOH/H2O
20_25oC, 30 h
4 eq NaOH/EtOH
20_25oC, 10 days
R
N
O
C(O)OMe
IVa, IVb
P(O)(OEt)OH
P(O)(OEt)2
N
N
AcOH/H2O
75oC, 7 h
R
N
R
N
O
O
C(O)OH
C(O)OH
O
VIa, VIb
Va, Vb
R
P(O)(OEt)2
N
AcOH/H2O
75oC, 7 h
N
C(O)OMe
H
O
O
VIIIa, VIIIb
AcOH/H2O
75oC, 30 h
R
P(O)(OEt)2
N
N
C(O)OH
H
O
VIIa, VIIb
O
O
R
N
P(O)(OEt)OH
N
R
P(O)(OH)2
N
N
C(O)OH
C(O)OH
H
H
O
O
Хa, Xb
IХa, IXb
R = Me (a), 4-MeC6H4 (b).
presence of PCHNH moiety in the cleavage products
geometry of the fragment is common enough for this
type compounds.
VII, VIII, and X is consistent with the signals
1
The N1N2 nitrogen atoms have a planar trigonal
environment, and the sum of bond angles of these
atoms is 360°, while the C2N1 and C3N2 bonds are
significantly shortened [to 1.333(4) and 1.333(4) Å,
respectively] compared with the standard value of the
single C–N bond (1.45 Å). It indicates the effective
conjugation of the unshared electron pair of the
nitrogen atom with the π-system of carbonyl groups.
The piperidine ring has a regular geometry and is in a
chair conformation. No other special features was found
in the structure of the molecule of compound VI.
assignment in the H NMR spectra in the range of
5.46–5.80 (CH) and 4.77–8.45 ppm (NH) [11–13]. In
the IR spectra of these compounds the intensive
absorption bands were found of C=O and P=O groups
at 1613–1734 and 1190–1247 cm–1, respectively.
The structure of one of the cleavage products VIIIa
was proved by the XRD analysis. The general view of
the VIIIa molecule and its main geometrical param-
eters are shown in the figure. The bond lengths in the
compound studied are close to the values in the related
compounds containing a similar (MeO)2P(=O)CH·
(NRCOPh)COOMe moiety [14]. The P–C bond in the
compound investigated by us is slightly shortened (P–C
1.859, P=O 1.463, P–Oav 1.575 Å). In general, the
The previous studies of the antiradical activity of
the synthesized compounds, which were performed in
the Zaporizhia National University, showed that oxazols
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REACTION OF DIETHYL 1-ACYLAMINO-2,2-DICHLOROETHENYLPHOSPHONATES
649
Table 3. Dynamics of IVb → VIIIb transformation at 75°С
in an acetic acid–water mixture (5:1)
Table 4. Dynamics of VIb → IXb → Xb transformation at
75°С in an acetic acid–water mixture (5:1)
Molar ratio, %
Molar ratio, %
Reaction time, h
Reaction time, h
IVb
VIIIb
VIb
IХb
Хb
0
100
0
0
100
0
0
0.5
1.0
18
0
60
85
70
60
45
30
25
0
22
15
30
40
55
70
75
0.5
1.0
2.0
3.5
5.0
7.0
84
75
23
7
16
25
2.0
0
77
3.0
0
4.5
0
93
8.0
0
3
97
10.0
30.0
0
0
100
0
100
IV have a significant effect on the reaction rate of
adrenalin autoxidation, which is associated with the
inhibition of reactive oxygen species [15]. The results
of the acute toxicity determination of compound IVa
show that this class of substances is nontoxic (LD50
1.200 mg kg–1) [16], which makes these compounds
promising to the search for bioregulators among them.
