Catechol-bisphosphonate conjugates: New types of chelators for metal intoxication therapy

Article abstract of DOI:10.1002/hc.20056

Three new types of bisphosphonates conjugated with catechol were synthesized to explore their possibilities for the treatment of metal intoxication. Chelating agents are the only choice for the treatment of such cases. The new chelators have mixed functio

Full text of DOI:10.1002/hc.20056

Heteroatom Chemistry
Volume 15, Number 7, 2004
Catechol–Bisphosphonate Conjugates:
New Types of Chelators for Metal
Intoxication Therapy
Huasheng Ding, Guangyu Xu, Junbo Wang, Yunlong Zhang,
Xihan Wu, and Yuyuan Xie
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes
for Biological Sciences, Shanghai 201203, People’s Republic of China
Received 15 July 2004; revised 6 September 2004
synthesis of conjugates in which bisphosphonate
ABSTRACT: Three new types of bisphosphonates
was linked with catechol by an amide bond or a
nitrogen–carbon single bond. The preliminary as-
sessment on the chelating potency of those catechol–
bisphosphonates conjugates was encouraging, thus
it prompted us to further our efforts in studies on this
type of chelators. Here, we would like to report the
synthesis of new chelating agents (compounds 5, 9,
11) in which bisphoshonate and catechol were linked
by carbon–carbon single or double bond directly.
conjugated with catechol were synthesized to explore
their possibilities for the treatment of metal intoxica-
ꢀ
C
tion.
2004 Wiley Periodicals, Inc. Heteroatom Chem
15:549–555, 2004; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20056
INTRODUCTION
Human metal intoxication has caused more and
more concerns in modern society. Chelating agents
are the only choice for the treatment of such cases.
Bisphosphonates have received considerable atten-
tion because of their high efficiency in binding with
various metal ions such as Ca(II), Mg(II), Fe(II),
Fe(III), Cu(II), and Al(III) [1]. On the other hand, cat-
echolate ligands bearing a variety of electron with-
drawing substituents have been extensively studied
for their extraordinary high affinity with high oxida-
tion state metals such as Fe(III) and actinides such
as uranium(IV) and thorium(IV) [2].
The purpose of this investigation is to synthe-
size new chelators that have mixed functional groups
such as bisphosphonate and catechol in order to en-
hance their binding affinity with concerned metal
ions. In the previous paper [3], we described the
RESULTS AND DISCUSSION
Compounds 5 were prepared as shown in scheme 1.
The polybenzyloxy phenylalkenylaldehydes 1 [4]
were condensed with tetraethyl bisphosphonates
catalyzed by titanium tetrachloride and N-methyl-
morpoline at room temperature [5]. The obtained
alkenylidene bisphosphonates 3 were then hydro-
genated with Pd/C to give polybenzyloxy phenylalkyl
bisphosphonates 4. Considering the sensitivity of
catechol moiety, bromotrimethylsilane (Me3SiBr)
was used to convert the alkyl bisphosphonates 4 into
the corresponding trimethylsilyl bisphosphonates,
which were readily transformed into the disodium
salt of catechol bisphosphonic acids 5 by hydrolysis
with aq. NaOH.
Similarly, we synthesized compounds 9 in which
the central carbon atom was substituted by alkyl
group (Scheme 2). The reduction of the alkenylidene
Correspondence to: Xihan Wu; e-mail: xhwu@mail.shcnc.ac.cn.
2004 Wiley Periodicals, Inc.
c
ꢀ
549

550 Ding et al.
SCHEME 1
bisphosphonates 3 was accomplished by using
NaBH4 at r.t. Compounds 6 thus formed were then
alkylated with sodium hydride and alkyl halide to
give compounds 7. Deprotection of 7 with Pd/C
in ethanol provided compounds 8, which was sub-
sequently converted to compounds 9 by similar
method as described for preparing of compounds 5.
A disodium salt of alkenylidene bisphosphonic
acid 11 was also prepared (Scheme 3). To obtain the
intermediate 10, several attempts had been made to
remove the benzyl group while having the carbon–
carbon double bond retained. At last, a thioanisole–
trifluoroacetic acid reagent system [6] was found
to be most suitable for this purpose, by which
SCHEME 2

Catechol–Bisphosphonate Conjugates 551
SCHEME 3
compound 10 was obtained in good purity. Com-
pound 11 was finally prepared by using TMSBr fol-
lowed by hydrolysis with aq. NaOH.
