O, O ′-diester methylenediphosphonotetrathioate: Synthesis, characterization, and potential applications

Article abstract of DOI:10.1021/jo301786m

A new transformation of methylene-bis(phosphonic dichloride) into tetrathiobisphosphonate derivatives is reported. The reaction of methylene-bis(phosphonic dichloride) with 1,2-ethanedithiol in bromoform in the presence of AlCl₃ formed methylene-bis(1,3,2-dithiaphospholane-2- sulfide), which gave rise to O,O′-diester-methylenediphosphonotetrathioate analogues 1a-k upon reaction with phenols and alkyl alcohols in the presence of DBU. Reaction mechanisms are proposed, and all products were characterized by ³¹P, ¹³C, and ¹H NMR. An X-ray crystal structure was obtained for intermediate 2. The potential of the novel scaffold for selective coordination of metal-ions was examined by coordination of Hg(II) and Pb(II) by 1f, as determined by FT-IR, and chelation of Zn(II), but not Ca(II), by 1b, as determined by ³¹P/¹H NMR. UV-vis measurements of 1g-Ni(II) mixture revealed a 2:1 ligand:metal complex. These derivatives are potential antioxidants, and their ability to inhibit ·OH formation in Fenton reactions was quantified by ESR measurements. Analogue 1g proved to be a most potent antioxidant (IC₅₀ 53 μM), inhibiting the Cu(I)-catalyzed Fenton reaction at lower concentrations than GSH, ascorbic acid, and EDTA. Analogue 1c inhibited the Fe(II)-catalyzed Fenton reaction at about the same concentrations as ascorbic acid (IC₅₀ 83 vs 93 μM). In summary, the novel compounds, 1a-k, proved to chelate various borderline/soft Lewis acid metal-ions, and may be useful as antioxidants and metal extractors.

Full text of DOI:10.1021/jo301786m

Article
pubs.acs.org/joc
O,O′‑Diester Methylenediphosphonotetrathioate: Synthesis,
Characterization, and Potential Applications
Aviran Amir, Alon H. Sayer, Rostislav Zagalsky, Linda J. W. Shimon, and Bilha Fischer*
†
†
†
‡
,†
†
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
‡
Department of Chemical Research Support, The Weizmann Institute of Science, Rehovot 76100, Israel
*
S Supporting Information
ABSTRACT: A new transformation of methylene-bis-
phosphonic dichloride) into tetrathiobisphosphonate deriva-
(
tives is reported. The reaction of methylene-bis(phosphonic
dichloride) with 1,2-ethanedithiol in bromoform in the
presence of AlCl formed methylene-bis(1,3,2-dithiaphospho-
3
lane-2-sulfide), which gave rise to O,O′-diester-methylenedi-
phosphonotetrathioate analogues 1a−k upon reaction with
phenols and alkyl alcohols in the presence of DBU. Reaction
mechanisms are proposed, and all products were characterized
by 31P, C, and H NMR. An X-ray crystal structure was
13
1
obtained for intermediate 2. The potential of the novel scaffold for selective coordination of metal-ions was examined by
coordination of Hg(II) and Pb(II) by 1f, as determined by FT-IR, and chelation of Zn(II), but not Ca(II), by 1b, as determined
by 31P/ H NMR. UV−vis measurements of 1g−Ni(II) mixture revealed a 2:1 ligand:metal complex. These derivatives are
potential antioxidants, and their ability to inhibit ·OH formation in Fenton reactions was quantified by ESR measurements.
Analogue 1g proved to be a most potent antioxidant (IC50 53 μM), inhibiting the Cu(I)-catalyzed Fenton reaction at lower
concentrations than GSH, ascorbic acid, and EDTA. Analogue 1c inhibited the Fe(II)-catalyzed Fenton reaction at about the
same concentrations as ascorbic acid (IC50 83 vs 93 μM). In summary, the novel compounds, 1a−k, proved to chelate various
borderline/soft Lewis acid metal-ions, and may be useful as antioxidants and metal extractors.
1
INTRODUCTION
which confer a “soft-base” character. Analogues of tetrathiobi-
sphosphonate diester 1 (Scheme 1) may be potential
therapeutic agents for the removal of soft/borderline metal-
ions, as well as useful industrial agents for metal extraction as in
antiwear additives. Specifically, we describe the synthesis of a
novel series of O,O′-diester-methylenediphosphonotetrathioate
derivatives, their mechanism of formation, their characterization
as metal-ion chelators, and their potential application as
antioxidants.
■
Metal chelators containing sulfur are important agents in the
treatment of heavy metal (e.g., Hg(II), Pb(II)) poisoning.
Specifically, these agents chelate the metal-ion and induce its
1
,2
elimination through the urine. Metal chelators containing
sulfur have also been proposed as a treatment for Alzheimer’s
3
,4
5
disease, Wilson’s disease, and other physiological conditions
caused by metal abnormalities. Furthermore, related meta6l
chelators are important for industrial use as metal extractors
7
and lubricant additives. For instance, the zinc complex of
phosphorodithioic acid (ZDDP) is widely used as an antiwear
agent and an antioxidant.
RESULTS AND DISCUSSION
■
2
8
Synthesis of Methylene-bis(1,3,2-dithiaphospholane-
9
−11
-sulfide), 2. We targeted the preparation of O,O′-diester-
Bisphosphonate analogues are known as hard/borderline
Lewis acid metal chelators and have been used for treating
methylenediphosphonotetrathioate, 1, from a commercially
available starting material using a minimal number of synthetic
steps. Our synthetic plan involved the intermediacy of 2,
synthesized from the commercially available methylene-bis-
1
2
13
osteoporosis, multiple myeloma, and other bone abnormal-
ities. By binding to Ca(II) ions they adsorb to bone and
14
interfere with bone resorption. The bisphosphonate scaffold
is an enzymatically stable analogue of pyrophosphate.
