Acyloxy derivatives of trivalent phosphorus in amidoalkylation of hydrophosphoryl compounds

Article abstract of DOI:10.1134/S1070363213100150

In order to model the previously suggested mechanism of the P-C bond formation via the Arbuzov reaction, we have studied the interaction of diethylacylphosphite (prepared beforehand as well as generated in situ from tetraethylpyrophosphite) with the in situ generated acyliminium cation. Various conditions of in situ generation of acylphosphite derivatives of P(III) from hydrophosphoryl compounds and acyliminium ions from N,N′- alkylidenebiscarbamates have been investigated: solvent nature, acid catalyst, and the reagents mixing order). The results obtained have confirmed the suggested mechanism of three-component reaction of amidoalkylation of hydrophosphoryl compounds with the formation of P-C bond via the Arbuzov reaction of in situ formed intermediates.

Full text of DOI:10.1134/S1070363213100150

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 10, pp. 1888–1894. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © M.E. Dmitriev, V.V. Ragulin, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 10, pp. 1681–1687.
Acyloxy Derivatives of Trivalent Phosphorus
in Amidoalkylation of Hydrophosphoryl Compounds
M. E. Dmitriev and V. V. Ragulin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Sevenyi proezd 1, Chernogolovka, 142432 Russia
e-mail: rvalery@dio.ru
Received May 14, 2013
Abstract—In order to model the previously suggested mechanism of the P–C bond formation via the Arbuzov
reaction, we have studied the interaction of diethylacylphosphite (prepared beforehand as well as generated in
situ from tetraethylpyrophosphite) with the in situ generated acyliminium cation. Various conditions of in situ
generation of acylphosphite derivatives of P(III) from hydrophosphoryl compounds and acyliminium ions from
N,N'-alkylidenebiscarbamates have been investigated: solvent nature, acid catalyst, and the reagents mixing
order). The results obtained have confirmed the suggested mechanism of three-component reaction of
amidoalkylation of hydrophosphoryl compounds with the formation of P–C bond via the Arbuzov reaction of
in situ formed intermediates.
DOI: 10.1134/S1070363213100150
Studies of the synthesis of N-alkyloxycarbonyl-α-
aminophosphoryl compounds I via the three-com-
ponent reaction of hydrophosphoryl compounds, alde-
hydes, and alkyl carbamates in acetic anhydride upon
cooling suggested a new version of this multi-stage
reaction. The mechanism involved the stage of P–C
bond formation via the Arbuzov reaction, namely,
nucleophilic attack of acetyloxy derivative of trivalent
phosphorus II at the positively charged carbon atom of
iminium cation III (Scheme 1). Components II and III
were generated in situ from the starting hydro-
phosphoryl compound and N,N'-alkylidenebis(alkyl-
carbamate), respectively [1, 2]. The latter was
identified as a stable intermediate forming from
aldehyde and alkylcarbamate, and was isolated from
reaction medium [1, 2]. The subsequent attack of the
anion Z at electrophilic carbon atom of POAc fragment
of phosphonium intermediate IV led to the formation
of the target N-protected α-aminophosphoryl com-
pound I with the elimination of AcZ (Scheme 1) via
the Arbuzov reaction [1, 2].
This work was aimed to model the assumed stage of
P–C bond formation basing on the previously suggested
mechanism [1, 2]. We studied the interaction of the
acyloxy derivative of trivalent phosphorus II (prepared
beforehand) with N-alkyloxycarbonyl-iminium cation
III (generated in situ from N,N'-alkylidenebiscarbamate
V under conditions of acid catalysis) [1–4].
It was found that the interaction of N,N'-benzyl-
idenebis(benzylcarbamate) Va with diethylacetylphos-
phite IIa in acetic anhydride did not lead to the
Scheme 1.
O
Y
H
X
H
R
OAlk
O
H
H
N
P
X
P+
N
H
X
R
OAlk
C+
P+
Y
OAlk
N
−AcZ
H
O
O−
R
O
O
Y
O
Z−
Z−
IV
O
III
II
I
Z = Cl, OAc.
