Synthesis and characterization of novel 1,2,3-triazoles containing a 1-hydroxyalkane-1,1-bisphosphonate substituent

Article abstract of DOI:10.1080/10426507.2017.1417299

An efficient and facile synthetic approach towards a variety of novel 1,2,3-triazole derivatives containing a 1-hydroxyalkane-1,1-bisphosphonate moiety has been developed through the copper-catalyzed ultrasound-assisted 1,3-dipolar cycloaddition reaction

Full text of DOI:10.1080/10426507.2017.1417299

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and characterization of novel 1,2,3-
triazoles containing a 1-hydroxyalkane-1,1-
bisphosphonate substituent
Mingxiu Lv, Mengwei Wang, Kui Lu, Lu Peng & Yufen Zhao
To cite this article: Mingxiu Lv, Mengwei Wang, Kui Lu, Lu Peng & Yufen Zhao (2017):
Synthesis and characterization of novel 1,2,3-triazoles containing a 1-hydroxyalkane-1,1-
bisphosphonate substituent, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2017.1417299
To link to this article: https://doi.org/10.1080/10426507.2017.1417299
View supplementary material
Accepted author version posted online: 15
Dec 2017.
Published online: 15 Jan 2018.
Submit your article to this journal
Article views: 3
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gpss20

PHOSPHORUS, SULFUR, AND SILICON
https://doi.org/./..
Synthesis and characterization of novel ,,-triazoles containing a
-hydroxyalkane-,-bisphosphonate substituent
Mingxiu Lva, Mengwei Wanga,b, Kui Lua, Lu Penga, and Yufen Zhaob,c
aSchool of Material and Chemical Engineering, Henan University of Engineering, Zhengzhou, China; bCollege of Chemistry and Molecular Engineering,
Zhengzhou University, Zhengzhou, China; cDepartment of Chemistry, Xiamen University, Xiamen, China
ABSTRACT
ARTICLE HISTORY
Received  October 
Accepted  November 
An efficient and facile synthetic approach towards a variety of novel 1,2,3-triazole derivatives containing a
1-hydroxyalkane-1,1-bisphosphonatemoietyhasbeendevelopedthroughthecopper-catalyzedultrasound-
assisted 1,3-dipolar cycloaddition reaction and the following hydrolysis and phosphorylation reaction. The
structures of all the new compounds were elucidated by 1H, 13C, 31P NMR spectroscopy and HR MS.
KEYWORDS
ultrasound-assisted reaction;
,-dipolar cycloaddition;
,,-triazoles;
bisphosphonates
GRAPHICAL ABSTRACT
introduce 1,2,3-triazole groups into organic molecules, the most
traditional and useful approach is the copper-catalyzed 1,3-
dipolar cycloaddition (“click chemistry”), discovered by the
groups of Sharpless and Meldal.[11,12] However, this method still
suffers from obvious drawbacks, such as low regioselectivity and
efficiencies. Recently, our group discovered that the regioselec-
tivity of the 1,3-dipolar cycloaddition reaction could be notably
improved with the assistance of ultrasound (US) irradiation. As
our work ongoing, we describe a synthetic method to construct
the novel 1,2,3-triazole containing geminal 1-hydroxyalkane-
1,1-bisphosphonates through the copper-catalyzed ultrasound-
assisted 1,3-dipolar cycloaddition reaction and the following
hydrolysis reaction and phosphorylation reaction. Based on
the 1,3-dipolar cycloaddition reaction, this method allows the
simultaneous incorporation of two functional groups, 1,2,3-
triazole and geminal 1-hydroxy-1,1-bisphosphonates, into one
molecule.
Introduction
Bisphosphonates, especially nitrogen-containing bisphospho-
nates, represent an important class of pharmacologically active
molecules, which are widely used in the treatment of various
bone diseases, such as osteoporosis, Paget’s disease, hypercal-
cemia and bone metastases secondary to breast cancer and
prostate cancer.[1–3] Recent studies have shown that nitrogen-
containing bisphosphonates also have anti-tumor properties,
including inhibition of tumor cell proliferation and invasion,
inhibition of tumor cell adhesion to bone, inhibition of angio-
genesis or induction of apoptosis.[4,5] Bisphosphonates formally
are stable pyrophosphate analogs, in which the oxygen atom
between the two phosphorus atoms is replaced by a methylene
group. Substitutions at the methylene carbon atom with differ-
ent side chains have generated a large variety of bisphosphonate
compounds. Three nitrogen-containing bisphosphonates,
Pamidronate, Risedronate and Zoledronate, are in clinical use
for the treatment and prevention of bone diseases (Scheme 1).
It is especially worth emphasizing that the nitrogen-containing
heterocyclic bisphosphonates, Risedronate and Zoledronate,
have higher biological activity than Pamidronate. Therefore,
the purposeful synthesis of new nitrogen heterocyclic bisphos-
phonates should be beneficial for further development of more
potent bisphosphonate drugs.
Results and discussion
Generally, the novel 1,2,3-triazole containing geminal
1-hydroxyalkane-l 1,1-bisphosphonate derivatives were syn-
thesized through three steps: the copper-catalyzed ultrasound-
assisted 1,3-dipolar cycloaddition reaction, the following ester
hydrolysis reaction, and the final phosphorylation reaction, as
shown in Scheme 2. Among these steps, the 1,3-dipolar cycload-
dition reaction is the most important step for the preparation
of the target compounds. Therefore, we initiated the synthetic
Azoles, especially 1,2,3-triazoles, are also widely used anti-
fungal agents in clinical use[6] and exhibit diverse biologically
activities, such as anti-HIV,[7] antimicrobial,[8] antiallergic,[9]
and selective adrenergic receptor agonist.[10] With respect to
CONTACT Mingxiu Lv
Henan, , P. R. China.
mingxiulv@.com
School of Material and Chemical Engineering, Henan University of Engineering, No., Xianghe Road, Zhengzhou,
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/././...
©  Mingxiu Lv, Mengwei Wang, Kui Lu, Lu Peng, and Yufen Zhao