1
5
(
phosphonic dichloride), 3 (Scheme 1). We envisaged that
bisphosphonate 2 would subsequently undergo ring-opening
Although bisphosphonate analogues are Ca(II) and Mg(II)
ion-selective, they are not suitable for chelating borderline/soft
metal-ion Lewis acids such as Cu(I) and Fe(II)-ions, and they
are not effective for removing heavy metal ions from
contaminated areas. For this purpose, we targeted the
development of a novel scaffold bearing both a bisphospho-
nate-like moiety, to provide metabolic and chemical stability,
and the replacement of oxygen atoms with four sulfur atoms,
upon reaction with alcohol in the presence of DBU to form
1
6,17
analogues 1 (Scheme 1).
In our first attempt to obtain compound 2, we reacted
18
starting material 3 with Lawesson’s reagent hoping to replace
Received: August 30, 2012
Published: December 3, 2012
©
2012 American Chemical Society
270
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Article
Scheme 1. O,O′-Diester-methylenediphosphonotetrathioate, 1
the phosphonate oxygen atoms with sulfur atoms to form
compound 4 (Scheme 2). However, the reaction resulted in
mixture of 4 and many side-products.
Table 1. Optimization of Reaction Conditions for the
Synthesis of Compound 2 with 5 Day Reaction Times for All
Experiments
temp
catalyst/
additive
1,2-ethanedithiol
[equiv]
isolated
Scheme 2. Synthesis of Compound 2
entry
1
[°C]
solvent
CHCl3
yield [%]
60
10 mol %
AlCl3
5
5
5
6
6
traces
2
3
4
5
65
THF
10 mol %
AlCl3
145
155
170
C H Cl
4
10 mol %
AlCl3
24
2
2
triglyme 10 mol %
AlCl3
CHBr3
10 mol %
AlCl3
6
7
155
155
CHBr3
CHBr3
none
6
2
17
10 mol %
AlCl3
traces
8
155
CHBr3
10 mol %
TiCl4
5
10
9
155
155
155
155
CHBr3
1 eq AlCl3
5
6
6
6
In our second attempt we reacted 3 with 1,2-ethanedithiol in
a first step to produce 5 and then used Lawesson’s reagent in an
attempt to produce compound 2. Compound 3 was treated
with 1,2-ethanedithiol under several conditions: in pyridine,
THF/Et N, or heated under reflux in CHCl . However, no
1
1
1
0
1
2
triglyme 2 eq CaCl2
24
24
44
CHBr3
CHBr3
2 eq CaCl2
10 mol %
AlCl
3
a
13
145
CHBr
none
6
80
3
3
3
a
product 5 was obtained. When 3 was treated with 1,2-
A 2-step synthesis as depicted in Scheme 3.
ethanedithiol in the presence of 10 mol % of AlCl in hot
3
CHCl for 5 days, traces of compound 2 were formed.
3
We optimized the latter reaction to obtain 2 in a reasonably
good yield, applying various solvents and catalysts, and
changing the number of reactant equivalents (Table 1). The
optimal reaction time was found to be 5 days when using hot
bromoform as a solvent.
As shown in Table 1, no detectable reaction occurred
between 3 and 5 equiv of 1,2-ethanedithiol in the presence of
Elimination of water in the reaction may decrease the yield of
2. Therefore, CaCl was used as both a desiccant and Lewis
acid in either triglyme or CHBr . However, the yield was still
low, 24% yield for each case (entries 10−11). Finally, the
optimal yield of compound 2 (44%) was obtained in CHBr
with 10 mol % AlCl and 6 equiv of 1,2-ethanedithiol at 155 °C
2
3
3
3
for 5 days (entry 12). Although the reaction temperature in
entry 12 was 15° lower than the reaction in entry 5, we
obtained the product in a higher yield. Monitoring the reaction
progress by 31P NMR revealed that a reaction temperature
higher than 160 °C leads to many other signals that do not
appear in reactions conducted in lower temperatures. Thus,
1
0 mol % AlCl in THF under reflux conditions (entry 2), but
3
the product was obtained in 24% yield when 1,1,2,2-
tetrachloroethane was used as a solvent (at 145 °C) (entry
3
). Triglyme at 155 °C gave a product that was highly
contaminated (entry 4), as did the reaction in CHBr at 170 °C
when AlCl was present (entry 5).
3
31
although P NMR confirmed the formation of the product, the
latter was inseparable from the byproducts. Moreover,
extending the reaction time to 7 days at 155 °C did not result
in a higher yield, and when the reaction time was shortened to
4 or 3 days, lower yields were obtained.
3
To reduce byproducts, 3 was treated with 6 equiv of 1,2-
ethanedithiol in CHBr at 155 °C without AlCl . This gave
3
3
more pure product, but the yield was reduced to 17% (entry 6).
Reaction of 3 with 10 mol % AlCl and a reduced amount (2
3
equiv) of 1,2-ethanedithiol in CHBr at 155 °C gave traces of
Mechanism of Formation of Compound 2. The
mechanism of the reaction was investigated by analyzing
3
the product along with methylenediphosphonic acid (entry 7),
leading us to conclude that at least 4 equiv of 1,2-ethanedithiol
were needed for the formation of 2.
aliquots from the reaction mixtures in CDCl
or DMSO-d
solution, a signal at 50−52 ppm emerged
several hours after the reaction had started. This signal implies
by
3
6
31
P NMR. In CDCl
3
The role of AlCl as a catalyst was investigated by replacing it
3
19
with TiCl . The latter was less effective than AlCl in C H Cl
the formation of intermediate 4. In wet DMSO-d solution, a
4
3
2
4
4
6
(
24%, entry 3), decreasing the yield to 10% (entry 8) with the
50−52 ppm signal could not be observed, possibly due to
hydrolysis of 4. To validate the hypothesis that 4 is an
intermediate in the reaction we synthesized 4 according to the
same product purity. The role of AlCl in the reaction was also
evaluated by addition of 1 equiv of AlCl . Under this condition,
compound 2 could not be recovered due to highly
3
3
20
literature. Briefly, bis(dichlorophosphino)methane 6 (which
contaminated product (entry 9).
is commercially available) was treated with neat PSCl in the
3
2
71
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Scheme 3. Synthesis of Compound 2 Starting from Bis(dichlorophosphino)methane 6
Scheme 4. Proposed Mechanism for Formation of Compounds 2
Table 2. Yields and 31P NMR Data of Derivatives 1a
a
N/O: not obtained. N/A: not applicable. Procedure A is not applicable. The given 31P NMR data are for products as the corresponding disodium
b
salts.
presence of AlCl at 110 °C for 2 h and then at 140 °C for 4 h.
