A method for preparing phosphinic acids from hypophosphites: III. Synthesis of α-hydroxy phosphinic acids

Article abstract of DOI:10.1023/B:RUGC.0000045869.52822.6f

A one-pot method is proposed for preparing unsymmetrical α-hydroxy phosphinic acids from ammonium hypophosphite. Bis(trimethylsilyl) phosphonites formed in situ on addition of bis(trimethylsilyl) hypophosphite to activated unsaturated compounds are brough

Full text of DOI:10.1023/B:RUGC.0000045869.52822.6f

Russian Journal of General Chemistry, Vol. 74, No. 7, 2004, pp. 1087 1090. Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 7, 2004,
pp. 1177 1181.
Original Russian Text Copyright
2004 by Rozhko, Ragulin.
A Method for Preparing Phosphinic Acids from Hypophosphites:
III.1 Synthesis of -Hydroxy Phosphinic Acids
L. F. Rozhko and V. V. Ragulin
Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
Received November 12, 2002
Abstract A one-pot method is proposed for preparing unsymmetrical -hydroxy phosphinic acids from
ammonium hypophosphite. Bis(trimethylsilyl) phosphonites formed in situ on addition of bis(trimethylsilyl)
hypophosphite to activated unsaturated compounds are brought without isolation into the Abramov reaction
with an aldehyde or ketone. A series of new -hydroxy phosphinic acids are obtained.
A method for the synthesis of functionally substi-
tuted phosphinic acids starting from hypophosphites
is based on the ability of hydrophosphoryl compounds
to transform into trivalent phosphorus silyl esters.
This allows formation of two P C bond in the
sequence of reactions performed in one vessel [1 5].
With haloalkanes, symmetrical phosphinic acids are
obtained by two successive reactions of the Arbuzov
type [2 5]. Reaction of bis(trimethylsilyl) hypophos-
phite with aldehydes in the presence of trimethylchlo-
rosilane and triethylamine yields symmetrical bis- -
hydroxy phosphinic acids [6], and with , -dihaloal-
kanes in hexamethyldisilazane and high-boiling sol-
vents, cyclic phosphinic acids can be obtained [7, 8].
Scheme 1.
(Me3Si)2NH
H2POONH4
[HP(OSiMe3)2]
III
CH2=X
1) RR C(O);
HX
OSiMe3
O
P
OH
R
HX
2) EtOH(H2O)
P
R
OSiMe3
II
OH
I
R = Me, CHMe2, Ph, p-C6H4OMe, p-C6H4NMe2; R = H,
Me, Ph; X = CHPh, CHC(O)OEt.
The one-pot procedure with an active unsaturated
compound used in the first step and a haloalkane used
to form the second P C bond allows synthesis of
unsymmetrical phosphinic acids [1, 4, 9 14].
In this work we showed that the phosphonite
HXCH2P(OSiMe3)2 (II) (Scheme 1) formed by in situ
addition
of
bis(trimethylsilyl)
hypophosphite
HP(OSiMe3)2 (III) to activated unsaturated compound
CH2=X further reacts without isolation with an al-
dehyde or ketone molecule, following the scheme of
the Abramov reaction and yielding -hydroxy phos-
phinic acid after treatment of the corresponding silyl
esters with aqueous ethanol (Scheme 1).
It was shown previously that trimethylsilyl phos-
phonites II (Scheme 1) formed by in situ addition of
bis(trimethylsilyl) hypophosphite HP(OSiMe3)2 (III)
to the C C double bond of styrene [1, 4, 10, 11],
acrylate [4, 7, 13, 14], or vinylphosphonate [12] react
in situ with a haloalkane [1, 4], -functionalized halo-
alkane [1, 4, 9, 10], or , -dihaloalkane [1, 11 14]
molecule following the scheme of the Arbuzov
reaction.
As an unsaturated component, we tested ethyl
acrylate and styrene. Acetone, isobutyraldehyde,
benzaldehyde, p-methoxybenzaldehyde, p-dimethyl-
aminobenzaldehyde, acetophenone, and benzophenone
were tested as the carbonyl component.
This study further develops this procedure, with
an active unsaturated compound used for the forma-
tion of the first P C bond and a carbonyl compound
used subsequently for the formation of the second
bond. This allows preparation of a series of new un-
symmetrical -hydroxy phosphinic acids I (Scheme 1).
