Method of synthesis of phosphinic acids based on hypophosphites: VIII.1 synthesis of α-aminoalkylphenethylphosphinic acids

Article abstract of DOI:10.1134/S107036321109009X

Development of methodology of double Arbuzov rearrangement based on hypophosphites allows a one-pot formation of two unsymmetrical phosphorus-carbon bonds by the Michael-Pudovik type reaction of stepwise addition of the intermediately forming silyl esters of trivalent phosphorus to different unsaturated compounds. A procedure was developed of the synthesis of α-aminoalkylphenethylphosphinic acids. Bis-(trimethylsilyl) phenethylphosphonite formed as a result of the addition of bis(trimethylsilyl) hypophosphite to styrene in situ was added without isolation from the reaction mixture to Schiff bases obtained preliminary from benzylamine or diphenylmethylamine and various aldehydes. The subsequent removal of N-protecting groups by hydrogenation or acidic hydrolysis gave a number of new α-aminoalkylphenethylphosphinic acids.

Full text of DOI:10.1134/S107036321109009X

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 9, pp. 1786–1791. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © M.E. Dmitriev, V.V. Ragulin, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 9, pp. 1446–1451.
Method of Synthesis of Phosphinic Acids
Based on Hypophosphites:
VIII.1 Synthesis of α-Aminoalkylphenethylphosphinic Acids
M. E. Dmitriev and V. V. Ragulin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: rvalery@dio.ru
Received July 20, 2010
Abstract—Development of methodology of double Arbuzov rearrangement based on hypophosphites allows a
one-pot formation of two unsymmetrical phosphorus–carbon bonds by the Michael–Pudovik type reaction of
stepwise addition of the intermediately forming silyl esters of trivalent phosphorus to different unsaturated
compounds. A procedure was developed of the synthesis of α-aminoalkylphenethylphosphinic acids. Bis-
(trimethylsilyl)phenethylphosphonite formed as a result of the addition of bis(trimethylsilyl)hypophosphite to
styrene in situ was added without isolation from the reaction mixture to Schiff bases obtained preliminary from
benzylamine or diphenylmethylamine and various aldehydes. The subsequent removal of N-protecting groups
by hydrogenation or acidic hydrolysis gave a number of new α-aminoalkylphenethylphosphinic acids.
DOI: 10.1134/S107036321109009X
isosteres of amino acids [9–12], the key intermediates
in the synthesis of pseudo-peptides can be synthesized,
which are analogs of natural peptides but the peptide
fragment is replaced by an nonhydrolyzable methylene-
phosphoryl fragment. The approach we developed to
the synthesis of pseudo-peptides on the basis of hypo-
phosphites allowed us the development of general
methods for the synthesis of pseudo-γ-glutamyl
peptides [11, 12] and pseudo-γ-aminobutanoyl
peptides [1].
The ability of hydrophosphoryl compounds to be
converted into silyl esters of trivalent phosphorus acids
allows the creation of two phosphorus–carbon bonds in
a single reaction vessel using hypophosphites [1–10].
The introduction to the reaction medium of an α-
dihaloalkane or two equivalents of a haloalkane leads
to the formation of cyclic phosphinic acid or a
dialkylphosphinic acid of symmetric structure, respec-
tively, as a result of two series of the reactions of the
Arbuzov reaction type [2–4]. Further development of
the methodology of the double Arbuzov rearrangement
with the use of oppositely charged electrophiles pro-
vides a possibility of obtaining a variety of unsym-
metrical dialkylphosphinic acids through stepwise
formation of two phosphorus–carbon bonds [5–8]. The
application of unsaturated compounds for the
formation of the first phosphorus–carbon bond allows
the use of the phosphonous acids silyl esters formed in
various transformations of the type of the Arbuzov,
Abramov, and Kabachnik–Fields reactions in situ with
the formation of the second phosphorus–carbon bond
[5–8].
The main problem in the development of
methodology for the synthesis of phosphinic pseudo-
α,α'-dipeptides is to find suitable procedures for construct-
ing the α-aminophosphoryl function containing two
phosphorus–carbon bonds. In this regard, we suggested
previously a procedure of amidoalkylation of phos-
phonous structural isosteres of amino acids [13], a
three-component procedure for the reaction of silylphos-
phonite, benzylamine, and a carbonyl component in
situ [14], and a procedure for the addition of the silyl
ether of phosphonous isosteres of amino acids in situ
to N-tritylmethaneimine [10].