We concluded that formation of 2 from 3 involves first
replacement of oxygen atoms by sulfur atoms, and then P−Cl
bonds are broken upon reaction with 1,2-ethanedithiol to form
dithiophospholane rings.
3
The product was obtained as a liquid upon high vacuum
distillation which then solidified to give a white solid in 89%
yield. Compound 4 was further reacted with 1,2-ethanedithiol
in the absence of AlCl in CHBr at 145 °C resulting in the
Although the bond energy of PO is higher than that of
3
3
PS (120 kcal/mol for PO in POCl vs 76 kcal/mol for
3
21
formation of compound 2 in 90% yield. The overall yield of 2
from compound 6 was 80% (Scheme 3) (Table 1, entry 13).
PS in PSCl ), we hypothesized that formation of thiirane as
3
a leaving group can trigger the transformation of PO bond to
2
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PS (Scheme 4). To corroborate this hypothesis we used
silica gel column separation. No product was detected upon
treatment of 2 with primary amine (e.g., benzylamine) 13.
Products 1a−j were separated over silica gel with
CHCl :MeOH (0−20%), and CHCl :iPrOH (91:9%) for
PPh as a scavenger of thiirane. PPh can react with thiirane to
3
3
2
2
form triphenylphosphine sulfide and ethylene. Thus,
compound 3 was treated with 6 equiv of 1,2-ethanedithiol
and 2 equiv of PPh in CHBr at 155 °C. After 19 h, compound
3
3
+
compound 1k, and obtained as the corresponding DBUH
3
3
3
1
+
+
2
, triphenylphosphine sulfide ( P NMR: 43.9 ppm), and
salts. The exchange of (DBUH ) counterion with Na or
+
ethylene were formed. Almost no PPh remained which led us
pyridinium ions, using Dowex 50W, -Na or -pyridinium form,
3
conclude that the driving force for the formation of 2 is indeed
thiirane elimination.
did not proceed well, resulting in a contaminated product.
+
+
Alternatively, the (DBUH ) counterion was replaced with Na
+
The role of AlCl as a catalyst is described in Scheme 4. AlCl3
on Sephadex CM-Na form column. The ammonium salt of 1
3
probably coordinates the phosphonate oxygen atom in 3
resulting in a more electrophilic phosphorus atom susceptible
to nucleophilic reaction with 1,2-ethanedithiol. Consequently, a
pentavalent phosphorus intermediate 7/8 is formed with the
was obtained by washing a CHCl
HCl to get the neutral product, which was then extracted with 3
M NH OH, followed by freeze-drying to give 1 as a white
3
solution of 1 with 0.25 M
4
powder of the ammonium salt.
concomitant elimination of AlCl , thiirane, and water to form
intermediate 4. Next, 4 reacts with an additional equivalent of
In addition to the desired O,O′-diester-methylenediphos-
phono-tetrathioate derivative, 1, two byproducts were usually
obtained. This is exemplified by 1k. The reaction to form 1k
took place in acetonitrile at RT for 18 h. Besides bi-
sphosphonate 1k (14% yield), product 14 (33% yield) and
product 15 (9% yield) were obtained (Figure 2). Side product
3
1,2-ethanedithiol to form the dithiaphospholane ring 10/11
followed by elimination of HCl and formation of PS bond.
AlCl catalyst is possibly recycled by the reaction of HCl with
3
Al(Cl) (OH) .
n
3‑n
The structure of product 2 was verified by X-ray diffraction
of crystals obtained by slow evaporation of CHBr solution of 2
3
2
3
(
Figure S50). Compound 2 demonstrates a gauche con-
formation between the two rings. Selected bond lengths and
angles are presented in Table S1.
Synthesis of O,O′-Diester-methylenediphosphonote-
trathioate, 1. To obtain derivatives 1, compound 2 was
treated with various alcohols in the presence of DBU (Table 2).
The reaction was performed, either in neat alcohol for 0.45−2.5
h (reaction procedure A), or in CHCl with 4 equiv of alcohol
3
for 24 h (reaction procedure B) (Table 2). In both procedures
the solutions were heated at 60 °C.
The reaction yield depended on the properties of the alcohol.
When the reactions were carried out in neat and relatively low
molecular weight primary alcohols, yields ranged from 60% to
8
3% (entries 1−2). When the reactions were carried out in
Figure 2. Byproducts formed in the reaction of 2 with N-benzoyl-L-
tyrosine ethyl ester.
CHCl3 with 4 equiv of alcohol, yields were reduced
considerably. Furthermore, with secondary or tertiary alcohols,
no reaction was observed (entries 4−5). When 2 was reacted
with long alkyl chain alcohols, the reaction yield decreased
dramatically, e.g., from 83% for butanol to 19% for octanol
1
4 is due to reaction of tyrosine at one dithiophospholane ring,
while side product 15 is due to reaction of H O molecule at the
2
dithiophospholane ring in side-product 14 during workup,
followed by air oxidation to form the disulfide product.
However, by applying procedure B, compound 1k was formed
in 54% yield.
Characterization of Compounds 1 as Metal-Ion
Chelators. In order to demonstrate the ability of compounds
(
entries 2 and 3). It is noteworthy that compound 1b was
obtained via procedure A in 83% versus 60% yield of 1a. This is
probably due to the low solubility of both the reactant 2 and
product 1a in methanol giving rise to a suspension, while the
reaction to form 1b results in a clear mixture.
The reaction progression could be easily monitored by 31P
1
to bind borderline metal-ions we titrated compound 1b with
NMR, since the signal of starting material 2 appeared at ∼90.5
ppm and the products were observed at 101−107 ppm.
