A novel and convenient method for synthesizing unsymmetrical - Benzyloxycarbonyl-protected 1-amino-1-arylalkylphosphonate mixed diesters

Article abstract of DOI:10.1039/b008340m

Unsymmetrical N-benzyloxycarbonyl-protected 1-amino-1-arylalkylphosphonate mixed diesters were synthesized using a one-pot reaction involving benzyl carbamate, aromatic aldehydes and alkoxydichlorophosphine, followed by treatment with alcohols in the presence of triethylamine. The reactions were followed by ³¹P NMR and a mechanism is proposed.

Full text of DOI:10.1039/b008340m

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A novel and convenient method for synthesizing unsymmetrical N-
benzyloxycarbonyl-protected 1-amino-1-arylalkylphosphonate
mixed diesters
1
Jiaxi Xu* and Nanyan Fu
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
Received (in Cambridge, UK) 17th October 2000, Accepted 3rd April 2001
First published as an Advance Article on the web 26th April 2001
Unsymmetrical N-benzyloxycarbonyl-protected 1-amino-1-arylalkylphosphonate mixed diesters were synthesized
using a one-pot reaction involving benzyl carbamate, aromatic aldehydes and alkoxydichlorophosphine, followed by
treatment with alcohols in the presence of triethylamine. The reactions were followed by 31P NMR and a mechanism
is proposed.
Table 1 Synthesis of unsymmetrical N-protected 1-aminoalkylphos-
Introduction
phonate mixed diesters 4 and monoacids 5
Phosphonate esters are recognized as an important class of
R1
R2
Yield of 4 (%)
Yield of 5 (%)
enzyme inhibitors either as transition-state analogues1 or as
nonhydrolyzable phosphate surrogates.2 They are also widely
used in the design of transition-state analogues as haptens
for the production of catalytic antibodies with esterase or
amidase activity.3 Thus, it is very important to develop a general
and convenient synthetic method that allows the synthesis
of phosphonates, especially unsymmetric phosphonate mixed
diesters.
Entry
Ar
a
b
c
d
e
f
Ph
o-MeOPh
p-ClPh
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
Me
Me
Me
Me
Me
Me
Me
Ph
Et
Et
Et
Et
Pri
Bu
Ph
Et
47
31
35
45
41
24
11
38
39
32
45
29
27
31
37
24
g
h
Symmetric 1-aminoalkylphosphonates have been synthesized
using Mannich-type reactions of aldehydes, amines and dialkyl
or trialkyl phosphites,4,5 phosphite addition to imines,6 Arbuzov–
Michaelis reactions followed by reductive amination,7 conver-
sion of the hydroxy group in 1-hydroxyalkylphosphonates to an
amino group to synthesize 1-aminoalkylphosphonates,8 and
our recent method through reaction of carbamate, aldehydes
and dialkoxychlorophosphines.9 Unsymmetrical phosphonate
mixed diesters have been prepared from the reactions of
alcohols with phosphonochloridates.10,11 These phosphono-
chloridates can be prepared by treating phosphonate diesters
Results and discussion
We report a novel, facile method to synthesize unsymmetrical
N-protected 1-aminoalkylphosphonate diesters using a four
component one-pot reaction. Benzyl carbamate and an
aldehyde are first treated with an alkoxydichlorophosphine,
followed by the addition of an alcohol and triethylamine in
anhydrous benzene. It is not necessary to synthesize phos-
phonic acids, their monoacids or their symmetric diesters. This
reaction yielded unsymmetrical phosphonate mixed diesters 4
in satisfactory yields under simple and mild conditions and gave
the corresponding monoacids 5 simultaneously as the main
byproducts (Scheme 1, Table 1).
