Facile high yielding synthesis of symmetric esters of methylenebisphosphonic acid

Article abstract of DOI:10.1016/S0040-4020(01)00846-8

The 1H-tetrazole catalyzed coupling of methylenebis(phosphonic dichloride), CH₂(POCl₂)₂, with primary alkyl, cyclic secondary alkyl, aromatic, and silicon- and fluorine-containing alcohols selectively affords symmetric P,P′-dialkyl partial esters as well as homoleptic and mixed tetraesters. Two partial ester intermediates, methylenebis(2-ethylhexyl phosphonic chloride) and 2-ethylhexyl methylenebisphosphonic trichloride, were observed by ¹H- and ³¹P NMR spectroscopy in the esterification of CH₂(POCl₂)₂ with 2-ethyl-1-hexanol.

Full text of DOI:10.1016/S0040-4020(01)00846-8

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 8637±8645
Facile high yielding synthesis of symmetric esters of
methylenebisphosphonic acid
Dominique C. Stepinski, Derek W. Nelson, Peter R. Zalupski and Albert W. Herlingerp
Department of Chemistry, Loyola University Chicago, 6525 N. Sheridan Road, Chicago, IL 60626, USA
Received 9July 2001; revised 15 July 2001; accepted 16 July 2001
AbstractÐThe 1H-tetrazole catalyzed coupling of methylenebis/phosphonic dichloride), CH2/POCl2)2, with primary alkyl, cyclic
secondary alkyl, aromatic, and silicon- and ¯uorine-containing alcohols selectively affords symmetric P,P0-dialkyl partial esters as well
as homoleptic and mixed tetraesters. Two partial ester intermediates, methylenebis/2-ethylhexyl phosphonic chloride) and 2-ethylhexyl
methylenebisphosphonic trichloride, were observed by 1H- and 31P NMR spectroscopy in the esteri®cation of CH2/POCl2)2 with 2-ethyl-1-
hexanol. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
desired number and location of ester substituents. One
selective method that has been used for the preparation of
P,P0-dialkyl partial esters is the carbodiimide-promoted
coupling of an alkylenebisphosphonic acid with a primary
alcohol.6,9 The procedure, however, requires long reaction
times at elevated temperature and it is not applicable for
water soluble, phenyl, ¯uoroalkyl or some silicon-contain-
ing esters.10 Separation of the desired product also requires a
series of tedious acid±base extractions that generate large
volumes of waste and render a large-scale synthesis
laborious and costly.
Bisphosphonic acids and their ester derivatives are among
the most important of the organophosphorus compounds.1,2
These molecules form very stable complexes with a wide
variety of metal ions,3,4 and many applications rely on their
strong metal ion complexing ability.1,5,6 In our laboratory,
the design and functionalization of bisphosphonates is
motivated by their ability to extract actinides under highly
acidic conditions and their potential for use in transuranic
mixed waste treatment. Partial esteri®cation of a bis-
phosphonic acid can enhance its solubility in non-aqueous
solvents and modify its aggregation or solvent extraction
properties, while leaving the remaining acidic hydrogen
atoms available for charge neutralization.3±6
Methods for the deprotection of tetraesters to the corre-
sponding partial esters of dichloromethylenebisphosphonic
acid using tertiary and secondary amines as dealkylating
reagents have been developed. The deprotection, however,
requires the presence of an activating group to instigate the
reaction.11,12 Dealkylation of methylenebisphosphonate
tetraesters may be achieved with acids, bases and silylating
reagents, but these methods generally are not selective,
producing a mixture of products that require chromato-
graphy or ef®cient fractional crystallization for separation.13
Bisphosphonates are also widely used for the treatment of
diseases of the skeletal system as well as bone formation and
resorption disorders.2,7 Chelation of a metal ion by a bis-
phosphonate may increase its toxicological acceptability,
facilitate its transport and ensure its selective concentration
in target organs.2 Partial ester derivatives are particularly
good candidates as drugs for the treatment of bone diseases
since their lower polarity and acidity should lead to better
binding to bone, improved bio-availability and superior
therapeutic behavior.8
Recently, we reported a highly ef®cient method for
selectively coupling methylenebis/phosphonic dichloride),
1, with two equivalents of alcohol under mild, anhydrous
conditions to form water-immiscible P,P0-dialkyl partial
esters of methylenebisphosphonic acid /2a±2f).14 The
method, which draws upon earlier work describing the
formation of mixed dialkyl phosphonates15 and nucleoside
50-methylenebisphosphonates,16 uses 1H-tetrazole to
catalyze the coupling reaction. The procedure does not
require chromatographic or acid±base extractive puri®ca-
tion and offers substantial advantages over the carbo-
diimide-promoted coupling route.14 This method has been
expanded here to include water-soluble P,P0-disubstituted
Utilization of partial esters has been limited to some extent
by the lack of ef®cient synthetic methods for their prepara-
tion. The main dif®culty in preparing partial esters is the
selectivity of the reactions used to obtain a product with the
Keywords: phosphonic acids and derivatives; esteri®cation; tetrazoles;
aggregation.
Corresponding author. Tel.: 11-773-508-3127; fax: 11-773-508-3086;
e-mail: aherlin@luc.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00846-8

8638
D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
partial esters as well as symmetric mixed and homoleptic
methylenebisphosphonate tetraesters which are viable
precursors to the symmetric partial esters.
ing a high purity product are careful control of reagent
stoichiometry, use of anhydrous solvents, and slow simul-
taneous addition of alcohol and hindered base to the acid
chloride. Pyridine has been used as an HCl binder in a very
high yielding preparation of tetraalkyl methylenebis-
phosphonates,7 but under the conditions reported here, it is
not effective in catalyzing the selective formation of
symmetric partial esters from 1. Further, it has been
reported that pyridine does not catalyze the direct formation
of mixed diesters from phosphonic dichlorides.15 Advan-
tages of Path I over existing methods for preparing
symmetric bisphosphonate partial esters include: higher
yields, shorter reaction times, milder conditions, less
expensive and less toxic starting reagents, smaller second-
ary waste streams and simpler isolation and puri®cation
procedures.
