Tetrakis(trimethylsilyl) ethenylidene-1,1-bisphosphonate: A mild and convenient Michael acceptor for the synthesis of 2-aminoethylidene-1,1- bisphosphonic acids and their potassium salts

Article abstract of DOI:10.1055/s-0030-1260566

A straightforward synthesis of highly functionalized 2-aminoethylidene-1,1- bisphosphonic acids via the Michael addition of amines to easily available tetrakis(trimethylsilyl) ethenylidene-1,1-bisphosphonate, H₂C=C[P(O) (OTMS)₂]

Full text of DOI:10.1055/s-0030-1260566

1370
LETTER
Tetrakis(trimethylsilyl) Ethenylidene-1,1-bisphosphonate: A Mild and
Convenient Michael Acceptor for the Synthesis of 2-Aminoethylidene-1,1-
bisphosphonic Acids and Their Potassium Salts
T
etrakis(trimethylsilyl
i
E
then
c
ylidene-1,1
h
-bisphospho
a
a
Fax +38(044)5732552; E-mail: kukhar@bpci.kiev.ua
Institut Pluridisciplinaire de Recherche sur l’Environnement et les Matériaux, UMR-CNRS 5254,
b
Université de Pau et des Pays de l'Adour, Hélioparc 2 Avenue du Président Angot, 64053 Pau cedex 09, France
Received 15 February 2011
a final stage is not compatible with acid-sensitive func-
tionalities and is not suitable for thermodynamically labile
addition adducts which prone to undergo retro-Michael
reaction. Moreover, silylation–dealkylation reactions are
Abstract: A straightforward synthesis of highly functionalized 2-
aminoethylidene-1,1-bisphosphonic acids via the Michael addition
of amines to easily available tetrakis(trimethylsilyl) ethenylidene-
1,1-bisphosphonate, H2C=C[P(O)(OTMS)2]2, has been described.
The potassium salts of the title compounds were also easily often incomplete leading to mixtures of products.10 To
achieved in high yield by reacting the Michael adducts with potas-
sium fluoride.
avoid these obstacles Page and co-workers have proposed
the catalytic hydrogenolysis of tetrabenzyl bisphospho-
Key words: ethenylidene-1,1-bisphosphonates, 2-aminoethylidene-
1,1-bisphosphonic acids, Michael addition, amines, silicon
nate esters as a clean and high-yielding route to function-
alized 2-aminoethylidene-1,1-bisphosphonic acids.11
However, the synthesis of tetrabenzyl methylene-1,1-bis-
phosphonate derivatives requires a multistep procedure
Nitrogen-containing bisphosphonic acids and their salts including a tedious preparation of methylene bisphospho-
(N-BP) represent an important class of phosphorus com- nic tetrachloride CH2(POCl2)2.
pounds possessing a pyrophosphate-like chemical struc-
Here we demonstrate that tetrakis(trimethylsilyl) ethe-
ture that confers a strong affinity for calcium.1 Several N-
nylidenebisphosphonate is a valuable acceptor in the
BP are established as effective treatments for diseases
Michael additions which provides an operationally simple
such as osteoporosis (alendronate, ibandronate, and
access to diversely functionalized N-substituted 2-amino-
residronate) and disorders associated with the hypercalce-
ethylidene-1,1-bisphosphonic acids and their salts.
