Copper-mediated 1,4-conjugate addition of boronic acids and indoles to vinylidenebisphosphonate leading to gem-bisphosphonates as potential antiresorption bone drugs

Article abstract of DOI:10.1002/cctc.201402346

A wide range of gem-bisphosphonate tetraethyl esters as precursors for bisphosphonic acids, which are potent inhibitors of bone resorption, bearing alkyl, aryl, and indole substituents in the β position were prepared through the Cu^II-catalyzed 1,4-conjugate addition of boronic acids and indoles to vinylidenebisphosphonate tetraethyl ester.

Full text of DOI:10.1002/cctc.201402346

Supporting Information
ꢀ Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2014
Copper-mediated 1,4-Conjugate Addition of Boronic Acids
and Indoles to Vinylidenebisphosphonate leading to gem-
Bisphosphonates as Potential Antiresorption Bone Drugs
Andrea Chiminazzo, Laura Sperni, Martina Damuzzo, Giorgio Strukul, and
Alessandro Scarso*[a]
cctc_201402346_sm_miscellaneous_information.pdf

Scheme S1. Investigation of the asymmetric conjugate addition of phenyl boronic acid and indole to
prochiral unsaturated bisphosphonates did not led to the formation of the desired products, neither
using electron rich nor electron poor prochiral vinylidenebisphosphonate esters. Tests were performed
with free Cu(OTf)2 as well as in the presence of chiral ligands like (+)-2,2′-Isopropylidenebis[(4R)-4-
benzyl-2-oxazoline] or 2,6-Bis[(4S)-(−)-isopropyl-2-oxazolin-2-yl]pyridine.
Reagents and Materials
1
31
General. H NMR, P{1H} NMR, spectra were run on a Bruker Avance 300 spectrometer operating at
300.15, 121.5, MHz, respectively, at 298 K, unless otherwise stated.  values in ppm are relative to
Si(CH3)4, 85% H3PO4.
GC-MS analyses were performed on a GC Trace GC 2000 coupled with a quadrupole MS Thermo
Finnigan Trace MS with Full Scan method. Experimental conditions are reported in the following table.
Experimental conditions for GC-MS analysis
Capillary column:
Initial T, C:
Rate, C/min:
HP5-MS 30 m, 0.25 mm x 0.25 m
80°C for 5 min
30°C/min
280°C for 30 min
280°C
Final T, C:
Injector T (split), C:
Gas carrier flow, mL/min.
Injected volume, L
Solvent delay, min.
Mass range, amu:
Detector voltage, V:
0.8 mL/min
0.8-1 L
4 min.
35-500 amu
350 V
1

280°C
200°C
Interface T, C
Source T, C:
All the aromatic derivatives and indoles used as substrates are commercial products (Aldrich) and were
used without any purification. Vinylidenebisphosphonate tetraethyl ester (VBP) was prepared as
reported in the literature.1 All the synthetic work was carried out without the exclusion of atmospheric
oxygen. Solvents were dried and purified according to standard methods. Flash chromatography was
performed on 230-400 mesh silica and thin layer chromatography was carried out on 20 cm x 20 cm
ALUGRAM® Xtra SIL G/UV254 MACHEREY-NAGEL.
2