2. Results and discussion
A facile, high yielding synthesis of symmetric esters of
methylenebisphosphonic acid from the corresponding acid
chloride has been developed. The method has general
synthetic applicability for the preparation of P,P0-disubsti-
tuted partial esters /2a±2h) as well as symmetric mixed
dimethyl /3c±3i) and homoleptic /4c±4i) tetraesters
/Scheme 1). Primary alkyl, cyclic secondary alkyl,
aromatic, and ¯uoro- and silicon-containing alcohols
were utilized in this method. The procedures afford the
best yields with primary and cyclic secondary alcohols;
typical yields of puri®ed esters range from 85±98%.
Lower yields /,25%) are obtained with highly hindered
secondary alcohols, e.g. sec-butyl alcohol, as well as for
the mixed aryl and ¯uoroalkyl tetraesters. No esteri®cation
products were obtained in the reaction of CH2/POCl2)2 with
tert-butyl alcohol. The product, if formed, presumably
undergoes rapid hydrolysis.13,15
An excess of methanol or the ®rst alcohol is used in Path II
or III in place of water to form a mixed P,P0-dimethyl /3c±
3i) or homoleptic tetraester /4c±4i), respectively. The
tetraesters, which are amenable to separation and puri®ca-
tion by ¯ash chromatography, are viable precursors to
water-soluble symmetric P,P0-disubstituted partial esters.
This modi®ed version of the procedure provides an attrac-
tive alternate route to partial esters when the ®rst alcohol
reacts vigorously with the acid chloride to produce a
mixture of all possible bisphosphonate esters. A variety of
mineral acid /HCl), lithium halide17 and trimethylsilyl
halide18 reagents were investigated in attempts to deprotect
the bisphosphonate precursors to the partial esters. Selective
dealkylation of the mixed dimethyl esters to the correspond-
ing partial esters was achieved using bromotrimethylsilane
/TMSBr) as the deprotecting agent as reported by McKenna
and coworkers.18 The selective deprotection achieved using
TMSBr exploits the greater reactivity of the methyl ester to
silylation and the signi®cantly higher hydrolysis rate of the
resulting silyl ester compared to that of a primary, secondary
or aryl ester.13,18 The bromotrimethylsilane dealkylation is
milder than most other deprotection procedures and
provides an added advantage of simplicity of workup.
Under the conditions described below, dealkylation of the
mixed dimethyl esters 3c±3h is highly selective. The yield
of high purity partial ester achieved using this method is
Reaction Paths I±III shown in Scheme 1 use 1H-tetrazole to
catalyze the regioselective coupling of methylenebis-
/phosphonic dichloride) with two equivalents of alcohol
under mild, anhydrous conditions to initially form a P,P0-
disubstituted bisphosphonate partial ester acid chloride
/vide infra). The resulting diester acid chloride is subse-
quently reacted with an excess of a hydroxylated compound
that can be water, methanol or the same alcohol to form the
corresponding partial ester, mixed methyl or homoleptic
tetraester, respectively.
The desired P,P0-dialkyl partial ester /2a±2f) is formed
directly when the unreacted P±Cl groups of the diester
acid chloride are quenched with excess water by Path I. If
the partial ester formed is water immiscible, it remains in
the organic phase while the tetrazole and diisopropylethyl-
amine partition into the aqueous phase as their respective
salts.15 Features of the process which are critical to obtain-
Scheme 1. a, Rˆoctyl; b, Rˆ2,4,4-trimethylpentyl; c, Rˆhexyl; d, Rˆcyclohexyl; e, Rˆ2-ethylhexyl; f, Rˆ3-/trimethylsilyl)propyl; g, Rˆbutyl; h,
Rˆphenyl; i, Rˆ2,2,3,3,4,4,4-hepta¯uorobutyl; DIEAˆdiisopropylethylamine, TMSBrˆbromotrimethylsilane.

D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
8639
in a variety of aprotic aromatic /benzene and toluene) and
chlorinated hydrocarbon /CH2Cl2 and CHCl3) solvents.
Aromatic solvents afford the highest yields and best purity.
Toluene with its lower vapor pressure and toxicity appears
to be the solvent of choice. Yields are generally 20±25%
lower with chlorinated hydrocarbon solvents and product
purity is lowered by the presence of non-phosphorus
containing hydrocarbon byproducts.
Fig. 1 compares the results of the vapor pressure osmometry
/VPO) measurements for a symmetric partial ester,
H2DcHe[MBP] /2d), with those for the corresponding
mixed methyl and homoleptic tetraesters, Me2cHe2[MBP]
/3d) and cHe4[MBP] /4d). As previously observed for
H2DEH[MBP] /2e)19,20 and H2DTMSP[MBP] /2f),9 the
VPO data indicates that the partial esters are dimeric in
toluene at 258C in the 0.01±0.12 m concentration range.
The linearity of the data indicates that the aggregation
constants are suf®ciently large that the aggregation of
the partial esters remains essentially unchanged over the
concentration range studied. The VPO data for the
tetraesters in contrast to that for the partial esters indicates
that the tetraesters are monomeric.
The 31P NMR spectra of the H2R2[MBP] partial esters /2a±
2h) and the R4[MBP] homoleptic tetraesters /4c±4i) consist
of a single sharp resonance. The position of this resonance at
,19and ,20 ppm for the H2R2[MBP] and R4[MBP] esters,
respectively, is in¯uenced by the nature of the ester-
substituent. The resonance occurs at slightly higher d values
in the ¯uoroalkyl esters and considerably lower d values in
Figure 1. Vapor pressure osmometry measurements /microvolts, mV,
versus molality, m) for H2DcHe[MBP] /2d), Me2cHe2[MBP] /3d), and
cHe4[MBP] /4d) relative to the monomeric standard sucrose octaacetate
in toluene at 258C. The average aggregation number, n, for the bisphos-
phonate was determined from the ratio of the slope of the best ®t straight
line for the sucrose octaacetate data to the slope of the best ®t straight line
1
the aryl esters. The H NMR spectra of these esters exhibit
resonances of the expected intensity and splitting patterns in
the appropriate spectral regions. There is no evidence of
unreacted alcohol in the samples.
for the bisphosphonate data, i.e. n ˆ ꢀmV=m†standard=ꢀmV=m†
:
bisphosphonate
higher than that previously obtained using carbodiimide-
promoted coupling procedures.6,9 Dealkylation of the
¯uoroalkyl ester Me2/C4H2F7)2[MBP] /3i) using TMSBr
was not selective. Consequently, isolation of the corre-
sponding ¯uoroalkyl partial ester, H2/C4H2F7)2[MBP], was
not attempted.
