Efficient synthesis of isoxazolidine-substituted bisphosphonates by 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1016/j.tet.2011.05.098

Several bisphosphonates bearing a substituted isoxazolidine ring have been synthesized in good yield by direct 1,3-dipolar cyclization reaction, under microwaves catalysis, in the absence of solvent. The method allows the simultaneous incorporation, on the geminal position of the bisphosphonate framework, of a basic nitrogen and of an oxygen atom, as third hook. Hydrophobicity-hydrophilicity of BPs is discussed with the help of distribution coefficients.

Full text of DOI:10.1016/j.tet.2011.05.098

Tetrahedron 67 (2011) 5635e5641
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of isoxazolidine-substituted bisphosphonates by 1,3-dipolar
cycloaddition reactions
,
b
b
b
,
b
b
c
O. Bortolini a , I. Mulani , A. De Nino , L. Maiuolo , M. Nardi , B. Russo , S. Avnet
*
*
a
ꢀ
Dipartimento di Chimica, Universita di Ferrara, Via Borsari 46, 44121 Ferrara, Italy
b
ꢀ
Dipartimento di Chimica, Universita della Calabria, Via Bucci 12 C, 87036 Rende (CS), Italy
c Istituto Ortopedico Rizzoli Laboratorio di Fisiopatologia e Medicina Rigenerativa, Via Barbiano 1/10, 40136 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Several bisphosphonates bearing a substituted isoxazolidine ring have been synthesized in good yield by
direct 1,3-dipolar cyclization reaction, under microwaves catalysis, in the absence of solvent. The method
allows the simultaneous incorporation, on the geminal position of the bisphosphonate framework, of
a basic nitrogen and of an oxygen atom, as third hook. Hydrophobicityehydrophilicity of BPs is discussed
with the help of distribution coefficients.
Received 21 February 2011
Received in revised form 2 May 2011
Accepted 23 May 2011
Available online 30 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazolidine bisphosphonates
1,3-Dipolar cycloadditions
Microwaves catalysis
1. Introduction
The studies on the inhibitory potency of cyclic nitrogen-
containing bisphosphonates indicate that the presence of two
Geminal bisphosphonates (BPs) are structural and stable an-
alogues of naturally occurring pyrophosphates and constitute an
important class of pharmacologically active molecules used in the
treatment of bone diseases as osteoporosis, Paget’s disease, and
tumor bone diseases.1e3 In addition bisphosphonates are com-
monly prescribed for prevention and treatment of several skeletal
problems associated with low bone density and osteogenesis
imperfecta. To date, most of the highly potent third-generation BP
drugs include an additional moiety in the molecule, namely
a nitrogen heterocycle, as in risedronate 1 and zoledronate 2 that
make these cyclic nitrogen-containing derivatives up to 10,000-
fold more active than the first generation bisphosphonates
(Fig. 1).4ꢀ7
geminal phosphonate groups is responsible for interaction with
the molecular target. In addition, a basic nitrogen in the hetero-
cyclic side chain affects potency and its orientation is critical for
effective inhibition. Accordingly, we considered the synthesis of
a new class of bisphosphonates 3 having in gem position an iso-
xazolidine ring, that simultaneously holds the required basic ni-
trogen and an oxygen atom in place of the hydroxy group, acting
as third hook. Some authors have suggested that the absence of
the gem hydroxyl function should increase the oral absorption of
this class of drugs.6,7 In addition, the tuning of the molecular
lipophilicity, an additional parameter affecting absorption and
estimated by measuring the distribution coefficient, is obtained by
the introduction of suitable alkyl and aryl substituents.
O
O
P
O
P
OH
OH
OH
OH
OH
OH
OH
OH
OH
R'
P
OH
N
OH
P
P
P
N
HO
HO
O
N
OH
R
N
1
2
3
O
O
O
Fig. 1. Structure of model bisphosphonates and of our target compounds.
Different synthetic strategies have been proposed to insert
heterocyclic rings directly on the geminal position, including the
reaction of phosphorus electrophiles with enolates,8 the reaction
* Corresponding authors. Tel.: þ39 0532 455171 (O.B.); tel.: þ39 0984 492853
(L.M.); e-mail addresses: olga.bortolini@unife.it (O. Bortolini), maiuolo@unical.it
(L. Maiuolo).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.098

5636
O. Bortolini et al. / Tetrahedron 67 (2011) 5635e5641
with diazo compounds,9 and the condensation of oxaphospholenes
with isocyanates.10 Previously we have developed an efficient
method for the preparation of substituted isoxazolidines using the
classical 1,3-dipolar cycloaddition of an alkene as dipolarophile
with a suitable nitrone, under microwave irradiation, in the
absence of solvent, Scheme 1.11,12 Following this strategy it was
Derivative 7 was obtained from 6 by the reaction with para-
formaldehyde under basic conditions and converted to tetrae-
thylvinylidene-1,1-bisphosphonate 5 by the reaction with para-
toluenesulfonic acid, for a final overall yield, after three steps, of 73%.
With the set of nitrones 4aeh in our hands we initially in-
vestigated the 1,3-dipolar cycloadditions with 5 in conventional
O
NH
O
O
P
OEt
OEt
EtO
EtO
P
5
N
O
R
H
O
O
R
N
path b
path a
N
O
1
2
N
R'
O
P
O
P
O
N
R'
3
R
R'
OEt
OEt
4
EtO
EtO
NH
O
5
Scheme 1. Synthesis of substituted isoxazolidines via 1,3-dipolar cycloaddition of nitrones and substituted alkenes: vinyl nucleobases to N,O-nucleosides, path a, vinyl
bisphosphonates to isoxazolidine bisphosphonates, path b.
possible to prepare several N,O-nucleosides by the reaction of
nitrones with unprotected vinylated nucleobases, as shown in path
a of the Scheme 1. In the present case we have replaced the vinyl
nucleobases with vinyl bisphosphonates for the preparation of
isoxazolidine-substituted bisphosphonates, path b of Scheme 1,
maintaining in the same time the microwaves catalysis in the ab-
sence of solvent successfully tested in previous studies. 1,3-Dipolar
cycloadditions have been used for the preparation of functionalized
bisphosphonates under Cu(I) catalysis (click methodology)5 and for
the synthesis of substituted isoxazolidines using phosphorylated
nitrones.13
In this paper we wish to report a simple route to isoxazolidine-
substituted bisphosphonates, new valuable precursors in the syn-
thesis of biologically active molecules, that allowed the insertion of
different aromatic and heteroaromatic rings bearing suitable
substituents.
conditions, that is, in organic solvents (toluene, dichloromethane),
by heating (from 0 ꢁC up to reflux in toluene) and in the presence of
a Lewis acid (ZnCl2, AlCl3, Er(OTf)3, and Cu(OTf)3) as catalyst, path
b of Scheme 1. In the best cases, a conversion of 65e75% is obtained
in 14 h reaction time, for a 35% of isolated yield. The poor results
prompt us to test different experimental conditions as the use of
microwaves catalysis,17 successfully applied in similar reactions.11,12
Table 1 illustrates the optimization of the reaction parameters using
the N-methyl-C-phenyl nitrone 4a as model compound. A low MW
power and a slight excess of nitrone are required to complete the
cycloaddition with formation of the tetraethyl-2-methyl-3-phenyl-
isoxazolidinyl-5,5-bisphosphonate 3a in 75% isolated yield, entry
6 of Table 1.
