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

Article abstract of DOI:10.1002/hc.20552

The interaction of esters of trivalent organophosphorus acids containing PH and POSiMe₃ fragments with various derivatives of formamide is proposed as convenient methods for the synthesis of new N-substituted aminomethylenebisorganophos-phorus acids and their derivatives with three-, four-, and five-coordinated phosphorus. Also the new functionalized derivatives of the new aminomethylenebisphosphinic acids with substituted hydroxymethyl moieties are synthesized, and some properties of the obtained compounds are presented.

Full text of DOI:10.1002/hc.20552

Heteroatom Chemistry
Volume 20, Number 6, 2009
S
ynthesis of the New Types of N-Substituted
Aminomethylenebisorganophosphorus Acids
and Their Derivatives
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 18 June 2009; revised 3 July 2009
of N-substituted aminomethylenebisorganophos-
ABSTRACT: The interaction of esters of trivalent
phorus acids and their derivatives in high yield.
organophosphorus acids containing PH and POSiMe
3
Also for the first time we have prepared the
aminomethylenebisorganophosphorus compounds
with three- and five-coordinated phosphorus.
fragments with various derivatives of formamide is
proposed as convenient methods for the synthesis of
new N-substituted aminomethylenebisorganophos-
phorus acids and their derivatives with three-,
four-, and five-coordinated phosphorus. Also
the new functionalized derivatives of the new
aminomethylenebisphosphinic acids with substituted
hydroxymethyl moieties are synthesized, and some
properties of the obtained compounds are presented.
RESULTS AND DISCUSSION
An excess of dibutoxyphosphine slowly reacts with
◦
dimethylformamide dimethylacetal at 20 C, and this
reaction is easily completed under heating of the re-
◦
ꢀ
2
C
2009 Wiley Periodicals, Inc. Heteroatom Chem
0:319–324, 2009; Published online in Wiley InterScience
action mixture at 130 C giving aminomethylenebis-
phosphonite 1 (Eq. (1)). The suggested scheme of
this reaction includes an electrophilic attack of ac-
etal on the trivalent phosphorus followed by the de-
composition of the phosphorane intermediate with
methanol being eliminated.
(
www.interscience.wiley.com). DOI 10.1002/hc.20552
INTRODUCTION
OMe
The numerous aminomethylenebisorganophospho-
rus compounds present a great interest as promising
polydentate ligands and prospective biologically ac-
tive compounds [1–7]. In the present work, we re-
port the results of the interaction of the esters
of trivalent organophosphorus acids with PH and
(MeO)2CHNMe2
2
(BuO)2PH
[(BuO)2P]2CHNMe2
H
(1)
[
(BuO)2P]2CHNMe2
–
2MeOH
1
POSiMe fragments with various derivatives of for-
mamide resulting in formation of the new types
3
Several aminomethylenebisphosphonites 2–5 are
synthesized by the unique reaction of diethyl pi-
valoylphosphonite with dialkylformamide diethylac-
etals in the presence of excess ethanol and zinc
Dedicated to Prof. Ivan F. Lutsenko (1912–1993).
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic
Research.
◦
chloride as a catalyst at 80–110 C with a good
yields (Eq. (2)). Thus diethyl pivaloylphosphonite
containing labile P C bond (cf. [8,9]) may be suc-
cessfully applied in aminomethylation as a syn-
thetic analog of unstable diethoxyphosphine. The
Contract grant number: 08-03-00282.
ꢀ
c 2009 Wiley Periodicals, Inc.
319

