Synthesis and reactivity of the new trimethylsilyl esters of aminomethylenebisorganophosphorus acids

Article abstract of DOI:10.1002/hc.21100

The interaction of trimethylsilyl esters of trivalent organophosphorus acids containing PH and POSiMe₃ fragments in the presence of trimethylsilyl trifluoromethanesulfonate as catalyst is proposed as a convenient method for the synthesis of new trimethylsilyl esters of aminomethylenebisorganophosphorus acids with three and four coordinated phosphorus. Also the new functionalized derivatives of the aminomethylenebisphosphinic acids with substituted hydroxymethyl moieties are synthesized, and some properties of the obtained compounds are presented.

Full text of DOI:10.1002/hc.21100

Heteroatom Chemistry
Volume 24, Number 5, 2013
Synthesis and Reactivity of the New
Trimethylsilyl Esters of
Aminomethylenebisorganophosphorus Acids
Andrey A. Prishchenko, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, Ivan S. Ershov, and Valery S. Petrosyan
Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119991 Russia
Received 25 February 2013; revised 13 May 2013
various derivatives of these bisphosphonic acids are
ABSTRACT: The interaction of trimethylsilyl es-
good complexones and widely used in medicine
as important organophosphorus biomimetics of hy-
droxyl or amino acids and natural pyrophosphates
[7–10]. Also some of these compounds are used
ters of trivalent organophosphorus acids contain-
ing PH and POSiMe3 fragments in the pres-
ence of trimethylsilyl trifluoromethanesulfonate as
catalyst is proposed as
a convenient method
by us as effective antioxidants with the multifunc-
tional mode of action [11–14]. Previously some of
the N-substituted aminomethylenebisorganophos-
phorus compounds have been synthesized by us us-
ing various formamide derivatives like dialkylfor-
mamide dialkylacetals, and ethoxymethylene imines
[15]. In the present work we report the results of
the interaction of the trimethylsilyl esters of trivalent
organophosphorus acids with PH and POSiMe3 frag-
ments with various formamides, resulting in forma-
tion of the new trimethylsilyl esters of N-substituted
aminomethylenebisorganophosphorus acids with
three and four coordinated phosphorus.
for the synthesis of new trimethylsilyl esters
of aminomethylenebisorganophosphorus acids with
three and four coordinated phosphorus. Also the new
functionalized derivatives of the aminomethylenebis-
phosphinic acids with substituted hydroxymethyl
moieties are synthesized, and some properties of the
ꢀC
obtained compounds are presented.
2013 Wiley Pe-
riodicals, Inc. Heteroatom Chem 24:355–360, 2013;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21100
INTRODUCTION
The functionalized aminomethylenebisorganophos-
phorus acids and their derivatives containing aro-
matic and heterocyclic fragments with various hy-
droxyl, amino, or amido groups present great
interest as promising polydentate ligands and
prospective biologically active compounds [1–6]. So
RESULTS AND DISCUSSION
To synthesize the new types of N-substituted
aminomethylenebisphosphonates, we studied the re-
action of tris(trimethylsilyl)phosphite directly with
the most available N-substituted formamides; how-
ever, we obtained the new O-trimethylsilyl N-
formylproline 1 in 72% yield specifically through
the L-proline formylation followed by treating with
bis(trimethylsilyl)amine and chlorotrimethylsilane
as silylating reagents under heating up to 130◦C
(Eq. 1).
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic Research,
Moscow, Russia.
Contract grant numbers: 11-03-00402 and 12-03-00003.
ꢀC
2013 Wiley Periodicals, Inc.
355

