Synthesis and characterization of new symmetrical bisphosphonates

Article abstract of DOI:10.1080/10426500210231

In order to search for new chelating agents, widely employed methodologies in the chemistry of organophosphorus compounds such as the Michaelis-Arbuzov and Michaelis-Becker reactions were used to synthesize new bisphosphonates in high yields. The importance of the synthesis of these compounds resides in their potential capability of complexing different metals, all the more so because bisphosphonates have been widely employed in the diagnosis and therapy of several bone diseases, such as osteoporosis and hypercalcemia, as extracting agents for alkaline, alkaline earth, and transition metals, and also as reaction catalysts. All bisphosphonates synthesized were characterized by IR, ¹H-NMR, ¹³C-NMR, ³¹P-NMR, and mass spectroscopy.

Full text of DOI:10.1080/10426500210231

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis and Characterization of New Symmetrical
Bisphosphonates
Janaína Marques Rodrigues a & João Batista Neves DaCosta a
a Departamento de Química, ICE, Universidade Federal Rural do Rio de Janeiro, km 47 da
Antiga Rio-São Paulo, Seropédica 23851-970, Rio de Janeiro, Brazil
Published online: 27 Oct 2010.
To cite this article: Janaína Marques Rodrigues & João Batista Neves DaCosta (2002) Synthesis and Characterization
of New Symmetrical Bisphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:1, 137-149, DOI:
10.1080/10426500210231
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Phosphorus, Sulfur and Silicon, 2002, 177:137–149
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
SYNTHESIS AND CHARACTERIZATION OF NEW
SYMMETRICAL BISPHOSPHONATES
Janaı´na Marques Rodrigues and Joa˜o Batista Neves DaCosta
Departamento de Qu´ımica, ICE, Universidade Federal Rural
do Rio de Janeiro, km 47 da Antiga Rio-Sa˜o Paulo, Serope´dica
23851-970, Rio de Janeiro, Brazil
(Received May 11 2001.)
In order to search for new chelating agents, widely employed method-
ologies in the chemistry of organophosphorus compounds such as the
Michaelis-Arbuzov and Michaelis-Becker reactions were used to syn-
thesize new bisphosphonates in high yields. The importance of the syn-
thesis of these compounds resides in their potential capability of com-
plexing different metals, all the more so because bisphosphonates have
been widely employed in the diagnosis and therapy of several bone dis-
eases, such as osteoporosis and hypercalcemia, as extracting agents for
alkaline, alkaline earth, and transition metals, and also as reaction
catalysts. All bisphosphonates synthesized were characterized by IR,
1H-NMR, 13C-NMR, 31P-NMR, and mass spectroscopy.
Keywords: Bisphosphonates; diamines; organophosphorus compounds
INTRODUCTION
The chemistry of organophosphorus compounds started to be inves-
tigated around the end of the nineteenth century by Michaelis and
3
Arbuzov.1 One of the most valuable contributions coming from this
study is the Michaelis-Arbuzov reaction, which involves formation of a
C P bond. This reaction is widely used for the preparation of phospho-
6
nates from trialkyl phosphites and alkyl halides.4
The Michaelis-Arbuzov reaction does not work well for the prepa-
ration of -ketophosphonates from -haloaldehydes and ketones. In
this case, the Perkow reaction takes place affording the dialkyl vinyl
phosphate, where the P O bond is formed instead of the P C bond.7
Address correspondence to Joa˜o Batista Neves DaCosta, Departamento de Qu´ımica,
ICE, Universidad Federal Rural do Rio de Janeiro, km 47 da Antiga Rio-Sa˜o Paulo,
Serope´dica 23851-970, Rio de Janeiro, Brazil. E-mail: dacosta@ufrrj.br
137