When as the unsaturated component is used an
appropriately α-substituted acrylate, phosphonous
This work reports on further development of the
methodology for the one-pot formation of two
phosphorus–carbon bonds using a pair of different
1
For communication VII, see [1].
1786

METHOD OF SYNTHESIS OF PHOSPHINIC ACIDS BASED ON HYPOPHOSPHITES: VIII.
1787
unsaturated compounds. The formation of the first
phosphorus–carbon bond is performed by adding bis
(trimethylsilyl) hypophosphite I formed in situ to an
unsaturated component, followed by the addition of the
formed in situ silylphosphonite II to an appropriate
Schiff base III in the reaction of the Michael–Pudovik
type to create the second phosphorus–carbon bond
(Scheme 1). Extremely easy formation of bis
(trimethylsilyl)hypophosphite I at the silylation of
ammonium hypophosphite (IV) [15, 16] and its high
reactivity determine the high performance of this
compound as a key intermediate in the proposed chain
of reactions leading to the formation of N-protected α-
aminoalkylphosphinic acids V and VI (Scheme 1).
Scheme 1.
O
P
R
Ph
4
N
OH
H
Ph
O
NH2
R
V
Ph
OSiMe3
OSiMe3
Ph
Z = NH2Ph
Z = NHPh2
3
P
P
OH
5
VII
II
2
Ph
Ph
H
O
P
N
Ph
OSiMe3
1
H2POONH4
HP
IV
OSiMe3
R
OH
I
VI
(1): (Me3Si)2NH; (2): CH2=CHPh; (3): (а) R–CH=N–Z (III), (b) EtOH/H2O; (4): HCOONH4, Pd/C; (5) HCl or HBr.
R = H, Me, i-Pr, i-Bu, Ph.
As the intermediately forming phosphonous com-
ponents we used bis(trimethylsilyl) phenethylphos-
phonite II in situ, because this compound is added in
situ to styrene selectively affording 1:1 adduct [17],
unlike acrylates which can form the products of 1:2
addition [5].
and nickel halides. Unfortunately, we failed to reveal
any effect of nickel salts, but found a slight increase in
the yield of N-benzyl-α-aminoalkylphenethylphos-
phinous acid (V) at the use of cadmium salts.
The procedure for the synthesis of pseudo-glycyl-
peptides, the α-aminomethylphosphinic acids, which
we suggested earlier [10], involved the use of N-
tritylmethaneimine that is a little unstable under the
conditions of addition of the trivalent phosphorus silyl
esters. Therefore in this work we used for the synthesis
of aminomethylphenethylphosphinic acid VIIa the
iminie trimers, 1,3,5-tris-(Z)-hexahydro-s-triazines
(VIII) containing a more stable benzyl or diphenyl-
methyl substituent at the nitrogen atom (Scheme 2).
The Schiff bases were obtained preliminary on the
basis of benzylamine and diphenylmethylamine and
used an electrophilic component in the Michael–
Pudovik type reaction of silylphosphonite II addition.
We showed that the activity of the (N-benzyl)-Schiff
bases is somewhat higher than that of N-(diphenyl-
methyl)-derivatives, however, a possibility of acid
hydrolysis of the adducts VI without isolation and
purification from the reaction medium greatly
simplifies obtaining the target amino acids VII.
EXPERIMENTAL
The 1H, 31P, and 13C NMR spectra were recorded on
Brucker DPX-200 and Brucker CXP-300 Fourier
spectrometers with internal reference TMS and
external reference 85% H3PO4. Melting temperatures
of the compounds were determined on a Boetius-
PHMK device or on a block in an open capillary.
A positive effect of cadmium iodide was found
earlier in the addition of diethylphosphite to aldo- and
keto-imines [18]. In this paper we attempted to
increase the yield of reaction of the phenethylphos-
phonous acid silyl esters to N-benzyl Schiff bases in
the presence of catalytic amounts of some cadmium
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1788
DMITRIEV, RAGULIN
Scheme 2.
O
O
NZ
NZ
OSiMe3
1
2
1/3 ZN
+
Ph(CH2)2
P
Ph(CH2)2
P
Ph(CH2)2
P
OSiMe3
NHZ
NH2
OH
OH
II
VIII
VIа
VIIа
Vа or
(1): EtOH/H2O; (2) HCOONH4, Pd/C OR HCl (HBr); Z = CH2Ph, CHPh2.