Compound 2 was also treated with thiols and primary amines
in the presence of DBU (Figure 1). With thiols (e.g.,
0
.45 and 1.45 equiv of ZnCl . Titration was monitored by
2
31
1
P/ H NMR in DMSO-d (Figure 3). When 0.45 equiv of
6
ZnCl was added to 1b (Figure 3b) the PCH P triplet signal in
2
2
1
31
benzylthiol), product 12 was obtained, as observed by 31
H NMR spectrum shifted from 3.16 to 3.03 ppm and the P
P
NMR signal at 102.4 shifted to 98.6 ppm. When 1b was treated
NMR (76 ppm). However, it completely decomposed during
with 1.45 equiv of ZnCl the PCH P triplet signal (3.13 ppm)
2
2
31
significantly broadened. Likewise, the P NMR signal at 97.9
ppm further shifted and significantly broadened.
To establish the metal-ion selectivity of analogues 1, we
repeated the above NMR-monitored metal-ion titration, this
time with CaCl . Addition of up to 2 equiv of CaCl did not
2
2
change at all the chemical shift of the PCH P signal, thus
2
indicating no binding of Ca(II) ion by analogue 1b (Figure S2).
Next, we demonstrated the ability of compound 1 to bind
heavy metal-ions, e.g., Hg(II) and Pb(II). For this purpose we
Figure 1. Products 12 and 13 (not isolated).
2
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discrimination from the signal of compound 1 at 230 nm is
expected. Thus, solutions of Ni(BF ) dissolved in EtOH and
4
2
1
g−DBU dissolved in DCM were mixed, and the organic phase
turned yellow. DBU salt of 1g was diluted, and Ni(BF ) was
4
2
added. After each addition the absorbance was measured at 321
nm (Figure 5a). The complex absorbance was metal-
concentration dependent up to 2:1 ligand:metal ratio (Figure
5
b).
Figure 3. 31P/ H NMR spectra in DMSO-d of 1b−Zn(II) complex at
1
6
(
81 and 200 MHz): (a) 1b; (b) 1b with 0.45 equiv of Zn(II); (c) 1b
with 1.45 equiv of Zn(II).
prepared the corresponding complexes as follows: The 1f−
M(II) complex was obtained by addition of methanol dissolved
HgCl or PbCl into 1f in water at 2:1 ligand:metal ratio. The
2
2
complex precipitated as a white solid, and the solvent was
removed by decantation. The solid was washed with methanol
and dried under vacuum.
The binding properties of compound 1f with Hg(II) and
Pb(II) were assayed using FT-IR (Figure 4). The PS
Figure 5. Titrations of 1g with Ni(II) as monitored by UV−vis
spectra: (a) UV−vis spectra of 1g−Ni(II), (b) UV−vis cross-section at
3
21 nm of the nickel titration of 1g.
The ability of derivatives 1 to chelate borderline/soft metal-
Figure 4. FT-IR (KBr plates) region 1900−560 cm−1 of (a)
compound 1f, (b) 1f−Pb(II) 2:1, (c) 1f−Hg(II) 2:1.
ions was further demonstrated by measuring inhibition of
Cu(I) and Fe(II) induced Fenton reactions. Specifically, we
measured the antioxidant effect of compounds 1 by quantifying
the formation of OH radical from H O induced by Cu(I) or
2
4,25
of 1f lie at 804 and 650 cm−1 (Figure 4a),
stretching bands
2
2
−1
while the stretching band of the 1f−Pb(II) complex (800 cm )
became wider and more intense, implying Pb(II)-binding
Fe(II) ions. OH radicals formed in the reaction were trapped
by 5,5′-dimethyl-1-pyrroline-N-oxide (DMPO), and the
amount of DMPO−OH adduct was then measured by ESR.
Generally, addition of chelators to Fe(II)/Cu(I)−H O mixture
(
Figure 4b). PS stretching bands for the 1f−Hg(II) complex
−1
−1
shifted from 804/650 cm to a lower frequency, 590 cm , and
became wider and more intense, indicating coordination of
sulfur with Hg(II) ion. Yet, S−Hg−S absorptions were not
observed, possibly because they are weak and appear at
2
2
lowers DMPO−OH signal due to metal-ion chelation and
27
radical scavenging.
Our data (Table 3) demonstrate the high ability of the tested
compounds to reduce the amount of OH radical in the Cu(I)-
induced Fenton reaction. Compounds 1a/g/k were found to be
superior antioxidants as compared to EDTA. In the Fe(II)−
H O system, compound 1c was the most promising
−1
26
frequencies below 400 cm (Figure 4c). The P−O−(C)
stretching bands of 1f−Pb(II) and 1f−Hg(II), 1100−1000 and
−1
1
001−958 cm , respectively, exhibit greater intensity versus
−1
the P−O−(C) bands in free 1f (1025−1002 cm ).
2
2
The metal-binding stoichiometry and metal extractive
properties of analogues 1 with Ni(II) were assayed using
UV−vis measurements. The Ni(II) complexes of many organic
molecules are colored. Hence, complex detection and
antioxidant, IC50 83 μM versus 61.5 μM for EDTA. The
greater ability of compounds 1a,g,c,k to lower the radical
formation in Cu(I)−H O versus Fe(II)−H O system is
2
2
2
2
attributed to the presence of tetrathio groups, making these
2
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ethanedithiol (0.23 g, 2.4 mmol). The mixture was heated to 145 °C
Table 3. Antioxidant Capacity of Derivatives 1 As Compared
to Standard Metal Ion Chelators/Antioxidants
a
for 3 days. The mixture was hot filtered, and another portion of CHBr3
(2 mL) was used for rinsing. After the mixture cooled down to rt, n-
IC50 μM
IC90 μM
hexane was added, and the product was precipitated. The white
precipitate was collected by vacuum filtration and washed with n-
hexane to give compound 2 as a white solid (0.11g, 90% yield).
