Synthesis of phosphorus-substituted dialkylamides of organophosphorus acids, containing P-C-N-P Moiety

Article abstract of DOI:10.1002/hc.20468

Reactions of N-(trimethylsilyl)amino-methylphosphonates with organophosphorus acid chlorides were studied, which allowed to develop convenient synthetic approaches to novel phosphorus-substituted dialkylamides of organophosphorus acids, including a P-C-N-P moiety. Certain properties of the resulting compounds are presented.

Full text of DOI:10.1002/hc.20468

Heteroatom Chemistry
Volume 19, Number 5, 2008
Synthesis of Phosphorus-Substituted
Dialkylamides of Organophosphorus Acids,
Containing P–C–N–P Moiety
Andrey A. Prishchenko, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, and Valery S. Petrosyan
Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia
Received 20 June 2007; revised 7 April 2008
N-(trimethylsilyl)aminomethylphosphonates A [4]
ABSTRACT: Reactions of N-(trimethylsilyl)amino-
are convenient synthons for preparing promising
methylphosphonates with organophosphorus acid
phosphorus-containing carboxamides and sulfon-
chlorides were studied, which allowed to develop con-
amides containing PCH2NC(O) and PCH2NSO2
venient synthetic approaches to novel phosphorus-
fragments [5,6].
substituted dialkylamides of organophosphorus acids,
including a P–C–N–P moiety. Certain properties
ꢀ
C
of the resulting compounds are presented.
2008
RESULTS AND DISCUSSION
Wiley Periodicals, Inc. Heteroatom Chem 19:495–
499, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20468
In the present study, we found that the reaction of
phosphonates A with chlorides of three- and four-
coordinate organophosphorus acids in methylene
chloride leads to phosphorus-substituted amides 1–6
in high yields (Eq. (1)).
INTRODUCTION
Organophosphorus acid amides of various struc-
tures are widely used in organic synthesis as
highly reactive synthons [1] and ligands in a
series of catalytic systems [2]. They are also of
interest as biologically active compounds [3]. In
the present work, we have developed convenient
methods for preparing novel organophospho-
rus acid amides containing P C N P moiety.
It was previously shown that easily available
Dedicated to academician Martin I. Kabachnik (1908–1997).
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic Re-
search.
Bisphosphorus-substituted methylphosphonic di-
amide 7 was prepared by the reaction of an excess
of phosphonate A with methylphosphonic dichloride
under mild conditions (Eq. (2)).
Contract grant number: 08-03-00282.
2008 Wiley Periodicals, Inc.
c
ꢀ
495

496 Prishchenko et al.
TABLE 1 Yields, Product Constants, and NMR Spectral Data for the P1C1HmN(C2Hn)P2 Fragments (δ, ppm; J, Hz) of
Compounds 1–14a
bp (◦)
No. Yield (%) (p mm Hg) nD20
δ (C1Hm) JPH 3JPH δ(C1) dd JPC JPC δ(C2)d 2JPC δ(P1), d δ(P2), d JPP
2
1
2
3
H
1a
1b
2a
2b
2c
2d
3
98
98
84
86
81
74
85
83
81
81
78
89
87
85
74
64
–
–
–
–
3.4–3.5m
3.4–3.5m
2.98 t
–
–
–