138
J. M. Rodrigues and J. B. N. DaCosta
FIGURE 1 Novel synthesized bisphosphonates.
However, when -haloamides are employed, the corresponding phos-
phonates are obtained in good yields.8
Another common method for preparing organophosphorus com-
pounds is the Michaelis-Becker reaction,4 which involves the synthesis
of dialkylphosphonates through the alkylation of a salt obtained by the
reaction between a dialkylphosphite with a strong base. When an
-
haloaldehyde or ketone is used, the Michaelis-Becker reaction affords a
1,2-epoxyalkylphosphonate.9,10 However, when an -haloamide is em-
ployed, the desired -ketophosphonate is also obtained.
In this work, seven new bisphosphonates (Figure 1) were prepared
through the Michaelis-Arbuzov reaction (1 to 4), the Michaelis-Becker
reaction (5), and through transesterification of triethyl phosphonoac-
etate (6 and 7).
The importance in the synthesis of these compounds resides in their
potential capability of complexing different metals.11
Analogous compounds, as shown in Figure 2, have had their metal
complexing ability investigated and have been widely used in the diag-
16
nosis and treatment of several diseases (8),12
as extracting agents
for alkaline, alkaline earth and transition metals (9)14,15,17,18 and also
as reaction catalysts (10).19
RESULTS
The bisphosphonates where X N were synthesized in two steps. The
first one involved the preparation of N,N0-bis(chloroacetyl)diamines,20
where the yields varied from 50 to 70% according to Scheme 1.
FIGURE 2 Analogous compounds with high complexing ability.

Bisphosphonates
139
SCHEME 1 Synthesis of N,N0-bis(chloroacetyl)diamine.
The second step is the Michaelis-Arbuzov reaction,4,21 where 1 mol of
each N,N0-bis(chloroacetyl)diamine reacts with 2 mol of triethyl phos-
phite according to Scheme 2.
SCHEME 2 Synthesis of N,N0-bis(diethyl phosphonoacetyl)diamine.
The N,N0-bis(dibutyl phosphonoacetyl)ethylenediamine (5) was syn-
thesized via the Michaelis-Becker reaction4,22 in three steps according
to Scheme 3.
Ethyleneglycol-bis(diethyl phosphonoacetyl) (6) and diethylene-
glycol-bis(diethyl phosphonoacetyl) (7) were synthesized in two steps.
The second step involves a transesterification23,24 between the triethyl
SCHEME 3 Synthesis of 5.

140
J. M. Rodrigues and J. B. N. DaCosta
phosphonoacetate and ethyleneglycol or diethyleneglycol as described
in Scheme 4.
SCHEME 4 Synthesis of 6 and 7.
STRUCTURAL DETERMINATION OF THE
BISPHOSPHONATES
IR spectra of these compounds show absorption bands at 1240–
1
1276 cm 1, relative to P O stretching and also at 1023–1030 cm
27
which refer to P O asymmetric stretching25
(Table I).
The main indication that the Michaelis-Arbuzov reaction took place
can be seen in the 1H NMR spectrum, where the formation of a
P CH2 bond is represented by a doublet at 2.8–3.0 ppm with J=22
Hz28,29 (Table II). The formation of the P C bond can also be evidenced
in the 13C NMR spectrum with a doublet at 34 ppm with a coupling
constant in the range of 127–134 ppm30 (Table III).
Other important signals in the spectra of the amide bisphosphonates
are at 16 and 62.0 ppm, which are relative to the ethoxy groups of the
ester. The coupling of these carbon atoms with the phosphorus atom (J =
6 Hz)31 can also be seen. Compound 4 shows two signals belonging to the
piperazine ring, C at 41.5 ppm and C at 46.3 ppm,32 which is due to
the diamagnetic anisotropy effect. Thus, as is shown in Figure 3, the C ,
which is on the same side as the carbonyl, is deshielded relative to C .
The conformational analysis of this compound, through the use of
PM3 Hamiltonian from the MOPAC package, shows that the most sta-
ble conformation is a chair in which the substituents of the nitrogen
atom are equatorial, as can be seen in Figure 4.
All bisphosphonates synthesized are symmetrical and their 31P
NMR spectra show only one peak at 20–25 ppm, suggesting that the
1
two phosphorus atoms are in identical environments. The H coupled

141

142

143

144
J. M. Rodrigues and J. B. N. DaCosta
FIGURE 2 Anisotropic effect in compound 4.
phosphorus spectra show a quintuple triplet, which is due to the cou-
pling of P with the methylene next to it (H2C P O) and also with the
methylenes of the alkoxide portion (PO CH2CHn, n = 2, 3).
The mass spectra of the bisphosphonates did not show the molecular
ion, which may be due to the high energy of the electron beam. However,
the fragmentation pattern is in accordance with the structures.
EXPERIMENTAL
All solvents used for reactions and in the purification procedures were
previously distilled or purified according to usual methods described in
the literature.33 Melting points were determined with a Buchi 510 and
are uncorrected.
FIGURE 3 Tridimensional structures of compound 4.