All reactions involving intermediate formation of
silyl esters of hypophosphorous and phosphonous
acids were carried out in an argon atmosphere.
Solvents used were thoroughly dried. TLC analysis of
the individual compounds and the reaction mixtures
was performed on Silufol plates [eluent chloroform–
acetone (5–7):1]. For the analysis of amino acid were
used the Merck glass plates with the silica gel UV-254
layer thickness 0.2 mm [eluent 1-butanol–acetic acid–
water (5–8):1:1], and ninhydrin.
The reaction was monitored by 31P NMR spectroscopy.
To the reaction mixture cooled to room temperature
was slowly added dropwise 5–10 ml of water while
stirring. The precipitated crystalline product was
separated by filtration, the filtrate was evaporated in a
vacuum. The residue was partitioned between 40 ml of
chloroform and 10 ml of water. The organic phase was
dried over sodium sulfate and evaporated in a vacuum.
The residue was crystallized from ether, combined
with the bulk of the crystalline product isolated
initially, and recrystallized from isopropanol to afford
respective 1-(N-benzylamino)alkylphenethylphosphinic
acid V. 1-(N-Diphenylmethylamino)alkylphenethyl-
phosphinic acids VI usually were not isolated in pure
form, except for the acid VIc (R = i-Pr), which was
isolated and characterized (see below). The organic
and aqueous phases were separated, the chloroform
solution was evaporated, and the residue was subjected
to acid hydrolysis for 15–17 h with concentrated
hydrochloric or hydrobromic acid, the reaction mixture
was evaporated in a vacuum, the residue was dissolved
in aqueous alcohol and treated with an excess of
propylene oxide, followed by separation and crys-
tallization of target amino acids VII. Constants of α-
aminoalkyl phenethylphosphinic acids VII were
consistent with the data for the same compounds
obtained by hydrogenation of N-benzyl derivatives V.
The total yield of amino acids VII obtained by
hydrogenation and isolated in individual form as N-
benzyl-α-aminoalkyl-phenethylphosphinic acids V was
slightly higher (23–37%) or comparable with the
overall yield of the aminophosphinic acids VII (17–
29%) obtained by acid hydrolysis of N-(diphenyl-
methyl)-α-aminoalkylphenethylphosphinic acids VI
without isolation from the reaction mixture, calculated
on the initial ammonium hypophosphite.
Benzylamine, diphenylmethylamine, hexamethyldi-
silizane, and hypophosphorous acid were provided by
Acros Organics. Styrene, benzaldehyde, acetic, iso-
butyric, and isovaleric aldehydes were provided by
Alfa Aesar. For the treatment of the reaction mixture
containing palladium on carbon was used celite.
Ammonium hypophosphite was obtained in accor-
dance with the procedure [19].
The general procedure for the synthesis of 1-(N-
benzylamino)alkyl- (V) and 1-(N-diphenylmethyl-
amino)alkylphenethylphosphinic (VI) acids. The
Schiff bases on the basis of benzylamine and diphenyl-
methylamine used in the synthesis of acids VII were
prepared preliminary along the following general
procedure. To a solution of 0.1 mol of benzylamine or
diphenylmethylamine in 70 ml of benzene was added
0.1 mol of an appropriate aldehyde, the reaction
mixture was stirred for 1 h, anhydrous sodium sulfate
was added, and the resulting mixture was left
overnight. The sulfate was filtered off and the filtrate
was carefully evaporated in a vacuum. According to
1H NMR spectrum, the residue consisted of the
respective Schiff base, which was used for further
transformation without purification.
A mixture of 1.5 g (18.2 mmol) of ammonium
hypophosphite and 1.9 g (18.2 mmol) of styrene in
8.1 ml (36.4 mmol) of hexamethyldisilazane was
stirred at boiling for 3 h, and then 2.18 mmol of the
corresponding Schiff base was slowly added dropwise.
The reaction mixture was stirred at boiling for 6–9 h.
In the syntheses of the corresponding N-benzylamino-
methyl- (V, R = H) and N-(diphenylmethyl)amino-
methyl- (VI, R = H) phenethylphosphinic acids the
corresponding iminium trimers, 1,3,5-trisbenzyl- and
1,3,5-tris(diphenylmethyl)hexahydro-s-triazines were
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METHOD OF SYNTHESIS OF PHOSPHINIC ACIDS BASED ON HYPOPHOSPHITES: VIII.