In summary, three new types of disodium salts
of bisphosphonic acid bearing catechol moiety were
efficiently prepared, their chelating properties will
be reported elsewhere.
2H, ArCH2O), 4.22–4.00 (m, 8H, CH2CH3), 1.40–1.14
(m, 12H, CH2CH3). Compounds 3b–d were prepared
using the method described for the preparation
of 3a.
Tetraethyl 2,3-dibenzyloxyphenylethenyl-
idenebisphosphonate (3b)
1
70.0%, pale yellow oil, H NMR (CDCl3): δ 8.45 (dd,
EXPERIMENTAL
J = 28.7, 47.9 Hz, 1H, CH), 7.44–7.00 (m, 13H, ArH),
5.13 (s, 2H, ArCH2O), 5.05 (s, 2H, ArCH2O), 4.16–3.89
(m, 8H, CH2CH3), 1.33–1.10 (m, 12H, CH2CH3).
Melting points were determined using a Bu¨chi 510
melting point apparatus and are uncorrected. NMR,
1H (400.13 MHz), 13C (100.61 MHz), and 31P (161.99
MHz), spectra were recorded on a Brucker-400 NMR
spectrometer with TMS as internal standard (1H and
13C) and 85% H3PO4 as an external standard (31P).
Microanalyses were carried out on a Leco CHN-2000
elemental analyzer.
Tetraethyl 2,3,4-tribenzyloxyphenylethenyl-
idenebisphosphonate (3c)
1
61.1%, pale yellow oil, H NMR (CDCl3): δ 8.47 (dd,
J = 28.9, 48.3 Hz, 1H, CH), 7.80–6.77 (m, 17H, ArH),
5.15 (s, 2H, ArCH2O), 5.09 (s, 2H, ArCH2O), 5.04 (s,
2H, ArCH2O), 4.20–3.90 (m, 8H, CH2CH3), 1.35–1.10
(m, 12H, CH3).
Tetraethyl 3,4-dibenzyloxyphenylethenyl-
idenebisphosphonate (3a)
Under nitrogen, 10 mL of dry THF was placed in a
25 mL flask and was cooled to 0◦C. Titanium tetra-
chloride (380 mg, 2.00 mmol), 3,4-dibenzyloxyben-
zaldehyde (245 mg, 0.77 mmol), tetraethyl methyl-
enebisphosphonate (288 mg, 0.77 mmol), and N-
methylmorpholine (404 mg, 4.00 mmol) were added
successively. The mixture was stirred for 2 h at room
temperature and concentrated under vacuum. The
residue was partitioned between Et2O and H2O. The
ether phase was washed with aqueous NaHCO3 to
neutral, dried over anhydrous Na2SO4, and evapo-
rated to dryness. The residue was purified by col-
umn chromatography (SiO2, 1/30 MeOH/CH2Cl2) to
Tetraethyl 3,4-dibenzyloxyphenylbutadienyl-
idenebisphosphonate (3d)
75.0%, pale yellow oil, 1H NMR (CDCl3): δ 8.40–7.69
(m, 3H, Ar CH CH CH), 7.48–6.85 (m, 13H, ArH),
5.23 (s, 2H, ArCH2O), 5.20 (s, 2H, ArCH2O), 4.22–4.06
(m, 8H, CH2CH3), 1.37–1.32 (t, 12H, CH2CH3).
Tetraethyl 3,4-dihydroxyphenylethyl-
idenebisphosphonate (4a)
Compound 3a (2.00 g, 3.40 mmol) was dissolved
in ethanol (25 mL), and the solution was hydro-
genated over 0.5 g of 10% palladium on carbon
at room temperature for 8 h. The catalyst was fil-
tered, the solvent was removed, and the residue
1
give 320 mg (70.1%) of pale yellow oil 3a. H NMR
(CDCl3): δ 8.17 (dd, J = 29.5, 47.8 Hz, 1H, CH), 7.77–
6.90 (m, 13H, ArH), 5.21 (s, 2H, ArCH2O), 5.19 (s,