1888

ACYLOXY DERIVATIVES OF TRIVALENT PHOSPHORUS
1889
formation of the target N-benzyloxycarbonyldi-
ethylphosphonate Ia (Scheme 2); the reason of that
was the absence of acid catalysis required for the in
situ generation of the cation IIIa from N,N'-benzyl-
idenebis(benzylcarbamate) Va (Scheme 2). The possible
attack of the trivalent phosphorus atom of diethyl-
acetylphosphite IIa at the electrophilic carbon atom of
benzylidene fragment in Va did not result in the target
P–C bond formation, in contrast with the successful
attack of IIa at the positively charged carbon atom of
the cation IIIa that could only be generated under acid
catalysis conditions [1–4].
Scheme 2.
OBn
O
OEt
P
CH3
H
N
BnO
HN
H
Ph
P
O
Ph
O
O
O
O
Ac2O(+H+)
EtO
IIа
EtO
EtO
IIа
NH
OBn
N
−H2NC(O)OBn
O
−
O
Iа
−Ac2O
H
C+
CH3
Ac2O
O
OBn
Ph
H
IIIа
Iа
Vа
The obtained result confirmed our suggestion on
the required reaction conditions: not only PIIIOAc
component II should have been generated, but also the
acid catalysis was necessary for in situ generation of
N-alkyloxycarbonyliminium cation III [1, 2]. Indeed,
addition of catalytic amounts of trifluoroacetic acid or
p-toluenesulfonic acid led to formation of the target
product Ia in satisfactory yields.
Further, we studied the effect of acid catalysis on
the interaction of N,N'-isoamylidenebis(ethylcarbamate)
Vb with methylphosphonous acid in acetic anhydride
(Scheme 3) by means of 31P NMR spectroscopy.
Scheme 3.
O
O
O
H
N
O
O
O
O
HN
+ H+
P
H
N
O
+
+ Ac2O
H
+
P
OH
H2N
OH
O
O
Vb
Ib
The results confirmed the acid-catalysed mechanism
of the reaction, p-toluenesulfonic acid (2%) being
more efficient catalyst than trifluoroacetic acid (10%)
(see figure).
Tetraethylpyrophosphite was shown to interact with
one equivalent of acetic acid with the formation of
diethylacetylphosphite IIa and diethylphosphite [5];
we confirmed that by results of 31Р NMR spectroscopy
in the presence of acetic and trifluoroacetic acids
(Scheme 4). Previously, we found that in chloroform,
toluene, ethanol, dioxane, tetrahydrofuran, and in
acetic acid media the interaction of biscarbamates V
with hydrophosphoryl compounds did not occur [1, 2].
The satisfactory reaction course in acetic anhydride
without additionally introduced catalyst could be
described as the transformation of hydrophosphoryl
compound into acetyloxy derivative of trivalent
phosphorus with the formation of acetic acid; the
acidity of the latter likely was enough to induce the
formation of the corresponding N-(alkyloxycarbonyl)-
iminium cation III [1, 2].
Therefore, in the organic solvent containing an
equivalent of acetic acid, pyrophosphite should act as a
source of reactive diacetylphsphite IIa capable of
reacting with acyliminium cation IIIa, whereas
diethylphosphite in the absence of acetic anhydride
should not be reactive under those conditions [1, 2]
Another approach to the reaction mechanism
modeling implied using pyrophosphite as the source of
trivalent phosphorus acyloxy derivative in situ.
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1890
DMITRIEV, RAGULIN
Scheme 4.
EtO
H
Vа
P
H
Ph
P
O
EtO
O
OEt
δP 9.1 ppm
EtO
EtO
EtO
EtO
P
P
AcOH
OBn
N
H
O
or
X
O
Vа
CF3COOH
Iа
δP 21.7 ppm
O
EtO
−Ac2O
OEt
δP 129.7 ppm
P
O
AcOC(O)CF
or
3
EtO
IIа
IIb
δP 138.0 ppm
δP 134.6 ppm
X = Me (IIа), CF3 (IIb).
and should be accumulated unchanged in the reaction
medium.
was in contact with the acid for some period of time
before pyrophosphite was added; that was likely due to
the instability of the iminium cation IIIa in acidic
medium.
