Synthesis of N,N-disubstituted aminomethylenediphosphonates and their derivatives

Full text of DOI:10.1134/S1070363212090265

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 9, pp. 1593–1595. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.A. Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, I.S. Ershov, V.S. Petrosyan, 2012, published in Zhurnal
Obshchei Khimii, 2012, Vol. 82, No. 9, pp. 1559–1561.
LETTERS
TO THE EDITOR
Synthesis of N,N-Disubstituted Aminomethylenediphosphonates
and Their Derivatives
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova,
L. I. Livantsova, I. S. Ershov, and V. S. Petrosyan
Lomonosov Moscow State University, Vorobiovy Gory, Moscow, 119991 Russia
e-mail: aprishchenko@yandex.ru
Received June 4, 2012
DOI: 10.1134/S1070363212090265
The substituted aminomethylene-containing organo-
phosphorus compounds are analogs of amino acids and
natural pyrophosphates and are of interest as promising
ligands and biologically active substances with diverse
properties [1]. Previously some of the compounds of
this type have been synthesized using various form-
amide derivatives like dialkylformamide dialkylacetals
and ethoxymethylene imines [2]. Aiming to synthesize
the new types of N,N-disubstituted aminomethylene-
diphosphonates we studied the reaction of tris(tri-
methylsilyl)phosphite directly with the most available
N,N-disubstituted formamides A [3]. Formylproline N-
trimethylsilyl ether I we obtained specifically through
the proline formylation followed by the treating with
bis(trimethylsilyl)amine and trimethylchlorosilane as
the silylating reagents at heating to 130°C.
(
1) HCOOH, (2) (Me Si) NH, Me SiCl
3
2
3
COOH
N
H
COOSiMe
3
N
C(O)H
I
Formamides A were found to react readily with an
excess of tris(trimethylsilyl)phosphite in methylene
chloride in the presence of trimethylsilyl trifluoro-
methanesulfonate as a catalyst to give diphosphonates
II–IV in high yields.
The structural analogue of aminomethylene-
diphosphonate IV, hydroxymethylenediphosphonate
V, formed in a high yield by the sequential treatment
of formamide I with thionyl chloride, an excess of
diethyl(trimethylsilyl)phosphate, and ethanol [4].
SOCl2
I
_
_
COCl
Me SiCl, SO
3
2
N
2
(Me SiO) P + HC(O)NR
3 3 2
C(O)H
A, I
(Me SiO) P] CHNR
CF SO SiMe
3
2(EtO) POSiMe
2 3
3
3
[
3
2
2
2
_
C[P(O)(OEt )]2
_(
Me SiCl
2
Me Si) O
3
N
3
2
O
II IV
OSiMe3
_
C(O)H
I
EtOH
NR = NMe (II), N
O (III),
2
2
_
C[P(O)(OEt )]2
Me SiOEt
2
3
N
OH
C(O)H
(IV).
COOSiMe3
V
N
1
593

1
594
PRISHCHENKO et al.
The reactions of diphosphonates II–IV with an
excess of methanol under mild conditions result in amino-
methylenediphosphonic acids VI–VIII in high yields.
They are white hygroscopic crystalline substances.
4
MeOH
_
II IV
[(HO) P] CHNR
2
2
2
_4
Me SiOMe
3
O
_
VI VIII
NR = NMe (VI), N
O (VII),
(VIII).
2
2
COOSiMe3
N
Aminomethylenediphosphonic acids VI and VII ob-
tained previously were described as crystal hydrates [5].
mixture was kept at 20°С for 24. After removing the
solvent 3 ml of hexane was added to the residue at
cooling to 5°С. The solvent was decanted from the
mixture, and the white crystals were kept in a vacuum
The NMR spectra of compounds I–VIII contain the
1
2
3
characteristic
signals
of
P C HNC H (C H ),
2 n m
1
3
4
5
2
6
1
of 0.5 mm Hg. Yield 87% (8.8 g), mp 42°С. Н NMR
{
C H C H C H C H[C (P )]}NC H(P )
fragments
2
2
2
2
2
1
2
spectrum, δ, ppm: 3.05 t (С H, J 24.4 Hz), 2.40 s
PH
whose parameters are listed below. According to the
NMR spectra, compounds I, IV, and VIII are mixtures
of two stereoisomers, the ratio of which was
2
13
(
2С Н N), –0.08 s (Me Si). С NMR spectrum, δ ,
3 3 C
1
1
2 3
ppm: 62.77 t (С , J 147.7 Hz), 43.53 t (С , J 4.3 Hz),
PС
PС
3
1
1
31
0.48 (Me
3
Si). Р NMR spectrum: δ
P
–2.87 ppm.
determined by the H and P NMR. The predominant
isomer data are given the first. Two diastereotopic
diethoxyphosphoryl groups of V differ in the NMR
Found, %: С 35.26; Н 8.49. С Н NО · P Si .