552 Ding et al.
was purified by column chromatography on silica
gel (1/30 MeOH/CH2Cl2) to give 1.30 g (93.2%) of a
white solid. mp 71–73◦C, 1H NMR (CDCl3): δ 6.85 (s,
1H, Ar-2H), 6.75 (d, J = 8.1 Hz, 1H, A-5H), 6.62 (d,
J = 8.1 Hz, 1H, Ar-6H), 4.10–4.00 (m, 8H, O CH2),
3.13 (dt, J = 6.2, 16.7 Hz, 2H, Ar CH2), 2.80–2.60
(m, 1H, CH), 1.30–1.20 (m, 12H, CH3); 13C NMR
(CDCl3): δ 144.31, 143.40, 130.68, 120.41, 116.02,
115.18 (6s, Ph C), 62.97 (t, OCH2), 38.87 (t, CH),
30.48 (s, Ph CH2), 16.23 (s, CH3); 31P NMR (CDCl3):
δ 24.98; Anal. Calcd for C16H28O8P2: C, 46.83; H, 6.82.
Found: C, 47.02; H, 6.88. Compounds 4b–d were pre-
pared using the method described for the prepara-
tion of 4a.
was treated with 3 mL of aqueous NaOH (30 mg,
0.76 mmol). Seventy four milligram of product 9e
(54.5%) was obtained after removing the excess wa-
ter under reduced pressure and recrystalized from
water and methanol as a white solid. mp >300◦C,
1H NMR (D2O): δ 6.71 (d, J = 1.5 Hz, 1H, Ar-2H),
6.64 (d, J = 8.1 Hz, 1H, Ar-5H), 6.61 (dd, J = 1.5, 8.1
Hz, 1H, Ar-6H), 2.82 (dt, J = 6.2, 16.1 Hz, 2H, CH2),
2.06 (tt, J = 6.2, 22.0 Hz, 1H, CH); 13CNMR (D2O):
δ 143.92, 142.33, 134.88, 121.58, 117.14, 116.42 (6s,
Ph C), 41.24 (s, CH2), 30.85 (s, CH); 31P NMR (D2O):
δ 20.32; Anal. Calcd for C8H10O8P2Na2.H2O: C, 26.67;
H, 3.33. Found: C, 26.78; H, 3.62. Compounds 5b–d
were prepared using the method described for the
preparation of 5a.
Tetraethyl 2,3-dihydroxyphenylethyl-
idenebisphosphonate (4b)
2,3-Dihydroxyphenylethylidenebisphosphonic
90.1%, white solid, mp 134–136◦C, 1H NMR (CDCl3):
δ 9.20 (s, 1H, OH), 6.83–6.67 (m, 3H, ArH), 6.10 (s,
1H, OH), 4.30–4.00 (m, 8H, O CH2), 3.23 (dt, J =
5.8, 17.0 Hz, 2H, Ar CH2), 2.55 (tt, J = 5.8, 23.9 Hz,
1H, CH), 1.40–1.20 (m, 12H, CH3); 31P NMR (CDCl3):
δ 26.48; Anal. Calcd for C16H28O8P2: C, 46.83; H, 6.82.
Found: C, 47.09; H, 6.66.
Acid Disodium (5b)
54.4%, white solid, mp > 300◦C, H NMR (D2O): δ
7.15–7.00 (m, 3H, ArH), 3.36 (dt, J = 5.9, 16.1 Hz,
2H, CH2), 2.48 (tt, J = 5.9, 22.0 Hz, 1H, CH); 31P
NMR (D2O): δ 20.81; Anal. Calcd for C8H10O8P2Na2·
CH3OH·H2O: C, 27.55; H, 4.08. Found: C, 27.50;
H, 4.04.
1
Tetraethyl 2,3,4-trihydroxyphenylethyl-
idenebisphosphonate (4c)
2,3,4-Trihydroxyphenylethylidenebisphosphonic
Acid Disodium (5c)
87.1%, white solid, mp 127–129◦C, 1H NMR (CDCl3):
δ 6.58 (dd, J = 1.4, 8.4 Hz, 1H, Ar-6H), 6.45 (dd, J =
3.6, 8.4 Hz, 1H, Ar-5H), 4.20–4.00 (m, 8H, O CH2),
3.16 (dt, J = 5.9, 16.6 Hz, 2H, Ar CH2), 2.69 (tt, J =
5.9, 24.0 Hz, 1H, CH), 1.40–1.20 (m, 12H, CH3); 31P
NMR (CDCl3): δ 26.36; Anal. Calcd for C16H28O9P2: C,
45.07; H, 6.57. Found: C, 45.05; H, 6.63.