We studied the interaction of tetraethylpyro-
phosphite with a solution of N,N'-benzylidenebis-
(benzylcarbamate) Va in anhydrous chloroform or
toluene with varied amount of acetic or trifluoroacetic
acid (0.5–1.5 equivalents). The results confirmed the
formation of target phosphonate Ia; as expected, the
second P-containing reaction product was diethyl-
phosphite that was formed from pyrophosphite and
was stable under the reaction conditions. However,
yield of Ia was relatively low, 15% to 23% depending
on the nature and amount of the acid catalyst.
Furthermore, we observed lower yields of Ia in the
case when N,N'-benzylidenebis(benzylcarbamate) Va
Therefore, we changed the order of reactants
mixing. In particular, we studied the interaction of acid
catalyst with a mixture of tetraethylpyrophosphite and
biscarbamate Va in toluene, methylene chloride, or
chloroform, in order to generate IIa or IIb and the
acyliminium cation simultaneously. That increased the
yield of Ia to 32–45%, catalysis by CF3COOH being
more efficient. The results confirmed validity of the
suggested reaction mechanism, as described above.
The particular case of pyrophosphite as a phosphorous-
containing component could be generalized to other
compounds.
The above-described approach to generate the
reactive intermediates by addition of acetic or tri-
fluoroacetic anhydride to a mixture of hydrophos-
phoryl compound and alkylidenebiscarbamate could be
promising in the preparatory syntheses of N-protected
α-aminophosphoryl compounds. The initial interaction
of anhydride with the hydrophsphoryl component VI
should lead to in situ formation of reactive acyloxy
form of trivalent phosphorus II and the corresponding
acid that would facilitate generation of acyliminium
cation III.
Addition of trifluoroacetic anhydride to a mixture
of N,N'-alkylidenebiscarbamate Vc–Vf and hydro-
phosphoryl compound VIc–VIf in the methylene
chloride of toluene solution upon cooling and
subsequent treatment of the mixture with water
(Scheme 5) led to reasonably high yields of the target
acids Ic–If (52–65%) [3, 4].
Time, h
Kinetics of Ib accumulation in the reaction mixture (time
in h, acetic anhydride medium): (1) with p-toluenesulfonic
acid (2 mol%), (2) with trifluoroacetic acid (10 mol %),
(3) without catalyst. The Ib content was calculated as
integral intensity of 31P signal of Ib with respect to sum of
the signals of Ib and of methylphosphonous acid.
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ACYLOXY DERIVATIVES OF TRIVALENT PHOSPHORUS
1891
Scheme 5.
O
O
H
N
(1) [CF3C(O)]2O
(2) H2O
AlkO
R
O
P
O
NH
OAlk
+
X
OH
X
P
OAlk
O
−AlkOC(O)NH2
R
H
OH
N
H
Vc−Vf
VIc−VIf
Ic−If
X = R = Me, Alk = Bn (Ic); X = EtOC(O)CH2CH2, R = i-Pr, Alk = Bn (Id); R = Ph, Alk = Et (Ie);
X = EtOC(O)CH(Me)CH2, R = Me, Alk = Bn (If).
To conclude, this model study confirmed the
previously assumed mechanism [1, 2]. of the
generation in situ of the acetyloxy derivative of
phosphorus(III) and of iminium cation (salt) under the
conditions of the reaction of amidoalkylation in the
acetic anhydride environment followed by their
interaction of the type of Arbuzov reaction with the
formation of the target P–C bond.