15
43
6
2
4
Calculated, %: С 35.48; Н 8.53.
3
1
spectra, and in the P NMR spectrum they are
observed as a characteristic AB-system.
Diphosphonates III and IV were obtained similarly.
Tetra(trimethylsilyl) N-morpholinomethylenedi-
1
phosphonate (III). Yield 85%, viscous oil. Н NMR
Trimethylsilyl ether of N-formylproline (I). A
mixture of 20 g of proline and 50 g of formic acid was
heated with stirring on a boiling water bath for 5 h.
Then the solvent was distilled off in a vacuum of 7 mm
Hg. To the residue was added 56 g of bis(trimethyl-
silyl)amine and 8 g of trimethylchlorosilane. The mix-
ture was refluxed to complete sublimation of ammo-
nium chloride. The residue was distilled. Yield 72%
1
2
spectrum, δ, ppm: 2.76 t (С H, J 25.6 Hz), 2.7–2.8
РH
2
3
13
m (2С H ), 3.3–3.4 m (2С H ), 0.07 s (4Me Si).
С
2
2
3
1
1
NMR spectrum, δ , ppm: 63.82 t (С , J 148.9 Hz),
C
PС
2
3
3
5
1.33 t (С , J 4.4 Hz), 67.11 s (С ), 0.75 s (Me Si).
PС 3
3
1
Р NMR spectrum: δ –0.62 ppm. Found, %: С 36.94;
P
Н 8.16. С Н NО P Si . Calculated, %: С 37.14; Н 8.25.
17 45
7
2
4
Tetra(trimethylsilyl) N-(O-trimethylsilylprolino)-
methylenediphosphonate (IV). Yield 89%, viscous
(
6
27 g), bp 133°С (2 mm Hg). The first isomer, content
1
1
1
0%. Н NMR spectrum, δ, ppm: 7.91 s (С Н), 4.08
oil. The first isomer, content 60%. Н NMR spectrum,
2
3
3
1
2
d.d (С Н, JННА 8.4,
J
3.6 Hz), 3.25–3.35 m
ННВ
δ, ppm: 3.42 br.t (С H, J 26.2 Hz), 3.6–3.8 m
РH
3
4
5
13
2
3
4
5
(
С Н ), 1.5–2.0 m (С Н , С Н ,), –0.06 s (Me Si). С
2 2 2 3
(С H), 2.6–2.8 m (С H ), 1.3–1.7 m (С H , С H ),
2 2 2
1
2
1
3
NMR spectrum, δ , ppm: 160.18 (С ), 57.17 (С ),
5.90 (С ), 23.63 (С ), 29.03 (С ), 171.43 (С ). The
second isomer. Н NMR spectrum, δ, ppm: 7.86 s
С Н), 3.99 d.d (С Н, J
C
–0.17 s (4Me Si). С NMR spectrum, δ , ppm: 58.41 t
3
C
3
4
5
6
1
1
2
4
(
С , J 155.7 Hz), 63.8–64.5 m (С ), 48.9–49.6 m
С ), 22.97 (С ), 27.98 (С ), 171.82 (С ), 0.43 (Me Si).
Р NMR spectrum: δ –0.42 ppm. The second isomer.
H NMR spectrum, δ, ppm: 3.42 br.t (С H, J 26.2 Hz),
3.6–3.8 m (С H), 2.6–2.8 m (С H ), 1.3–1.7 m (С H ,
2 2
С H ), –0.17 s (4 Me Si). С NMR spectrum, δ , ppm:
PС
1
3
4
5
6
(
3
1
2
3
3
3
1
(
3
(
5
8.4, J
4 Hz), 3.08–
ННА
ННВ
Р
3
4
5
1
1
2
.19 m (С Н ), 1.5–2.0 m (С Н , С Н ), –0.06 s
2
2
2
РH
1
3
1
2
3
4
Me Si). С NMR spectrum, δ , ppm: 161.21 (С ),
3
C
2
3
4
5
5
13
9.27 (С ), 43.43 (С ), 22.43 (С ), 29.31 (С ), 171.82
С ). Found, %: С 49.97; Н 7.82. С Н NО Si.