1
49.3%, white solid, mp > 300◦c, H NMR (D2O): δ
6.78 (d, J = 8.4 Hz, 1H, Ar-6H), 6.55 (d, J = 8.4 Hz,
1H, Ar-5H), 3.12 (dt, J = 5.6, 16.0 Hz, 2H, CH2),
2.35 (tt, J = 5.6, 22.5 Hz, 1H, CH); 31P NMR (D2O):
δ 21.73; Anal. Calcd for C8H10O9P2Na2·CH3OH: C,
27.69; H, 3.59. Found: C, 27.37; H, 3.59.
3,4-Dihydroxyphenylbutylidenebisphosphonic
Acid Disodium (5d)
Tetraethyl 3,4-dihydroxyphenylbutyl-
idenebisphosphonate (4d)
1
47.3%, white solid, mp > 300◦C, H NMR (D2O): δ
1
91.2%, pale yellow oil, H NMR (CDCl3): δ 6.76 (d,
6.90 (d, J = 8.1 Hz, 1H, Ar-5H), 6.88 (s, 1H, Ar-
2H), 6.78 (dd, J = 1.4, 8.1 Hz, 1H, Ar-6H), 2.58
(t, J = 6.8 Hz, 2H, Ar CH2), 2.13 (tt, J = 5.5, 22.8
J = 8.2 Hz, 1H, Ar-5H), 6.70 (d, J = 2.2 Hz, 1H, Ar-
2H), 6.50 (dd, J = 2.2, 8.2 Hz, 1H, Ar-6H), 4.20–4.08
(m, 8H, OCH2), 2.48 (t, J = 7.0 Hz, 2H, Ar CH2),
2.31 (tt, J = 6.0, 24.4 Hz, 1H, CH2CH), 2.00–1.80 (m,
4H, Ar CH2CH2CH2), 1.34–1.27 (m, 12H, CH3).
Hz, 1H, CH(P2)), 1.98–1.83 (m, 4H, CH2CH2CH); 31
P
NMR (D2O): δ 21.97; Anal. Calcd for C10H14O8P2Na2·
CH3OH: C, 32.83; H, 4.46. Found: C, 32.60; H, 4.28.
3,4-Dihydroxyphenylethylidenebisphosphonic
Acid Disodium (5a)
Tetraethyl 3,4-dibenzyloxyphenylethyl-
idenebisphosphonate (6a)
Under N2, 312 mg (2.05 mmol) of Me3SiBr was added
dropwise to a solution of compound 4a (154 mg, 0.38
mmol) in 20 mL of dry dichloromethane. The mix-
ture was stirred at r.t. for 30 h . Then the reaction so-
lution was evaporated in vacuum, and the red residue
Compound 3a (1.99 g, 3.38 mmol) was added to a so-
lution of 0.19 g NaBH4 (5 mmol) in EtOH (25 mL),
and the mixture was stirred at r.t. for 3 h. The
ethanol solution was evaporated, and the residue

Catechol–Bisphosphonate Conjugates 553
was partitioned between 2.5 N HCl and EtOAc.
Evaporation of the dried organic phase gave an
oil that was purified by silica gel chromatography
(1/30 MeOH/CH2Cl2), to give 1.80 g (90.0%) of col-
Tetraethyl 1-(3,4-dibenzyloxybenzyl)-1-ethyl-
methylene-bisphosphonate (7f)
1
37.2%, colorless oil, H NMR (CDCl3): δ 7.45–7.26
(m, 10H, ArH CH2O), 6.95 (d, J = 1.7 Hz, 1H,
O Ar 2H), 6.84 (dd,J = 1.7, 8.4 Hz, 1H, O Ar 6H),
6. 81 (d, J = 8.4 Hz, 1H, O Ar 5H), 5.16 (s, 2H,
ArCH2O), 5.14 (s, 2H, ArCH2O), 4.14–4.00 (m,
8H, OCH2CH3), 3.15 (dd, J = 12.2, 16.7 Hz, 2H,
ArCH2C(P2)), 1.88–1.76 (m, 2H, C(P2)CH2CH3), 1.28–
1.16 (m, 12H, OCH2CH3), 1.12 (t, 3H, J = 7.4 Hz,
C(P2)CH2CH3).
