Simple, efficient one-pot method for synthesis of novel N-attached 1,2,3-triazole containing bisphosphonates

Article abstract of DOI:10.1016/j.tet.2013.03.078

A practical and efficient one-pot method for synthesis of a novel kind of N-attached 1,2,3-triazole-containing bisphosphonates was developed. Michael addition reaction of sodium azide with ethylidene bisphosphonates and 1,3-dipolar click cycloaddition were reasonably integrated into one-pot reaction in the presence of sonication. Vinylidene bisphosphonate, NaN₃, and terminal alkyne were employed as the reactants, CuSO₄·5H ₂O sodium ascorbate was employed as the catalyst system, and AcOH/H₂O (1:1 v/v) were employed as the solvent system to create an acidic environment to achieve optimal efficiency.

Full text of DOI:10.1016/j.tet.2013.03.078

Tetrahedron 69 (2013) 4047e4052
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Simple, efficient one-pot method for synthesis of novel N-attached
1,2,3-triazole containing bisphosphonates
,
a
b
a,
b,
a
a
Xiaolan Chen a , Xu Li , Jinwei Yuan , Lingbo Qu
, Shaohui Wang , Hanyu Shi ,
*
*
Yuchun Tang a, Likun Duan a
a College of Chemistry and Molecular Engineering, Zhengzhou University, Key Laboratory of Organic Chemistry and Chemical Biology, Henan Province,
Zhengzhou, 450052, PR China
b Chemistry and Chemical Engineering School, Henan University of Technology, Henan Province, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient one-pot method for synthesis of a novel kind of N-attached 1,2,3-triazole-
containing bisphosphonates was developed. Michael addition reaction of sodium azide with ethylidene
bisphosphonates and 1,3-dipolar click cycloaddition were reasonably integrated into one-pot reaction in
the presence of sonication. Vinylidene bisphosphonate, NaN3, and terminal alkyne were employed as the
reactants, CuSO4$5H2O sodium ascorbate was employed as the catalyst system, and AcOH/H2O (1:1 v/v)
were employed as the solvent system to create an acidic environment to achieve optimal efficiency.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 December 2012
Received in revised form 9 March 2013
Accepted 19 March 2013
Available online 22 March 2013
Keywords:
1,2,3-Triazole
Bisphosphonates
Michael-type
1,3-Dipolar cycloaddition
pH-dependent reaction
1. Introduction
containing N-BP family should be beneficial for further development
of more potent bisphosphonates.
Nitrogen-containing bisphosphonate (N-BPs) drugs are used to
treat a variety of bone resorption diseases, such as osteoporosis,
Paget’s disease, and hypercalcemia due to malignancy.1 They are
thought to act by inhibiting the enzyme farnesyl diphosphate syn-
thase,2 resulting in inhibition of protein prenylation in osteoclasts. In
addition totheir usein treatingthese diseases, bisphosphonates have
direct activity against tumor cell growth, as well as the growth of
a variety of pathogenic protozoa and some bacteria.2e4 It is worth
mentioning that most of the highly potent third-generation BP drugs
contain the nitrogen heterocyclic component in their molecular
structures, as those in risedronate and zoledronate (Fig. 1). For the
treatment of bone diseases associated with excessive resorption, the
cyclic nitrogen bisphosphonates (N-BPs) are up to 10,000-fold more
active than the first-generation non-nitrogen containing BP.5e8 Two
heterocyclic nitrogen-containing bisphosphonates, risedronate, and
zoledronate, are C-attached and N-attached, respectively, as illus-
trated in Fig. 1. It is especially worth emphasizing that zoledronic
acid, a N-attached 1,3-diazole bisphosphonate, is the most potent
inhibitor of bone resorption identified to date. Therefore, the pur-
poseful synthesis of new members of N-attached cyclic nitrogen
It is noted that despite the 1,2,3-triazole structural moiety itself
does not occur in nature, a wide range of compounds containing
this functionality have exhibited diverse biologically activities, such
as anti-HIV9 and antimicrobial activities.10 With respect to in-
troducing 1,2,3-triazole groups into organic molecules, one of the
most popular reactions within the click chemistry concept,
copper(I)-catalyzed azideealkyne cycloaddition (CuAAC ‘click’ re-
action), discovered by the groups of Sharpless and Meldal11,12 is
a useful approach leading to 1,4-substituted products with high
regioselectivity. Our group has recently discovered that the highly
regioselective copper(I)-catalyzed 1,3-dipolar cycloaddition re-
action can be notably improved in rates and yields in the presence
of ultrasound irradiation.13 Reportedly, simple bisphosphonates
could be synthesized by using conjugate addition reactions of nu-
cleophiles, such as amines and Grignard reagents to vinylidene
bisphosphonates, followed by treatment with trimethylsilyl bro-
mide (TMSBr) and then methanolysis.14e19 It is especially worth
mentioning here that an important synthetic method, as shown in
Scheme 1, finally leading to the N-attached bisphosphonates via
Michael addition reaction of sodium azide to vinylidene
bisphosphonate, followed by reaction with terminal alkynes, has
not yet been described. Obviously, it is an extremely attractive idea
to create a novel kind of N-attached 1,2,3-triazole bisphosphonates
* Corresponding authors. Tel./fax: þ86 371 67767051; e-mail address: chenxl@
zzu.edu.cn (X. Chen).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.078