The synthtic potential of the method can be
extended by using a Schiff base (imine) as the un-
saturated component. We tested N-tritylmethanimine
and N-benzylideneaniline, with p-methoxybenzal-
dehyde as the carbonyl component (Scheme 2). We
demonstrated the principal possibility of preparing
-amino -hydroxy phosphinic acid derivatives.
1
For communication II, see [1].
1070-3632/04/7407-1087 2004 MAIK Nauka/Interperiodica

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ROZHKO, RAGULIN
Scheme 2.
Y
OSiMe3
OSiMe3
Y
NZ
[III]
P
ZHN
1) p-MeOC6H4CH(O)
2) EtOH
O
P
O
H+
OH
OH
Y
P
Y = H, Z = CPh3
ZHN
OH
OH
H2N
OMe
OMe
Ik
Il
Il, Y = Z = Ph.
The use of the N-trityl protecting group followed
by its removal under mild conditions allows synthesis
of -amino -hydroxy phosphinic acids with un-
substituted amino group, as we showed by the ex-
ample of the synthesis of amino acid Ik (Scheme 2).
references. The melting points were measured on a
Boetius PHMK device or in a block in an open
capillary.
All the reactions with silyl hypophosphites and
intermediate phosphonous acids were performed under
argon. The solvents used were carefully dried.
Ammonium hypophosphite was prepared according
to [16]. Carbonyl compounds were purchased from
Khimeks (St. Petersburg, Russia). TLC of individual
compounds and reaction mixtures was performed
using Silufol plates [eluent chloroform acetone,
(5 7):1] and on Merck glass plates with a 0.2-mm
layer of silica gel UV-254 [for the analysis of hydroxy
and amino acids, eluent 1-butanol acetic acid water,
(5 8):1:1].
The newly synthesized -hydroxy phosphinic acids
Ia Il are crystalline substances showing relatively
low thermal stability. -Hydroxy acids Ib and Ig
containing
a
1-hydroxy-1-methylethyl fragment
(formed in reaction with acetone) are the least stable.
For example, recrystallization of acid Ib from an al-
cohol-ether mixture was accompanied by partial dis-
sociation into 2-ethoxycarbonylethylphosponous acid
(
25 ppm) and acetone. The capability of -hydroxy
P
phosphinic acids for the similar dissociation in 10%
ammonia solution was noted previously [15]. We have
not examined systematically the thermal lability of
these compounds. Nevertheless, we tried to avoid the
use of high-boiling solvents in synthesis, isolation,
and recrystallization of -hydroxy phosphinic acids
I.
Synthesis of -hydroxy phosphinic acids with
ethyl acrylate as unsaturated component. A mix-
ture of 0.05 mol of H2POONH4 and 0.06 mol of
(Me3Si)2NH [17, 18] was stirred for 1.5 h at 120 C,
cooled under argon to 40 C, and then freshly distilled
ethyl acrylate was added dropwise to the reaction
mixture. The mixture was stirred at this temperature
for 1.5 h, and then 0.05 mol of the appropriate al-
dehyde or ketone in 3 5 ml of absolute benzene or
chloroform was added slowly dropwise, and the mix-
ture was stirred at 50 80 C for 2 3 h. After cooling
to room temperature, 20 ml of alcohol was added
dropwise, and the mixture was refluxed for 15 min
and then evaporated in a vacuum. The residue was
dissolved in 50 70 ml of chloroform and washed with
water (2 10 ml). The organic layer was dried over
MgSO4 and evaporated in a vacuum. The oily residue
was crystallized from ether or an ether acetone or
ether alcohol mixture. Yields of -hydroxy phos-
phinic acids Ia Ie 43 57% based on H2POONH4.
Thus, we suggested a one-pot method for preparing
unsymmetrical -hydroxy phosphinic acids from
ammonium hypophosphite, using styrene and acrylate
as unsaturated component for the formation of the first
P C bond and carbonyl compounds for the formation
of the second bond by the Abramov reaction. It is
possible to use N-tritylmethanimine and N-benzyl-
ideneaniline as unsaturated components for the syn-
thesis of -amino -hydroxy phopsphinic acids.