These conditions were next applied to the entire collection of
available nitrones and the pertinent results are shown in Table 2.
Short reaction times, max 20 min, were required for a complete
conversion, although in some cases the isolated yield is lowered by
formation of minor amounts of side-products.
2. Results and discussion
The regiochemistry of the reaction followed the usual pattern
with exclusive formation of the 3,5-isomer over the 3,4-derivative.18
Accordingly, the cycloaddition takes place between the nitrone in
the more reactive (Z) configuration and the vinylidene bisphosph-
onate, with attack of the N-oxygen atom on the germinal carbon of
the vinylidene group. The regiochemistry has been further con-
firmed by decoupling 1H NMR experiments using 3g as model
compound. Fig. 2 shows the expansion of the NMR spectrum in the
region 2.5e5.0 ppm where the signals of protons HC4 (2.84 ppm),
Although the synthesis of the different nitrones 4 and tetrae-
thylvinylidene-1,1-bisphosphonate 5 are described in the literature
by several authors,14,15 we have partially modified the procedures
with the result of a substantial increase in the yields of both de-
rivatives. Nitrones 4aeh were obtained in excellent yields and high
purity by condensation of the precursor aldehydes with N-methyl-
or N-benzylhydroxylamine in acetate-buffered16 water/ethanol
solution, Scheme 2.
0
HC4 (3.28 ppm), and HC3 (4.66 ppm) are located. Fig. 2B refers to
R=Me, R’=Ph
4a
4b
4c
4d
4e
4f
R
H
O
absence of irradiation, whereas Fig. 2A and C describe the NMR
spectra upon decoupling at 2.84 and 3.28 ppm, respectively. In the
latter cases the signal of HC3, originally a doublet of doublets, is
modified to a doublet thus confirming the proximity of HC3 to both
HC4 and HC40. On the other hand, the multiplicity of the signals
pertaining to HC4 and HC40, although simplified by this decoupling,
O
N
RNHOH.HCl
CH3COONa
R=Me, R’=o-Cl-C6H4
R=Me, R’=3-pyridyl
R=Me, R’=2-furyl
R=Bn, R’=p-OH-C6H4
R=Bn, R’=Ph
R'
H
R'
4a-h
R=Bn, R’=o-Cl-C6H4
R=Bn, R’=o-F-C6H4
4g
4h
Scheme 2. Synthesis of alkyl, aryl substituted nitrones 4aeh.
necessarily accounts for coupling with phosphorous nuclei and HC3
.
Bisphosphonate esters 3aeh were next hydrolyzed by reaction
with trimethylsilyl bromide in dichloromethane, followed by
treatment with MeOH, according to Scheme 4. As reported in the
Experimental section, the conversion ester to acid is quite efficient,
with formation of 8aeh in yields ranging from 82% up to 92%.
The isoxazolidinyl-substituted bisphosphonic acids may then be
transformed into the corresponding disodium salts by reaction
Furthermore, the vinylidene derivative 5 has been obtained
in three steps, according to the reaction sequence shown in
Scheme 3. The commercially available tetraethyl methylene-1,1-
bisphosphonate 6 was prepared by direct reaction of diethyl phos-
phite in the presence of sodium ethoxide. The long reaction times
(2 months) are balanced by the low cost of the reagents and work-up.

O. Bortolini et al. / Tetrahedron 67 (2011) 5635e5641
5637
O
O
(CH2O)n
Et2NH
O
P
O
P
EtONa / EtOH
CH2Cl2
O
O
O
O
P OH
6
O
O
P
O
P
O
P
TsOH
O
O
O
O
O
O
O
P
O
toluene
OMe
7
5
Scheme 3. Synthetic sequence for the preparation of tetraethylvinylidene-1,1-bisphosphonate 5.
Table 1
3. Conclusions
Optimization of the reaction conditions for the cycloaddition of 5 (1 equiv) with
nitrone 4a
In this paper we have described an efficient and general syn-
thetic approach to bisphosphonates bearing in geminal position
a substituted isoxazolidine ring. The method, based on 1,3-dipolar
cycloadditions, allows the simultaneous incorporation of the re-
quired basic nitrogen and that of an oxygen atom acting, together
with the bisphosphonate groups, as third hook. Studies on the bi-
ological potential of the different salts and comparison with
bisphosphonate salts of well established activity are currently un-
der way.
Entry
Power (W)
Time (min)
4a (equiv)
Conversion (%)
Yield (%)
1
2
3
4
5
6
750
750
600
400
400
200
5
8
10
10
15
10
2
1.6
2
2
1.5
1.2
85
90
84
88
83
99
10
13
24
37
40
75
4. Experimental section
4.1. General
Table 2
1,3-Dipolar cycloadditions of 4aeh with tetraethylvinylidene-1,1-bisphosphonate
5 at 200 W
O
O
P
OEt
OEt
EtO
EtO
Commercial starting materials were used without further pu-
rification. Solvents were distilled prior to use. 1H and 13C NMR
spectra were recorded at 300 and 500 MHz and 75.5 and
125.7 MHz, respectively, in CDCl3, DMSO-d6 or D2O using tetra-
methylsilane (TMS) as internal standard (Bruker ACP 300 MHz and
500 MHz), whereas for 1H-decoupled 31P NMR (202.4 MHz) an
external standard was used. Chemical shifts are given in parts per
million and coupling constants in Hertz. The regiochemistry was
established by decoupling experiments of selected signals. The ESI
mass spectrometric data were acquired on a Finnigan LCQ Deca,
equipped with an electrospray ionization source. Standard experi-
mental conditions are as follows: sample concentration10ꢀ6 M;
P
R
H
O
(EtO)2OP
PO(OEt)2
N
5
MW
O
1
2
+
4
3
N
R'
R
R'
4a-h
3a-h
Entry
R
R0
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Ph
10
12
13
15
14
18
18
20
3a
3b
3c
3d
3e
3f
75
77
73
68
74
83
85
86
o-CleC6H4
3-Pyridyl
2-Furyl
p-OHeC6H4
Ph
o-CleC6H4
o-FeC6H4
elution solvent MeOH; flow rate 8 m
L minꢀ1; nebulizing gas 40 units
3g
3h
flow rate; spray voltage 4 kV; capillary voltage 14 V; capillary
temperature 270 ꢁC. High resolution mass spectra (HRMS) were
acquired on a Q-star pulsar-i (MDS Sciex Applied Biosystems, Tor-
onto, Canada) equipped with an ion-spray source, at 10,000 reso-
lution. Melting points were obtained on a Kofler apparatus. GC/MS
spectra were carried out on a Shimadzu QP 5000. Elemental anal-
yses (C, H, and N) were obtained using a Flash 2000, Thermo Fisher
Scientific elemental analyzer. Infrared spectra were recorded on
a PerkineElmer 2000 FT-IR, using KBr plates or KBr as matrixes.