1789
used synthesized preliminary from formalin and the
corresponding amines with a small amounts of
potassium hydroxide as a catalyst [20].
d (2JPC 2.9 Hz), 31.4 d (1JPC 95.5 Hz), 49.6 d (3JPC 5.5 Hz),
51.3 d (1JPC 85.3 Hz), 126.5, 128.4 (2C), 128.9 (2C),
129.7 (2C), 130.0, 130.2 (2C), 131.2, 142.4 d (3JPC
14.6 Hz). 31P NMR spectrum (CDCl3 + CD3OD, 5:1):
δP 33.0 ppm.. 31P NMR spectrum (CD3OD): δP 32.8
ppm.. 31P NMR spectrum (D2O + NaOD, pH ~10): δP
44.1 ppm.. Found, %: C 67.13, 67.17; H 7.37, 7.41; P
10.03, 9.93. C17H22NO2P. Calculated, %: C 67.31; H
7.31; P 10.21.
When cadmium and nickel salts were used as a
catalyst, the reaction mixture before adding Schiff base
was cooled to room temperature, and in a weak flow of
argon to the reaction mixture was added 0.6 mmol of
the calcined catalyst, then the reaction mixture was
heated while the corresponding Schiff base was slowly
added dropwise at stirring. Further procedure and
treatment of the reaction mixture are similar to that
described above. Addition of the nickel salts has no
effect on the reaction of silylphosphonite II with the
Schiff base on the basis of benzylamine, however, at
the use of cadmium salts the yield of target N-benzyl-
derivatives V slightly increased (by 5–12%).1
1-(N-Benzylamino)-2-methylpropylphenethylphos-
phinic acid (Vc). Yield 41.4% (53.7%), mp 131–134°C.
1H NMR spectrum (D2O + NaOD, pH 9–10), δ, ppm:
3
0.85 d (6H, 2 CH3, JHH 4.5 Hz), 1.63 m (2H, CH2P),
2.02 m [1H, CH(CH3)2], 2.35 m (1H, CHP), 2.58 m
(2H, CH2CH2P), 3.65 m (2H, CH2NH), 7.05–7.35 m
1
(10H, 2Ph). H NMR spectrum (CDCl3), δ, ppm: 1.08
d (3H, CH3CH, 3JHH 5.9 Hz), 1.18 d (3H, CH3CH, 3JHH
5.9 Hz), 1.88 m (2H, CH2P), 2.30 m (1H, CH), 2.74 m
(3H, CHP, CH2CH2P), 4.21 d (1H, CHN, 2JHH 12.7 Hz),
(N-Benzylamino)methylphenethylphosphinic acid
(Va). Yield 62.0%, mp 200–203°C. 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.10 m (2H, CH2P), 2.75 m (2H,
2
4.51 d (1H, CHN, JHH 12.7 Hz), 7.05–7.65 m (10H,
2
CH2CH2P), 3.18 d (2H, PCH2NH, JPH 9.3 Hz), 4.19
2Ph). 13C NMR spectrum (CD3OD), δC, ppm: 19.9 d
(3JPC 5.5 Hz), 20.7 d (3JPC 4.8 Hz), 28.4, 29.5 d (2JPC
3.3 Hz), 35.3 d (1JPC 95.5 Hz), 49.6 d (3JPC 5.5 Hz),
52.2, 63.2 d (1JPC 82.0 Hz), 127.1, 129.2 (2C), 129.5
(2C), 130.3 (2C), 130.8, 131.3 (2C), 132.7, 143.6 d
(3JPC 14.6 Hz). 31P NMR spectrum (CDCl3): δP 32.8 ppm.
31P NMR spectrum (D2O + NaOD, pH ~10): δP 41.7
ppm. Found, %: C 68.67, 68.57; H 8.03, 7.97; P 9.17,
9.23. C19H26NO2P. Calculated, %: C 68.86; H 7.91; P
9.35.
br.s (2H, CH2NH), 7.10–7.55 m (10H, 2Ph). 13C NMR
spectrum (CD3OD), δC, ppm: 28.3, 32.5 d (1JPC 93.3 Hz),
52.4 d (1JPC 91.9 Hz), 54.0 d (3JPC 5.9 Hz), 127.5 (2C),
129.2 (2C), 129.7 (2C), 130.2, 130.4, 131.5, 132.9
(2C), 141.8 d (3JPC 15.0 Hz). 31P NMR spectrum
(DMSO-d6): δP 38.7 ppm. 31P NMR spectrum
(CD3OD): δP 42.5 ppm.. Found, %: C 66.17, 66.29; H
7.05, 7.11; P 10.57, 10.63. C16H20NO2P. Calculated,
%: C 66.42; H 6.97; P 10.71.
