Amidoalkylation of hydrophosphoryl compounds

Article abstract of DOI:10.1134/S1070363211060041

A new mild procedure of the amidoalkylation of hydrophosphoryl compounds in a mixture of acetic anhydride and acetyl chloride was developed as a convenient method of constructing the a-aminophosphoryl fragment of the pseudo-a,a'-dipeptide molecule. The reaction intermediates N,N'-benzylidene- and N,N'-alkylidenebiscarbamates were detected, isolated, and identified. The report presents the results of studying the direct interaction of hydrophosphoryl compounds previously synthesized with biscarbamates in acetic anhydride and other solvents, the influence of the structure of phosphorus component and biscarbamate, and the effect of acid catalysis on the course of this two-component reaction. A new version of the mechanism of the three-component reaction of amidoalkylation of hydrophosphoryl compounds is suggested: it is regarded as a multistage process involving the stage of biscarbamate formation followed by the stage of Arbuzov-type reaction with the intermediate formation of acyliminium cation and P-OAc derivative with trivalent phosphorus. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070363211060041

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 6, pp. 1092–1104. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © M.E. Dmitriev, E.A. Rossinets, V.V. Ragulin, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 6, pp. 898–910.
Amidoalkylation of Hydrophosphoryl Compounds
M. E. Dmitriev, E. A. Rossinets, and V. V. Ragulin
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Severnyi pr. 1, Chernogolovka, Moscow oblast, 142432 Russia
e-mail: rvalery@dio.ru
Received June 3, 2010
Abstract—A new mild procedure of the amidoalkylation of hydrophosphoryl compounds in a mixture of acetic
anhydride and acetyl chloride was developed as a convenient method of constructing the α-aminophosphoryl
fragment of the pseudo-α,α'-dipeptide molecule. The reaction intermediates N,N'-benzylidene- and N,N'-alkyl-
idenebiscarbamates were detected, isolated, and identified. The report presents the results of studying the direct
interaction of hydrophosphoryl compounds previously synthesized with biscarbamates in acetic anhydride and
other solvents, the influence of the structure of phosphorus component and biscarbamate, and the effect of acid
catalysis on the course of this two-component reaction. A new version of the mechanism of the three-com-
ponent reaction of amidoalkylation of hydrophosphoryl compounds is suggested: it is regarded as a multistage
process involving the stage of biscarbamate formation followed by the stage of Arbuzov-type reaction with the
intermediate formation of acyliminium cation and P–OAc derivative with trivalent phosphorus.
DOI: 10.1134/S1070363211060041
A suitable imitation of the substrate in the transition
state of the reactions involving hydrolytic enzymes,
Zn-metalloproteinases and aspartylproteinases is the
replacement of the peptide bond with a non-hydrolized
phosphinate fragment [1].
the protective groups. Introduction of aminoalkyl-
phosphonic component into the acrylates as a silyl
ether [4] has a limitation in the construction of the
complex aminoalkylphosphonic building-blocks. The
attempts to obtain the phosphine pseudo-AspAla-di-
peptide via the addition of trimethylsilyl ethers of
aminophosphonic analog of aspartic acid to ethyl
methacrylate failed [4].
The known approach to constructing molecular
phosphinic analogs I of α,α'-dipeptides II is the
synthesis of N-protected aminoalkylphosphonic com-
ponent of the pseudopeptide, phosphonic analog A of
amino acid, followed by adding the latter to the
appropriate α-substituted acrylate and the formation of
pseudopeptide fragment B [2–4].
In this regard, the development of alternative
methods of constructing pseudopeptides is actual.
Previously we have developed new synthesis methods
of pseudo-γ-glutamylpeptides [5] and pseudo-γ-
aminobutanoylpeptides [6] with the inverse order of
constructing the target molecule: First adding hypo-
phosphite to the corresponding acrylate to form phos-
phonic acids containing structural isostere of amino
acids followed by the addition of amino acid function
and the formation of pseudopeptide molecules [5, 6].
B
R
O
R*
R*
O
H
N
HN
H2N
HO
P
OH
N
H
R
O
O
A
Further development of this methodology in the
synthesis of phosphinic peptidomimetics, the promis-
ing pseudo-α,α'-dipeptide building-blocks I for com-
binatorial chemistry, includes finding a convenient
procedure for constructing α-aminophosphoryl func-
tions involving phosphonic acids III containing a
structural isosteres of the corresponding amino acids
[7, 8].
II
Peptide fragment
I
Phosphinic acidic pseudo-
{Ψ(P(O)(OH)CH2}-α,α'-dipeptide
In this case, the synthesis of an aminoalkyl-
phosphoryl peptide fragment requires three or more
stages [2–4], due to the incorporation and removal of
1092

1093
AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
Scheme 1.
B
B
O
R
O
O
*R
OAlk
O
*R
OAlk
O
O
P
O
P
H
N
NH2
+
H
_H2O
R
OH
OH
A
I
III
In this regard, the development of the amido-
alkylation procedure of the trivalent phosphorus com-
pounds via the Kabachnik–Fields type reaction using
the carbonyl compounds and amides as an amino
component of the synthesis [9, 10] may be a promising
way to the construction of N-protected pseudopeptide
molecule I.
acid in the acetyl chloride medium resulted in a
significant loss of ester groups in phosphoryl and
carboxyl fragments of the target molecule, hampering
the isolation of the target product. Typically, crude N-
acylated α-aminophosphonic derivatives were sub-
jected to the acid hydrolysis to isolate free α-amino-
alkylphosphonic acids [9–11]. In this regard, a search
for milder conditions for the synthesis of N-protected
derivatives of α-aminoalkylphosphoryl compounds is
urgent. The relatively mild amidoalkylation procedure
has been developed for the phosphorous acid amides,
which consists in adding the aldehyde to a preheated
mixture of the reagents in acetic anhydride [11]. An
attempt to further development of this synthetic
approach to the pseudo-α,α'-dipeptides using acet-
amide as amino component and phosphonic acids
containing the amino acid structural isosteres led to the
satisfactory results only in the case of aromatic
aldehydes [7]. However, this procedure can underlie a
more efficient and mild procedure of amidoalkylation
of the hydrophosphoryl compounds.
The amidoalkylation reaction originally developed
for the trivalent phosphorus chlorides in acetic acid
(Oleksyszyn reaction) [9] was further modified into the
procedure of dialkylphosphites amidoalkylation in
acetyl chloride or in a mixture of acetic acid and
thionyl chloride with aldehydes or ketones, amides or
carbamates [10]. The use of benzyl carbamate in acetyl
chloride medium allows to obtain the α-amino-
alkylphosphoryl N-benzyloxycarbonyl derivatives,
which are of interest for peptide synthesis [10]. The
procedure of amidoalkylation of hydrophosphoryl
compounds in a mixture of acetyl chloride and acetic
acid has been used in the synthesis of phosphinic
pseudopeptide blocks involving the prehydrolyzed
phosphonous component [8], probably due to the
partial dealkylation of alkoxyphosphoryl and
alkoxycarboxyl fragments occuring in acetyl chloride
medium. Our attempt to amidoalkylate dimethyl-
phosphite and 2-(ethoxycarbonyl)propylphosphonic
Earlier N,N'-alkylidenebisamides IV [11] and O,N-
hemiaminals, 1-(acylamino)alkyl acetates V, have
been suggested as possible intermediates in the amido-
alkylation reaction of trivalent phosphorus compounds
[12] (Scheme 2).
Scheme 2.
R
R
R'
NH
O
Me
O
NH
R'
RCH(O) + R'C(O)NH
AcOH, AcCl, Ac2O
NH
R'
O
O
O
IV
V
N,N'-Arylidene or N,N'-alkylidene bisamides IV
were suggested in [11] as probable intermediates in the
amidoalkylation reaction due to their easy formation
from carbonyl compounds and amides [13], but they
were not isolated from the reaction mixture [11]. The
hemiaminals V have also been postulated as inter-
mediates in this reaction, but these compounds also
were not isolated from the reaction mixture [12].