–
46.54 160.5 28.1 37.43 14.3 18.54 162.49 12.9
41.92 159.4 22.9 43.81 19.7 18.90 163.13 8.5
42.97 159.3 24.1 32.17 13.7 22.29 142.72 18.3
37.86 157.9 17.3 38.80 20.5 22.59 143.19 12.2
111 (1) 1.4472
8.0
8.4
8.6
–
8.0
8.0
9.2
8.0
8.8
8.0
6.8
8.6
–
8.0
8.0
9.2
8.0
8.8
9.2
9.2
8.6
–
115 (1) 1.4485 3.01 dd
129 (1.5) 1.4742 3.03 t
123 (1) 1.4735 2.9–3.1m
39.09 158.3 22.6 39.35 16.7 21.24 141.25
37.95 158.0 15.7 39.54 23.5 21.85 142.37
9.7
8.6
7.0
108 (1) 1.4672
128 (1) 1.4680
139 (1) 1.4418
168 (1) 1.4630
202 (1) 1.4705
138 (1) 1.4718
160 (2) 1.5018
2.90 t
2.87 t
3.06 t
3.02 t
3.05 t
3.34 dd 12.0
3.35 t
3.30 t
44.47 156.0 15.1 43.83 11.3 23.02
67.89
4
51.28 157.1 28.4 34.88 s
44.05 159.7 4.8 34.34 s
–
–
–
–
–
–
–
22.54
20.97
21.10
21.19
21.23
21.83
21.44
63.71 23.8
6.96 19.5
48.23 15.3
34.41 t 18.5
73.60 12.9
5
6
41.31 d 160.6
42.29 d 159.9
–
–
33.35 s
32.83 s
7
12a
12b
12c
13
14
40.57 158.6 6.6 40.54 s
39.09 157.8 3.1 40.63 s
9.2
8.6
–
84.55
81.16 14.7
30.79 8.5
7.09 29.2
8.3
169 (1)b
152 (2) 1.4498 2.9–3.1m
178(1)
–
43.75 d 160.8
38.26 156.2 4.5 39.11
55.53 158.9
29.11c 6.2 19.03
–
34.87 s
4.6 21.69
1.4981 4.81 dd 23.6 11.2
5
aAll signals of the alkyl and ethoxy groups are in the standard area. Fragment C2H3. % 1H NMR spectrum, δ, ppm (J, Hz): 2a: 2.37 dd (3JPH
=
4
4
4
4
7.6, JPH = 1.2); 4: 2.54 dd (3JPH = 5.2, JPH = 1.6); 5: 2.40 dd (3JPH = 9.2, JPH = 1.2); 6: 2.35 dd (3JPH = 9.2, JPH = 1.2); 7: 2.43 dd (3JPH
4
= 9.6, JPH = 2.8); 12c: 2.52 d (2JPH = 10.4); 14: 2.27 d (3JPH = 9.6 Hz); the signals of the C2H2 fragments of the other compounds appear
as multiplets in the range 2.6–3.1 ppm. Fragment PCH3, δ, ppm (J, Hz): 7: δH 1.25 d (2JPH = 15.2), δC 9.37 d (1JPC = 116.3); 13: δH 1.32 d
(2JPH = 16.8), δC 11.40 d (1JPC = 134).
bmp 43◦C.
cdd, 3JPC 3 Hz.
Amides 2a and 2b were also prepared from
tetraethyl pyrophosphite, but the latter proved to be
less reactive in analogous transformations. Thus, its
reaction with phosphonates A could only be effected
on heating at 130◦C in the presence of a catalyst,
zinc chloride. As a result, amides 2a and 2b were
obtained in high yields (Eq. (3)).
Hence, under conditions of these reactions, ring
cleavage in compounds B occurs mainly by a sym-
metric pathway (cf. [4]).
Substituted amidophosphorous dichlorides 1a
and 1b were prepared in quantitative yields, but, un-
like amides 2–7, they are thermally unstable. They
can be stored for a long time at 20◦C but polymer-
ize on distillation. Treatment of amidochlorides 1a
and 1b with a mixture of ethanol and triethylamine
gives phosphoroamidites 2a and 2b in high yields
(Eq. (5)).
The reaction of tetraethyl pyrophosphite with
symmetrical hexahydrotriazines
B under simi-
lar conditions leads to amides 2a and 2b
in high yields. Along with these products,
bis(phosphonomethyl)amines 8a and 8b were iso-
lated in low yields (10%–15%), and the 31P NMR
spectra of low-boiling fractions displayed signals of
amides 9a and 9b (Eq. (4)).