1
orless oil. H NMR (CDCl3): δ 7.46–7.27 (m, 10H,
ArH CH2O), 6.90 (d, J = 2.1 Hz, 1H, O Ar 2H),
6.83 (d, J = 8.2 Hz, 1H, O Ar 5H), 6.77 (dd, J = 2.1,
8.2 Hz, 1H, O Ar 6H), 5.14 (s, 2H, ArCH2O), 5.13
(s, 2H, ArCH2O), 4.14–3.98 (m, 8H, CH2CH3), 3.14
(dt, J = 6.2, 16.6 Hz, 2H, CH2CH), 2.54 (tt, J = 6.2,
23.8 Hz, 1H, CH2CH), 1.28–1.22 (m, 12H, CH2CH3).
Compounds 6b and 6c were prepared using the
method described for the preparation of 6a.
Tetraethyl 1-(3,4-dibenzyloxybenzyl)-1-phenyl-
methylene-bisphosphonate (7g)
Tetraethyl 2,3-dibenzyloxyphenylethyl-
idenebisphosphonate (6b)
48.7%, colorless oil, 1H NMR (CDCl3): δ 7.45–7.19 (m,
15H, Ar CH2O), 7.10 (d, J = 2.0 Hz, 1H, O Ar 2H),
6.98 (dd, J = 2.0, 8.2 Hz, 1H, O Ar 6H), 6.82 (d,
J = 8.2 Hz, 1H, O Ar 5H), 5.15 (s, 4H, ArCH2O),
4.04–3.87 (m, 8H, CH2CH3), 3.24 (t, J = 16.1 Hz, 4H,
C(P2)-CH2), 1.14–1.09 (m, 12H, CH2CH3).
90.1%, colorless oil, 1H NMR (CDCl3): δ 7.46–7.27 (m,
10H, ArH CH2O), 6.97–6.88 (m, 3H, ArH CH2CH),
5.12 (s, 2H, ArCH2O), 5.08 (s, 2H, ArCH2O), 4.10–
3.90 (m, 8H, CH2CH3), 3.26 (dt, J = 7.2, 16.6 Hz,
2H, CH2CH), 3.09 (tt, J = 7.2, 22.7 Hz, 1H, CH2CH),
1.21–1.16 (m, 12H, CH2CH3).
Tetraethyl 2,3,4-tribenzyloxyphenylethyl-
idenebisphosphonate (6c)
Tetraethyl 1-(2,3-dibenzyloxybenzyl)-1-methyl-
methylene-bisphosphonate (7h)
67.0%, pale yellow oil, 1H NMR (CDCl3): δ 7.47–
7.27 (m, 15H, ArH CH2O), 6.95 (d, J = 8.5 Hz, 1H,
O Ar 6H), 6.68 (d, J = 8.5 Hz, 1H, O Ar 5H), 5.13
(s, 2H, ArCH2O), 5.11 (s, 2H, ArCH2O), 5.02 (s, 2H,
ArCH2O), 4.1–3.9 (m, 8H, CH2CH3), 3.20 (dt, J = 7.0,
15.9 Hz, 2H, CH2CH), 3.05 (tt, J = 7.0, 22.7 Hz, 1H,
CH2CH), 1.20–1.13 (m, 12H, CH2CH3).
1
43.1%, colorless oil, H NMR (CDCl3): δ 7.45–7.27
(m, 10H, ArH CH2O), 7.14 (dd, J = 1.9, 7.3 Hz, 1H,
O Ar 6H), 6.93 (t, J = 7.3, 8.1 Hz, 1H, Ar 5H), 6.90
(dd, J = 1.9, 8.1 Hz, 1H, O Ar 4H), 5.12 (s, 2H,
ArCH2O), 4.95 (s, 2H, ArCH2O), 4.20–4.00 (m, 8H,
CH2CH3), 3.35 (dd, J = 13.5, 16.1 Hz, 2H, CH2C),
1.40 (t, J = 17.0 Hz, 3H, C(P2)CH3), 1.24–1.18 (m,
12H, CH2CH3).
Tetraethyl 1-(3,4-dibenzyloxybenzyl)-1-methyl-
methylene-bisphosphonate (7e)
Tetraethyl 1-(3,4-dihydroxybenzyl)-1-methyl-
Compound 6a (0.78 mg, 1.32 mmol) was added
slowly to a suspension of 60% NaH (0.11 g,
2.75 mmol) in 5 mL of dry THF at r.t., and the mix-
ture was stirred for 30 min. Methyl iodide (0.75 g,
5.28 mmol) was then added, and the reaction mixture
was stirred at 40◦C for 20 h. After CH2Cl2/H2O par-
tition, the organic phase was dried and evaporated.