Reaction of diethylacetylphosphite with N,N'-
benzylidenebis(benzylcarbamate). Freslhly distilled
diethylacetylphosphite IIa (5 mmol) in 5 mL of acetic
anhydride was added to a solution of N,N'-benzyl-
idenebis(benzylcarbamate) Va (5 mmol) in 3 mL of
anhydrous chloroform (or methylene chloride); the
mixture was stirred during 2 days. TLC and 31Р NMR
showed that the initial compounds remained practically
unchanged [formation of some diethylphosphite
(δP ~ 12 ppm) and may be acetylphosphonate
(δP ~ 19 ppm) was detected; in total, no more than 9–
11%]. To that solution, trifluoroacetic acid was added
(10 mol %), and the mixture was stirred during 20 h.
From 31Р NMR, the initial IIa was completely
consumed (signal at ~135 ppm disappeared), and the
target product Ia was formed (intense phosphonate
signal appeared at ~22 ppm). The reaction mixture was
evaporated in a vacuum; the residue was dissolved in
chloroform (15 mL) and washed with water (3–5 mL).
The organic phase was dried over sodium sulfate and
evaporated in a vacuum. The residue was crystallized
from petroleum ether and recrystallized from ether.
Yield 28%, with respect to diethylacetylphosphite.
EXPERIMENTAL
1H, 31P, and 13S NMR spectra were registered on a
Brucker spectrometer DPX-200, the references used
were TMS (internal) and 85% H3PO4 (external).
Melting points were determined with Boetius-PHMK
or in open capillary.
Thin layer chromatography analysis of the
individual compounds and the reaction mixtures was
performed using Silufol plates, glass plates (Merck
silica gel UV-254 layer of 0.2 mm) [eluent: chloro-
form–acetone, (4–5):1], or Alufol plates (Kavalier)
(neutral aluminum oxide on aluminum foil); the plates
were developed in iodine vapor or by UV irradiation.
Column chromatography was performed using Silpearl
silica gel and L100/160 (Chemapol) or Silica gel 60
(Alfa Aesar).
Upon addition of the catalytic amounts of p-
toluenesulfonic acid (2 mol %) or trifluoroacetic acid
(10 mol %) to a freshly prepared solution of di-
ethylacetylphosphite and N,N'-benzylidenebid(benzyl-
carbamate) in a mixture of acetic anhydride and
chloroform or methylene chloride (1:1) yields of Ia
were 53% (p-TsOH) and 37% (CF3COOH).
N,N'-Alkylidenebis(alkylcarbamates) were prepared
from the corresponding aldehyde and two equivalents
of ethyl or benzyl carbamate in acetic aldehyde [1, 2].
Diethylacetylphosphite was prepared from diethyl-
chlorophosphite and sodium acetate as described in
[7]. 2-(Ethoxycarbonyl)propylphosphonous acid and
2-(ethoxycarbonyl)propylphosphonous acid were acid
were synthesized by in situ addition of bis(tri-
methylsilyl)hypophosphite to ethyl acrylate and ethyl
methacrylate, respectively, with subsequent alcohol-
lysis of the formed silylphosphonites [8].
Reaction of methylphosphonous acid with N,N'-
isoamylidenebis(ethylcarbamate) (Vb) in acetic
anhydride. The catalyst p-TsOH (2 mol %) or CF3COOH
(10 mol %) was added to a freshly prepared solution of
N,N'-isoamylidenebis(ethylcarbamate) Vb (5 mmol)
and methylphosphonous acid (5 mmol) in 5 mL of
acetic anhydride, or the reaction was performed
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 10 2013

1892
DMITRIEV, RAGULIN
without catalyst. The course of the reaction was
monitored by 31Р NMR; the signals of initial methyl-
phosphonic acid at ~35 ppm and of the forming
phosphinic acid at 55 ppm were followed. The change
of content of the target product Ib with time (h) is
given in the figure at different catalysis conditions.
