Synthesis of aminomethylenediphosphonates and their derivatives containing PCNH2 fragments

Full text of DOI:10.1134/S1070363214030347

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 3, pp. 608–610. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.A. Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, V.S. Petrosyan, 2014, published in Zhurnal Obshchei Khimii,
2014, Vol. 84, No. 3, pp. 524–526.
LETTERS
TO THE EDITOR
Synthesis of Aminomethylenediphosphonates
and Their Derivatives Containing PCNH2 Fragments
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, and V. S. Petrosyan
Lomonosov Moscow State University, Moscow, 119991 Russia
е-mail: aprishchenko@yandex.ru
Received November 28, 2013
DOI: 10.1134/S1070363214030347
Aminomethylenediphosphonic acids containing
free amino group are of interest as promising ligands
and biologically active substances with diverse
properties [1]. We recently developed several con-
venient methods for the synthesis of N-substituted
aminomethylenediphosphonates starting from N-
substituted formamides and imines [2]. For the
synthesis of new trimethylsilyl-containing amino-
methylenediphosphonates and their derivatives with
PCNH2 fragments we studied the interaction of tris-
(trimethylsilyl)phosphate with easily accessible hydro-
chlorides of substituted ethoxymethyleneimines A [3]
in the presence of trimethylsilyl trifluoromethane-
sulfonate as a catalyst. Thus, substituted ethoxymethyl-
eneimines hydrochlorides A reacted with an excess of
tris(trimethylsilyl)phosphite in methylene chloride
under mild conditions to form diphosphonates I–III
with good yields.
2(Me3SiO)3P, CF3SO3SiMe3
−Me3SiCl, −Me3SiOEt
C(R)NH2
(Me3SiO)2P
EtOC(R)=NH HCl
A
O
2
I−III
t-Bu
OH (III).
t-Bu
R = Me (I), Ph (II),
Apparently, mild reaction conditions are caused
triflate, generating a highly reactive intermediate B
by activation of the starting imines A with silicon
(see [4]).
CF3SO3SiMe3
2(Me3SiO)3P
I−III
EtOC(R)=NH HCl
CF3SO3C(R)=NH HCl
−Me3SiOEt
−Me3SiCl, −CF3SO3SiMe3
A
B
Trimethylsilyl-containing diphosphonates I–III re-
acted with an excess of methanol under mild condi-
tions to form diphosphonic acids IV–VI. The latter are
white hygroscopic crystalline substances (Scheme 1).
Compounds I–VI with unsubstituted amino group
are convenient synthons for the preparation of new
functionalized aminomethylenediphosphorus-containing
substances like diphosphorus-containing peptides. In
608

