Synthesis of new functionalized mono- and bisorganophosphorus acids and their derivatives with unsaturated and aromatic fragments

Article abstract of DOI:10.1002/hc.20749

Convenient procedures for the synthesis of functionalized mono- and bisorganophosphorus acids and their derivatives with unsaturated and aromatic fragments, starting from the available derivatives of trivalent phosphorus acids, unsaturated and aromatic al

Full text of DOI:10.1002/hc.20749

Heteroatom Chemistry
Volume 23, Number 1, 2012
Synthesis of New Functionalized Mono- and
Bisorganophosphorus Acids and Their
Derivatives with Unsaturated and
Aromatic Fragments
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 April 2011; revised 14 June 2011
natural pyrophosphates. Various derivatives of sub-
ABSTRACT: Convenient procedures for the synthe-
stituted hydroxymethylenebisphosphonic acids are
sis of functionalized mono- and bisorganophosphorus
good complexones and widely used in medicine [1–
acids and their derivatives with unsaturated and aro-
3]. Recently, we have proposed convenient proce-
matic fragments, starting from the available deriva-
dures for synthesis of a series of organophospho-
tives of trivalent phosphorus acids, unsaturated and
rus derivatives of 2,6-di-tert-butyl-4-methylphenol
aromatic aldehydes, and carboxylic acid chlorides, are
(ionol) with one, two, or three phosphorus-
proposed, and some properties of the new unsaturated
containing groups [4,5]. These compounds were
ꢀ
C
organophosphorus compounds are presented. 2011
used by us for the preparation of stable phenoxyl
Wiley Periodicals, Inc. Heteroatom Chem 23:32–40, 2012;
radicals [6] and were interesting as effective antioxi-
View this article online at wileyonlinelibrary.com. DOI
dants with the multifunctional mode of action [7]. In
10.1002/hc.20749
this study, we propose the convenient methods for
the synthesis of new functionalized mono- and bis-
phosphinates, including unsaturated and aromatic
INTRODUCTION
fragments, starting from the readily accessible un-
saturated aldehydes and carboxylic acid chlorides,
which were prepared by the procedures in Ref. [8],
and trimethylsilyl esters of various trivalent phos-
phorus acids, which were prepared by us previ-
ously as unique organophosphorus synthons [9,10].
In the present study, we found that the unsaturated
aldehydes and carboxylic acid chlorides smoothly
react with various trimethylsilyl esters of trivalent
phosphorus acids under mild conditions to form
new functionalized mono- and bisorganophospho-
rus acids and their derivatives with unsaturated and
aromatic fragments, which are of great interest as
promising polydentate ligands and effective multi-
functional antioxidants.
The functionalized derivatives of mono- and
bis(organophosphorus) acids containing aromatic
and heterocyclic fragments with various hydroxy,
amino, or amido groups present great interest as
promising polydentate ligands and organophospho-
rus biomimetics of hydroxyl and amino acids and
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic
Research.
Contract grant number: 11-03-00402.
2011 Wiley Periodicals, Inc.
c
ꢀ
32