Bisphosphonates
145
Infrared spectra were run on a Perkin-Elmer 1600 FT apparatus,
using NaCl cells for liquid samples and KBr pellets for solid samples.
Gas chromatography was carried out with a Finnigan model 9001 and
a Varian 3000.
Mass spectra were run on a HP-5890—70 eV, 1H (200 MHz) and 13
C
P
NMR (50.3 MHz) spectra were obtained with a Bruker AC-200 and 31
NMR (121 MHz) spectra were obtained with a Varian VXR 300. TMS
1
was used as internal standard for the H and 13C spectra and 85%
phosphoric acid for the 31P spectra.
Molecular modelling of compound 4 was carried out using a Pentium
200 MHz computer with 32 MB of RAM. The PM3 Hamiltonian from
the MOPAC package was employed and the calculations were done con-
sidering the final value of the energy when the gradient reached a value
1
lower than 0.1 kcal (rad or A)
.
Synthesis of N,N0-bis(diethyl phosphonoacetyl)diamines
General Procedure. The corresponding N,N0-bis(chloroacetyl)dia-
mine and triethyl phosphite in excess were mixed in a 50 mL round
flask fitted with a reflux condenser and the mixture was refluxed at
150 C for 5 h. At the end of this period, a white solid precipitated,
which was collected and dried under vacuum for 4 h.
Synthesis of N,N0-bis(diethyl
phosphonoacetyl)ethylenediamine (1)
3
N,N0-bis(chloroacetyl)ethylenediamine (11) 0.5 g (2.39
10 mol)
3
was mixed with 1.6 mL (1.6 g, 9.34 10 mol) of triethyl phosphite.
The reaction yielded 0.6 g (60%) of (1). White solid, m.p. 105–107 C.
1
IR see Table I. H NMR (CDCl3) see Table II. 13C NMR (CDCl3) see
Table III. 31P NMR-(H3PO4) decoupled see Table III, coupled JP
=
CH2
21.08 Hz, JP
= 6.90 Hz.
OCH2
Synthesis of N,N0-bis(diethyl
phosphonoacetyl)propylenediamine (2)
3
N,N0-bis(chloroacetyl)propylenediamine (12) 0.5 g (2.33 10 mol)
3
and 1.2 mL (1.2 g, 7.0
10 mol) of triethyl phosphite afforded a
viscous brown oil, which was dissolved in dichloromethane and treated
with active charcoal. The filtrate was dried with magnesium sulfate and
the solvent was evaporated under vacuum, affording 0.8 g of product
1
(80%) yellow oil. IR see Table I. H NMR (CDCl3) see Table II. 13C
NMR (CDCl3) see Table III. 31P NMR (H3PO4) decoupled see Table III,
coupled JP
= 21.72 Hz, JP
= 7.96 Hz.
CH2
OCH2