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DMITRIEV et al.
This paper presents the results of the study of
amino component and aldehydes with various
hydrophosphoryl compounds VI in acetic anhydride in
the cold to form N-benzyloxycarbonyl-α-aminoalkyl-
phosphoryl compounds VII in moderate yields
(Scheme 3).
amidoalkylation of the hydrophosphoryl compounds in
acetic anhydride medium. We have found that the
milder Oleksyszyn modification of the procedure [11]
allows to carry out the reaction of benzyl carbamate as
Scheme 3.
X
Y
O
H
O
P
R
Y
O
Ac2O or
O
X
Ac2O/AcCl
HN
O
OBn
NH
VI
P
N
H
OBn
RCH(O) + BnOC(O)NH2
or Ac2O (H+)
_BnOC(O)NH2
R
VII
OBn
IV
A mixture of acetic anhydride and acetyl chloride is
a more effective medium for amidoalkylation of PH-
compounds (Table 1), however, the search for the
optimum mixture was not performed. The use of
methyl and ethyl carbamates as amino components in
acetic anhydride gives a positive result [14]. The
attempts to use in these conditions phthalimide, acet-
amide, trifluoroacetamide, and tert-butyl carbamate
proved to be unsuccessful or ineffective.
time the reaction intermediates N,N'-benzylidene- and
N,N'-alkylidenebis(benzyl carbamates) (IV, R' =
OCH2Ph). The initially formed biscarbamate IV
rapidly accumulates and often crystallizes from the
reaction solution, but then it dissolves again and
interacts with the PH-component VI to give the target
N-Cbz-α-aminoalkylphosphoryl
compound
VII
(Scheme 3). The latter sometimes also crystallizes
from the reaction solution.
The mild conditions of amidoalkylation of hydro-
phosphoryl compounds VI in acetic anhydride using
benzyl carbamate allowed us to isolate for the first
When the three-component reaction was stopped at
the early stages the isolated products contained a
mixture of N-Cbz-α-aminoalkylphosphoryl compound
N-Benzyloxycarbonyl-α-aminoalkylphosphoryl compounds VIIа–VIIn
Comp. no.
X
Y
R
Yield, %
OMe
Me
Me
Me
Me
Me
OMe
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Et
Ph
Me
Et
i-Pr
i-Bu
Ph
63а, 73б, 69c, 56d
27а,f, 67c, 51e, 62а,e
61c, 31d
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
VIIm
VIIn
57c, 30d
46b, 53c, 33d, 41д, 59b,e
69б, 76c, 61d, 63e, 69а,e
59c, 35d
PhCH2CH2
PhCH2CH2
PhCH2CH2
HOCH2
Et
i-Pr
i-Bu
i-Bu
Ph
Me
Ph
63c, 29d
31а, 68с
33а,g
HOCH2
42а,g
EtOOCCH(Me)CH2
EtOOCCH(Me)CH2
Et
33а, 57c
54а, 63b, 69c, 43d
51а, 67c, 41d
Ph
Reaction was catalyzed with: Trifluoroacetic acid (10 mol %); b p-TsH (2 mol%). In the absence of a catalyst: c in the medium of AcCl/
a
d
e
Ac2O (1:4) or Ac2O. Relative to PH-component for the two-component synthesis, the reaction of methylphosphonic acid with the
f
g
corresponding biscarbamate IV. Using acetaldehyde diethylacetal. The amidoalkylation products of hydroxymethylphosphonic acid
were hydrolyzed; the free aminophosphinic acids yields are given, calculated on benzyl carbamate.
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AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
VII and the corresponding biscarbamate IV in
different ratios depending on the reagents reactivity
and reaction time. Compounds IV and VII were
isolated using chromatography on silica gel and were
characterized by TLC and 1H, 13C, and 31P NMR spec-
troscopy.
acetoxy group. The results of the research suggest that
the mixture of acetic anhydride and acetyl chloride is
the optimum medium for the three-component
reaction.
The data obtained are a good justification for the
study of the two-component reaction between
biscarbamates IV and hydrophosphoryl compounds
VI. We found that the pre-synthesized biscarbamates
IV are able to react in the cold with hydrophosphoryl
compounds VI in acetic anhydride or a mixture of
acetyl chloride and acetic anhydride (1:4) to give the
target α-aminoalkylphosphoryl compounds VII
(Scheme 4) .
These data are surprising because the more
probable intermediates of the three-component reac-
tions are acetates V (Scheme 2) [12]. They are more
favorable, if we accept the reaction mechanism
comprising the step of nucleophilic attack of PH-
component phosphorus atom on the electrophilic
carbon center of acetate V containing a good leaving
Scheme 4.
Ac2O or
H
N
Ac2O + H+
O
R
O
OBn
+
VII
+
VI
or Ac2O/AcCl
H2N
OBn
BnO
NH
O
R = Me, i-Bu, Ph; X = Me, OMe, Y = OH, OMe.
The amidoalkylation of the hydrophosphoryl
compounds VI in a mixture of acetic anhydride and
acetyl chloride (4:1) proceeds with a higher yield of
target compounds VII than in acetic anhydride. The
Ac2O/AcCl mixture is a suitable medium for the three-
component reaction. However, the focused search for
the optimal ratio of acetic anhydride and acetyl
chloride for the amidoalkylation of hydrophosphoryl
compounds was not performed.
the presence of the corresponding signals in the NMR
spectra of these compounds.
Synthesis of 1-(benzyloxycarbonylamino)ethyl-
methylphosphinic acid VIIb was performed using
acetaldehyde or its diethylacetal, or in a two-com-
ponent reaction of methylphosphonic acid with the
preliminary synthesized N,N'-ethylidenebis(benzyl car-
bamate) IVa. The use of aldehyde gives the desired
product VIIb in high yield. An alternative way of
synthesis of the target molecules could be the use of
the preliminary synthesized biscarbamate (see the
table). However, the use of acetaldehyde diethylacetal
decreases significanty the yield of VIIb. Ethyl acetate,
which was detected in the reaction mixture, probably
causes a poor result, because its formation consumes
acetyl chloride and (or) acetic anhydride, which affects
significantly the catalytic properties of the reaction
medium. Perhaps the reason for the yield decrease is
more profound, and the use of aldehyde acetals in this
reaction requires an additional investigation.
The amidoalkylation of 2-(ethoxycarbonyl)propyl-
phosphonic acid containing the structural isostere of
alanine is a way to phosphine pseudoalanine peptides.
In this work 1-(benzyloxycarbonylamino)ethyl-2-
(ethoxycarbonyl)propylphosphinic VIIl and α-(ben-
zyloxycarbonylamino)benzyl-2-(ethoxycarbonyl)propyl-
phosphinic VIIm acids were synthesized. These com-
pounds are ethyl esters of N-Cbz-protected phosphinic
acid analogs of alanylalanine N-Cbz-Ala-ψ{P(O)(OH)·
CH2}Ala and phenylglycylalanine N-Cbz-PhGly-
ψ{P(O)(OH)CH2}Ala peptides, respectively. Due to
the presence of a chiral center in the molecule of 2-
(ethoxycarbonyl)propylphosphonic acid along with the
formation of the second chiral α-carbon of amino-
phosphoryl fragment in the course of amidoalkylation,
the target compounds VIIl and VIIm are formed as
mixtures of two diastereomers, which is manifested in
The reaction monitoring with the use of the 31P
NMR spectroscopy revealed a greater reactivity of
benzylidenebiscarbamate compared with alkylidene-
biscarbamate. In addition, we found that N,N'-benzyl-
idenebis(benzyl carbamate) IVe (R = Ph) reacts with
methylphosphonic acid to form compound VIIf in
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DMITRIEV et al.
higher yield than in the case of N,N'-isoamylidenebis-
(benzyl carbamate) IVd (R = i-Bu) in the reaction with
methylphosphonic acid to form VIIe both in acetic
anhydride medium and in Ac2O/AcCl (4:1) mixture.