General procedure for the catalytic addition of boronic acids to VBP
In a vial equipped with magnetic stirring bar 100 mg of VBP (3.3∙10-1 mmol), 12 mg of Cu(OTf)2 (10 mol%
with respect to VBP), 1.5 equivalents of boronic acid with respect to VBP were added followed by 2 mL
di anhydrous toluene. The vial was thermostatted at 70°C for 18h under vigorous stirring. Subsequently,
the mixture was diluted with 5 mL of dichloromethane the organic phase was extracted with a saturated
aqueous solution of EDTA and washed with water. The product of the reaction was isolated by means of
1
preparative TLC with 6:4 n-hexane:acetone eluent and was characterized with H, 31P and GC-MS
analysis.
O O
O
O
P
P
O
O
1H-NMR (300.15 MHz, CDCl3): δ1.21-1.31 (m, 12H), 2.65 (tt, J = 24.0, 6.3 Hz, 1H), 3.24 (td, J = 16.5, 6.3
Hz, 2H), 3.97-4.21 (m, 8H), 7.15-7.28 (m, 5H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.20 (s, 2P) ppm
Elemental Analysis C16H28O6P2: Calculated C, 50.79; H, 7.46; Found: C, 50.77; H, 7.49; %
MS, m/z: 378 [M+], 241 [M+-PO(OCH2CH3)2], 185 [241-2(CH2CH2)]
1H-NMR (300.15 MHz, CDCl3): δ 1.16 (t, J = 7.5 Hz, 3H), 1.20-1.31 (m, 12H), 2.69 (tt, J = 24.0, 6.0 Hz, 1H),
3.89 (m, 2H), 4.02-4.22 (m, 8H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.71 (s, 2P) ppm
Elemental Analysis C11H26O6P2: Calculated C, 41.77; H, 8.29; Found: C, 41.79; H, 8.31; %
1H-NMR (300.15 MHz, CDCl3): δ 1.16 (d, J = 6.1 Hz, 6H), 1.21-1.29 (m, 12H), 1.61 (m, 1H), 2.64 (tt, J =
24.0, 6.0 Hz, 1H), 3.92 (m, 2H), 4.00-4.21 (m, 8H) ppm
3

31P {1H}-NMR (121.5 MHz, CDCl3): δ 19,97 (s, 2P) ppm
Elemental Analysis C13H30O6P2: Calculated C, 45.35; H, 8.78; Found: C, 45.33; H, 8.80; %
1H-NMR (300.15 MHz, CDCl3): δ 1.21-1.32 (m, 14H), 2.67 (t, J=24.0, Hz, 1H), 2.87 (m, 2H), 3.86 (td,
J=16.0, 6.0 Hz, 2H), 4.01-4.25 (m, 8H), 7.30-7.50 (m, 5H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 20.00 (s, 2P) ppm
Elemental Analysis C18H32O6P2: Calculated C, 53.20; H, 7.94; Found: C, 53.16; H, 7.95; %
O O
O
O
P
P
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.05 (s, 9H), 1.18-1.27 (m, 12H), 2.64 (tt, J = 23.4, 6.3 Hz, 1H), 3.21 (td, J
= 16.5, 6.3 Hz, 2H), 3.96 – 4.18 (m, 8H), 7.19 (d, J = 7.50 Hz, 2H), 7.29 (d, J = 7.50 Hz, 2H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 21.70 (s, 2P) ppm
Elemental Analysis C20H36O6P2: Calculated C, 55.29; H, 8.35; Found: C, 55.31; H, 8.33; %
MS, m/z: 434 [M+], 297 [434-PO(OCH2CH3)2], 269 [297-CH2CH2], 241 [269-CH2CH2], 185 [241-C4H9]
O O
O
O
P
P
O
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.28 (m, 12H), 2.59 (tt, J = 23.7, 6.0 Hz, 1H), 3.19 (td, J = 16.5, 6.0 Hz,
2H), 3.78 (s, 3H), 4.02 – 4.19 (m, 8H), 6.81 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.33 (s, 2P) ppm
Elemental Analysis C17H30O7P2: Calculated C, 50.00; H, 7.40; Found: C, 49.97; H, 7.44; %
4

O O
O
O
P
P
O
O
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.21-1.27 (m, 12H), 3.04 (tt, J = 23.2, 7.1 Hz, 1H), 3.24 (td, J = 15.8, 7.1
Hz, 2H), 3.85 (s, 6H), 4.01 – 4.13 (m, 8H), 6.77-6.99(m, 3H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 21.81 (s, 2P) ppm
Elemental Analysis C18H32O8P2: Calculated C, 49.32; H, 7.36; Found: C, 49.36; H, 7.37; %
O
O
P
O
O
P
O
O
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.24-1.33 (m, 12H), 2.57 (tt, J = 23.7, 6.0 Hz, 1H), 3.13 (td, J = 16.5, 6.0
Hz, 2H), 4.02 – 4.19 (m, 8H), 4.22 (s, 4H), 6.70 – 6.75 (m, 3H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.26 (s, 2P) ppm
Elemental Analysis C18H30O8P2: Calculated C, 49.54; H, 6.93; Found: C, 49.57; H, 6.95; %
O O
O
O
P
P
O
O
N
1H-NMR (300.15 MHz, CDCl3): δ 1.28 (m, 12H), 2.59 (tt, J = 23.7, 6.0 Hz, 1H), 2.90 (s, 6H), 3.16 (td, J =
16.7, 6.0 Hz, 2H), 4.00 – 4.30 (m, 8H), 6.67 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.59 (s, 2P) ppm
Elemental Analysis C18H33NO6P2: Calculated C, 51.30; H, 7.89; N, 3.32; Found: C, 51.31; H, 7.87; N, 3.31;
%
O O
O
O
P
P
O
O
NO2
5