1-(N-Benzylamino)ethylphenethylphosphinic acid
(Vb). Yield 47.8% (53.8%), mp 209– 211°C. 1H NMR
spectrum (D2O + NaOD, pH ~10), δ, ppm: 1.15 d. d
1-(N-Benzylamino)-3-methylbutylphenethylphos-
phinic acid (Vd). Yield 41.3% (46.6%), mp 189–191°C.
1H NMR spectrum (D2O + NaOD, pH ~10), δ, ppm:
0.68 d (3H, CHCH3, 3JHH 6.2 Hz), 0.81 d (3H, CHCH3,
3JHH 6.2 Hz), 1.38 m (2H, CHCH2CH), 1.58 m (1H,
CHCH3), 1.76 m (2H, CH2P), 2.53 m (1H, CHP), 2.69
3
3
(3H, CH3, JHH 10.0, JPH 15.2 Hz), 1.72 m (2H,
CH2P), 2.60 m (3H, CHP, CH2CH2P), 3.60 d (1H,
2
CHN, JHH 12.0 Hz), 3.80 d (1H, CHN, 2JHH 12.0 Hz),
7.10–7.40 m (10H, 2Ph). 1H NMR spectrum (CDCl3 +
CD3OD, 5:1), δ, ppm: 1.37 d. d (3H, CH3CH, 3JHH 7.0,
3JPH 13.3 Hz), 1.81 m (2H, CH2P), 2.80 m (3H, CHP +
2
m (2H, CH2CH2P), 3.67 d (1H, CHN, JHH 13.2 Hz),
2
3.79 d (1H, CHN, JHH 13.2 Hz), 7.10–7.35 m (10H,
1
2Ph). H NMR spectrum (CDCl3 + CD3OD, 5:1), δ,
2
CH2CH2P), 4.07 d (1H, CHN, JHH 12.9 Hz), 4.59 d
3
ppm: 0.77 d (3H, CH3CH, JHH 6.5 Hz), 0.84 d (3H,
(1H, CHN, 2JHH 12.9 Hz), 7.05–7.30 m (5H, Ph), 7.35–
3
CH3CH, JHH 5.6 Hz), 1.68 m (3H, CH2CHCH3), 1.82
7.50 m (5H, Ph). 1H NMR spectrum [CD3OD +
m (2H, CH2P), 2.77 m (3H, CHP + CH2CH2P), 4.08 d
3
CF3COOH (drop)], δ, ppm: 1.53 d. d (3H, CH3, JHH
2
2
(1H, CHN, JHH 13.0 Hz), 4.44 d (1H, CHN, JHH
13.0 Hz), 7.1–7.55 m (10H, Ph). 13C NMR spectrum
(CD3OD), δC, ppm: 22.5, 22.6, 26.0 d (3JPC 4.8 Hz),
29.1, 33.1 d (1JPC 95.1 Hz), 37.3, 50.9, 54.5 d (1JPC
83.8 Hz), 126.8, 128.8 (2C), 129.3 (2C), 130.1 (2C),
130.4, 130.9 (2C), 132.1, 143.1 d (3JPC 15.4 Hz). 31P
NMR spectrum (D2O + NaOD, pH ~10): δP 44.6 ppm.
31P NMR spectrum (CDCl3 + CD3OD, 5:1): δP 33.3 ppm.
3
6.8, JPH 14.8 Hz), 2.18 m (2H, CH2P), 2.91 m (2H,
CH2CH2P), 3.35 m (1H, CHP), 4.39 m (2H, CH2NH),
7.1–7.35 m (5H, Ph), 7.4–7.6 m (5H, Ph'). 13C NMR
spectrum (CDCl3 + CD3OD, 5:1), δC, ppm: 11.9, 28.6
1
Yields of target compounds V obtained at the addition of
catalytic amount of cadmium chloride are given in parentheses.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

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DMITRIEV, RAGULIN
Found, %: C 69.33, 69.41; H 8.03, 8.04; P 9.03, 8.95.
C20H28NO2P. Calculated, %: C 69.54; H 8.17; P 8.97.