These data indicate the electrophilic nature of bis-
carbamates IV. However, it should be noted that while
studying hydrophosphoryl compounds VI of different
structures and potentially different nucleophilicity
(dimethyl phosphite–alkylphosphonic acid–diethyl-
phosphinic acid) we found no explicit nucleophilic
nature of the phosphorus components, both in three-
and two-component versions of the synthesis.
important to note that in benzene or toluene, ethanol,
dioxane, and tetrahydrofuran the reaction of bis-
carbamate IV with hydrophosphoryl compounds fails.
The reaction of biscarbamates IV with PH-compounds
in acetic anhydride proceeds satisfactorily in the cold
without a catalyst, better with acid catalyst (CF3COOH
or p-TsOH), and significantly better in a mixture of
acetic anhydride and acetyl chloride or acetyl chloride
medium. But in the last case there is a significant
dealkylation of alkoxyphosphoryl and alkoxycarboxyl
fragments.
The results obtained suggest that amidoalkylation
of hydrophosphoryl compounds is a multistep process,
and the rate-determining stage is probably the pro-
tonation of oxygen (C=O) or nitrogen atoms in the
amide fragment of the biscarbamate IV intermediate,
followed probably by the release of benzyl carbamate
molecule (Schemes 4, 5) and the formation of a
reactive intermediate N-(benzyloxycarbonyl)iminium
cation VIII (Scheme 5). The conditions for the
formation of similar acyliminium ions and their re-
activity data were published earlier [13].
The reaction of biscarbamate IV with PH-
component in acetic anhydride medium was found to
be acid-catalyzed, in contrast to the previously pub-
lished negative data for the three-component reaction
[11]. Adding trifluoroacetic acid or p-toluenesulfonic
acid (p-TsOH) to a mixture of reactants in acetic
anhydride or performing the reaction in a mixture of
acetyl chloride and acetic anhydride (1:4) leads to a
marked increase in the reaction rate, as confirmed by
the increase in the reaction product yield. It is
Scheme 5.
O
HN
O
H
Ac2O или AcCl
+H+ из РН components
OBn
NH2
OBn
OBn
R
O
C+ NH
O
NH
+
Z_
R
OBn
IV
VIII
Z = OAc or Cl.
We assume that all subsequent stages of the
amidoalkylation process are extremely fast and do not
affect the overall reaction rate.
Study of the reaction of methylphosphonic acid
with biscarbamates IV by means of the 31P NMR spec-
troscopy showed greater reactivity of N,N'-benzyl-
idenebiscarbamate IVe as compared with N,N'-alkyl-
idenebiscarbamates IVa–IVd (the reaction progress
was monitored observing the relative content of the
target product VII in the reaction mixture). This is
confirmed by the high yield of α-(benzyloxycarbonyl-
amino)benzylmethylphosphinic acid VIId (63%) in the
reaction of methylphosphonic acid with N,N'-benzyl-
idenebiscarbamate IVe in comparison with the yield of
N-protected α-aminoalkylmethylphosphinic acids VIIb
(R = Me) (51%) and VIIe (R = i-Bu) (41%) (see the
table).
It is interesting to note that in an excess of acetic
anhydride the formation is possible of the intermediate
salts VIII (Z = OAc), a ionic analog of 1-(acylamino)-
alkyl acetate V (Scheme 2) suggested early [12] as an
intermediate of the reaction. However, we believe that
the formation of acetate V molecules does not occur,
since in the course of the cation VIII formation the
trivalent phosphorus atom having a lone electron pair
attacks the positively charged carbon atom of N-
(benzyloxycarbonyl)iminium cation VIII to give the
desired phosphorus–carbon bond.
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AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
The addition of trifluoroacetic acid (TFA) (5–
10 mol %) or p-toluenesulfonic acid (p-TSA) (2 mol%)
into the acetic anhydride accelerated the two-
component reaction (the process rate was assessed by
the 31P NMR spectroscopy) and increased the yields of
the reaction products to 62% (VIIb), 59% (VIId), and
69% (VIIe) (see the table). A stronger effect of p-
toluenesulfonic acid should be noted.
with a significant dealkylation of the ester frag-ments
of the target molecule of dimethyl α-(benzyl-
oxycarbonylamino)benzylphosphonate VIIa. Probably
it affects the relative decrease in the yield of acid VIIa
during the three-component reaction in a mixture of
acetic anhydride and acetyl chloride (4:1) (see the
table).
N-Benzyloxycarbonyl-α-aminoalkylphosphoryl com-
pounds VII, the target products of the reaction of
biscarbamates IV with methylphosphonic acid or di-
methylphosphite, were not detected while carrying out
reaction in benzene, toluene, ethanol, dioxane, or tetra-
hydrofuran medium. In this context, it is extremely im-
portant that biscarbamates IV react with methyl-
phosphonic acid or dimethylphosphite in acetic
anhydride in the cold and without any acid catalysis,
whereas in acetic acid the formation of the cor-
responding α-amidoalkylphosphoryl compounds VII
in the cold does not occur (Scheme 6).
The reaction of biscarbamates IV with hydrophos-
phoryl compounds VI in a mixture of acetyl chloride
and acetic anhydride gives good results, which is
consistent with the results of the three-component
reaction. However, the search for the optimal ratio of
acetyl chloride and acetic anhydride, and the optimal
contents of p-TSA and TFA in acetic anhydride for the
two-component reaction was not performed.
The reaction of dimethylphosphite with bis-
carbamates IV in the acetyl chloride medium proceeds
Scheme 6.
XYPH(O)
XYPH(O)
O
VI
BnO
O
BnO
NH
R
HN
VII
VI
X
P
O
O
VII
Ac2O, 15_20oC, 5_15 h
AcOH, 15_20oC, 3 days
NH
Y
R
OBn
IV
R = i-Bu, Ph; X = Me, MeO; Y = MeO, OH.
Note that in both cases the same acid catalysis
occurs by the acetic acid that is either used as a
reaction medium or is formed during the reaction of
PH-component with acetic anhydride.
(3) The initial phosphoric component in acetic
anhydride medium can form
a
more reactive
compoundwith respect to acyliminium cation VIII.
We assume that the trivalent phosphorus P–OAc
derivative IX can interact directly with acyliminium
cation VIII (Scheme 7).
This result may indicate the following:
(1) The starting PH-component VI and intermediate
biscarbamate IV are not involved directly into the
formation of the target phosphorus-carbon bond;
Probably, in the acetyl chloride medium, the hyd-
rophosphoryl compounds VI are converted into the
corresponding trivalent phosphorus chlorides X with
the initial formation of the P–OAc compounds IX
(Scheme 7). The P–OAc form IX can be regarded as
(2) The relatively weak acetic acid is able to
provide formation of acyliminium intermediate cation
VIII in accordance with Scheme 5;
Scheme 7.
O
X
Y
X
Y
O
O
H
+Ac2O (or AcCl)
_HOAc (or HCl)
+AcCl
_Ac2O
Me
Cl
P
P
P:
Y
X
VI
IX
X
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DMITRIEV et al.
the intermediate between the PH and PCl forms
participating in the equilibrium processes occurring in
the AcOH–Ac2O–AcCl medium (Scheme 7). The
increase in acetyl chloride content in the mixture shifts
the equilibrium toward the formation of trivalent
phosphorus chlorides X, while increase in the acetic
acid content in the mixture shifts the equilibrium
toward the formation of hydrophosphoryl form VI.
