Simple synthesis of oxiranylidene-2,2-bis(phosphonic acid): Tetrabenzyl geminal bisphosphonate esters as useful intermediates

Article abstract of DOI:10.1081/SCC-120002004

Tetrabenzyl geminal bisphosphonate esters are shown to be useful synthetic equivalents of 1,1-bis(phosphonic acid)s which may be easily functionalized at the central carbon atom without phosphonate ester hydrolysis. The parent bis(phosphonic acid) unit is readily regenerated by hydrogenolysis. The chemistry is used to prepare the elusive epoxide oxiranylidene-2,2-bis(phosphonic acid) by a short and reliable procedure.

Full text of DOI:10.1081/SCC-120002004

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SIMPLE SYNTHESIS OF OXIRANYLIDENE-2,2-
BIS(PHOSPHONIC ACID): TETRABENZYL GEMINAL
BISPHOSPHONATE ESTERS AS USEFUL INTERMEDIATES
Philip C. Bulman Page a , Michael J. McKenzie a & James A. Gallagher b
a Department of Chemistry , Loughborough University , Loughborough, Leicestershire,
LE11 3TU, England
b Department of Human Anatomy and Cell Biology , University of Liverpool , Liverpool,
L69 3BX, England
Published online: 16 Aug 2006.
To cite this article: Philip C. Bulman Page , Michael J. McKenzie & James A. Gallagher (2002) SIMPLE SYNTHESIS OF
OXIRANYLIDENE-2,2-BIS(PHOSPHONIC ACID): TETRABENZYL GEMINAL BISPHOSPHONATE ESTERS AS USEFUL INTERMEDIATES,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:2,
211-218, DOI: 10.1081/SCC-120002004
To link to this article: http://dx.doi.org/10.1081/SCC-120002004
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SYNTHETIC COMMUNICATIONS, 32(2), 211–218 (2002)
SIMPLE SYNTHESIS OF
OXIRANYLIDENE-2,2-BIS(PHOSPHONIC
ACID): TETRABENZYL GEMINAL
BISPHOSPHONATE ESTERS
AS USEFUL INTERMEDIATES
1,
1
*
Philip C.Bulman Page,
Michael J.McKenzie,
2
and James A.Gallagher
1Department of Chemistry,
Loughborough University, Loughborough,
Leicestershire LE11 3TU, England
2Department of Human Anatomy and
Cell Biology, University of Liverpool,
Liverpool L69 3BX, England
ABSTRACT
Tetrabenzyl geminal bisphosphonate esters are shown to
be useful synthetic equivalents of 1,1-bis(phosphonic acid)s
which may be easily functionalized at the central carbon
atom without phosphonate ester hydrolysis. The parent
bis(phosphonic acid) unit is readily regenerated by hydroge-
nolysis. The chemistry is used to prepare the elusive epoxide
oxiranylidene-2,2-bis(phosphonic acid) by a short and reliable
procedure.
*Corresponding author.
211
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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PAGE, MCKENZIE, AND GALLAGHER
Geminal bisphosphonates are stable pyrophosphate analogues which
bind efficiently to bone surface.1 They have been used in the clinic to inhibit
bone resorption, in most cases with few side effects.2 Some simple examples,
for example etidronate and alendronate, are already marketed for the
treatment of osteoporosis and Paget’s disease.3 It has been suggested that
bisphosphonates are general metabolic inhibitors.4 The low level of side
effects has been attributed to the rapid absorption of the geminal bispho-
sphonate to the bone surface and incorporation within the bone matrix,
thereby preventing undesired effects within other organs.2 Other clinically
used treatments for osteoporosis, such as hormone replacement therapy, are
effective, but can have effects on other tissues.5 We are interested in using
geminal bisphosphonates as bone-targeting moieties for the treatment of
bone-related disease;6 our aim is to use the bone tropism to deliver thera-
peutics at the desired site of action, thus reducing unwanted side effects in
other tissues.
Bis(phosphonic acid)s are typically produced from tetraalkyl bispho-
sphonate esters either by acid hydrolysis7 or through silylation-dealkylation
using bromotrimethylsilane.8 While acid hydrolysis is reliable it is often
incompatible with other functionalities. Silylation-dealkylation is a milder
method, however, in our hands reactions were often incomplete, leading to
mixtures of products. This prompted us to investigate the benzyl group as a
potential protecting group for bis(phosphonic acid)s which might be easily
and selectively removed.9 Hydrogenolysis of benzyl phosphonates has been
widely utilized,10 however, to our knowledge geminal bis(phosphonic acid)s
have rarely been synthesized in this way. Mioskowski has shown that simple
benzyl bisphosphonate esters can be deprotected by the use of catalytic
transfer hydrogenolysis11 or with DABCO in boiling toluene,12 or
even converted into chlorophosphonates.13 More recently, a 2-substituted
geminal bis(phosphonic acid) has also been prepared by catalytic transfer
hydrogenolysis of the benzyl bisphosphonate.14
We chose oxiranylidene-2,2-bis(phosphonic acid) 1 as a target around
which to develop the chemistry. This epoxide is a notoriously elusive com-
pound potentially valuable as a synthetic intermediate: Johnson has shown
that its esters undergo epoxide cleavage followed by an unusual rearrange-
ment upon reaction with nitrogen nucleophiles.15 Reported briefly in the
patent literature twenty-five years ago,16 two further reports of its attempted
synthesis have since appeared: Gatrone reported that the sodium tungstate/
hydrogen peroxide oxidation of ethylidene-1,1-bis(phosphonic acid) at pH
6–7 produced 1,2-dihydroxy-1,1-bis(phosphonic acid), identified by 31P and
1HNMR spectroscopy, rather than 1.17 More recently, McKenna described
an unambiguous synthesis of 1 via the bromohydrin derived from ethyli-
dene-1,1-bis(phosphonic acid).18