Phosphonate Ib was isolated from the reaction mixture
as described in [2].
bamate Vc–Vf (3 mmol) and the corresponding
hypophosphorus acid VIc–VIf (3 mmol) in toluene or
methylene chloride (5 mL). The reaction mixture was
stirred during 10–48 h at room temperature, the course
of the reaction was monitored by 31P NMR. The semi-
crystalline residue (after evaporation of the reaction
mixture) was partitioned between saturated aqueous
solution of sodium carbonate (15 mL) and ether
(15 mL). Alkylcarbamate from the solution was filtered
off; the aqueous part of the filtrate was acidified to рН
1~2 and extracted with chloroform (3×10 mL). The
organic phase was dried over magnesium sulfate and
then subjected to chromatography on silica gel
Tetraethylpyrophosphite as a source of diethyl-
acetylphosphite in situ. a. Tetraethylpyrophosphite
(4 mmol) in 3 mL of anhydrous toluene was added to a
freshly prepared solution of N,N'-benzylidenebis
(benzylcarbamate) Va (4 mmol) in 3 mL of anhydrous
chloroform containing acetic or trifluoroacetic acid
(0.5–1.5 equivalent); the solution was stirred at room
temperature. The course of the reaction was monitored
by 31P NMR. The reaction mixture was diluted with
10–15 mL of toluene, and then evaporated in a vacuum.
The semicrystalline precipitate was partitioned
between sodium carbonate saturated aqueous solution
(15 mL) and ether (15 mL). Benzyl carbamate from the
solution was filtered off, aqueous part of the filtrate
was acidified to рН ~ 6–7 and extracted with
chloroform (3×10 mL). The combined organic extract
was dried over magnesium sulfate and evaporated in a
vacuum. The residue was subjected to chromatography
on silica gel (CHCl3:i-PrOH, 20:1). Phosphonate Ia
was crystallized from petroleum ether and
recrystallized from ether. Yield from 15% (catalysis
with 1.5 eq. of АsОН) to 23% (1.0 eq. of CF3COOH)
with respect to pyrophosphite. The phosphonate yield
was significantly decreased when tetraethylpyrophos-
phite was added long time after the acid catalyst
mixing with biscarbamate.
(CHCl3:i-PrOH:AcOH
=
95:4:1) to obtain the
corresponding N-protected α-aminophosphinic acids
(Id, If) in the form of white crystals. In some cases, the
residue crystallized spontaneously or after treatment
with ether or petroleum ether, and the target
compounds were isolated after additional crystallize-
ation from ether without chromatography (Ic, Ie).
Yields of the products were 52–65% with trifluoro-
acetic anhydride; the of use of acetic anhydride
decreased the yields to 23–31%. The evaporation of
the hypophosphorus acid with acetic anhydride without
heating before introducing it to the reaction mixture
was found to increase the yields of I.
Diethyl ether of α-(N-benzyloxycarbonyl)amino-
benzylphosphonic acid (Ia), mp 110–111°C (ether)
(mp 113–114°C [6]), Rf ~ 0.70 [CHCl3:CO(CH3)2 =
1
4:1]. H NMR spectrum (CCl4 + CD3OD), δ, ppm:
4
1.23 d.t (6Н, CH3SH2, JPH 2.0 Hz), 4.03–4.23 m (4Н,
OSH2CH3), 5.04–5.26 m (2H, OSH2Ph), 6.26 br.s (1Н,
CH), 7.50–7.70 m (10Н, 2Ph). 31Р NMR spectrum
(CDCl3): δP 22.1 ppm.
b. Upon cooling, acetic or trifluoroacetic acid (4–
6 mmol) was slowly dropwise added to a solution of
the mixture of tetraethylpyrophosphite (4 mmol) and
N,N'-benzylidenebis(benzylcarbamate) Va (4 mmol) in
5–6 mL of anhydrous methylene chloride, chloroform,
or toluene. The formed solution was stirred at room
temperature, the course of the reaction was monitored
with 31Р NMR. Subsequently, the mixture was treated
as discussed above. The target product yield was 32–
45% with respect to pyrophosphite. CF3COOH was
more efficient as catalyst.