The 31P NMR spectra of the mixed tetraesters Me2R2[MBP]
/3a±3i) consist of two singlets /d,21) of approximately
equal intensity suggesting that diastereomers, a dl enantio-
meric pair and a meso form, are present. This product distri-
bution is further con®rmed by the 1H NMR behavior of the
P±CH2±P, OCH3 and OCH2 functionalities. These groups
show additional resonances of expected intensities for the
The tetrazole catalyzed esteri®cation of 1 was investigated
Figure 2. The 400 MHz 1H NMR spectrum of Me2Ph2[MBP] /3h) in CD2Cl2.

8640
D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
presence of two diastereomers in approximately equal
the appearance of two doublets of equal intensity at d 25.4
and 21.3 /Jˆ39.4 Hz) that are assigned to the ester triacid
chloride 6. During the early stages of the reaction, the
CH2/POCl2)2 singlet disappeared at approximately the
same rate as the Cl3EH[MBP] doublets appeared. Through-
out the latter stages of the reaction, the doublets disappear at
1
amounts. The 31P- and H NMR spectra of the methylene-
bisphosphonic acids /2a±2h) do not contain additional
resonances due to the presence of diastereomers because
their acidic hydrogen atoms undergo rapid exchange on
the NMR time scale. The position of the 31P resonance in
the mixed methyl esters is also in¯uenced by the nature of
the substituent as described above for the partial and
homoleptic esters.
The 31P NMR spectrum of methylenebis/phenyl methyl
phosphonate) Me2Ph2[MBP] /3h) shows the two singlets
indicative of diastereomers, consistent with the behavior
1
discussed for the other mixed tetraesters. The H NMR
spectrum shows three resonances as expected for the
bridging methylene /P±CH2±P), however, additional
resonances rather than the two expected for the methoxy
/±OCH3) groups are observed /Fig. 2). This behavior may
arise from the diamagnetic anisotropy of the phenyl ring.
Because of the anisotropy of the magnetic ®eld exerted by
an aromatic ring, protons of groups close to the ring may
resonate at different values of the applied magnetic ®eld.
This phenomenon was previously observed by Siddall and
Prohaska for certain phosphinyl chlorides, phosphinates,
phosphonates, phosphates and phosphonites which
1
contained a phenyl ring.21,22 The H NMR spectrum of the
diphenyl methylenebisphosphonic acid H2DPh[MBP] /2h)
does not show the additional resonances. This is consistent
with the observations previously made by Siddall and
Prohaska,21,22 and it is due to rapid exchange of the acidic
hydrogen atoms.
The infrared spectra of the symmetric partial esters have
three broad bands of medium intensity, characteristic of
the P/O)/OH) group, which appear at approximately 2715,
2325, and 1675 cm21. The presence of these bands is
indicative of a strongly hydrogen-bonded alkylenebis-
phosphonic acid.23 These characteristic features have been
previously discussed in detail for H2DEH[MBP] /2e)19,20
and H2DTMSP[MBP] /2f).9 The P/O)/OH) bands are not
present in the spectra of the tetraesters and, as expected,
the phosphoryl /PvO) band in the partial esters
/t1240 cm21) is lower in energy than in the tetraesters
/t1260 cm21). While the PvO band position generally is
not strongly in¯uenced by the nature of the alkyl-sub-
stituent, the band appears ,15 cm21 higher in the aryl
compounds and ,30 cm21 lower in the ¯uoroalkyl
compounds as previously reported for related organo-
phosphorus extractants.24 The ¯uoroalkyl and aryl
compounds show stretching and bending vibrations in the
characteristic C±F and aromatic regions, respectively.25
The selective esteri®cation of 1 with 2-ethyl-1-hexanol was
carried out under anhydrous conditions in a NMR tube using
benzene-d6 as the solvent and tetrazole as the catalyst and
base. The reaction was followed by 31P- and 1H NMR spec-
troscopy. Two principal reaction intermediates were
observed and identi®ed on the basis of chemical shifts and
splitting patterns as methylenebis/2-ethylhexyl phosphonic
chloride), Cl2EH2[MBP] /5) and 2-ethylhexyl methylene-
bisphosphonic trichloride, Cl3EH[MBP] /6). As the reaction
proceeded, the 31P NMR spectrum, Fig. 3, showed the
disappearance of the singlet at d 22.1 due to 1, as well as
Fig. 3. The tetrazole catalyzed esteri®cation of methylenebis/phosphonic
dichloride) with 2-ethyl-1-hexanol in d6-benzene followed by 31P NMR
spectroscopy. CH2/POCl2)2 /1) is converted to H2DEH[MBP] /2e) through
the partial ester acid chloride intermediates Cl2EH2[MBP] /5) and
Cl3EH[MBP] /6).

D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
8641
about the same rate as two singlets of nearly equal intensity
appear at d 24.6 and 24.4. The singlets are attributed to the
formation of the ester diacid chloride 5 that exists in
solution as a mixture of diastereomers.
tion of ¯uoroalkyl partial esters of methylenebisphosphonic
acid, nor do they work well with highly hindered alcohols.
The symmetric partial esters are dimeric in toluene at 258C
whereas the mixed methyl esters and the homoleptic
tetraesters are monomeric. Two partial ester acid chloride
reaction intermediates Cl2EH2[MBP] /5) and Cl3EH[MBP]
/6) were observed in the esteri®cation of CH2/POCl2)2 /1)
with 2-ethyl-1-hexanol. The diester acid chloride
Cl2EH2[MBP] /5) and the Me2R2[MBP] mixed tetraesters
/3c±3i) exist in solution as a mixture of diastereomers, a dl
enantiomeric pair and a meso form.
1
The H NMR spectrum is less informative because of its
complexity, but the presence of 2-ethyl-1-hexanol as well as
several phosphorus-containing partial esters is evident. The
signals in the P±CH2±P and O±CH2 chemical shift regions
change in intensity as the reaction proceeds. The 1H
resonances associated with the P±CH2±P groups of the
phosphorus-containing intermediates appear ,0.3 ppm
down®eld from the corresponding signal in the symmetric
partial ester. This down®eld shift is consistent with the
presence of electron-withdrawing chloro groups on the
phosphorus atoms of the bisphosphonate intermediates.