356 Prishchenko et al.
(1)
The highly reactive trimethylsilyl esters of the trivalent phosphorus acids add readily to the carbonyl
group of aldehydes and ketones to form a variety of the functionalized hydroxymethyl organophosphorus
compounds, nevertheless, their interaction with amides of carboxylic acids is mostly unexplored [16–19].
We demonstrate that formamides react readily with an excess of tris(trimethylsilyl)phosphite in methylene
chloride only in the presence of trimethylsilyl trifluoromethanesulfonate, as a catalyst to give diphosphonates
2–6 in high yields. Evidently, the catalytic effect of trimethylsilyl trifluoromethanesulfonate is connected with
its ability to generate electrophilic carbonio-immonium ions in the course of this reaction (Eq. 2).
(2)
It should be noted that hydroxymethylenediphosphonate 7, which is a structural analogue of
aminomethylenediphosphonate 6, is formed in a high yield by the sequential treatment of formamide 1
with thionyl chloride, an excess of diethyl trimethylsilyl phosphite, and ethanol at 20◦C (Eq. 3, cf. [20]).
(3)
The excess of the most active bis(trimethylsiloxy)phosphine smoothly reacts with formamides under
the same conditions to form intermediate diphosphonites with PH fragments which are easily silylated by
bis(trimethylsilyl)amine giving diphosphonites 8–10 in good yield (Eq. 4).
(4)
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactivity of the New Trimethylsilyl Esters of Aminomethylenebisorganophosphorus Acids 357
Diphosphonite 8 is a key synthon for obtaining the several functionalized diphosphinates. So diphospho-
nite 8 readily adds by the carbonyl group of some aldehydes in methylene chloride to give diphosphinates
A as intermediates, and functionalized diphosphinic acids 11,12 are prepared in high yields by treatment of
the reaction mixture with methanol (Eq. 5).
(5)
Also, the treatment of diphosphonite 8–10 with a dilute solution of sodium methylate in methanol
results in formation of water-soluble disodium diphosphonite 13–15, as well as under similar conditions
diphosphonates 2–6 are easily transformed to corresponding diphosphonic acids 16–20 by treatment with
methanol in high yields (Eq. 6). The compounds 13–20 are white hygroscopic crystals (cf. [21]).
(6)
In summary, a simple synthesis of functionalized aminomethylenebisorganophosphorus acids and their
derivatives as useful and perspective compounds has been elaborated by us. This synthesis is substantially
more expedient than previous routes to corresponding compounds because of the application of trimethylsilyl
trifluoromethanesulfonate as an efficient catalyst.
The structures of N-substituted aminomethylenebisorganophosphorus acids and their derivatives were
1
confirmed by the H, 13C, and 31P NMR spectra that show characteristic signals of fragments B,C (Fig. 1),
whose parameters are presented in Table 1.
According to the NMR spectral data compounds 1,6,11,12, and 20 are the mixtures of stereoisomers,
the ratio of which was determined by the 1H and 31P NMR. The major isomer data are given the first.
Two diastereotopic phosphoryl groups of diphosphonate 7 and of the first isomers of acids 11,12 differ in the
FIGURE 1
Heteroatom Chemistry DOI 10.1002/hc