with 2 equiv of aqueous NaOH. Bisphosphonates are calcium-
regulating agent used in the form of the sodium salt for a number
of reasons that include the specific delivery and absorption of the
drug. At physiological pH, bisphosphonates are expected to be
highly ionized and negatively charged.1 The overall hydrophilicity
of BPs has been shown to influence their bone targeting ability and
this property is usually obtained by measuring or calculating the
distribution coefficient (log D) for octanol/water mixtures.1,19 The
log D values at pH 7.4 for our compounds are: 8a (ꢀ5.20), 8b
(ꢀ4.72), 8c (ꢀ6.51), 8d (ꢀ6.23), 8e (ꢀ3.84), 8f (ꢀ3.55), 8g (ꢀ2.99),
and 8h (ꢀ3.41).20 Taking into account that BPs with small sub-
stituents and high hydrophilic character, i.e., very negative log D,
are the ideal bone-specific carriers, the pyridyl 8c and furyl 8d
derivatives are expected to have the best biological osteotropic
activity.1,21
4.2. General procedure for the synthesis of nitrones 4aeh
Most of the substituted nitrones were synthesized under stir-
ring and in short reaction times,10e15 min, via condensation of the
suitable aldehyde (1 mol) with N-methyl- or N-benzylhydroxyl-
amine hydrochloride (1 mol) in the presence of sodium acetate
(1.2 mol) dissolved in EtOH/H2O 1:1 (10 mL) at room temperature.
The bulk of the solvent was removed under reduced pressure and

5638
O. Bortolini et al. / Tetrahedron 67 (2011) 5635e5641
Fig. 2. Expansion of the 1H NMR spectra of compound 3g in: (B) absence of decoupling, (A) decoupling at 2.84 ppm, and (C) decoupling at 3.28 ppm.
O
P
O
P
O
P
O
P
O
P
O
P
ONa
OH
OEt
OEt
OH
OH
NaO
HO
EtO
EtO
HO
HO
5
5
5
NaOH, 2 eq
O
O
Me3SiBr, CH2Cl2, rt
MeOH
O
1
1
1
4
4
3
4
3
2
2
2
3
N
N
N
R
R
R
R'
R'
R'
3a-h
8a-h
9
Scheme 4. Conversion of bisphosphonate esters 3aeh to free acids 8aeh and related disodium salts 9.
the residue was extracted with dichloromethane (3ꢂ20 mL). The
combined organic layers were dried over anhydrous sodium sulfate
and the solvent was evaporated under reduced pressure.
7.93 (s, 1H, ]CH), 9.30 (m, 1H, Ar); 13C NMR (500 MHz, CDCl3)
71.90, 126.90, 128.09, 128.76, 128.84, 128.91, 129.12, 129.20,
129.77, 130.86, 132.71, 133.23. Anal. Calcd (%) for C14H12ClNO: C,
68.44; H, 4.92; N, 5.70. Found (%) C, 68.33; H, 4.98; N, 5.73.
d
4.2.1. N-Methyl-C-o-chloro phenyl nitrone (4b). White solid; Rf
0.72; yield 96% (1.15 g), mp¼73e74 ꢁC, GC/MS m/z 169; IR (KBr,
cmꢀ1) 1173, 1393, 1421, 1561, 1583, 1651, 3067, 3090; 1H NMR
4.2.4. N-Benzyl-C-o-fluoro phenyl nitrone (4h). White solid; Rf 0.83;
yield 97% (1.79 g), mp¼84e85 ꢁC, GC/MS m/z 229; IR (KBr, cmꢀ1
)
(500 MHz, CDCl3)
d
3.93 (s, 3H, NeCH3) 7.29e7.41 (m, 3H, Ar), 7.86
1153, 1197, 1472, 1561, 1575, 1609, 2955, 3038; 1H NMR (500 MHz,
(s, 1H, ]CH), 9.30 (dd, 1H, J¼2.1, 7.7 Hz, Ar); 13C NMR (500 MHz,
CDCl3) d 5.07 (s, 2H, CH2), 7.02e7.51 (m, 8H, Ar), 7.75 (s, 1H, ]CH),
CDCl3)
d
55.13, 126.92, 128.13, 128.80, 129.28, 130.68, 130.90, 132.5.
9.24 (td, 1H, J¼1.8, 7.8 Hz, Ar); 13C NMR (500 MHz, CDCl3)
d 71.68,
Anal. Calcd (%) for C8H8ClNO: C, 56.65; H, 4.75; N, 8.26. Found (%) C,
56.72; H, 4.78; N, 8.21.
114.47 (d, J¼21.3 Hz), 119.00 (d, J¼8.5 Hz), 124.31 (d, J¼3.2 Hz),
126.37 (d, J¼9.6 Hz), 128.63, 128.84, 128.90, 129.11, 131.64 (d,
J¼8.5 Hz), 133.26, 159.01 (d, J¼252.9 Hz). Anal. Calcd (%) for
C14H12FNO: C, 73.35; H, 5.28; N, 6.11. Found (%) C, 73.43; H, 5.32; N,
6.07.
4.2.2. N-Benzyl-C-p-hydroxy phenyl nitrone (4e). White solid; Rf
0.37; yield 93% (1.73 g), mp¼206e207 ꢁC, GC/MS m/z 227; IR (KBr,
cmꢀ1) 1125, 1316, 1415, 1513, 1599, 1670, 2942, 3066; 1H NMR
The full characterization of nitrones 4a,22 4c,23 4d,22,23 and 4f24
may be found in literature reports.