4. Experimental
4.1. General methods
All reagents were supplied by Aldrich and used as received
without further puri®cation. Methylenebis/phosphonic
dichloride) was handled under anhydrous conditions.
Anhydrous solvents were dispensed from Aldrich Sure-
Seal bottles and all glassware was oven dried at 1208C.
Flash column chromatography was performed using silica
gel /32±63 mm, Selecto, Fisher Scienti®c). The purity of
the compounds was established by 1H- and 31P NMR
spectroscopy, potentiometric titration, elemental analysis
and infrared spectroscopy.
In this work, no attempt was made to isolate the acid
chloride intermediates. A report in the literature describes
the isolation of ethylenebis/cyclohexyl phosphonic
chloride) prepared by reacting ethylenebis/dicyclohexyl
phosphonate) with phosphorus pentachloride.26 Attempts
to purify this diester acid chloride precursor resulted in
decomposition, but the impure product was successfully
converted to P,P0-dicyclohexyl ethylenebisphosphonic
acid by hydrolysis with water. Attempts to prepare the
methylenebis/cyclohexyl phosphonic chloride) homologue
by this method, however, were unsuccessful.26
1
The H- and 31P NMR spectra were recorded on a VXR
400 MHz spectrometer using CDCl3 as the solvent /unless
stated otherwise). The d values in parts per million /ppm)
are relative to internal CHCl3 /unless stated otherwise) and
external 85% H3PO4, respectively. Infrared spectra were
obtained on a Mattson Genesis series FTIR spectrometer
operating in the 4000±600 cm21 region using a liquid IR
cell with NaCl windows. Spectra were recorded for 0.10 M
solutions of the esters in CCl4 using 64 scans at 4 cm21
resolution with solvent as the background.
The mechanism for the tetrazole catalyzed coupling of
methylenebis/phosphonic dichloride) with alcohol has not
been established, but it has been postulated that tetrazole
functions as a nucleophilic catalyst.15 In this role, tetrazole
adds to 1 forming a trigonal bipyramidal pentacovalent
intermediate that subsequently ejects the leaving group in
the microscopic reverse of the nucleophilic addition reac-
tion.27,28 The pentacovalent intermediate is short lived and
not observed in the 31P NMR spectrum.27 Tetrazole is also a
good leaving group that enhances the susceptibility of
phosphorus to alcoholysis.29
The aggregation properties of the partial and tetraesters
were measured in toluene at 258C by vapor pressure
osmometry as previously described.19 The instrument was
calibrated using standard toluene solutions of sucrose octa-
acetate. A plot of the measured voltage /mV) versus sucrose
octaacetate molality /m) gave a slope of 1964 mV m21 for
the instrument calibration constant.
An investigation of the solvent extraction of metal ions by
the bisphosphonate ligands reported here is currently under-
way in our laboratory. Initial results indicate that the
extraction performance of H2DEH[MBP] /2e) and
H2DTMSP[MBP] /2f) formed by the 1H-tetrazole catalyzed
esteri®cation of methylenebis/phosphonic dichloride) is as
good if not better than the performance of these extractants
formed by carbodiimide-promoted coupling procedures.30
The equivalent weight of the partial esters was determined
by titration with 0.1 M NaOH in an isopropanol±toluene
mixture using an Orion EA 940 pH meter. Combustion
analyses were performed by Galbraith Laboratories, Inc.,
Knoxville, TN. High-resolution fast atom bombardment
/HRFAB) mass spectrometry was performed by the
Washington University Resource for Biomedical and Bio-
organic Mass Spectrometry, St. Louis, MO. Melting points
were measured using an Arthur H. Thomas, Hoover capil-
lary melting point apparatus with a calibrated thermometer.
3. Conclusion
A facile, high yielding synthesis of symmetric esters of
methylenebisphosphonic acid by the 1H-tetrazole catalyzed
coupling of methylenebis/phosphonic dichloride) with a
variety of alcohols has been developed. The procedures,
which are carried out under mild conditions, have general
synthetic applicability for the preparation of P,P0-disubsti-
tuted partial esters as well as homoleptic and symmetric
mixed tetraesters. The catalyzed coupling works best
when employed with primary and cyclic secondary
alcohols. The procedures are not applicable for the prepara-
4.2. A representative synthetic procedure for the
preparation of water-immiscible P,P0-partial esters of
methylenebisphosphonic acid (2a±2f), Path I
Methylenebis/phosphonic dichloride) /4.00 mmol) and

8642
D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
1H-tetrazole /0.6 mmol) were placed in a 100 mL Schlenk
¯ask under a nitrogen atmosphere and dissolved with
vigorous stirring in 50 mL of toluene. When the dissolution
was complete, a solution of the alcohol /7.92 mmol) and
diisopropylethylamine /8.80 mmol) in 20 mL of toluene
was added dropwise through an addition funnel over a 2 h
period. After stirring overnight at room temperature, the
reaction was quenched with water /30 mL) and the stirring
was continued for 15 min. The reaction mixture was trans-
ferred to a separatory funnel and the organic phase washed
with two 30 mL portions of 0.1 M HCl. The tetrazole and
diisopropylethylamine partitioned into the aqueous phase as
the salts and the partial ester remained in the organic phase.
The ®nal product was obtained by removing the solvent
under reduced pressure at 608C on a rotary evaporator
equipped with a water aspirator.
4.3.2. P,P0-Dibutyl methylenebisphosphonic acid,
H2DBu[MBP] (2g). This water-soluble partial ester,
obtained as a colorless oil in 96% yield, is dimeric in toluene
/slope 950 mV m21). 1H NMR /CDCl3) d 8.81 /s, 2H, OH),
4.11 /dt, 4H, JP,HˆJˆ6.8 Hz, OCH2), 2.45 /t, 2H,
JP,Hˆ21.6 Hz, P±CH2±P), 1.68 /tt, 4H, Jˆ6.8 Hz,
OCH2CH2), 1.46±1.36 /m, 4H, CH2CH3), 0.95 /t, 6H,
Jˆ7.2 Hz, CH2CH3); 31P NMR /CDCl3) d 19.4 /s). IR
/CCl4) n /cm21) 2962, 2933, 2902, 2875, 2615, 2318,
1674, 1466, 1369, 1240, 1190, 1063, 1032, 1001, 895,
816, 777, 739. Equiv. wt.: calcd 144 g mol21, found
139g mol 21
.