4048
X. Chen et al. / Tetrahedron 69 (2013) 4047e4052
NON-NITROGEN CONTAINING BPs
OH
OH
OH
OH
OH
O
Cl
OH
P
O
P
Cl
O
O
P
Cl
OH
S
O
P
O
OH
OH
P
OH
OH
P
OH
OH
tiludronate
clodronate
edidronate
NITROGEN CONTAINING BPs
OH
OH
OH
OH
OH
OH
OH
C-attached
N-attached
O
O
O
O
O
O
O
O
OH
P
P
P
P
H2N
N
N
OH
H2N
OH
OH
OH
P
P
P
N
P
OH
OH
OH
OH
OH
OH
OH
OH
pamidronate
alendronate
risedronate
zoledronate
Fig. 1. Structure of bisphosphonics. The acid forms are depicted.
O
N-attached
P(OEt)2
O
O
2
4
N
N
P(OEt)2
O
P(OEt)2
P(OEt)2
R
NaN3
P(OEt)2
O
P(OEt)2
O
t-BuOH:H2O
Cu(I)
R
N
N3
EtOH:H2O
5
Yield < 20%
3
1
Scheme 1. Synthetic route leading to N-attached 1,2,3-triazole-containing bisphosphonates. Reaction condition: 1 (0.1 mmol) reacted with NaN3 (0.15 mmol) using C2H5OH/H2O
(10 mL, v/v, 1/1) as solvent at room temperature around half an hour. The solvents were removed. The residues were diluted with water and extracted with methylene chloride. The
residual oil was used directly to react with 40-methylphenyl acetylene, a terminal alkyne (0.12 mmol), using CuSO4$5H2O (10% mmol) sodium ascorbate (20% mmol) as its catalyst
and t-BuOH/H2O (15 mL, v/v, 1/1) as solvent at room temperature around 9 h in the presence of ultrasound irradiation.
via this method. But it was extremely astonished that, at the very
beginning, when the plotted two-step synthetic route, as shown in
Scheme 1, was actually carried out in our lab, we obtained the
target N-attached bisphosphonates in extremely low yield, sug-
gesting that some existing synthetic obstacles, which had seriously
prevented from effectively obtaining these especially important
novel N-attached bisphosphonates, should be known and removed.
Herein, we disclose our skillfully designed, so-called a facile and
efficient one-pot synthetic method for synthesis of a series of these
novel N-attached 1,2,3-triazole-containing bisphosphonates, by
means of a controlled Michael-type addition followed by ultra-
sound irradiation promoted-click reaction.
acetylene in the next step 2 using our previously reported pro-
cedure.13 It is especially worth emphasizing that, after having most
comp-1 chemically reacted to produce comp-3 within 11 min, the
following stepwise procedures did not lead to an efficient synthesis
of the final cyclic product 5 (yield<20%), strongly suggesting that
there might be something wrong with the following stepwise
procedures. Therefore, much more influential factors concerning
the reactions were subsequently investigated.
Even though most comp-1 chemically reacted to produce comp-
3 within 11 min using EtOH/H2O (v/v, 1/1) as reaction solvent,
2. Results and discussion
We designed a two-step involving synthetic route as shown in
Scheme 1. However we initially failed to obtain the target N-at-
tached bisphosphonates effectively. The reason for the failure was
investigated and the overall synthetic procedures were re-exam-
ined. Initially the step 1 of Scheme 1 was carried out using EtOH/
H2O (v/v, 1/1) as reaction solvent based on the literature.20 For-
mation of comp-3 was traced by 31P NMR spectra techniques as
Fig. 2 shown. Although several detectable by-products were pro-
duced accompanying with the main reaction, most comp-1 (
d
13.9 ppm) had chemically reacted to produce comp-3 ( 21.7 ppm)
d
within 11 min under the reaction condition. All solvents were
subsequently removed by evaporation under reduced pressure. The
residues were then diluted with water and extracted with methy-
lene chloride. The organic layer was washed, dried, and evaporated.
The residual oil was used directly to react 40-methylphenyl
Fig. 2. Stacked plot of the 31P NMR spectra regarding reaction of comp-1 with NaN3 in step
1 of Scheme 1. The reaction was carried out using (Comp 1) vinylidene bisphosphonate
12.5mg (0.042 mmol) and NaN3 4.4 mg (0.061 mmol) inthe solvent: C2H5OH/H2O (v/v,1/1)
0.5 mL at room temperature (comp-1: d 13.9 ppm, comp-3: d 21.7 ppm).