O,O′-Diester-methylenediphosphonotetrathioate, 1, Typical Pro-
cedure A. Compound 2 (100 mg, 0.31 mmol) was suspended in dry
alcohol (3 mL) followed by the addition of DBU (100 mg, 0.66
mmol). The reaction mixture was heated in an oil bath set to 60 °C for
0.45−2.5 h (reaction time was determined by monitoring the reaction
by 31P NMR). After cooling to rt the reaction mixture was separated
compd
Fe(II)
Cu(I)
Fe(II)
Cu(I)
EDTA
ascorbic acid
GSH
61.5 ± 1
92.5 ± 8
63.0 ± 5
114.5 ± 3
115.5 ± 2
83.0 ± 2
94.5 ± 7
64.0 ± 2
N/A
98.0 ± 1
N/A
110.0 ± 8
N/A
216.0 ± 40
56.0 ± 1
53.0 ± 5
67.5 ± 1
59.5 ± 1
N/A
490.5 ± 6
83.0 ± 1
80.5 ± 4
97.0 ± 6
86.5 ± 1
1a
1g
1c
374.5 ± 22
287.0 ± 28
209.0 ± 6
330.5 ± 15
by flash chromatography (CHCl to CHCl :MeOH 80:20) to give a
1k
3
3
colorless oil. The colorless oil was dissolved in a water:THF 6:4
a
N/A = not available, the minimal amount of radical production
exceeds 50% (IC ) or 10% (IC ).
+
mixture and passed through CM Sephadex Na . THF was evaporated,
50
90
and the remaining aqueous solution was freeze-dried to give a white
solid. In cases where further purification was needed, the crude
product was separated over RP-flash chromatography eluting with 0.1
M triethylammonium acetate−acetonitrile (TEAA−ACN) 40:60. The
solvent mixture was freeze-dried several times until a constant weight
was attained. Triethyl ammonium counterion was replaced by sodium
by passing the triethyl ammonium salt solution through CM Sephadex
compounds soft chelators that preferably chelate Cu(I) over
Fe(II) ions.
CONCLUSIONS
■
+
+
We synthesized a novel family of O,O′-diester-methylene-
diphosphonotetrathioate analogues, 1a−h, by a two-step
process from commercially available methylene-bis(phos-
phonic-dichloride) or a three-step process from bis(dichloro-
phosphino)methane in reasonable to good yields. Formation of
Na or Dowex 50wx8−20 Na form resin and freeze-drying again to
obtain 1 as white products.
O,O′-Diester-methylenediphosphonotetrathioate, 1, Typical Pro-
cedure B. Compound 2 (100 mg, 0.31 mmol) was suspended in dry
CHCl (3 mL). The alcohol (1.86 mmol) was added followed by the
3
addition of DBU (100 mg, 0.66 mmol). The reaction mixture was
1
involved the intermediacy of methylene-bis(1,3,2-dithiaphos-
heated under reflux for 0.45−24 h (reaction time was determined by
pholane 2-sulfide), 2, the mechanism of formation of which was
elucidated. Compounds 1a,b,c,d,g,h were found to selectively
chelate soft/borderline metal-ions, i.e., Zn(II), Ni(II), Cu(I),
and Fe(II) ions, and to function as potent antioxidants, superior
to EDTA, ascorbic acid, and GSH in Cu(I)−H O system. In
31
monitoring the reaction by P NMR). After cooling, the mixture was
loaded on a flash chromatography column (CHCl to CHCl :MeOH
3
3
80:20 for compounds 1a−j or CHCl3 to CHCl :iPrOH 91:9 for
3
compound 1k) to give a colorless oil. The colorless oil was dissolved in
+
a water:THF 6:4 mixture and passed through CM Sephadex Na . THF
2
2
was evaporated, and the remaining aqueous solution was freeze-dried
to give a white solid. In cases where further purification was needed,
the crude product was separated over RP-flash chromatography eluting
with 0.1 M TEAA−ACN 40:60. The solvent mixture was freeze-dried
several times until a constant weight was attained. Triethyl ammonium
counterion was replaced by sodium by passing the triethyl ammonium
addition, compound 1f chelated heavy metal-ions, e.g., Pb(II)
and Hg(II) ions. Compound 1g was found to efficiently bind
Ni(II) in a 2:1 stoichiometry by UV−vis monitored titrations.
Our studies on the application of derivatives 1 as extreme
pressure lubrication additives will be published in due course.
+
+
salt solution through CM Sephadex Na or Dowex 50wx8−20 Na
EXPERIMENTAL SECTION
Precautions must be taken when synthesizing these phosphorus
products due to their resemblance to neurotoxins.
■
form resin and freeze-drying again to obtain 1 as white products.
Disodium-O,O′-dimethyl-methylenediphosphonotetra-
thioate, 1a. Product 1a was obtained from reaction of 2 (100 mg,
0.31 mmol) with methanol (3 mL, procedure A) (or 60 mg, 1.86
mmol, procedure B) as a white solid (58 mg, 60% and 19 mg, 20%
Methylene-bis(1,3,2-dithiaphospholane-2-sulfide), 2. Meth-
ylene-bis(phosphonic dichloride) 3 (5 g, 20 mmol) was dissolved in
dry CHBr (48 mL). 1,2-Ethanedithiol (11.42 g, 121 mmol) was
yield via procedure A and B, respectively). Melting point 200−202 °C
3
1
added via syringe followed by addition of anhydrous AlCl (0.25 g,
(dec). H NMR (200 MHz, D
2
O): δ 3.65 (second order A
3
A′
2
3
XX′,
3
13
1
.87 mmol). The reaction mixture was heated to 155 °C for 5 days.
6H), 3.48 (t, J = 13.73 Hz, 2H) ppm. C NMR (50 MHz, D
O): δ
56.2 (t, J = 64.2 Hz), 50.7 (t, J = 3.4 Hz) ppm. 31P NMR (81 MHz,
The resulting yellow mixture contained brown greenish precipitate,
−
which was hot filtered. An additional amount of hot CHBr (20 mL)
D O): δ 105 ppm. HRMS (MALDI) m/z: calcd for C H O P S [M
− H] 266.896, found 266.893. FT-IR(ATR): 2994w, 2938w, 2832w,
1453w, 1433w, 1351w, 1143w, 1007s, 992s, 755s, 742s, 637s cm .
Disodium-O,O′-dibutyl-methylenediphosphonotetra-
thioate, 1b. Product 1b was obtained from reaction of 2 (100 mg,
0.31 mmol) with n-butanol (3 mL, procedure A) as a white solid (102
3
2
3
9
2 2 4
−
was added for rinsing. The mixture was left at rt for several hours until
turquoise needles formed. The needles were collected by vacuum
filtration and washed with methanol, water, and methanol again, and
were left to dry. The dry needles were dissolved in hot DMSO. After
cooling down to rt, water was added until a white precipitate formed.