4.3.3. Methylenebis(hexyl methyl phosphonate) mono-
hydrate, Me2He2[MBP]´H2O (3c) and P,P0-dihexyl
methylenebisphosphonic acid, H2DHe[MBP] (2c). The
mixed ester, obtained as a colorless oil in 85% yield after
puri®cation by ¯ash chromatography /5:95 v/v CH3OH/
ethyl acetate; Rfˆ0.8), is monomeric in toluene /slope
1905 mV m21). 1H NMR /CDCl3) d 4.10 /dt, 4H,
JP,HˆJˆ7.0 Hz, OCH2),31 3.81 /d, 6H, JP,Hˆ11.2 Hz,
OCH3),31 2.45 /t, 2H, JP,Hˆ21.0 Hz, P±CH2±P), 1.87 /br
s, 2H, H2O), 1.68 /tt, 4H, Jˆ6.9Hz, OCH 2CH2), 1.41±
1.24 /m, 12H, CH2), 0.89/t, 6H, Jˆ7.0 Hz, CH2CH3); 31P
4.3. A representative synthetic procedure for the
preparation of P,P0-dialkyl dimethyl methylene-
bisphosphonates (3c±3i) and P, P0-dialkyl methylene-
bisphosphonic acids (2c±2h), Path II
Methylenebis/phosphonic dichloride) /4.00 mmol) and 1H-
tetrazole /0.6 mmol) were placed in a 100 mL Schlenk ¯ask
and dissolved in 50 mL of toluene with vigorous stirring
under a nitrogen atmosphere. When the dissolution was
complete, a solution of the alcohol /8.00 mmol) and diiso-
propylethylamine /8.80 mmol) in 20 mL of toluene was
added dropwise through an addition funnel over a 2 h
period. After stirring overnight at room temperature under
an atmosphere of nitrogen, a solution of methanol
/10.0 mmol) and diisopropylethylamine /8.80 mmol) in
20 mL of toluene was added over a 20 min period. After
stirring for an additional 15 min, the diisopropylethyl-
ammonium and tetrazonium salts were removed by ®ltration
and the crude product was puri®ed by ¯ash chromatography.
The mixed tetraester product was obtained by removing the
solvent under reduced pressure at 608C on a rotary evapora-
tor equipped with a water aspirator.
NMR /CDCl3) d 21.40 /s), 21.38 /s). IR /CCl4) n /cm21
)
3473, 2958, 2931, 2860, 1741, 1468,1379, 1259, 1178,
1043, 1018, 962, 835, 779. Anal. calcd for
C15H34O6P2´H2O: C, 46.15; H, 9.29, found: C, 46.31; H,
8.88. The yield of the hydrolysis of the mixed ester to the
partial ester32 was 90%. Equiv. wt.: calcd 172 g mol21
,
found 181 g mol21. The H2DHe[MBP] partial ester is
dimeric in toluene /slope 949 mV m21). IR /CCl4) n
/cm21) 2960, 2931, 2860, 2603, 2326, 1672, 1468, 1368,
1241, 1189, 1042, 1003, 855, 811.
4.3.4. Methylenebis(cyclohexyl methyl phosphonate)
monohydrate, Me2cHe2[MBP]´H2O (3d) and P,P0-di-
cyclohexyl methylenebisphosphonic acid, H2DcHe[MBP]
(2d). The mixed methyl ester, obtained as a colorless oil in
85% yield after puri®cation by ¯ash chromatography
/25:75 v/v hexane/acetone; Rfˆ0.7), is monomeric in
Bromotrimethylsilane /7.50 mmol) was added at room
temperature to a stirred solution of the methylenebis-
phosphonate /3.00 mmol) in 5 mL of CH2Cl2. After stirring
for 30 min, the alkyl bromide byproducts and excess bromo-
silane were removed in vacuo and the reaction was
quenched with water /5 mL). The partial ester was obtained
by removing the water under reduced pressure at 608C on a
rotary evaporator equipped with a water aspirator.
1
toluene /slope 1931 mV m21). H NMR /CDCl3) d 4.54±
4.44 /m, 2H, CH), 3.78 /d, 6H, JP,Hˆ11.4 Hz, OCH3),31 2.43
/t, 2H, JP,Hˆ21.0 Hz, P±CH2±P), 2.06±1.17 /m, 20H); 31P
NMR /CDCl3) d 19.97 /s), 19.91/s). IR /CCl4) n /cm21
)
3454, 2939, 2860, 1450, 1371, 1255, 1178, 1047, 1009,
895, 825, 766. Anal. calcd for C15H30O6P2´H2O: C, 46.63;
H, 8.35, found: C, 46.98; H, 8.19. The yield of the
hydrolysis of the mixed methyl ester to the H2DcHe[MBP]
partial ester32 was 94%. Equiv. wt.: calcd 184 g mol21
,
4.3.1. Methylenebis(butyl methyl phosphonate) mono-
hydrate, Me2Bu2[MBP]´H2O (3g). This mixed tetraester,
obtained as a colorless oil in 85% yield after puri®cation by
¯ash chromatography /5:95 v/v CH3OH/CH2Cl2; Rfˆ0.9),
found 174 g mol21. The H2DcHe[MBP] partial ester is
dimeric in toluene /slope 964 mV m21). IR /CCl4) n
/cm21) 2939, 2861, 2659, 2322, 1674, 1451, 1371, 1235,
1188, 1124, 1081, 1012, 892, 872.
