Tetrakis(Trimethylsilyl) ethenylidenebisphosphonate: A mild and useful reagent for the synthesis of substituted 2-aminoethylidene-1,1-bisphosphonic acids

Article abstract of DOI:10.1080/10426507.2010.500640

Tetrakis(trimethylsilyl) ethenylidenebisphosphonate is proposed as a substrate in the preparations of N-substituted 2-aminoethylidene-1,1- bisphosphonic acids. The method provides an extremely mild protocol for the synthesis of these compounds and is compatible with a wide range of functional groups. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.500640

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Phosphorus, Sulfur, and Silicon and the
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Tetrakis(trimethylsilyl)
Ethenylidenebisphosphonate: A Mild
and Useful Reagent for the Synthesis
of Substituted 2-Aminoethylidene-1,1-
bisphosphonic Acids
Michael V. Shevchuk a , Vadim D. Romanenko b & Valery P. Kukhar b
a Taras Shevchenko National University of Kyiv , Department of
Organic Chemistry , Kyiv , Ukraine
b Institute of Bioorganic Chemistry and Petrochemistry , Department
of Fine Organic Synthesis , Kyiv , Ukraine
Published online: 25 Apr 2011.
To cite this article: Michael V. Shevchuk , Vadim D. Romanenko & Valery P. Kukhar (2011)
Tetrakis(trimethylsilyl) Ethenylidenebisphosphonate: A Mild and Useful Reagent for the Synthesis
of Substituted 2-Aminoethylidene-1,1-bisphosphonic Acids, Phosphorus, Sulfur, and Silicon and the
Related Elements, 186:4, 799-801, DOI: 10.1080/10426507.2010.500640
To link to this article: http://dx.doi.org/10.1080/10426507.2010.500640
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Phosphorus, Sulfur, and Silicon, 186:799–801, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.500640
TETRAKIS(TRIMETHYLSILYL)
ETHENYLIDENEBISPHOSPHONATE: A MILD AND
USEFUL REAGENT FOR THE SYNTHESIS OF
SUBSTITUTED
2-AMINOETHYLIDENE-1,1-BISPHOSPHONIC ACIDS
Michael V. Shevchuk,1 Vadim D. Romanenko,2
and Valery P. Kukhar2
1Taras Shevchenko National University of Kyiv, Department of Organic Chemistry,
Kyiv, Ukraine
2Institute of Bioorganic Chemistry and Petrochemistry, Department of Fine
Organic Synthesis, Kyiv, Ukraine
Abstract Tetrakis(trimethylsilyl) ethenylidenebisphosphonate is proposed as a substrate in
the preparations of N-substituted 2-aminoethylidene-1,1-bisphosphonic acids. The method
provides an extremely mild protocol for the synthesis of these compounds and is compatible
with a wide range of functional groups.
Keywords Aminobisphosphonic acids; Michael addition; tetrakis(trimethylsilyl) ethenyli-
denebisphosphonate
Aminomethylenebisphosphonic acids are approved drugs for the treatment of bone diseases
and have been widely used as antiresorptive agents for over two decades.1 Their antiparasitic
activity as well as their ability to stimulate γ δ T cells of the immune system that kill tumor
cells are also rigorously studied.2,3 So far, the widely used method of methylenebisphospho-
nic acids synthesis is based on the Michael addition of a nucleophilic reagent to tetraalkyl
ethenylidenebisphosphonate 1 followed by hydrolysis of tetraalkyl bisphosphonate in boil-
ing hydrochloric acid2 or bromotrimethylsilane-mediated methanolysis.4 Unfortunately,
these reaction conditions are incompatible with acid- and bromotrimethylsilane-labile func-
tionalities (ester, amide, phosphonate to aq. HCl, phosphonate to bromotrimethylsilane).
Moreover, under these conditions a retro-Michael reaction can take place in some cases.
To overcome these difficulties, the use of ethenylidenebisphosphonic acid
tetrakis(trimethylsilyl) ester (2) instead of conventional tetraethyl ester is proposed.
According to a slightly modified original procedure,5,6 bisphosphonate 1 when treated with
bromotrimethylsilane is fully converted to a silylated product with only trace amounts of
by-products. Purification via distillation affords pure tetrasilyl ester 2 in 90% yield that
can be stored for months (Scheme 1).
Received 9 April 2010; accepted 1 June 2010.
Addresscorrespondence to Michael V. Shevchuk, Taras Shevchenko National University of Kyiv, Department
of Organic Chemistry, Volodymyrska str., 62a, Kyiv 01033, Ukraine. E-mail: m.shev4uk@gmail.com
799