The reaction of amidochloride 1a with an ex-
cess of triethyl orthoformate involves cleav-
age of the P N bond. Subsequent reactions of
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Phosphorus-Substituted Dialkylamides of Organophosphorus Acids, Containing P–C–N–P Moiety 497
the intermediates and triethyl orthoformate lead
terest as promising ligands and biologically active
compounds. Their structure was confirmed by the
NMR spectra containing characteristic signals of the
to N-formylaminomethylphosphonate 10 and di-
ethoxymethylphosphonate 11 (Eq. (6)). The pre-
sented reaction scheme agrees with data in [7–9].
P1C1HmN(C2Hn)P2 fragments (see Table 1). The
31P NMR signals of the obtained compounds are lo-
cated in the ranges characteristic of their simplest
analogs with the same coordination of the phospho-
rus atoms. The elemental analyses data of synthe-
sized compounds, confirmatory of their composi-
tion, are summarized in Table 2.
Amides 2–4 containing a three-coordinate phos-
phorus atom were used by us to prepare novel four-
coordinate phosphorus compounds with a PCH2NP
fragment. So amides 2b–4 smoothly take up sulfur
in benzene to form thio derivatives 12 (Eq. (7)).
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were obtained
on a Varian VXR-400 spectrometer (400, 100, and
162 MHz, respectively) in CDCl3 against TMS (1H,
13C) and 85% H3PO4 in D2O (31P). All reactions were
carried out under dry argon in anhydrous solvents.
Amide 2b reacts with an excess of methyl io-
dide under mild conditions by an Arbuzov reaction
scheme, yielding amidophosphonate 13 (Eq. (8)).
O,O-Diethyl N-(dichlorophosphino)-N-methyl-
aminomethylphosphonate (1a)
To a solution of 10 g of O,O-diethyl N-methyl-N-
(trimethylsilyl)aminomethylphosphonate in 40 mL
of methylene chloride, a solution of 6.5 g of phos-
phorus trichloride in 20 mL of methylene chloride
was added dropwise with stirring at 0◦C. The solvent
was removed at 20◦C, and the residue was kept
in a vacuum (1 mmHg) at 20◦C to give 10.9 g of
phosphonate 1a.
The unique route to novel four-coordinate
phosphorus-substituted amide of diethyl phospho-
ric acid 14 was found by us. So the adduct
of benzal(methyl)amine and diethyl chlorophos-
phate C, prepared under mild (cf. [10]) condi-
tions, reacts with diethyl trimethylsilyl phosphite to
form phosphorus-substituted amidophosphate with
PCHNP fragment 14 (Eq. (9)).
Phosphonate 1b was obtained analogously.
O,O-Diethyl N-(diethoxyphosphino)-N-methyl-
aminomethylphosphonate (2a)
(a) To a solution of 6.5 g of diethyl N-methyl-N-
(trimethylsilyl)aminomethylphosphonate in 10 mL
of methylene chloride, a solution of 4.1 g of diethyl
phosphorochloridite in 5 mL of methylene chloride
was added dropwise with stirring at 10◦C. The sol-
vent was removed, and the residue was distilled in a
vacuum to give 6.5 g of phosphonate 2a.
The novel phosphorus-substituted organophos-
phorus acid amides 1–7 and 12–14 present in-
Heteroatom Chemistry DOI 10.1002/hc