Perhaps, acetic anhydride is milder and the most
convenient solvent-reagent for the formation of P–OAc
derivatives IX (Scheme 7).
We found two 31P signals in the region charac-
teristic of the trivalent phosphorus compounds in the
31P NMR spectrum of the solution of methylphos-
phonous acid in acetyl chloride, as well as in the 31P
NMR spectrum of methyldichlorophosphine solution
in acetic anhydride. The signal at δ 198 ppm cor-
responds to the phosphorus atom of methyldichloro-
phosphine. Probably, the second signal at δ 185 ppm
belongs to any of the two formally possible P–OAc
derivatives of methylphosphonic acid, MeP(OAc)Cl or
MeP(OAc)2, and the formation of the latter in the
acetic anhydride excess is more likely.
The acyl derivatives of trivalent phosphorus IX
may be more reactive with respect to cations VIII in
comparison with the starting PH-compounds VI,
because they contain in the molecule both nucleophilic
phosphorus atom and the electrophilic carbon atom of
AcO-group, and therefore can easily participate in the
Arbuzov-type transformations [15] (Scheme 8).
Scheme 8.
H
C+
O
R H
X
H
N
R
X
Y
OBn
P+
N
OBn
P:
O
_AcZ
O_
H
Y
O
Z_
VIII
O
IX
VII
X
Z = Cl, OAc.
The nucleophilic phosphorus atom can attack the
positively charged carbon atom of the formed iminium
cation VIII, probably, with the simultaneous attack of
the anion (Z–) on the electrophilic carbon atom of
AcO-fragment of the intermediately formed acyl-
phosphite, acylphosphonite or acylphosphinite IX
(Scheme 8).
Better understanding of the reaction mechanism
requires further study, however, the formation of the
reaction intermediate complex X is quite likely in the
amidoalkylation reaction of hydrophosphoryl com-
pounds (Scheme 8), and may explain the unique
positive role of acetic anhydride (or acetic acid,
trivalent phosphorus chlorides or acetylchloride in the
case of hydrophosphoryl compounds) for the discussed
reactions type.
Thus, in the reaction of amidoalkylation of the
hydrophosphoryl compounds in acetic anhydride the
N,N'-alkylidene biscarbamates IV were obtained,
isolated and identified as intermediates; the two-
component reaction of hydrophosphoryl compounds
VI with the previously synthesized biscarbamates IV
in acetic anhydride and other solvents was studied; the
effect of the structure of biscarbamates IV and
phosphate components VI, as well as acid catalysis in
the course of a two-component reaction were examined.
The data obtained suggest the formation of iminium
cation VIII as a result of protonation of the amide
fragment of the intermediate biscarbamate IV,
followed by probable release of benzyl carbamate
molecule. Furthermore, we assume the intermediate
formation of P–OAc derivatives IX of trivalent
phosphorus as more reactive compounds than the
original hydrophosphoryl compounds in the three-
component reaction with the probable formation of the
reaction complex X (Scheme 8).
The research results suggest a new version of the
mechanism of the three-component reaction of the
amidoalkylation of hydrophosphoryl compounds: This
is a multistage process involving the stage of
biscarbamates IV formation, and subsequent stages
probably occurring through the Arbuzov type reaction
involving the intermediately formed N-(benzyloxy-
carbonyl)iminium cation VIII and P–OAc derivative
IX of trivalent phosphorus (Scheme 8).
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AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
We developed a new mild version of the amido-
alkylation procedure of hydrophosphoryl compounds
in a mixture of acetic anhydride and acetyl chloride in
the cold using both aromatic and less reactive aliphatic
aldehydes, which yielded N-protected α-amino-
phosphoryl compounds VII with retention of alkoxy-
phosphoryl and alkoxycarbonyl fragments in the target
molecule.
anhydride (4 ml) was added acetyl chloride or other
catalyst1 and then the corresponding aldehyde
(5.0 mmol) was added dropwise at room temperature.
The reaction mixture was stirred for 10–50 h. The
reaction progress was monitored using the 31P NMR
and TLC methods. The reaction mixture was diluted
with toluene (5–10 ml) and evaporated in a vacuum.
The residue was dissolved in chloroform (20–30 ml)
and washed with water (3–5 ml), the organic phase
was dried over sodium sulfate and evaporated in a
vacuum. The residue was chromatographed on silica
gel (eluent chloroform, chloroform–isopropanol (3–
5%), and (or) was crystallized from diethyl ether or
hexane and recrystallized from hexane–ethanol (7–
10:1) or diethyl ether–alcohol mixture (10:1) to give
N-benzyloxycarbonyl-α-aminoalkylphosphinic acids VII.
EXPERIMENTAL
The 1H, 31P, and 13C NMR spectra were recorded on
a Bruker DPX-200 Fourier spectrometer relative to
TMS (internal standard) and 85% H3PO4 (external
standard). Melting points of the compounds were
determined on a Boetius PHMK device or in a block in
an open capillary. The TLC analysis of the individual
compounds and the reaction mixture was performed on
Silufol plates, glass plates (Merck) with a layer of
silica gel UV-254 0.2 mm thick (eluent chloroform–
acetone, 4–5:1) as well as on Alufol plates (Kavalier)
(neutral aluminum oxide on aluminum foil) detecting
with the iodine vapor, UV irradiation, or with a
solution of ninhydrin for amino acid analysis. The
column chromatography was performed on silica gel
Silpearl L100/160 (Chemapol) or Silica gel 60 (Alfa
Aesar).
The exceptions are 1-(benzyloxycarbonilamino)-3-
methylbutylhydroxymethylphosphinic (VIIj) and α-
(benzyloxycarbonilamino)benzylhydroxymethylphos-
phinic (VIIk) acids isolated as oily substances, which
according to the NMR data may contain an admixture
of the O-acetylated derivatives, so that the compounds
VIIj and VIIk were hydrolyzed to form the free amino
acids VIIj' and VIIk', which were isolated and
characterized.
Dimethyl
α-(benzyloxycarbonylamino)benzyl-
phosphonate (VIIа), mp 119–120°С (published data
Benzyl carbamate, tert-butyl carbamate, acetic
anhydride, acetic acid, trifluoroacetic acid, trifluoro-
acetamide, phthalimide, acetyl chloride, dimethyl
phosphite were provided by Alfa Aesar company.
Benzaldehyde, acetaldehyde diethyl acetal and iso-
valeric aldehyde were purchased from Acros Organics.
Methylphosphonic, hydroxymethylphosphonic and di-
ethylphosphinic acids were synthesized in accordance
with the previously developed method [16]. The
synthesis of 2-(ethoxycarbonyl)propylphosphonic and
2-phenylethylphosphonic acids was performed by
adding in situ the bis(trimethylsilyl)hypophosphite
formed in the reaction of a salt of hypophosphoric acid
with hexamethyldisilazane, to ethylmethacrylate and
styrene, respectively, followed by the mild hydrolysis
of the formed bis(trimethylsilyl)-2-(ethoxycarbonyl)
propylphosphonite or bis(trimethylsilyl)-2-phenyl-
ethylphosphonite according to the previously pub-
lished procedures [7, 16].