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TETRABENZYL GEMINAL BISPHOSPHONATE ESTERS
213
Our initial target, tetrabenzyl methylene bisphosphonate 2, has
previously been reported only rarely, assembled for example by a
Michaelis-Arbuzov reaction of tribenzyl phosphite and dibenzyl (chloro-
methyl)phosphonate,11 by heating the bis(phosphonic acid) with tribenzyl
orthoformate,14 and by a transesterification process.21 We required rela-
tively large quantities of 2, and therefore sought a synthesis more amenable
to scale-up. Vepsalainen has synthesized a range of tetraalkyl methylene
bisphosphonate esters by reaction of methylene bis(phosphonic dichloride)
3 with alcohols using pyridine as the base.19 Using this method, we found
the synthesis of 2 from 3 and benzyl alcohol to be readily achieved on a
multigram scale (Scheme 1).
Scheme 1.
Initially we hydrogenolysed 2 to give the known methylene bis(pho-
sphonic acid) 4, the reaction proving efficient and simple.
Elaboration of 2 to tetrabenzyl ethylidene-1,1-bisphosphonate 5
required a modification of Degenhardt’s method (Scheme 2).20 Compound
2 was stirred with paraformaldehyde and diethylamine in methanol at room
temperature for four days to give the tetrabenzyl 2-methoxyethylene bis-
phosphonate intermediate 6. Attempts to increase the reaction rate by
heating led to complicated mixtures of mixed methyl and benzyl ester
products. Acid catalysed elimination in toluene under reflux using a soxhlet
apparatus containing 4 A molecular sieves gave 5 in ca quantitative yield.
Scheme 2.

