Synthesis of the new types of N-unsubstituted aminomethylenebisorganophosphorus acids and their derivatives

Article abstract of DOI:10.1002/hc.21220

The interaction of trimethylsilyl esters of trivalent organophosphorus acids containing PH and POSiMe₃ groups with hydrochlorides of ethoxymethylene imines is a convenient method for the synthesis of new trimethylsilyl esters of N-unsubstituted aminomethylenebisorganophosphorus acids with three and four coordinated phosphorus. Also trimethylsilyl trifluoromethanesulfonate as effective catalyst is used for the similar interaction of hydrochlorides of ethoxymethylene imines with tris(trimethylsilyl)phosphite. The corresponding bisorganophosphorus acids and their derivatives are presented.

Full text of DOI:10.1002/hc.21220

Heteroatom Chemistry
Volume 26, Number 1, 2015
Synthesis of the New Types of
N-Unsubstituted
Aminomethylenebisorganophosphorus Acids
and Their Derivatives
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 December 2013; revised 3 July 2014
with the multifunctional mode of action [1–9]. Re-
ABSTRACT: The interaction of trimethylsilyl es-
cently, we developed the convenient synthetic meth-
ters of trivalent organophosphorus acids contain-
ods for the preparation of the some bisorganophos-
ing PH and POSiMe3 groups with hydrochlorides
phorus compounds of the similar structure using
of ethoxymethylene imines is a convenient method
various formamides and their derivatives [10–12].
for the synthesis of new trimethylsilyl esters of N-
In the present work, we report the results of the
unsubstituted aminomethylenebisorganophosphorus
interaction of the trimethylsilyl esters of trivalent
acids with three and four coordinated phospho-
organophosphorus acids including PH and POSiMe3
rus. Also trimethylsilyl trifluoromethanesulfonate as
groups with various hydrochlorides of ethoxymethy-
effective catalyst is used for the similar interac-
lene imines (Pinner compounds) [13] resulting in
tion of hydrochlorides of ethoxymethylene imines
the formation of the new trimethylsilyl esters of
with tris(trimethylsilyl)phosphite. The corresponding
N-unsubstituted
phorus acids with three and four coordinated
phosphorus.
aminomethylenebisorganophos-
bisorganophosphorus acids and their derivatives are
presented. 2014 Wiley Periodicals, Inc. Heteroatom
Chem. 26:101–105, 2015; View this article online at
wileyonlinelibrary.com. DOI 10.1002/hc.21220
ꢀC
RESULTS AND DISCUSSION
So the excess of most reactive bis(trimethy-
lsiloxy)phosphine smoothly reacts with substituted
hydrochlorides of ethoxymethylene imines in methy-
lene chloride to give diphosphonites 1a–d. Evi-
dently, there are three simultaneous reactions of
the transformation of the NH.HCl moiety into the
imino group, the addition to C(R)=N moiety, and
the substitution of the ethoxy group in course
of this process. Diphosphonites 1a–d are easily
silylated by bis(trimethylsilyl)amine in the presence
of trimethylchlorosilane to form diphosphonites 2a–
d in good yields, and diphosphonites 3a-d with
NHSiMe3 groups are observed by NMR spectra only
as by-products of slow trimethylsilylation of amino
groups (Eq. (1)). Note that the route of formation of
INTRODUCTION
The numerous aminomethylenebisorganophospho-
rus acids and their derivatives containing aromatic
and heterocyclic moieties as well as unsubstituted
amino groups are interesting organophosphorus
biomimetics of amino acids and natural pyrophos-
phates and widely used as effective polydentate lig-
ands and prospective biologically active compounds
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic
Research.
Contract grant numbers: 12-03-00003 and 14-03-00001.
2014 Wiley Periodicals, Inc.
ꢀC
101

102 Prishchenko et al.
compounds 1–3 is similar to the routes, which are
proposed by us recently (cf [10–12]).