–100°C on a Bruker Smart Apex II diffractometer
(λMoKα-radiation, graphite monochromator, θmax
26.48°, sphere segment –10 ≤ h ≤ 10 , –10 ≤ k ≤ 12,
–15 ≤ l ≤ 14). 14 302 reflections were collected, of
which 3991 were independent (R-factor 0.0476). The
crystals of compound VIIIa are triclinic, C15H27N2O7P,
M 378.36, space group Р–1, а 8.6163(3), b 10.0939(4),
c 12.5698(6) Å, α 66.521(2), β 75.917(3), γ 81.608(2)°;
V 971.10(7) Å3, Z 2, dcalc 1.294, μ 0.178 mm–1, F(000)
404. The structure was solved by the direct method and
refined by a least-squares method in a full-matrix
anisotropic approximation using a SHELXS97 and
SHELXL97 software [17, 18]. The correction for
extinction was done using a SADABS software by a
multiscanning method (Tmin/Tmax = 0.595083). The
EXPERIMENTAL
The NMR spectra were obtained on a Bruker
Avance DRX-500 and Varian Unityplus-400 instru-
ments [1H (500 MHz and 400 MHz), 31P (202 MHz),
13C (125 MHz)] in a solution of DMSO-d6, CDCl3 or
D2O relative to internal TMS or external 85% phos-
phoric acid. The IR spectra were recorded on a Vertex
70 spectrometer from KBr pellets or dichloromethane
solution. The melting points were determined on a
Fisher Johns instrument. The chromato-mass spectra
were recorded on an Agilent 1100 Series high
performance liquid chromatograph equipped with a
diode matrix with an Agilent LC\MSD SL mass
selective detector allowing a fast switching the
ionization modes positive/negative. The chromato-
mass spectral analysis parameters: column Zorbax SB-
C18 1.8 μm, 4.6×15 mm (PN 821975-932); solvents:
A, acetonitrile–water mixture (95:5), 0.1% trifluoro-
acetic acid, B, 0.1% aqueous trifluoroacetic acid;
eluent flow 3 ml min–1, injection volume 1 μl, UV
detectors 215, 254, 285 nm; the ionization method is
atmospheric-pressure chemical ionization (APCI),
scanning range m/z 80–1000. The reaction progress
was monitored by the TLC method.
General view of the molecule of VIIIa. Some bonds
lengths (Å) and bond angles (deg): P1–O1 1.454(2), P1–O2
1.562(3), P1–O3 1.565(2), P1–C1 1.815(3), C1–C2 1.530(4),
C1–N2 1.443(3), C2–N1 1.333(4), N2–C3 1.333(4); O1P1C1
114.13(13), O2P1C1 105.36(14), O3P1C1 101.50(12),
N2C1C2 111.5(2), N2C1P1 110.40(19), C2C1P1 110.49(19).
The X-ray diffraction study on a single-crystal of
VIIIa of 0.10×0.12×0.40 mm size was performed at
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 4 2012

650
KONDRATYUK et al.
hydrogen atoms were located geometrically. In the
refinement 2443 reflections with I > 2σ(I) were used
(231 refined parameter), the number of reflections per
a parameter is 10.57, the used weight scheme is ω = 1/
[σ2(Fo2) + (0.0727Р)2 + 0.404Р], where Р = (Fo2 +
2Fc2)/3, the ratio of the maximal (average) shift to the
error in a last cycle is 0.016(0.002). The final diver-
gence factors are R1(F) 0.0627, wR2(F2) 0.1532 for the
reflections with I > 2σ(I), R1(F) 0.1085, wR2(F2)
0.1775, GOF 1.115 for all independent reflections. The
residual electron density of the difference Fourier
series after the last refinement cycle is 0.61 and
–0.42 e Å–3. A complete set of the X-ray diffraction
data for compound VIIIa was deposited in the
Cambridge Structural Database (CCDC 798674).
decanting. The combined ether extracts were
evaporated to dryness at a reduced pressure. The
products are colorless or light yellow viscous oils.
Methyl N-[4-(diethoxyphosphoryl)-2-methyl-(4-
methylphenyl)-1,3-oxazol-5-yl]isonipecotinates
(IVa, IVb) were obtained similarly to compounds III
from enamides I and methyl isonipecotinate.
Ethyl
N-[4-(diethoxyphosphoryl)-2-methyl-(4-
methylphenyl)-1,3-oxazol-5-yl]nipecotinates (IVc,
IVd) were obtained similarly to compounds III from
enamides I and ethyl nipecotinate.
1-[4-(Diethoxyphosphoryl)-2-methyl-(4-methyl-
henyl)-1,3-oxazol-5-yl]piperidin-4-ylcarboxylic
acids (Va, Vb). To a solution of 0.01 mol of
compound IV in 5 ml of ethanol was added a solution
of 0.01 mol of sodium hydroxide in 100 ml of water.