320 Prishchenko et al.
proposed scheme of this reaction involves the cleav-
age of the P C bond of the pivaloylphosphonite by
ethanol, resulting in diethoxyphosphine, which un-
dergoes further aminomethylation similarly to dib-
utoxyphosphine.
dimethylformamide dimethylacetal under the same
conditions. There is no P C bond formation, but
only trans-esterification of acetal with tautomer A
occurs yielding via intermediate B the mixture of
cyclic compounds 13 and 14 (Eq. (5)).
EtOH, ZnCl2
H
O
O
O
O
O
O
2 2
(MeO) CHNMe
2
(EtO)2PC(O)Bu-t
2 (EtO)2PH
–
2t-BuCOOEt
P
PO(CH2)2OH
–
MeO H
A
(
EtO)2CHNR2
[
(EtO)2P]2CHNR2
–
2EtOH
(2)
OMe
O
MeOH
2–5
PO(CH2)2OCHNMe2
O
B
NR2 = NMe2 (2), NPr2 (3), N
(4), N
O (5).
H
O
O
OMe
O
O
(5)
POMe
Also it was shown by us that the interaction of P(O)H
acids with dimethylformamide dialkyl acetals pro-
ceeds as a two-step process. So diethyl phosphite
and dipropyl phosphinoxide react with formamide
acetals under heating at 110–130 C, giving mono- or
bisorganophosphorus compounds 6–10 (Eq. (3); cf.
PO(CH2)2OCHNMe2
OMe
13
O
O
◦
+
HO(CH2)2OCHNMe2
OMe
CHNMe2
–
MeOH
1
4
[10,11]).
The excess of dialkyl trimethylsilyl phosphites easily
reacts with dimethylformamide acetal in the pres-
ence of zinc chloride by heating at 130 C, giving
NMe2
X2PCHOR
O
(
RO)2CHNMe2
X2P(O)H
– ROH
[
X2P]2CHNMe2
X2PH
O
–
ROH
◦
O
6
–8
9,10
bisphosphonates 9,15–17 in high yields (cf. [13]
(
Eq. (6)).
X = EtO (6,7,9), Pr (8,10); R = Me (6), Et (7,8).
(3)
(
MeO)2CHNMe2, ZnCl2
2
(RO)2POSiMe3
[(RO)2P]2CHNMe2
O
The compounds 6 and 8 were used as aminome-
thylating reagents to obtain aminomethylenebiso-
rganophosphorus substances with two different
phosphorus-containing groups. So, diethyl phos-
phite easily reacts with phosphinoxide 8 yielding
nonsymmetrical compound 11, and methoxy(di-
methylamino)methylphosphonate 6 reacts smoothly
with hydrospirophosphorane to give the amino-
methylenebisphosphorus compound 12 with tetra-
and penta-coordinated phosphorus (Eq. (4)).
–2MeOSiMe 3
9,15–17
R = Me (15), Et (9), Pr (16), i-Pr (17).
(6)
Also in the present work, we propose a convenient
synthesis of amido(ethoxy)methylphosphonates 18–
20 containing pyrrolidone, valero- and caprolac-
tams fragments. Hence N-diethoxymethyl lactams
C, which were obtained by the procedure as de-
scribed in [14], react with diethyl trimethylsilyl and
◦
diethyl phosphites at 130–150 C in the presence of
NMe2
(
EtO)2P(O)H
zinc chloride to form phosphonates 18–20 (Eq. (7)).
Using diethyl trimethylsilyl phosphite is optimal and
provides high yields of phosphonates, whereas with
diethyl phosphite the yield is much lower.
8
Pr2PCHP(OEt)2
–
EtOH
O
O
H
11
O
O
O
(4)
P
NMe2
O
O
O
O
O
(CH2)n
(
EtO)2PCH
O
P
(CH2)n
EtO)2CHN C O
6
–
MeOH
(
EtO)2POX, ZnCl2
(EtO)2PCH(OEt)N
18–20
C O
(
–
EtOX
12
C
O
(
CH2)n
The proposed scheme of last reaction involves an
electrophilic attack of an aminomethylating reagent
on the trivalent phosphorus of hydrospirophospho-
rane tautomer A in the common manner (cf. [12]);
the elimination of methanol followed by the rebuild-
ing of the phosphorane structure of compound 12.
Another route of the similar reaction was realized
by the interaction of hydrospirophosphorane with
(EtO) POX, ZnCl
(7)
2
2
[
(EtO)2P]2CHN C O
–
EtOX
O
D
X = Me3Si , H ; n= 3 (18) , 4 (19) , 5 (20).
Using an excess of phosphites in this reaction
unfortunately did not lead to formation of diphos-
phorylation products, amidomethylenebisphos-