(XO)2PH, CH2Cl2, 100C
(XO)2PH
(XO)2PH
- XOEt
EtOC(R)=NH HCl
EtOC(R)=NH
(XO)2PC(R)NH2
OEt
- XOP(O)H2, - XCl
NH2
XO
X NH, XCl, 1200C
X2NH, XCl
- NH4Cl
2
(1)
[(XO)2P]2C(R)NH2
[(XO)2P]2C(R)NHX
PC(R)P(OX)2
- NH Cl
4
H
O
3 a-d
1 a-d
2 a-d
X = Me3Si; R = H (a), Me (b), Ph (c),
(d).
N
Also hydrochlorides of ethoxymethylene imines
react with an excess of tris(trimethylsilyl)phosphite
under the same conditions only in the presence of
trimethylsilyl trifluoromethanesulfonate as a cata-
lyst to give diphosphonates 4a–d in good yields. Ev-
idently the catalytic effect of trimethylsilyl trifluo-
romethanesulfonate is based on activation of the
C=N groups via generation of electrophilic adducts
A in the course of this reaction (Eq. (2)) (cf [12,14]).
Under similar conditions, diphosphonates 4a–d
are easily transformed to corresponding diphospho-
nic acids 6a–d via treatment with methanol excess
in high yields (Eq. (4)).
SiMe3
2 (Me3SiO)3P, CH2Cl2, 400C
CF3SO3
CF3SO3SiMe3, CH2Cl2
C(R)NH HCl
EtOC(R)=NH HCl
- Me SiOEt
- Me3SiCl, - CF3SO3SiMe3,
3
EtO
A
(Me3SiO)2P 2C(R)NH2
O
(2)
4a-d
t-Bu
OH (d).
t-Bu
R = H (a), Me (b), Ph (c),
The treatment of diphosphonites 2a–d with a di-
lute solution of sodium methylate in methanol re-
sults in the formation of the water-soluble disodium
diphosphonites 5a–d as white hygroscopic crystals
in high yields (Eq. (3)).
4 MeOH, 100C
- 4 Me3SiOMe
[(HO)2P]2C(R)NH2
4a-d
O
6a-d
t-Bu
(4)
NaO
2 MeONa, 4 MeOH, 50C
R = H (a), Me (b), Ph (c),
OH (d)
t-Bu
P
2C(R)NH2
2a-d
H
O
(3)
5a-d
The structures of obtained bisphosphorus acids
1
and their derivatives 1–6 are confirmed by the H,
13C, and 31P NMR spectra, which show charac-
teristic signals of the P2CR(NH2) moieties whose
R = H (a), Me (b), Ph (c),
(d)
N
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of the New Types of N-Unsubstituted Aminomethylenebisorganophosphorus Acids and Their Derivatives 103
TABLE 1 Yields, Products Constants, and NMR Spectral Data (δ (ppm), J (Hz)) for Diphosphonites 1a–dawith the
Р1С1(R)P2(O)H Groups
Yield
(%)
Bp (°С)
Number
(p (mm Hg)) Ratio (%) δH (PH) d 1J(P2H) δ(C1)t 1J(P1C) 1J(P2C) δ(P1)d δ(P2) d 2JPP
1a
78
68
122 (1)
60
40
35
30
20
15
80
20
70
30
6.91
6.92
6.58
6.64
6.57
6.54
–
–
–
–
551.2
551.2
550.8
551.2
545.2
546.8
–
–
–
–
59.24
59.90
55.81
56.15
55.47
54.73
–
–
–
–
38.2
40.1
34.3
34.7
32.7
34.3
–
–
–
–
91.0
94.1
67.0
68.7
66.3
71.1
–
–
–
–
147.25
146.32
145.83
146.34
145.39
144.97
142.45
141.04
142.15
141.24
23.88
25.58
30.74
29.05
28.14
31.91
28.88
24.96
27.51
23.61
39.7
50.2
53.6
51.5
41.6
55.4
65.4
71.4
61.4
65.4
1bb
121 (0.5)
a
a
a
a
1c
1d
aDiphosphonites 1a–d are the mixtures of stereoisomers, their ratio is determined by the 31P NMR spectra, and diphosphonites 1c,d are
observed only as intermediates by 31P NMR spectra. The data of 31P–{1H} spectra are presented. In 1H NMR spectra, the signals of Me3Si,
NH2, CH3C1, C6H5, C5H4N, and C1H groups are overlapping multiplets in the standard area.
bIn 13C NMR spectra for the MeC1 group of compound 1b, δC, d (2JPC): 15.8 (19.1), 15.29 (18.3), 14.04 (22.4), and 13.61 (20.8)—for each
stereoisomer.