2
M. LV ET AL.
20 mol % of NaAsc in H2O under US irradiation (150 W) at
room temperature for 2 h.
In the course of our synthesis, due to the great difference
between the ester and the carboxylic acid obtained in the
following hydrolysis, the intermediates 3 were simply purified
by recrystallization from the mixed solvent of petroleum ether
and ethyl acetate and used directly in the following step without
further purification and spectroscopic characterization. As
shown in Table 2, the intermediate carboxylic acids 4 were
obtained through hydrolysis of the esters 3 by use of the strong
base LiOH in CH3OH/THF (v/v = 1/1) at room temperature
for 12 h. The excellent isolated yields (70%-85%) of the overall
two steps indicated that the first two steps had high efficiencies
and high tolerance of a wide variety of substituents, including
aryl, alkyl and heterobenzyl groups.
Finally, the novel 1,2,3-triazole containing 1-hydroxyalkane-
1,1-bisphosphonates were obtained by reaction of the carboxylic
acids 4a-4g with phosphorous acid and phosphorus trichlo-
ride in molar ratio of 1:3:3 at 80 °C for 3–4 h, addition of
water (20 mL) to the mixture and subsequent continuous stir-
ring for 3–4 h at 95 °C. The isolated yields of target products
(5a-5g) were approximately 40∼56% (cf. Table 3), which may
be attributed to loss in the purification process.
Scheme . Examples of some nitrogen-containing bisphosphonates
approach by screening for the optimal reaction conditions for
the cycloaddition reactions employing phenylacetylene (1) and
2-azidoethyl acetate (2) as the model reaction. As shown in
Table 1, firstly the model reaction was carried out in several
different solvents: t-BuOH, DMSO, DMF, DMSO/H2O (v/v =
1/1), DMF/H2O (v/v = 1/1) as well as H2O, with 10 mol% of
CuSO4ꢀ5H2O and 20 mol% of sodium ascorbate (NaAsc) under
US irradiation (150 W) at room temperature for 2 h. The yields
of 3a were relatively low in traditionally used polar solvents and
mixed solvents (entries 1–5, 8%-47%). However, a significantly
higher yield of 3a was obtained when H2O was used as the
solvent (entry 6, 91%). Following that, the influence of the
power of US irradiation was screened. As shown in Table 1, the
yield of 3a gradually increased from 55% to 91% (entries 6–11)
with different US irradiation power, 0 W, 90 W, 105 W, 120 W,
and 150 W, respectively. However, the yield of 3a ceased to
increase as the power of the US irradiation continuously raised
from 150 W to 180 W (entries 6, 12–13). Therefore, the optimal
Conclusion
reaction conditions for the 1,3-dipolar cycloaddition reaction An efficient and general synthetic approach for the facile and
are 0.01 mol of phenylacetylene (1) and 0.01 mol of 2-azidoethyl cheap synthesis of a wide range of novel 1,2,3-triazole con-
acetate (2) in the presence of 10 mol % of CuSO4ꢀ5H2O and taining geminal 1-hydroxyalkane-1,1-bisphosphonates has been
Scheme . Synthesis of ,,-triazole containing geminal hydroxyl bisphosphonates.
Table . General screening for the optimal reaction conditions.a
Entry
Solvent
US Irradiation (W)
Yield (%)b