The precipitate was collected by vacuum filtration, washed with water
and methanol, and dried under vacuum to give product 2 (2.86 g, 44%
yield) as a white solid. Suitable crystals for X-ray diffraction were
−1
1
mg, 83% yield via procedure A). Melting point 195−198 °C (dec). H
NMR (200 MHz, D O): δ 4.1−4.06 (m, 4H), 3.51 (t, J = 13.5 Hz,
2
2H), 1.8−1.66 (m, 4H), 1.57−1.39 (m, 4H), 0.99 (t, J = 7.47 Hz, 6H)
obtained by slow evaporation of the white product from CHBr .
ppm. 13C NMR (50 MHz, D O): δ 64.6 (t, J = 3.8 Hz), 56.9 (t, J =
3
2
1
31
Melting point 244−245 °C (dec). H NMR (200 MHz, DMSO-d ):
63.4 Hz), 31.8 (t, J = 4.2 Hz), 18.4, 13 ppm. P NMR (81 MHz,
6
1
3
−
δ 4.64 (t, J = 12.3 Hz, 2H), 3.8−3.6 (m, 8H) ppm. C NMR (50
D O): δ 101.9 ppm. HRMS (MALDI) m/z: calcd for C H O P S
2
9
21
2 2 4
3
1
−
MHz, DMSO-d ): δ 60.3 (t, J = 41.23 Hz), 41.9 ppm. P NMR (81
[M-H] 350.989, found 350.988. FT-IR (ATR): 2958m, 2900m,
1467w, 1381w, 1230w, 1065m, 1057m, 978m, 883w, 790m, 765s, 617s
6
MHz, DMSO-d ): δ 90.5 ppm. HRMS (MALDI) m/z: calcd for
6
+
−1
C H NaP S [M + Na] 346.847, found 346.844. IR (ATR): 2950w,
cm .
5
10
2 6
2
7
914w, 2890w, 1403w, 1344w, 1272w, 1239w, 1151w, 937w, 847w,
75m, 750m, 719m, 628s, 548s cm .
Methylene-bis(1,3,2-dithiaphospholane-2-sulfide), 2. Meth-
Disodium-O,O′-dioctyl-methylenediphosphonotetrathioate,
1c. Product 1c was obtained from reaction of 2 (100 mg, 0.31 mmol)
with octanol (3 mL, procedure A) (or 242 mg, 1.86 mmol, procedure
B) as a white solid (30 mg, 19%, and 16 mg, 10% yield via procedure A
−1
ylene-bis(phosphonothioic dichloride) 4 (0.1 g, 0.35 mmol) was
dissolved in dry CHBr3 (1.5 mL) followed by addition of 1,2-
1
and B, respectively). Melting point 168−170 °C (dec). H NMR (200
2
75
dx.doi.org/10.1021/jo301786m | J. Org. Chem. 2013, 78, 270−277

The Journal of Organic Chemistry
Article
MHz, D O): δ 4.07−3.96 (m. 4H), 3.48 (t, J = 13.22 Hz, 2H), 1.76−
Triethylammonium-O-(4-((S)-2-benzamido-3-ethoxy-3-oxo-
propyl)phenyl)((2-sulfido-1,3,2-dithiaphospholan-2-yl)-
methyl)phosphonodithioate, 14. Compound 2 (100 mg, 0.31
mmol) was suspended in dry ACN (10 mL). N-Benzoyl-L-tyrosine
ethyl ester (1.86 mmol) was added followed by the addition of DBU
2
13
1
.63 (m, 4H), 1.44−1.27 (m, 20H), 0.94−0.87 (m, 6H) ppm.
C
NMR (100 MHz, CD OD): δ 65.4, 60.1 (t, J = 62.2 Hz), 33.1, 31.7 (t,
3
31
J = 4.2 Hz), 30.7, 30.5, 27.1, 23.7, 14.4 ppm. P NMR (81 MHz,
D O): δ 101.8 ppm. HRMS (MALDI) m/z: calcd for C H O P S
M-H] 463.115, found 463.116. FT-IR(ATR): 2920s, 2852m, 1467w,
83s, 776s, 762s, 742s, 637s cm .
−
2
17 37
2 2 4
−
(100 mg, 0.66 mmol). The crude products were separated over
[
9
−1
semipreparative RP-C18-HPLC eluting with 0.1 M TEAA-ACN 65:35
for 5 min then with a linear gradient of 40:60 up to 16 min (t = 12.5
Disodium-O,O′-bis(2-(ethyl)butyl)-methylenediphosphono-
R
tetrathioate, 1f. Product 1f was obtained from reaction of 2 (100
min). The relevant fraction was freeze-dried several times until a
mg, 0.31 mmol) with 2-ethylbutanol (172 mg, 1.86 mmol) as a white
constant weight was attained. Product 14 was obtained as a clear oily
1
solid (17 mg, 12% yield via procedure B). Melting point 170−173 °C
solid (59 mg, 33% yield). H NMR (600 MHz, CDCl
): δ 9.41 (br, s,
3
1
(
1
(
=
dec). H NMR (200 MHz, D O): δ 4.0−3.85 (m, 4H), 3.47 (t, J =
1H), 7.70 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 7 Hz, 1H), 7.45−7.40 (m,
4H), 7.06 (d, J = 8.16 Hz, 2H), 6.56 (d, J = 7.44 Hz, 1H), 5.03−4.97
(m, 1H), 4.21 (q, J = 7.19 Hz, 2H), 4.06 (t, J = 13.08 Hz, 2H), 3.70−
3.60 (m, 2H), 3.55−3.45 (m, 2H), 3.21 (ddd, J = 29.4, 14.08, 5.44 Hz,
2H), 3.11 (q, J = 7.16 Hz, 6H), 1.29 (t, J = 7.19 Hz, 3H), 1.24 (t, 7.16
2
13
3.62 Hz), 1.67−1.18 (m, 10H), 0.89 (t, J = 7.26 Hz) ppm. C NMR
50 MHz, D O): δ 66.7 (t, J = 3.9 Hz), 57.1 (t, J = 64.5 Hz), 40.8 (t, J
4 Hz), 22.2, 10.1 ppm. P NMR (81 MHz, D O): δ 101.9 ppm.
2
HRMS (MALDI) m/z: calcd for C H O P S [M-H] 407.052,
2
31
−
−
13
29
2 2 4
Hz, 9H) ppm. 13C NMR (150 MHz, D
O): δ 171.7, 167, 150.86 (d, J
found 407.050. FT-IR(ATR): 2960m, 2932m, 2874w, 1458w, 1378w,
2
−1
1
000s, 956s, 794s, 756s, 621s cm .