Synthesis of Mono- and Bisorganophosphorus Acids and Their Derivatives 33
RESULTS AND DISCUSSION
Thus, trimethylsilyl hypophosphite A formed in situ from ammonium hypophosphite and chlorotrimethyl-
silane easily reacts with 1 or 2 equiv of unsaturated and aromatic aldehydes in methylene chloride to give
either phosphonites 1–3 or phosphinates 4–7, depending on the reagents ratio, in quite a high yield. Phos-
phonites 1–3 were isolated by additional treatment of the reaction mixture with bis(trimethylsilyl)amine,
and phosphinic acids 4–7 were recrystallized from aqueous ethanol (Eq. (1)).
Me3SiCl
- NH4Cl
(1) RCHO; (2) (Me3Si)2NH
(Me3SiO)2PCH(OSiMe3)R
NH4H2PO2
Me3SiOP(O)H2
A
1-3
(1) 2 RCHO;
(2) EtOH, H2O
HOP[CH(OH)R]2
O
4-7
R = Ph (1,4), 4-MeOC6H4 (2,5), 4-BrC6H4 (3,6), PhCH=CH (7).
(1)
Also, we developed a convenient method of synthesis of the similar phosphonites 8,9 and phosphinates
10,11 using the highly reactive bis(trimethylsiloxy)phosphine (cf. [11]), which readily adds to the carbonyl
group of the corresponding aldehydes in methylene chloride to give the compounds 8–11 in high yields (Eq.
(2)).
Me3SiO
RCHO
(Me3Si)2NH
- NH3
(Me3SiO)2PH
(Me3SiO)2PCH(OSiMe3)R
PCH(OSiMe3)R
O
H
8,9
RCHO
CH(OSiMe3)R
(Me3Si)2NH
- NH3
Me3SiOP
O
Me3SiOP[CH(OSiMe3)R]2
CH(OH)R
O
10,11
(9,11).
R = (CH=CH)2Me (8,10),
N
(2)
Phosphonite 8 is a suitable synthon for a series of trimethylsiloxymethylphosphinates, including un-
saturated fragments and pyridine moieties. Thus, phosphonite 8 adds readily to the carbonyl group of
3-pyridinecarboxaldehyde and reacts smoothly with cinnamoyl chloride via the route of Arbuzov reaction in
methylene chloride to form phosphinates 12,13 (Eq. (3)).
CH(OSiMe3)R
CH(OSiMe3)R
PyCHO
PhCH=CHCOCl
- Me3SiCl
Me3SiOP
O
8
Me3SiOP
O
C(O)CH=CHPh
CH(OSiMe3)Py
12
13
R = (CH=CH)2Me, Py =
.
N
(3)
Also, we showed that the reactions of trimethylsilyl esters of trivalent phosphorus acids with readily
available unsaturated carboxylic acid chlorides yield the new diphosphorylated trimethylsiloxymethylene
Heteroatom Chemistry DOI 10.1002/hc