TABLE 2 Yields, Products Constants, and NMR Spectral Data (δ (ppm), J (Hz)) for Compounds 2a–d, 3a–d, and 4a–da with
the Р2С1(R)NH2 Groups
Bp (°С)
Yield
(%)
(p (mm Hg))
Number
(mp (°C))
δ(H) NH 2t
3JPH
δ(H) SiMe3 s
δ(C1)t
1JPC
δ(C)SiMe3 s
δ(P)s
2a
2b
2c
2d
4a
4b
4c
4d
84
88
74
72
69
73
72
89
126 (1)
124 (0.5)
144 (1)
145 (1)
139 (2)
127 (1)
152 (1)
(52)
2.21b
0.92
1.60
1.42
1.19b
1.13
1.72
1.20
6.2b
10.2
7.6
0.10, 0.11
0.01, 0.02
68.98
60.30
70.35
69.16
50.66
51.58
59.63
59.65
38.0
32.8
41.5
1.37
1.24
153.83
154.54
149.74
148.07
3.43
6.65
2.23
–0.16, 0.04
–0.28, –0.13
–0.02, 0.01
–0.08c, 0.09c
–0.24c, –0.20c
0.06, 0.07
0.92, 1.35
0.80, 1.14
0.72, 0.87
0.73, 0.78
0.45, 0.52
0.68, 0.77
9.6
41.5
13.6b
12.8
13.0
br. s
155.1
152.5
147.7
149.3
3.27
aIn 1H NMR spectra, C1H groups for compounds: 2a, δH 2.6–2.7 m; 4a, δH 2.6–2.9 m. In NMR spectra, the CH3 group for compounds: 2b, δH
0.76 t, 3JPH 12.4, δC314.55 t, 2JPC 17.6; 4b, δH 0.99 t, 3JPH 16.8, δC 20.03 s; group B for compounds: 2c, δH 6.9–7.4 m, δC 138.75 t (C2, 2JPC
10.4), 126.73 t (C3, JPC 8.8), 127.43 s (C4), 125.26 s (C5); 4c, δH 6.8–7.6 m, δC 135.77 br. s (C2), 127.18 s and 127.25 s (C3, C4), 126.79
3
3
3
s (C5); group C for compound: 2d, δH 6.92 dd (C4H, JHH 4.8 and 8), 7.52 d (C3H, JHH 8), 8.10 d (C5H, JHH 4.8), 8.48 s (C6H), δC 151.61
s (C2), 134.05 t (C3, JPC 7.2), 135.03 s (C4), 146.07 s (C5), 148.28 t (C6, JPC 9.6); group D for compound: 4d, δH 1.34 s (Me3C), 5.08 br.
s (OH), 7.63 s (C6H2); δC 126.42 s (C2), 125.03 (C3), 139.46 s (C4), 152.31 s (C5), 35.12 s (Me3C), 30.98 s (Me3C); by-products, for: 3a, δP
151.33 s; 3b, δC 62.36 t (C1, 1JPC 33.5), 13.09 t (Me, 2JPC 19.2), δP 151.21; 3c, δP 141.14 s; 3d, δP 141.18 s.
3
3
t-Bu
3
4
3
4
3
4
2
2
5
5
2
5
Groups:
OH
(D).
(B),
(C),
N
6
t-Bu
bdt, 3JHH for compounds: 2a, 12; 4a, 8.
cd, 4JPH for compounds: 4b, 2 and 1.6; 4c, 2.8 and 2.8.
parameters are presented in Tables 1–3. The elemen-
tal analysis data of synthesized compounds are sum-
marized in Table 4.
ing PH and POSiMe3 groups and hydrochlo-
rides of ethoxymethylene imines were developed.
Also the synthesized compounds 1–6 containing
some reactive groups (NH2, POSi, PH) are the
promising synthons for the preparation of vari-
ous functionalized aminomethylenebisphosphorus-
containing substances such as bisphosphorus-
containing peptides. Also these compounds are per-
spective polydentate ligands and biologically active
substances with versatile properties.