EXPERIMENTAL
1
The H and 31P NMR spectra were taken on Bruker
DPX-200 and Bruker CXP-300 Fourier spectrometers,
with TMS as internal and 85% H3PO4 as external
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 7 2004

A METHOD FOR PREPARING PHOSPHINIC ACIDS FROM HYPOPHOSPHITES: III.
1089
2-Ethoxycarbonylethyl- -hydroxybenzylphos-
Synthesis of -hydroxy phosphinic acids with
styrene as unsaturated component. A mixture of
0.05 mol of H2POONH4, 0.08 mol of (Me3Si)2NH,
and 0.05 mol of styrene was stirred for 2 h under
argon at 120 130 C. The reaction mixture was cooled
under argon to 50 C, and 0.05 mol of the correspond-
ing carbonyl compound in 3 5 ml of absolute benzene
was slowly added dropwise. The stirring was con-
tinued at 50 80 C for 3 h. The subsequent alcoholysis
and isolation of compounds I were performed sim-
ilarly to acids Ia Ie. The yields of -hydroxy phos-
phinic acids Ig Ii were 53 73% based on H2POONH4.
phinic acid Ia. Yield 43%, mp 111 113 C (ether
1
alcohol). H NMR spectrum (DMSO-d6 CCl4, 1:3),
, ppm: 1.25 t (3H, CH3), 1.83 m (2H, CH2), 2.42 m
(2H, CH2), 4.07 q (2H, CH2O), 4.75 d (1H, CH, JPH
11 Hz), 7.25 m (3H, Ph), 7.45 m (2H, Ph). 31P NMR
spectrum (DMSO-d6 CCl4, 1:3), P, ppm: 45.4.
Found, %: C 52.67, 52.49; H 6.47, 6.41; P 10.87,
11.03. C12H17O5P. Calculated, %: C 52.94; H 6.29; P
11.38.
2-Ethoxycarbonylethyl(1-hydroxy-1-methyl-
ethyl)phosphinic acid Ib. Yield 57%, mp 101 103 C
1
(ether). H NMR spectrum (CD3OD), , ppm: 1.25 t
2-Phenylethyl(1-hydroxy-1-methylethyl)phos-
phinic acid Ig. Yield 53%, mp 153 155 C (ether). 1H
NMR spectrum (CD3OD), , ppm: 1.40 d (6H, 2CH3,
JPH 13.3 Hz), 2.08 m (2H, CH2), 2.94 m (2H, CH2),
(3H, CH3), 1.38 d (6H, 2CH3, JPH 14 Hz), 2.10 m (2H,
CH2), 2.63 m (2H, CH2), 4.13 q (2H, CH2O). 31P
NMR spectrum (CD3OD), P, ppm: 52.0. Found, %:
C 43.05, 42.91; H 7.59, 7.50; P 13.70, 13.73.
C8H17O5P. Calculated, %: C 42.86; H 7.64; P 13.82.
7.23 m (5H, Ph). 31P NMR spectrum (CD3OD),
,
ppm: 54.7. Found, %: C 57.76, 58.05; H 8.06, 7.59; PP
13.41, 13.37. C11H17O3P. Calculated, %: C 57.89; H
7.51; P 13.57.
2-Ethoxycarbonylethyl(1-hydroxy-1-phenyl-
ethyl)phosphinic acid Ic. Yield 47%, mp 105 107 C
1
(ether acetone). H NMR spectrum (CD3OD), , ppm:
2-Phenylethyl(1-hydroxy-2-methylpropyl)phos-
phinic acid Ih. Yield 67%, mp 123 125 C (ether).
1.22 t (3H, CH3), 1.75 d (3H, CH3, JPH 14 Hz),
1.86 m (2H, CH2), 2.35 m (2H, CH2), 4.08 q (2H,
CH2), 7.32 m (3H), 7.60 m (2H) (Ph). 31P NMR spec-
trum (CD3OD), P, ppm: 51.4.
1H NMR spectrum (CD3OD), , ppm: 1.10 d (6H,
2CH3, JHH 7 Hz), 2.12 m [3H, CH2 + CH(Me2)],
2.92 d.t (2H, CH2), 3.50 d.d (1H, JPH 7 Hz), 7.23 m
(5H, Ph). 31P NMR spectrum (CD3OD), P, ppm: 52.6.
Found, %: C 57.11, 56.85; H 8.06, 8.39; P 12.11,
12.01. C12H19O3P 0.5H2O. Calculated, %: C 57.36;
H 8.02; P 12.33.