1H-NMR (300.15 MHz, CDCl3): δ 1.27 (m, 12H), 2.62 (tt, J = 23.7, 6.3 Hz, 1H), 3.33 (td, J = 16.5, 6.3 Hz,
2H), 4.00 – 4.20 (m, 8H), 7.45 (d, J = 8.7 Hz, 2H), 8.14 (d, J = 8.7 Hz, 2H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 23.38 (s, 2P) ppm
Elemental Analysis C16H27NO8P2: Calculated C, 45.39; H, 6.43; N, 3.31; Found: C, 45.36; H, 6.40; N, 3.34;
%
O O
O
O
P
P
O
O
Br
1H-NMR (300.15 MHz, CDCl3): δ 1.27 (m, 12H), 2.57 (tt, J = 23.7, 6.3 Hz, 1H), 3.19 (td, J = 16.5, 6.3 Hz,
2H), 4.00 – 4.21 (m, 8H), 7.15 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 23.89 (s, 2P) ppm
Elemental Analysis C16H27BrO6P2: Calculated C, 42.03; H, 5.95; Found: C, 42.00; H, 5.97; %
O O
O
O
P
P
O
O
I
1H-NMR (300.15 MHz, CDCl3): δ 1.18-1.27 (m, 12H), 3.10 (tt, J = 23.0, 7.6 Hz, 1H), 3.36 (td, J= 16.2, 7.6
Hz, 2H), 3.96 – 4.18 (m, 8H), 6.90 (dt, J = 7.7, 1.6 Hz, 1H), 7.26 (dt, J = 7.7, 1.6 Hz, 1H), 7.39 (dd, J = 7.8,
1.3 Hz, 1H), 7.8 (dd, J = 7.8, 1.3 Hz, 1H).
31P {1H}-NMR (121.5 MHz, CDCl3): δ 20.68 (s, 2P) ppm
Elemental Analysis C16H27IO6P2: Calculated C, 38.11; H, 5.40; Found: C, 38.15; H, 5.43; %
MS, m/z: 504 [M+], 459 [M-OCH2CH3]+, 377 [M-I]+, 367 [M-PO(OCH2CH3)2]+.
1H-NMR (300.15 MHz, CDCl3): δ 1.20-1.33 (m, 12H), 2.65 (tt, J = 24.0, 6.0, 1H), 3.27 (td, J = 15.0, 6.0, 2H),
3.98-4.22 (m, 8H), 7.10-7.20 (m, 2H), 7.78 (t, J=6.0 Hz, 1H), 10.31 (s, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 20.50 (s, 2P) ppm
6

Elemental Analysis C17H27FO7P2: Calculated C, 48.12; H, 6.41; Found: C, 48.10; H, 6.38; %
1H-NMR (300.15 MHz, CDCl3): δ 1.23 (m, 12H), 2.75 (tt, J = 24.0, 6.3 Hz, 1H), 3.41 (td, J = 16.5, 6.3 Hz,
2H), 4.00-4.22 (m, 8H), 7.36 – 7.48 (m, 3H), 7.69-7.82 (m, 4H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.21 (s, 2P) ppm
Elemental Analysis C20H30O6P2: Calculated C, 56.07; H, 7.06; Found: C, 56.04; H, 7.07; %
O O
O
O
P
P
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.16-1.28 (m, 12H), 2.66 (s, 3H), 2.87 (tt, J = 23.4, 6.6 Hz, 1H), 3.70 (td, J
= 15.9, 6.6 Hz, 2H), 3.94 – 4.24 (m, 8H), 7.22 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.50 – 7.55 (m,
2H), 8.01 (d, J= 9.0 Hz, 1H), 8.13 (d, J= 9.0 Hz, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.21 (s, 2P) ppm
Elemental Analysis C21H32O6P2: Calculated C, 57.01; H, 7.29; Found: C, 56.97; H, 7.32; %
O O
O
O
P
P
O
O
H3CO
1H-NMR (300.15 MHz, CDCl3): δ 1.08-1.23 (m, 12H), 3.12 (tt, J = 23.7, 6.9 Hz, 1H), 3.73 (td, J = 15.3, 6.9
Hz, 2H), 3.96 (s, 3H), 4.00-4.24 (m, 8H), 7.21 (d, J = 7.90Hz, 1H), 7.34 (t, J = 6.9Hz, 1H), 7.45 (t, J = 6.9 Hz,
1H), 7.76 (m, 3H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.04 (s, 2P) ppm
Elemental Analysis C21H32O7P2: Calculated C, 55.02; H, 7.04; Found: C, 55.04; H, 7.05; %
7

