Hydrophosphorylation of imines catalyzed by tosyl chloride for the synthesis of α-Aminophosphonates

Article abstract of DOI:10.1055/s-2008-1078509

A simple, efficient, and general method has been developed for the synthesis of α-aminophosphonic esters using TsCl as an efficient catalyst. α-Aminophosphonic acids were obtained in good to high yields (65-85%) and purity under mild conditions by the rea

Full text of DOI:10.1055/s-2008-1078509

LETTER
A
Hydrophosphorylation of Imines Catalyzed by Tosyl Chloride for the
Synthesis of a-Aminophosphonates
TsClasCatalyst
a
b
a
-A
a
minophosp
khonates Kaboudin,* Elaheh Jafari
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
Fax +98(241)4214949; E-mail: kaboudin@iasbs.ac.ir
Received 18 February 2008
O
OR
Abstract: A simple, efficient, and general method has been devel-
H
P(OR)2
HO P
oped for the synthesis of a-aminophosphonic esters using TsCl as
an efficient catalyst. a-Aminophosphonic acids were obtained in
good to high yields (65–85%) and purity under mild conditions by
the reaction of diethyl phosphite with imines in the presence of
TsCl.
OR
phosphonate
phosphite
O
OR
OR
Me3Si P(OR)2
Me3SiO
P
Key words: a-aminophosphonates, imines, alkyl phosphite, p-tosyl
chloride, addition reaction
Scheme 1
ating an electron pair on phosphorus which makes it easier
to carry out many reactions at the phosphorus centre
(Scheme 1).14 However, use of this reagent brings prob-
lems, including inconvenient reaction conditions, anaero-
bic and anhydrous conditions, and also some severe side
reactions.
Phosphorus–carbon bond formation reactions have at-
tracted growing attention because of their novel applica-
tion in organic synthesis and bioorganic chemistry. a-
Functionalized phosphonic acids are valuable intermedi-
ates for the preparation of medicinal compounds and syn-
thetic intermediates.1–4 Among the a-functional
phosphonic acids, 1-aminophosphonic acids are an impor-
tant class of compounds that exhibit a variety of interest-
ing and useful properties. The 1-aminophosphonic acids
are important substitutes for the corresponding a-amino
acids in biological systems.5 Indeed a number of potent
antibiotics,6 enzyme inhibitors,7 and pharmacological
agents8 are 1-aminophosphonic acids or peptide ana-
logues. Aminophosphonic acids are also found as constit-
uents of natural products.9 Many effective methods for the
preparation of 1-aminoalkylphosphonic acids have been
developed. Of these methods, the Kabachnik–Fields10
synthesis of 1-aminoalkyl phosphonates via hydrophos-
phorylation of a Schiff base catalyzed by a base or an acid
is the most convenient. The addition of a H-phosphonic
acid diester to structurally diverse imines appears to be a
general method for the preparation of N-substituted 1-
aminoalkanephosphinic acids.11 The diesters of H-phos-
phonic acids are important reagents in organophosphorus
chemistry for the synthesis of a variety of bioactive prod-
ucts including aminophosphonates, aminophosphonic
acids, P–C phosphonates, etc.12 These important reagents
have tautomeric forms in the form of phosphite–phospho-
nate in equilibrium with each other (Scheme 1) which is
shifted mainly toward phosphonate. In fact the chemical
reactivity of dialkyl phosphonates refers to nucleophilic
properties of the phosphite form in equilibrium
(Scheme 1).13 The silylation of the diesters of H-phospho-
nic acid shifts this equilibrium to a P(III) form, thus liber-
In recent years, the development of more economical and
environmentally friendly conversion processes has gained
interest. In continuation of our interest in developing nov-
el methodologies for the synthesis of organophosphorous
compounds,15 herein we report an efficient, practical, en-
vironmentally benign and high yielding method for the
synthesis of 1-aminophosphonates via hydrophosphoryla-
tion of imines using TsCl as catalyst.16
First, benzylideneaniline (1a) was treated with diethyl
phosphite in the presence of 10 mol% of TsCl in dichlo-
romethane at room temperature. The reaction proceeded
smoothly to afford the corresponding a-aminophospho-
nate 2a in excellent yield (83%). The reaction failed after
48 hours without any catalyst. The reactions of several
imines were examined in the presence of catalytic amount
(10 mol%) of TsCl in dichloromethane at room tempera-
ture, and the results are summarized in Table 1. It has
been suggested that TsCl has two main roles in this reac-
tion: shift of the tautomeric equilibrium to the phosphite
form and imine activation by in situ protonation of the
imine (Scheme 2).
As shown in Table 1, a mixture of imine 1 with diethyl
phosphite in the presence of TsCl as catalyst, afforded the
desired product 2 in 65–85% yields.
To our knowledge, many imines are hygroscopic, unsta-
ble at high temperatures, and difficult to purify by distil-
lation or column chromatography. Thus it is desirable
from a synthetic point of view that imines, generated in
situ from aldehydes and amines, immediately react with
H-phosphonate to afford 1-aminophosphonate. We thus
examined the addition of diethyl phosphite to a mixture of
benzaldehyde and aniline in the presence of TsCl as cata-
SYNLETT 2008, No. x, pp 000A–000C
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0
8
Advanced online publication: xx.xx.2008
DOI: 10.1055/s-2008-1078509; Art ID: D05508ST
© Georg Thieme Verlag Stuttgart · New York