1-(Ethyloxycarbonylamino)-3-methylbutylphos-
phinic acid (Ib), mp 143–144°C (ether) (mp 144–146°C
1
[1]), Rf ~ 0.10 [CHCl3:CO(CH3)2 = 4:1]. H NMR
spectrum (CCl4 + CD3OD), δ, ppm: 0.93 d (3Н, JHH
6.6 Hz), 0.97 d (3Н, JHH 6.6 Hz), 1.26 t (3H, CH3),
1.38 d (3H, CH3, JPH 14.1 Hz), 1.40–1.55 m (2H,
CH2), 1.60–1.85 m (1H, CH), 3.74–3.88 m (1H, CH),
3
4.08 q (2H, CH2, JHH 7.0 Hz). 31Р NMR spectrum
(CCl4 + CD3OD, 5:1): δP 52.2 ppm.
1-(Benzyloxycarbonylamino)ethylmethylphos-
phinic acid (Ic), mp 121–122°C (ether) (mp 100–101°C
1
Acetic and trifluoroacetic anhydrides in generat-
ing reactive intermediates. Upon cooling, acetic or
trifluoroacetic anhydride (3 mmol) was slowly drop-
wise added to a mixture of N,N'-alkylidenebiscar-
[2]), Rf ~ 0.15 [CHCl3:CO(CH3)2 = 4:1]. H NMR
spectrum (CDCl3), δ, ppm: 1.35 d.d (3Н, CH3CH, 3JHH
3
2
7.1, JPH 15.0 Hz), 1.45 d (3Н, CH3P, JPH 15.4 Hz),
3.85–4.10 m (1Н, SНN), 4.90–5.15 m (2Н, CH2Ph),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 10 2013

ACYLOXY DERIVATIVES OF TRIVALENT PHOSPHORUS
1893
3
5.40 d (1H, NH, JHH 9.7 Hz), 7.23–7.38 m (5H, Ph),
(CDCl3), δP, ppm: 52.3, 51.0 [4]. 31Р NMR spectrum
(CCl4 + CD3OD, 5:1): δP 46.1 ppm. MS spectrum, m/z
(Irel, %): 344 (3.4) [M + H]+, 178 (100) PhC+HNHC(O)
OCH2CH3, 165 (44) EtO(O)CCH2CH2P+H(O)OH.
Found, %: C 52.54, 52.61; H 6.39, 6.41; N 4.11, 4.11.
C15H22NO6P. Calculated, %: C 52.48; H 6.46; N 4.08.
10.60 br.s (1Н, POOH). 13C NMR spectrum (CDCl3),
δC, ppm: 12.4 d (1JPC 93.3 Hz), 13.9, 46.0 d (1JPC
1
07.6 Hz), 67.2, 128.1, 128.2, 128.5, 136.1, 155.9 d
(3JPC 5.1 Hz). 31Р NMR spectrum (CDCl3): δP 54.9
ppm. 31Р NMR spectrum (DMSО-d6), δP 47.1 ppm.