The mixture was stirred for 24–30 h at 20–25°C (TLC
control). To the mixture 20 ml of ethyl acetate was
added, the aqueous layer was separated, acidified with
10 ml of 20% aqueous acetic acid solution. The
product was extracted with ethyl acetate (4×25 ml).
The combined extracts were washed with 25 ml of the
saturated aqueous sodium chloride solution and dried
over anhydrous magnesium sulfate. The solvent was
evaporated at a reduced pressure at the temperature
below 20°C to dryness, and then kept for several hours
in a vacuum at 1 mm Hg for a more complete removal
of acetic acid traces. Compounds Va and Vb were
analyzed without further purification and used for
further syntheses.
Methyl esters of N-[4-(diethoxyphosphoryl)-2-
methyl-(4-methylphenyl)-1,3-oxazol-5-yl]-β-alanine
and γ-aminobutyric acid (IIa–IId). To a solution of
0.01 mol of compound I in 50 ml of methanol was
added 0.011 mol of the corresponding amino acid
methyl ester hydrochloride and 0.055 mol of
triethylamine. The mixture was kept at 20–25°C for
80–100 days (31P NMR and TLC control). The
reaction mixture was evaporated at a reduced pressure
to dryness, the residue was dissolved in 100 ml of
ethyl acetate, washed succesively with water, 20%
aqueous acetic acid solution, water, and concentrated
aqueous solution of potassium carbonate, dried over
anhydrous magnesium sulfate. The solvent was removed
at a reduced pressure to dryness. The residue was
treated with the boiling hexane (3×50 ml) with decant-
ing. The combined hexane extracts were evaporated to
dryness at a reduced pressure. The products are
colorless or light yellow viscous oils. Only compounds
IIa and IIb were isolated individually, compounds IIc
and IId were contaminated with p-toluamide.
1-[4-Hydroxy(ethoxy)phosphoryl-2-methyl-(4-
methylphenyl)-1,3-oxazol-5-yl]piperidin-4-car-
boxylic acids (VIa, VIb). To a solution of 0.01 mol of
compound IV in 5 ml of anhydrous ethanol was added
a solution of 0.05 mol of sodium hydroxide in 100 ml
of anhydrous ethanol. The mixture was stirred at 20–
25°C for 10 days (31P NMR monitoring). The reaction
mixture was evaporated to dryness at a reduced
pressure at the temperature not exceeding 30ºC. The
residue was triturated in anhydrous dioxane, the
precipitate was filtered off, washed on a filter with a
small amount of anhydrous dioxane, and then
dissolved in a minimal amount of ice water, the solu-
tion was carefully acidified with 10% aqueous
hydrochloric acid solution to pH ~ 1–2 with cooling,
extracted with ethyl acetate (3×25 ml). The combined
extracts were washed with brine, dried with
magnesium sulfate, the solvent was removed in a
vacuum at the temperature above 20°C. Compound
Methyl esters of N-[4-(diethoxyphosphoryl)-2-
methyl-(4-methylphenyl)-1,3-oxazol-5-yl]proline
(IIIa, IIIb). To a solution of 0.01 mol of compound I
in 50 ml of methanol was added 0.011 mol of proline
methyl ester hydrochloride and 0.066 mol of triethyl-
amine. The mixture was boiled for 3 h (TLC control).
The reaction mixture was evaporated at a reduced
pressure to dryness, the residue was triturated in 100 ml
of ethyl acetate, washed in succession with water, 20%
acetic acid aqueous solution, water, and concentrated
aqueous solution of potassium carbonate, dried over
anhydrous magnesium sulfate, the solvent was
removed at a reduced pressure to dryness. The oil was
treated with boiling petroleum ether (3×50 ml) with
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REACTION OF DIETHYL 1-ACYLAMINO-2,2-DICHLOROETHENYLPHOSPHONATES
651
3. Scheidecker, S., Köckrits, A., and Schnell, M., J. Prakt.
Chem., 1990, vol 332, no. 6, p. 968.
VIb was purified by the recrystallization from 2-
propanol. Compound VIa we failed to isolate in an
analytically pure form owing to its degradation.
4. Matsumura, K., Shimadzu, H., Miyashita, O., and
Hashimoto, N., Chem. Pharm. Bull., 1976, vol. 24, no. 5,
p. 941.