2
3
C
6
1
1
2
(
9 17 3
58.16 t (С , J 156.5 Hz), 63.8–64.5 m (С ), 48.9–
PС
3
4
5
6
Calculated, %: С 50.20; Н 7.96.
4
(
9.6 m (С ), 22.97 (С ), 27.98 (С ), 171.54 (С ), 0.43
3
1
Me Si). Р NMR spectrum: δ 3.16 ppm. Found, %:
3
Р
Tetra(trimethylsilyl) dimethylaminomethylenedi-
phosphonate (II). To a solution of 15 g of tris(tri-
methylsilyl)phosphate and 1.5 g of dimethylformamide
in 8 ml of methylene chloride was added with stirring
С 38.72; Н 8.14. С Н NО P Si . Calculated, %: С
2
1
53
8
2
5
3
8.96; Н 8.22.
Tetraethyl (N-formylpyrrolidin-2-yl)hydroxymethyl-
enediphosphonate (V). To a solution of 6.1 g of ether
3
ml of trimethylsilyl trifluoromethanesulfonate. The
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

SYNTHESIS OF N,N-DISUBSTITUTED AMINOMETHYLENEDIPHOSPHONATES
1595
I in 10 ml of methylene chloride was added with the
stirring at cooling to 5°С a solution of 3.6 g of thionyl
chloride in 5 ml of methylene chloride. The mixture
was heated to reflux, and the solvent was removed.
The residue was kept in a vacuum of 1 mm Hg for 0.5 h.
Then it was dissolved in 15 ml of methylene chloride.
To the obtained solution cooled to 5°С was added a
solution of 18 g of diethyl(trimethylsilyl)phosphite in
N-Prolinomethylenediphosphonic acid (VIII).
Yield 95%, mp 187°С. The first isomer, content 55%.
1
1
2
H NMR spectrum, δ, ppm: 4.29 t (С H, J 20 Hz),
РH
2
3
5.1–5.2 m (С H), 3.95–4.05 m (С H ), 2.0–2.5 m
(С H , С H ). С NMR spectrum, δ , ppm: 58.31 t
2
4
5
13
2
1
2
C
1
2
3
(С , J 127.7 Hz), 67.54 t (С , J 5.6 Hz), 54.09
PС
PС
3
4
5
6
31
(С ), 22.84 (С ), 28.06 (С ), 170.20 (С ). Р NMR
1
spectrum: δ 7.04 ppm. The second isomer. Н NMR
Р
1
2
1
5 ml of methylene chloride under stirring. After
spectrum, δ, ppm: 4.32 t (С H, J 20 Hz), 5.1–5.2 m
РH
2
3
4
5
13
removing the solvent, to the residue was added 30 ml
of ethanol. The mixture was heated to 40°С. Trimethyl
(С H), 4.1–4.2 m (С H ), 2.0–2.5 m (С H , С H ). С
2 2 2
1
1
NMR spectrum, δ, ppm: 58.39 t (С , J 128.5 Hz),
PС
2
3
3
4
(
ethoxy)silane and ethanol were distilled off. The
67.21 t (С , J 5.4 Hz), 54.21 (С ), 22.64 (С ), 27.78
PС
5
6
31
residue was dissolved in 15 ml of diethyl ether and
mixed with 10 ml of hexane and 10 ml of water. The
formed oily substance was kept in a vacuum of 1 mm
(С ), 168.97 (С ). Р NMR spectrum: δ 7.89 ppm.
P
Found, %: С 24.69; Н 4.42. С Н NО P . Calculated,
6
13
8 2
%: С 24.93; Н 4.53.
1
Hg for 0.5 h. Yield 91% (10.3 g), viscous oil. Н NMR
The NMR spectra were obtained on a Bruker
Avance 400 spectrometer using CDCl3 (I–V), a
mixture of D O and C D N (VI, VII) or CD OD
1
2
spectrum, δ, ppm: 7.84 s (С H), 3.6–4.0 m (С H,
3
4
4
2
СН ОР), 3.15–3.65 m (С Н ), 1.3–1.6 m (С Н ), 1.9–
2 2 2
5
13
2
5
5
3
.3 m (С Н ), 0.9–1.0 (4СН ). С NMR spectrum, δ ,
1
13
2
3
C
(
VIII) as the solvents and TMS ( H, C) or 85%
H PO in D O ( Р) as the reference.