358 Prishchenko et al.
TABLE 1 Yields, Products Constants, and NMR Spectral Data (δ, ppm, J, Hz) for the РС1H(NС2)P Fragments of Compounds
2–20a
No.
Yield (%)
Bp,◦С (p, mm Hg) (mp, ◦C)
δH(C1H) (t)
2JPH
δC (C1) (t)
1JPC
δC(C2) s
δP, sb
2
3
4
5
6
78
83
87
85
89
139 (1)
159 (1)
(42)
Oil
Oil
2.57
4.21
3.05
2.76
3.42
3.42
21.6
27.2
24.4
25.6
26.2
26.2
–
–
5.6
6.2
16.2
58.25
58.16
62.77
63.82
58.41
58.16
77.90d
71.78
82.37
82.34
48.39
151.3
153.3
147.7
148.9
155.7
156.7
154.9
38.5
37.20c
149.39
43.53c
51.33c
64.20
1.77
–1.67
–2.87
–0.62
–0.42
64.20
3.16
e
7
91
74
52
72
87
Oil
152 (1)
119 (1)
7.84 s
15.87 df,16.22 d
155.78
166.82
165.33
38.17 d f,
39.07 d
39.80
e
8
151.03
45.19c
53.11c
147.68
9
2.11
2.08
4.71
41.6
42.8
78.7
10
11
144 (1),
g
4.78
4.41
4.14
16.0
16.2
16.4
48.59
49.64
50.24
81.2
79.8
84.8
147.85
148.09
146.33
39.08
g
12
89
29.98 d f,
31.19 d
30.22
4.31
3.92
3.64
2.59
2.55
2.94
4.20
3.05
3.08
4.29
4.32
16.0
16.3
16.4
15.2
15.8
17.2
22.2
18.4
17.6
20.0
20.0
48.51
51.89
56.24
65.16
64.98
55.95
50.95
62.24
62.99
58.31
58.39
86.9
87.6
85.3
70.2
72.4
117.4
142.4
115.8
111.0
127.7
128.5
146.91
146.10
147.80
44.21
52.83
34.07
30.67
20.06
9.78
12.05
7.78
16.99
6.29
6.22
g
g
g
13
14
15
16
17
18
19
20
94
95
94
96
97
97
96
95
(178)
(182)
(212)
(202)
(187)
147.03
43.67
51.74
67.54c
67.21c
7.04
7.89
aAll signals of alkyl, aryl, pyridine, and trimethylsilyl groups are in the standard area. The 1H NMR spectra of products fragments show
expected signals that sometimes look like overlapping multiplets. According to the NMR spectra, the compounds 6 and 20 are the mixtures of
two stereoisomers, and the compounds 11 and 12 are the mixtures of three stereoisomers. Their ratio was determined from the 1H and 31P
NMR spectra. The spectral parameters of the major isomer are given first. The ratio for compounds: 6, 60: 40; 20, 55: 45; 11, 40:35:25, 12,
40:35:25. In 1H NMR spectra, fragment PH for compounds: 13, 7.04 d, 1JPH 532; 14, 7.16 d, 1JPH 563; 15, 7.09 d, 1JPH 557; fragment PCHOH
2
2
for compounds: 11, 4.89 d, JPH 16.1; 12, 4.95 d, 4.97 d, 5.05 d, all JPH 12.4. In 13C NMR spectra, fragment PCHOH for compounds: 11,
70.27 d, 1JPC 103.3, 70.96 d, 1JPC 105.2, and 69.20 d, 1JPC 106.4; 12, 69.74 d, 1JPC 104.2, 69.97 d, 1JPC 106.4, and 69.13 d, 1JPC 97.8.
bData of 31P–{1H}spectra.
ct, 3JPC for compounds: 2, 6.4; 4, 4.3; 5, 4.4; 9, 7.2; 10, 6.8; and 20, 5.6 and 5.4.
d Fragment P2C6.
eThe signals of these fragments are overlapping multiplets.
fTwo phosphorus groups are nonequivalent for the first stereoisomer of compounds 7,11, and 12; 2JPP for compounds: 7, 28.7; 11, 24.3; and
12, 30.3.
gThese compounds are decomposed by heating at 100◦C.
NMR spectra, and in the 31P NMR spectrum they
are observed as characteristic AB-systems. The ele-
mental analysis data of synthesized compounds are
summarized in Table 2.
trimethylsilyl esters of trivalent phosphorus acids
were prepared as described in [16].
O-Trimethylsilyl N-formylproline (1)
A mixture of 20 g of L-proline and 50 g of formic acid
was heated, with stirring, in a boiling water bath for
5 h. Then the solvent was distilled off in a vacuum of
7 mm Hg, and 56 g bis(trimethylsilyl)amine and 8 g
trimethylchlorosilane were added to the residue. The
mixture was refluxed to complete the sublimation
of ammonium chloride. The residue was distilled to
obtain 27 g of formamide 1, yield 72%, boiling point
133◦С (2 mm Hg). The first isomer, content 60%:
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were registered
on the Bruker Avance–400 spectrometer (400, 100,
and 162 MHz, respectively) in CDCl3 (1–10), D2O
(11–15), a mixture of D2O and C5D5N (16–19), or
CD3OD (20) against TMS (1H and 13C) and 85%
H3PO4 in D2O (31P). All reactions were carried out
under dry argon in anhydrous solvents. The starting
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactivity of the New Trimethylsilyl Esters of Aminomethylenebisorganophosphorus Acids 359
TABLE 2 Elemental Analyses Data of Compounds 1–28a
Calcd., %
Found, %
No.
Empirical Formula
Formula Weight
C
H
C
H
1
C9H17NO3Si
C14H41NO6P2Si4
C19H43NO6P2Si4
C15H43NO6P2Si4
C17H45NO7P2Si4
215.33
493.77
555.85
507.81
549.85
650.04
401.34
507.42
449.35
279.09
231.04
273.09
205.05
267.13
219.08
261.12
289.13
50.20
34.05
41.06
35.48
37.14
38.96
41.90
54.44
50.79
30.13
15.59
21.99
11.71
31.48
16.45
23.00
24.93
7.96
8.37
7.80
8.53
8.25
8.22
7.28
5.36
4.71
3.25
3.93
4.06
4.42
4.15
5.06
5.02
4.53
49.97
33.89
40.94
35.26
36.94
38.72
41.71
54.26
50.57
30.03
15.46
21.73
11.57
31.37
16.23
22.83
24.69
7.82
8.26
7.74
8.49
8.16
8.14
7.22
5.28
4.78
3.28
3.98
4.11
4.51
4.19
4.92
4.92
4.42
2
3
4
5
6
C21H53NO8P2Si5
7
C14H29NO8P2
C23H27NO8P2
C19H21N3O6P2
C7H9NNa2O4P2
C3H9NNa2O4P2
C5H11NNa2O5P2
C2H9NO6P2
C7H11NO6P2
C3H11NO6P2
C5H13NO7P2
C6H13NO8P2
11
12
13
14
15
16
17
18
19
20
aThe air-sensitive compounds 8–10 were analyzed as their air-stable derivatives 13–15.
ing to 5◦С to a solution of 6.1 g of ester 1 in 10 mL of
methylene chloride. The mixture was refluxed, 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, and a solution of
18 g of diethyl trimethylsilyl phosphite in 15 mL
of methylene chloride was added under stirring at
5◦С. After removing the solvent, ethanol, 30 mL,
was added to the residue. The mixture was heated
to 40◦С. Trimethyl(ethoxy)silane and ethanol were
distilled off. The residue was dissolved in 15 mL of
diethyl ether and mixed with 10 mL of hexane and
10 mL of water. The oily substance formed was kept
in a vacuum of 1 mm Hg for 0.5 h to obtain 10.3 g of
diphosphonate 7 as viscous oil.
1Н NMR spectrum, δ, ppm: 7.91 s (С1Н), 4.08 dd
(С2Н, 3J(ННА) 8.4 Hz, 3J(ННВ) 3.6 Hz), 3.25–3.35 m
(С3Н2), 1.5–2.0 m (С4Н2, С5Н2,), –0.06 s (Me3Si). 13
C
NMR, δ, ppm: 160.18 s (С1), 57.17 s (С2), 45.90 s (С3),
23.63 s (С4), 29.03 s (С5), 171.43 s (С6). The second
isomer: 1Н NMR spectrum, δ, ppm: 7.86 s (С1Н), 3.99
3
3
dd (С2Н, J(ННА) 8.4 Hz, J(ННВ) 4 Hz), 3.08–3.19
m (С3Н2), 1.5–2.0 m (С4Н2, С5Н2,), –0.06 s (Me3Si).
13C NMR, δ, ppm: 161.21 s (С1), 59.27 s (С2), 43.43 s
(С3), 22.43 s (С4), 29.31 s (С5), 171.82 s (С6).
Tetra(trimethylsilyl) dimethylaminomethylenedi-
phosphonate (4)
Trimethylsilyl trifluoromethanesulfonate, 2 mL, was
added, with stirring, to a solution of 15 g of
tris(trimethylsilyl)phosphite and 1.5 g of dimethyl-
formamide in 8 mL of methylene chloride. The
mixture was kept at 20◦С for 24 h. After remov-
ing 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 of 0.5 mm Hg to obtain 8.8 g of
diphosphonate 4.
Tetra(trimethylsilyl) N-anilinomethylene
diphosphonite (8)
Trimethylsilyl trifluoromethanesulfonate, 1 mL, was
added, with stirring, to a solution of 18 g of
bis(trimethylsiloxy)phosphine and 2.4 g of for-
manilide in 10 mL of methylene chloride. The mix-
ture was kept at 20◦С for 4 h. After removing the
solvent, 20 g of bis(trimethylsilyl)amine and 2 mL of
chlorotrimethylsilane were added to the residue, and
the mixture was refluxed with stirring for 1 h, and
the residue was distilled to obtain 7.7 g of diphos-
phonite 8.
Diphosphonates 2, 3, 5, and 6 were obtained
similarly.
Tetraethyl (N-formylpyrrolidin-2-yl)
hydroxymethylenediphosphonate (7)
A solution of 3.6 g of thionyl chloride in 5 mL of
methylene chloride was added, with stirring, at cool-
Diphosphonites 9 and 10 were obtained simi-
larly.
Heteroatom Chemistry DOI 10.1002/hc