1
is monomeric in toluene /slope 1803 mV m21). H NMR
/CDCl3) d 4.11 /dt, 4H, JP,HˆJˆ6.8 Hz, OCH2),31 3.81 /d,
6H, JP,Hˆ11.2 Hz, OCH3),31 2.46 /t, 2H, JP,Hˆ21.2 Hz,
P±CH2±P), 1.67 /tt, 4H, Jˆ6.8 Hz, OCH2CH2), 1.46±1.36
/m, 4H CH2CH3), 0.94 /t, 6H, Jˆ7.4 Hz, CH2CH3); 31P
4.3.5. Methylenebis(2-ethylhexyl methyl phosphonate)
half-hydrate, Me2EH2[MBP]´1/2 H2O (3e) and P,P0-
di(2-ethylhexyl)
methylenebisphosphonic
acid,
NMR /CDCl3) d 21.40 /s), 21.38 /s). IR /CCl4) n /cm21
)
H2DEH[MBP] (2e). The mixed methyl ester, isolated as a
colorless oil in 82% yield after puri®cation by ¯ash
chromatography /25:75 v/v hexane/acetone; Rfˆ0.8), is
monomeric in toluene /slope 1960 mV m21). 1H NMR
/CDCl3) d 4.06±3.95 /m, 4H, OCH2), 3.82 /d, 6H,
3462, 2962, 2935, 2875, 1466, 1369, 1261, 1180, 1028, 987,
901, 818, 781, 756. Anal. calcd for C11H26O6P2´H2O: C,
39.52; H, 8.44, found: C, 39.77; H, 8.09. HRMS-FAB
/m/z): [M1H]1 calcd 317.1284, found 317.1276.

D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
8643
JP,Hˆ11.2 Hz, OCH3),31 2.45 /t, 2H, JP,Hˆ21.2 Hz, P±CH2±
P),31 1.70 /br s, ,1H, H2O), 1.61±1.54 /m, 2H, CH), 1.47±
1.23 /m, 16H, CH2), 0.92±0.88 /m, 12H, CH3); 31P NMR
/CDCl3) d 21.01 /s), 20.97 /s). IR /CCl4) n /cm21) 3473,
2960, 2931, 2860, 1464, 1381, 1259, 1178, 1026, 868, 818,
787. Anal. calcd for C19H42O6P2´1/2 H2O: C, 52.16; H, 9.91,
found: C, 52.29; H, 9.70. The yield of the hydrolysis of
the mixed methyl ester to the H2DEH[MBP] partial
ester32 was 92%. Equiv. wt.: calcd 200 g mol21, found
yield after puri®cation by ¯ash chromatography /40:60 v/v
ethyl acetate/CH2Cl2, Rfˆ0.7), is monomeric in toluene
1
/slope 1584 mV m21). H NMR /CDCl3) d 4.71±4.54 /m,
4H, OCH2), 3.85 /d, 6H, JP,Hˆ12.0 Hz, OCH3),31 2.62 /t,
2H, JP,Hˆ21.6 Hz, P±CH2±P);31 31P NMR /CDCl3) d 21.8
/s), 21.6 /s). IR /CCl4) n /cm21) 2960, 2931, 2856, 1458,
1404, 1356, 1269, 1232, 1207, 1184, 1124, 1092, 1039,
1014, 966, 926, 868, 820, 800, 766, 706, 633. Anal. calcd
for C11H12F14O6P2: C, 23.26; H, 2.13, found: C, 23.14; H,
2.30. Dealkylation of 3i was not selective and isolation of
the ¯uoroalkyl partial ester was not attempted.
203 g mol21
.
4.3.6. Methylenebis(3-(trimethylsilyl)propyl methyl
phosphonate) monohydrate, Me2TMSP2[MBP]´H2O
(3f) and P,P0-di(3-(trimethylsilyl)propyl) methylene-
bisphosphonic acid, H2DTMSP[MBP] (2f). The silyl-
containing mixed methyl ester, obtained as a colorless oil
in 65% yield after puri®cation by ¯ash chromatography
/20:80 v/v CH2Cl2/acetone; Rf1ˆ0.8), is monomeric in
toluene /slope 1980 mV m21). H NMR /CDCl3) d 4.06
4.4. A representative synthetic procedure for the
preparation of homoleptic tetraesters of methylene-
bisphosphonic acid (4c±4i), Path III
Methylenebis/phosphonic dichloride) /4.00 mmol) and 1H-
tetrazole /0.6 mmol) were placed in a 100 mL Schlenk ¯ask
under a nitrogen atmosphere and dissolved in 50 mL of
toluene with vigorous stirring. When the dissolution was
complete, a solution of the alcohol /16.0 mmol) and diiso-
propylethylamine /17.6 mmol) in 20 mL of toluene was
added dropwise through an addition funnel over a 2 h
period. After stirring overnight at room temperature, the
diisopropylethylammonium and tetrazonium salts were
removed by ®ltration and the product was puri®ed by
¯ash chromatography. The homoleptic tetraester product
was obtained by removing the solvent under reduced pres-
sure at 608C on a rotary evaporator equipped with a water
aspirator.
/dt, 4H, JP,HˆJˆ7.2 Hz, OCH2),31 3.82 /d, 6H JP,H
ˆ
11.2 Hz, OCH3),31 2.46 /t, 2H, JP,Hˆ21.0 Hz, P±CH2±
P),31 1.72±1.64 /m, 4H, OCH2CH2), 0.52±0.48 /m, 4H,
CH2Si), 20.02 /s, 18H Si/CH3)3); 31P NMR /CDCl3) d
20.93 /s), 20.91 /s). IR /CCl4) n /cm21) 3444, 2954, 2896,
2853, 1467, 1369, 1252, 1183, 1045, 1007, 933, 841, 694.
HRMS-FAB /m/z): [M1H]1 calcd 433.1716, found
433.1745. Anal. calcd for C15H38O6P2Si2´H2O: C, 39.98;
H, 8.95, found: C, 40.11; H, 9.09. The yield of the
hydrolysis of the mixed ester to the silyl-containing
H2DTMSP[MBP] partial ester32 was 95%. Equiv. wt.:
calcd 202 g mol21, found 194 g mol21
.