34 Prishchenko et al.
derivatives containing pyridine moieties, and unsaturated and aromatic fragments (cf. [5,12]). As initial
compounds, we used accessible trimethylsilyl phosphites and 2-pyridylethylphosphonite that were success-
fully applied earlier to the synthesis of organophosphorus analogs of amino acids containing amino and
carboxyl groups [13]. Therefore, trimethylsilyl phosphites and bis(trimethylsilyl) 2-pyridylethylphosphonite
readily react with acid chlorides in methylene chloride to form bisphosphonate 14–18 or bisphosphinates
19–22, respectively, in high yields (Eq. (4)).
R
Me3SiO
2 (XO)2POSiMe3
- Me3SiCl
2 (Me3SiO)2PY
- Me3SiCl
[(XO)2P]2CR
OSiMe3
RCOCl
P
2C
Y
OSiMe3
O
O
14-18
19-22
(CH )
N.
X = Et (14,15), Me3Si (16-18); Y=
2 2
(CH2)7
(CH2)7Me
H
R = CH=CHMe (19), (CH=CH)2Me (14,17,20), CH=CHPh (16,21),
C=C
(15,18,22).
H
(4)
Under similar conditions, the reaction of diethyl trimethylsilyl phosphite with unsaturated carboxylic
acid chlorides in 1:1 ratio gives unsaturated keto phosphonates 23–25 in high yields (Eq. (5)).
RC(O)Cl
(EtO)2POSiMe3
(EtO)2P-CR
O O
- Me3SiCl
23-25
(CH2)7Me
(CH2)7
R = CH=CHMe (23), (CH=CH)2Me (24),
C=C
(25).
H
H
(5)
Here, we found a facile route to new derivatives of unsymmetrical trimethylsiloxymethylenebisphos-
phorus acids containing unsaturated fragments starting from keto phosphonates 23–25. Tris(trimethylsilyl)
phosphite as well as bis(trimethylsilyl) 2-pyridylethylphosphonite readily add to the carbonyl group of keto
phosphonates 23–25 with the formation of bisphosphonates 26,27 and phosphonate-phosphinates 28,29,
respectively, in high yields (Eq. (6)).
O
O
R
(EtO)2P
R
(EtO)2P
(Me3SiO)3P
(Me3SiO)2PY
23-25
C
C
Me3SiO
OSiMe3
P
OSiMe3
(Me3SiO)2P
O
Y
O
26,27
28,29
(CH2)7Me
(CH2)7
R = CH=CHMe (26), (CH=CH)2Me (28),
C=C
(CH2)2
N.
(27,29); Y=
H
H
(6)
The treatment of phosphonite 8 and phosphinate 10 with dilute sodium methoxide in methanol gave the
corresponding sodium salts 30,31 (Eq. (7)).
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Mono- and Bisorganophosphorus Acids and Their Derivatives 35
thick oils. Yellow crystalline salts 30,31 decompose
on heating above 120–130◦C without definite melting
points. The structures of compounds 1–45 were con-
firmed by the 1H, 13C, 31P NMR spectra, which show
characteristic signals of the PCHOX and PCP frag-
ments, and signals of substituted unsaturated and
aromatic fragments (see Tables 1–3). According to
the NMR spectra, some compounds are mixtures
of stereoisomers. Their ratio was determined from
the 1H NMR and 31P spectra. The elemental analysis
data of synthesized compounds are summarized in
Table 4.
NaO
H
MeONa, 2 MeOH
- 3 Me3SiOMe
8
P-CH(CH=CH)2Me
O OH
30
MeONa, 2 MeOH
- 3 Me3SiOMe
10
NaOP[
O
CH(OH)(CH=CH)2Me]2
31
(7)
The reactions of trimethylsilyl esters of
organophosphorus acids 10–12, 16–22, and 26–
29 with an excess methanol gave functionalized
mono- and bisorganophosphorus acids 32–45 with
unsaturated and aromatic fragments in high yields
(Eq. (8)).
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were registered
3 MeOH
on a Bruker Avance-400 spectrometer (400, 100, and
162 MHz, respectively) in CDCl3 (1–3, 8–29), CD3OD
(4–7, 30–37, 42–45), or DCOOD (38–41) against
TMS (1H and 13C) and 85% H3PO4 in D2O (31P).
All reactions were performed under dry argon in
anhydrous solvents. Starting unsaturated acid chlo-
rides and trimethylsilyl esters of trivalent phospho-
rus acids were prepared according to the procedures
in Ref. [8–10], respectively.
10,11
HOP[CH(OH)R]2
- 3 Me3SiOMe
O
32,33
CH(OH)R
3 MeOH
HOP
12
- 3 Me3SiOMe
CH(OH)Py
O
34
(33,34)
R = (CH=CH)2Me (32,34), Py =
N
O,O-Bis(trimethylsilyl) phenyl(trimethylsiloxy)
methylphosphonite (1). A mixture of 8.3 g ammo-
nium hypophosphite, 10.6 g of benzaldehyde, and
26 g of chlorotrimethylsilane in 50 mL of methylene
chloride was heated under reflux with stirring for
2 h. Ammonium chloride was filtered off, the solvent
was distilled off, and 65 g of bis(trimethylsilyl)amine
was added to the residue. The mixture was refluxed
until ammonia no longer evolved and then distilled
to obtain 26.4 g of phosphonite 1 (see Table 1).
5 MeOH
- 5 Me3SiOMe
16-18
[(HO)2P]2CR
O
OH
35-37
R
HO
3 MeOH
- 3 Me3SiOMe
2C
19-22
P
Y
OH
O
38-41
O
R
(EtO)2P
3 MeOH
- 3 Me3SiOMe
Phosphonites 2 and 3 Were Synthesized
by the Same Method
26,27
28,29
C
OH
(HO)2P
O
Bis[hydroxy(phenyl)methyl]phosphinic acid (4). A
mixture of 8.3 g ammonium hypophosphite, 22.4
g of benzaldehyde, and 40 g of chlorotrimethylsi-
lane in 60 mL of methylene chloride was heated un-
der reflux with stirring for 2 h. Ammonium chloride
was filtered off and 60 mL ethanol was added to the
residue. The mixture was heated to boil, ethanol was
distilled off, and the residue was recrystallized from
70% aqueous ethanol. The white crystals that formed
were kept in a vacuum (1 mm Hg) to obtain 21.7 g
of acid 4.
42,43
O
(EtO)2P
R
2 MeOH
- 2 Me3SiOMe
C
HO
OH
P
Y
O
44,45
R = CH=CHMe (38,42), (CH=CH)2Me (36,39,44), CH=CHPh (35,40),
(CH2)7Me
(CH2)7
(CH )
N .
C=C
(37,41,43,45); Y=
2 2
H
H
(8)
Acids 5–7 Were Prepared by the Same Method
Acids 4–7, 32–34, and 38–41 are obtained as
O,O-Bis(trimethylsilyl)
1-(trimethylsiloxy)-2,4-
white or yellow hygroscopic crystals; other acids are
hexadien-1-ylphosphonite (8). A solution of sorbic
Heteroatom Chemistry DOI 10.1002/hc