= 10.2 Hz), 134.1, 131.9, 131.5, 130.7, 129.76, 128.8, 127.17, 123.6,
Disodium-O,O′-dibenzyl-methylenediphosphonotetra-
123.5, 115.6, 61.8, 60.7 (dd, J = 66.9, 42.8 Hz), 53.7, 46.2, 41.6, 37.4,
14.4, 8.6 ppm. 31P NMR (243 MHz, CDCl ) 100.9 (d, J = 12.68 Hz),
thioate, 1g. Product 1g was obtained from reaction of 2 (100 mg,
3
−
0.31 mmol) with benzyl alcohol (3 mL, procedure A) (or 201 mg, 1.86
89.8 (d, J = 12.68 Hz) ppm. ESI-MS m/z: 576 [M − H] . HRMS
−
mmol, procedure B) as a white solid (108 mg, 75% and 24.5 mg, 17%
(MALDI) m/z: calcd for C H NO P S [M] 575.978, found
21
24
4 2 5
yield via procedures A and B, respectively). Melting point 248−249
575.978
1
(
(
dec). H NMR (200 MHz, D O): δ 7.49−7.36 (m, 10H), 5.07−5.03
Tetrasodium-O,O′-bis(4-((S)-2-benzamido-3-ethoxy-3-oxo-
propyl)phenyl)((oxido((2-((2((oxidohydrophospho-
rothioatothio)thio)ethyl)disulfanyl)ethyl)thio)phospho-
rothioyl)bis(methylene))diphosphonodithioate, 15. Product 15
was obtained by the same procedure as for 14. After the HPLC
separation (t = 6 min), product 15 triethylammonium salt was
exchanged to the corresponding sodium salt by passing through CM
2
13
m, 4H), 3.59 (t, J = 13.4 Hz, 2H) ppm. C NMR (50 MHz, D O): δ
2
1
37.5, 128.3, 127.9, 127.8, 65.7 (t, J = 3.3 Hz), 57.3 (t, J = 63.5 Hz)
31
ppm. P NMR (81 MHz, D O): δ 103.4 ppm. HRMS (MALDI) m/z:
2
−
−
calcd for C H O P S [M − H] 418.958, found 418.954. FT-IR
15
17
2 2 4
(
ATR): 2922w, 1496w, 1454w, 1373w, 1210w, 1123w, 977m, 949m,
R
−1
761s, 725s, 693s, 617s cm .
+
Sephadex Na . Product 15 was obtained as a white-yellowish solid (35
mg, 9% yield) (exists with 10% of the thiol). Melting point 206−212
Disodium-O,O′-[2-(methoxybenzyl)]-methylenediphospho-
notetrathioate, 1h. Product 1h was obtained from reaction of 2
1
°
C (dec). H NMR (600 MHz, D O): δ 7.64 (d, J = 7.68 Hz, 4H),
7
(
100 mg, 0.31 mmol) with 2-methoxybenzyl alcohol (3 mL, procedure
2
.60 (t, J = 7.31 Hz, 2H), 7.48 (t, J = 7.48 Hz, 4H), 7.38 (d, J = 7.83
Hz, 4H), 7.26 (d, J = 8.15 Hz, 4H), 4.27−4.21 (m, 4H), 3.57 (t, J =
3.84 Hz, 4H), 3.34−3.30 (m, 2H), 3.20−3.14 (m, 6H), 2.90−2.85
m, 4H), 1.27 (t, J = 7.15 Hz, 6H) ppm. 13C NMR (150 MHz, D O):
A) (or 257 mg, 1.86 mmol, procedure B) as a white solid (60 mg, 37%,
and 3 mg, 2% yield, for procedures A and B, respectively). Melting
1
1
(
point 249−250 °C (dec). H NMR (200 MHz, D O): δ 7.50 (d, J =
2
7
.47 Hz, 4H), 7.32 (t, J = 8.04 Hz, 4H), 7.05−6.90 (m, 4H), 5.09−
2
.00 (m, 4H), 3.80 (s, 6H), 3.60 (t, J = 13.58 Hz, 2H) ppm. 13C NMR
δ 173.2, 170.67, 150.4, 150.3, 132.8, 132.5, 132.3, 129.8, 129.6, 128.7,
5
1
22.6, 122.5, 62.6, 57.4 (t, J = 65.71 Hz), 54.8, 38, 35.7, 32, 13.3 ppm.
P NMR (243 MHz, D O): δ 104.6 (d, J = 20.7 Hz), 67.5−67.3 (m)
(
6
75 MHz, D O): δ 156.6, 129.4, 129.2, 125.8 (t, J = 4.6 Hz), 120.8,
2
1.4 (t, J = 2.9 Hz), 57.6 (t, J = 63.2 Hz), 55.7 ppm. P NMR (81
31
31
2
‑
MHz, D O): δ 103.6 ppm. HRMS (MALDI) m/z: calcd for
ppm. ESI-MS m/z: 1187 [M − H] . HRMS (MALDI): m/z: calcd for
2
−
−
−1 −
C H O P S [M − H] 478.979, found: 478.976. FT-IR(ATR):
C H K N Na O P S10 [M + K + Na − H] 1246.907, found
42 49 1 2 1 10 4
17
21
4 2 4
2
9
937w, 2836w, 2360w, 1493m, 1463w, 1244m, 1121s, 1025m, 981m,
1246.905.