4.3.7. Methylenebis(methyl phenyl phosphonate) mono-
hydrate, Me2Ph2[MBP]´H2O (3h). The preparation of
Me2Ph2[MBP] was carried out as described above with the
reaction mixture at 2788C. This mixed aryl ester, obtained
as a colorless oil in 25% yield after puri®cation by ¯ash
chromatography /30:70 v/v acetone/ethyl acetate; Rfˆ0.5),
4.4.1. Methylenebis(dibutyl phosphonate), Bu4[MBP]
(4g). This previously reported ester,7 obtained as a colorless
oil in 98% yield, is monomeric in toluene /slope
1897 mV m21). 1H NMR /CDCl3) d 4.10 /dt, 8H,
JP,HˆJˆ6.7 Hz, OCH2), 2.44 /t, 2H, JP,Hˆ21.0 Hz, P±
CH2±P), 1.67 /tt, 8H, Jˆ6.8 Hz, OCH2CH2), 1.46±1.36
/m, 8H, CH2CH3), 0.93 /t, 12H, Jˆ7.2 Hz, CH3); 31P
NMR /CDCl3) d 19.7 /s). IR /CCl4) n /cm21) 2962, 2940,
2875, 1466, 1380, 1259, 1182, 1026, 906, 823, 746.
1
is monomeric in toluene /slope 1654 mV m21). H NMR
/CD2Cl2) d 7.44±7.16 /m, 10H, Ar), 3.88 /d, 6H,
JP,Hˆ11.6 Hz, OCH3),33 2.75 /t, 2H, JP,Hˆ21.2 Hz, P±
CH2±P)33; 31P NMR /CD2Cl2) d 16.7 /s), 16.6 /s). IR
/CCl4) n /cm21) 3072, 2958, 2927, 2856, 1593, 1491,
1367, 1275, 1205, 1180, 1165, 1056, 933, 903, 843, 688.
Anal. calcd for C15H18O6P2´H2O: C, 48.14; H, 5.39, found:
C, 48.01; H, 5.41.
4.4.2. Methylenebis(dihexyl phosphonate), He4[MBP]
(4c). This previously reported compound,7 isolated as a
colorless oil in 85% yield, is monomeric in toluene /slope
1967 mV m21). 1H NMR /CDCl3) d 4.09/dt, 8H,
JP,HˆJˆ6.9Hz, OCH 2), 2.45 /t, 2H, JP,Hˆ21.0 Hz, P±
CH2±P), 1.68 /tt, 8H, Jˆ6.9Hz, OCH 2CH2), 1.41±1.20
/m, 24H, CH2), 0.89/t, 12H, Jˆ7.0 Hz, CH3); 31P NMR
/CDCl3) d 19.7 /s). IR /CCl4) n /cm21) 2958, 2931, 2860,
1467, 1379, 1259, 1176, 1039, 999, 815, 733.
4.3.8. P, P0-Diphenyl methylenediphosphonic acid,
H2DPh[MBP] (2h). This partial aryl ester was obtained as
a white solid in 85% yield from the mixed tetraester after
recrystallization from water. Mp 181±1838C /lit. 177±
1798C).34 1H NMR /CD3OD) d 7.28±7.06 /m, 10H, Ar),
2.65 /t, 2H, JP,Hˆ21.4 Hz, P±CH2±P); 31P NMR /CD3OD)
d 15.4 /s). IR /CCl4) n /cm21) 2983, 2927, 2854, 2633,
2327, 1714, 1491, 1460, 1392, 1228, 1167, 1095, 1051,
1034, 991, 966, 730. Equiv. wt.: calcd 164 g mol21, found
167 g mol21. The toluene solubility of H2DPh[MBP] is too
low to permit measurement of its aggregation properties by
vapor pressure osmometry.
4.4.3. Methylenebis(dicyclohexyl phosphonate) half-
hydrate, cHe4[MBP]´1/2 H2O (4d). This compound,26
obtained as a colorless oil in 85% yield after puri®cation
by ¯ash chromatography /25:75 v/v acetone/hexane;
Rfˆ0.9), is monomeric in toluene /slope 2003 mV m21).
1H NMR /CDCl3) d 4.54±4.40 /m, 4H, OCH), 2.41 /t,
2H, JP,Hˆ21.0 Hz, P±CH2±P), 2.08±1.15 /m, 40H, CH2);
31P NMR /CDCl3) d 17.7 /s). IR /CCl4) n /cm21) 2937,
2860, 1452, 1371, 1253, 1176, 1039, 993, 895, 868, 829,
785, 758. Anal. calcd for C25H46O6P2´1/2 H2O: C, 58.47; H,
9.23, found: C, 58.72; H, 9.43.
4.3.9. Methylenebis(2,2,3,3,4,4,4-hepta¯uoro-1-butyl
methyl phosphonate), Me2(C4H2F7)2[MBP] (3i). This
mixed ¯uoroalkyl ester, obtained as a colorless oil in 25%

8644
D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
2. Zolotukhina, M. M.; Krutikov, V. I.; Lavrent'ev, A. N. Russ.
4.4.4.
Methylenebis(di-2-ethylhexyl
phosphonate),
Chem. Rev. *Engl. Transl.) 1993, 62, 647±659.
3. Rizkalla, E. N. Rev. Inorg. Chem. 1983, 5, 223±304.
4. Nash, K. L. J. Alloys Compd. 1994, 213/214, 300±304.
5. Chiarizia, R.; Horwitz, E. P.; Alexandratos, S. D.; Gula, M. J.
Sep. Sci. Technol. 1997, 32, 1±35.
EH4[MBP] (4e). This compound, obtained as a colorless
oil in 85% yield after puri®cation by ¯ash chromatography
/10:90 v/v acetone/hexane; Rfˆ0.85, ®rst band), is mono-
meric in toluene /slope 2049 mV m21). 1H NMR /CDCl3) d
4.05±3.94 /m, 8H, OCH2), 2.44 /t, 2H, JP,Hˆ21.2 Hz, P±
CH2±P), 1.62±1.53 /m, 4H, CH), 1.49±1.22 /m, 32H, CH2),
0.89/t, 24H, Jˆ7.6 Hz, CH3); 31P NMR /CDCl3) d 19.9 /s).
IR /CCl4) n /cm21) 2961, 2931, 2861, 1464, 1380, 1259,
1176, 1013, 878, 842, 823, 779, 762, 742. Anal. calcd for
C33H70O6P2: C, 63.43; H, 11.29, found: C, 63.41; H, 11.51.
HRMS-FAB /m/z): [M1H]1 calcd 625.4727, found
625.4702.