t-BuOH
DMSO
DMF
DMSO/HO
DMF/HO
HO






—













HO
HO
HO
HO
HO
HO
HO






aReaction condition: 1a (. mol), 2a (. mol), CuSOꢀHO ( mol%), NaAsc ( mol%), solvent ( mL) under US irradiation at room temperature for  h. bYields deter-
mined by H NMR.

PHOSPHORUS, SULFUR, AND SILICON
3
Table . The synthesis of ,,-triazole containing carboxylic acid 4.a
aReaction conditions I: 1 (. mol) and 2 (. mol), CuSO·HO ( mol%), NaAsc ( mol%) in HO (. mL) under US irradiation at room temperature for  h. reaction
conditions II: LiOH (. eq.), CHOH/THF(v/v = /,  mL) at room temperature for  h. bThe isolated yields of the overall two steps. cn = .
developed. Based on the 1,3-dipolar cycloaddition reaction, a Waters Micromass Q-Tof Micro instrument using the ESI
1
this method allows the simultaneous incorporation of two technique. The Supplemental Materials contains sample H,
functional groups, a 1,2,3-triazole and a geminal 1-hydroxy- 13C and 31P NMR spectra of products 5 (Figures S 1 – S 35).
1,1-bisphosphonate moieties, into one molecule. Further stud-
ies on the biological activities of these compounds are in
progress.
General procedure for the synthesis of compounds 3a-3g
Substituted terminal alkynes (0.01 mol), ethyl azidoalkanoates
(0.01 mol), CuSO4·5H2O (10 mol%) and sodium ascorbate
Experimental
(20 mol%) were suspended in H2O (50 mL) in a 100 mL flask.
TLC was performed on silica gel plates and preparative chro- Then, the mixture was sonicated in a laboratory ultrasonic
matograph on columns of silica gel (200–300 mesh). H, 13C, cleaning bath at room temperature for 2 h. After completion
1
and 31P NMR spectra were recorded with a Bruker Avance of the reaction, as indicated by TLC, the reaction mixture
400 MHz spectrometer operating at 400.13, 100.61, and was diluted with saturated aqueous NH4Cl solution (30 mL)
161.98 MHz, respectively, with 13C and 31P NMR spectra being and extracted with CH2Cl2 (3 × 20 mL). The combined
recorded with broad band proton decoupling. NMR spectra organic layer were washed with brine (20 mL) and dried over
were recorded in DMSO-d6 or D2O at room temperature anhydrous Na2SO4. The solvent was removed completely
(20 2 °C). 1H and 13C chemical shifts are quoted in parts per under vacuum and the obtained white solid was recrystal-
million downfield from TMS. 31P chemical shifts are quoted in lized from ethyl acetate and petroleum ether to give 3a-3g,
parts per million relative to 85% H3PO4 as an external standard. which were directly used in the next step without further
High resolution mass spectra (HRMS) were obtained with purification.