36 Prishchenko et al.
b
,s
P
,s
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
(C
e
e
,s
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
(C
H
J
PC
J
,d
d
d
d
d
d
d
d
d
(C
PC
J
,d
c
c
c
c
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
(C
PC
n
J
g
g
,d
(C
PH
J
J
d
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
f
f
f
f
f
f
f
f
c
H),
(C
H
)
%
(
o
i
t
a
,
)
g
H
m
CR
h
h
h
m
,
,
p
p
(
m
C,
,
H
Bp
J
(%)
PH
J
ield
Y
H
a
J
PC
J
.
N
a
b
c
d
e
f
g
h
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Mono- and Bisorganophosphorus Acids and Their Derivatives 37
d
d
d
d
b
,
d
d
d
d
P
PH
J
PC
J
,
H
J
(C
,s
c
c
(
H
J
PC
c
c
Py
J
PH
J
PH
,d
J
c
c
(C
,s
c
c
c
c
c
(
PC
c
c
J
t
PH
J
c
c
c
c
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J
(C
H
J
PC
J
,t
c
c
(
PH
PC
J
J
t
H
J
(C
()%
aito
R
%
PH
J
edl,
i
Y
a
P
J
H
J
N
a
b
c
d
Heteroatom Chemistry DOI 10.1002/hc

38 Prishchenko et al.
P
J
(P
PC
J
(P
PC
J
d
d
d
d
PC
,d
J
Py
(C
s
c
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(
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,d
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b
a
d
(C
)
(
Rtaio
()%
iled
Y
PC
J
PC
J
.
N
a
b
c
d
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Mono- and Bisorganophosphorus Acids and Their Derivatives 39
TABLE 4 Elemental Analyses Data of Compounds 4–7,10–45a
Calcd. (%)
Found (%)
No.
Empirical Formula
Formula Weight
C
H
C
H
4
C14H15O4P
C16H19O6P
C14H13Br2O4P
278.25
338.30
436.03
330.32
474.80
496.78
485.79
436.63
442.51
612.85
655.05
619.02
789.36
626.90
652.94
688.97
823.27
206.18
232.21
402.55
504.73
701.10
547.72
718.07
184.11
280.23
258.25
280.23
269.24
294.14
258.11
428.45
410.35
436.39
472.42
606.72
288.18
484.55
403.36
573.70
60.43
56.81
38.56
65.45
53.12
50.78
51.92
57.77
46.14
56.84
44.01
40.75
50.21
51.73
53.35
55.79
59.82
46.60
51.72
65.64
40.46
53.11
50.44
58.54
39.15
51.43
55.81
51.44
53.53
36.75
27.92
50.46
52.69
55.05
58.48
65.35
33.34
54.53
50.62
60.71
5.43
5.66
3.00
5.78
9.13
7.51
8.30
7.62
8.20
60.09
56.69
38.40
65.23
52.98
50.59
51.81
57.65
45.96
56.68
43.89
40.61
50.03
51.52
53.23
55.65
59.68
46.49
51.57
65.52
40.30
52.96
50.23
58.42
39.01
51.28
55.66
51.26
53.41
36.64
27.78
50.26
52.54
54.91
58.40
63.20
33.15
54.40
50.49
60.59
5.49
5.72
2.91
5.69
9.03
7.42
8.23
7.57
8.11
5
6
7
C18H19O4P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
C21H43O4PSi3
C21H37N2O4PSi3
C21H40NO4PSi3
C21H33O4PSi2
C17H36O7P2Si
C29H62O7P2Si
C24H52O7P2Si3
C21H52O7P2Si5
10.20
8.00
8.47
9.96
7.72
7.72
7.32
9.30
7.33
7.38
10.77
8.39
10.06
7.91
9.69
5.47
6.47
7.42
4.68
5.99
4.11
4.68
8.94
5.89
6.01
5.55
8.64
6.29
9.57
6.75
9.31
10.12
7.91
8.40
9.88
7.65
7.64
7.26
9.22
7.26
7.29
10.68
8.28
10.01
7.83
9.59
5.40
6.42
7.38
4.72
5.87
4.07
4.59
8.86
5.78
6.09
5.59
8.58
6.22
9.52
6.70
9.26
C
33H78O7P2Si5
C27H48N2O5P2Si3
C29H50N2O5P2Si3
C32H50N2O5P2Si3
41H76N2O5P2Si3
C8H15O4P
C
C10H17O4P
C22H43O4P
17H42O7P2Si3
C31H70O7P2Si3
C23H43NO6P2Si2
35H69NO6P2Si2
C6H10NaO3P
C
C
C
12H18NaO4P
C12H19O4P
C12H13N2O4P
C12H16NO4P
C9H12O7P2
C6H12O7P2
C18H38O7P2
C18H24N2O5P2
20H26N2O5P2
23H26N2O5P2
C32H52N2O5P2
C8H18O7P2
C22H46O7P2
C
C
C
C
17H27NO6P2
29H53NO6P2
aPhosphonites 1–3,8,9 are extremely readily oxidized and hydrolyzed, and therefore they were analyzed in the form of the corresponding
derivatives 4–6, 10,11.
aldehyde 18.3 g in 50 mL of methylene chloride
was added with stirring to a solution of 52 g of
bis(trimethylsiloxy)phosphine in 100 mL methylene
chloride, cooled to 0◦C. The mixture was stirred
for 0.5 h, then the solvent was distilled off, and
100 g bis(trimethylsilyl)amine was added to the
residue. The mixture was refluxed until ammonia
no longer evolved and then distilled to obtain 56 g
of phosphonite 8.
Compounds 9–11 Were Prepared Similarly
O-Trimethylsilyl[pyrid-3-yl(trimethylsiloxy)methyl]
(1-trimethylsiloxy-2,4-hexadien-1-yl)phosphinate
(12). 3-Pyridinecarboxaldehyde, 3.2 g, was added
with stirring to a solution of 11.3 g of phosphonite
8 in 40 mL of methylene chloride, cooled to 10◦C.
The mixture was stirred for 0.5 h, the solvent was
then distilled off, the residue was distilled to obtain
13.3 g of phosphinate 12.
Heteroatom Chemistry DOI 10.1002/hc