mia caused by malignancy (ibandronate, pamidronate,
Although
ethenylidene-1,1-bisphosphonate
ester
residronate, and zoledronic acid).2 There are still consid-
erable opportunities for extension of the use of N-BP in
clinical medicine. In particular, there is current interest in
the use of N-BP in immunotherapy of cancer since they
activate gd T cells of the immune system to kill tumor
cells.3 In addition, N-BP are promising candidate drugs to
treat pathogenic parasitic infections caused by Plasmodi-
um spp, Leishmania species, Trypanosoma cruzi and oth-
er protozoan parasites.4 Increasing interest in the nitrogen-
containing bisphosphonic acids resulted in the develop-
ment of different strategies for their synthesis.5 One of the
most effective routes exploits the Michael-type addition
of a nitrogen nucleophile to the tetraethyl ethenylidene-
1,1-bisphosphonate, H2C=C(PO3Et)2.6 Unfortunately, in
human plasma tetraethyl bisphosphonate esters did not re-
lease free bisphosphonic acids and thus, they are not bis-
phosphonate prodrugs.7 The desired 2-aminoethylidene-
H2C=C[P(O)(OSiMe3)2]2 was reported in 1995,12 it did
not find synthetic application until our own disclosure.13
The reaction sequence used to synthesize this compound
is shown in Scheme 1. Tetraethyl ethenylidene-1,1-bis-
phosphonate (1) was prepared from commercially avail-
able tetraethyl methylene-1,1-bisphosphonate using the
procedure developed by Degenhardt and co-workers.14
O
P
O
P
O
P
OEt
OEt
OEt
OEt
OEt
OEt
OSiMe3
OSiMe3
OSiMe3
OSiMe3
i,ii
iii
OEt
OEt
P
P
P
O
O
O
1 (81%)
2 (90%)
Scheme 1 Synthesis of tetrakis(trimethylsilyl) ethenylidene-1,1-
bisphosphonate (2). Reagents and conditions: (i) (CH2O)n, Et2NH,
MeOH, reflux; (ii) TsOH, PhMe, reflux; (iii) TMSBr (4.3 equiv),
1,1-bisphosphonic acids are typically produced from the MeCN, r.t.
corresponding tetraethyl bisphosphonate esters by hydro-
lysis in boiling hydrochloric acid8 or through bromo- or
Transsilylation of 1 with bromotrimethylsilane to give the
iodotrimethylsilane-mediated alcoholysis.9 In both cases,
desired tetrasilyl ester 2 was achieved in excellent yield
using a modification of McKenna’s procedure.12 The re-
action was carried out in acetonitrile at room temperature
and the tetrasilyl ester 2 was isolated as low-melting solid
by distillation in high vacuum. It can be stored in dry at-
SYNLETT 2011, No. 10, pp 1370–1374
x
x
.x
x
.2
0
1
1
Advanced online publication: 16.05.2011
DOI: 10.1055/s-0030-1260566; Art ID: B04411ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Tetrakis(trimethylsilyl) Ethenylidene-1,1-bisphosphonate
1371
mosphere for months without any sign of decomposi- To get insight on the peculiarities of the electronic struc-
tion.15
ture of this compound, we carried out DFT calculations16
on molecules H2C=C[P(O)(OR)2]2, R = Et (1) and
R = TMS (2) which give information on the energetic po-
sition of the molecular orbitals (MO). For comparison, we
also
calculated
the
carboxylate
species
H2C=C[C(O)(OR)]2, R = Et (1¢) and R = TMS (2¢). The
pc=c orbital in antibonding combination with the oxygen
lone pairs from the P=O or C=O moieties is found to be
the HOMO for 1 and 2 but only the HOMO-2 for 1¢and 2¢
(Figure 1). The two first occupied MO for the compounds
1¢ and 2¢ are mainly a combination of the carbonyl moi-
eties. The HOMO in tetrasilyl ester 2 is slightly more de-
stabilized than the HOMO of tetraethyl ester 1 and thus is
more accessible. Moreover, both pc=c MO are more desta-
bilized than those of 1¢ and 2¢ (ca. 0.5–0.7 eV). Concern-
ing the LUMO, they reveal the same character (p*c=c). The
LUMO of the silyl ester is less accessible than all others
ones. Note that the role of the silyl groups is essentially
electronic and no specific steric effects are found. Indeed,
compounds 1 and 2 represent quasi-similar geometrical
Figure 1 Plot and energetic positions KS (Kohn–Sham energies) of
the pc = c and p*c = c for compounds 1, 2 and 1¢, 2¢
R2
P(O)(OH)2
P(O)(OH)2
N
H
3h–j (57–75%)
R2 = 4-MeOC6H4 (h),
(i),
(j)
N
N
P(O)(OH)2
RF
N
1. R2NH2,
MeCN, 60 °C
2. MeOH, r.t.
R1
P(O)(OH)2
H
N
P(O)(OH)2
3k–m (27–82%)
RF = CF3 (k), HCF2CF2 (l), HCF2(CF2)3 (m)
H
P(O)(OH)2
3a–g (55–99%)
1. R1NH2,
CH2Cl2, r.t.