(500 MHz, DMSO-d6)
7.34e7.49 (m, 5H, Ar), 7.91 (s,1H, ]CH), 8.10e8.15 (m, 2H, Ar),10.04
(br s,1H, OH); 13C NMR (500 MHz, DMSO-d6)
69.33, 115.06,122.37,
d 4.99 (s, 2H, NeCH2) 6.79e6.83 (m, 2H, Ar),
d
4.3. Synthesis of bisphosphonate precursors
128.05, 128.24,128.76, 130.03, 133.05, 134.98, 158.87. Anal. Calcd (%)
for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found (%) C, 74.05; H, 5.74;
N, 6.11.
4.3.1. Tetraethyl methylene-1,1-bisphosphonate (6)15. A solution of
sodium ethoxide was prepared by adding sodium (10.01 g,
770 mmol) in portions to absolute ethanol (250 mL). Then diethyl
phosphite (100 mL, 770 mmol) was added and the mixture was
stirred for 1 h at room temperature. The excess of alcohol was
4.2.3. N-Benzyl-C-o-chloro phenyl nitrone (4g). White solid; Rf 0.81;
yield 96% (1.67 g), mp¼86e87 ꢁC, GC/MS m/z 245; IR (KBr, cmꢀ1
)
1150, 1437, 1467, 1556, 1573, 1699, 3032,3079; 1H NMR
evaporated using
a rotary evaporator. Dry dichloromethane
(500 MHz, CDCl3)
d 5.09 (s, 2H, NeCH2) 7.28e7.52 (m, 8H, Ar),
(300 mL) was added and the mixture was stirred for 2 months in

O. Bortolini et al. / Tetrahedron 67 (2011) 5635e5641
5639
a round bottom flask. The reaction mixture was washed with water
(2ꢂ500 mL) and the organic phase was dried over anhydrous so-
dium sulfate. The solvent was evaporated and the product was
purified by distillation. Colorless liquid (114.7 g, yield 55%),
bp¼138 ꢁC (0.03 mm/Hg). IR (film, cmꢀ1) 977, 1025, 1251, 1444,
63.80, 72.77, 128.01, 128.32, 128.74, 136.91; 31P NMR (500 MHz,
CDC13) 20.43. Anal. Calcd (%) for C18H31NO7P2: C, 49.66; H, 7.18; N,
3.22. Found (%) C, 49.75; H, 7.21; N, 3.18.
d
4.4.2. Tetraethyl-2-methyl-3-o-Cl-phenyl-isoxazolidinyl-5,5-
bisphosphonate (3b). Flash chromatography eluent chloroform/ac-
etone (93:7 v/v) Rf 0.55, yield 77% (0.361 g). IR (film, cmꢀ1) 975,
1042,1255,1441,1454, 2930, 2983, 3468; ESI-MS positive ion-mode
1647, 2907, 2984, 3467; 1H NMR (300 MHz, CDCl3)
d 1.35 (t, 12H,
J¼7 Hz, CH3) 2.52 (t, 2H, J¼21.0 Hz, PCH2P), 4.15 (m, 8H, CH2); 13C
NMR (300 MHz, CDCl3)
NMR (500 MHz, CDC13)
d
16.30, 25.44 (t, JPCP¼136.21 Hz), 62.63; 31
P
d
19.10. Anal. Calcd (%) for C9H22O6P2: C,
[MþNa]þ m/z 492; 1H NMR (500 MHz, CDCl3)
d 1.35e1.43 (m, 12H,
37.51; H, 7.69. Found (%) C, 37.44; H, 7.73.
CH3), 2.68 (s, 3H, NeCH3), 2.72e2.86 (m, 1H, HC4), 3.19e3.27 (m, 1H,
H’C4), 4.28e4.40 (m, 9H, OCH2, HC3), 7.20 (td, 1H, J¼1.4, 7.7 Hz,
AreH5), 7.28 (t, 1H, J¼7.8 Hz, AreH4), 7.36 (dd, 1H, J¼0.7, 7.8 Hz,
AreH6), 7.61 (dd, 1H, J¼1.4, 7.7 Hz, AreH3); 13C NMR (300 MHz,
4.3.2. Tetraethyl 2-methoxyethylene-1,1-bisphosphonate
(7)14,15. Paraformaldehyde (2.6 g, 86.7 mmol) and diethylamine
(1.26 g, 17.3 mmol) were combined in methanol (50 mL). The
mixture was warmed until dissolution, cooled to room temperature
and added of 6 (5.0 g, 17.3 mmol). The resulting mixture was
refluxed for 24 h, additional methanol was added (50 mL) and the
solution was concentrated under vacuum. A portion of toluene was
added (25 mL) and the solution was concentrated. This last step was
repeated for two times to ensure the complete removal of metha-
nol. Compound 7 (4.90 g) was obtained in 85% yield. Colorless
liquid, GC/MS m/z 332; IR (film, cmꢀ1) 973, 1026, 1249, 1445, 1646,
CDCl3)
d 16.57, 43.39, 43.80, 63.85, 67.98, 127.47, 128.26, 128.92,
129.54,133.96, 135.00; 31P NMR (500 MHz, CDC13)
d 19.26 (d,
J¼55.8 Hz), 19.35 (d, J¼55.8 Hz). Anal. Calcd (%) for C18H30ClNO7P2:
C, 46.01; H, 6.44; N, 2.98. Found (%) C, 45.96; H, 6.40; N, 3.04.
4.4.3. Tetraethyl-2-methyl-3-(30-pyridyl)-isoxazolidinyl-5,5-
bisphosphonate (3c). Flash chromatography eluent chloroform/ac-
etone (93:7 v/v) Rf 0.49, yield 73% (0.318 g). IR (film, cmꢀ1) 970,
1024, 1251, 1443, 1476, 2927, 2983, 3449; ESI-MS positive ion-mode
2933, 2984, 3480; 1H NMR (300 MHz, CDCl3)
d
1.34 (t, 12H,
[MþNa]þ m/z 459; 1H NMR (300 MHz, CDCl3)
d 1.33e141 (m, 12H,
J¼7.02 Hz, CH3), 2.70 (tt, 1H, J¼5.5, JHP¼23.8 Hz, PCHP), 3.37 (s, 3H,
CH3), 2.64 (s, 3H, NeCH3), 2.89e3.17 (m, 2H, HC4, HC40), 3.84e3.91
CH3O), 3.63 (td, 2H, J¼5.5, JHP¼16.1 Hz, CH2O), 4.04e4.27 (m, 8H,
(m, 1H, HC3), 4.14e4.32 (m, 8H, OCH2), 7.29e8.59 (m, 4H, Ar); 13C
OCH2CH3); 13C NMR (300 MHz, CDC13)
d
16.38 (d, J¼6.6 Hz), 38.83
NMR (300 MHz, CDCl3)
123.84, 132.90, 135.55, 149.73,149.94; 31P NMR (500 MHz, CDC13)
d 18.77. Anal. Calcd (%) for C17H30N2O7P2: C, 46.79; H, 6.93; N, 6.42.
d 16.55, 43.21, 45.53, 62.68, 63.88, 70.26,
(t, JPCP¼132.6 Hz), 58.74, 62.65 (d, J¼6.6 Hz), 68.10; 31P NMR
(500 MHz, CDC13,)
d
21.05. Anal. Calcd (%) for C11H26O7P2: C, 39.76;
H, 7.89. Found (%) C, 39.88; H, 7.82.