2.80 m (2H, CH2CH2P), 5.36 с (1H, CHPh2), 6.86 br.s
(1H, NH), 7.1–7.55 m (18H, 3Ph + OH + HOH). 13C
NMR spectrum (CDCl3), δC, ppm: 19.2, 21.3 d (3JPC
8.8 Hz), 27.9 (2C), 31.4 d (1JPC 88.6 Hz), 58.3 d (1JPC
92.6 Hz), 65.7 d (3JPC 7.0 Hz), 126.1, 127.8 (2C),
127.9, 128.1, 128.5, 128.7, 128.8, 141.3 d (3JPC 26.4 Hz).
31P NMR spectrum (CDCl3): δP 51.9 ppm. Found, %:
C 70.34, 70.28; H 7.75, 7.65; P 7.03, 7.13. C25H30NO2P·
H2O. Calculated, %: C 70.57; H 7.58; P 7.28.
α-(N-Benzylamino)benzylphenethylphosphinic
1
acid (Ve). Yield 43.7% (55.3%), mp 201–203°C. H
NMR spectrum (CDCl3 + CD3OD, 5:1), δ, ppm: 1.60
m (2H, CH2P), 2.67 m (2H, CH2CH2P), 3.93 d (1H,
2
2
CHP, JPH 9.6 Hz), 3.75 d (1H, CHN, JHH 14.3 Hz),
2
4.23 d (1H, CHN, JHH 14.3 Hz), 7.05–7.40 m (15H,
1
3Ph). H NMR spectrum (D2O + NaOD, pH 9–10), δ,
Synthesis of amino acids VII by hydrogenation
of N-(benzyl)-α-aminoalkylphenethylphosphinic acids
Va–Ve. A solution of 2 mmol of 1-(N-benzylamino)
alkylphenethylphosphinic acid V and 5 mmol of
ammonium formate, and a suspension of 0.5 g of 5%
or 10% palladium on carbon was stirred in 5.7 ml of
alcohol at room temperature. The degree of conversion
was monitored by TLC and 1H, 31P NMR spec-
troscopy. The catalyst was removed by filtration
through a celite bed and the filtrate was evaporated in a
vacuum. The residue was crystallized from an alcohol/
ether mixture and recrystallized from aqueous alcohol.
ppm: 1.72 m (2H, CH2P), 2.43 m (2H, CH2CH2P), 3.17
2
2
d (1H, CHN, JHH 13.2 Hz), 3.53 d (1H, CHN, JHH
13.2 Hz), 3.58 d (1H, CHP, 2JPH 14.4 Hz), 7.00–7.40 m
(15H, 3Ph). 13C NMR spectrum (CD3OD), δC, ppm:
28.1 d (2JPC 4.0 Hz), 30.8 d (1JPC 93.7 Hz), 51.7 d (3JPC
4.8 Hz), 60.9 (1JPC 89.7 Hz), 127.5, 129.0 (2C), 129.3
(2C), 129.6 (2C), 130.1, 130.2 (2C), 130.6 (2C), 130.7,
130.8 (2C), 131.1, 131.6 (2C). 31P NMR spectrum
(CDCl3): δP 33.1 ppm. 31P NMR spectrum (D2O +
NaOD, pH 9–10): δP 39.3 ppm. Found, %: C 72.11,
72.05; H 6.85, 6.81; P 8.42, 8.51. C22H24NO2P.
Calculated, %: C 72.31; H 6.62; P 8.48.
The amino acids obtained are white crystalline
powders with a characteristic high melting point (with
decomposition). Yields of aminophosphinic acids VII
based on the initial N-benzylamino-substituted phos-
phinic acid V are 52–71%.
Constants, H, 13C, and 31P NMR spectral data
and analyses of α-aminoalkyl-phenethylphosphinic
In the event of N-diphenylmethyl-containing Schiff
bases or 1,3,5-tris(diphenylmethyl)hexahydro-s-triazine
(the synthesis of VIa, Scheme 2) after the reaction
completion the mixture was cooled to room tem-
perature, to the mixture was slowly added dropwise
10–15 ml of alcohol, and it was evaporated in a
vacuum. The residue was partitioned between 40 ml
chloroform and 10 ml of water, and the organic layer
was evaporated in a vacuum. Typically, the oily
residue was boiled with 20–30 ml of concentrated
hydrochloric or hydrobromic acid for 15 h and the
mixture was evaporated in a vacuum. Then the residue
was dissolved in aqueous alcohol and treated with an
excess of propylene oxide. The resulting crystalline
product was recrystallized from aqueous alcohol to
afford free amino acid VII.
