Studies on the synthesis of 1-aminoalkylphosphonates from aldehydes using silica-supported ammonium hydrogen carbonate

Article abstract of DOI:10.1055/s-2004-822350

Studies on the use of silica-supported ammonium hydrogen carbonate as an efficient reagent for the synthesis of 1-amino-phosphonates under microwave irradiation in solvent-free conditions is reported. Investigations showed that this reaction proceeds by the formation of methanediamine as an intermediate. The reaction in the absence of diethyl phosphite gave cis-imidazolines as the major products.

Full text of DOI:10.1055/s-2004-822350

PAPER
1249
Studies on the Synthesis of 1-Aminoalkylphosphonates from Aldehydes Using
Silica-Supported Ammonium Hydrogen Carbonate
S
tudies on the Sy
a
nthesis of
1
b
-Aminophos
a
phonates k Kaboudin,* Fariba Saadati
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-159, Iran
Fax +98(241)4249023; E-mail: kaboudin@iasbs.ac.ir
Received 8 February 2004; revised 27 February 2004
As part of our studies on the solvent-free reactions for the
Abstract: Studies on the use of silica-supported ammonium hydro-
synthesis of organophosphorus compounds using immo-
gen carbonate as an efficient reagent for the synthesis of 1-amino-
phosphonates under microwave irradiation in solvent-free
conditions is reported. Investigations showed that this reaction pro-
bilized reagents on inorganic solid phases,19–23 we recent-
ly found that silica-supported ammonium hydrogen
ceeds by the formation of methanediamine as an intermediate. The carbonate is a suitable and efficient reagent for the one-
reaction in the absence of diethyl phosphite gave cis-imidazolines
as the major products.
pot synthesis of 1-aminophosphonates from aldehydes
(Scheme 1).24
Key words: 1-aminophosphonates, silica, ammonium hydrogen
carbonate, methanediamines, imidazolines
O
C
O
P
O
P
SiO2/NH4HCO3
MW/ 2-5 min
R
H
H
OCH2CH3
OCH2CH3
R
CH
OCH2CH3
OCH2CH3
+
NH2
In recent years, considerable interest has been focused on
the synthesis of phosphonic acids, particularly the a-sub-
stituted analogs that are an important class of compounds
with applications as antibiotics, antiviral agents and en-
zyme inhibitors. Among the a-functionalized phosphonic
acids, a-aminophosphonic acid derivatives are gaining in-
terest in medicinal chemistry. a-Aminophosphonic acids
are analogues of naturally occurring a-amino acids in bi-
ological systems. Extensive investigations over the last
twenty years have shown that they are of particular impor-
tance in biological and medicinal research.1–4 In this re-
spect, the uses of a-amino alkyl phosphonates as enzyme
inhibitors,5 antibiotics and pharmacological agents,6 her-
bicides,7 and haptens of catalytic antibodies8 are well doc-
umented. Although there are many classical methods for
synthesizing a-aminophosphonic acids,9–14 these involve
either long reaction times, expensive reagents, or the use
of conditions which are amenable to aliphatic aminophos-
phonic acids rather than aromatic aminophosphonic ac-
ids.15 The most typical procedure is a Strecker-type
reaction16 which involves the treatment of an aldehyde
with ammonia and dialkyl phosphite. This method, how-
ever, is not high yielding nor is it suitable for large-scale
production since the reaction is performed in a sealed ves-
sel with heating at 100 °C.
Scheme 1
We decided to analyze this reaction and report further in-
vestigations on the synthesis of 1-aminophosphonates us-
ing silica-supported ammonium hydrogen carbonate
under microwave irradiation. Thus, the reaction of benzal-
dehyde, chosen as a model compound, was studied in the
presence of silica-supported ammonium hydrogen car-
bonate under microwave irradiation. As described below,
treatment of benzaldehyde (1a) with diethyl phosphite in
the presence of silica-supported ammonium hydrogen
carbonate gave diethyl-N-(phenylmethylene)-1-ami-
nophenyl methylphosphonate (2a) in 92% yield
(Scheme 1). The 1H NMR spectrum of 2a exhibits a dou-
blet at d = 8.42 indicative of the HC–P coupling (4JHP
4.7 Hz). The hydrolyses of 2a with hydrochloric acid
(5%), followed by neutralization of the chloride salt, gave
1-(aminophenylmethyl)phosphonate 3a (Scheme 2).
=
The question arises here as to how it is possible to obtain
diethyl-N-(phenylmethylene)-1-aminophenylmethyl-
phosphonate (2a) in the reaction of benzaldehyde (1a)
with diethyl phosphite in the presence of silica-supported
O
C
O
P
O
P
SiO2/NH4HCO3
MW/ 2.5 min
2
Ph
H
H
OCH2CH3
OCH2CH3
+
Ph CH
N
OCH2CH3
OCH2CH3
Surface-mediated solid phase reactions are of growing
interest17 because of their advantages of ease of set up,
mild conditions, rapid reactions, selectivity, increased
yields of the products and low cost compared with their
homogeneous counterparts. The application of micro-
wave energy to accelerate organic reactions is of increas-
ing interest and offers several advantages over
conventional techniques.18
1a
CH
2a
Ph
HCl
O
O
P
NH4OH
Ph CH
NH2
OCH2CH3
OCH2CH3
Ph CH
P
OCH2CH3
OCH2CH3
NH3Cl
SYNTHESIS 2004, No. 8, pp 1249–1252
Advanced online publication: 26.04.2004
x
x
.
x
x
.2
0
0
4
3a
DOI: 10.1055/s-2004-822350; Art ID: Z02604SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1250