Found (%) C, 46.85; H, 6.97; N, 6.38.
4.3.3. Tetraethylvinylidene-1,1-bisphosponate (5)14. A solution of 7
(5.04 g, 15.1 mmol) in 50 mL of toluene was added to p-toluene-
sulfonic acid monohydrate (0.006 g, 0.03 mmol) under stirring. The
reaction mixture was heated to reflux for 24 h and methanol was
removed by collection in a DeaneStark trap. The solution was con-
centrated to dryness. The crude product was diluted with 50 mL of
chloroform and washed with water (2ꢂ100 mL). Combined organic
layers were dried over anhydrous sodium sulfate, concentrated and
the product was purified by distillation. Clear liquid (3.59 g, yield
4.4.4. Tetraethyl-2-methyl-3-(20-furyl)-isoxazolidinyl-5,5-
bisphosphonate (3d). Flash chromatography eluent chloroform/ac-
etone (93:7 v/v) Rf 0.62, yield 68% (0.289 g). IR (film, cmꢀ1) 975,
1035,1253,1444,1479, 2910, 2984, 3486; ESI-MS positive ion-mode
[MþNa]þ m/z 448; 1H NMR (300 MHz, CDCl3)
d 1.29e1.34 (m, 12H,
CH3), 2.68 (s, 3H, NeCH3), 2.90e3.03 (m, 1H, HC4), 3.18e3.26 (m, 1H,
H’C4), 3.88e3.96 (m, 1H, HC3), 4.22e4.27 (m, 8H, OCH2), 6.33e7.40
(m, 3H, Ar); 13C NMR (300 MHz, CDCl3)
d
16.53, 40.92, 43.72, 62.68,
64.01, 65.74, 108.85, 110.44, 142.92, 149.10; 31P NMR (500 MHz,
CDC13)
79%), bp¼125e126 ꢁC (0.03 mm/Hg), GC/MS m/z 300; IR (film, cmꢀ1
)
d
21.87 (d, J¼52.4 Hz), 22.35 (d, J¼52.4 Hz). Anal. Calcd (%)
978, 1027, 1241, 1444, 1647, 2911, 2984, 3436; 1H NMR (300 MHz,
for C16H29NO8P2: C, 45.18; H, 6.87; N, 3.29. Found (%) C, 45.10; H,
6.91; N, 3.32.
CDCl3)
d
1.35 (t, 12H, J¼7.1 Hz, CH3), 4.11e4.19 (m, 8H, CH2), 6.99
(distorted dd, 2H, J¼33.75, 37.8 Hz, ]CH2); 13C NMR (300 MHz,
CDCl3)
d
16.30 (t, J¼2.67 Hz), 62.66 (d, J¼2.68 Hz), 132.80 (t,
4.4.5. Tetraethyl-2-benzyl-3-p-hydroxyphenyl-isoxazolidinyl-5,5-
bisphosphonate (3e). Flash chromatography eluent chloroform/
acetonitrile (98:2 v/v) Rf 0.51, yield 74% (0.390 g). IR (film, cmꢀ1) 974,
1026,1252,1444,1478, 2909, 2984, 3480; ESI-MS positive ion-mode
JPCP¼166.78 Hz), 149.21; 31P NMR (500 MHz, CDC13)
d 18.29. Anal.
Calcd (%) for C10H22O6P2: C, 40.01; H, 7.39. Found (%) C, 39.95; H, 7.44.
4.4. Typical experimental procedure for 1,3-cycloaddition
[MþNa]þ m/z 550; 1H NMR (300 MHz, CDCl3)
d 1.30e1.38 (m, 12H,
CH3), 2.71e2.91 (m,1H, H4C), 3.16e3.28 (m, 2H, H4C0, OH) 3.84 (s, 2H,
A mixture of 5 (0.1 mmol) and the selected nitrone 4aeh
(0.12 mmol) was placed in a 10 mL Pyrex container and irradiated at
200 W power using an unmodified household microwave oven.
After the appropriate time the reaction mixture is submitted to
flash chromatography, using variable mixtures of chloroform and
acetone or acetonitrile. Pure compounds 3aeh were collected as
colorless thick mass. The nitrone in excess is recovered and may be
re-used.
HBn), 4.11e4.19 (m, 9H, OCH2, HC3), 7.26e7.38 (m, 9H, Ar); 13C NMR
(300 MHz, CDCl3)
127.37, 127.90, 128.06, 128.39, 128.71, 128.83, 129.73, 133.12, 136.94;
31P NMR (500 MHz, CDC13)
19.48. Anal. Calcd (%) for C24H35NO8P2:
d
16.29 (d, J¼3.4 Hz), 43.95, 54.58, 63.75, 68.47,
d
C, 54.65; H, 6.69; N, 2.66. Found (%) C, 54.75; H, 6.64; N, 2.63.