O O
O
O
P
P
O
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.14 (m, 12H), 1.49 (t, J = 6.9 Hz, 3H), 3.18 (tt, J = 23.4, 6.9 Hz, 1H), 3.73
(td, J= 15.8, 6.9 Hz, 2H), 3.87-4.10 (m, 8H), 4.19 (q, J = 7.2 Hz, 2H), 7.21 (d, J = 9.0 Hz, 1H), 7.34-7.27 (m,
1H), 7.51-7.42 (m, 1H), 7.73 (m, 2H), 8.17 (d, J = 8.4 Hz, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.70 (s, 2P) ppm
Elemental Analysis C22H34O7P2: Calculated C, 55.93; H, 7.25; Found: C, 55.95; H, 7.23; %
O O
O
O
P
P
O
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.23 (m, 12H), 2.72 (tt, J = 23.7, 6.3 Hz, 1H), 3.37 (td, J = 16.5, 6.3 Hz,
2H), 3.90 (s, 3H), 4.02 – 4.18 (m, 8H), 7.07– 7.15 (m, 2H), 7.33 – 7.38 (m, 1H), 7.63-7.70 (m, 3H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.29 (s, 2P) ppm
Elemental Analysis C21H32O7P2: Calculated C, 55.02; H, 7.04; Found: C, 55.00; H, 7.01; %
O O
O
O
P
P
O
O
OH
1H-NMR (300.15 MHz, CDCl3): δ 1.25 (m, 12H), 2.77 (tt, J = 24.0, 6.3 Hz, 1H), 3.38 (td, J = 16.5, 6.3 Hz,
2H), 4.00 – 4.24 (m, 8H), 6.97-7.08 (m, 2H), 7.29 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.7
Hz, 1H), 7.61 (s, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.66 (s, 2P) ppm
Elemental Analysis C20H30O7P2: Calculated C, 54.05; H, 6.80; Found: C, 54.08; H, 6.83; %
1H-NMR (300.15 MHz, CDCl3): δ 1.15-1.40 (m, 12H), 2.85 (tt, J = 23.1, 6.9 Hz, 1H), 3.70 (td, J = 15.6, 6.9
Hz, 2H), 3.98-4.26 (m, 8H), 7.10-8.30 (m, 6H) ppm
8