1-[2-Acylamino-2-(diethoxyphoshoryl)acetyl]-
piperidin-4-ylcarboxylic acids (VIIa, VIIb). A solu-
tion of 0.01 mol of compound V in 50 ml of an acetic
acid–water mixture (5:1) was heated for 7 h at 75°C in
a water bath. The reaction mixture was evaporated at a
reduced pressure to dryness. The residue was rapidly
triturated in anhydrous acetone, the precipitate was
filtered off, dried in a vacuum at 75°C. Compounds
VII were analyzed without further purification.
5. Drach, B.S., Mis’kevich, G.N., and Martynyuk, A.P.,
Zh. Org. Khim., 1978, vol. 14, no. 3, p. 508.
6. Protopopova, G.V., Dzyuban, A.D., Nesterenko, N.I.,
Reidalova, L.I., Drach, B.S., Sviridov, E.P., and Shatur-
skii, Ya.P., Author’s Certificate no. 488527, 1974; С. А.,
1979, 91:205664v.
7. Brovarets, V.S., Sharykina, N.I., Kudryavtseva, I.G.,
Ovrutskii, V.M., Stepko, O.P., and Drach, B.S., Ukraine
Patent no. 17144 А, 1997.
Methyl 1-[2-acylamino-2-(diethoxyphoshoryl)-
acetyl]piperidin-4-ylcarboxylates (VIIIа, VIIIb). A
solution of 0.01 mol of compound IV was heated in
50 ml of an acetic acid–water mixture (5:1) for 7 h at
75ºC in a water bath. The reaction mixture was
evaporated at a reduced pressure to dryness. The
precipitated oil was treated with boiling petroleum
ether (3×50 ml) with decanting. The combined ether
extracts were evaporated to dryness at a reduced
pressure. The products are pale yellow viscous oils.
Compound VIIIa crystallizes after 3 days, and com-
pound VIIIb, after 3 months.
8. Röhr, G., Schnell, M., and Köckritz, A., Synthesis,
1992, no. 10, p. 1031.
9. Köckritz, A. and Schnell, M., Phosph., Sulf., Silicon,
Relat. Comp., 1993, vol. 83, p. 125.
10. Galkin, V.I., Sayakhov, R.D., Garifzyanov, A.R., Cher-
kasov, R.A., and Pudovik, A.N., Dokl. Akad. Nauk
SSSR, Ser. Khim., 1991, vol. 318, no. 1, p. 116.
11. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S.,
Chernega, A.N., and Drach, B.S., Synthesis, 2003,
no. 18, p. 2851.
12. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S., and
Drach, B.S., Zh. Obshch. Khim., 2003, vol. 73, no. 11,
p. 1933.
1-{2-(Dihydroxyphosphoryl)-2-[(4-methylphenyl)-
formamido]acetyl}piperidin-4-ylcarboxylic acid (Хb).
A solution of 0.01 mol of acid VIb in 50 ml of an
acetic acid–water mixture (5:1) was heated for 30 h at
75°C in a water bath. The reaction mixture was
evaporated at a reduced pressure to dryness. The
residue was rapidly triturated in anhydrous acetone
with filtration, dried in a vacuum at 75°C. The product
is white hygroscopic powder, which melts in air.
13. Golovchenko, A.V., Pilyo, S.G., Brovarets, V.S., Cher-
nega, A.N., and Drach, B.S., Zh. Obshch. Khim., 2005,
vol. 75, no. 3, p. 461.
14. Puff, H. and Reuter, H., Z. Kristallogr., 1997, vol. 195,
p. 89.
15. Sirota, T.V., Voprosy Med. Khim., 1999, no. 31, p. 3.
16. Sidorov, K.K., Toksikol.Nnovykh Prom. Khim.
Veshchestv, 1973, no. 13, p. 47.
17. Sheldrick, G.M., SHELXS97. Program for the Solution
of Crystal Structure, University of Göttingen:
Göttingen, Germany, 1997.
REFERENCES
1. Drach, B.S. and Sviridov, E.P., Zh. Obshch. Khim.,
1973, vol. 43, no. 7, p. 1648.
2. Drach, B.S. , Sviridov, E.P., and Shaturskii, Ya.P., Zh.
Obshch. Khim., 1974, vol. 44, no. 8, p. 1712.
18. Sheldrick, G.M., SHELXL97. Program for the
Refinement of crystal Structures, University of Göt-
tingen: Göttingen, Germany, 1997.
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