with POCl3,12 PCl5 or by chlorinating phosphonate mono-
11
acids with thionyl chloride10 or oxalyl chloride.13 Phosphonic
acid monoesters are readily synthesized by saponification of
dialkyl alkylphosphonates10 or by direct synthesis via Mannich-
type reactions of carbamates, aldehydes and alkoxydichloro-
phosphine, followed by hydrolysis.14 An interesting modification
of these procedures involves the in situ formation of phos-
phonochloridates from the corresponding phosphonates in an
oxidative Atherton–Todd process.15 An alternative synthesis
of unsymmetrical 1-aminoalkylphosphonate mixed diesters
involves the condensation of phosphonate monoacids with
alcohols as in Karenewsky’s coupling method.16 The condens-
ation has been improved by the use of coupling reagents such
as DCC,17 trichloroacetonitrile,18 BOP [(benzotriazol-1-yloxy)-
tris(dimethylamino)phosphonium hexafluorophosphate] or
PyBOP,19 or Campbell’s extended and modified Mitsunobu
condensation method.20 The third method involves phosphonic
dichlorides, which are prepared from phosphonic acids
Scheme 1
Attempts to improve the yields of the desired products 4 by
avoiding the formation of 5 were unsuccessful. Varying the
reaction solvents (e.g. ether, THF, CH2Cl2, alcohol-free CHCl3,
DMSO, toluene), extending the reaction time, or raising the
reaction temperature only succeeded in reducing the formation
of 5, not eliminating it.
From the reaction, we know that the two alkyl groups of the
unsymmetrical phosphonate mixed diesters may be introduced
from different starting materials, either the alkoxydichloro-
phosphine or alcohols in the alcoholysis step. Phenol was intro-
21
and PCl5 followed by successive treatment with different
alcohols.22 In all of the above methods, it is necessary to first
synthesize phosphonic acid, phosphonate monoacid, or
symmetric phosphonate diester.23 A shorter synthesis of this
important class of molecules would be beneficial.
DOI: 10.1039/b008340m
J. Chem. Soc., Perkin Trans. 1, 2001, 1223–1226
This journal is © The Royal Society of Chemistry 2001
1223

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Scheme 2
duced more easily from phenoxydichlorophosphine than it was
in the phenolysis step due to its weak nucleophilicity (entries g
and h). Alcoholysis with tert-butyl alcohol was unsuccessful
due to steric encumbrance.
In order to expand this reaction, amides (MeCONH2 and
PhCONH2) were also used instead benzyl carbamate, but this
was unsuccessful. Aliphatic aldehydes (BuCHO and PhCH2-
CHO) were also unsuccessful.
Scheme 3
In order to gain a better understanding of this reaction, 31P
NMR was used to follow the reaction. In entry a, both
phosphonochloridate 6a (38 ppm in 31P NMR) and phosphonic
anhydride 7a (6 ppm in 31P NMR) were observed as reaction
intermediates by 31P NMR. The signals were confirmed by
comparison with the corresponding authentic samples,
phosphonochloridate 6a and phosphonic anhydride 7a, which
were synthesized from the corresponding monoacid 5a using
the standard thionyl chloride method.10
According to 31P NMR tracing analysis, after an equivalent
amount or less of water was added to a solution of methoxy-
dichlorophosphine in anhydrous benzene, methyl phosphono-
chloridate (MeO)HP(O)Cl (Ϫ4.0 ppm in 31P NMR) and also
monomethyl phosphonate (MeO)HP(O)(OH) (8.7 ppm in 31P
NMR) were observed.25 Only monomethyl phosphonate
(MeO)HP(O)(OH) was observed after more than two equiva-
lents of water were added to the solution.
All products were characterized by 1H NMR, 31P NMR and
MS spectrometries and elemental analyses. The data of com-
pounds 5 are in good agreement with the data in the liter-
A possible mechanism is shown in Scheme 2, based on the
identification by 31P NMR of compounds 6a and 7a.
1
ature.14,26 In most cases the H NMR spectra showed the CH3
Although the yields of phosphonates 4 are modest, the
method is quick and convenient for synthesizing unsymmetrical
1-aminoalkylphosphonate mixed diesters while at the same time
synthesis of 1-aminoalkylphosphonate monoacids occurs in
the second phase of the reaction. Furthermore, the byproducts,
1-aminoalkylphosphonate monoacids are also very useful as
precursors for other phosphonic derivatives.