31P {1H}-NMR (121.5 MHz, CDCl3): δ 21.29 (s, 2P) ppm
Elemental Analysis C20H29BrO6P2: Calculated C, 47.35; H, 5.76; Found: C, 47.33; H, 5.80; %
MS, m/z: 506 [M+], 369 [M+-PO(OCH2CH3)2], 341 [369-(CH2CH2)], 313 [341-(CH2CH2)], 233 [313-Br], 152
[233-PO3H2]
O O
O
O
P
P
O
O
N
NH2
1H-NMR (300.15 MHz, CDCl3): δ 1.18-1.30 (m, 12H), 2.81 (tt, J = 23.1, 6.3 Hz, 1H), 3.30 (td, J = 14.8, 6.3
Hz 2H), 4.06 – 4.28 (m, 8H), 6.42 (d, J = 6.40 Hz, 1H), 7.74 (d, J = 6.6 Hz, 1H), 8.46 (s, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 20.47 (s, 2P) ppm
Elemental Analysis C15H28N2O6P2: Calculated C, 45.69; H, 7.16; N, 7.10; Found: C, 45.71; H, 7.12; N, 7.13;
%
O O
O
O
P
P
O
O
S
1H-NMR (300.15 MHz, CDCl3): δ 1.28 (m, 12H), 2.61 (tt, J = 23.7, 6.0 Hz, 1H), 3.27 (td, J = 16.5, 6.0 Hz,
2H), 4.04-4.20 (m, 8H), 7.01 (d, J = 4.9 Hz, 1H), 7.10 (s, 1H), 7.23 (d, J = 4.9 Hz, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.10 (s, 2P) ppm
Elemental Analysis C14H26O6P2S: Calculated C, 43.75; H, 6.82; Found: C, 43.78; H, 6.84; %
O O
O
O
P
P
O
O
S
1H-NMR (300.15 MHz, CDCl3): δ 1.20-1.31 (m, 12H), 2.80 (tt, J = 23.7, 6.3 Hz, 1H), 3.51 (td, J = 16.1, 6.3
Hz, 2H), 4.00-4.22 (m, 8H), 7.31 (s, 1H), 7.33-7.42 (m, 2H), 7.81-7.90 (m, 2H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 23.99 (s, 2P) ppm
Elemental Analysis C18H28O6P2S: Calculated C, 49.77; H, 6.50; Found: C, 49.79; H, 6.54; %
9

O O
O
O
P
P
O
O
N
H
1H-NMR (300.15 MHz, CDCl3): δ 1.19-1.30 (m, 12H), 2.97 (tt, J = 23.5, 6.2 Hz, 1H), 4.05 – 4.19 (m, 8H),
4.74 (td, J = 14.1, 6.2 Hz, 2H), 6.44 (d, J = 3.2 Hz, 1H), 7.10 (t, J = 7.0 Hz, 1H), 7.21 (s, 1H), 7.44 (d, J= 7.6
Hz, 1H), 7.60 (d, J= 7.6 Hz, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 19.29 (s, 2P) ppm
Elemental Analysis C18H29NO6P2: Calculated C, 51.80; H, 7.00; N, 3.36; Found: C, 51.84; H, 6.98; N, 3.35;
%
O
O
O
P
P
O
O
O
O
P
O
O
P
O
O
O
1H-NMR (300.15 MHz, CDCl3): δ 1.28 (m, 24 H), 2.59 (tt, J = 23.4, 6.3 Hz, 2H), 3.20 (td, J = 15.0, 6.3 Hz,
4H), 4.00 - 4.22 (m, 16H), 7.18 (s, 4H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 24.32 (s, 2P) ppm
Elemental Analysis C26H50O12P4: Calculated C, 46.02; H, 7.43; Found: C, 46.06; H, 7.45; %
10

General procedure for the catalytic addition of indoles to VBP
Catalytic tests in organic solvent
In a vial equipped with magnetic stirring bar 100 mg of VBP (3.3∙10-1 mmol), 12 mg of Cu(OTf)2 (10 mol%
with respect to VBP), 1.5 equivalents of indole with respect to VBP were added followed by 2 mL of
anhydrous 1,2-dichloroethane. The vial was thermostatted at 70°C for 18h under vigorous stirring.
Subsequently, the mixture was diluted with 5 mL of dichloromethane the organic phase was extracted
with a saturated aqueous solution of EDTA and washed with water. The product of the reaction was
1
isolated by means of preparative TLC with 6:4 n-hexane:acetone eluent and was characterized with H,
31P and GC-MS analysis.
Catalytic tests in water
In a vial equipped with magnetic stirring bar 100 mg of VBP (3.3∙10-1 mmol), 12 mg of Cu(OTf)2 (10 mol%
with respect to VBP), 1.5 equivalents of indole with respect to VBP, 100 mg of sodium dodecylsulfate
(SDS) were added followed by 2 mL of distilled water. The vial was thermostatted at 70°C for 18h under
vigorous stirring. Subsequently, the mixture was diluted with 5 mL of ethyl acetate and the organic
phase was extracted with a saturated aqueous solution of EDTA and washed with water. The product of
the reaction was isolated by means of preparative TLC with 6:4 n-hexane:acetone eluent and was
characterized with 1H, 31P and GC-MS analysis.
O O
O
O
P
P
O
O
NH
1H-NMR (300.15 MHz, CDCl3): δ 1.19-1.31 (m, 12H), 2.78 (tt, J = 24.0, 6.3 Hz, 1H), 3.43 (td, J = 16.5, 6.3
Hz, 2H), 3.99-4.28 (m, 8H), 7.07-7.22 (m, 3H), 7.35 (d, J = 8.10, 1H), 7.67 (d, J = 8.06, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.14 (s, 2P) ppm
Elemental Analysis C18H29NO6P2: Calculated C, 51.80; H, 7.00; N, 3.36; Found: C, 51.83; H, 7.02; N, 3.35;
%
MS,m/z: 417 [M+] 280 [M+-PO(OCH2CH3)2], 252[280-CH2CH2], 224 [252-CH2CH2], 143 [(C10H9N)+], 130
[143-CH]
11