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PAGE, MCKENZIE, AND GALLAGHER
Clean conversion into tetrabenzyl oxiranylidene-2,2-bisphosphonate 7
was accomplished with alkaline hydrogen peroxide in ethanol (Scheme 3);18
compound 7 was sufficiently pure to be used without further purification.
Initially, our attempts to debenzylate 7 by hydrogenolysis in solvents such as
methanol, acetone or tetrahydrofuran led to acid 1 together with minor
1
impurities visible by HNMR spectroscopy. However, hydrogenolysis in
ethanol using 10% Pd(C) yielded acid 1 cleanly and in ca quantitative
yield after filtration and evaporation (Scheme 3). Acid 1 was converted
into the tetrasodium salt by treatment with sodium hydroxide in water.
We are currently extending and investigating the use of this mild synthetic
procedure for synthesising bis(phosphonic acid)s and various conjugates.
Scheme 3.
In conclusion, the synthesis of oxiranylidene-2,2-bis(phosphonic acid)
1 described here is high yielding, and requires no chromatography and
relatively little purification between steps. We have also demonstrated the
applicability of the benzyl group as a protecting group for bis(phosphonic
acid)s and have described the synthesis of several key intermediates.
EXPERIMENTAL SECTION
Tetrabenzyl Methylene Bisphosphonate 2: A suspension of methylene
bis(phosphonic dichloride) (5.00 g, 20.0 mmol) was stirred rapidly in
dry toluene (10 mL) at 0ꢀC. A mixture of dry benzyl alcohol (8.66 mL,
83.0 mmol) and dry pyridine (6.15 mL, 76.1 mmol) was added over 80 min
by syringe pump while the temperature was maintained. After the addition
was complete the reaction was allowed to reach 20ꢀC and stirred for a
further 3 h. The solids were removed by filtration and washed with toluene
(2 ꢁ 20 mL). The filtrate was washed with 2 M NaOH(2 ꢁ 15 mL), water
(15 mL), dried (MgSO4) and concentrated in vacuo. Removal of benzyl
alcohol impurity by distillation (120ꢀC, 1 mmHg) left 2 as a colourless oil

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TETRABENZYL GEMINAL BISPHOSPHONATE ESTERS
215
(8.11 g, 76%): IR (liq) 998, 1260. 1HNMR (CDCl 3, 250 MHz) d 2.51 (2H, t,
J ¼ 21.2 Hz), 5.02 (8H, dd, J ¼ 8.7 and 2.2 Hz), 7.28 (20H, br s). 13C NMR
(CDCl3, 62.8 MHz) d 26.7 (t, J ¼ 136 Hz), 68.5 (t, J ¼ 2.9 Hz), 128.5, 128.9,
129.0, 136.4 (t, J ¼ 3.4 Hz). 31P NMR (CDCl3, 101.2 MHz) d 20.81. MS (EI)
536.15082, C29H30P2O6 requires 536.1517.
Methylene bis(Phosphonic Acid) 4:
A solution of 2 (0.100 g,
0.187 mmol) and 10% Pd(C) (10 mg) in dry EtOAc (2 mL) was stirred
under a hydrogen atmosphere for 16 h. The Pd(C) was removed by filtra-
tion, washed with methanol (2 mL) and the combined filtrate concentrated
1
in vacuo to give 4 as a colourless solid (0.031 g, 94%): HNMR (D 2O,
400 MHz) d 2.11 (2H, t, J ¼ 21.0 Hz). 13C NMR (CDCl3, 100 MHz) d 27.1
(t, J ¼ 129 Hz). 31P NMR (D2O, 101.2 MHz) d 22.25.
Tetrabenzyl Ethylidene-1,1-bisphosphonate 5: Paraformaldehyde
(1.35 g, 45.0 mmol) and diethylamine (0.68 g, 9.33 mmol) were dissolved in
dry methanol (30 mL) with warming. A solution of 2 (5.00 g, 9.33 mmol) in
dry methanol (30 mL) was added at 20ꢀC and the reaction stirred for 5 d.
The reaction was concentrated in vacuo, toluene (20 mL) added and the
solution concentrated again. This last step was repeated to remove all
traces of methanol, yielding tetrabenzyl methoxymethyl methylene bispho-
1
sphonate 6 as a colourless oil. HNMR (CDCl 3, 250 MHz) d 2.86 (1H, tt,
J ¼ 5.5 and 23.9 Hz), 3.30 (3H, s), 3.93 (2H, td, J ¼ 5.6 and 16.3 Hz),
4.99–5.06 (8H, m), 7.28–7.33 (20H, m).
Intermediate 6, pTSA and toluene (100 mL) were placed into a round
bottomed flask fitted with a soxhlet apparatus containing 4 A molecular
sieve. The solution was heated under reflux for 16 h, allowed to cool to
20ꢀC and washed with water (2 ꢁ 20 mL). Drying (MgSO4) and concentra-
tion in vacuo gave 5 as a colourless viscous oil (5.10 g, 99%): IR (liq) 996,
1248. 1HNMR (CDCl 3, 400 MHz) d 4.95–5.05 (8H, m), 6.98 (2H, dd,
J ¼ 34.4 and 38.9 Hz), 7.24–7.30 (20H, m). 13C NMR (CDCl3, 100 MHz)
d 68.5 (d, J ¼ 3.0 Hz), 128.4, 128.8, 128.9, 136.3 (t, J ¼ 3.0 Hz), 150.1.
31P NMR (CDCl3, 101.2 MHz) d 15.33 MS (EI) 548.1524, C30H30P2O6
requires 548.1517.
Tetrabenzyl Oxiranylidene-2,2-bisphosphonate 7: A solution of 5
(1.00 g, 1.82 mmol), NaHCO3 (0.162 g, 193 mmol) and 30% aqueous H2O2
(0.40 mL) in ethanol (4 mL) was stirred at 20ꢀC for 16 h. The reaction was
diluted with water (10 mL), extracted with CH2Cl2 (2 ꢁ 40 mL), dried
(MgSO4), and concentrated in vacuo to give 7 as a colourless viscous oil
1
(0.971 g, 94%): IR (liq) 997, 1259. HNMR (CDCl 3, 400 MHz) d 3.23 (2H,
t, J ¼ 5.4 Hz), 5.01–5.28 (8H, m), 7.25–7.31 (20H, m). 13C NMR (CDCl3,
100 MHz) d 48.4 (t, J ¼ 182.6 Hz), 50.0, 69.1 (t, J ¼ 2.4 Hz), 128.0, 128.1,
128.6, 135.6 (q, J ¼ 3.3 Hz). 31P NMR (CDCl3, 101.2 MHz) d 17.33. Anal.
Calcd for C30H30P2O7: C, 63.83; H, 5.36. Found: C, 63.36; H, 5.36.