phonates D. This is connected with the fact that
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of the New Types of N-Substituted Aminomethylenebisorganophosphorus Acids and Their Derivatives 321
phosphonates 18–20 are much weaker amino-
Also the treatment of bisphosphonite 24 with a
diluted solution of sodium methylate in methanol
results in formation of water-soluble disodium
bisphosphonite 25 as white hygroscopic crystals.
Under similar conditions, bisphosphonate 22 was
easily transformed to corresponding bisphosphonic
acid 26 via treatment with methanol in high yield
(Eq. (11)).
methylating agents compared with substituted
amino(alkoxy)methylphosphonates 6 and 8 because
of the electronic and steric effects of the lactam-
containing fragments. Evidently, the catalytic effect
of zinc chloride is connected with its ability to
generate electrophilic carbonio-immonium ions E
as well as nucleophilic zinc-containing salts F in the
course of the process (Eq. (8)).
+
–
(RO)2CHNR2 ZnCl2
ROCHNR2 [ROZnCl2]
E
(RO)2PCH(OR)NR2 + Me3SiOR + 2ZnCl2
(8)
(RO)2POSiMe3 ZnCl2
(RO)2POZnCl + Me3SiCl
O
F
The new derivatives of N-anilinomethylenebiso-
rganophosphorus acids were synthesized by us via
interaction of N-phenyl ethoxymethylenimine G and
NaO
2
MeONa, 2 MeOH
P
CHNHPh
2
4
2
ꢁ
– 2 Me3SiOMe
N,N -diphenylformamidine H [15] with trimethylsi-
H
2
O
lyl esters of phosphorous and hypophosphorous
acids. Hence, imine G reacts with a mixture of
diethyl- and diethyl-trimethylsilyl phosphites in the
presence of boron trifluoride-diethyl etherate as
2
5
(11)
4
MeOH
2
[(HO) P] CHNHPh
2
2
–
4 Me3SiOMe
◦
a catalyst for 2 weeks at 20 C, yielding bispho-
O
26
sphonate 21 as white crystals. The similar re-
action of imine G with a mixture of bis- and
Bisphosphonite 24 is a key synthon for obtaining
the several functionalized bisphosphinates. So bis-
phosphonite 24 readily adds by the carbonyl group
of aldehydes in methylene chloride to give phosphi-
nates I as intermediates (cf. [17]), and functionalized
bisphosphinic acids 27 and 28 were prepared in high
yields by the treatment of the reaction mixture with
methanol (Eq. (12)).
tris(trimethylsilyl)phosphites proceeds by heating at
◦
1
40 C in the presence zinc chloride, giving bisphos-
phonate 22 in high yield (Eq. (9)).
(
XO)2POSiMe3, (XO)2P(O)H
EtOCH=NPh
(XO) P CHNHPh
2
–
EtOSiMe3
G
O
2
2
1,22
X = Et (21), Me3Si (22).
(9)
2
ArCHO
Ar(Me3SiO)CH
Me3SiO
24
P CHNHPh
O 2
Evidently, there are two simultaneous reactions of
the addition to CH N fragment and substitution of
the ethoxy group in the course of this process (cf.
I
4
MeOH
Ar(HO)CH
HO
[
12]). The excess of bis(trimethylsiloxy)phosphine
P CHNHPh
O 2
–
4 Me3SiOMe
(12)
◦
smoothly reacts with formamidine H at 140 C to give
phosphonite 23 in high yield that was easily silylated
by bis(trimethylsilyl)amine to form bisphosphonite
2
7,28
24 (Eq. (10); cf. [16]).
Ar = 4-MeOC6H4 (27),
(28).
N
NHPh
XO
H
PhNHCH=NPh, H
PhNHX
The synthesized compounds 1–28 are the promis-
ing synthons, polydentate ligands and biologically
active substances. The structures of N-substituted
aminomethylenebisorganophosphorus acids and
2
(XO)2PH
PCHP(OX)2
–
O
2
3
(10)
X2NH
NH3
[
(XO)2P]2CHNHPh
–
1
13
their derivatives. were confirmed by the H, C,
3
1
2
4
P NMR spectra, which show characteristic signals
X = Me3Si.
1
2
of the PC H(NC )P fragments (see Table 1). The
Heteroatom Chemistry DOI 10.1002/hc