4
M. LV ET AL.
Table . The synthesis of ,,-triazole containing geminal hydroxyl ,-bisphosphonates.a,b
aReaction condition: 4 (. mol), HPO (. mol), PCl (. mol) were reacted at  °C for  h. Then, water ( mL) were added to the mixture and continue to stir at
 °C for  h. bIsolated yield.
General procedure for the synthesis of compounds 4a-4g
(D2O) δ: 8.75 (s, 1H), 8.12 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H),
5.52 (s, 2H), 5.25 (s, 2H). 13C NMR (D2O) δ: 170.5, 140.7, 134.8,
126.7, 121.8, 120.0, 51.2, 43.4. HRMS: m/z [M+Na]+ calcd. for
C8H9N5NaO2: 230.0648, found: 230.0651.
The esters 3a-3g (5.0 mmol) and LiOH (2.64 g, 11.0 mmol) were
stirred in THF/CH3OH (v/v = 1:1, 30 mL) in a 100 mL flask
at room temperature for 24 h. After completion of the reaction,
monitored by TLC, the organic solvents were evaporated under
vacuum and the obtained residue was diluted with H2O (40 mL).
Then, the pH value of the aqueous solution was adjusted to
3–4 with HCl (1.0 mol/L). The obtained white participation
was filtered and dried under vacuum to give the corresponding
4a-4g.
2-(4-Benzylaminomethyl-1H-1,2,3-triazol-1-yl)acetic
1
acid (4e): White solid. M.p. 166–168 °C. H NMR (D2O) δ:
8.06 (s, 1H), 7.42–7.38 (m, 5H), 5.19 (s, 2H), 4.36 (s, 2H), 4.24
(s, 2H). 13C NMR (D2O) δ: 171.0, 138.1, 130.4, 129.8, 129.7,
129.3, 127.5, 51.5, 50.5, 40.8. HRMS: m/z [M+Na]+ calcd. for
C12H14N4NaO2: 269.1009, found: 269.1011.
3-(4-Phenyl-1H-1,2,3-triazol-1-yl)propanoic acid (4f):
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)acetic acid (4a): White
1
White solid. M.p. 178–180 °C. H NMR (DMSO) δ: 8.56 (s,
1
solid. M.p. 166–168 °C. H NMR (MHz, DMSO) δ: 13.45 (s,
1H), 7.83 (t, J = 7.2 Hz, 2H), 7.44 (d, J = 7.2 Hz, 2H), 7.32
(t, 1H), 4.59 (t, 2H), 2.95 (t, 2H). 13C NMR (DMSO) δ: 172.2,
146.6, 131.2, 129.4, 128.3, 125.5, 122.1, 46.0, 34.4. HRMS:
m/z [M+Na]+ calcd. for C11H11N3NaO2: 240.0743, found:
240.0741.
1H, OH), 8.55 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H,), 7.45 (t, J =
7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 5.33 (s, 1H, 2-H). 13C NMR
(MHz, δ-DMSO) δ: 169.1, 146.7, 131.1, 129.4, 128.4, 125.6,
123.2, 51.1. HRMS: m/z [M+Na]+ calcd. for C10H9N3NaO2:
226.0587, found: 226.0588.
3-(4-p-Tolyl-1H-1,2,3-triazol-1-yl)propanoic acid (4g):
2-(4-p-Tolyl-1H-1,2,3-triazol-1-yl)acetic acid (4b): White
1
White solid. M.p. 177–179 °C. H NMR (DMSO) δ: 12.50 (s,
1
solid. M.p. 147–149 °C. H NMR (MHz, δ-DMSO) δ: 13.45
1H), 8.50 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz,
2H), 4.57 (t, 2H), 2.94 (t, 2H), 2.32 (s, 3H). 13C NMR (DMSO)
δ: 172.2, 146.7, 137.6, 129.9, 128.5, 125.5, 121.6, 46.0, 34.4, 21.3.
HRMS: m/z [M+Na]+ calcd. for C12H13N3NaO2: 254.0900,
found: 254.0903.
(s, 1H, OH), 8.48 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.26 (d, J
= 8.0 Hz, 2H), 5.31 (s, 2H), 2.32 (s, 3H). 13C NMR (DMSO)
δ: 169.1, 146.8, 137.7, 129.9, 128.3, 125.5, 122.8, 51.1, 21.3.
HRMS: m/z [M+Na]+ calcd. for C11H11N3NaO2: 240.0743,
found: 240.0745.
2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)acetic acid (4c):
White solid. M.p. 164–167 °C. 1H NMR (DMSO) δ: 7.82 (s, 1H),
5.18 (s, 2H), 1.97–1.91 (m, 1H), 0.91–0.87 (m, 2H), 0.72–0.68
(m, 2H). 13C NMR (DMSO) δ: 168.8, 148.8, 123.3, 51.2, 8.2,
6.6. HRMS: m/z [M+Na]+ calcd. for C7H9N3NaO2: 190.0587,
found: 190.0585.
General procedure for the synthesis of compounds 5a-5g
The carboxylic acids 4a-4g, H3PO3 and PCl3 (molar ratio of
1:3:3) were stirred at 80 °C for 3–4 h. Then water (20 mL) was
added to the mixture. The resulting solution was continuously
stirred for 3–4 h at 95 °C. The obtained solution was discolored
with activated carbon, filtered and concentrated. After that,
2-{4-[(1H-Imidazol-1-yl)methyl]-1H-1,2,3-triazol-1-
1
yl}acetic acid (4d): White solid. M.p. 186–188 °C. H NMR