4.4.6. Tetraethyl-2-benzyl-3-phenyl-isoxazolidinyl-5,5-
bisphosphonate (3f). Flash chromatography eluent chloroform/
acetonitrile (98:2 v/v) Rf 0.53, yield 83% (0.424 g). IR (film, cmꢀ1
)
4.4.1. Tetraethyl-2-methyl-3-phenyl-isoxazolidinyl-5,5-
bisphosphonate (3a). Flash chromatography eluent chloroform/ac-
etone (93:7 v/v) Rf 0.48, yield 75% (0.326 g). IR (film, cmꢀ1) 974,
1021, 1254, 1444, 1456, 2931, 2985, 3479; ESI-MS positive ion-mode
977, 1022, 1252, 1440, 1476, 2920, 2973, 3475; ESI-MS positive ion-
mode [MþNa]þ m/z 534; 1H NMR (300 MHz, CDCl3)
d 1.21e1.28 (m,
6H, CH3), 1.33e1.38 (m, 6H, CH3) 2.85e3.18 (m, 2H, HC4, HC40), 3.75
(d, 1H, J¼14.2 Hz, HBn), 3.97 (d, 1H, J¼14.2 Hz, HBn), 4.01e4.16 (m,
[MþNa]þ m/z 458; 1H NMR (500 MHz, CDCl3)
d
1.30e1.48 (m, 12H,
5H, OCH2, HC3), 4.21e4.33 (m, 4H, OCH2), 7.19e7.50 (m,10H, Ar); 13
C
CH3), 2.63 (s, 3H, NeCH3), 2.88e3.14 (m, 2H, HC4, HC40), 3.81 (dd,1H,
J¼6.5, 9.8 Hz, HC3), 4.29e4.42 (m, 8H, OCH2), 7.30e7.49 (m, 5H, Ar);
NMR (300 MHz, CDCl3)
70.32, 127.11, 127.87, 128.09, 128.31, 128.82, 129.12, 137.19, 137.42;
31P NMR (500 MHz, CDC13)
18.74 (d, J¼52.1 Hz), 18.79 (d,
d
16.49 (d, J¼3.9 Hz), 45.27, 60.08, 64.05,
13C NMR (500 MHz, CDCl3)
d
16.54 (d, J¼3.46 Hz), 43.20, 45.57,
d

5640
O. Bortolini et al. / Tetrahedron 67 (2011) 5635e5641
J¼52.1 Hz). Anal. Calcd (%) for C24H35NO7P2: C, 56.36; H, 6.90; N,
(500 MHz, DMSO-d6)
Anal. Calcd (%) for C10H14ClNO7P2: C, 33.58; H, 3.95; N, 3.92. Found
(%) C, 33.52; H, 3.99; N, 3.86.
d
19.04 (d, J¼50.2 Hz), 19.14 (d, J¼50.2 Hz).
2.74. Found (%) C, 56.43; H, 6.87; N, 2.78.
4.4.7. Tetraethyl-2-benzyl-3-o-Cl-phenyl-isoxazolidinyl-5,5-
bisphosphonate (3g). Flash chromatography eluent chloroform/
4.5.3. 2-Methyl-3-(30-pyridyl)-isoxazolidinyl-5,5-bisphosphonic acid
(8c). Colorless oil, yield 82% (0.121 g). IR (film, cmꢀ1) 938,1011,1220,
1467, 1491, 2878; ESI-MS negative ion-mode [MꢀH]ꢀ m/z 323; 1H
acetonitrile (98:2 v/v) Rf 0.58, yield 85% (0.463 g). IR (film, cmꢀ1
)
974, 1022, 1255, 1441, 1475, 2929, 2981, 3468; ESI-MS positive ion-
mode [MþNa]þ m/z 568; 1H NMR (300 MHz, CDCl3)
d
1.20e1.29 (m,
NMR (300 MHz, D2O) d 2.88 (s, 3H, NeCH3), 3.02e3.07 (m, 1H, HC4),
6H, CH3), 1.34e1.40 (m, 6H, CH3), 2.67e2.90 (m, 1H, HC4), 3.15e3.31
(m, 1H, HC40), 3.84 (d, 1H, J¼14.2 Hz, HBn), 3.99 (d, 1H, J¼14.2 Hz,
HBn), 4.06e4.17 (m, 4H, OCH2), 4.22e4.34 (m, 4H, OCH2), 4.66 (dd,
1H, J¼6.6, 10.4 Hz, HC3), 7.19e7.76 (m, 9H, Ar); 13C NMR (300 MHz,
3.78e3.91 (m, 1H, HC40), 4.55e4.65 (m, 1H, HC3), 8.20e9.03 (m, 4H,
Ar); 13C NMR (300 MHz, D2O)
43.20, 49.65, 59.09, 70.14, 128.71,
142.24, 142.71, 147.06, 147.83; 31P NMR (500 MHz, D2O)
18.52 (d,
d
d
J¼50.5 Hz), 18.69 (d, J¼50.5 Hz). Anal. Calcd (%) for C9H14N2O7P2: C,
CDCl3)
d
16.44 (d, J¼2.7 Hz), 16.53 (d, J¼2.7 Hz), 43.45, 60.22, 63.57,
33.35; H, 4.35; N, 8.64. Found (%) C, 33.28; H, 4.38; N, 8.59.
63.88, 65.59, 127.20, 127.53, 127.94, 128.44, 128.99, 129.16, 129.55,
133.92, 135.23, 137.03; 31P NMR (500 MHz, CDC13)
d
18.73 (d,
4.5.4. 2-Methyl-3-(20-furyl)-isoxazolidinyl-5,5-bisphosphonic
acid
J¼54.1 Hz), 18.77 (d, J¼54.1 Hz). Anal. Calcd (%) for C24H34ClNO7P2:
(8d). Colorless oil, yield 85% (0.147 g). IR (film, cmꢀ1) 929,1021,1223,
1465, 1493, 2886; ESI-MS negative ion-mode [MꢀH]ꢀ m/z 312; 1H
C, 52.80; H, 6.28; N, 2.57. Found (%) C, 52.88; H, 6.24; N, 2.53.
NMR (300 MHz, D2O) d 2.90 (s, 3H, NeCH3), 3.76e3.89 (m, 1H, HC4),
4.4.8. Tetraethyl-2-benzyl-3-o-fluoro-phenyl-isoxazolidinyl-5,5-
bisphosphonate (3h). Flash chromatography eluent chloroform/
4.10e4.22 (m,1H, HC40), 4.31e4.43 (m,1H, HC3), 6.57.6.62 (m,1H, Ar),
6.90.6.98 (m,1H, Ar), 7.51e7.78 (m,1H, Ar),13C NMR (300 MHz, D2O)
acetonitrile (98:2 v/v) Rf 0.56, yield 86% (0.455 g). IR (film, cmꢀ1
)
d
44.51, 48.75, 60.15, 71.24, 140.33, 143.81, 148.13, 148.72; 31P NMR
975, 1024, 1254, 1455, 1493, 2910, 2983, 3468; ESI-MS positive ion-
(500 MHz, D2O) d 18.90. Anal. Calcd (%) for C8H13NO8P2: C, 30.68; H,
4.18; N, 4.47. Found (%) C, 30.62; H, 4.22; N, 4.52.