X. Chen et al. / Tetrahedron 69 (2013) 4047e4052
4049
several detectable phosphorus-containing by-products were still
produced as shown in Fig. 2. There was still a need to develop
a better solvent system. The reaction of comp 1 with sodium azide
was further investigated in different solvents and 31P NMR traced
the processes of these reactions (Fig. 3). It can be seen that none of
any comp-3 was detected within 5 h when acetone was used as the
solvent (Fig. 3i), and another polar aprotic solvent DMSO brought
about not only a small amount of comp 3 in 50 min, but meanwhile
some un-negligible phosphorus-containing by-products at
d
20.1 ppm and d 14.5 ppm, respectively (Fig. 3ii). The use of acetic
acid, a polar protic solvent, greatly enhanced the addition reaction,
leading most of comp 1 to comp 3 in 1.5 h, but the process was
accompanied by formation of a detectable by-product at d 20.9 ppm
(Fig. 3iii). Correspondingly, the influence of three mixed solvents of
acetone, DMSO and acetic acid with water, on Michael addition
reaction of sodium azide was subsequently studied, respectively.
The reaction in H2O-acetone resulted in a formation of many un-
wanted by-products besides producing the targeted product 3
(Fig. 3iv). The reaction in H2O/DMSO mixed solvent made little
improvement in transformation of compound 1 to 3 in comparison
with that in DMSO (Fig. 3ii and v). The best solvent among those
investigated was H2O/AcOH solution, by which a complete and
clean transformation was made within 15 min (Fig. 3vi).
Again, the H2O/AcOH reaction solvent was removed by evapo-
ration under reduced pressure, and the residues were subsequently
diluted with water and extracted with methylene chloride. Fig. 4
shows two 31P NMR spectra, one taken directly with the H2O/ace-
tic acid reaction solution (Fig. 4a), and the other with methylene
chloride extraction solution (Fig. 4b). More than one-third original
amount of comp-3 astonishingly decomposed back into comp-1
after extraction with methylene chloride. That is to say the low yield
of the final cyclic product 5 was mostly due to the unwanted de-
composition of comp-3 in this extraction process. The main factors
that influence the stability of comp-3 were therefore investigated.
It was shown above that the best solvent system for reaction of
comp-1 with NaN3 was H2O/AcOH, in which a complete and clean
transformation was made within 15 min (Fig. 3vi). The effect of
temperature on the stability of comp-3 was investigated by directly
Fig. 4. a: 31P NMR spectrum of the H2O/AcOH reaction solvent; b: 31P NMR spectrum
of the CH2Cl2 extraction solution. The reaction was carried out using (Comp 1) vinyl-
idene bisphosphonate (0.1 mmol) and NaN3 (0.15 mmol) in the solvent: CH3COOH/H2O
(v/v, 1/1) 10 mL at room temperature. Comp-1 (d 13.9 ppm) and 3 (d 21.7 ppm).
using this H2O/AcOH reaction solution. Fig. 5 shows 31P NMR
spectra taken with H2O/AcOH reaction solution at different tem-
perature (25 ꢀC, 30 ꢀC, 40 ꢀC, 50 ꢀC, 60 ꢀC, respectively). Considering
that the following stepwise procedures would all be performed at
temperatures below 50 ꢀC, 60 ꢀC was chosen as the highest tem-
perature reached for this study. It can be seen that only small
amount of comp-3 begun to decompose after temperature reached
40 ꢀC and then the rate of decomposition increase only slightly
afterward with the temperature, exhibiting a higher thermal sta-
bility of comp-3 in the temperature range 25e60 ꢀC.
The effect of pH on the stability of comp-3 was subsequently
investigated. Fig. 3 clearly shows that the transformation efficien-
cies heavily depend on solvent systems chosen. Increased trans-
formation efficiency resulting from using acetic acid and H2O/acetic
acid as the reaction solvents, seems to indirectly indicate the im-
portance of acidic reaction condition. It’s necessary to find out
whether or not the stability of comp-3 relies heavily on the pH of
the solution. The H2O/acetic acid reaction solution was then
Fig. 3. Stacked plots of the 31P NMR spectra via the synthetic route shown in Scheme 1 in different solvent. The reaction was carried out using (Comp 1) vinylidene bisphosphonate
(0.04 mol), NaN3 (0.061 mmol) in different solvent (0.5 mL) at room temperature (i. acetone, 5 h; ii. DMSO, 1 h; iii. CH3COOH, 1.5 h; iv. acetone/H2O (v/v, 1/1), 1 h; v. DMSO/H2O (v/v,
1/1), 1.5 h; vi. CH3COOH/H2O (v/v, 1/1), 15 min).

