Reactions of C-phosphorylated acetamidines with dialkylchlorophosphates

Article abstract of DOI:10.1134/S1070363211040037

The reactions of the C-phosphorylated acetamidines sodium derivatives with dialkylchlorophosphates were studied. They occur selectively to afford N ¹,N ¹-dialkyl-N ²- benzoylbis(dialkoxyphosphoryl)-acetamidines. Based on t

Full text of DOI:10.1134/S1070363211040037

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 4, pp. 639–641. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.E. Shishkin, E.V. Mednikov, Yu.V. Popov, M.A. Shevchenko, O.V. Anishchenko, E.V. Gurba, Chau Nhat Bang, B.D. Emenka,
2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 4, pp. 546–548.
Reactions of C-Phosphorylated Acetamidines
with Dialkylchlorophosphates
V. E. Shishkin, E. V. Mednikov, Yu. V. Popov, M. A. Shevchenko,
O. V. Anishchenko, E. V. Gurba, Chau Nhat Bang, and B. D. Emenka
Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
e-mail: tons@vstu.ru
Received April 22, 2010
Abstract—The reactions of the C-phosphorylated acetamidines sodium derivatives with dialkylchloro-
phosphates were studied. They occur selectively to afford N1,N1-dialkyl-N2-benzoylbis(dialkoxyphosphoryl)-
acetamidines. Based on the CH-acid properties of C-phosphorylated acetamidines, we developed a convenient
method for the synthesis of new diphosphorylated amidines.
DOI: 10.1134/S1070363211040037
Interest in the chemistry of amidines is due to their
unique structure and versatile properties [1, 2].
Amidines exhibit the biological activity of various
kinds, and they are widely used in medicine and
agriculture. Therefore the synthesis of new structures
of amidines is very important.
midines. The starting C-phosphorylated acetamidines
do not contain NH-bond in their structures and
therefore no interference occurs in the studying and
using the CH-acid properties of these compounds.
Dimethyl chlorophosphate and diethyl chlorophos-
phate were used as phosphorylating reagents.
So far, the methods of obtaining phosphorus
amidines based on the use of CH-acid properties of the
activated methylene group were poorly described in
the literature. But we believe these methods to be
promising. It was found that the methylene group of C-
phosphorylated acetamidines connected with the
electron-withdrawing phosphonate and amidine groups
possesses acidic properties. The reaction of these
compounds with sodium proceeds via the substitution
of one of the methylene hydrogen atom to form the
sodium derivative [3]. Aiming to synthesize new
structures of amidines we carried out phosphorylation
of the sodium derivatives of C-phosphorylated aceta-
Sodium derivatives were obtained by the action of
metallic sodium on the C-phosphorylated acetamidines
in dioxane. Reaction (1) was carried out at heating to
40–50°C and vigorous stirring until complete
conversion of sodium. Since the yield of the sodium
derivative is close to quantitative, the second stage of
the process, the phosphorylation [reaction (2)], was
performed without isolation of the sodium derivative.
For this purpose, to the reaction mixture obtained as
described above was added dropwise the required
amount of dialkyl chlorophosphate in dioxane under
stirring at 20–30°C. Then the temperature was raised
to 50°C, and the stirring was continued for 3 h. The
O
O
NC(O)C6H5
NC(O)C6H5
R2
(R1O)2PCH2C
(R1O)2PCHNaC
(1)
+ Na
−1/2H2
R2
O
O
NC(O)C6H5
NC(O)C6H5
R2
+ (R3O)2P(O)Cl
(2)
(R1O)2PCHNaC
(R1O)2PCHC
−NaCl
R2
(R3O)2P=O
3
R1 = i-С3H7, С4H9; R2 = N(C2H5)2, N(C3H7)2, N(C4H9)2,
N
O;
R = СH3, С2H5.
639