2. MeOH, r.t.
1. RFCH2NH2,
MeCN, 60 °C
2. MeOH, r.t.
R1 = c-Pr (a), n-Bu (b), t-Bu (c), c-Hex (d),
O
O
O
B
OSiMe3
OSiMe3
N
O
(e),
(g),
1.
P
NH
O
1.
N
OSiMe3
OSiMe3
P
EtO2C
CH2Cl2, r.t.
NH2
O
O
O
toluene, 80 °C
2. MeOH, r.t.
(f)
2. MeOH, r.t.
2
OH
O
O
OMe
NH2
(HO)2B
1.
1.
P(O)(OH)2
N
toluene, 80 °C
2. MeOH, r.t.
P(O)(OH)2
P(O)(OH)2
N
P(O)(OH)2
N
(EtO)2(O)P
NH2
H
EtO2C
MeCN, 60 °C
2. MeOH, r.t.
3n (68%)
3q (70%)
OMe
OH
P(O)(OH)2
P(O)(OH)2
N
H
P(O)(OH)2
P(O)(OH)2
(EtO)2(O)P
N
H
3p (75%)
3o (62%)
Scheme 2 Synthesis of 2-aminoethylidene-1,1-bisphosphonic acids
Synlett 2011, No. 10, 1370–1374 © Thieme Stuttgart · New York

1372
M. V. Shevchuk et al.
LETTER
parameters with in particular the two P=O bonds in the phonate (2). Even if DFT calculation notes a less electro-
same position (H2CCPP dihedral angle of ca. 30–40°).
philic character of the H2C=C[P(O)(OTMS)2]2 species
compared with vinylidene carboxylate compounds or
compared with tetraethyl 1,1-ethenylidenebisphospho-
nate, nucleophilic attack on the activated C=C bond of the
tetrasilyl substrate easily proceeds. In general the process
tolerates base- and acid-sensitive functional groups. The
potassium salts of the title bisphosphonic acids can be ob-
tained by treatment of the Michael adducts in acetonitrile
with potassium fluoride.
Aminocyclopropane, n- and tert-butylamine, a-methyl-
benzylamine, cyclohexylamine, and 4-(2-amino-
ethyl)morpholine, all reacted smoothly with ethen-
ylidenebisphosphonate 2 in dichloromethane at room
temperature. Reactions with 2- and 3-aminopyridine,
2,2,2-trifluoroethylamine, and fluorinated alkylamines
HCF2(CF2)nCH2NH2 (n = 1, 3) did not proceed at 20 °C in
dichloromethane, but the Michael additions occurred in
acetonitrile at 60 °C. The progress of the reactions was
followed by 31P NMR spectroscopy. Treatment of the re-
action mixtures with methanol at room temperature
smoothly yielded the corresponding bisphosphonic acids
3a–m in 27–99% yields. This reaction sequence was ap-
plied successfully to functionalized amines such as ethyl
1-piperazinocarboxylate, 4-aminophenylboronic acid pi-
nacol ester, and (S)-(+)-2-phenylglycinol to afford prod-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the Science and Technology Center in Ukraine (Project
5215) for financial support. The theoretical work was granted
ucts 3n,p,q in 68–75% yields.17 By using the reaction of access to the HPC resources of Idris under allocation
2010(i2010080045) made by GENCI (Grand Equipement National
diethyl 1-amino-1-(4-methoxyphenyl)methylphospho-
nate with ethenylidenebisphosphonate 2, compound 3o
de Calcul Intensif).
bearing phosphonate groups simultaneously in highly po-
lar saltlike form and lipophilic ester form has been ob-
tained.