B
B. Kaboudin, E. Jafari
LETTER
O
sion of the substrates to their corresponding a-
aminophosphonate was clean. Workup of the reaction
mixture was very easy and gave highly pure products,
which did not need further purification. All NMR data
could be assigned and were in accord with the proposed
structures of the products.17
O
R
P(OEt)2
H
P(OEt)2
TsCl
N
H
R'
OEt
P
TsO
OEt
OTs
R
H
R
P
OEt
Acknowledgment
N
H
Cl
OEt
N
R'
The Institute for Advanced Studies in Basic Sciences (IASBS) is
thanked for supporting this work.
H
R'
Scheme 2
References and Notes
Table 1 One-Pot Synthesis of 1-Aminophosphonates Using TsCl as
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Catalyst
O
O
TsCl (0.1 equiv)
CH2Cl2, r.t.
H
C
+
R
P(OEt)2
H
P(OEt)2
RCH=N-R'
NH
R'
2
1
Entry
R
R¢
Time Yield 31P NMR
(h) (%)a
[d (ppm)]
23.31
23.49
23.58
23.53
21.41
22.67
22.39
21.41
22.69
22.61
24.59
24.91
a
b
c
d
e
f
Ph
Ph
2
3
3
3
3
2
2
3
4
3
4
3
83
85
80
72
76
71
82
81
68
73
65
73
4-MeC6H4
4-(i-Pr)C6H4
4-MeOC6H4
4-O2NC6H4
PhCH=CH
Ph
Ph
Ph
Ph
Ph
Ph
(6) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
g
h
i
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
cyclohexyl
cyclohexyl
Chem. 1986, 29, 29.
(7) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M.
J. Med. Chem. 1989, 32, 1652.
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Springer Verlag: Berlin, 1983, 1.
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Aminophosphinic Acids; John Wiley & Sons: Chichester,
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177, 1749.
4-MeC6H4
4-(i-Pr)C6H4
4-MeOC6H4
Ph
j
k
l
PhCH=CH
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1953, 1126. (b) Kabachnik, M. J.; Medved, T. Izv. Akad.
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a Yield refers to isolated yield by column chromatography.
O
O
TsCl (0.1 equiv)
H
Ph
P(OEt)2
C
PhCHO + PhNH2
+
H P(OEt)2
CH2Cl2, r.t.
MS, 5 h
80%
NH
Ph
2a
Scheme 3
lyst. It was found that the reaction of benzaldehyde,
aniline, and diethyl phosphite took place smoothly within
five hours in the presence of 10 mol% of TsCl and 4 Å
molecular sieves at room temperature to give the desired
1-aminophosphonate 2a in 80% isolated yield
(Scheme 3). The reaction failed using aliphatic aldehydes.
In all the reactions we have reported in this paper, cleav-
age of the Et–O–P bond was not detected and the conver-
Synlett 2008, No. x, A–C © Thieme Stuttgart · New York

LETTER
TsCl as Catalyst for the Synthesis of a-Aminophosphonates
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C
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(17) TsCl (1 mmol, 0.18 g) was added to a stirred mixture of
diethyl phosphite (0.012 mol) in CH2Cl2 (10 mL) at r.t.
Imine (0.01 mol) was added to the reaction mixture and the
mixture was stirred for 2–4 h at r.t. H2O (50 mL) was added
to the reaction mixture and the organic layer was extracted
with EtOAc (4 × 50 mL), dried with CaCl2, and the solvent
was evaporated to give the crude product. Chromatography
on silica gel with EtOAc–n-hexane (1:9 → 5:5) and
evaporation of the solvent under reduced pressure gave the
pure products in 65–85% yields. All the products gave
satisfactory spectral data in accordance with the assigned
structures and literature reports.12a,16b
Diethyl[phenyl(phenylamino)methyl]phosphonate (2a):
1H NMR (250 MHz, CDCl3): d = 1.13 (t, J = 7.0 Hz, 3 H),
1.29 (t, J = 7.0 Hz, 3 H), 3.60–3.75 (m, 1 H), 3.85–4.01 (m,
1 H), 4.03–4.22 (m, 2 H), 4.76 (d, JHP = 24.2 Hz, 1 H), 6.59
(d, J = 8.5 Hz, 2 H), 6.69 (t, J = 7.2 Hz, 1 H), 7.11 (t, J = 8.3
Hz, 2 H), 7.22–7.52 (m, 5 H). 31P NMR (101.2 MHz, CDCl3,
H3PO4): d = 23.31. 13C NMR (62.9 MHz, CDCl3): d = 16.2
(d, JPC = 6.3 Hz), 16.4 (d, JPC = 6.3 Hz), 56.1 (d, JPC = 150.3
Hz), 63.1, 63.2, 113.8, 118.3, 127.9 (d, JPC = 5.7 Hz), 128.5
(d, JPC = 2.5 Hz), 129.2, 136.0 (d, JPC = 2.5 Hz), 146.3 (d,
JPC = 14.5 Hz).
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