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X. Chen et al. / Tetrahedron 69 (2013) 4047e4052
(20 mol %) were added to as the catalyst system of the 1,3-dipolar
cycloaddition of azides with terminal alkynes. The resulting mix-
ture was subjected to sonication at room temperature for 9 h. In the
one-pot synthesis, a low pH reaction environment was created by
employing AcOH/H2O (1:1 v/v) as the reaction solvent. The equi-
librium position of Michael addition reaction (Fig. 6) lay far to the
right. Once unstable comp-3 was synthesized in this acidic solvent,
it reacted with the terminal alkyne to form a stable end product 5. An
efficient synthesis of comp-5 was thereby achieved expectedly. It is
well known that an overall yield is always slightly lower than that
attained in a single step. Two reactions, one Michael addition re-
action of sodium azide and the other 1,3-dipolar cycloaddition were
90
80
70
60
50
40
30
20
10
0
Fig. 5. 31P NMR spectra taken with H2O/AcOH reaction solution at different temper-
atures (25 ꢀC, 30 ꢀC, 40 ꢀC, 50 ꢀC, 60 ꢀC).
adjusted to different pH with different amount saturated NaOAc
solution. 31P NMR spectra of the reaction solution at different pH
are shown in Fig. 6i. It can be seen that the Michael addition re-
action of sodium azide to
a,b-unsaturated bisphosphonates in-
volves an equilibrium process, which depends heavily upon solvent
acidity (Fig. 6ii). Comp-3 began to decompose when the pH reached
4.69. More than half the original amount of comp-3 decomposed
back into comp-1 when the pH reached 5.60. The study of the effect
of pH on the stability of comp-3 thereby well disclose the reason
why, as illustrated in Fig. 4(a), one-third original amount of comp-3
decomposed back into comp-1 after extraction by non-acidic
methylene chloride solvent.
Here we propose a novel one-pot synthesis of these novel N-at-
tached 1,2,3-triazole containing bisphosphonates, as described in
Scheme 2. Tetraethylvinylidene bisphosphonate (1), sodium azide
(2), and 40-methylphenyl acetylene terminal alkyne (4) were added
to AcOH/H2O (1:1 v/v) solvents. Following our previously reported
procedure,13 CuSO4$5H2O (10 mol %) and sodium ascorbate
1
2
3
4
5
6
7
8
9
Catalyst
Fig. 7. The yields of one-pot reaction using vinylidene bisphosphonate, sodium azide,
and 1-ethynyl-4-methylbenzene as reactants, CH3COOH/H2O (1:1, v/v) as the reaction
solvent. The reaction was catalyzed by different catalyst systems under sonication for
9 h at room temperature, respectively.
Fig. 6. i. 31P NMR spectra of comp-3 (
-unsaturated bisphosphonates. The different pH solutions were made from 0.5 mL CH3COOH/H2O (v/v, 1/1) reaction solution with different amount saturated NaOAc solution.
d 21.7 ppm) at different pH (1.85, 2.82, 3.72, 4.69, 5.60, respectively); ii. A pH-dependent equilibrium of Michael addition reaction of sodium azide to
a,b
O
P(OEt)2
O
CuSO4 ·5H2O(10% mmol)
P(OEt)2
Sodium ascorbate(20% mmol)
P(OEt)2
O
N
N
+ NaN3
+
R
P(OEt)2
O
AcOH:H2O(v/v, 1/1)
rt
R
N
1
2
4
5
Scheme 2. One-pot synthesis of novel N-attached 1,2,3-triazole-containing bisphophonates 5. Yield: 80.5%. Catalyzed by CuSO4$5H2O (10% mmol), sodium ascorbate (20% mmol),
vinylidene bisphosphonate (1) (0.1 mmol), NaN3 (2) (0.15 mmol), and (40-methylphenyl acetylene)terminal alkyne (4) (0.12 mmol) reacted in AcOH/H2O (1:1 v/v) 10 mL at room
temperature around 9 h in the presence of ultrasound irradiation to form 5. The residues were subsequently diluted with water and then extracted with methylene chloride. The
crude product was purified by column chromatography eluted with ethyl acetate.