2-Ethoxycarbonylethyl(1-hydroxy-1,1-diphenyl-
methyl)phosphinic acid Id. Yield 53%, mp 128
1
129 C (ether). H NMR spectrum (CD3OD), , ppm:
1.19 t (3H, CH3), 1.95 m (2H, CH2), 2.36 m (2H,
CH2), 4.05 q (2H, CH2), 7.28 m (6H), 7.71 m (4H)
(2Ph). 31P NMR spectrum (CD3OD), P, ppm: 50.0.
Found, %: C 62.25, 62.15; H 5.93, 6.02; P 8.61, 8.77.
C18H21O5P. Calculated, %: C 62.07; H 6.08; P 8.89.
2-Phenylethyl- -hydroxybenzylphosphinic acid
1
Ii. Yield 70%, mp 143 145 C (hexane acetone). H
NMR spectrum (CD3OD), , ppm: 1.95 m (2H, CH2),
2.80 m (2H, CH2), 4.90 d (1H, CH, JPH 11 Hz),
7.20 m (10H, 2Ph). 31P NMR spectrum (CD3OD),
,
2-Ethoxycarbonylethyl( -hydroxy-p-methoxy-
benzyl)phosphinic acid Ie. Yield 51%, mp 141
P
ppm: 46.0. Found, %: C 62.87, 63.03; H 6.53, 6.57;
P 10.51, 10.37. C15H17O3P 0.5H2O. Calculated, %:
C 63.15; H 6.36; P 10.86.
1
143 C (ether alcohol). H NMR spectrum (CD3OD),
, ppm: 1.25 t (3H, CH3), 2.05 m (2H, CH2), 2.55 m
(2H, CH2), 3.77 s (3H, CH3O), 4.13 q (2H, CH2O),
4.85 d (1H, CH, JPH 10 Hz), 6.90 s (1H, Ph), 6.92 s
(1H, Ph), 7.38 s (1H, Ph), 7.40 s (1H, Ph). 31P NMR
spectrum (CD3OD), P, ppm: 48.0. Found, %: C
51.95, 52.09; H 6.59, 6.50; P 9.90, 9.83. C13H19O6P.
Calculated, %: C 51.66; H 6.34; P 10.25.
2-Phenylethyl( -hydroxy-p-methoxybenzyl)-
phosphinic acid Ij. Yield 73%, mp 173 174 C
(hexane acetone). 1H NMR spectrum (DMSO-d6
CCl4, 1:3), , ppm: 1.87 m (2H, CH2), 2.77 m (2H,
CH2), 3.75 m (3H, CH3O), 4.70 d (1H, CH, JPH
11 Hz), 6.83 d (2H, Ph), 7.15 m (5H, Ph), 7.35 d (2H,
Ph). 31P NMR spectrum (DMSO-d6 CCl4, 1:3),
,
P
2-Ethoxycarbonylethyl( -hydroxy-p-dimethyl-
aminobenzyl)phosphinic acid If. Yield 43%, mp
ppm: 46.5. Found, %: C 62.47, 62.44; H 6.43, 6.31;
P 9.90, 9.67. C16H19O4P. Calculated, %: C 62.74;
H 6.25; P 10.11.
1
133 135 C (ether). H NMR spectrum (CD3OD), ,
ppm: 1.20 t (3H, CH3), 1.81 m (2H, CH2), 2.45 m
(2H, CH2), 2.88 s (6H, 2CH3N), 4.10 q (2H, CH2O),
4.75 d (1H, CH, JPH 13.5 Hz), 6.88 s (1H, Ph), 6.90 s
(1H, Ph), 7.39 s (1H, Ph), 7.41 s (1H, Ph). 31P NMR
spectrum (CD3OD), P, ppm: 39.0. Found, %: C
52.95, 53.09; H 7.19, 7.20; P 9.90, 9.83. C14H22NO5P.
Calculated, %: C 53.33; H 7.03; P 9.82.