498 Prishchenko et al.
TABLE 2 Elemental Analyses Data of Synthesized Compoundsa
Calcd. (%)
Found (%)
Empirical
Formula
Formula
Weight
No
C
H
C
H
2a
2b
2c
2d
5
C10H25NO5P2
301.27
315.29
285.23
299.25
317.27
341.37
422.33
347.36
315.36
357.44
301.27
393.37
39.87
41.90
37.90
40.14
37.86
49.26
36.97
38.04
41.89
47.04
39.87
48.85
8.36
8.57
7.42
7.75
7.94
9.74
7.88
7.83
8.63
9.31
8.36
7.43
39.65
41.78
37.73
40.02
37.62
48.98
36.75
37.89
41.74
46.88
39.69
48.64
8.26
8.52
7.29
7.64
7.87
9.66
7.81
7.72
8.57
9.23
8.22
7.26
C11H27NO5P2
C9H21NO5P2
C10H23NO5P2
C10H25NO6P2
C14H33NO4P2
C13H33N2O7P3
C11H27NO5P2S
6
7
12a
12b
12c
13
14
C
C
11H27NO3P2S
14H33NO3P2S
C10H25NO5P2
C16H29NO6P2
aThe compounds 1a, 1b, 3, 4 are unstable in the air atmosphere; therefore, these substances were analyzed as their derivatives 2a, 2b, 12b,
and 12c.
Compounds 2b, 2c, and 2d–7 were obtained
analogously.
low-boiling fraction contains a signal of N,N-
bis(diethoxyphosphino)-N-ethylamine
(9b),
δP
(b) To a mixture of 5.1 g of diethyl N-methyl-
N-(trimethylsilyl)aminomethylphosphonate, 5.4 g of
tetraethyl pyrophosphite, and 0.2 g of zinc chloride
was heated at 130◦C for 1 h and then distilled to give
4.9 g of phosphonate 2a, yield 81%.
143.72 ppm (cf. [12]).
(d) To a solution of 10.9 g of phosphonate 1a in
50 mL of diethyl ether, a solution of 3.6 g of ethanol
and 8.2 g of triethylamine in 30 mL of ether was
added dropwise with stirring at 0◦C. The resulting
mixture was left for a day at 20◦C, the triethylamine
hydrochloride was filtered off, the solvent was re-
moved, and the residue was distilled to give 8.9 g of
phosphonate 2a, yielding 76%.
Phosphonate 2b was obtained analogously,
yielding 83%.
(c) To a mixture of 6.3 g of tetraethyl pyrophos-
phite, 1 g of 1,3,5-trimethylhexahydrotriazine, and
0.2 g of zinc chloride was heated at 135◦C for 1 h
and then distilled to give 5.2 g of phosphonate
2a, yield 74%. Repeated distillation of the high-
boiling fraction gave 0.5 g of N,N-bis(diethoxy-
phosphinoylmethyl)-N-methylamine (8a). Yield
20%, bp 155◦C (1 mmHg), nD20 1.4530. PC1H2NC2H3
fragment: 1H NMR spectrum, δ, ppm: 3.01 d
Phosphonate 2b was obtained analogously,
yielding 78%.
Reaction of Phosphonate 1a with Triethyl
Orthoformate
To a solution of 10.9 g of phosphonate 1a in 20 mL
of methylene chloride, a solution of 12.6 g of tri-
ethyl orthoformate in 20 mL of methylene chlo-
ride was added dropwise with stirring at 0◦C. The
resulting mixture was left for a day at 20◦C, the
solvent was removed, and the residue was dis-
tilled to give 6.3 g (78%) of O,O-diethyl N-formyl-
N-methylaminomethylphosphonate (10), bp 125◦C
(1 mmHg), n2D01.4570. According to NMR data, phos-
phonate 10 is a 4:1 ratio of two stereoisomers. First
isomer: PC1H2N(C2H3)C3(O)H fragment: 1H NMR
spectrum, δ, ppm: 3.25 d (C1H2, 2 JPH = 11.3 Hz), 2.65
s (C2H3), 7.56 s (C3H); 13C NMR spectrum, δC, ppm:
2
(C1H2, JPH = 9.6 Hz); 13C NMR spectrum, δC,
1
3
ppm: 54.02 dd (C1, JPC = 157.5, JPC = 10.4 Hz),
46.22 t (C2, JPC = 7.9 Hz); 31P NMR spectrum, δP,
3
ppm: 21.55 s (cf. [11]). The 31P NMR spectrum of
the low-boiling fraction [bp 75–85◦C (1 mmHg)]
contains, together with the signal of the starting
tetraethyl pyrophosphite (δP 125.5 ppm), a signal of
N,N-bis(diethoxyphosphino)-N-methylamine (9a),
δP 143.22 ppm (cf. [12]).