mode [MþNa]þ m/z 552; 1H NMR (500 MHz, CDCl3)
d
1.24e1.28 (m,
6H, CH3), 1.34e1.38 (m, 6H, CH3), 2.86e3.00 (m, 1H, HC4), 3.09e3.18
(m, 1H, HC40), 3.83 (d, 1H, J¼14.3 Hz, HBn), 3.98 (d, 1H, J¼14.3 Hz,
HBn), 4.06e4.16 (m, 4H, OCH2), 4.25e4.29 (m, 4H, OCH2), 4.52 (dd,
1H, J¼6.4, 10.6 Hz, HC3), 7.02e7.69 (m, 9H, Ar); 13C NMR (500 MHz,
4.5.5. 2-Benzyl-3-p-hydroxy-phenyl-isoxazolidinyl-5,5-
bisphosphonic acid (8e). Colorless oil, yield 83% (0.182 g). IR (film,
cmꢀ1) 936, 1015,1232, 1448,1496, 2888; ESI-MS negative ion-mode
CDCl3)
d
14.98e17.04 (m), 42.80e45.13 (m), 59.44e65.04 (m),
[MꢀH]ꢀ m/z 414; 1H NMR (300 MHz, DMSO-d6)
d 2.63e2.75 (m, 1H,
114.88e116.22 (m), 124.17e137.12 (m), 137.16, 161.10 (d,
HC4), 3.25e3.33 (m, 1H, HC40) 3.82e3.89 (m, 2H, HBn), 4.40e4.51 (m,
JCF¼258.26 Hz); 31P NMR (500 MHz, CDC13)
d 18.75. Anal. Calcd (%)
for C24H34FNO7P2: C, 54.44; H, 6.47; N, 2.65. Found (%) C, 54.50; H,
6.51; N, 2.59.
1H, HC3), 7.25e7.90 (m, 14H, Ar, OH); 13C NMR (300 MHz, DMSO-d6)
d
45.86, 49.23, 59.23, 71.61, 126.12, 126.80, 127.72, 127.93, 128.33,
128.59, 129.00, 135.16; 31P NMR (500 MHz, DMSO-d6)
d
18.66. Anal.
Calcd (%) for C16H19NO8P2: C, 46.28; H, 4.61; N, 3.37. Found (%) C,
46.32; H, 4.56; N, 3.41.
4.5. General procedure for hydrolysis of tetraethyl
isoxazolidinyl bisphosphonate
4.5.6. 2-Benzyl-3-phenyl-isoxazolidinyl-5,5-bisphosphonic acid (8f).
Yield 90% (0.224 g), mp¼143e144 ꢁC. IR (KBr, cmꢀ1) 919,1003,1230,
1457, 1498, 2885; ESI-MS negative ion-mode [MꢀH]ꢀ m/z 398; 1H
A solution of trimethylsilyl bromide (3.7 mmol) dissolved in
dichloromethane (1 mL) was added drop wise to a solution of 3
(0.230 g, 0.52 mmol) in dichloromethane (2 mL). The reaction
mixture was stirred at room temperature for 3 days, monitoring the
reaction with 1H NMR. The solvent was removed under reduced
pressure and the residue dissolved in methanol (2 mL). After stir-
ring for 1 h, the methanol was evaporated in vacuo. The crude was
precipitated in methanol/diethyl ether mixture (2:8), filtered and
the residue was dried under vacuum to give a white solid.
NMR (500 MHz, DMSO-d6)
d
2.68e2.95 (m, 2H, HC4, HC40), 3.82 (d,
1H, J¼15.7 Hz, HBn), 3.90 (d, 1H, J¼15.7 Hz, HBn), 3.96e4.21(m, 1H,
HC3), 6.37 (br s, 4H, OH), 7.18e7.64 (m, 10H, Ar); 13C NMR (300 MHz,
DMSO-d6)
d 43.51, 59.34, 65.35, 79.69, 128.28, 129.11, 129.41, 129.62,
129.92, 131.20, 135.02, 138.52; 31P NMR (500 MHz, DMSO-d6)
d
18.54 (d, J¼52.3 Hz), 18.72 (d, J¼52.3 Hz). Anal. Calcd (%) for
C16H19NO7P2: C, 48.13; H, 4.80; N, 3.51. Found (%) C, 48.20; H, 4.74;
N, 3.48.
4.5.1. 2-Methyl-3-phenyl-isoxazolidinyl-5,5-bisphosphonic
acid
(8a). Yield 89% (0.151 g), mp¼165e166 ꢁC. IR (KBr, cmꢀ1) 939, 1011,
4.5.7. 2-Benzyl-3-o-chloro-phenyl-isoxazolidinyl-5,5-bisphosphonic
acid (8g). Yield 92% (0.255 g), mp¼152e153 ꢁC. IR (KBr, cmꢀ1) 938,
1087, 1227, 1443, 1486, 2889; ESI-MS negative ion-mode [MꢀH]ꢀ
1224, 1463, 1497, 2654; ESI-MS negative ion-mode [MꢀH]ꢀ m/z
322; 1H NMR (500 MHz, DMSO-d6)
d 2.51 (s, 3H, NeCH3), 2.72e2.85
(m, 1H, HC4), 2.89e2.98 (m, 1H, HC40), 3.76e3.84(m, 1H, HC3), 7.30
m/z 432; 1H NMR (300 MHz, DMSO-d6)
d: 2.61e2.72 (m, 1H, HC4),
(br s, 4H, OH), 7.33e7.41 (m, 5H, Ar); 13C NMR (500 MHz, DMSO-d6)
3.04e3.11 (m, 1H, HC40), 3.82 (d, 1H, J¼15.5 Hz, HBn), 3.95 (d, 1H,
J¼15.5 Hz, HBn), 4.56 (dd, 1H, J¼6.3, 9.6 Hz, HC3), 7.16e7.85 (m, 13H,
d
43.38, 44.76, 72.70, 79.18 (t, JPCP¼152.0 Hz), 128.49, 128.90, 129.19,
137.5; 31P NMR (500 MHz, DMSO-d6)
d
18.50 (d, J¼53.2 Hz), 18.67
OH, Ar); 13C NMR (300 MHz, DMSO-d6)
d
43.15 (d, J¼38.7 Hz), 59.85
(d, J¼53.2 Hz). Anal. Calcd (%) for C10H15NO7P2: C, 37.16; H, 4.68; N,
(t, J¼101.7 Hz), 66.10 (d, J¼145.5 Hz), 79.16 (t, JPCP¼151.7 Hz),
4.33. Found (%) C, 37.25; H, 4.64; N, 4.29.
125.90, 127.07, 127.18, 127.36, 128.28, 128.77, 129.72, 132.73, 135.90,
137.95; 31P NMR (500 MHz, DMSO-d6)
(d, J¼54.8 Hz). Anal. Calcd (%) for C16H18ClNO7P2: C, 44.31; H, 4.18;
N, 3.23. Found (%) C, 44.37; H, 4.21; N, 3.17. HRMS: calculated for
C16H17NO7P2Cl 432.0168 and found 432.0163.