X. Chen et al. / Tetrahedron 69 (2013) 4047e4052
4051
Table 1
One-pot preparation of N-attached 1,2,3-triazoles bisphosphonate
Compd
Product
Isolated yield (%)
80.5
Compd
Product
Isolated yield (%)
a
h
76.4
78.6
73.4
b
c
84.7
82.6
i
j
d
e
f
82.3
70.1
75.2
79.3
k
71.1
72.6
79.2
77.4
l
m
n
g
Reaction condition: CuSO4$5H2O (10% mol) sodium ascorbate (20% mmol), vinylidene bisphosphonate (1) (10 mmol), NaN3 (2)(15 mmol) and terminal alkyne (4) (12 mmol)
reacted in AcOH/H2O (1:1 v/v) 30 mL at room temperature around 9 h in the pressure of ultrasound irradiation.
involved in the one-pot reaction. If one-step is a 90% yield, the
overall final product yield is 81%. It is to saythat the 81% overallyield,
in this case, is a relatively high overall yield considering a two-step
involving reaction. Consequently, as illustrated in Scheme 2, a rela-
tively high overall yield (80.5%) of final product 5 was subsequently
achieved via this specially designed one-pot synthesis.
More catalyst systems were then explored using the above one-
pot synthesis as illustrated in Fig. 7. It can be concluded that the
CuSO4,5H2O/sodium ascorbate was still the best catalyst system
among the nine catalyst systems tested. The scope of the reactants
was then enlarged to cover more different terminal alkynes as
shown in Table 1. The optimized one-pot method practically and
efficiently brought about a successful synthesis of a series of novel
N-attached 1,2,3-triazole-containing bisphosphonates as expected.
As could be seen from Table 1, in all cases, N-attached 1,2,3-triazole-
containing bisphosphonates 5aen were obtained in good to
excellent yields. Furthermore the yields of the corresponding target
products are not influenced obviously by various substituted
groups attached to the benzene ring, no matter electron with-
drawing groups such as eNO2, eX, or electron donating groups
such as eOCH3. This observation is also consistent with earlier re-
search in terms of the influence of functional groups upon click
chemistry synthesis.21
3. Conclusions
In conclusion, a practical and efficient one-pot method for
synthesis of a novel kind of N-attached 1,2,3-triazole-containing
bisphosphonates was developed. Two reactions, one Michael ad-
dition reaction of sodium azide with vinylidene bisphosphonate
and the other 1,3-dipolar click cycloaddition, in this case, were
skillfully integrated into one-pot reaction in the presence of

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X. Chen et al. / Tetrahedron 69 (2013) 4047e4052
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were employed as the reactants, CuSO4$5H2O sodium ascorbate
was employed as the catalyst system, and AcOH/H2O (1:1 v/v) were
employed as the solvent system to create an acidic environment to
achieve optimal efficiency. The approaches described here
obviously have significant advantages in terms of experimental
simplicity, mild reaction condition and easy work-up, and
would surely represent a convenient tool for the synthesis of a va-
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This work was supported by the National Natural Science
Foundation of China (No. 21072178), Innovation Specialist Projects
of Henan Province (No. 114200510023) and Innovation Scientists,
Technicians Troop Construction Projects of Zhengzhou City (No.
112PLJRC359), foundational and frontier technology research
foundation of Henan Province for their financial support.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.03.078.
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