1
acids (VIIa–VIIe). Aminomethylphenethylphos-
1
phinic acid (Va). Yield 52.3%, mp 279–281°C. H
NMR spectrum (D2O), δ, ppm: 1.88 m (2H,
CH2CH2P), 2.71 m (2H, CH2CH2P), 2.85 d (2H,
2
PCH2NH2, JPH 9.3 Hz), 7.10–7.30 m (5H, Ph). 13C
NMR spectrum (D2O), δC, ppm: 27.5, 30.9 d (1JPC
95.1 Hz), 37.3 d (1JPC 89.3 Hz), 126.4, 128.2 (2C),
128.8 (2C), 141.7 d (3JPC 14.6 Hz). 31P NMR spectrum
(D2O): δP 36.2 ppm. Found, %: C 54.11, 54.03; H 7.17,
7.23; P 15.41, 15.34. C9H14NO2P. Calculated, %: C
54.27; H 7.08; P 15.55.
The product of addition of silylphenethylphos-
phonite to the Schiff base derived from diphenyl-
methylamine and isobutyraldehyde after alcoholysis
(VIc, R = i-Pr) was isolated in the individual state by
crystallization from ether followed by recrystallization
from ether–alcohol.
1-Aminoethylphenethylphosphinic acid (VIIb).
Yield 61.9%, mp 244–246°C. 1H NMR spectrum
3
3
(D2O), δ, ppm: 1.37 d. d (3H, CH3, JHH 7.4, JPH
14.1 Hz), 2.00 m (2H, CH2P), 2.84 m (2H, CH2CH2P),
3.28 m (1H, CHP), 7.2–7.40 m (5H, Ph). 13C NMR
spectrum (D2O), δC, ppm: 12.0, 26.4 d (3JPC 3.7 Hz),
28.1 d (1JPC 91.8 Hz), 44.8 d (1JPC 93.3 Hz), 126.1,
127.7 (2C), 128.4 (2C), 140.9 d (3JPC 14.4 Hz). 31P
NMR spectrum (D2O): δP 40.2 ppm. Found, %: C 56.19,
56.13; H 7.51, 7.61; P 14.44, 14.31. C10H16NO2P.
Calculated, %: C 56.33; H 7.56; P 14.53.
1-(N-diphenylmethyl)amino-2-methylpropylphe-
nethylphosphinic acid (VIc, R = i-Pr). Yield 32.6%,
1
mp 90–92°C. H NMR spectrum (CDCl3), δ, ppm:
1.07 d (3H, CH3CH, 3JHH 6.8 Hz), 1.15 d (3H, CH3CH,
3JHH 6.8 Hz), 2.03 m (2H, CH2P), 2.38 m (1H,
3
2
CHCH3), 2.65 d. d (1H, CHP, JHH 4.8, JPH 9.7 Hz),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

METHOD OF SYNTHESIS OF PHOSPHINIC ACIDS BASED ON HYPOPHOSPHITES: VIII.
1791
1-Amino-2-methylpropylphenethylphosphinic
ACKNOWLEDGMENTS
1
acid (VIIc). Yield 71.0%, mp 192–194°C. H NMR
3
This work was supported by the Russian Founda-
tion for Basic Research (grant no. 09-03-12157 and
grant no. 10-03-01058-a).
spectrum (D2O), δ, ppm: 1.01 d (3H, CH3CH, JHH
3
6.2 Hz), 1.03 d (3H, CH3CH, JHH 6.6 Hz), 2.01 m
(2H, CH2P), 2.20 m [1H, CH(CH3)2], 2.87 m (3H,
CHP, CH2CH2P), 7.15–7.4 m (5H, Ph). 13C NMR
spectrum (D2O), δC, ppm: 17.1 d (3JPC 4.8 Hz), 19.4 d
(3JPC 7.0 Hz), 26.3, 26.7 d (2JPC 3.7 Hz), 30.2 d (1JPC
91.4 Hz), 54.8 d (1JPC 91.4 Hz), 126.1, 127.8 (2C),
128.4 (2C), 140.6 (3JPC 14.4 Hz). 31P NMR spectrum
(D2O): δP 39.2 ppm. Found, %: C 59.67, 59.53; H 8.23,
8.19; P 12.73, 12.65. C12H20NO2P. Calculated, %: C
59.74; H 8.36; P 12.84.