Phosphonate 2b (yield 72%) and N,N-bis(di-
ethoxyphosphinoylmethyl)-N-ethylamine (8b) were
obtained analogously, yield 15%, bp 159◦C
(1 mmHg), n2D0 1.4480. PC1H2NC2H2 fragment:
1
38.40 d (C1, JPC = 155.2 Hz), 34.35 s (C2), 161.20 s
2
1H NMR spectrum, δ, ppm: 3.10 d (C1H2, JPH
(C3); 31P NMR spectrum, δP, ppm: 18.61 s. Second iso-
= 9.2 Hz); 13C NMR spectrum, δC, ppm: 49.00
mer: PC1H2N(C2H3)C3(O)H fragment: 1H NMR spec-
1
3
2
dd (C1, JPC = 156.9, JPC = 7.5 Hz), 49.97 t (C2,
3 JPC = 7.8 Hz). 31P NMR spectrum, δP, ppm:
22.01 s (cf. [11]). The 31P NMR spectrum of the
trum, δ, ppm: 3.15 d (C1H2, JPH = 10.0 Hz), 2.45 s
(C2H3), 7.53 s (C3H); 13C NMR spectrum, δC, ppm:
43.95 d (C1, JPC = 158.0 Hz), 30.10 s (C2), 162.00 s
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Phosphorus-Substituted Dialkylamides of Organophosphorus Acids, Containing P–C–N–P Moiety 499
(C3); 31P NMR spectrum, δ, ppm: 18.20 s (cf. [13]).
Repeated distillation of the low-boiling fraction gave
6.7 g of O,O-diethyl (diethoxymethyl)phosphonate
(11), yield 72%, bp 79◦C (1 mmHg), n2D01.4255. PCH
fragment: 1H NMR spectrum, δ, ppm: δ 4.55 d
(2 JPH = 5.0 Hz); 13C NMR spectrum, δC, ppm: 98.19
d (1 JPC = 207.0 Hz); δP 11.15 ppm (cf. [14]).
was added. The resulting mixture was left to stand
for 48 h at 20◦C. The solvent was removed, and the
residue was distilled in a vacuum to give 9.4 g of
phosphonate 14.
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ethylaminomethylphosphonate (12a)
A mixture of 3.2 g of phosphonate 2b, 0.4 g of sulfur,
and 10 mL of benzene was heated on a water bath
for 1 h and then cooled. The residual sulfur was then
filtered off, the solvent was removed, and the residue
was distilled to give 2.9 g of phosphonate 12a.
Compounds 12b and 12c were obtained analo-
gously.
O,O-Diethyl N-[ethoxy(methyl)phosphinoyl]-N-
ethylaminomethylphosphonate (13)
To a solution of 4.2 g of phosphonate 2b in 15 mL of
ether, a solution of 6 g of methyl iodide in 5 mL of
ether was added dropwise with stirring at 10◦C. The
resulting mixture was refluxed for 1 h, the solvent
was removed, and the residue was distilled to give
3 g of phosphonate 13.
O,O-Diethyl N-methyl-N-(diethoxyphosphoryl)-
amino(phenyl)methylphosphonate (14)
To a solution of 4.5 g of benzal(methyl)amine in 15
mL of methylene chloride, a solution of 6.4 g of di-
ethyl chlorophosphate in 10 mL of methylene chlo-
ride was added dropwise with stirring at 10◦C. Af-
ter 30 min, diethyl trimethylsilyl phosphite, 8.6 g,
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Heteroatom Chemistry DOI 10.1002/hc