B. Kaboudin, F. Saadati
PAPER
ammonium hydrogen carbonate under microwave irradia-
tion. We therefore decided to study the reaction of benzal-
dehyde (1a) with silica-supported ammonium hydrogen
carbonate in the absence of diethylphosphite. We found
that the reaction gave cis-2,4,5-triphenylimidazoline (4a)
as the major product (Scheme 3). The addition of diethyl
phosphite to the reaction mixture did not give 2a under
microwave irradiation.
Ph
O
C
SiO2/NH4HCO3
MW
N
N
Ph
H
Ph
Ph
5a
1a
O
H
P(OEt)2
MW
MW
Ph
O
Ph
O
SiO2/NH4HCO3
Ph CH
N
P
OCH2CH3
OCH2CH3
N
NH
Ph
C
H
N
Ph
NH
Ph
MW/ 4 min
Ph
Ph
CH
Ph
1a
4a: 83%
4a
2a
Scheme 3
Scheme 5
The reaction of benzaldehyde with ammonia leads to the
long-known substance ‘N,N¢-bis(phenylmethylidene)phe-
nylmethanediamine’.25 Deprotonation of N,N¢-bis(aryl-
methylidene) arylmethanediamines (5a) with a strong
base (PhLi) or under thermal conditions results in forma-
tion of the transient 2,4-diazapentadienyl anion (6a)
which cyclises in a disrotatory fashion to furnish the cis-
2,4,5-triphenylimidazoline (4a) (Scheme 4).26
In conclusion, we have found that the reaction of benzal-
dehyde with silica-supported ammonium hydrogen
carbonate gave N,N¢-bis(phenylmethylidene)phenyl-
methanediamine that cyclises under microwave
irradiation to form cis-2,4,5-triphenylimidazoline. Tri-
phenylimidazolines are good precursors for the synthesis
of imidazoles and diphenylethylenediamines that can be
used as chiral ligands in asymmetric synthesis.28 Herein,
we introduced a new method for the synthesis of imidazo-
lines of aldehydes using silica-supported ammonium
carbonate under microwave irradiation. N,N¢-Bis(phenyl-
methylidene)phenylmethanediamine reacts with dieth-
ylphosphite, before cyclisation, to give diethyl N-
(phenylmethylene)-1-aminophenyl methylphosphonate
(2a), which can be easily hydrolysed to diethyl-1-amino-
1-phenylmethylphosphonate (3a). Thus, one-pot reaction
of diethylphosphite with aldehydes in the presence of sil-
ica-supported ammonium carbonate is important for the
preparation of 1-aminophosphonates under microwave ir-
radiation. Further investigations of the reaction of diethyl
phosphite with cis-2,4,5-triphenylimidazoline are now in
progress.
Scheme 4
All chemicals were commercial products and distilled or recrystal-
lised before use. A commercially available kitchen-type pulse mi-
crowave at 2450 MHz (600 W) was used in all experiments. The IR
spectra were determined using a FT-IR Brucker-Vector 22. NMR
spectra were taken with a DMX-500 Bruker Avance instrument
with the chemical shifts reported as d and couplings expressed in
Hertz. Silica gel column chromatography was carried out with Sili-
ca gel 100 (Merck No. 10184). Merck Silica-gel 60 F254 plates (No.
5744) were used for the preparative TLC.
The reaction of benzaldehyde (1a) in the presence of sili-
ca-supported ammonium hydrogen carbonate gave N,N¢-
bis(phenylmethylidene)phenylmethanediamine (5a). De-
protonation of 5a under microwave irradiation gave cis-
2,4,5-triphenylimidazoline (4a) as the major product in
83% yield (Scheme 3).
Thus
N,N¢-bis(phenylmethylidene)phenylmethanedi-
amine reacts with diethylphosphite, before cyclization, to
give diethyl-N-(phenylmethylene)-1-aminophenylmeth-
ylphosphonate (2a), which can be easily hydrolysed to di-
ethyl-1-amino-1-phenylmethylphosphonate (3a). We
found that the reaction of N,N¢-bis(phenylmeth-
ylidene)phenylmethanediamine with diethyl phosphite
under microwave irradiation gave diethyl-N-(phenyl-
cis-2,4,5-Triphenylimidazoline (4a) from Benzaldehyde (1a) us-
ing Silica-Supported Ammonium Hydrogen Carbonate under
Microwave Irradiation
This solvent-free reaction is operationally simple. The reagent (6
mmol) was prepared by grinding together ammonium hydrogen car-
bonate (6 mmol, finely ground) and silica (2 g) with mortar and pes-
tle until a fine, homogeneous, powder was obtained (5–10 min).
Benzaldehyde (6 mmol) was added to the powder and the mixture
was irradiated in a microwave for 4 min using 600 W power. The
mixture was then washed with EtOAc (200 mL). Chromatography
methylene)-1-aminophenylmethylphosphonate
(2a,
Scheme 5).27
Synthesis 2004, No. 8, 1249–1252 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of 1-Aminoalkylphosphonates
1251
through a plug of silica gel with EtOAc–n-hexane (1:9–5:5) as elu-
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83% yield; mp 126–127 °C (washed with n-hexane–EtOAc) (Lit.29
mp 127–128 °C, Lit.30 mp 129–130 °C).
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One-Pot Synthesis of Diethyl-N-(Phenylmethylene)-1-ami-
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Reaction of N,N¢-Bis(phenylmethylidene) phenylmethanedi-
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Diethyl phosphite (6 mmol) was added to N,N¢-bis(phenylmeth-
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irradiated by microwave for 2 min using 600 W power. The reaction
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Acknowledgment
The Institute for Advanced Studies in Basic Sciences (IASBS) is
thanked for supporting this work.
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