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PAGE, MCKENZIE, AND GALLAGHER
Oxiranylidene-2,2-bis(phosphonic Acid) 1: A solution of 7 (0.100 g,
0.177 mmol) and 10% Pd(C) (5 mg) in dry ethanol (1.5 mL) was stirred
under an atmosphere of hydrogen for 5 h. The Pd(C) was removed by
filtration, washed with ethanol (1 mL) and the combined filtrate concen-
trated in vacuo to give 1 as a colourless viscous oil (0.035 g, 97%):
1HNMR (D 2O, 400 MHz) d 3.22 (2H, t, J ¼ 6.0 Hz). 13C NMR (D2O,
100 MHz) d 52.1 (t, J ¼ 169.7 Hz), 52.7. 31P NMR (D2O, 101.2 MHz) d 17.12.
Oxiranylidene-2,2-bis(phosphonic Acid), Tetra Sodium Salt: NaOH
(0.0275 g, 0.686 mmol) was added to a solution of 1 (0.035 g, 0.172 mmol)
in D2O (1 mL). Concentration in vacuo gave the product as a colourless
1
solid (0.0500 g, 99%): HNMR (D 2O, 400 MHz) d 2.95 (2H, t, J ¼ 5.8 Hz).
13C NMR (D2O, 100 MHz) d 51.7, 54.6 (t, J ¼ 149.1 Hz), 31P NMR (D2O,
101.2 MHz) d 17.33.
ACKNOWLEDGMENT
This investigation has enjoyed the support of Shire Pharma-
ceuticals plc.
REFERENCES
1. Geddes, A.D.; D’Souza, S.M.; Ebetino, F.H.; Ibbotson, K.J. Bone
Mineral Research 1994, 9, 265; Geddes, A.D.; Bevan, J.A.; Kasting,
G.B.; Francis, M.D.; Mosekilde, L.; Hasling, C. J. Bone Mineral
Research 1992, 7, S328; Storm, T.; Thamsborg, G.; Steiniche, T.;
Genant, H.K.; Sorensen, O.H. New Engl. J. Med. 1990, 332, 1265;
Fleisch, H. Bone, 1999, 25, 158; Vitte, C.; Fleisch, H.; Guenther, H.L.
Endocrinology 1996, 137, 2324; Fleisch, H. Osteoporosis Int. 1996,
6, 166.
2. Fleisch, H. Br. J. Clin. Pract. 1994, 48, 323; Body, J.J.; Bartl, R.;
Buckhardt, P.; Delmers, P.D.; Fleisch, H.; Kanis, J.A.; Kyle, R.A.;
Mundy, G.R.; Paterson, A.H.G.; Rubens, R.D. J. Clin. Oncol. 1998,
16, 3890; Guenther, H.L.; Fleisch, H.; Walz, A. J. Bone Min. Res. 1997,
12, 111; Jowsey, J.; Hopkins, S.G. J. Lab. Clin. Med. 1970, 76, 126;
Dodwell, D.J.; Howell, A.; Ford, J. Br. J. Cancer 1990, 61, 123; Sahni,
M.; Guenther, H.L.; Fleisch, H.; Collin, P.; Martin, T.J. J. Clin. Invest.
1993, 91, 2004.
3. Fleisch, H. Int. J. Clin. Pract. 1999, 2; Fleisch, H. Scand, J. Rheumatol.
1998, 64; Russell, R.G.G.; Croucher, P.I.; Rogers, M.J. Osteoporosis
Int. 1999, 9, 66; Li, Q.N.; Liang, N.C.; Huang, L.F.; Wu, T.; Hu, B.;