O O
O
O
P
P
O
O
N
1H-NMR (300.15 MHz, CDCl3): δ1.22-1.31 (m, 12H), 2.74 (tt, J = 24.0, 5.9 Hz, 1H), 3.41 (td, J = 16.5, 5.9
Hz, 2H), 3.73 (s, 3H), 4.00-4.75 (m, 8H), 7.06 (m, 2H), 7.21 (t, J=8.10, 1H), 7.31 (d, J= 8.2 Hz, 1H), 7.66 (d, J
= 8.2, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.22 (s, 2P) ppm
Elemental Analysis C19H31NO6P2: Calculated C, 52.90; H, 7.24; N, 3.25; Found: C, 52.87; H, 7.26; N, 3.22;
%
O O
O
O
P
P
O
O
N
1H-NMR (300.15 MHz, CDCl3): δ 1.14-1.30 (m, 12H), 2.40 (s, 3H), 2.79 (tt, J = 23.7, 6.4 Hz, 1H), 3.40 (td, J
= 15.6, 6.4 Hz, 2H), 3,64 (s, 3H), 3.93-4.19 (m, 8H), 7.05 (t, J=6.9, 1H), 7.14 (t, J=6.9, 1H), 7.23 (d, J = 8.1,
1H), 7.57 (d, J = 7.8, 1H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.20 (s, 2P) ppm
Elemental Analysis C20H33NO6P2: Calculated C, 53.93; H, 7.47; N, 3.14; Found: C, 53.90; H, 7.45; N, 3.11;
%
MS, m/z: 445 [M+], 308 [M+-PO(OCH2CH3)2], 158 [308-CHPO(OCH2CH3)]
1H-NMR (300.15 MHz, CDCl3): δ 1.23-1.40 (m, 12H), 2.73 (tt, J=23.0, 6.0 Hz, 1H), 3.42 (td, J = 16.2, 6.0 Hz,
2H), 3.93 (s, 3H), 4.05-4.30 (m, 8H), 7.20-7.31 (m, 4H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.10 (s, 2P) ppm
Elemental Analysis C19H31NO7P2: Calculated C, 51.01; H, 6.98; N, 3.13; Found: C, 51.03; H, 6.95; N, 3.16;
%
12