40 Prishchenko et al.
REFERENCES
Phosphinate 13 Was Prepared Similarly
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Russian).
[2] Ebetino, F.H. Phosphorus Sulfur Silicon Relat Elem
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[3] Matkovskaya, T.A., Popov, K.I.; Yurieva, E.A.
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chloride was added with stirring and cooling to
10◦C to a solution of 21 g of diethyl trimethylsilyl
phosphite in 20 mL of methylene chloride. The
mixture was stirred for 0.5 h and heated to reflux;
then the solvent was distilled off and the residue
was kept in a vacuum (0.5 mm Hg) for 1 h at 30◦C.
Bisphosphonate 14 was obtained as a thick oil, a
yield of 19.5 g.
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Compounds 15–29 Were Prepared Similarly
Sodium
(1-hydroxy-2,4-hexadien-1-yl)phosphonite
(30). A solution of 15.2 g of phosphonite 8 in 20 mL
of diethyl ether was added with stirring and cooled
at 10◦C to a solution of 2.16 g of sodium methylate
in 30 mL of methanol. The resulting mixture was
heated to a boil, the solvent was removed in a
vacuum, and the residue was kept in a vacuum
(1 mm Hg) for 1 h to obtain 7.1 g of salt 30 as yellow
hygroscopic crystals.
Salt 31 Was Obtained Similarly
[10] Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45,
2465–2524.
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Bis(1-hydroxy-2,4-hexadien-1-yl)phosphinic
acid
(32). Phospinate 10, 18 g, was added with stirring
to 60 mL of methanol cooled to 10◦C. The mixture
was heated to boiling and then was distilled off; the
residue was kept in a vacuum (1 mm Hg) for 1 h to
obtain 9.5 g of acid 32. Acids 33–45 were prepared
similarly.
Heteroatom Chemistry DOI 10.1002/hc