Column chromatography (SiO2, 1/50 MeOH/CH2Cl2)
gave 0.39 g (37.6%) of colorless oil 7e. 1H NMR
(CDCl3): δ 7.46–7.28 (m, 10H, ArH CH2O), 6.92 (s,
1H, O Ar 2H), 6.80 (s, 2H, O Ar 5, 6H), 5.15 (s,
2H, ArCH2O), 5.14 (s, 2H, ArCH2O), 4.14–4.04 (m,
8H, CH2CH3), 3.18–3.08 (dd, J = 13.4, 15.8 Hz, 2H,
C(P2)-CH2), 1.33 (t, J = 16.7 Hz, 3H, C(P2) CH3),
1.27–120 (m, 12H, CH2CH3). Compounds 7f–h were
prepared using the method described for the prepa-
ration of 7e.
methylene-bisphosphonate (8e)
Compound 7e (0.51 g, 0.84 mmol) in 10 mL EtOH
was hydrogenated over 0.2 g of 10% palladium on
carbon at r.t. for 6 h. Then the solution was filtered
through Celite, concentrated, and the residue was
chromatographed on silica gel (1/20, MeOH/CH2Cl2)
to yield 0.32 g (89.4%) of white solid 8e. mp 159–
1
161◦C, H NMR (CDCl3): δ 8.02 (s, 1H, OH), 7.97
(s, 1H, OH), 6.74–6.60 (m, 3H, ArH), 4.22–4.02
(m, 8H, CH2CH3), 3.14 (dd, J = 13.6, 15.8 Hz, 2H,
Ar CH2), 1.44 (t, J = 16.7 Hz, 3H, C(P2)CH3), 1.34–
1.21 (m, 12H, CH2CH3); 31P NMR (CDCl3): δ 27.05;
Anal. Calcd for C17H30O8P2: C, 48.11; H, 7.08. Found:
C, 48.33; H, 6.83. Compounds 8f–h were prepared
using the method described for the preparation
of 8e.

554 Ding et al.
were prepared using the method described for the
preparation of 9e.
Tetraethyl 1-(3,4-dihydroxybenzyl)-1-ethyl-
methylene-bisphosphonate (8f)
85.1%, white solid, mp 133–135◦C, 1H NMR (CDCl3):
δ 7.02 (d, J = 2.0 Hz, 1H, Ar-2H), 6.73 (d, J = 8.2 Hz,
1H, Ar-5H), 6.63 (dd, J = 2.0, 8.2 Hz, 1H, Ar-6Hz),
4.19–3.98 (m, 8H, OCH2CH3), 3.17 (dd, J = 12.7, 16.7
Hz, 2H, Ar CH2), 2.01–1.91 (m, 2H, C(P2)CH2CH3),
1.32–1.18 (m, 15H, OCH2CH3, C(P2)CH2CH3); 31P
NMR (CDCl3): δ 27.05; Anal. Calcd for C18H32O8P2:
C, 49.32; H, 7.31. Found: C, 49.30; H, 7.27.
1-(3,4-Dihydroxybenzyl)-1-ethyl-methylene-
bisphosphonic Acid Disodium (9f)
43.2%, white solid, mp > 300◦C, 1H NMR (D2O):
δ 7.25 (d, J = 1.7 Hz, 1H, Ar-2H), 7.09 (dd, J =
1.7, 8.1 Hz, 1H, Ar-6H), 7.04 (dd, J = 1.3, 8.1
Hz, 1H, Ar-5H), 3.30 (t, J = 14.6 Hz, 2H, ArCH2),
2.00 (m, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H,
CH2CH3); 31P NMR (D2O): δ 24.33; Anal. Calcd
for C10H14O8P2Na2·CH3OH·H2O: C, 31.43; H, 4.76.
Found: C, 31.51; H, 4.75.
