One-pot synthesis of α-amino phosphinic acids

Full text of DOI:10.1023/B:RUGC.0000025183.35779.1f

Russian Journal of General Chemistry, Vol. 74, No. 1, 2004, pp. 142 143. Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 1, 2004,
pp. 154 156.
Original Russian Text Copyright
2004 by Ragulin.
LETTERS
TO THE EDITOR
One-Pot Synthesis of -Amino Phosphinic Acids
V. V. Ragulin
Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
Received November 12, 2002
A promising line in the search for new physiolog-
ically active compounds involves synthesis of
phosphinic acids, the pseudopeptides, potential in-
hibitors of natural enzymes [1, 2]. In this connection,
development of methods for the synthesis of -amino
phosphinic acids, which can be considered as phos-
phoryl analogs of dipeptides formed by -amino acids
[2 4], is an important challenge.
1.3 ml of benzylamine and then 1.2 ml of benzal-
dehyde were added. The temperature of the reaction
mixture rose to 90 C, and the mixture was stirred at
110 120 C for 3 h. The mixture was cooled to room
temperature, 15 ml of aqueous ethyl alcohol was
added dropwise, and the mixture was evaporated in a
vacuum. The residue was dissolved in 50 ml of
methylene chloride and washed with water (2 10 ml).
The organic layer was dried over MgSO4, concentra-
ted, and filtered through a Celite bed. The eluate was
evaporated, and residue was crystallized from ether.
For additional purification, the amino acid was dis-
solved in a minimal volume of water and subjected to
chromatography on Diasorb-Sulfo (H+) weakly acidic
cation exchanger. The aqueous eluate was evaporated
in a vacuum, and the residue was crystallized from an
alcohol ether mixture. 2-(Ethoxycarbonyl)ethyl- -
Here we suggest an approach to the synthesis of
such -amino phosphinic acids I based on the method
that we develop for the synthesis of functionally
substituted phosphinic acids [5 7], in which silyl-
phosphinic intermediates are involved in the Kabach-
nik Fields reaction. We found that bis(trimethylsilyl)
phosphonites II formed in situ by adding bis(tri-
methylsilyl) hypophosphite III to activated CH2=X
compounds are capable, in turn, of in situ reaction
with an equimolar mixture of benzylamine with the
(benzylamino)benzylphosphinic acid Ia
was
isolated, yield 1.3 g (31% based on ammonium hypo-
phosphite), mp 131 134 C. 1H NMR spectrum
(CD3OD, , ppm): 1.20 t (3H, CH3), 1.75 m (2H,
CH2), 2.38 m (2H, CH2), 4.04 br.s (2H, CH2), 4.08 q
(2H, CH2O), 4.70 d (1H, CH, JPH 13 Hz), 7.40 m
(10H, 2Ph). 31P NMR spectrum, P, ppm: 37.1
(CD3OD), 50.1 (D2O + DCl).
appropriate aldehyde, yielding
-(N-benzylamino)
phosphinic acids I according to the following scheme:
H2POONH4 (Me Si) NH [HP(OSiMe3)2]
3
2
III
CH2=X
(1) PhCH2NH2;
Ph
H
N
A mixture of 0.9 g of acid Ia and 10 ml of 8 N HCl
was refluxed for 8 h and then evaporated in a vacuum;
the residue was dissolved in a 1:3:1 water alcohol
ether mixture and treated with 1 ml of propylene
oxide. 2-(Hydroxycarbonyl)ethyl- -(N-benzylamino)-
benzylphosphinic acid Ia was isolated, yield 0.7 g
(84% based on Ia ), mp 163 166 C. 1H NMR spec-
trum (D2O + DCl), , ppm: 1.12 m (2H, CH2), 1.50 m
(2H, CH2), 3.28 d (1H, CH2Ph), 3.45 d (1H, CH2Ph),
3.72 d (1H, CH, JPH 11 Hz), 6.50 m (10H, 2Ph). 31P
NMR spectrum (D2O + DCl), P, ppm: 41.8. Found,
%: C 61.45; 61.48; H 5.87, 5.78; P 9.31, 9.43.
C17H20NO4P. Calculated, %: C 61.26; H 6.05; P 9.29.
(2) RCH(O);
O
OSiMe3
OSiMe3
HY
HY
(3) HCl (H2O)
P
P
R
OH
I
II
R = i-Pr, Ph; X = CHPh, CHC(O)OEt, C(i-Bu)C(O)OEt;
Y = CHPh, CHC(O)OH, C(i-Bu)C(O)OH.
2-Hydroxycarbonylethyl- -(benzylamino)-
benzylphosphonic acid Ia. A mixture of 1.0 g of
H2POONH4 and 5 ml of hexamethyldisilazane was
stirred for 1.5 h at 120 C. The reaction mixture was
cooled to room temperature in an argon flow, 1.3 ml
of ethyl acrylate was slowly added dropwise, and the
stirring was continued for 2.5 h at 5 C. After that,
2-Phenylethyl-1-(benzylamino)-2-methylpropyl-
phosphinic acid Ib. A mixture of 1.0 g of H2POONH4
and 1.4 g of styrene in 5 ml of hexamethyldisilazane
1070-3632/04/7401-0142 2004 MAIK Nauka/Interperiodica