Further evidence for the proposed mechanism has been
acquired from the reaction of methyl phosphonochloridate
(MeO)HP(O)Cl, which was prepared by adding an equivalent
amount of water to a solution of methoxydichlorophosphine
MeOPCl2 in anhydrous benzene prior to use, with the imine Z–
and CH3CH2 of the methoxy or ethoxy groups of compounds 4
are magnetically nonequivalent due to chiral carbon and/or
phosphorus atoms in the molecules. The signals were split into
doublets but with different chemical shifts.
In conclusion, a novel and facile method for the synthesis of
unsymmetrical N-protected 1-aminoalkylphosphonate diesters
has been developed using in situ one-pot reactions of com-
mercially available benzyl carbamate, aldehydes and alkoxy-
dichlorophosphine, followed by alcoholysis in the presence of
triethylamine. The reaction procedure was traced by 31P NMR
analysis and a mechanism has been proposed.
N᎐CHPh–NO -p, which was prepared from benzyl carbamate
᎐
2
and p-nitrobenzaldehyde diethyl acetal,24 followed by ethan-
olysis in the presence of triethylamine. In the reaction an
unsymmetrical diester 4d was obtained in satisfactory yield
and monoacid 5d was also obtained simultaneously (Scheme 3).
Experimental
Melting points were obtained on a Yanaco melting point
apparatus and are uncorrected. 1H NMR spectra were recorded
1224
J. Chem. Soc., Perkin Trans. 1, 2001, 1223–1226

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on a Varian Mercury 200 spectrometer in CDCl3 with TMS as
an internal standard. 31P NMR spectra were recorded on the
same spectrometer at 81 MHz, and the chemical shifts were
referenced to 85% H3PO4 with negative shifts upfield. Mass
spectra were obtained on a VG-ZAB-HS mass spectrometer.
CHN analyses were recorded on a Vario EL analyzer. Methoxy-
dichlorophosphine,27 and phenoxydichlorophosphine28 were
synthesized following literature procedures. All remaining
chemicals were purchased from Beijing Chemical Co. Benzene
was refluxed over sodium and distilled prior to use. Triethyl-
amine was also refluxed over sodium hydroxide and distilled
prior to use.
O7P: C, 52.94; H, 5.18; N, 6.86. Found: C, 52.93; H, 5.29;
N, 6.45%.
Isopropyl methyl (N-benzyloxycarbonylamino)(4-nitrophenyl)-
methylphosphonate (4e). White solid; mp 141–143 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 20.16; 1H NMR (200 MHz, CDCl3)
δ: 1.02–1.33 (m, 6 H, 2 CH3), 3.55 and 3.78 (d, JPH = 11 Hz, 3 H,
POMe), 4.64–4.74 (m, 1 H, OCH), 5.03–5.31 (m, 3 H, PhCH2O
and CHP), 6.03 (br s, 1 H, CONH), 7.29–7.34 (m, 5 H, ArH),
7.60 and 8.21 (d, J = 8.0 Hz, 4 H, PhNO2); FAB-MS m/z: 423
(MH+, 17%). Anal. calcd. for C19H23N2O7P: C, 54.03; H, 5.49;
N, 6.63. Found: C, 53.82; H, 5.50; N, 6.49%.
Butyl methyl (N-benzyloxycarbonylamino)(4-nitrophenyl)-
methylphosphonate (4f). White solid; mp 88–91 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 21.34; H NMR (200 MHz, CDCl3) δ:
0.81–0.99 (m, 3 H, CH3), 1.16–1.76 (m, 4 H, CH2CH2), 3.57 and
3.74 (d, JPH = 10.6 Hz, 3 H, POMe), 4.06 (dt, JPH = 10.7, J = 6.9
Hz, 2 H, OCH2), 5.03–5.38 (m, 3 H, PhCH2O and CHP), 6.39
(br s, 1 H, CONH), 7.33 (s, 5 H, Ph), 7.62 and 8.20 (d, J = 7.7
Hz, 4 H, PhNO2); FAB-MS m/z: 437 (MH+, 42%). Anal. calcd.
for C20H25N2O7P: C, 55.05; H, 5.77; N, 6.42. Found: C, 55.41;
H, 5.59; N, 6.10%.