−1
Coordination of Zn(II)/Ca(II) by 1b Monitored by 1H/31P
55m, 754s, 727m, 637m cm .
NMR. Compound 1b (3.4 mg, 0.0086 mmol) was dissolved in DMSO-
Disodium-O,O′-bis((1H-benzo[d]imidazol-2-yl)methyl)-
1
31
methylenediphosphonotetrathioate, 1j. Product 1j was obtained
from reaction of 2 (100 mg, 0.31 mmol) with 2-benzimidazolemetha-
nol (276 mg, 1.86 mmol), as a white solid (56 mg, 36% yield via
d
6
(0.6 mL), and H/ P NMR spectra were measured at 200 and 81
MHz, respectively. ZnCl (0.52 mg, 0.0038 mmol, 0.45 equiv, and then
1.2 mg, 0.0088, overall 1.45 equiv) was added, and the H/ P NMR
spectra were measured.
2
1
31
1
procedure B). Melting point 210−212 °C (dec). H NMR (200 MHz,
D O): δ 7.24−7.19 (m, 4H), 7.07−7.02 (m, 4H), 5.28−5.23 (m, 4H),
Compound 1b (2 mg, 0.005 mmol) was dissolved in D
2
O (0.6 mL),
and 1H/ P NMR spectra were measured at 200 and 81 MHz,
respectively. CaCl (0.75 mg, 0.005 mmol, 1 equiv and then additional
2
13
31
3
.82 (t, J = 13.06 Hz, 2H) ppm. C NMR (50 MHz, D O): δ 151.1 (t,
J = 5.5 Hz), 122.2, 114.1, 58.3, 57.6 (t, J = 63.3 Hz) ppm. P NMR
2
31
2
1
31
(
81 MHz, D O): δ 106.7 ppm. HRMS (MALDI) m/z: calcd for
0.75 mg, overall 2 equiv) was added, and the H/ P NMR spectra
were measured.
UV−Vis Measurements of 1g−Ni(II) Complex. A 0.05 mM
DCM solution of DBU 1g salt was titrated by 5 mM Ni(BF ) in
EtOH; 1 μL of the Ni(II) solution was added each time. After each
addition the absorbance was measured at 321 nm.
ESR OH Radical Assay. ESR settings for OH radicals detection
were as follows: microwave frequency, 9.76 GHz; modulation
frequency, 100 kHz; microwave power, 6.35 mW; modulation
amplitude, 1.2 G; time constant, 655.36 ms; sweep time 83.89 s;
2
−
−
C H N O P S [M − H] 498.970, found 498.968. FT-IR(ATR):
2
17
17
4
2 2 4
924w, 1435w, 1043m, 995w, 740s, 632s.
Disodium-O,O′-bis(4-((S)-2-benzamido-3-ethoxy-3-oxo-
4 2
propyl)phenyl)-methylenediphosphonotetrathioate, 1k. Prod-
uct 1k was obtained from reaction of 2 (100 mg, 0.31 mmol) with s-
ethyl-2-benzamido-3-(4-hydroxyphenyl)propanoate (583 mg, 1.86
mmol, procedures B), as a white solid (146 mg, 54% yield via
1
procedure B). Melting point >175 °C (slow decomposition). H NMR
(
600 MHz, D O): δ 7.63 (d, J = 7.53 Hz, 4H), 7.59 (t, J = 7.18 Hz,
2
5
2
7
H), 7.47 (t, J = 7.18 Hz, 4H), 7.32 (d, J = 8.11 Hz, 4H), 7.19 (d, J =
.53 Hz, 4H), 4.27−4.19 (m, 4H), 3.79 (t, J = 13.06 Hz, 2H), 3.30
and receiver gain 2 × 10 in experiments with Cu(I) and Fe(II).
A 1 mM Cu(CH CN) PF solution in acetonitrile (10 μL) or 1 mM
3
4
6
(
dd, J = 14.22 Hz, 5.90 Hz, 2H), 3.16 (dd, J = 14.22 Hz, 9.4 Hz, 2H),
FeSO (10 μL) was added to 5−500 μM of tested compound (10 μL)
4
1
1
.25 (t, J = 7.08 Hz, 6H) ppm. 13C NMR (150 MHz, D O): δ. 173.2,
solutions. All final solutions of Cu(CH CN) PF contained 10% v/v
2
3
4
6
70.7, 150.5, 132.9, 132.4, 132.2, 129.7, 128.6, 127.1, 122.5, 62.6, 58.7
acetonitrile. Afterward, 1 mM Tris buffer, pH 7.4, (10 μL) was added
to the mixture. After mixing for 2 s, 100 mM DMPO (10 μL) was
quickly added followed by the addition of 100 mM H O (10 μL).
1
(
t, J = 64.8 Hz), 54.8, 35.6, 13.2 ppm. 3 P NMR (243 MHz, D O): δ
2
−
1
04.7 ppm. ESI-MS m/z: 829 [M − H] . HRMS (MALDI) m/z: calcd
2
2
−
−
for C H N O P S [M] 829.106, found 829.107.
Final sample pH values for the Cu(I) and Fe(II) systems ranged
37
39
2
8 2 4
2
76
dx.doi.org/10.1021/jo301786m | J. Org. Chem. 2013, 78, 270−277

The Journal of Organic Chemistry
Article
between 7.2 and 7.4. Each ESR measurement was performed 150 s
after the addition of H O . All experiments were performed at room
temperature, in a final volume of 100 μL.
(26) Canty, A. J.; Kishimoto, R. Inorg. Chim. Acta 1977, 24, 109−122.
(27) Richter, Y.; Fischer, B. JBIC, J. Biol. Inorg. Chem. 2006, 11,
1063−1074.
2
2
ASSOCIATED CONTENT
■
*
S
Supporting Information
Drawing of the system used to synthesize 2, copies of H, 13C,
1
3
1
and P NMR spectra, copies of FT-IR spectra of the
compounds, and X-ray data for compound 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Fax: 972-3-6354907. Phone: 972-3-5318303. E-mail: bilha.
fischer@biu.ac.il
■
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to thank Dr. Laurent Benisvy, Bar-Ilan
University, for allowing us to use his FT-IR equipment.
■
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