322 Prishchenko et al.
b
c
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J
J
J
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a
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J
J
J
J
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e
d
d
d
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Heteroatom Chemistry DOI 10.1002/hc

Synthesis of the New Types of N-Substituted Aminomethylenebisorganophosphorus Acids and Their Derivatives 323
TABLE 2 Elemental Analyses Data of Compounds 1–28a
Calcd. (%)
Found (%)
Compound
Empirical Formula
C19H43NO P2
Formula Weight
C
H
C
H
1
2
3
4
5
6
7
8
9
411.51
299.29
355.39
339.35
341.32
225.23
239.25
235.31
331.29
323.39
327.34
345.27
275.19
387.41
387.41
279.27
293.30
307.33
379.34
555.85
279.09
267.13
507.42
449.35
55.46
44.15
50.69
49.55
45.75
42.66
45.18
56.15
39.88
55.71
47.70
38.27
30.55
46.51
46.51
47.31
49.14
50.81
47.50
41.06
30.13
31.48
54.44
50.79
10.53
9.09
9.93
9.21
8.56
8.95
9.27
11.14
8.21
10.91
9.55
7.30
6.96
9.11
9.11
7.94
8.25
8.53
7.17
7.80
3.25
4.15
5.36
4.71
55.09
44.01
50.55
49.64
45.81
42.52
44.86
55.88
39.64
55.49
47.54
38.14
30.43
46.40
46.42
47.03
48.87
50.64
47.29
40.94
30.03
31.37
54.26
50.57
10.37
9.03
9.89
9.18
8.49
8.87
8.95
11.02
8.12
11.07
9.26
7.49
6.83
9.03
9.06
7.81
8.03
8.42
7.08
7.74
3.28
4.19
5.28
4.78
4
C11H27NO P2
4
C15H35NO P2
4
C14H31NO P2
4
C13H29NO5P2
C H NO P
8
20
4
C H NO P
9
22
4
C11H26NO P
2
C11H27NO P2
6
10
11
12
15
16
17
18
19
20
21
22
25
26
27
28
C15H35NO P2
2
C13H31NO P2
4
C11H25NO7P2
C7H19NO P2
6
C15H35NO P2
6
C15H35NO P2
6
C11H22NO5P
C12H24NO5P
C13H26NO5P
C15H27NO P2
6
C19H43NO P Si
6
2
4
C7H NNa O P
9
2
4 2
C7H11NO P2
6
C23H27NO P2
8
C19H21N O P
3
6 2
aThe air-sensitive compounds 23 and 24 were analyzed as their air-stable derivative 25. The compounds 13 and 14 were obtained as a mixture.
elemental analysis data of synthesized compounds
are summarized in Table 2.
Dipropyl Ethoxy(dimethylamino)methyl Phosphi-
noxide (8). A mixture of 7 g of dipropyl phosphinox-
ide and 7.7 g of dimethylformamide dimethylacetal
◦
was heated to 110–130 C for 2.5 h and then distilled
in a vacuum to obtain 8.5 g phosphinoxide 8.
EXPERIMENTAL
The compounds 6,7,9–12 were prepared simi-
larly. At the same conditions from the mixture of 9 g
of hydrospirophosphorane A and 9.5 g of dimethyl-
formamide dimethylacetal, it was obtained 7 g of
the mixture 2-methoxy-1,3,5-dioxaphospholane 13,
1
13
31
The H, C, and P NMR spectra were registered on
the Varian VXR-400 and Bruker Avance-400 spec-
trometer (400, 100, and 162 MHz, respectively) in
C
6
D
6
, CDCl
3
(1–24) or CD
3
OD, (CD
3
)
2
SO, D
PO
P). All reactions were carried out under dry ar-
2
O(25–
1
13
2
8)against TMS ( H and C) and 85% H
3
4
in D
2
O
δ
P
132.3 ppm and 2-dimethylamino-1,3-dioxolane
3
1
◦
(
14, δ
[18,19]).
O, O, O, O-Tetramethyl Dimethylaminomethyl-
H
(CH) 5.33 ppm, bp 30–34 C at 1 mmHg (cf.
gon in anhydrous solvents. The starting derivatives
of formamide were prepared as described in [15],
and the starting esters of trivalent phosphorus acids
were discussed in [12].
O, O, O, O-Tetrabutyl Dimethylaminomethylene-
bisphosphonite (1). A mixture of 6.3 g of dibu-
toxyphosphine and 2.7 g of dimethylformamide
dimethylacetal was heated to 120–130 C for 1 h
and then distilled in a vacuum to obtain 4.5 g of
phosphonite 1.
enebisphosphonate (15). A mixture of 16.1 g of
dimethyl trimethylsilyl phosphite, 4.8 g of dimethyl-
formamide dimethylacetal, and 0.2 g zinc chloride
◦
was heated to 130 C for 1.5 h and then distilled in a
vacuum to obtain 8.5 g of bisphosphonate 15.
The compounds 9,16–20 were prepared simi-
larly.
◦
O, O, O, O-Tetraethyl
N-Anilinomethylenebis-
Phosphonites 2–5 and 23 were prepared simi-
larly. Phosphonites 2–5 were synthesized in the pres-
ence of 2 mL of ethanol and 0.1 g of zinc chloride,
phosphonate (21). To a stirredmixture of diethyl
phosphite (4.3 g), diethyl trimethylsilyl phosphite
(8.4 g), and N-phenyl ethoxymethylenimine (4.5 g),
boron trifluoride diethyl etherate (0.1 g) was added.
The mixture was stirred for 0.5 h and was left for
phosphonite 23 was synthesized without catalyst at
◦
1
40 C.
Heteroatom Chemistry DOI 10.1002/hc

324 Prishchenko et al.
2
weeks. The white crystals were washed with the
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◦
[
[
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[
[
[
[
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◦
1
0 C to a solution of 3.5 g of bisphosphonite 24
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diethyl ether (20 mL) was added to the residue, and
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2
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Acid 27 was prepared similarly.
Heteroatom Chemistry DOI 10.1002/hc