640
SHISHKIN et al.
Physicochemical properties of diphosphorylated acetamidines
O
NC(O)C6H5
R2
(R1O)2PCHC
(R3O)2P=O
MRD
Found, %
Calculated, %
Yield,
R1
R2
R3
nD20
d420
Formula
found
calculated
N
P
N
P
%
C4H9
C4H9
C4H9
N(C4H9)2
N(C2H5)2
N(C4H9)2
C2H5
CH3
89
87
86
84
87
85
1.4875 1.0753 161.15
1.4625 1.0402 133.85
1.4915 1.0925 156.01
1.4865 1.0409 111.28
1.4918 1.1388 139.12
1.4975 1.1709 133.07
160.98
133.09
155.04
110.52
138.22
132.66
4.80 10.52 C29H52O7N2Р2 4.65 10.30
5.64 12.36 C22H40O7N2Р2 5.53 12.25
4.81 10.61 C28H50O7N2P2 4.76 10.54
5.35 11.54 C25H44O7N2Р2 5.13 11.35
5.04 11.18 C25H44O7N2Р2 5.13 11.35
5.33 11.59 C23H32O8N2P2 5.26 11.65
I
II
CH3
III
IV
V
i-C3H7 N(C3H7)2
C2H5
C2H5
C4H9
C4H9
N(C2H5)2
N(CH2CH2)2O CH3
VI
molar ratio sodium–C-phosphorylated acetamidine–
dialkyl chlorophosphate was 1:1:(1–1.05). To isolate
the target product the reaction mixture was cooled to
20°C, sodium chloride was filtered off, and the solvent
was removed by distillation in a vacuum. The yield of
the reaction products was 84–89%. N1,N1-Dialkyl-N2-
benzoylbis(dialkoxyphosphoryl)acetamidines are the
target compounds of the phosphorylation reaction.
Physicochemical properties of the compounds I–VI are
listed in the table.
of 2 g (0.0043 mol) of N1,N1-dibutyl-N2-benzoyl(dibut-
oxyphosphoryl)acetamidine in 4 ml of anhydrous
dioxane was added by portions 0.1 g (0.0043 mol) of
sodium under stirring at the temperature 20–30°C. The
reaction mixture was stirred to complete conversion of
sodium. To a solution of the resulting acetamidine sodium
derivative was added dropwise 0.74 g (0.0043 mol) of
diethyl chlorophosphate in 2 ml of dioxane at stirring
at 20–30°C. The molar ratio N1,N1-dibutyl-N2-benzoyl-
(dibutoxyphosphoryl)acetamidine–sodium–diethyl-
chlorophosphate was 1:1:1. The temperature was raised
to 40°C, and the stirring was continued for 3 h. Sodium
chloride was filtered off; the solvent was removed by
distillation in a vacuum at 15–20 hPa. The residue was
evacuated for 1 h at 50°C and 2–4 hPa. Yield 2.3 g
(89%). IR spectrum, ν, cm–1: 952–1026 (РОС), 1212–
The compounds obtained were purified by column
chromatography using silica gel LC 5/40μ. The
composition and the structure of the synthesized
compounds were confirmed by the elemental analysis,
molecular refraction, 1H NMR and IR spectra.
The obtained compounds are viscous pale orange
liquids, well soluble in organic solvents and poorly
soluble in water.
1236 (Р=О), 1686 (С=N), 1720 (С=О), 1630 (C—C).
---
1H NMR spectrum (CCl4), δ, ppm: 0.89 t (18Н, СН3),
1.33 m (16Н, СН2), 2.76 d (1Н, СНР), 3.48 t (4Н,
NСН2), 3.97 m (8Н, СН2ОР), 7.24 m (5Н, С6Н5).
The screening for biological activity of the obtained
N1,N1-dialkyl-N2-benzoylbis(dialkoxyphosphoryl)acet-
amidines performed by means of PASS program
predicted with high probability anticancer, anti-
inflamatory activity. They can be used as regulators of
calcium metabolism and hypolipidemic drugs.
N1,N1-Diethyl-N2-benzoyl-(2-dimethoxyphosphoryl-
2-dibutoxyphosphoryl)acetamidine (II) was prepared
similarly from 1.50 g (0.0037 mol) of N1,N1-diethyl-
N2-benzoyl(dibutoxyphosphoryl)acetamidine, 0.08 g
(0.0037 mol) of sodium and 0.56 g (0.0039 mol) of
dimethyl chlorophosphate. The molar ratio N1,N1-
diethyl-N2-benzoyl(dibutoxyphosphoryl)acetamidine–
sodium–dimethylchlorophosphate was 1:1:1.05. Yield
1.63 g (87%). IR spectrum, ν, cm–1: 992–1061 (РОС),
Thus, the reaction of sodium derivatives of C-
phosphorylated acetamidines with dialkylchlorophos-
phates affords N1,N1-dialkyl-N2-benzoylbis(dialkoxy-
phosphoryl)acetamidines in high yield.
1215–1237 (Р=О), 1655 (С=N), 1725 (С=О), 1626
1
(C—C). H NMR spectrum (CCl4), δ, ppm: 0.90 t
EXPERIMENTAL
---
(12Н, СН3), 1.37 m (8Н, СН2), 2.77 d (1Н, СНР), 3.31
q (4Н, NСН2), 3.62 d (6Н, СН3ОР), 3.89 m (4Н,
СН2ОР), 7.32 m (5Н,С6Н5).
N1,N1-Dibutyl-N2-benzoyl-(2-diethoxyphosphoryl-
2-dibutoxyphosphoryl)acetamidine (I). To a solution
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 4 2011