References and Notes
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Furthermore, potassium salts of 2-aminoethylidene-1,1-
bisphosphonic acids bearing moisture-sensitive 1,3,2-di-
oxaborolan-2-yl group and acid-sensitive tert-butyl ester
group could be prepared directly from the corresponding
Michael adducts and KF (Scheme 3). Thus, when inter-
mediately formed tetrakis(trimethylsilyl) 2-aminoeth-
ylidene-1,1-bisphosphonates were treated with KF, the
reaction furnished the potassium salts 4a,b (Scheme 3) in
almost quantitative yield.18
36, 507. (b) Russell, R.; Rogers, M. Bone 1999, 25, 97.
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(f) Clézardin, P.; Ebetino, F. H.; Fournier, P. G. J. Cancer
Res. 2005, 65, 4971.
O
OSiMe3
R
P(O)(OSiMe3)2
P(O)(OSiMe3)2
P
i
OSiMe3
N
H
OSiMe3
OSiMe3
P
(3) (a) Simoni, D.; Gebbia, N.; Invidiata, F. P.; Eleopra, M.;
Marchetti, P.; Rondanin, R.; Baruchello, R.; Provera, S.;
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O
2
R
P(O)(OK)2
ii
N
H
P(O)(OK)2
4a,b (89–96%)
O
B
O
O
R =
(a),
(b)
O
Scheme 3 Direct synthesis of potassium salts of 2-amino-ethylide-
ne-1,1-bisphosphonic acids (4a,b). Reagents and conditions: (i)
RNH2 (1 equiv), MeCN, 60 °C or PhMe, 80 °C; (ii) KF (4 equiv),
MeCN, 50 °C.
In summary, we have shown that potentially bioactive
functionalized 2-aminoethylidene-1,1-bisphosphonates
can easily be synthesized by a new reaction sequence
from tetrakis(trimethylsilyl) ethenylidene-1,1-bisphos-
Synlett 2011, No. 10, 1370–1374 © Thieme Stuttgart · New York

LETTER
Tetrakis(trimethylsilyl) Ethenylidene-1,1-bisphosphonate
1373
Guiglia, G.; Jeker, H.; Klein, R.; Ramseier, U.; Schmid, J.;
were confirmed as true minima on the potential energy
through vibrational analysis. The frequencies were
calculated with analytical second derivatives. All total
energies have been zero-point energy (ZPE) and temperature
corrected using unscaled density functional frequencies.
Molecular orbitals have been plotted with the Molekel
package.22
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bisphosphonic acid (3n)
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Eur. J. Org. Chem. 2006, 29.
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Chem. 2001, 66, 3704.
(12) Duncan, G. D.; Li, Z.-M.; Khare, A. B.; McKenna, C. E.
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(13) Shevchuk, M. V.; Romanenko, V. D.; Kukhar, V. P. Book of
Abstracts 18th International Conference on Phosphorus
Chemistry, Wroclaw, Poland, July 11-15th, 2010; ICPC:
Wroclaw, 2010, 131.
Solution of tetrasilyl ester 2 (890 mg, 1.87 mmol) and 1-
carbethoxypiperazine (346 mg, 1.87 mmol) in CH2Cl2 was
stirred at r.t. overnight. Solvent was evaporated, and the
resulting oil was treated with methanol to precipitate 3n (440
mg, 68%). Colorless crystals; mp 223 °C. 1H NMR (400
MHz, D2O): d = 1.20 (t, 3JHH = 7.3 Hz, 3H, CO2CH2CH3),
2.71 (tt, 2JHP = 21.5 Hz, 3JHH = 8.2 Hz, 1 H, NCH2CHP2),
3.05–3.10 (m, 2 H, CH2), 3.16–3.26 (m, 2 H, CH2), 3.51 (td,
3JHP = 14.2 Hz, 3JHH = 8.2 Hz, 2 H, NCH2CHP2), 3.60–3.68
(m, 2 H, CH2), 4.10 (q, 3JHH = 7.3 Hz, CO2CH2CH3), 4.20–
4.30 (m, 2 H, CH2) ppm. 13C{1H} NMR (100 MHz, D2O):
d = 13.7, 33.9 (t, 1JCP = 120.3 Hz, NCH2CHP2), 41.1, 51.4,
54.3, 63.2, 156.4 (CO2Et) ppm. 31P{1H} NMR (162 MHz,
D2O): d = 15.5 ppm. Anal. Calcd for C9H20N2O8P2 (346.07):
N, 8.09. Found: N, 8.40.