N-Tritylmethanimine and N-benzylideneaniline
as unsaturated component. Aminomethyl( -hy-
droxy-p-methoxybenzyl)phosphinic acid Ik. A mix-
ture of 0.8 g of H2POONH4 and 5.5 ml of (Me3Si)2
NH was stirred for 1.5 h at 120 130 C [17, 18]. After
cooling to room temperature, a suspension of 2.7 g of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 7 2004

1090
ROZHKO, RAGULIN
N-tritylmethanimine suspended in 10 ml of absolute
benzene was added under argon. The mixture was
slowly heated to 70 80 C and stirred at this tempera-
ture for 5 h. Then 1.2 ml of p-methoxybenzaldehyde
was added, and stirring at 70 80 C was continued for
4 h. After cooling to room temperature, 20 ml of
alcohol was slowly added dropwise, and the mixture
was refluxed for 15 min and then evaporated in a
vacuum. The residue was dissolved in 50 ml of chloro-
form and washed with water (2 10 ml). The organic
layer was evaporated. The residue consisted mainly of
N-tritylaminomethyl( -hydroxy-p-methoxybenzyl)-
phosphinic acid [31P NMR data (CDCl3): 40 ppm],
which without isolation was dissolved in 20 ml of
chloroform and mixed with 30 ml of 1 M HCl; the
resulting two-phase mixture was vigorously stirred
for 3-4 h. The acidic aqueous phase was evaporated,
then again evaporated with water, and the residue was
dissolved in aqueous ethanol and treated with excess
propylene oxide. The free amino acid was additionally
purified by chromatography on Diasorb-Sulfo (weakly
acidic) cation exchanger, eluent water. The fractions
with positive ninhydrin reaction were collected and
evaporated, and the residue was recrystallized from
acetone. After recrystallization from aqueous ethanol,
acid Ik was isolated. Yield 0.53 g (23% based on
JPH 13 Hz), 4.50* d (1H, CH, JPH 13 Hz), 4.70 d (1H,
CH, JPH 13 Hz), 6.40 m (1H, Ph), 6.55 m (1H, Ph),
6.80 m (3H, Ph), 6.95 m (1H, Ph), 6.95 m (3H, Ph),
7.37 m (5H, Ph). 31P NMR spectrum (CD3OD),
,
P
ppm: 32.1, 31.0* (2:1). Found, %: C 66.13, 65.91; H
5.66, 5.43; P 8.21, 8.03. C21H22NO4P. Calculated, %:
C 65.79; H 5.78; P 8.08.
ACKNOWLEDGMENTS
The authors are grateful to G.D. Shishko for the
elemental analysis of the new compounds.
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1
ammonium hypophosphite), mp 168 169 C. H NMR
spectrum (D2O), , ppm: 3.07 d (2H, CH2, JPH 10 Hz),
3.13 d (1H, CH, JPH 10 Hz), 3.78 s (3H, CH3), 6.93 s
(1H, Ph), 6.98 s (1H, Ph), 7.32 s (1H, Ph), 7.36 s (1H,
Ph). 31P NMR spectrum (D2O), P, ppm: 27.3 (pH 1),
36.7 (pH 9). Found, %: C 46.51, 46.45; H 6.26, 6.09;
P 13.21, 13.33. C9H14NO4P. Calculated, %: C 46.76;
H 6.10; P 13.40.
-(N-Phenylamino)benzyl( -hydroxy-p-meth-
oxybenzyl)phosphinic acid Il. A mixture of 0.8 g of
H2POONH4 and 5.0 ml of (Me3Si)2NH was stirred for
1.5 h at 120 130 C [17, 18]. After cooling under
argon to 80 C, a solution of 1.8 g of N-benzylidene-
aniline in 3 ml of absolute benzene was added, and
the mixture was stirred at this temperature for 3 h.
Then 1.2 ml of p-methoxybenzaldehyde was added,
and the mixture was stirred at 80 C for 3 h. After
cooling to room temoerature, 15 ml of alcohol was
slowly added dropwise, and the reaction mixture was
evaporated in a vacuum. The residue was dissolved in
minimal amount of methylene chloride and passed
through a Celite bed (eluent methylene chloride). The
organic phase was washed with water (2 10 ml),
dried over MgSO4, and evaporated in a vacuum. The
residue was recrystallized from petroleum ether and
then from alcohol ether, 1:4. 1.1 g (29%) of acid Il
was obtained as a diastereomeric mixture (resolved
signals of the minor diastereomer are marked with an
asterisk), mp 178 181 C. 1H NMR spectrum
(CD3OD), , ppm: 3.70 s (3H, CH3), 4.40 d (1H, CH,
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 7 2004