General procedure
Alkoxydichlorophosphine 2 (3 mmol) was slowly added drop-
wise to a stirred mixture of benzyl carbamate (0.45 g, 3 mmol)
and aldehyde 1 (3 mmol) in anhydrous benzene (15 mL) at room
temperature. After stirring the reaction mixture for 6 h at RT, it
was then refluxed for 1 h. After cooling, alcohol 3 (6 mmol) was
added dropwise (ice–water bath). After about 10 min, triethyl-
amine (0.67 g, 6.6 mmol) was added dropwise, and then the
reaction mixture was allowed to stir overnight. After adding
ethyl acetate and water to make the reaction solution clear, the
organic phase was separated and washed with saturated
aqueous NaCl solution 3 to 5 times, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue was
separated on a silica gel column with petroleum ether and ethyl
acetate (1 : 1) as eluent to yield phosphonate mixed diester 4.
The aqueous phase was acidified with 10% HCl to precipitate
the byproduct monoacid 5.
1
Methyl phenyl (N-benzyloxycarbonylamino)(4-nitrophenyl)-
methylphosphonate (4g). White solid; mp 138–143 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 17.59; 1H NMR (200 MHz, CDCl3) δ: 3.63
and 3.80 (d, JPH = 11 Hz, 3 H, POMe), 5.07–5.11 (m, 2 H,
PhCH2O), 5.38–5.58 (m, 1 H, CHP), 6.16 (br s, 1 H, CONH),
6.78–7.34 (m, 10 H, ArH), 7.62 and 8.19 (d, J = 7.5 Hz, 4 H,
PhNO2); FAB-MS m/z: 457 (MH+, 27%). Anal. calcd. for
C22H21N2O7P: C, 57.90; H, 4.64; N, 6.14. Found: C, 58.23; H,
4.63; N, 5.77%.
Ethyl methyl (N-benzyloxycarbonylamino)(phenyl)methyl-
phosphonate (4a). White solid; mp 95–97 ЊC (lit.,29 103–105 ЊC,
no spectral data reported). 31P NMR (81 MHz, CDCl3)
δ: 23.39; 1H NMR (200 MHz, CDCl3) δ: 1.09 and 1.26 (t, J = 7
Hz, 3 H, CH3), 3.48 and 3.72 (d, JPH = 10.6 Hz, 3 H, POMe),
3.88–4.14 (m, 2 H, OCH2), 5.02–5.25 (m, 3 H, PhCH2O and
CHP), 5.90 (br s, 1 H, CONH), 7.33–7.40 (m, 10 H, ArH);
EI-MS m/z: 363 (M+, 28%). Anal. calcd. for C18H22NO5P:
C, 59.50; H, 6.10; N, 3.85. Found: C, 59.89; H, 6.32; N, 3.64%.
Ethyl phenyl (N-benzyloxycarbonylamino)(4-nitrophenyl)-
methylphosphonate (4h). White solid; mp 114–117 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 16.52; 1H NMR (200 MHz, CDCl3) δ: 1.11
and 1.23 (t, J = 7.2 Hz, 3 H, CH3), 3.84–4.20 (m, 2 H, OCH2),
5.01–5.15 (m, 2 H, PhCH2O), 5.35–5.51 (m, 1 H, CHP), 6.07
(br s, 1 H, CONH), 6.91–7.33 (m, 10 H, ArH), 7.63 and 8.21
(d, J = 7.8 Hz, 4 H, PhNO2); FAB-MS m/z: 471 (MH+, 20%).