6
2
1
ppm: 77.90 t (С H, J 154.9 Hz), 164.22 (С ), 62.7–
31
РС
2
3
4
3
4
2
6
(
4.3 m (С , СH ОР), 48.50 s (С ), 24.18 s (С ), 27.71 s
2
5
31
С ), 15.9–16.2 m (Me). Р NMR spectrum, δ , ppm:
ACKNOWLEDGMENTS
This work was supported by the Russian Founda-
tion for Basic Research (grants no. 11-03-00402, 12-
3-00003).
P
2
1
5.87 and 16.22 (АВ-system, J 28.7 Hz). Found, %:
PР
С 41.71; Н 7.22. С Н NО P . CAlculated, %: С
1
4
29
8 2
4
1.90; Н 7.28.
0
Dimethylaminomethylenediphosphonic acid (VI).
REFERENCES
To 30 ml of methanol was added 8.8 g of diphos-
phonate II with the stirring and cooling to 10°С. The
mixture was heated to reflux, and the solvent was
1
2
.
.
Ebetino, F.H., Phosphorus, Sulfur, Silicon, Relat. Elem.,
1
999, vols. 144–146, p. 9; Widler, L., Jaeggi, K.A., and
Green, J.R., Phosphorus, Sulfur, Silicon, Relat. Elem.,
999, vols. 144–146, p. 5.
removed. The white crystals were kept in a vacuum of
1
1
1
mm Hg for 1 h. Yield 97% (3.7 g), mp 212°С. Н
Prishchenko, А.А., Livantsov, M.V., and Petrosyan, V.S.,
Zh. Obshch. Khim., 1994, vol. 64, no. 8, p. 1316;
Prishchenko, А.А., Livantsov, M.V., Novikova, O.P.,
and Livantsova, L.I., Zh. Obshch. Khim., 2009, vol. 79,
no. 9, p. 1580; Prishchenko, А.А., Livantsov, M.V.,
Novikova, O.P., and Livantsova, L.I., Zh. Obshch.
Khim., 2010, vol. 80, no. 9, p. 1574.
1
2
NMR spectrum, δ, ppm: 3.05 t (С H, J 18.4 Hz),
.57 s (2С Н ). С NMR spectrum, δ , ppm: 62.24 t
PH
2
13
2
(
3
C
1
1
2
31
С , J 115.8 Hz), 43.67 (С ). Р NMR spectrum: δ
P
С
P
6
.29 ppm. Found, %: С 16.23; Н 4.92. С Н NО P .
3 11 6 2
Calculated, %: С 16.45; Н 5.06.
3
.
Weigandt-Hilgetag. Metody eksperimenta v organi-
cheskoi khimii (Experimental Methods in Organic
Chemistry), Suvorov, N.N. Ed., Moscow: Khimiya, 1968.
Acids VIII and VIII were obtained similarly.
N-Morpholinomethylenediphosphonic acid (VII).
1
4. Kolodyazhnaya, O.O. and Kolodyazhnyi, O.I., Zh.
Obshch. Khim., 2011, vol. 81, no. 1, p. 147.
5
Yield 96%, mp 202°С. Н NMR spectrum, δ, ppm:
1
2
2
3
.08 t (С H, J 17.6 Hz), 2.54 s (2С H ), 3.2–3.3 m
РH 2
.
Gross, H., Costisella, B., Gnauk, T., and Brennecke, L.,
J. App. Chem., 1976, vol. 318, p. 116; Gross, H.,
Medved’, T.Ya., Costisella, B., Bel’skii, F.I., and
Kabachnik, M.I., Zh. Obshch. Khim., 1978, vol. 48,
no. 9, p. 1914.
3
13
1
(
С H ). С NMR spectrum, δ , ppm: 62.99 t (С ,
2
C
1
2
3
31
JPС 111 Hz), 51.74 (С ), 64.07 (С ). Р NMR spec-
trum: δ 6.22 ppm. Found, %: С 22.83; Н 4.92.
P
С Н NО P . Calculated, %: С 23.00; Н 5.02.
5
13
7 2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012