Tetraethyl 1-(3,4-dihydroxybenzyl)-1-phenyl-
methylene-bisphosphonate (8g)
83.7%, white solid, mp 145–147◦C, 1H NMR (CDCl3):
δ 7.44–7.18 (m, 7H, OH, CCH2ArH), 7.05 (d, J = 2.0
Hz, 1H, Ar-2H), 6.78 (dd, J = 2.0, 8.1 Hz, 1H, Ar-
6H), 6.72 (d, J = 8.1 Hz, 1H, Ar-5H), 4.10–3.85 (m,
8H, CH2CH3), 3.38–3.18 (m, 4H,CH2), 1.21–1.11 (m,
12H, CH3); 31P NMR (CDCl3): δ 26.70; Anal. Calcd
for C23H34O8P2: C, 55.20; H, 6.80. Found: C, 55.21; H,
6.82.
1-(3,4-Dihydroxybenzyl)-1-phenyl-methylene-
bisphosphonic Acid Disodium (9g)
63.7%, white solid, mp > 300◦C, 1H NMR (D2O):
δ 7.80–7.47 (m, 5H, 3-ArH), 7.28 (d, J = 2.0 Hz,
1H, 1-Ar 2H), 7.15 (dd, J = 2.0, 8.1 Hz, 1H, 1-
Ar 6H), 7.04 (d, J = 8.1 Hz, 1H, 1-Ar 5H), 3.41
(t, J = 16.8 Hz, 2H, CH2), 3.32 (t, J = 16.8 Hz,
2H, CH2); 31P NMR (D2O): δ 23.49; Anal. Calcd for
C15H16O8P2Na2·CH3OH·1.5H2O: C, 39.10; H, 4.68.
Found: C, 38.94; H, 4.74.
Tetraethyl 1-(2,3-dihydroxybenzyl)-1-methyl-
methylene-bisphosphonate (8h)
75.8%, white solid, mp 124–126◦C, 1H NMR (CDCl3):
δ 9.55 (s, 1H, OH), 6.82 (dd, J = 1.7, 7.9 Hz, 1H, Ar-
6H), 6.74 (t, J = 7.6, 7.9 Hz, 1H, Ar-5H), 6.60 (dd,
J = 1.7, 7.6 Hz, 1H, Ar-4H), 6.15 (s, 1H, OH), 4.30–
3.90 (m, 8H, CH2CH3), 3.23 (t, 2H, Ar CH2), 1.45
(t, J = 16.7 Hz, 3H, C(P2)CH3), 1.40–1.15 (m, 12H,
CH2CH3); 31P NMR (CDCl3): δ 29.00; Anal. Calcd for
C17H30O8P2: C, 48.11; H, 7.08. Found: C, 48.31; H,
7.08.
1-(2,3-Dihydroxybenzyl)-1-methyl-methylene-
bisphosphonic Acid Disodium (9h)
1
42.9%, white solid, mp > 300◦C, H NMR (D2O): δ
7.09–7.05 (m, 3H, ArH), 3.42 (t, J = 15.1 Hz, 2H,
CH2), 1.55 (t, J = 16.1 Hz, 3H, CH3); 31P NMR (D2O):
δ 26.68; Anal. Calcd for C9H12O8P2Na2·1.5CH3OH: C,
31.19; H, 4.46. Found: C, 31.06; H, 4.59.
1-(3,4-Dihydroxybenzyl)-1-methyl-methylene-
bisphosphonic Acid Disodium (9e)
Tetraethyl 2,3-dihydroxyphenylethenyl-
idenebisphosphonate (10)