SYNTHESIS OF AMINOMETHYLENEDIPHOSPHONATES
609
spectrum, δC, ppm: 59.63 t (С1, 1JPС 147.7 Hz), 135.77
br.s (С2), 127.18 and 127.25 (С3, С4), 126.79 (С5), 0.45
(2Me3Si), 0.52 (2Me3Si). 31Р NMR spectrum: δP 2.23
ppm. Found, %: С 40.74; Н 7.72. С19Н43NО6P2Si4.
Calculated, %: С 41.06; Н 7.80.
Scheme 1.
4MeOH
−4Me3SiOMe
I−III
[(HO)2P]2C(R)NH2
O
IV−V
O,O,O,O-Tetra(trimethylsilyl)-1-amino-1-(3,5-di-
tert-butyl-4-hydroxyphenyl)methylenediphosphonate
(III). Yield 89%, mp 52°C. Н NMR spectrum, δ,
t-Bu
1
R = Me (IV), Ph (V),
OH (VI).
t-Bu
ppm: 0.06 s (2Me3Si), 0.07 s (2Me3Si), 1.19 br.s
(NH2), 1.34 s (Ме3С), 5.08 br.s (ОН), 7.63 s (С6Н2).
1
13С NMR spectrum, δC, ppm: 59.65 t (С1, JPС
149.3 Hz), 126.42 (С2), 125.03 (С3), 139.46 (С4),
152.31 (С5), 35.12 (Ме3С), 30.98 (Ме3С), 0.68
(2Me3Si), 0.77 (2Me3Si). 31Р NMR spectrum: δP 3.27 ppm.
Found, %: С 47.26; Н 8.61. С27Н59NО7P2Si4. Cal-
culated, %: С 47.41; Н 8.69.
Scheme 2.
t-Bu
OH
t-Bu
4
3
2
P2C1(R)NH2,
,
5
R = Me,
1-Aminoethylidenediphosphonic acid (IV). A
solution of 3.8 g of diphosphonate I in 5 mL of diethyl
ether was added to 20 mL of methanol with stirring
under cooling to 10°C. The mixture was heated to
boiling, and the solvent was distilled off. White
crystals were kept in a vacuum (1 mm Hg) for 1 h.
X
the NMR spectra of compounds I–VI there were
characteristic signals of the fragments X, whose struc-
ture is shown in Scheme 2.
1
Yield 1.5 g, 96%, mp 252°C. Н NMR spectrum, δ,
The signals of hydroxy and amino groups of IV–VI
are broadened due to the proton exchange.
3
ppm: 1.12 t (Ме, JPH 13.2 Hz). 13С NMR spectrum,
1
δC, ppm: 51.69 t (С1, JPС 122.2 Hz), 15.64 (Ме). 31Р
NMR spectrum: δP 11.15 ppm. Found, %: С 11.58; Н
4.47. С2Н9NО6P2. Calculated, %: С 11.71; Н 4.42.
O,O,O,O-Tetra(trimethylsilyl)-1-aminoethylidene-
diphosphonate (I). To a solution of 10 g of tris-
(trimethylsilyl)phosphite in 10 mL of methylene
chloride was added 1.3 g of 1-ethoxyethylideneimine
and then 0.2 mL of trifluoromethanesulfonic acid
trimethylsilyl ester. The mixture was refluxed for 1 h,
and then the solvent was distilled off. To the residue
was added 10 g of bis(trimethylsilyl)amine, and the
mixture was refluxed for 1 h. After the solvent
removal, the residue was distilled. Yield 3.8 g, 73%,
Acids V, VI were prepared similarly.
1-Aminobenzylidenediphosphonic acid (V). Yield
1
97%, mp 223°C. Н NMR spectrum, δ, ppm: 6.8–7.6
m (С6Н5). 13С NMR spectrum, δC, ppm: 60.26 t (С1,
1JPС 120.5 Hz), 131.22 (С2), 125.52 (С3), 126.20 (С4),
124.27 (С5). 31Р NMR spectrum: δP 8.54 ppm. Found,
%: С 31.32; Н 4.19. С7Н11NО6P2. Calculated, %: С
31.48; Н 4.15.
1
bp 127°C (1 mm Hg). Н NMR spectrum, δ, ppm:
4
4
–0.09 d (2Ме3Si, JРH 2 Hz), –0.08 d (2Ме3Si, JРH
1-Amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-
methylenediphosphonic acid (VI). Yield 98%, mp
183–184°C. 1Н NMR spectrum, δ, ppm: 1.30 s
(Ме3С), 5.29 br.s (ОН), 7.50 s (С6Н2). 13С NMR spec-
3
3
1.6 Hz), 0.99 t (СН3, JРH 16.8 Hz), 1.13 t (NH2, JРH
12.8 Hz). 13С NMR spectrum, δC, ppm: 51.58 t (С1,
1JPС 152.5 Hz), 20.03 (Ме), 0.73 (2Me3Si), 0.78
(2Me3Si). 31Р NMR spectrum: δP 6.65 ppm. Found, %:
С 33.78; Н 8.23. С14Н41NО6P2Si4. Calculated, %: С
34.05; Н 8.37.
1
trum, δC, ppm: 62.84 t (С1, JPС 118.2 Hz), 126.89
(С2), 124.43 (С3), 138.65 (С4), 151.09 (С5), 34.35
(Ме3С), 30.08 (Ме3С). 31Р NMR spectrum: δP 11.06 ppm.
Found, %: С 45.43; Н 6.94. С15Н27NО7P2. Calculated,
%: С 45.57; Н 6.88.
Diphosphonates II, III were prepared similarly.
O,O,O,O-Tetra(trimethylsilyl)-1-aminobenzyl-
idenediphosphonate (II). Yield 72%, bp 152°C
NMR spectra were recorded on a Bruker Avance-
400 spectrometer in CDCl3 (I–III), СD3OD or C5D5N
(IV–VI), internal reference TMS (1H, 13C) or external
reference 85% phosphoric acid solution in D2O (31Р).
1
(1 mm Hg). Н NMR spectrum, δ, ppm: –0.24 d
4
4
(2Ме3Si, JРH 2.8 Hz), –0.20 d (2Ме3Si, JРH 2.8 Hz),
1.72 t (NH2, JРH 13 Hz), 6.8–7.6 m (С6Н5). 13С NMR
3
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610
PRISHCHENKO et al.
2. Prishchenko, A.A., Livantsov, M.V., Novikova, O.P.,
AKCNOWLEDGMENTS
Livantsova, L.I., Ershov, I.S., and Petrosyan, V.S., Russ.
J. Gen. Chem., 2012, vol. 82, no. 9, p. 1593. DOI:
10.1134/s1070363212090265; Prishchenko, A.A., Li-
vantsov, M.V., Novikova, O.P., and Livantsova, L.I.,
Russ. J. Gen. Chem., 2009, vol. 79, no. 9, p. 1936. DOI:
10.1134/s1070363209090230; Prishchenko, A.A., Li-
vantsov, M.V., Novikova, O.P., and Livantsova, L.I.,
Russ. J. Gen. Chem., 2010, vol. 80, no. 9, p. 1889. DOI:
10.1134/s1070363210090318.
This work was supported by the Russian Founda-
tion for Basic Research (grants no. 12-03-00003 and
14-03-00001).
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