1
[7]: 120–121°С). H NMR spectrum [Me2C(O)-d6], δ,
3
ppm: 3.51 d (3Н, CH3O, JPH 10.6 Hz), 3.67 d (3Н,
3
CH3O, JPH 10.6 Hz), 5.07 m (2Н, CH2Ph), 5.19 d.d
2
3
(1Н, CHN, JPH 20.5, JHH 7.3 Hz), 7.2–7.6 m (10Н,
2Ph), 8.04 d (1H, NH, 3JHH 7.3 Hz). 1H NMR spectrum
(DMSO-d6:CCl4 = 1:3), δ, ppm: 3.51 d (3Н, CH3O,
3JPH 10.6 Hz), 3.59 d (3Н, CH3O, JPH 10.6 Hz), 5.04
3
2
3
m (2Н, CH2Ph), 5.15 d.d (1Н, CHN, JPH 21.6, JHH
10.1 Hz), 7.25–7.55 m (10Н, 2Ph), 8.51 d (1H, NH,
3JHH 10.1 Hz). 13C NMR spectrum (DMSO-d6), δC,
ppm: 51.8 d (1JPC 164.0 Hz), 53.1 d (2JPC 7.0 Hz), 53.3
d (2JPC 7.0 Hz), 66.0, 127.7, 127.8 (2С), 127.9, 128.1,
128.2 (2С), 128.4 (2С), 128.7, 135.6, 136.8, 155.9 d
(3JPC 8.5 Hz). 31Р NMR spectrum [Me2C(O)-d6]: δP
24.6 ppm. 31Р NMR spectrum (DMSO-d6:CCl4 = 1:3):
δP 20.2 ppm.
1-(Benzyloxycarbonylamino)ethylmethylphos-
1
phinic acid (VIIb), mp 100–101°С. H NMR spec-
General procedure of hydrophosphoryl com-
pounds amidoalkylation in acetic anhydride. To a
stirred solution of hydrophosphoryl compound VI
(4.5 mmol) and benzyl carbamate (4.5 mmol) in acetic
1
Catalyst is acetyl chloride (1ml) and trifluoroacetic acid (TFA)
(0.45 mmol, 0.1 equiv) or p-toluenesulfonic acid (p-TSA)
(0.09 mmol, 0.02 equiv).
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DMITRIEV et al.
3
trum (DMSO-d6), δ, ppm: 1.19 d.d (3Н, CH3СH, JHH
1-(Benzyloxycarbonylamino)-2-methylbutyl-
7.5, JPH 10.2 Hz), 1.24 d (2JPH 13.7 Hz), 3.69 m (1Н,
methylphosphinic acid (VIIe), mp 167–168°С (pub-
3
1
СНN), 5.04 АВ (2H, СH2O), 7.35 m (5Н, Ph), 7.52 d
lished data [10]: 162–164°С). H NMR spectrum
3
1
(1Н, NH, JHH 9.3 Hz). H NMR spectrum (CDCl3), δ,
(DMSO-d6:CCl4 = 1:3), δ, ppm: 0.81 d (3Н, CH3СH,
3
3
ppm: 1.33 d.d (3Н, CH3CH, JHH 7.1, JPH 15.0 Hz),
3JHH 5.6 Hz), 0.87 d (3Н, CH3СH, 3JHH 6.5 Hz), 1.21 d
2
2
1.42 d (3Н, CH3P, JPH 15.4 Hz), 3.99 m (1Н, СНN),
(3H, CH3P, JPH 13.0 Hz), 1.45 m (2Н, СH2CH), 1.60
3
2
3
5.09 АВ (2Н, CH2Ph), 5.37 d (1H, NH, JHH 9.7 Hz),
m (1Н, СHCH3), 3.67 d.d (1Н, CHN, JPH 16.8, JHH
9.3 Hz), 5.01 АВ (2Н, CH2Ph), 7.3 m (5Н, Ph), 7.44 d
7.32 m (5H, Ph), 10.56 br.s (1Н, POOH). 13C NMR
spectrum (DMSO-d6), δC, ppm: 15.4 d (1JPC 89.6 Hz),
16.4 d (2JPC 5.5 Hz), 50.4 d (1JPC 90.5 Hz), 65.7, 127.6,
127.7, 127.8, 128.4 (2С), 137.2, 155.6. 13C NMR
spectrum (CDCl3), δC, ppm: 12.4 d (1JPC 93.3 Hz),
13.9, 46.0 d (1JPC 107.6 Hz), 67.2, 128.1 (2С), 128.2,
128.5 (2С), 136.1, 155.9 d (3JPC 5.1 Hz). 31Р NMR
spectrum (DMSO-d6): δP 47.0 ppm. 31Р NMR
spectrum (CDCl3): δP 54.8 ppm. Found, %: C 51.21,
51.23; H 6.31, 6.37; N 5.37, 5.34. C11H16NO4P.
Calculated, %: C 51.36, H 6.27, N 5.45.
3
(1Н, NH, JHH 9.3 Hz). 13C NMR spectrum (DMSO-
d6), δC, ppm: 12.5 d (1JPC 89.5 Hz), 20.9, 23.3, 24.1 d
(3JPC 11.5 Hz), 35.9, 49.2 d (1JPC 107.5 Hz), 65.5,
127.6, 127.7, 127.8, 128.4 (2С), 137.2, 156.2 d (3JPC
3.6 Hz). 31Р NMR spectrum (DMSO-d6:CCl4 = 1:3): δP
47.2 ppm.
α-(Benzyloxycarbonylamino)benzylmethylphos-
phinic acid (VIIf), mp 191–192°С. (published data [10]:
1
193–194°С). H NMR spectrum (DMSO-d6:CCl4 =
1:3), δ, ppm: 1.22 d (3H, CH3P, 2JPH 13.7 Hz), 4.87 d.d
2
3
1-(Benzyloxycarbonylamino)propylmethylphos-
phinic acid (VIIc), mp 109–111°С. 1H NMR spectrum
(DMSO-d6), δ, ppm: 0.88 t (3Н, CH3CH2), 1.22 d (3Н,
(1Н, CHN, JPH 18.1, JHH 9.7 Hz), 5.04 br.s (2H,
CH2Ph), 7.36 m (10H, 2Ph), 8.25 d (1H, NH, 3JHH 9.7 Hz).
13C NMR spectrum (DMSO-d6), δC, ppm: 13.5 d (1JPC
92.3 Hz), 56.0 d (1JPC 97.4 Hz), 65.8, 127.1, 127.7,
127.8, 127.85, 127.9, 128.0, 128.4 (2C), 128.6, 129.3,
136.8, 136.9 156.1 d (3JPC 5.1 Hz). 31Р NMR spectrum
(DMSO-d6:CCl4 = 1:3): δP 42.8 ppm.
2
CH3P, JPH 13.7 Hz), 1.43 m (1Н, CH2CH), 1.75 m
(1Н, CH2CH), 3.47 m (1H, PCH), 5.05 AB (2Н,
3
PhCH2O), 7.34 m (5Н, Ph), 7.43 d (1Н, NH, JHH
1
9.7 Hz). H NMR spectrum (CDCl3), δ, ppm: 0.98 t
2
(3Н, CH3CH2), 1.42 d (3Н, CH3P, JPH 14.1 Hz), 1.55
1-(Benzyloxycarbonylamino)propyl-2-phenyl-
ethylphosphinic acid (VIIg), mp 101–103°С. 1H NMR
spectrum (DMSO-d6), δ, ppm: 0.89 t (3Н, CH3CH2),
1.49 m (1Н, СН2СН), 1.80 m (3Н, СН2СН + СН2P),
2.73 m (2Н, СН2Ph), 3.59 m (1Н, СНP), 5.05 AB (2Н,
m (1Н, CH2CH), 1.88 m (1Н, CH2CH), 3.82 m (1H,
3
PCH), 5.11 AB (2Н, PhCH2O), 5.24 d (1H, NH, JHH
13
9.3 Hz), 7.32 m (5H, Ph), 10.71 br.s (1Н, POOH). C
NMR spectrum (CDCl3), δC, ppm: 10.5 d (2JPC 11.7 Hz),
12.7 d (1JPC 93.0 Hz), 21.0, 52.0 d (1JPC 107.6 Hz),
67.1, 127.9 (2С), 128.1, 128.5 (2С), 136.2, 156.4 d
(3JPC 4.0 Hz). 31Р NMR spectrum (DMSO-d6): δP 46.6
ppm. 31Р NMR spectrum (CDCl3): δP 54.6 ppm.