REACTIONS OF C-PHOSPHORYLATED ACETAMIDINES
641
N1,N1-Dibutyl-N2-benzoyl-(2-dimethoxyphosphoryl-
2-dibutoxyphosphoryl)acetamidine (III) was prepared
similarly from 2 g (0.0043 mol) of N1,N1-dibutyl-N2-
N2-benzoyl(dibutoxyphosphoryl)acetamidine–sodium–
diethylchlorophosphate was 1:1:1.Yield 2.1 g (87%).
IR spectrum, ν, cm–1: 998–1054 (РОС), 1223–1245
1
benzoyl(dibutoxyphosphoryl)acetamidine, 0.099
g
(Р=О), 1682 (С=N), 1740 (С=О), 1635 (C—C). H
---
(0.0043 mol) of sodium and 0.63 g (0.0044 mol) of
dimethylchlorophosphate. The molar ratio N1,N1-
dibutyl-N2-benzoyl(dibutoxyphosphoryl)acetamidines–
sodium–dimethylchlorophosphate was 1:1:1.03. Yield
2.17 g (86%). IR spectrum, ν, cm–1: 992–1062 (РОС),
NMR spectrum (CCl4), δ, ppm: 0.92 t (18Н, СН3),
1.26 m (8Н, СН2), 2.75 d (1Н, СНР), 3.25 q (4Н,
NСН2), 4.61 m (8Н, СН2ОР), 7.32 m (5Н, С6Н5).
N1-Morpholino-N2-benzoyl-(2-dimethoxyphos-
phoryl-2-dibutoxyphosphoryl)acetamidine (VI) was
prepared similarly from 1.38 g (0.0033 mol) of N1-
morpholino-N2-benzoyl(dibutoxyphosphoryl)acet-
amidine, 0.07 g (0.0033 mol) of sodium and 0.49 g
(0.0034 mol) of dimethylchlorophosphate. The molar
ratio N1-morpholino-N2-benzoyl(dibutoxyphosphoryl)-
acetamidines–sodium–dimethylchlorophosphate was
1:1:1.03. Yield 1.5 g (85%). IR spectrum, ν, cm–1:
1215–1240 (Р=О), 1684 (С=N), 1734 (С=О), 1636
1
(C—C). H NMR spectrum (CCl4), δ, ppm: 0.93 t
---
(12Н, СН3), 1.27 m (16Н, СН2), 2.77 d (1Н, СНР),
3.23 t (4Н, NСН2), 3.91 d (6Н, СН3ОР), 4.65 m (4Н,
СН2ОР), 7.30 m (5Н, С6Н5).
N1,N1-Dipropyl-N2-benzoyl-(2-diethoxyphosphoryl-
2-diisopropoxyphosphoryl)acetamidine (IV) was
prepared similarly from 2 g (0.0049 mol) of N1,N1-
dipropyl-N2-benzoyl(diisopropoxyphosphoryl)acetamidine,
0.11 g (0.0049 mol) of sodium and 0.84 g (0.0049 mol)
of diethylchlorophosphate. The molar ratio N1,N1-di-
propyl-N2-benzoyl(diisopropoxyphosphoryl)acet-
amidine–sodium–diethylchlorophosphate was 1:1:1.
Yield 2.25 g (84%). IR spectrum, ν, cm–1: 998–1064
996–1072 (РОС), 1210–1230 (Р=О), 1676 (С=N),
1
1725 (С=О), 1627 (C—C). H NMR spectrum (CCl4),
---
δ, ppm: 0.84 t (6Н, СН3), 1.31 m (8Н, СН2), 2.83 d
(1Н, СНР), 3.45 q (4Н, NСН2), 3.65 t (4Н, СН2О),
3.85 d (6Н, СН3ОР), 4.01 m (4Н, СН2ОР), 7.34 m
(5Н, С6Н5).
(РОС), 1217–1245 (Р=О), 1677 (С=N), 1740 (С=О),
1
The Н NMR spectra were recorded on a Varian
1
1625 (C—C). H NMR spectrum (CCl4), δ, ppm: 0.92
---
Mercury 300 BB spectrometer operating at 300 MHz.
d (18Н, СН3), 1.05 t (6Н, СН3), 1.23 m (4Н, СН2),
2.80 d (1Н, СНР), 3.23 t (4Н, NСН2), 4.46 m (6Н,
СНОР), 7.29 m (5Н, С6Н5).
REFERENCES
N1,N1-Diethyl-N2-benzoyl-(2-diethoxyphosphoryl-
2-dibutoxyphosphoryl)acetamidine (V) was prepared
similarly from 1.8 g (0.0044 mol) of N1,N1-diethyl-N2-
1. Shishkin, V.E., Doctoral Sci. (Chem.) Dissertation,
Kazan, 1988.
2. Bibhesh, K. and Singh, B.K., International Journal of
ChemTech Research, 2009, vol. 1, no. 2, p. 250.
benzoyl(dibutoxyphosphoryl)acetamidine, 0.11
g
(0.0044 mol) of sodium and 0.84 g (0.0049 mol) of
3. RF Patent no. 2334753, 2008, Byull. Izobret., 2008,
diethylchlorophosphate. The molar ratio N1,N1-diethyl-
no. 3.
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