P. Tortorella et al.
MED
Tetraethyl [(4’-nitro-biphenyl-4-sulfonylamino)methyl)]-1,1-bis-
phosphonate (27): Yellow solid, 75% yield; mp: 146–1478C;
1H NMR ([D6]DMSO): d=1.10–1.19 (m, 12H, CH2CH3), 3.85–4.06 (m,
8H, CH2CH3), 4.07–4.26 (td, JHH =9.6, JHP =23.1, 1H, PCHP), 7.9–8.02,
8.30–8.35 (m, 6H, 2H, aromatics), 8.88 ppm (d, JHH =9.6, 1H, NH);
MS (ESI): m/z: 587 [M+Na]+; MS2: m/z (%): 449 (100).
General procedure for the preparation of 1,1-bisphosphonic
acids 1–15. Method A: A solution of the appropriate tetraalkyl bis-
phosphonate (29 or 30) (0.6 mmol) in 4n HCl (48 mmol) was kept
at reflux for 8–10 h. After removal of the aqueous phase under re-
duced pressure, the crude bisphosphonic acids were triturated
with Et2O and filtered to afford the final compounds as white
solids.
Tetraethyl [(4’-chloro-biphenyl-4-sulfonylamino)methyl)]-1,1-bis-
phosphonate (28): White solid, 39% yield; mp: 124–1268C;
1H NMR ([D6]DMSO): d=1.23–1.29 (m, 12H, CH2CH3), 4.01–4.20 (m,
8H, CH2CH3), 4.24 (td, JHH =9.6, JHP =22.1, 1H, PCHP), 5.21–5.26 (m,
1H, NH), 7.43–7.53, 7.65–7.69, 7.93–7.98 ppm (m, 4H, 2H, 2H aro-
matics); MS (ESI): m/z: 578 [M+2+Na]+, 576 [M+Na]+; MS2: m/z
(%): 410 (100).
(4-Bromophenylthio)methyl-1,1-bisphosphonic acid (31): 98%
1
yield; mp: 2078C (dec); H NMR ([D6]DMSO): d=3.23–3.36 (m, 1H,
PCHP), 5.39 (br, 4H, OH), 7.39–7.5 ppm (m, 4H, aromatics); 31P NMR
([D6]DMSO): d=14.9 ppm (d, JPH =18.3, 2P, PCHP); MS (ESI): m/z:
363 [M+2ꢀH]ꢀ (100), 361 [MꢀH]ꢀ (85); MS2: m/z (%): 345 (100).
[2-(4-Bromo-phenylsulfonyl)ethyl]-1,1-bisphosphonic acid (5):
1
Tetraethyl
[2-(4-bromo-phenylsulfonyl)ethyl]-1,1-bisphospho-
79% yield; mp: 200–2038C; H NMR ([D6]DMSO): d=2.43 (tt, JHH
=
nate (29): 4-Bromothiophenol (6.4 mmol) was added to a solution
of tetraethyl ethenylidenebisphosphonate[43] (2.5 mmol) in CHCl3
(6 mL). After heating for 40 h at 408C, the organic solvent was
evaporated and the resulting yellow oil was purified by flash chro-
matography on silica gel (eluent from CHCl3/CH2Cl2 1:1 to CHCl3) to
give the tetraethyl [2-(4-bromo-phenylthiol)ethyl]-1,1-bisphospho-
nate as a yellow oil (0.67 g, 56%): 1H NMR (CDCl3): d=1.32 (td,
4.6, JHP =12.4, 1H, PCHP), 3.61 (td, JHH =4.6, JHP =6.5, 2H, CH2CHP),
7.75–7.78, 7.82–7.85 (m, 2H, 2H, aromatics), 8.04 ppm (br, 4H, OH);
31P NMR ([D6]DMSO): d=17.8 ppm (dt, JPH =24.1, JPH =15.2, 2P,
PCH2CHP); MS (ESI): m/z: 409 [M+2ꢀH]ꢀ, 407 [MꢀH]ꢀ; MS2: m/z
(%): 391 [M+2ꢀHꢀH2O]ꢀ (97), 389 [MꢀHꢀH2O]ꢀ (100); Anal. calcd
for C8H11BrO8P2S: C 23.49%, H 2.71%, found: C 23.25%, H 2,63%.
Method B: A solution of the suitable tetraalkyl bisphosphonate
(16–18, 20, 21, 24–26, 28 and commercially available tetraethyl
methylenebisphosphonate) (0.86 mmol) in 6 n HCl/dioxane (1:2,
15 mL) was refluxed for 7–30 h. After removal of the solvents
under reduced pressure, the crude bisphosphonic acids were crys-
tallized or triturated with EtOAc or Et2O and filtered affording the
final compounds as white solids in 53–98% yields.
