A mild and efficient one-pot synthesis of 1-hydroxymethylene-1,1-bisphosphonic acids. Preparation of new tripod ligands

Article abstract of DOI:10.1016/S0040-4039(01)01844-5

A simple and efficient one-pot procedure for synthesis of 1-hydroxymethylene-1,1-bisphosphonic acids by reaction of acyl chlorides and tris(trimethylsilyl)phosphite is described. This method was applied to the synthesis of new phosphonated chelating tripod ligands.

Full text of DOI:10.1016/S0040-4039(01)01844-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8475–8478
A mild and efficient one-pot synthesis of
-hydroxymethylene-1,1-bisphosphonic acids. Preparation of new
tripod ligands
1
Marc Lecouvey,* Isabelle Mallard, Th e´ odorine Bailly, Ramon Burgada and Yves Leroux
Laboratoire de Chimie Structurale Biomol e´ culaire (FRE 2313-CNRS), UFR S.M.B.H., Universit e´ Paris 13,
74 Rue Marcel Cachin, F-93017 Bobigny Cedex, France
Received 17 September 2001; revised 1 October 2001; accepted 3 October 2001
Abstract—A simple and efficient one-pot procedure for synthesis of 1-hydroxymethylene-1,1-bisphosphonic acids by reaction of
acyl chlorides and tris(trimethylsilyl)phosphite is described. This method was applied to the synthesis of new phosphonated
chelating tripod ligands. © 2001 Elsevier Science Ltd. All rights reserved.
For some years, there has been considerable interest in
the derivatives of 1-hydroxymethylene-1,1-bisphospho-
nate because of their biological properties and medical
applications. 1-Hydroxymethylene-1,1-bisphosphonates
works on coordination ability of HMBP have shown
their very high efficiency in binding of metal ions or
metalloid ions.
7–9
(
HMBP) which are characterized by a P–C–P linkage,
These numerous applications require then the develop-
ment of an efficient and practical method to introduce
the HMBP group. Several methods have been reported
for the synthesis of HMBP. A common method
involves the reaction of a carboxylic acid and phospho-
rus trichloride. In this case, the synthesis is carried out
in the harsh acidic conditions and consequently it is not
suitable for the polyfunctional substrates. The second
pathway requires the synthesis of 1-hydroxymethylene-
1,1-bisphosphonate (HMBP) tetraester obtained from
the addition of dialkylphosphite to a-ketophosphonates
followed by a dealkylation reaction. Unfortunately,
HMBP tetraesters are not as stable as the correspond-
are stable analogues of pyrophosphate and are com-
pletely resistant to enzymatic hydrolysis. They are
widely used in the treatment of a number of diseases
1,2
characterized by an abnormal calcium metabolism.
Recently, a lot of studies have shown that the use of
bisphosphonates might be considered as an improve-
3
ment in the management of cancer. It has been shown
that HMBP inhibit the development of bone metastasis
4
,5
6
in breast
approach is the use of the chelating properties of the
-hydroxymethylene-1,1-bisphosphonic (HMBP) group
or prostate cancer patients. Another
1
for the treatment of human metal intoxications. Recent
OH
OSiMe3
O
O
R
O
P
OH
OH
OH
O
R
O
P
C
P
OSiMe3
MeOH
n P(OSiMe3)3
C
R
Cl
OSiMe3
OSiMe3
P
1
OH
OSiMe3
3
2
Scheme 1.
*
0
Corresponding author. Fax: 33 (0) 148387625; e-mail: m.lecouvey@smbh.univ-paris13.fr
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01844-5

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M. Lecou6ey et al. / Tetrahedron Letters 42 (2001) 8475–8478
ing acids or salts due to the rearrangement HMBP
tetraesters into the phosphonophosphate esters under
basic conditions or thermically.
Thus, treatment of acid chloride with 2 equiv. of
tris(trimethylsilyl)phosphite at room temperature leads
to the tetrakis(trimethylsilyl) ester of 1-trimethylsiloxy-
1
0–12
1
,1-bisphosphonic acid 2 in a single step within few
Our group has previously described a one-pot proce-
dure to obtain HMBP tetraesters from acyl chlorides
and trimethylphosphite in the presence of protic
reagent. In this communication, we report a very mild
and efficient one-pot method for the preparation of
HMBP tetraacids (Scheme 1).
minutes. The synthesis of 2 is based on an Arbuzov
reaction to give a bis(trimethylsilyl) a-ketophosphonate
followed by an immediate addition of a second equiva-
lent of tris(trimethylsilyl)phosphite. Hydrolysis of 2
was carried out in methanol at 25°C for 1 h. After
evaporation of volatile fractions, HMBP tetraacids 3
1
3
14
Table 1. HMBP derivatives 3a–i produced via Scheme 1

M. Lecou6ey et al. / Tetrahedron Letters 42 (2001) 8475–8478
8477
O
OH
OH
O
O
O
P
OH
OH
1
) 2 eq. P(OSiMe ) , THF, 25˚C
P
Cl
3 3
OH
O N
2
C
O N
2
CH
+
O N
2
2) MeOH, 25˚C, 1 h
O
P
OH
HO
P
OH
O
HO
1
g
3g
4g
Scheme 2.
OH
P
1
2
) 6 eq. P(OSiMe3)3
O
OH
OH
Benzene, reflux
H C C(CH O(CH ) COCl)
H C
3
C
CH2 O CH2 CH2
C
3
2
2 2
3
) MeOH, 25˚C, 1 h
O P OH
OH
1
k
3k
3
Scheme 3.
were obtained very pure in very good yields. As shown
in Table 1, the efficiency of the procedure was not
affected by the nature of acid chlorides. In aromatic or
aliphatic series, yields were always excellent. These
results are very interesting because no method previ-
ously described allowed the synthesis of aromatic
HMBP.
The synthesis was carried out from the acid chloride 1k
17
described by Martell et al.
and 6 equiv. of
tris(trimethylsilyl)phosphite in refluxing benzene for 15
31
h (the reaction was monitored by P NMR). After
methanolysis, the tripod 3k was obtained in 40% yield.
In this case, the yield decreased sensitively due to the
steric hindrance of HMBP groups.
In conclusion, the procedure described herein allowed
to introduce the HMBP group from various aromatic
or aliphatic acid chlorides. To our knowledge, the
synthesis of the tripod having HMBP functions as
terminal groups was carried out for the first time.
For the liquid acid chlorides 1a–e,i–j, the reaction can
be easily settled without solvent at room temperature.
The reaction is strongly exothermic but no side reaction
was observed. In particular, for the benzyl acetyl chlo-
ride, it has been shown that the Arbuzov reaction from
this substrate and trimethylphosphite did not lead to
15
the a-ketophosphonate but to the enol form. The
solid acid chlorides 1f–h were solubilized in THF. The
reaction was carried out at room temperature except
for the substrate 1h. In this case, it was necessary to
work at −70°C due to the high reactivity of p-nitroben-
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9
–10). It was just necessary to use 4 equiv. of
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1
6
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+
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3
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