PHOSPHORUS, SULFUR, AND SILICON
5
1H NMR (DMSO) δ: 8.54 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.43
(t, J = 7.2 Hz, 2H), 7.34 (m, 1H), 2.50–2.42 (m, JP-H = 2.0 Hz,
2H). 13C NMR (DMSO) δ: 146.8, 131.3, 129.3, 128.3, 125.6,
121.7, 71.5 (t, JP-C = 145 Hz), 46.1, 34.7. 31P NMR (DMSO)
δ: 18.5. HRMS: m/z [M+Na]+ calcd. for C11H15N3NaO7P2:
386.0277, found: 386.0280.
[1-Hydroxy-3-(4-p-tolyl-1H-1,2,3-triazol-1-yl)propane-
1,1-diyl]diphosphonic acid (5g): White solid. M.p.
205–206 °C. 1H NMR (DMSO) δ: 8.48 (s, 1H), 7.75 (d,
acetone (10 mL) and ethanol (10 mL) were added at room
temperature. The target compounds 5a-5g slowly precipitated
as white solids which were filtered off and dried under vacuum
to give the corresponding products.
[1-Hydroxy-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethane-
1,1-diyl]diphosphonic acid (5a): White solid. M.p.
1
217–219 °C. H NMR (D2O) δ: 8.43 (s, 1H), 7.85 (d, J =
7.6 Hz, 2H), 7.43 (t, J
= 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz,
P-H
1H), 4.86 (t, JP-H = 11.4 Hz, 2H). 13C NMR (D2O) δ: 146.2,
130.1, 129.1, 128.4, 125.7, 124.7, 74.7 (t, JP-C = 65 Hz), 55.7.
31P NMR (D2O) δ: 14.4. HRMS: m/z [M+Na]+ calcd. for
C10H13N3NaO7P2: 372.0121, found: 372.0125.
J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 4.65 (t, JP-H
=
8.0 Hz, 2H), 2.50 (s, 2H), 2.32 (s, 3H).13C NMR (DMSO)
δ: 146.8, 137.5, 129.9, 128.5, 125.6, 121.3, 71.4 (t, JP-C
=
43 Hz), 46.1, 34.7, 21.3. 31P NMR (DMSO) δ: 19.1. HRMS:
m/z [M+Na]+ calcd. for C12H17N3NaO7P2: 400.0434, found:
400.0437.
[1-Hydroxy-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethane-
1,1-diyl]diphosphonic acid (5b): White solid. M.p.
1
196–198 °C. H NMR (D2O) δ: 8.27 (s, 1H), 7.62 (d, J =
7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 4.82 (t, JP-H = 9.6 Hz,
2H), 2.25 (s, 3H). 13C NMR (D2O); δ: 146.6, 138.9, 129.7, 127.0,
125.6, 123.8, 73.0 (t, JP-C = 26 Hz), 54.1, 20.3. 31P NMR (D2O)
δ: 14.5. HRMS: m/z [M+Na]+ calcd. for C11H15N3NaO7P2:
386.0277, found: 386.0280.
References
[1] Roelofs, A. J.; Hulley, P. A.; Meijer, A.; Ebetino, F. H.; Russell,
R. G. G.; Shipman, C. M. Int. J. Cancer. 2006, 119, 1254–1261.
doi:10.1002/ijc.21977.
[2] Chuah, C.; Barnes, D. J.; Kwok, M.; Corbin, A.; Deininger, M.
W. N.; Druker, B. J.; Melo, J. V. Leukemia. 2005, 19, 1896–1904.
doi:10.1038/sj.leu.2403949.
[3] (a) Fromigue, O.; Lagneaux, L.; Body, J. J. Bone Miner. Res. 2000,
15, 2211–2221; doi:10.1359/jbmr.2000.15.11.2211. (b) Oleman, R. E.
Ann. Oncol. 2005, 16, 687–695. doi:10.1093/annonc/mdi162.
[4] Clézardin, P.; Ebetino, F. H.; Fournier, P. G. Cancer Res. 2005, 65,