800
M. V. SHEVCHUK ET AL.
Scheme 1
Reactions of various amines with tetrakis(trimethylsilyl) ethenylidenebisphosphonate
were investigated. Aliphatic amines react smoothly in dichloromethane at room tempera-
ture over several hours to produce the corresponding substituted 2-aminoethylidene-1,1-
bisphosphonic acids 3a-e upon treatment with methanol in moderate to excellent yields.7
Aromatic amines, heteroaromatic amines, and substituted benzylamines react somewhat
slower, and heating in more polar acetonitrile over a prolonged time is usually required to ob-
tain products 4a-c in satisfactory yields. In general, the reactivity of tetrakis(trimethylsilyl)
ester of ethenylidenebisphosphonic acid is lower compared to the corresponding tetraethyl
ester. This method opens access to bisphosphonic acids bearing amidate or phosphonate
groups (compounds 5 and 6, respectively). The reaction can be carried out in the presence
of a free hydroxyl group, and preparation of 7 is an example (Scheme 2).
Scheme 2

TETRAKIS(TRIMETHYLSILYL) ETHENYLIDENEBISPHOSPHONATE
801
REFERENCES
1. Russell, R. G.; Xia, Z.; Dunford, J. E.; Oppermann, U.; Kwaasi, A.; Hulley, P. A.; Kavanagh, K.
L.; Triffitt, J. T.; Lundy, M. W.; Phipps, R. J.; Barnett, B. L.; Coxon, F. P.; Rogers, M. J.; Watts,
N. B.; Ebetino, F. H. Ann. N. Y. Acad. Sci. 2007, 1117, 209–257.
2. Szajnman, S. H.; Linares, G. E.; Li, Z.; Jiang, C.; Galizzi, M.; Bontempi, E. J.; Ferella, M.;
Moreno, S. N.; Docampo, R.; Rodriguez, J. B.; Bioorg. Med. Chem. 2008, 16, 3283–3290.
3. Zhang, Y.; Cao, R.; Yin, F.; Lin, F.; Wang, H.; Krysiak, K.; No, J.; Mukkamala, D.; Houlihan, K.;
Li, J.; Morita, C. T.; Oldfield, E. Angew. Chem. 2010, 122, 1154–1156.
4. Fisher, K.; Woolard, F.; Leadbetter, M.; Gerdes, J. Herbicidal aza bisphosphonic acids and com-
positions containing the same. U.S. Patent #5728650, 1998.
5. Duncan, G. D.; Li, Z.; Khare, A. B.; McKenna, C. E. J. Org. Chem. 1995, 60, 7080–7081.
6. Modified experimental procedure for 2: to a stirred solution of 1 (4.5 g, 15 mmol) in dry acetonitrile
(5 mL) freshly distilled bromotrimethylsilane (8.9 mL, 67.5 mmol) was added dropwise at ambient
temperature. A slightly exothermic reaction was observed, and the reaction mixture was stirred
overnight. The next day the yellowish solution was concentrated in a vacuum to approximately
three-quarters of starting volume and transferred to a distillation flask. The remaining volatiles
(which kept the solution fluid to facilitate transportation) were completely removed and the silyl
ester 2 was distilled as clear viscous uncolored liquid (6.4 g, 13.5 mmol, 90%), b.p. 116–117◦C/0.05
mm. 1H-NMR (400 MHz, C6D6) δ = 0.29 (s, 36H, CH3), 6.68 (dd, JHP = 35 Hz, JHP = 39 Hz,
2H, CH2); 13C-NMR (100 MHz, C6D6) δ = 1.2 (s, CH3), 140.0 (t, JCP = 173 Hz, PCP), 142.8 (s,
CH2); 31P-NMR (162 MHz, C6D6) δ = −3.1 (dd, JPH = 35Hz, JPH = 39 Hz), 29Si-NMR (C6D6)
δ = 21.7 (m). Spectral data were in good agreement with those found in the literature5.
7. Experimental procedure for 2-(cyclopropylamino)ethane-1,1-diylbisphosphonic acid 3a: to a
stirred solution of 2 (436 mg, 0.92 mmol) in dry dichloromethane (2 mL) cyclopropylamine
(60 mg, 1.05 mmol) was added. The mixture was stirred for 2 h and the solvent was evaporated.
Methanol (3–5 mL) was added and the mixture was stirred for another 0.5 h. Precipitate was
collected on the filter and washed twice with methanol (3 mL) and then several times with ether
(20 mL). Compound 3a (209 mg, 0.86 mmol) was obtained as a colorless crystalline solid in 93%
1
yield. H-NMR (400 MHz, D2O) δ = 0.81–0.89 (m, 4H, CH2cyclopropane), 2.52 (tt, JHP = 22 Hz,
JHH = 7 Hz, 1H, PCHP); 2.74 (m, 1H, CHcyclopropane); 3.50 (td, JHP = 14 Hz, JHH = 7 Hz); 13C-NMR
(100 MHz, D2O) δ = 3.3 (s, CH2cyclopropane), 30.2, 36.4 (d, JCP = 122 Hz), 45.6; 31P-NMR (162
MHz, D2O) δ = 16.3.