Found, %: C 53.07, 52.95; H 6.73, 6.77; N 5.07, 5.11.
C12H18NO4P. Calculated, %: C 53.14, H 6.69, N 5.16.
3
CH2O), 7.25 m (10Н, 2Ph), 7.49 d (1Н, NH, JHH
1
8.8 Hz). H NMR spectrum (CDCl3), δ, ppm: 1.14 t
(3Н, CH3CH2), 1.68 m (1Н, СН2СН), 2.14 m (3Н,
СН2СН + СН2P), 3.02 m (2Н, СН2СН2Р), 4.07 m (1Н,
СНР), 5.24 AB (2Н, CH2O), 7.37 m (11Н, NH + 2Ph),
9.16 br.s (1Н, POOH). 13C NMR spectrum (CDCl3),
δC, ppm: 10.5 d (3JPC 11.4 Hz), 21.2, 27.2, 28.5 (1JPC
89.3 Hz), 46.2 (1JPC 104.3 Hz), 67.2, 126.3, 128.0
(3С), 128.2 (2С), 128.5 (4С), 136.2, 140.8 d (3JPC
16.1 Hz), 156.4 (3JPC 4.8 Hz). 31Р NMR spectrum
(DMSO-d6): δP 46.9 ppm. 31Р NMR spectrum (CDCl3):
δP 55.7 ppm. Found, %: C 63.07, 62.95; H 6.85, 6.81;
Р 8.43, 8.51. C19H24NO4P. Calculated, %: C 63.15, H
6.69, Р 8.57.
1-(Benzyloxycarbonylamino)-2-methylpropyl-
1
methylphosphinic acid (VIId), mp 107–109°С. H
NMR spectrum (DMSO-d6), δ, ppm: 0.90 d (3Н,
3
3
CH3CH, JHH 5.3 Hz), 0.93 d (3Н, CH3CH, JHH
5.3 Hz), 1.22 d (3Н, CH3P, 2JPH 13.7 Hz), 2.08 m (1Н,
СН), 3.50 m (1Н, СНP), 5.05 AB (2Н, CH2O), 7.33 m
(6Н, Ph+NH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 14.1 d (1JPC 89.9 Hz), 18.7 d (3JPC 5.5 Hz), 20.8 d
(3JPC 7.7 Hz), 27.6 (2JPC 3.3 Hz), 56.3 d (1JPC 105.0 Hz),
65.5, 127.5 (2С), 127.8, 128.4 (2С), 137.2, 156.7 d
(3JPC 5.2 Hz). 31Р NMR spectrum (DMSO-d6): δP 46.5
ppm. Found, %: C 54.47, 54.53; H 7.01, 6.95; N 4.67,
4.83. C13H20NO4P. Calculated, %: C 54.73, H 7.07, N
4.91.
1-(Benzyloxycarbonylamino)-2-methylpropyl-2-
phenylethylphosphinic acid (VIIh), mp 139–141°С.
1H NMR spectrum (DMSO-d6), δ, ppm: 0.94 d (3Н,
3
3
CH3CH, JHH 5.3 Hz), 0.96 d (3Н, CH3CH, JHH
5.3 Hz), 1.79 m (2Н, CH2P), 2.14 m (1Н, СHCH3),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 6 2011

1101
AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
2.74 m (2Н, CH2Ph), 3.65 m (1H, СHP), 5.04 АВ (2Н,
mixture was extracted with petroleum ether. The
aqueous acidic phase was evaporated in a vacuum. The
residue was dissolved in aqueous ethanol, treated with
excess of propylene oxide to obtain amino acid. The
product was recrystalled from aqueous ethanol. Yield
0.27 g (75%, 33% relative to benzyl carbamate), mp
243–244°С (published data [17]: 244–245°С). 1H
NMR spectrum (D2O + DCl), δ, ppm: 0.83 d (3H, CH3,
3
CH2O), 7.30 m (10Н, 2Ph), 7.47 d (1Н, NH, JHH
10.1). 1H NMR spectrum (CDCl3), δ, ppm: 1.16 d (3Н,
3
3
CH3СН, JHH 6.6 Hz), 1.18 d (3Н, CH3СН, JHH
6.6 Hz), 2.13 m (2Н, СН2Р), 2.49 m (1Н, СНСНР),
3.03 m (2Н, CH2СН2Р), 4.07 m (1Н, СНР), 5.25 АВ
(2Н, CH2O), 7.45 m (10Н, NH + 2Ph), 8.10 br.s (1Н,
13
POOH). C NMR spectrum (CDCl3), δC, ppm: 17.7 d
(3JPC 2.9 Hz), 20.8 d (3JPC 10.7 Hz), 27.3 d (2JPC
3.3 Hz), 27.7, 29.7 d (1JPC 88.8 Hz), 53.7 d (1JPC 103.9
Hz), 67.3, 126.3, 128.0 (3C), 128.2, 128.6 (4C), 136.2,
140.7, 141.0, 156.5 d (3JPC 6.3 Hz). 31Р NMR spectrum
(DMSO-d6): δP 47.1 ppm. 31Р NMR spectrum (CDCl3):
δP 56.3. Found, %: C 63.87, 63.75; H 6.95, 7.11; Р
8.20, 8.11. C20H26NO4P. Calculated, %: C 63.99, H
6.98, Р 8.25.
2JHН 5.6 Hz), 0.87 d (3H, CH3, JНH 5.8 Hz), 1.61 m
2
2
2
(3H, СНСН2СНN), 3.36 d.t (1Н, CHN, JPН 8.6, JHН
7.0 Hz), 3.75 ABX (2Н, CH2O, 2JPН 6.4 Hz). 13C NMR
spectrum (D2O), δC, ppm: 20.1, 22.4, 23.9 d (3JPC 8.8 Hz),
35.8, 47.8 d (1JPC 90.8 Hz), 59.1 d (1JPC 114.5 Hz). 31Р
NMR spectrum (D2O): δP 33.9 ppm. Found, %: C
39.67, 39.59; H 9.07, 9.13, N 7.57, 7.59. C6H16NO3P.
Calculated, %: C 39.78; H 8.90; N 7.73.
1-(Benzyloxycarbonylamino)-3-methylbutyl-2-
phenylethylphosphinic acid (VIIi), mp 161–163°С.
1H NMR spectrum (DMSO-d6), δ, ppm: 0.82 d (3Н,
α-(Benzyloxycarbonylamino)benzylhydroxy-
1
methylphosphinic acid (VIIk). Yield 53%, oil. H
NMR spectrum (CDCl3), δ, ppm: 4.30–4.50 m (2Н,
СН2О), 4.80–5.00 m (2Н, СН2ОPh), 5.10 m (1Н,
СНN), 7.2–7.5 (m, 10H, 2Ph). 31Р NMR spectrum
(CD3OD): δP 48.1 ppm. (The 1Н NMR spectrum contains
a singlet at ~2.0 ppm belonging probably to impurity
PCH2OAc-derivative). Compound VIIj was used
further without purification.