d
18.53 (d, J¼54.8 Hz), 18.70
4.5.2. 2-Methyl-3-o-Cl-phenyl-isoxazolidinyl-5,5-bisphosphonic acid
(8b). Yield 90% (0.191 g), mp¼160e161 ꢁC. IR (KBr, cmꢀ1) 936,1009,
1223, 1465, 1496, 2663; ESI-MS negative ion-mode [MꢀH]ꢀ m/z
356; 1H NMR (500 MHz, DMSO-d6)
d 2.58 (s, 3H, NeCH3), 2.60e2.64
(m,1H, HC4), 2.99e3.02 (m, 1H, HC40), 4.19e4.29 (m,1H, HC3), 7.34 (t,
1H, J¼7.5 Hz, AreH5), 7.40 (t, 1H, J¼7.5 Hz, AreH4), 7.47 (d, 1H,
J¼7.5 Hz, AreH6), 7.61 (d, 1H, J¼7.5 Hz, AreH3), 8.36 (br s, 4H, OH);
4.5.8. 2-Benzyl-3-o-fluoro-phenyl-isoxazolidinyl-5,5-bisphosphoꢀn1ic
acid (8h). Yield 91% (0.272 g), mp¼155e156 ꢁC. IR (KBr, cm
)
948, 1008, 1234, 1458, 1498, 2881; ESI-MS negative ion-mode
13C NMR (500 MHz, DMSO-d6)
d
42.89, 42.98, 67.35, 78.41 (t,
[MꢀH]ꢀ m/z 416; 1H NMR (500 MHz, DMSO-d6)
d 2.07e2.89 (m,
JPCP¼151.0 Hz), 127.62, 128.47, 129.26, 132.79, 135.25; 31P NMR
1H, H4C), 2.96e3.07 (m, 1H, H4C0), 3.84e3.98 (m, 2H, HBn),

O. Bortolini et al. / Tetrahedron 67 (2011) 5635e5641
5641
€
5. Skarpos, H.; Osipov, S. N.; Vorob’eva, D.; Odinets, I. L.; Lork, E.; Roschenthaler,
G.-V. Org. Biomol. Chem. 2007, 5, 2361e2367.
4.42e4.53 (m, 1H, H3C), 7.14e7.68 (m, 9H, Ar), 8.43 (br s, 4H, OH);
13C NMR (500 MHz, DMSO-d6)
42.10e43.20 (m), 58.70e59.49
d
6. Drake, M. T.; Clarke, B. L.; Khosla, S. Mayo Clin. Proc. 2008, 83, 1032e1045.
7. Cohen, H.; Alferiev, I. S.; Monkkonen, J.; Seibel, M. J.; Pinto, T.; Ezra, A.; Solomon,
V.; Stepensky, D.; Sagi, H.; Ornoy, A.; Patlas, N.; Hagele, G.; Hoffman, A.; Breuer,
(m), 62.11e63.01 (m), 77.40e80.41 (m), 124.51e124.96 (m),
126.39e126.76 (m), 127.23e127.31(m), 127.70e128.55 (m),
129.44e129.69 (m), 137.53e137.75 (m), 160.36 (d, J¼245.3 Hz);
€
€
€
E.; Golomb, G. Pharm. Res. 1999, 16, 1399e1406.
8. Du, Y.; Junga, K.-Y.; Wiemera, D. F. Tetrahedron Lett. 2002, 43, 8665e8668.
9. Nugent, R. A.; Murphy, M.; Schlachter, S. T.; Dunn, C. J.; Smith, R. J.; Staite, N. D.;
Galinet, L. A.; Shields, S. K.; Aspar, D. G.; Richard, K. A.; Rohlofft, N. A. J. Med.
Chem. 1993, 36, 134e139.
10. McClure, C. K.; Hausel, R. C.; Hansen, K. B.; Grote, C. W.; Jung, K. Y. Phosphorus,
Sulfur Silicon Relat. Elem. 1996, 111, 695e699.
31P NMR (500 MHz, DMSO-d6)
J¼54.3 Hz). Anal. Calcd (%) for C16H18FNO7P2: C, 46.06; H, 4.35; N,
3.36. Found (%) C, 46.16; H, 4.31; N, 3.40. HRMS: calculated for
C16H17NO7P2F 416.0464 and found 416.0471.
d
18.52 (d, J¼54.3 Hz), 18.68 (d,
11. Bortolini, O.; De Nino, A.; Eliseo, T.; Gavioli, R.; Maiuolo, L.; Russo, B.; Sforza, F.
Bioorg. Med. Chem. 2010, 18, 6970e6976.
12. Bortolini, O.; D’Agostino, M.; De Nino, A.; Maiuolo, L.; Nardi, M.; Sindona, G.
Tetrahedron 2008, 64, 8078e8081.
Acknowledgements
13. Piotrowska, D. G. Tetrahedron 2006, 62, 12306e12317.
14. Degenhardt, C. R.; Burdsall, D. C. J. Org. Chem. 1986, 51, 3488e3490.
15. Villemin, D.; Thibault, F. Molecules 2000, 5, M131eM132.
16. Nguyen, T. B.; Beauseigneur, A.; Martel, A.; Dhal, R.; Laurent, M.; Dujardin, G. J.
Org. Chem. 2010, 75, 611e620.
This project was supported by Italian Ministry of Research and
University (MIUR), PRIN 2008 ‘New catalytic strategies for the
synthesis of bisphosphonate based bioactive molecules for the
therapy and diagnosis of osteolytic diseases’.
17. Microwave methods in organic synthesis In Top. Curr. Chem.; Larhed, M.,
Olofsson, K., Eds.; Springer: Berlin, 2006.
Supplementary data
18. The Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; Wiley: Newyork, NY, 2002; Vol. 59.
19. Csizmadia, F.; Tsantili-Kakoulidu, A.; Panderi, I.; Darvas, F. J. Pharm. Sci. 1997, 86,
865e871.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.098.
20. Octanol/water distribution coefficient (log D) of bisphosphonates as a function
of pH were calculated using MarvinSketch software ver. 5.4.1.1 (http://www.
chemaxon.com).
References and notes
21. Hirabayashi, H.; Sawamoto, T.; Fujisaki, J.; Tokunaga, Y.; Kimura, S.; Hata, T.
Pharm. Res. 2001, 18, 646e651.
1. Zhang, S.; Gangal, G.; Uludag, H. Chem. Soc. Rev. 2007, 36, 507e531.
2. Rodan, G. A. Annu. Rev. Pharmacol. Toxicol. 1998, 38, 375e388.
3. Rodan, G. A.; Martin, T. J. Science 2000, 289, 1508e1514.
4. Fleisch, H. Breast Cancer Res. 2002, 4, 30e34.
22. Shimizu, T.; Ishizaki, M.; Nitada, N. Chem. Pharm. Bull. 2002, 50, 908e921.
23. Andrade, M. M.; Barros, M. T.; Pinto, R. C. Tetrahedron 2008, 64, 10521e10530.
24. Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473e476.