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5. Kurdyumova, N.R., Rozhko, L.F., Ragulin, V.V., and
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6. Ragulin, V.V., Kurdyumova, N.R., and Tsvetkov, E.N.,
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8. Kurdyumova, N.R., Ragulin, V.V., and Tsvetkov, E.N.,
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10. Rozhko, L.F. and Ragulin, V.V., Amino Acids, 2005,
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11. (a) Ragulin, V.V., Rozhko, L.F., Saratovskikh, I.V., and
Zefirov, N.S., Japan Patent, 2000–18568. Jan. 27, 2000;
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Rozhko, L.F., Saratovskikh, I.V., and Zefirov, N.S.,
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13. Dmitriev, M.E. and Ragulin, V.V., Tetrahedron Lett.,
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p. 154.
15. Voronkov, M.G. and Marmur, L.Z., Zh. Obshch. Khim.,
1970, vol. 40, no. 9, p. 2135.
1-Amino-3-methylbutylphenethylphosphinic acid
1
(VIId). Yield 57.3%, mp 225–226°C. H NMR spec-
trum (D2O), δ, ppm: 0.80 d (3H, CH3CH, 3JHH 5.8 Hz),
3
0.88 d (3H, CH3CH, JHH 5.8 Hz), 1.57 m (3H,
CH2CH), 1.98 m (2H, CH2P), 2.81 m (2H, CH2CH2P),
3.12 m (1H, CHP), 7.15–7.4 m (5H, Ph). 13C NMR
spectrum (D2O), δC, ppm: 20.0, 22.1, 23.8 d (3JPC
9.2 Hz), 26.5 d (2JPC 2.6 Hz), 27.9 d (1JPC 90.4 Hz),
35.5, 47.3 d (1JPC 94.4 Hz), 126.6, 128.1 (2C), 128.8
(2C), 140.5 d (3JPC 12.8 Hz). 31P NMR spectrum
(D2O): δP 39.9 ppm. Found, %: C 60.91, 60.97; H 8.77,
8.71; P 12.01, 12.05. C13H22NO2P. Calculated, %: C
61.16; H 8.69; P 12.13.
α-Aminobenzylphenethylphosphinic acid (VIIe).
Yield 68.4%, mp 221–223°C. 1H NMR spectrum
[DMSO-d6 + CF3COOH (drop)], δ, ppm: 1.92 m (2H,
2
CH2P), 2.65 m (2H, CH2CH2P), 4.63 d (1H, CH, JPH
12.4 Hz), 7.05–7.30 m (5H, Ph), 7.35–7.55 m (5H,
Ph). 13C NMR spectrum [CD3OD + D2O (9:1) + DCl
(drop)], δC, ppm: 28.5 (2JPC 4.0 Hz), 30.1 d (1JPC 91.8 Hz),
54.9 d (1JPC 92.6 Hz), 127.4, 129.0, 129.6 (2C), 130.3
(2C), 130.6, 130.8, 131.1, 131.6, 132.1 d (2JPC 2.9 Hz),
141.7 d (3JPC 15.7 Hz). 31P NMR spectrum [DMSO-
d6 + CF3COOH (drop)]: δP 39.8 ppm. Found, %: C
65.34, 65.21;
H 6.65, 6.73; P 11.13, 11.09.
C15H18NO2P. Calculated, %: C 65.45; H 6.59; P 11.25.
16. Issleib, K., Mogelin, W., and Balszuweit, A., Z. Anorg.
Allgem. Chem., 1985, vol. 530, no. 1, p. 16.
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no. 12, p. 1970.
18. Kabachnik, M.M., Zobnina, E.V., and Beletskaya, I.P.,
Zh. Org. Khim., 2005, vol. 41, no. 4, p. 517.
19. Boyd, E.A., Regan, A.C., and James, K., Tetrahedron
Lett., 1992. Vol. 33, no. 3, p. 813.
Thus, as a result of this work we developed a
convenient one-pot procedure for the synthesis of α-
aminoalkylphenethylphosphinic acids with two
unsymmetrical phosphorus-carbon bonds, by gradual
adding silyl esters of trivalent phosphorus formed in
situ to the dissimilar unsaturated compounds in the
Michael-Pudovik type reaction. The subsequent
removal of protecting groups at the nitrogen atom by
hydrogenation or by acid hydrolysis leads to target
aminophosphinic acids.
20. Baylis, E.K., Campbell, C.D., and Dingwall, J.G.,
J. Chem. Soc., Perkin Trans. 1, 1984, p. 2845.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011