1H-NMR (300.15 MHz, CDCl3): δ 1.21-1.35 (m, 12H), 2.74 (tt, J = 23.8, 6.0 Hz, 1 H), 3.42 (td, J = 15.0, 6.0
Hz, 2H), 3.95 (s, 3 H), 4.04 - 4.2 (m, 8H); 7.28 (s, 1H), 7.34 (s, 1H), 7.58 (s, 1H) ppm.
31P {1H}-NMR (121.5 MHz, CDCl3): δ 22.10 (s, 2P) ppm
Elemental Analysis C20H30F3NO7P2: Calculated C, 46.61; H, 5.87; N, 2.72; Found: C, 46.58; H, 5.85; N, 2.72;
%
MS, m/z: 515 [M+-H2], 378 [515-PO(OCH2CH3)2], 350 [378-(CH2CH2)], 322 [350-(CH2CH2)], 241 [322-
PO3H3]
1H-NMR (300.15 MHz, CDCl3): δ 1.24 – 1.31 (m, 12 H), 2.50 (s, 3H), 2.72 (tt, J = 23.8, 6.1 Hz, 1H), 3.39 (td,
J = 15.0, 6.1 Hz, 2H), 4.05 – 4.21 (m, 8 H), 7.15 (s, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H) ppm.
31P {1H} – NMR (121.5 MHz, CDCl3): δ 21.9 (s, 2P) ppm
Elemental Analysis C19H30BrNO6P2: Calculated C, 44.72; H, 5.93; N, 2.74; Found: C, 44.75; H, 5.90; N,
2.75; %
MS, m/z: 511 [M+], 372 [511-PHOH(OCH2CH3)2], 237 [372-PO(OCH2CH3)2], 224 [237-CH3]
O O
O
O
P
P
O
O
NH
O
OH
1H-NMR (300.15 MHz, CDCl3): δ 1.20-1.28 (m, 12H), 2.79 (tt, J = 24.61, 6.1 Hz, 1H), 3.45 (td, J = 16.2, 6.1
Hz, 2H), 4.02-4.26 (m, 8H), 7.20-7.32 (m, 2H), 7.34 (d, J=7.8, 1H), 7.91 (d, J=7.8, 1H) ppm.
31P {1H}-NMR (121.5 MHz, CDCl3): δ 21.87 (s, 2P) ppm
Elemental Analysis C19H29NO8P2: Calculated C, 49.46; H, 6.34; N, 3.04; Found: C, 49.45; H, 6.30; N, 3.01;
%
13

1H-NMR (300.15 MHz, CDCl3): δ 1.21-1.40 (m, 12H), 2.78 (tt, J = 23.4, 6.3 Hz, 1H), 3.43 (td, J = 16.2, 6.3
Hz, 2H), 3.9 (s, 3H), 4.04-4.27 (m, 8H), 7.22 (m, 1H), 7.42 (d, 8.6 Hz, 1H), 7.90 (d, 8.6 Hz, 1H), 8.42 (s, 1H)
ppm.
31P {1H}-NMR (121.5 MHz, CDCl3): δ 21.86 (s, 2P) ppm
Elemental Analysis C20H31NO8P2: Calculated C, 50.53; H, 6.57; N, 2.95; Found: C, 50.55; H, 6.60; N, 2.93;
%
MS, m/z: 475 [M+-H2], 338 [475-PO(OCH2CH3)2], 306 [338-CH3OH], 278 [306-CO], 250 [278-CH2CH2]
O O
O
O
P
P
O
O
NH
1H-NMR (300.15 MHz, CDCl3): δ 1.01-1.26 (m, 12H), 2.92 (tt, J=23.4, 6.5 Hz, 1H), 3.66 (td, J = 16.2, 6.5 Hz,
2H), 4.80-4.04 (m, 8H), 7.11-7.76 (m, 9H) ppm
31P {1H}-NMR (121.5 MHz, CDCl3): δ 21.74 (s, 2P) ppm
Elemental Analysis C24H33NO6P2: Calculated C, 58.41; H, 6.74; N, 2.84; Found: C, 58.38; H, 6.71; N, 2.82;
%
O O
O
O
P
P
O
O
NH
Cl
1H-NMR (300.15 MHz, CDCl3): δ 1.10 – 1.19 (m, 12 H), 2.89 (tt, J = 23.6, 6.8 Hz, 1H), 3.61 (td, J = 15.5, 6.8
Hz, 2H), 3.88 – 4.05(m, 8H), 7.11 – 7.22 (m, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.63 – 7.56
(m, 2H), 7.70 (d, J = 7.7 Hz, 1H) ppm.
31P {1H} – NMR (121.5 MHz, CDCl3): δ 21.6 (s, 2P) ppm
Elemental Analysis C24H32ClNO6P2: Calculated C, 54.60; H, 6.11; N, 2.65; Found: C, 54.64; H, 6.11; N, 2.64;
%
14