3
3
CH3CH, JHH 6.2 Hz), 0.89 d (3Н, CH3CH, JHH
6.6 Hz), 1.49 m (3Н, CHСН3 + CH2СН), 1.80 m (2Н,
СН2Р), 2.74 m (СН2Рh), 3.70 m (1Н, РСН), 5.05 АВ
(2Н, СН2О), 7.23 m (10Н, 2Ph), 7.52 d (1Н, NH, 3JHH
1
9.3). H NMR spectrum (CDCl3), δ, ppm: 0.98 d (6Н,
3
2CH3СН, JHH 5.7 Hz), 1.68 m (3Н, CHСН3
+
CH2СН), 2.07 m (2Н, СН2Р), 2.97 m (2Н, CH2СН2Р),
4.18 m (1Н, СНР), 5.16 АВ (2Н, СН2О), 7.30 m (11Н,
2Ph + NH), 9.67 br.s (POOH). 13C NMR spectrum
(CDCl3), δC, ppm: 21.1, 23.5, 24.3 d (2JPC 10.6 Hz),
27.2, 28.4 d (1JPC 89.3 Hz), 36.2, 47.6 d (1JPC 105.0 Hz),
67.2, 126.3, 128.0 (2С), 128.1 (3С), 128.5 (4С), 136.2,
140.8 d (3JPC 16.5 Hz), 156.1. 31Р NMR spectrum
(DMSO-d6): δP 47.4 ppm. 31Р NMR spectrum (CDCl3):
δP 56.3 ppm. Found, %: C 64.64, 64.59; H 7.25, 7.31;
Р 8.03, 8.01. C21H28NO4P. Calculated, %: C 64.77; H
7.25; Р 7.95.
α-Aminobenzylhydroxymethylphosphinic acid
(VIIk'). A mixture of 0.80 g of crude VIIk and 10 ml
of 6 M HCl was refluxed for 15 h. The cooled mixture
was extracted with toluene. The aqueous acidic phase
was evaporated in a vacuum. The residue was dis-
solved in aqueous ethanol, treated with excess
propylene oxide to obtain amino acid. The product was
recrystallized from aqueous ethanol. Yield 0.38 g
(80%, 42% relative to benzyl carbamate), mp 233–
1
235°С (published data [8]: 235–237°С). H NMR
spectrum (D2O), δ, ppm: 3.57 d (2H, CH2, 2JPH 6.2 Hz),
4.42 d (1H, CH, 2JPH 10.6 Hz), 7.35 m (5H). 13C NMR
spectrum (D2O), δC, ppm: 54.3 d (1JPC 85.1 Hz), 59.4 d
(1JPC 116.2 Hz), 128.1, 128.2, 129.3, 129.5 (2C), 132.2
d (2JPC 3.6 Hz). 31Р NMR spectrum (D2O + DCl): δP
34.5 ppm. Found, %: C 43.67, 43.59; H 6.51, 6.47, P
14.23, 14.17. C8H12NO3P·H2O. Calculated, %: C
43.84; H 6.44, P 14.13.
1-(Benzyloxycarbonylamino)-3-methylbutylhyd-
roxymethylphosphinic acid (VIIj). Yield 44%, oil.
1H NMR spectrum (CDCl3), δ, ppm: 0.87 d (3H, CH3,
2
2JHН 7.2 Hz), 0.91 d (3H, CH3, JHН 6.5 Hz), 1.37 m
(2Н, CH2СН), 1.66 m (1Н, CHСН3), 3.39 m (2Н,
PCH2O), 3.95 m (1Н, CHN), 5.04 AB (2H, PhCH2O),
7.30 m (Ph). 31Р NMR spectrum (CD3OD): δP 44.8 ppm.
(The 1Н NMR spectrum contains a singlet at ~2.0 ppm
belonging probably to impurity PCH2OAc-derivative).
Compound VIIj was used further without purification.
1-(Benzyloxycarbonylamino)ethyl-2-(ethoxy-
carbonyl)propylphosphinic acid (VIIl), mp 113–
1
115°С. H NMR spectrum (DMSO-d6), δ, ppm: 1.10–
1-Amino-3-methylbutylhydroxymethylphosphinic
acid (VIIj'). A mixture of 0.63 g of crude VIIj and
8 ml of 6 M HCl was refluxed for 17 h. The cooled
1.25 m (9Н, 2CH3СH + CH3CH2), 1.60 m (1Н, СН2P),
2.00 m (1Н, СН2P), 2.71 m [1Н, СНС(О)], 3.72 m
(2H, CH3CH2O), 4.04 m (1Н, СНN), 5.04 АВ (2Н, Ph
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DMITRIEV et al.
3
CH2O), 7.34 m (5Н, Ph), 7.53 d (1Н, NH, JHH 8.8
Hz). 13C NMR spectrum (DMSO-d6), δC, ppm: 13.8,
14.0, 18.6 d (2JPC 7.0 Hz), 18.8* d (2JPC 8.1 Hz), 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 (2С), 127.8, 128.4 (2С), 137.1, 155.8 d (3JPC
3.7 Hz), 175.1 d (3JPC 9.5 Hz). 31Р NMR spectrum
(DMSO-d6), δP, ppm: 46.6, 46.0* (signals of the second
diastereomer are marked with asterisk, ~13%). 31Р
NMR spectrum (CDCl3), δP, ppm: 55.0, 53.6*. Found,
%: C 53.68, 53.57; H 6.79, 6.87; P 8.53, 8.43.
C16H24NO6P. Calculated, %: C 53.78, H 6.77, P 8.67.
room temperature was added the corresponding
catalyst and then added dropwise the freshly distilled
aldehyde (5.0 mmol). The reaction mixture was stirred
for 15–40 min, diluted with excess toluene, evaporated
in a vacuum at the bath temperature below 40°С. The
semicrystalline residue was dissolved in 20 ml of
chloroform, washed with water (2×5 ml). The organic
layer was dried over magnesium sulfate, concentrated
in a vacuum, and chromatographed on silica gel
[eluents benzene, chloroform–benzene (1:1), chloro-
form, chloroform–isopropanol (5%)]. Biscarbamates
IVа–IVe [Rf 0.7–0.8, chloroform–acetone, (4–5):1]
were readily separated from N-benzyloxycarbonyl-α-
aminophosphinic acids VIIb–VIIh, VIIl and VIIm [Rf
0.1–0.2, chloroform–acetone, (4–5):1].
α-(Benzyloxycarbonylamino)benzyl-2-(ethoxy-
carbonyl)propylphosphinic (VIIm), mp 153–155°С.
1H NMR spectrum (DMSO-d6:CCl4 = 1:3), δ, ppm:
1.17 t (6H, 2CH3), 1.62 m (1Н, СН2P), 2.01 m (1Н,
СН2P), 2.67 m [1Н, СНС(O)], 4.03 q (2Н, СН2О),
4.88 d.d (1Н, СНN, JPH 18.1, JHH 10.2 Hz), 5.04 АВ
(2Н, OCH2Ph), 7.33 m (10Н, 2Ph), 8.16 d (1Н, NH,
3JHH 10.2 Hz). 13C NMR spectrum (DMSO-d6), δC,
ppm: 14.0, 18.6, 18.7*, 29.7 d (1JPC 91.4 Hz), 33.4,
33.7*, 55.7 d (1JPC 96.2 Hz), 55.9* d (1JPC 107.2 Hz),
60.1, 65.8, 127.2, 127.7 (2С), 127.9, 128.0 (2С),
128.1, 128.2, 128.4 (2С), 136.5, 137.0, 156.1 d (3JPC
7.7 Hz), 175.1 d (3JPC 10.3 Hz). 31Р NMR spectrum
(DMSO-d6:CCl4 = 1:3), δP, ppm: 42.3, 41.5* (~7%).
Found, %: C 60.09, 60.03; H 6.34, 6.27; P 7.30, 7.23.
C21H26NO6P. Calculated, %: C 60.14; H 6.25; P 7.38.
In the case of α-aminophosphonate VIIа [Rf 0.6,
chloroform–acetone, 4:1] and α-aminophosphine oxide
VIIn [Rf 0.4, chloroform–acetone, 4:1] the separation
of target compounds VII and IVe was done as follows.
After the reaction mixture concentrating, the residue
was refluxed in CCl4, cooled, and filtered off. Crys-
talline biscarbamate IVb was recrystallized from
hexane–ethanol mixture (~10:1). The filtrate was
concentrated and crystallized from diethyl ether–
ethanol mixture (~10:1) to obtain compound VIIn.