146
J. M. Rodrigues and J. B. N. DaCosta
Synthesis of N,N0-bis(diethyl
phosphonoacetyl)butylenediamine (3)
3
N,N0-bis(chloroacetyl)butylenediamine (13) 0.9 g (3.85
10 mol)
and 3.0 mL (2.9 g, 1.75
10 3) of triethyl phosphite afforded 1.6 g
1
(94%) of product. White solid, m.p. 80–82 C. IR see Table I. H NMR
(DMSO) see Table II. 13C NMR (CDCl3) see Table III. 31P NMR (H3PO4)
decoupled see Table III, coupled JP
= 21.18 Hz, JP
= 7.98 Hz.
CH2
OCH2
Synthesis of N,N0-bis(diethyl phosphonoacetyl)
piperazine (4)
3
N,N0-bis(chloroacetyl)piperazine (14) 0.5 g (2.26
10 mol) and
3
1.5 mL (1.5 g, 8.73
10 mol) of triethyl phosphite reacted for 5 h
at 100 C, affording 0.95 g (95%) of product. White solid, m.p. 49–51 C.
1
IR see Table I H NMR (CDCl3) see Table II. 13C NMR (CDCl3) see
Table III. 31P NMR (H3PO4) decoupled see Table III, coupled JP
=
CH2
22.05 Hz, JP
= 7.25 Hz.
OCH2
Synthesis of Dibutyl Phosphite34
In a two neck 125 mL round flask, equipped with an addition funnel
and a reflux condenser fitted with a device which prevents contact with
humidity, were added 100 mL (81 g, 1.09 mol) of butyl alcohol. Freshly
3
distilled phosphorus trichloride (32 mL, 3.64
10 mol) was added
dropwise with stirring at 0 C. After all the phosphorus trichloride had
been added, the mixture was heated at 50 C for approximately 1 h.
Distillation under reduced pressure (3 mm Hg) afforded 37.0 mL (52%)
of product.
Synthesis of N,N0 -bis(dibutyl
phosphonoacetyl)ethylenediamine (5)
In a three neck 125 mL round flask equipped with a reflux condenser
and a septum, were added 30.0 mL of dry toluene, 0.4 g (1.87 10 3 mol)
3
of metallic sodium and 3.7 mL (3.6 g, 1.87 10 mol) of dibutyl phos-
phite. The mixture was stirred and kept at room temperature until all
the metal had reacted, which took around 3 h.
3
N,N0-bis(chloroacetyl)ethylenediamine (2.0 g, 9.39 10 mol) was
rapidly added followed by reflux at 110 C for 4 h. The reaction mixture
was filtered and the filtrate was evaporated under reduced pressure at
120 C for 4 h affording 1.2 g of a yellowish solid, which was washed
with ethyl ether to give (5) with a 25% yield. White solid, m.p. 63–65 C.
1
IR see Table I H NMR (CDCl3) see Table II. 13C NMR (CDCl3) see

Bisphosphonates
147
Table III. 31P NMR (H3PO4) decoupled see Table III, coupled JP
=
CH2
21.17 Hz, JP
= 7.22 Hz.
OCH2
Synthesis of Triethyl Phosphonoacetate
2
To 4.0 mL (5.0 g, 3.61 10 mol) of ethyl -bromoacetate, in a 50 mL
round flask equipped with a reflux condenser, were added 7.4 mL (7.2 g,
4.32 10 2 mol) of triethyl phosphite. This mixture was stirred at 100 C
for 6 h. The reaction mixture was then submitted to reduced pressure
at 80 C for 5 h. This treatment afforded 7.0 g (87%) of product, which
did not need any further purification. Colorless liquid. IR see Table I
1H NMR (CDCl3) see Table II. 13C NMR (CDCl3) see Table III.
Synthesis of Ethyleneglycol-bis(diethyl
phosphonoacetyl) (6)
3
To 1.0 mL (1.1 g, 4.78
10 mol) of triethyl phosphonoacetate in a
50 mL round flask, connected to a vacuum line, were added 0.1 mL (0.2
g, 2.39 10 3 mol) of ethylene glycol. The reaction mixture was stirred
at 160 C for 7 h under vacuum. This reaction afforded 0.8 g (80%) of
(6). Colorless oil. IR see Table I 1H NMR (CDCl3) see Table II. 13C NMR
(CDCl3) see Table III. 31P NMR (H3PO4) decoupled see Table III coupled
JP
= 21.46 Hz, JP
= 7.98 Hz.
CH2
OCH2
Synthesis of Diethyleneglycol-bis(diethyl
phosphonoacetyl) (7)
3
To 0.9 mL (1.0 g, 4.29
10 mol) of triethyl phosphonoacetate in a
50 mL round flask, connected to a vacuum line, were added 0.2 mL
3
(0.2 g, 2.15 10 mol) of diethyleneglycol. This mixture was heated
at 160 C for 7 h, with stirring under vacuum. In this way, 0.8 g (80%)
of (7) were obtained. Yellowish oil. IR see Table I. 1H NMR (CDCl3) see
Table II. 13C NMR (CDCl3) see Table III. 31P NMR (H3PO4) decoupled
see Table III, coupled JP
= 21.71 Hz, JP
= 8.58 Hz.
CH2
OCH2
CONCLUSION
The methodology employing Michaelis-Arbuzov or Michaelis-Becker re-
actions for the synthesis of bisphosphonates is extremely satisfactory
since these compounds are obtained in good yield and in a simple way.

148
J. M. Rodrigues and J. B. N. DaCosta
ACKNOWLEDGMENTS
We thank the Brazilian agencies CAPES and CNPq for financial support
and Prof. Whei Oh Lin for some of the chemicals employed in this work.
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