6. Chiarizia, R.; Horwitz, E. P.; Rickert, P. G.; Herlinger, A. W.
Solvent Extr. Ion Exch. 1996, 14, 773±792.
Â
È È
7. Vepsalainen, J.; Nupponen, H.; Pohjala, E.; Ahlgren, M.;
Vainiotalo, P. J. Chem. Soc., Perkin Trans. 2 1992,
835±842.
Â
8. Hannuniemi, R.; Lauren, L.; Puolijoki, H. Drugs Today 1991,
27, 375±390.
9. Grif®th-Dzielawa, J. A.; Barrans, Jr., R. E.; McAlister, D. R.;
4.4.5. Methylenebis(di-3-(trimethylsilyl)propyl phospho-
nate), TMSP4[MBP] (4f). This silyl ester, obtained as a
colorless oil in 83% yield after puri®cation by ¯ash chro-
matography /50:50 v/v diethyl ether/ethyl acetate; Rfˆ0.8),
Dietz, M. L.; Herlinger, A. W. Synth. Commun. 2000, 30,
2121±2132.
10. Dzielawa, J. A. Ph.D. Dissertation, Loyola University
Chicago, Chicago, 2001.
Â
1
is monomeric in toluene /slope 2093 mV m21). H NMR
È È
11. Vepsalainen, J. J.; Kivikoski, J.; Ahlgren, M.; Nupponen,
H. E.; Pohjala, E. K. Tetrahedron 1995, 51, 6805±6818.
/CDCl3) d 4.04 /dt, 8H, JP,HˆJˆ7.2 Hz, OCH2), 2.45 /t,
2H, JP,Hˆ21.0 Hz, P±CH2±P), 1.72±1.64 /m, 8H,
OCH2CH2), 0.52±0.48 /m, 8H, CH2Si), 0.0 /s, 36H,
Si/CH3)3); 31P NMR /CDCl3) d 20.0 /s). IR /CCl4) n
/cm21) 2954, 2894, 1469, 1414, 1387, 1245, 1178, 1063,
1024, 999, 935, 856, 789, 762, 694, 606. Anal. calcd for
C25H62O6P2Si4: C, 47.43; H, 9.87, found: C, 47.11; H, 9.85.
HRMS-FAB /m/z): [M1H]1 calcd 633.3178, found
633.3164.
È È
12. Vepsalainen, J.; Nupponen, H.; Pohjala, E. Tetrahedron Lett.
1996, 37, 3533±3536.
È È
13. Vepsalainen, J.; Nupponen, H.; Pohjala, E. Tetrahedron Lett.
1993, 34, 4551±4554.
14. Stepinski, D. C.; Herlinger, A. W. Synth. Commun., submitted
for publication.
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16. Lesiak, K.; Watanabe, K. A.; George, J.; Pankiewicz, K. W.
J. Org. Chem. 1998, 63, 1906±1909.
4.4.6. Methylenebis(diphenyl phosphonate), Ph4[MBP]
(4h). This aryl ester, a white solid, was obtained in 85%
yield after recrystallization from diethyl ether, mp 81±
838C /lit. 82±838C).34 1H NMR /CD2Cl2) d 7.40±7.20 /m,
20H, Ar), 3.12 /t, 2H, JP,Hˆ21.0 Hz, P±CH2±P); 31P NMR
/CD2Cl2) d 10.7 /s).
17. Krawczyk, H. Synth. Commun. 1997, 27, 3151±3161.
18. McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M.
Tetrahedron Lett. 1977, 2, 155±158. McKenna, C. E.;
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19. Herlinger, A. W.; Ferraro, J. R.; Chiarizia, R.; Horwitz, E. P.
Polyhedron 1997, 16, 1843±1854.
20. Barrans, Jr., R. E.; McAlister, D. R.; Herlinger, A. W.;
Chiarizia, R.; Ferraro, J. R. Solvent Extr. Ion Exch. 1999,
17, 1195±1217.
4.4.7. Methylenebis(2,2,3,3,4,4,4-hepta¯uoro-1-butyl phos-
phonate), (C4H2F7)4[MBP] (4i). This ¯uoroalkyl tetraester
was obtained as a yellow oil in 82% yield after
puri®cation by ¯ash chromatography /50:50 v/v diethyl
ether/ethyl acetate; Rfˆ0.85). The solubility of this ester
in toluene is too low to permit aggregation
measurements by vapor pressure osmometry. 1H NMR
/CDCl3) d 4.71±4.54 /m, 8H, OCH2), 2.84 /t, 2H,
JP,Hˆ22.0 Hz, P±CH2±P); 31P NMR /CDCl3) d 21.3 /s).
IR /CCl4) n /cm21) 2972, 2931, 1456, 1406, 1356, 1279,
1232, 1186, 1132, 1072, 1014, 966, 926, 881, 835, 766, 727,
633. Anal. calcd for C17H10F28O6P2: C, 22.58; H, 1.11,
found: C, 22.25; H, 1.10.
21. Siddall III, T. H.; Prohaska, C. A. J. Am. Chem. Soc. 1962, 84,
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USSR 1969, 39, 809±811.
Acknowledgements
The authors thank Julie A. Dzielawa and Daniel R.
McAlister for helpful discussions and suggestions. This
work was supported by the PG Research Foundation, Inc.,
Darien, IL 60561.
27. Scudder, P. H. The Electron Flow Pathways: Electron Flow in
Organic Chemistry; Wiley: New York, 1992; p 123.
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Interscience: New York, 2000; pp 12±15.
30. McAlister, D. R.; Herlinger, A. W. Unpublished results.
31. A distinct additional resonance with the expected splitting

D. C. Stepinski et al. / Tetrahedron 57 *2001) 8637±8645
8645
pattern is observed for the other diastereomer at a d value that
is nearly identical to the reported chemical shift.
33. Additional resonances are observed at d 3.90±3.79 /m, OCH3)
and 2.754 /td, JP,Hˆ21.2 Hz, Jˆ5.6 Hz, P±CH2±P) for the
other diastereomer.
32. The complete characterization of this partial ester, which was
previously prepared by Path I quenching the reaction with
water as shown in Scheme 1, is reported in Ref. 14.
34. Lang, G.; Herrmann, E. Z. Anorg. Allg. Chem. 1986, 536,
187±196.