ONE-POT SYNTHESIS OF -AMINO PHOSPHINIC ACIDS
143
was stirred for 1.5 h at 120 C and then cooled under
argon to 50 C. To the reaction mixture 1.3 ml of
benzylamine and then 1.1 ml of isobutyric aldehyde
were added. The mixture warmed up to 70 80 C
spontaneously. The reaction mixture was stirred
additionally for 3 h at 90 100 C. To the mixture
cooled to room temperature, 10 ml of alcohol was
added dropwise, and then the reaction mixture was
evaporated in a vacuum. The residue was distributed
in a mixture of 40 ml of chloroform and 10 ml of
water, and the aqueous phase was extracted addition-
ally with 50 ml of methylene chloride. The com-
bined organic phase was dried over MgSO4 and
evaporated in a vacuum. The residue was dissolved in
a minimal volume of alcohol and passed through a
Celite bed (eluent alcohol). The eluate was evaporated
in a vacuum, and the residue was recrystallized from
acetone. For additional purification, the amino acid
was dissolved in 5 ml of 1 N HCl, the mixture was
evaporated with water, and the concentrated hydro-
chloride solution was evaporated on Diasorb-Sulfo
(H+) weakly acidic cation exchanger (eluent water
0.5 N HCl). The acidic eluate was evaporated in a
vacuum, and the residue was dissolved in aqueous
alcohol (1:3) and treated with 1 ml of propylene
oxide. Compound Ib was isolated, yield 1.2 g (30%
based on ammonium hypophosphite), mp 115 118 C.
1H NMR spectrum (D2O + NaOD, pH 10), , ppm:
0.88 br.d (6H, 2CH3), 1.62 m (2H, CH2), 2.02 m (1H,
CH), 2.37 d (1H, CHP, JPH 10 Hz), 2.57 m (2H, CH2),
vacuum, and the residue was dissolved in 40 ml of
chloroform and washed with water (2 10 ml). The
organic phase was dried over MgSO4, the solution
was concentrated and passed through a Celite bed, and
the eluate was evaporated. The residue was boiled in
15 ml of 8 N HCl for 10 h, and the resulting solution
was extracted with benzene (2 10 ml). The acidic
aqueous phase was evaporated, and the residue was
mixed with water, evaporated, dissolved in a minimal
amount of water, and separated on Diasorb-Sulfo (H+)
weakly acidic cation exchanger. The aqueous eluate
was evaporated in a vacuum, and the residue was
recrystallized from an alcohol ether mixture; 1.7 g
(29% based on ammonium hypophosphite) of Ic was
1
isolated, mp 187 189 C. H NMR spectrum (D2O +
DCl), , ppm: 0.15 m (6H, 2CH3), 0.70 m (1H,
CHMe2), 0.83 m (2H, CH2P), 1.43 m (2H, CH2),
1.98 m (1H, CHCOOH), 3.48 br.s (2H, CH2Ph),
4.38 d (1H, CHP, JPH 9 Hz), 6.74 m (10H, Ph). 31P
NMR spectrum, , ppm: 49.0, 48.9 (5:1) (D2O +
P
DCl, pH 1); 39.5, 38.7 (10:4) (D2O + NaOD, pH
10) (a mixture of diastereomers). Found, %: C 64.87;
64.98; H 6.97, 7.07; P 8.11, 8.13. C21H28NO4P.
Calculated, %: C 64.77; H 7.25; P 7.95.
1
The H, 13C and 31P NMR spectra were recorded
on a Bruker DPX-200 instrument with TMS (internal)
and 85% H3PO4 (external) references. Ion-exchange
chromatography was carried out on a Dowex 50WX8-
200 (H+) (Lancaster) and Diasorb-Sulfo (H+) (Bio-
ChemMac) cation exchangers. TLC analysis of
individual compounds and reaction mixtures was
carried out on Merck plates with 0.2-mm silica gel
UV-254 layer and on Alufol (Kavalier) plates (neutral
aluminum oxide on aluminum foil); eluents for the
analysis of amino acids were 1-butanol acetic acid
water, (5 8):1:1, or chloroform ethanol acetic acid,
(3 5):2:1.
1
3.70 br.s (2H, CH2Ph), 7.18 m (10H, 2Ph). H NMR
spectrum (CD3OD), , ppm: 1.08 d (3H, CH3), 1.18 d
(3H, CH3), 1.85 m (2H, CH2), 2.28 m (1H, CHMe2),
2.82 m (3H, CH2Ph + CHP), 4.30 d (1H, NCH2Ph),
4.47 d (1H, NCH2Ph), 7.21 m (5H, Ph), 7.47 m (3H,
Ph ), 7.58 m (2H, Ph ). 13C NMR spectrum (CD3OD),
C, ppm: 17.9 d (Me, J 5.6 Hz), 18.8 d (Me, J 4.8 Hz),
26.4 s (CHMe2), 27.5 d (CH2Ph, J 3.9 Hz), 33.4 d
(CH2P, J 95.3 Hz), 50.2 s (CH2N), 61.1 d (CHP, J
82.3 Hz), 125.1 130.8 m + 141.6 d (J 14.9 Hz) (2Ph).
31P NMR spectrum, P, ppm: 31.3 (CD3OD); 44.1
(D2O + NaOD, pH 10). Found, %: C 62.45; 62.48; H
7.97, 8.08; P 8.21, 8.03. C19H26NO2P 2H2O. Cal-
culated, %: C 62.11; H 8.23; P 8.43.
2-Hydroxycarbonyl-2-isobutylethyl- -(benzyl-
amino)benzylphosphinic acid Ic. A mixture of 1.2 g
of H2POONH4 and 7 ml of hexamethyldisilazane was
stirred for 2 h at 120 C. To the mixture cooled under
argon flow to 60 C, 2.3 ml of ethyl -isobutylacrylate
was slowly added dropwise. The mixture was stirred
for 2 h at 60 C, then heated to 100 C, and 1.6 ml of
benzylamine and then 1.5 ml of benzaldehyde were
added. The mixture warmed up to 110 C. The mixture
was stirred for 3 h at 110 120 C, then cooled to room
temperature, and 15 ml of aqueous alcohol was slowly
added dropwise. The mixture was evaporated in a
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 1 2004