1-(Benzyloxycarbonylamino)-2-methylpropyl-2-
1-(Benzyloxycarbonylamino)-ethyl-2-(ethyloxy-
(ethyloxycarbonyl)ethylphosphinic acid (Id), mp
86–88°C (ether), Rf 0.15 [CHCl3:CO(CH3)2 = 4:1]. H
carbonyl)propylphosphinic acid (If), mp 117–118°C
1
1
(ether), Rf 0.13 [CHCl3:CO(CH3)2 = 4:1]. H NMR
3
NMR spectrum (CDCl3), δ, ppm: 0.98 d (3H, CHCH3,
spectrum (CDCl3), δ, ppm: 1.22 t (3H, CH3, JHH
3
3
3JHH 6.6 Hz), 1.02 d (3H, CHCH3, JHH 5.3 Hz), 1.23 t
7.0 Hz), 1.24 d (3H, CH3, JHH 7.0 Hz), 1.34 d.d (3Н,
3
3
(3H, CH3), 1.88–2.08 m (2H, CH2), 2.22–2.34 m (1H,
CH3CH, JHH 7.5, JPH 14.9 Hz), 1.65–1.85 m (1H,
CH2P), 2.15–2.35 m (1H, CH2P), 2.58–2.97 m [1H,
CHC(O)], 3.95–4.15 m (1H, CHN), 4.11 q (2H, CH2O,
3JHH 7.0 Hz), 5.11 br.s (2H, OCH2Ph), 5.38 d (1H, NH,
3JHH 7.5 Hz), 7.20–7.45 m (5H, Ph), 9.72 br.s (1H,
CH), 2.51–2.62 m (2H, CH2), 3.89 d.d.d (1Н, CHN,
3
2
3JHH 4.0, JHH 10.6, JPH 10.1 Hz), 4.12 q (2H, CH2O,
3JHH 7.0 Hz), 5.12 br.s (2H, PhCH2O), 5.26 d (1H, NH,
3JHH 10.6 Hz), 7.25–7.40 m (5H, Ph), 10.88 br.s (1H,
1
1
POOH). H NMR spectrum (CD3OD), δ, ppm: 1.00 d
POOH). H NMR spectrum (CCl4:DMSО-d6 = 3:1), δ,
3
3
(3H, CHCH3, JHH 4.7 Hz), 1.03 d (3H, CHCH3, JHH
ppm: 1.12–1.17 m [6H, CH3CH2 + CH3CHC(O)], 1.19
3
3
3.3 Hz), 1.23 t (3H, CH3, JHH 7.0 Hz), 1.92–2.03 m
d.d (3H, CH3CH, JHH 7.5, 3JPH 10.6 Hz), 1.51–1.68 m
(2H, CH2), 2.15–2.28 m (1H, CH), 2.44–2.60 m (2H,
(1H, CH2P), 1.91–2.08 m (1H, CH2P), 2.57–2.77 m
[1H, CHC(O)], 3.58–3.83 m (1H, CHN), 3.87–4.13 m
(2H, CH2O), 4.93– 5.08 m (OCH2Ph), 7.23–7.42 m
CH2), 3.79 d.d (1H, CHN, 3JHH 5.1, 2JPH 10.2 Hz), 4.12
3
q (2H, CH2O, JHH 7.0 Hz), 5.08–5.17 m (2H,
PhCH2O), 7.25–7.40 m (5H, Ph). 13C NMR spectrum
(CD3OD), δ, ppm: 14.5, 18.8 d (3JPC 5.1 Hz), 21.2 d
(3JPC 9.1 Hz), 23.8 d (1JPC 91.5 Hz), 27.5 d (2JPC
2.6 Hz), 29.2 d (2JPC 1.5 Hz), 56.1 d (1JPC 106.1 Hz),
62.0, 67.9, 128.8, 129.0, 129.5, 138.2, 159.0 d (3JPC
5.5 Hz), 173.8 d (3JPC 15.7 Hz). 31Р NMR spectrum
(CDCl3), δC, ppm: 55.2, 53.9 (~13%) [4]. Found, %: C
55.03, 55.13; H 7.13, 7.20; P 8.39, 8.34. C17H26NO6P.
Calculated, %: C 54.98; H 7.06; P 8.34.
(5H, Ph), 7.53 d (1H, NH, JHH 8.8 Hz). 13C NMR
3
spectrum (DMSО-d6), δC, ppm: 13.8, 14.0, 18.6 d (2JPC
7.0 Hz), 18.8* d (2JPC 8.1 Hz) (hereinafter asterisk
marks the diastereomers signals), 29.3 d (1JPC
88.6 Hz), 29.4* d (1JPC 88.2 Hz), 33.4, 45.7 d (1JPC
105.8 Hz), 46.0* d (1JPC 105.8 Hz), 60.1, 65.6, 127.7,
127.8, 128.4, 137.1, 155.8 d (3JPC 3.7 Hz), 175.1 d
(3JPC 9.5 Hz). 31Р NMR spectrum (CDCl3), δP, ppm:
55.0, 53.6 [4]. Found, %: C 53.57, 53.49; H 6.92, 6.87;
P 8.37, 8.43. C16H24NO6P. Calculated, %: C 53.78; H
6.77; P 8.67.