General procedure for the ester deprotection of the BP
The tetraethyl ester of the bisphosphonic acid (0.2 mmol) was introduced in a vial under anhydrous
condition. To this 12 equivalents of bromotrimethylsilane (2.4 mmol) were added (MW 153.09, 1.16
g/mL). The vial was stirred under inert atmosphere at rt for 18 h. The crude mixture was concentrated
under reduced pressure, diluted with a 9:1 solution of methanol and water, stirred for 4 h at room
temperature and dried. The free bisphosphonic acid was obtained in quantitative yield and was
characterized by 1H and 31P NMR.
1H-NMR (300.15 MHz, D2O): δ 3.10 (tt, J = 23.0, 7.6 Hz, 1H), 3.36 (td, J= 16.2, 7.6 Hz, 2H), 6.87 (t, J = 7.2
Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 7.1 1H), 7.78 (d, J = 7.1 1H).
31P { 1H } -NMR (121.5 MHz, D2O): δ): δ 19.02 (bs, 2P) ppm
O
P
O
P
HO
HO
OH
OH
NH
1H-NMR (300.15 MHz, D2O): δ 2.62 (tt, J = 23.4, 6.3 Hz, 1H), 3.27 (dt, J =16.0, 6.3 Hz, 2H), 6.98 - 7.68
(m, 5H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): δ 20.47 (s, 2P) ppm.
HO
O
HO
OH
P
P
HO
O
N
1H-NMR (300.15 MHz, D2O): δ 2.59 (tt, J = 23.4, 6.3 Hz, 1H), 3.25 (dt, J =16.0, 6.3 Hz, 2H), 3.65 (s, 3H),
7.02 – 7.11 (m, 2H), 7.18 (d, J = 7.9, 1H), 7.35 (d, J = 8.3, 1 H), 7.62 (d, J = 7.9 Hz, 1H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): δ 20.4 (s, 2P) ppm.
HO
O
P
HO
OH
P
HO
O
N
15

1H-NMR (300.15 MHz, D2O): δ 2.29 (s, 3H); 2.57 (tt, J = 22.7 Hz, 6.1 Hz, 1H); 3.24 (dt, J = 16.0 Hz, 6.1 Hz,
2H); 3.54 (s, 3H); 6.98 – 7.13 (m, 2H); 7.30 (d, J = 8.1 Hz, 1H); 7.54 (d, J = 7.8 Hz, 1H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): δ 20.4 (s, 2P) ppm.
HO
O
HO
OH
P
P
HO
O
NH
H3CO
CF3
1H-NMR (300.15 MHz, D2O): δ 2.81 (tt, J = 23.5, 5.9 Hz, 1H), 3.72 (td, J = 16.7, 5.9 Hz, 2H), 3.87 (s, 3H),
7.33-7.39 (m, 2H), 7.67 (s, 1H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): δ 20.1 (s, 2P) ppm.
HO
O
HO
OH
P
P
HO
O
NH
Br
1H-NMR (300.15 MHz, D2O): δ 1.96 (s, 3H), 2.67 (tt, J = 21.0, 6.0 Hz, 1H), 3.70 (td, J = 15.0, 6.0 Hz, 2H),
7.18 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): δ 15.9 (s, 2P) ppm.
OH
OH
O
HO
P
P
HO
O
NH
1H-NMR (300.15 MHz, D2O): δ 2.63 (tt, J = 23.0, 6.2 Hz, 1H), 3.47 (dt, J = 15.6, 6.2 Hz, 2H), 7.06 - 7.13 (m,
2H), 7.28 – 7.41 (m, 3H), 7.44 (d, J = 7.4 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): δ 20.3 (s, 2P) ppm.
16

HO
O
HO
OH
P
P
HO
O
NH
Cl
1H-NMR (300.15 MHz, D2O): δ 2.68 (tt, J = 21.0, 6.1 Hz, 1H), 3.71 (td, J = 16.0, 6.1 Hz, 2H), 7.09 (d, J = 6.9
Hz, 1H), 7.16 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H),
7.68 (d, J = 7.9 Hz, 1H) ppm.
31P { 1H } -NMR (121.5 MHz, D2O): 20.2 (s, 2P) ppm.
1 R.A. Nugent, M. Murphy, S.T. Schlatchter, C.J. Dunn, R.J. Smith, N.D. Staite, L.A. Galinet, S.K. Shields, D.G. Aspar, K.A.
Richard, N.A. Rohloff, J. Med. Chem., 1993, 36, 134-139
17