4971–4974. doi:10.1158/0008-5472.CAN-05-0264.
[2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-1-
hydroxyethane-1,1-diyl]diphosphonic acid (5c): White solid.
1
M.p. 206–208 °C. H NMR (DMSO) δ: 7.75 (s, 1H), 4.72 (t,
JP-H = 10.4 Hz, 2H), 1.92–1.86 (m, 1H), 0.88–0.84 (m, 2H),
0.68–0.64 (m, 2H). 13C NMR (DMSO) δ: 148.1, 123.1, 72.6 (t,
JP-C = 56 Hz), 52.6, 8.0, 6.9. 31P NMR (DMSO) δ: 16.4. HRMS:
m/z [M+Na]+ calcd. for C7H13N3NaO7P2: 336.0121, found:
336.0123.
{2-[4-(1H-Imidazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl]-1-
hydroxyethane-1,1-diyl}diphosphonic acid (5d): White solid.
M.p. 205–208 °C. 1H NMR (D2O) δ: 8.47 (s, 1H), 8.17 (s, 1H),
7.36 (s, 1H), 7.26 (s, 1H), 5.42 (s, 2H), 4.82 (s, JP-H = 5.7 Hz,
2H). 13C NMR (D2O) δ: 139.9, 135.3, 127.2, 121.5, 121.4, 73.0,
43.1. 31P NMR (D2O) δ: 14.3. HRMS): m/z [M+Na]+ calcd. for
C8H13N5NaO7P2: 376.0182, found: 376.0185.
[5] Brown, H. K.; Holen, I. Curr Cancer Drug Targets. 2009, 9, 807–823.
doi:10.2174/156800909789760339.
[6] Odds, F. C.; Brown, A. J. P.; Gow, N. A. R. Trends Microbiol. 2003, 11,
272–279. doi:10.1016/S0966-842X(03)00117-3.
[7] Alvarez, R.; Velázquez, S.; San-Félix, A.; Aquaro S.; Perno, C. F.; Karls-
son, A.; Balzarini, J.; Camarasa, M. J.; J. Med. Chem. 1994, 37, 4185–
4194. doi:10.1021/jm00050a015.
[8] Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Garmon, S. A.; Hes-
ter, J. B.; Hutchinson, D. K.; Morris, J. J. Med. Chem. 2000, 43, 953–
970. doi:10.1021/jm990373e.
[9] Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A.; J. Med. Chem.
1984, 27, 223–227. doi:10.1021/jm00368a021.
[10] Brockunier, L. L.; Parmee, E. R.; Candelore, M. R.; Cascieri, M. A.;
Colwell, L. F.; Deng, L. Bioorg. Med. Chem. Lett. 2000, 10, 2111–2114.
doi:10.1016/S0960-894X(00)00422-4.
[11] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Edit. 2002, 41, 2596–2599. doi:10.1002/1521-
3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4.
[12] Tornøe, C. W.; Christiensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064. doi:10.1021/jo011148j.
{2-[4-(Benzylaminomethyl)-1H-1,2,3-triazol-1-yl]-1-
hydroxyethane-1,1-diyl}- diphosphonic acid (5e): White
solid. M.p. 222–224 °C. 1H NMR (D2O) δ: 8.09 (s, 1H), 7.36 (s,
5H), 4.81 (t, JP-H = 9.4 Hz, 2H), 4.09 (s, 2H), 4.01 (s, 2H). 13
C
NMR (D2O) δ: 140.3, 134.1, 129.4, 129.0, 128.7, 127.1, 73.0 (t,
JP-C = 125 Hz), 54.4, 51.1, 41.5. 31P NMR (D2O) δ: 14.5. HRMS:
m/z [M+Na]+ calcd. for C12H18N4NaO7P2: 415.0543, found:
415.0547.
[1-Hydroxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propane-
1,1-diyl]diphosphonic acid (5f): White solid. M.p. 223–226 °C.