ORDER
REPRINTS
TETRABENZYL GEMINAL BISPHOSPHONATE ESTERS
217
Mo, L.E. Acta Pharm. Sin. 1998, 19, 160; Kyriakidou Himonas, M.;
Aloia, J.F. Adv. Therapy 1997, 14, 281; Reginster, J.Y.L.; Halkin, V.;
Gosset, C.; Deroisy, R. Drugs Today 1997, 33, 563; Khan, S.A.; Kanis,
J.A.; Vasikaran, S.; Kline, W.F.; Matuszewski, B.K.; McCloskey, E.V.;
Beneton, M.N.C.; Gertz, B.J.; Sciberras, D.G.; Holland, S.D.; Orgee, J.;
Coombes, G.M.; Rogers, S.R.; Porras, A.G. J. Bone Mineral Res. 1997,
12, 1700; Fleisch, H. Hormone Metabolic Res. 1997, 29, 145; Black,
L.J.; Sato, M.; Rowley, E.R.; Magee, D.E.; Bekele, A.; Williams,
D.C.; Cullinan, G.J.; Bendele, R.; Kauffman, R.F.; Bensch, W.R.;
Frolik, C.A.; Termine, J.D.; Bryant, H.U. J. Clin. Invest. 1994, 93,
63; Heaney, R.P. Am. J. Med. 1991, 91, 238.
4. Fleisch, H.; Shinoda, H.; Adamek, G.; Felix, R.; Schenk, R.; Hagan, P.
Calc. Tissue Int. 1983, 35, 87.
5. Beresford, S.A.A.; Weiss, N.S.; Voight, L.F.; McKnight, B.
Lancet 1997, 349, 458; Colditz, G.A.; Hankinson, S.E.; Hunter,
D.J.; Willet, W.C.; Manson, J.E.; Stampfer, M.J.; Hennekens, C.;
Rosner, B.; Speizer, F.E. New Engl. J. Med. 1995, 332, 1589; Sturtz,
G.; Guervenou, J. Phosphorus Sulfur 1994, 88, 1; Sturtz, G.;
Guervenou, J. Fr. patent app 2683527 (1991); Hiroaki, U.;
Kadowaki, S.; Kamizono, A.; Masahiko, M.; Akihisa, M. Eur. patent
app. 0555845 (1993); Bosies, E.; Esswein, A.; Bauss, F. Int. patent
WO 92/05187 (1992); Saari, W.S.; Rodan, G.A.; Fisher, T.E.;
Anderson, P.S. Eur. patent app. 0496520 A (1992); Sugioka, T.;
Inazu, M. Eur. patent app. 0548884 A (1992); Sturtz, G.; Guervenou,
J. Synthesis 1991, 661; Bosies, E.; Esswein, A.; Bauss, F. Eur. patent
0 549 645 B1 (1991); Cust, M.P.; Gangar, K.F.; Whitehead, M.I. In HRT
and Osteoporosis, Eds. Studd, J.W.W.; Drife, J.O. Springer-Verlag,
London, 1990, 209.
6. Gallagher, J.A.; Bowler, W.; Moore, J.P.G.; Page, P.C.B. U.K. patent
app, 9613722.9 (1996).
7. For examples see: Mimura, M.; Hayashida, M.; Nomiyama, K.;
Ikegami, S.; Iida, Y. Chem. Pharm. Bull. 1993, 41, 1971; Dufau, C.;
Sturtz, G. Phosphorus Sulfur 1992, 69, 93; den Hartog, J.A.J.;
Wijnands, R.A.; van Boom, J.H.; Crea, R. J. Org. Chem. 1981, 46, 2242.
8. Clasen, R.; Haegele, G. J. Fluorine Chem. 1996, 77, 71; McKenna, C.E.;
Schmidhauser, J. J. Chem. Soc. 1979, 35, 739; McKenna, C.E.; Higa,
M.T.; Cheng, N.H.; McKenna, M.C. Tetrahedron Lett. 1977, 155.
9. For examples of the benzyl group as a protecting group in synthesis
see: Greene, T.W.; Wuts, P.G.M. In Protecting Groups in Organic
Synthesis, 2nd edition, Wiley Interscience: New York, 1991;
Kocienski, P.J. In Protecting Groups, Thieme: Stuttgart, 1994.