2
3
The separation procedure was monitored with TLC
1
and Н, 31Р NMR spectroscopy. The physicochemical
constants and spectral data of α-aminoalkylphosphoryl
compounds VII correspond to those of compounds
obtained by the three-component synthesis. Data of
biscarbamates IV correspond to those of compounds
synthesized in acetic anhydride (see below).
α-(Benzyloxycarbonylamino)benzyldiethylphos-
1
phine oxide (VIIn), mp 177–179°С. H NMR spec-
3
trum [Me2C(O)-d6], δ, ppm: 0.89 d.t (3Н, CH3, JPH
3
16.1 Hz), 1.07 d.t (3Н, CH3, JPH 16.1 Hz), 1.54 m
(d.q) (2Н, CH2P), 1.80 m (d.q) (2Н, CH2P), 5.03 d.d
2
3
Synthesis of biscarbamates IV in acetic an-
hydride medium. To a solution of benzyl carbamate
(5.0 mmol) in acetic anhydride (5 ml) at room tem-
perature was added TFA (0.05 mmol) and then slowly
aldehyde (2.5 mmol) or the corresponding acetal
(2.5 mmol) under stirring. The stirring was continued
for 3–10 h. The reaction progress was monitored by
TLC. The reaction mixture was concentrated in a
vacuum. The residue was dissolved in chloroform
(20 ml) and diluted with water (20 ml). The aqueous
layer (20 ml) was neutralized to рН 6–7. The organic
layer was separated, dried over MgSO4, and con-
centrated. The residue was crystallized from diethyl
ether or hexane and recrystallized from diethyl ether–
ethanol mixture.
(1Н, СНN, JPH 12.6 Hz, JHH 8.8 Hz), 5.10 m (2Н,
1
OCH2), 7.20–7.60 m (11Н, 2Ph + NH). H NMR
spectrum (DMSO-d6:CCl4 = 1:3), δ, ppm: 0.88 d.t (6H,
3
2CH3, JPH 15.9 Hz), 1.58 m (4Н, 2CH2), 5.04 br.s
2
3
(2Н, OCH2), 5.10 d.d (1Н, СНN, JPH 12.8, JHH
9.7 Hz), 7.20–7.50 m (10Н, 2Ph), 8.39 d (1Н, NH,
3JHH 9.7 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
5.1 d (2JPC 4.8 Hz), 5.4 d (2JPC 4.8 Hz), 17.7 d (1JPC
63.8 Hz), 18.0 d (1JPC 64.9 Hz), 53.5 d (1JPC 67.1 Hz),
66.0, 127.4, 127.7 (2С), 127.9 (3С), 128.1 (2С), 128.4
(2С), 136.3, 136.8, 156.1 d (3JPC 3.6 Hz). 31Р NMR
spectrum (DMSO-d6:CCl4 = 1:3): δP 57.2 ppm. Found,
%: C 66.03, 65.97; H 7.11, 7.13; N 3.93, 3.89.
C19H24NO3P. Calculated, %: C 66.08; H 7.00; N 4.06.
Synthesis of biscarbamets IV. To a stirred mixture
of hydrophosphoryl compound (4.5 mmol) and benzyl
carbamate (4.5 mmol) in acetic anhydride (3–4 ml) at
N,N'-Ethylidenebis(benzyl carbamate) (IVа).
Yield 64%, mp 203–204°С. 1H NMR spectrum
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 6 2011

1103
AMIDOALKYLATION OF HYDROPHOSPHORYL COMPOUNDS
(DMSO-d6:CCl4 = 1:3), δ, ppm: 1.23 d (3H, CH3, 3JHH
6.6 Hz), 5.00 br.s (4Н, 2CH2O), 5.14 m (1Н, CHN),
7.34 m (10Н, 2Ph), 7.61 d (2Н, 2NH, 3JHH 5.0 Hz). 13C
NMR spectrum (DMSO-d6), δC, ppm: 21.2 (CH3), 56.1
(CHN), 65.2 (2CH2O), (127.6, 127.7, 127.8, 128.4,
137.1) (12С, Ar), 154.6 (C=O). Found, %: C 65.57,
65.71; H 6.21, 6.27; N 8.61, 8.66. C18H20N2O4.
Calculated, %: C 65.84; H 6.14; N 8.53.
(2CH2O), 126.4, 127.8, 128.3, 128.4, 136.9, 140.0
(18С, Ar), 155.2 (С=O). Found, %: C 70.57, 70.54; H
5.81, 5.71; N 7.23, 7.11. C23H22N2O4. Calculated, %: C
70.75; H 5.68; N 7.17.
Reaction of biscarbamates IV with hydro-
phosphoryl compounds VI. To a solution of N,N'-
alkylidenebis(carbamate) IV (5 mmol) in 4 ml of
acetic anhydride under stirring was added dropwise
PH-component VI (5 mmol). The reaction progress
was monitored by the 31P NMR spectroscopy. As the
reaction completed, the mixture was concentrated in a
vacuum, diluted with 30 ml of chloroform and 10 ml
of water. The organic layer was dried over sodium
sulfate, concentrated, and crystallized twice from di-
ethyl ether or hexane. The physicochemical and spec-
tral constants of the obtained compounds VII were in
accordance with those for compounds obtained by the
three-component synthesis.
N,N'-Propylidene bis(benzyl carbamate) (IVb).
Yield 67%, mp 153–155°С. 1H NMR spectrum
(CDCl3), δ, ppm: 0.93 t (3H, CH3), 1.85 m (2Н, CH2),
4.91 m (1Н, СНN), 5.08 br.s (4Н, 2CH2O), 5.50 m
(2Н, 2NH), 7.33 m (10Н, 2Ph). 13C NMR spectrum
(CDCl3), δC, ppm: 10.1 (CH3), 27.5 (CH2), 61.9
(CHN), 66.8 (2CH2O), (128.0, 128.0, 128.4, 136.2)
(12С, Ar), 155.4 (C=O). Found, %: C 66.57, 66.51; H
6.54, 6.57; N 8.11, 8.20. C19H22N2O4. Calculated, %: C
66.65; H 6.48; N 8.18.
N,N'-Isobutylidene bis(benzyl carbamate) (IVc).
Yield 77%, mp 152–154°С. 1H NMR spectrum
(CDCl3), δ, ppm: 0.86 d (6H, 2CH3, 3JHH 6.6 Hz), 2.05
m (1Н, СНСН3), 4.64 m (1Н, СНN), 5.01 br.s (4Н,
ACKNOWLEDGMENTS
This work was supported by the Russian Founda-
tion for Basic Research (grants no 09-03-12157, 10-
03-01058-а).
1
2СН2О), 5.45 m (2Н, 2NH), 7.26 m (10Н, 2Ph). H
NMR spectrum (DMSO-d6), δ, ppm: 0.84 d (6H,
The authors are grateful to Professor J. Oleksyszyn
(Institute of Organic Chemistry, Biochemistry and
Biotechnology, Wroclaw, Poland) for his interest in
this work and useful discussion.
3
2CH3, JHH 6.8 Hz), 1.81 m (1Н, СНСHN), 4.82 m
(1Н, СHN), 5.01 br.s (4Н, 2СН2О), 7.33 m (10Н,
2Ph), 7.47 m (2Н, 2NH). 13C NMR spectrum (DMSO-
d6), δC, ppm: 18.4 (2CH3), 32.0 (СНСHN), 64.8
(СHN), 65.2 (2CH2O), (127.7, 128.3, 137.1) (12С,
Ar), 155.3 (C=O). Found, %: C 67.37, 67.31; H 6.94,
6.87; N 7.76, 7.63. C20H24N2O4. Calculated, %: C
67.40; H 6.79; N 7.86.
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