CONCLUSIONS
So the facile synthetic routes to N-unsubstituted
aminomethylenebisorganophosphorus acids and
their derivatives starting from trimethylsilyl es-
ters of trivalent organophosphorus acids contain-
Heteroatom Chemistry DOI 10.1002/hc

104 Prishchenko et al.
TABLE 3 Yields, Products Constants, and NMR Spectral Data (δ (ppm), J (Hz)) for Salts 5a–d and Acids 6a–da with the
Р2С1(R)NH2 Groups
Number
Yield (%)
Mp (°C)
δ(H)PH d
1JPH
δ (C1)t
1JPC
δ (P)bs
c
c
c
c
5a
5b
5c
5d
6a
6b
6c
6d
95
97
96
94
96
96
97
98
6.90
6.67
6.92
6.82
–
–
–
528.8
524.0
538.4
541.2
–
–
–
53.20
51.99
60.62
60.34
54.89
51.69
60.26
62.84
84.6
89.4
85.4
22.40
29.45
27.10
27.84
15.83
11.15
8.54
75.9
159
252
223
184
147.4
122.2
120.5
118.2
–
–
11.06
aIn 1H NMR spectra, C1H groups for compounds: 5a, δH 2.67 t, 2JPH 15.6; 6a, δH 3.82 t, 2JPH 19.2; there is a rapid exchange of OH and NH2
protons. The signals of C6H5 and C5H4N groups are multiplets in the standard area; fragment C6H2 of acid 6d, δH 7.50 s. In NMR spectra,
CH3 groups for compounds: 5b, δH 1.07 t, 3JPH 16, δC 15.26 s; 6b, δH 1.12 t, 3JPH 13.2, δC 15.64 s; group B for compounds: 5c, δC 135.93 s
(C2), 126.15 s (C3), 128.55 s (C4), 127.04 s (C5); 6c, δC 131.22 s (C2), 125.52 s (C3), 126.20 s (C4), 124.27 s (C5); group C for compound:
5d, δC 151.59 s (C2), 135.90 s (C3), 136.14 s (C4), 146.30 s (C5), 147.43 s (C6); group D for compound: 6d, δH 1.30 s (t-Bu), 5.30 br. s (OH),
δC 126.89 s (C2), 124.43 (C3), 138.65 s (C4), 151.09 s (C5), 34.35 s (Me3C), 30.08 s (Me3C).
t-Bu
3
4
3
4
3
4
2
2
5
5
2
5
Groups:
OH
(B),
(C),
(D).
N
6
t-Bu
bThe data of 31P–{1H} spectra are presented.
cThe compounds are decomposed by heating at 100°C.
TABLE 4 Elemental Analyses Data of Compounds 4b–d, 5a–d, and 6a–da
Calculated (%)
Found (%)
Number
Empirical Formula
Formula Weight
C
H
C
H
4b
4c
4d
5a
5b
5c
5d
6a
6d
6c
6d
C14H41NO6P2Si4
C19H43NO6P2Si4
C27H59NO7P2Si4
CH5NNa2O4P2
C2H7NNa2O4P2
C7H9NNa2O4P2
C6H8N2Na2O4P2
CH7NO6P2
493.77
555.85
684.07
203.07
217.02
279.09
280.07
191.03
205.05
267.13
395.34
34.05
41.06
47.41
5.91
11.07
30.13
25.73
6.29
8.37
7.80
8.69
2.48
3.25
3.25
2.88
3.70
4.42
4.15
6.88
33.78
40.74
47.26
5.79
10.88
29.98
25.59
6.12
8.23
7.72
8.61
2.52
3.13
3.28
2.97
3.74
4.47
4.19
6.94
C2H9NO6P2
C7H11NO6P2
C15H27NO7P2
11.71
31.48
45.57
11.58
31.32
45.43
aThe air-sensitive compounds 1a–d, 2a–d, 3a–d, and 4a were analyzed as their air-stable derivatives 5a–d and 6a–d.