α-(Ethyloxycarbonylamino)benzyl-2-(ethyloxy-
carbonyl)ethylphosphinic acid (Ie), mp 147–148°C
1
(ether), Rf 0.15 [CHCl3:CO(CH3)2 = 4:1]. H NMR
ACKNOWLEDGMENTS
3
spectrum (CDCl3), δ, ppm: 1.21 t (3H, CH3, JHH
3
The work was financially supported by Russian
Foundation for Basic Research (project no. 10-03-
01058-a).
7.1 Hz), 1.25 t (3H, CH3, JHH 7.1 Hz), 1.55–2.00 m
(2H, CH2), 2.30–2.45 m (2H, CH2), 4.10 q (2H, CH2,
3
3JHH 7.0 Hz), 4.14 q (2H, CH2, JHH 7.0 Hz), 5.02 d.d
3
3
(1H, PCH, JHH 10.0, JPH 10.0 Hz), 5.90–6.05 m (1H,
NH), 7.14 br.s (1H, POOH), 7.18–7.33 m (5H, Ph). 1H
NMR spectrum (CCl4 + CD3OD, 5:1), δ, ppm: 1.26 t
(3H, CH3, 3JHH 7.0 Hz), 1.29 t (3H, CH3, 3JHH 7.0 Hz),
1.78–2.06 m (2H, CH2), 2.39–2.60 m (2H, CH2), 4.00–
4.23 q (4H, 2CH2, JHH 7.0 Hz), 4.97 d (1H, CH, JРH
13.7 Hz), 7.20–7.45 m (5H). 13C NMR spectrum
(DMSО-d6), δC, ppm: 14.1, 14.6, 21.7 d (1JPC 91.6 Hz),
26.3 d (2JPC 2.9 Hz), 54.1 d (1JPC 99.6 Hz), 60.3, 60.4,
127.2, 127.3, 128.0, 128.2, 136.3, 156.3 d (3JPC
7.9 Hz), 172.1 d (3JPC 15.9 Hz). 31Р NMR spectrum
REFERENCES
1. Dmitriev, M.E. and Ragulin, V.V., Tetrahedron Lett.,
2010, vol. 51, no. 19, p. 2613.
3
2
2. Dmitriev, M.E., Rossinets, E.A., and Ragulin V.V.,
Russ. J. Gen. Chem., 2011, vol. 81, no. 6, p. 1092.
3. Dmitriev, M.E. and Ragulin, V.V., Russ. J. Gen. Chem.,
2012, vol. 82, no. 11, p. 1882.
4. Dmitriev, M.E. and Ragulin, V.V. Tetrahedron Lett.,
2012, vol. 53, no. 13, p. 1634.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 10 2013

1894
DMITRIEV, RAGULIN
5. Anderson, G.W., Blodinger, J., and Wether, A.D.,
J. Am. Chem. Soc., 1952, vol. 74, no. 21, p. 5309.
6. Yuan, S., Wang, G., and Chen, S., Synthesis, 1990,
no. 6, p. 522.
7. Pudovik, A.N., Kashevarova, E.I., and Gorchakova, V.M.
Zh. Obshch. Khim., 1964, vol. 34, no. 7, p. 2213;
Fursenko, I.V., Bakhvalov, G.T., and Nifantev, E.E., Zh.
Obshch. Khim., 1968, vol. 38, no. 4, p. 1299.
8. Kurdyukova, N.R., Rozhko, L.F., Ragulin, V.V., and
Tsvetkov, E.N., Zh. Obshch. Khim., 1997, vol. 67,
no. 12, p. 1965; Kurdyukova, N.R., Rozhko, L.F.,
Ragulin, V.V., and Tsvetkov, E.N., Zh. Obshch. Khim.,
1997, vol. 67, no. 12, p. 1970; Rozhko, L.F. and
Ragulin, V.V., Amino Acids, 2005, vol. 29, no. 2,
p. 139.
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