Under N2, Me3SiBr (325 g, 2.12 mmol) was added
to a stirred solution of compound 8e (150 mg, 0.35
mmol) in 20 mL of dry CH2Cl2 at r.t. After stirring
for 30 h, the alkyl bromide byproducts and excess
bromotrimethylsilane were removed in vacuo and
the residue was treated with 5 mL of aq. NaOH
(28 mg, 0.70 mmol). Sixty milligram of product 9e
(47.6%) was obtained after removing the excess wa-
ter under reduced pressure and recrystalized from
water and methanol as a white solid. mp > 300◦C,
1H NMR (D2O): δ 6.76 (s, 1H, ArH), 6.65 (s, 2H,
ArH), 2.87 (t, J = 14.5 Hz, 2H, CH2), 1.10 (t, J =
16.1 Hz, 3H, CH3); 31P NMR (D2O): δ 25.60; Anal.
Calcd for C9H12O8P2Na2·CH3OH·H2O: C, 29.55; H,
4.43. Found: C, 29.62; H, 4.51. Compounds 9f–h
A mixture of compound (3b) (0.52 g, 0.88 mmol) and
thioanisole (5.48 g, 44 mmol) in TFA (2 mL) was
kept at room temperature overnight. Then the so-
lution was concentrated in vacuum, and the residue
was dissolved in CH2Cl2. The solution was washed
with saturated NaHCO3 solution and water, dried
(MgSO4), filtered, concentrated. The residue was
purified by chromatography over silica gel (1/30,
MeOH/CH2Cl2) to yield 10 as a colorless oil (0.16 g,
1
44.4%). H NMR (CDCl3): δ 8.12 (dd, J = 24.1, 40.6
Hz, 1H, CH), 7.14 (dt, J = 1.7, 8.1 Hz, 1H, Ar-6H),
7.09 (t, J = 7.4, 8.1 Hz, 1H, Ar-5H), 6.99 (dd, J = 1.7,
7.4 Hz, 1H, Ar-4H), 4.34–4.18 (m, 8H, CH2), 1.43–1.33
(m , 12H, CH3); 31P NMR (CDCl3): δ 20.83 (d, J = 52.5
Hz), 15.71 (d, J = 51.0 Hz).

Catechol–Bisphosphonate Conjugates 555
Bojczuk, M. J.; Kiss, T.; Kozlowski, H. J Chem
Soc, Dalton Trans 1997, 973–976; (c) Gumienna-
Kontecka, E.; Jezierska, J.; Lecouvey, M.; Leroux, Y.;
Kozlowski, H. J Inorg Biochem 2002, 89, 13–17; (d)
Gumienna-Kontecka, E.; Silvagni, R.; Lipinski, R.;
Lecouvey, M.; Marincola, F. C.; Crisponi, G.; Nurchi,
V. M.; Leroux, Y.; Kozlowski, H. Inorg Chim Acta
2002, 339, 111–118.
2,3-Dihydroxyphenylethenylidenebisphosphonic
Acid Disodium (11)
TMSBr (225 mg, 1.47 mmol) was added dropwise to
a solution of bisphosphonate 10 (100 mg, 0.24 mmol)
in dry CH2Cl2 (10 mL) under N2. After stirred for 30
h, the reaction solution was concentrated, and the
residue was treated with 5 mL of aq. NaOH (20 mg,
0.48 mmol). Then the excess water was removed to
give a white precipitate, which was purified by re-
crystalization from water and methanol to provide
product 11 (41 mg, 49.4%) as a white solid. mp
[2] (a) Rastetter, W. H.; Erickson, T. J.; Venuti, M. C. J Org
Chem 1981, 46, 3579–3590; (b) Bergeron, R. J.; Kline,
S. J.; Stolowich, N. J.; McGovern, K. A.; Burton, P. S.
J Org Chem 1981, 46, 4524–4529; (c) Bergeron, R. J.;
Stolowich, N. J; Kline, S. J. J Org Chem 1983, 48,
3432–3439; (d) Pu, Y.; Lowe, C.; Sailer, M.; Vederas,
J. C. J Org Chem 1994, 59, 3642–3655; (e) Sofen,
S. R.; Abu-Dari, K.; Freyberg, D. P.; Raymond, K. N. J
Am Chem Soc 1978, 100, 7882–7887; (f) Sofen, S. R.;
Cooper, S. R.; Raymond, K. N. Inorg Chem 1979, 18,
1611–1616.
1
>300◦C, H NMR (D2O): δ 7.49–7.33 (m, 1H, CH),
6.90–6.87 (m, 3H, ArH); 31P NMR (D2O): δ 9.01 (d,
J = 44.1 Hz ), 5.59 (d, J = 45.2 Hz); Anal. Calcd for
C8H8O8P2Na2·1.5CH3OH: C, 29.38; H, 3.60. Found:
C, 29.68; H, 3.25.
[3] Xu, G.; Yang, C.; Liu, B.; Wu, X.; Xie, Y. Heteroatom
Chem 2004, 15, 251–257.
[4] Mendelson, W. L.; Holmes, M.; Dougherty, J. Synth
Commun 1996, 26, 593–601.
[5] Lehnert, W. Terahedron 1974, 30, 301–305.
[6] Kiso, Y.; Ukawa, K.; Nakamura, S.; Ito, K.; Akita, T.
Chem Pharm Bull 1980, 28, 673–676.
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