EXPERIMENTAL
O,O,O-Tris(trimethylsilyl)
1-Aminoethylidenediphosphonite (1b)
1
The H, 13C, and 31P NMR spectra were registered
on a Bruker Avance-400 spectrometer (400, 100, and
162 MHz, respectively) in CDCl3 (1–4), D2O (5), or a
mixture of CD3OD and C5D5N (6) against tetram-
ethylsilane (1H and 13C) and 85% H3PO4 in D2O
(31P). All reactions were carried out under dry argon
in anhydrous solvents. The starting trimethylsilyl es-
ters of trivalent phosphorus acids were prepared as
described in [15, 16], and the starting hydrochlo-
rides of ethoxymethylene imines were discussed in
Ref. [13].
A solution of bis(trimethylsiloxy)phosphine (13.0 g,
62.0 mmol) in 15 mL of methylene chloride
was added to a mixture of hydrochloride of 1-
ethoxyethylidene imine (2.5 g, 20.0 mmol) un-
der stirring at 10°С. The mixture was stirred for
1 h, then the solvent was removed, and 20 mL
of bis(trimethylsilyl)amine was added to the mix-
ture. The mixture was refluxed, the solvent was re-
moved, and the residue was distilled to give 5.4 g of
diphosphonite 1b. According to NMR spectra,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of the New Types of N-Unsubstituted Aminomethylenebisorganophosphorus Acids and Their Derivatives 105
diphosphonite 2b was observed as a by-product
(10%).
1-Aminoethylidenediphosphonic Acid (6b)
A solution of diphosphonate 4b (3.8 g, 7.7 mmol) in
ether (10 mL) was added with stirring in 20 mL of
methanol cooled to 10°С. The mixture was heated to
boiling. The solvent was removed, and white crys-
tals were kept in a vacuum (1 mm Hg) for 1 h to
give 1.5 g of acid 6b. Acids 6a,c,d were prepared
similarly.
Diphosphonite 1a was prepared similarly, and
diphosphonites 1c,d were observed only by 31P NMR
spectra as intermediates in the course of preparation
of diphosphonites 2c,d.
O,O,O,O-Tetra(trimethylsilyl)
1-Aminoethylidenediphosphonite (2b)
A
mixture of diphosphonite 1b (5.4 g,
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14.0 mmol), bis(trimethylsilyl)amine (20 mL)
and chlorotrimethylsilane (5.0 g, 46.0 mmol) was
refluxed to complete ammonium chloride subli-
mation. The excess of bis(trimethylsilyl)amine was
removed, and the residue was distilled to obtain 5.6
g of diphosphonites 2b. According to NMR spectra,
diphosphonite 3b was observed as a by-product
(15%).
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Diphosphonites 2a,c,d were prepared similarly,
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products (5–10%).
O,O,O,O-Tetra(trimethylsilyl)
1-Aminoethylidenediphosphonate (4b)
Trimethysilyl trifluoromethanesulfonate (0.3 g,
1.3 mmol) was added with stirring to a mixture of
tris(trimethylsilyl)phosphite (10.0 g, 33.5 mmol) and
hydrochloride of 1-ethoxyethylidene imine (1.3 g,
10.5 mmol) in 10 mL of methylene chloride. The mix-
ture was refluxed for 1 h, the solvent was removed,
and bis(trimethylsilyl)amine (15 mL) was added to
the residue. The mixture was refluxed to complete
sublimation of ammonium chloride, and the residue
was distilled to obtain 3.8 g of diphosphonate 4b.
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by the addition of 5 mL of diethyl ether and 10 mL of
hexane. The crystals of diphosphonate 4d were kept
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Disodium 1-Aminoethylidenediphosphonite
(5b)
A solution of diphosphonite 2b (5.6 g, 12.0 mmol)
in 15 mL of ether was added with stirring at 5°С to
a solution of sodium methylate (1.3 g, 24.0 mmol)
in 30 mL of methanol. The resulting mixture was
heated to boiling, the solvent was removed, and
residue was kept in a vacuum for for 1 h (1 mm
Hg) to give 2.5 g of salt 5b. The salts 5a,c,d were
prepared similarly.
Heteroatom Chemistry DOI 10.1002/hc