360 Prishchenko et al.
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N-Anilinomethylenebis[hydroxy(pyrid-3-yl)
methylphosphinic] acid (12)
A solution of 1.6 g of 3-pyridinecarboxaldehyde in
10 mL of methylene chloride was added, with stir-
ring and cooling to 10◦C, to a solution of 3.5 g of
diphosphonite 8 in 10 mL of methylene chloride. The
solvent was removed, and the mixture of methanol,
10 mL, and diethyl ether, 20 mL, was added to the
residue and the mixture was heated to boiling. The
crystals were filtered off, washed with ether, and ex-
posed to a vacuum of 1 mm Hg for 1 h to obtain 2.7 g
of acid 12.
Acid 11 was prepared similarly.
Disodium N-anilinomethylenediphosphonite
(13)
A solution of 4.5 g of bisphosphonite 8 in 10 mL of
ether was added with stirring at 5◦C to a solution of
0.93 g of sodium methylate in 30 mL of methanol.
The resulting mixture was heated to boiling, the sol-
vent was removed, and the residue was kept in a
vacuum of 1 mm Hg for 1 h to give 2.3 g of salt 13.
The salts 14 and 15 were obtained similarly.
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Diphosphonate 4, 8.8 g, was added with stirring and
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Heteroatom Chemistry DOI 10.1002/hc