Anal. calcd. for C23H23N2O7P: C, 58.72; H, 4.93; N, 5.95.
Found: C, 59.04; H, 5.00; N, 5.61%.
Ethyl methyl (N-benzyloxycarbonylamino)(2-methoxyphenyl)-
methylphosphonate (4b). White solid; mp 109–111 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 22.93; 1H NMR (200 MHz, CDCl3) δ: 1.11
and 1.26 (t, J = 6.8 Hz, 3 H, CH3), 3.49 and 3.72 (d, JPH = 10.6
Hz, 3 H, POMe), 3.80 (s, 3 H, o-MeOPh), 3.92 and 4.08
(q, J = 6.8 Hz, 2 H, OCH2), 5.00–5.18 (m, 3 H, PhCH2O and
CHP), 5.83 (br s, 1 H, CONH), 6.86–7.35 (m, 9 H, ArH);
FAB-MS m/z: 394 (MH+, 19%). Anal. calcd. for C19H24NO6P:
C, 58.01; H, 6.15; N, 3.56. Found: C, 58.29; H, 6.19; N, 3.20%.
Identification of phosphonochloridate 6a and phosphonic
anhydride 7a by 31P NMR data10
To a stirred solution of 335 mg (1 mmol) of the phosphonate
monoacid 5a (21 ppm in 31P NMR) in 2 mL of dry and ethanol-
free chloroform was added 0.15 mL (2 mmol) of SOCl2. After 4
h, the solvent and volatile materials were removed by a stream
of dry nitrogen and then by drying under vacuum. The residue,
phosphonochloridate 6a, was identified by 31P NMR (38 ppm
in 31P NMR).
The above residue was dissolved in 2 mL of dry and ethanol-
free chloroform. The phosphonate monoacid 5a (168 mg, 0.5
mmol) was added under stirring. After 1 h, the solvent was
removed under vacuum. The residue was determined by 31P
NMR. Two peaks at 38 and 6 ppm were observed for phos-
phonochloridate 6a and phosphonic anhydride 7a, respectively.
The residue was dissolved in dry and ethanol-free chloroform
again. The monoacid 5a (335 mg, 1 mmol) was then added
under stirring. After 1 h, the solvent was removed again under
vacuum. The residue was identified by 31P NMR. Two peaks at
6 and 21 ppm were observed for anhydride 7a and monoacid 5,
respectively.
Ethyl methyl (N-benzyloxycarbonylamino)(4-chlorophenyl)-
methylphosphonate (4c). White solid; mp 84-86 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 22.03; 1H NMR (200 MHz, CDCl3) δ: 1.13
and 1.26 (t, J = 7 Hz, 3 H, CH3), 3.52 and 3.72 (d, JPH = 11 Hz,
3 H, POMe), 3.91–4.16 (m, 2 H, OCH2), 5.02–5.17 (m, 3 H,
PhCH2O, CHP), 5.97 (br s, 1 H, CONH), 7.17–7.44 (m, 9 H,
ArH); EI-MS m/z: 397 (M+, 31%). Anal. calcd. for C18H21-
ClNO5P: C, 54.35; H, 5.32; N, 3.52. Found: C, 54.61; H, 5.43;
N, 3.57%.
Ethyl methyl (N-benzyloxycarbonylamino)(4-nitrophenyl)-
methylphosphonate (4d). White solid; mp 143–146 ЊC. 31P NMR
(81 MHz, CDCl3) δ: 21.08; 1H NMR (200 MHz, CDCl3) δ: 1.16
and 1.27 (t, J = 7.2 Hz, 3 H, CH3), 3.58 and 3.77 (d, JPH = 10.8
Hz, 3 H, POMe), 3.84–4.18 (m, 2 H, OCH2), 5.03–5.11 (s, 2 H,
PhCH2O), 5.17–5.35 (m, 1 H, CHP), 6.14 (br s, 1 H, CONH),
7.33 (s, 5 H, Ph), 7.61 and 8.21 (d, J = 7.9 Hz, 4 H, PhNO2);
FAB-MS m/z: 409 (MH+, 22%). Anal. calcd. for C18H21N2-
Evidence for the proposed mechanism
In a 25 mL flask equipped with magnetic stirring bar and short-
path distilling head were placed equivalent amounts of benzyl
J. Chem. Soc., Perkin Trans. 1, 2001, 1223–1226
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3 (a) J. W. Jacobs, P. G. Schultz, M. Powell and R. Sugasawara, J. Am.