(18) 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)benzeneamino]ethylidenebisphosphonic Acid
Tetrapotassium Salt (4a)
Solution of tetrasilyl ester 2 (340 mg, 0.71 mmol) and 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzeneamine
(171 mg, 0.78 mmol) in MeCN (8 mL) was stirred at 60 °C
for 90 h and then cooled to ambient temperature. KF (174
mg, 2.99 mmol) and dibenzo-18-crown-6 (32 mg, 0.09
mmol) were added, and the mixture was stirred at 50 °C for
another 24 h. Product was isolated via centrifugation as
colourless hygroscopic air-sensitive solid in 80% yield (350
mg); mp >250 °C. 1H NMR (500 MHz, D2O): d = 1.22 (s, 12
H, CCH3), 2.27 (m, 1 H, NCH2CHP2), 3.58 (m, 2 H,
NCH2CHP2), 6.87 (d, 3JHH = 7.8 Hz, 0.5 H, HAr), 6.92 (t,
3JHH = 7.8 Hz, 1.5 H, HAr), 7.32 (t, 3JHH = 7.8 Hz, 1.5 H,
HAr), 7.65 (d, 3JHH = 7.8 Hz, 0.5 H, HAr) ppm. 13C{1H} NMR
(100 MHz, D2O): d = 23.8, 42.1, 75.7, 111.5, 119.6, 129.6
ppm. 31P{1H} NMR (202.5 MHz, D2O): d = 17.0–19.0(br)
ppm. Anal. Calcd for C10H17NO7P2 (325.05): P, 11.07.
Found: P, 10.89.
(14) Degenhardt, C. R.; Burdsall, D. C. J. Org. Chem. 1986, 51,
3488.
(15) Tetrakis(trimethylsilyl) ethenylidenebisphosphonate (2)
A hot-gun dried Schlenk-type flask stopped with rubber
septum and flashed with argon was charged with tetraethyl
ester 1 (5.79 g, 0.0193 mol) and dry MeCN (10 mL).
Bromotrimethylsilane (12.8 g, 0.0833 mol) was added to this
solution via a syringe. After a mild exothermic period the
reaction mixture was allowed to stir overnight at 20 °C.
Volatiles were removed under vacuum, and the product was
distilled at 125–130 °C under 0.05 mm as clear viscous oil
(8.27 g, 90%) which formed air-sensitive needle-like
crystals when cooled below 20 °C. 1H NMR (400 MHz,
C6D6): d = 0.29 (s, 36 H, SiCH3), 6.68 (dd, 3JHP = 35.1 Hz,
3JHP = 38.8 Hz, 2 H, CH2=CP2) ppm. 13C{1H} NMR (100
MHz, C6D6): d = 1.5 (s, SiCH3), 140.3 (t, 1JCP = 173.4 Hz,
CH2=CP2), 143.1 (s, CH2=CP2) ppm. 31P{1H} NMR (162
MHz, C6D6): d = –3.1 (dd, 3JPH = 35.1 Hz, 3JPH = 38.8 Hz)
ppm. NMR spectral data were consistent with those
described previously.12
(16) Calculations were performed with the Gaussian 03
programs,19 using the density functional method.20 The
hybrid exchange functional B3LYP in conjunction with the
6-31+G** basis set was used. B3LYP21 is a three-parameter
functional developed by Becke which combines the Becke
gradient-corrected exchange functional and the Lee–Yang–
Parr and Vosko–Wilk–Nusair correlation functionals with
part of exact HF exchange energy. The optimized structures
(19) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, E. J.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
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