ORDER
REPRINTS
218
PAGE, MCKENZIE, AND GALLAGHER
10. For examples see: Amann, F.; Schaub, C.; Mueller, B.; Schmidt, R.R.
Chem. Eur. J. 1998, 4, 1106; Lampe, T.F.L.; Weitz-Schmidt, G.;
Wong, C.-H. Angew, Chem., Int. Ed. Engl. 1998, 37, 1707; Cristau,
H.-J; Lambert, J.-M.; Pirat, J.-L. Synthesis 1998, 8, 1167; Hoffman, M.
Synthesis 1988, 62; Alewood, P.F.; Johns, R.B.; Hoogenraad, N.J.;
Sutherland, T. Synthesis 1984, 403.
11. Saady, M.; Lebeau, L.; Mioskowski, C. Helv. Chim. Acta 1995, 78,
670; Hoffman, M.; Wasielewski, C. Phosphorus Sulfur, 1990, 53, 69;
Mikroyannidis, J.A.; Tsolis, A.K.; Gourhiotis, D.J. Phosphorus Sulfur
1982, 13, 279.
12. Saady, M.; Lebeau, L.; Mioskowski, C. J. Org. Chem. 1995, 60, 2946.
13. Mioskowski, C.; Saady, M.; Lebeau, L. Tetrahedron Lett. 1995, 36,
4785.
14. Gil, L.; Han, Y.; Opas, E.E.; Redan, G.A.; Ruel, R. Bioorg. Med.
Chem. 1999, 7, 901.
15. Burgos-Lepley, C.E.; Mizsak, S.A.; Nugent, R.A.; Johnson, R.A.
J. Org. Chem. 1993, 58, 4159.
16. Kerst, A.F. U. S. patent 3,808,237 (1974).
17. Gatrone, R.C. J. Org. Chem. 1989, 54, 4272.
18. Duncan, G.D.; Li, Z.-M.; Khare, A.B.; McKenna, C.E. J. Org. Chem.
1995, 60, 7080.
19. Vepsalainen, J.; Nupponen, H.; Pohjala, E.; Ahlgren, M.; Vainiotalo,
P. J. Chem. Soc., Perkin Trans. 1 1992, 835.
20. Degenhardt, C.R.; Burdsall, D.C. J. Org. Chem. 1986, 51, 3488.
21. Vepsalainen, J. Tetrahedron Lett. 1999, 40, 8491.
Received in the UK December 4, 2000

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