carbamate (0.9 g, 6 mmol) and p-nitrobenzaldehyde diethyl
acetal (1.35 g, 6 mmol), which was prepared from p-
nitrobenzaldehyde and triethyl orthoformate in the presence of
toluene-p-sulfonic acid.30 The reaction mixture was heated at
150–180 ЊC in an oil bath until all the ethanol had ceased distill-
ing over (about 0.5 h), at which time the solution was placed
under high vacuum (about 0.1 mmHg) and allowed to cool to
room temperature to give a solid residue, which showed an IR
Chem. Soc., 1987, 109, 2174; (b) S. J. Pollack, J. W. Jacobs and P. G.
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5888; (e) R. Hirschmann, A. B. Smith III, C. M. Taylor, P. A.
Benkovic, S. D. Taylor, K. M. Yager, P. A. Sprengeler and S. J.
Benkovic, Science, 1994, 265, 234.
4 J. Oleksyszyn and R. Tyka, Tetrahedron Lett., 1977, 18, 2823.
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985.
absorption at 1620 cmϪ1 (C᎐N). The residue was dissolved in 15
᎐
mL of anhydrous benzene. A mixture of methoxydichloro-
phosphine (0.80 g, 6 mmol) and water (0.10 g, 6 mmol) in
anhydrous benzene (5 mL) was added dropwise to the resulting
solution under stirring at room temperature. After stirring for
6 h at room temperature, it was refluxed for 1 h. After cooling to
room temperature, anhydrous ethanol (0.55 g, 12 mmol) was
added dropwise to the mixture in an ice–water bath. After
about 10 min, triethylamine (1.34 g, 13.2 mmol) was added
dropwise, and then the reaction mixture was allowed to stir
overnight. After adding ethyl acetate and water to make the
reaction solution clear, the organic phase was separated and
washed with saturated aqueous NaCl solution 4 times, dried
over anhydrous sodium sulfate, and concentrated under
vacuum. The residue was purified on a silica gel column with
petroleum ether and ethyl acetate (1 : 1) as eluent to yield the
unsymmetrical diester 4d in 67% yield. The aqueous phase was
acidified with 10% HCl to precipitate the monoacid 5d in 24%
yield.
6 (a) J. Lukszo and R. Tyka, Synthesis, 1977, 239; (b) D. Green,
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Identification of methyl phosphonochloridate (MeO)HP(O)Cl
by 31P NMR
To a solution of methoxydichlorophosphine (133 mg, 1 mmol)
in 0.5 mL of CDCl3 was added 0.005 mL of water. After
shaking for 5 min, 31P NMR showed three peaks at 180.5,
8.7 and Ϫ4.0 ppm for MeOPCl2, (MeO)HP(O)(OH) and
(MeO)HP(O)Cl, respectively. Another 0.010 mL of water was
added and the solution was shaken for 5 min. 31P NMR showed
the same peaks, but the intensity of the peak at 180.5 ppm was
reduced. After adding another 0.022 mL of water and shaking
for 5 min, the peaks at 180.5 and Ϫ 4.0 ppm disappeared. 31P
NMR showed no change after another 0.03 mL of water was
added.
16 D. S. Karanewsky and M. C. Badia, Tetrahedron Lett., 1986, 27,
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Acknowledgements
24 F. A. Davis, J. Lamendola, Jr., U. Nadir, E. W. Kluger, T. C.
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This project was supported by NSFC (29772002).
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