J
HH =7.1, JHP =1.9, 12H, CH2CH3), 2.59 (tt, JHH =6.3, JHP =23.6, 1H,
PCHP), 3.42 (td, JHH =6.3, JHP =15.7, 2H, CH2CHP), 4.08–4.23 (m, 8H,
CH2CH3), 7.24–7.28, 7.38–7.43 ppm (m, 2H, 2H, aromatics); MS
(ESI): m/z: 513 [M+2+Na]+, 511 [M+Na]+; MS2: m/z (%): 437 (100).
m-CPBA (70%, 0.53 g, 3.16 mmol) was added to an ice-cooled solu-
tion of this sulfide (0.3 g, 0.61 mmol) in CH2Cl2 (10 mL). After stir-
ring for 4 h, the organic phase was washed with 0.5 n NaOH and
brine, dried over Na2SO4, and evaporated to dryness to afford a
solid that was purified by silica gel chromatography (EtOAc) to
give 29 (0.28 g, 88%): 1H NMR (CDCl3): d=1.28–1.38 (m, 12H,
CH2CH3), 3.03 (tt, JHH =4.6, JHP =24.7, 1H, PCHP), 3.64–3.76 (m, 2H,
CH2CHP), 4.08–4.26 (m, 8H, CH2CH3), 7.69–7.73, 7.77–7.81 ppm (m,
2H, 2H, aromatics); MS (ESI): m/z: 545 [M+2+Na]+, 543 [M+Na]+;
MS2: m/z (%): 323 (100).
Methylen-1,1-bisphosphonic acid (MBP): 98% yield; mp: 192–
1958C; 1H NMR ([D6]DMSO): d=2.13 (t, JHP =20.6, 2H, PCH2P),
8.12 ppm (br, 4H, OH); 31P NMR ([D6]DMSO): d=17.73 ppm (dt,
J
PH =21.3, 2P, PCH2P); MS (ESI): m/z: 175 [MꢀH]ꢀ; MS2: m/z (%): 157
[MꢀHꢀH2O]ꢀ (100); Anal. calcd for CH6O6P2: C 6.82%, H 3.44%,
found: C 7.04%, H 3.48%.
(4-Chloro-phenylsulfonylamino)methyl-1,1-bisphosphonic acid
(1): 98% yield; mp: 240–2438C; 1H NMR ([D6]DMSO): d=3.79 (td,
Tetraethyl (4-bromo-phenylthio)methyl-1,1-bisphosphonate (30):
A solution of iodine (2.09 g, 8.22 mmol) in ethanol (10 mL) was
added dropwise to a solution of 4-bromothiophenol (1.34 g,
7.1 mmol) in the same solvent (4.5 mL) at reflux until a persistent
brown color was observed. After stirring for 10 min, a saturated so-
lution of Na2S2O3·5H2O (20 mL) was added. The organic solvent
was removed under reduced pressure, and the residue was extract-
ed with EtOAc. The organic phase was dried over Na2SO4 and
evaporated to dryness to obtain 1,1’-(4-bromodiphenyl)disulfide as
a yellowish solid in quantitative yield. mp: 88–908C; 1H NMR
(CDCl3): d=7.31–7.35, 7.41–7.45 ppm (m, 4H, 4H, aromatics); GC-
MS: m/z (%): 378 [M+4]+ (40), 376 [M+2]+ (74), 374 [M]+ (36), 108
(100).
J
HH =9.6, JHP =21.7, 1H, PCHP), 6.68 (br, 4H, OH), 7.5–7.55, 7.79–
7.83 (m, 2H, 2H, aromatics), 8.06 ppm (d, JHH =9.6, 1H, NH);
31P NMR ([D6]DMSO): d=14.95 ppm (d, JPH =21.3, 2P, PCHP); MS
(ESI): m/z (%): 366 [M+2ꢀH]ꢀ; MS2: m/z (%): 346 [MꢀHꢀH2O]ꢀ
(100); Anal. calcd for C7H10ClNO8P2S·0.5H2O: C 22.44%, H 2.96%, N
3.74%, found: C 22.74%, H 3.30%, N 3.37%.
(Benzensulfonylamino)methyl-1,1-bisphosphonic acid (2): 92%
yield; mp: 2178C (dec); H NMR ([D6]DMSO): d=3.84 (td, JHH =9.6,
J
7.80–7.95 ppm (m, 3H, 2H, aromatics); 31P NMR ([D6]DMSO): d=
15.15 ppm (d, JPH =21.3, 2P, PCHP); MS (ESI): m/z: 330 [MꢀH]ꢀ;
MS2: m/z (%): 312 [MꢀHꢀH2O]ꢀ (100); Anal. calcd for
C7H11NO8P2S·H2O: C 24.08%, H 3.75%, N 4.01%, found: C 24.21%,
H 4.14%, N 3.68%.
1
HP =21.7, 1H, PCHP), 6.68 (br, 4H, OH and 1H, NH), 7.42–7.55,
To an ice-cooled suspension of 95% NaH (0.05 g, 2.1 mmol) in an-
hydrous DMF (3 mL) a solution of tetraethyl methylenebisphospho-
nate (0.12 mL, 0.48 mmol) in anhydrous DMF (4 mL) was added
under N2 atmosphere. After stirring for 30 min at 08C, a solution of
the previous disulfide (0.2 g, 0.53 mmol) in anhydrous DMF (5 mL)
was added dropwise. The resulting mixture was stirred for 24 h,
then the solvent was removed under reduced pressure. The result-
ing oily residue was purified by flash chromatography on silica gel
(eluent: CHCl3/iPrOH 98:2) to give the desired compound 30 as a
yellowish oil (0.21 g, 89%): 1H NMR (CDCl3): d=1.32 (t, JHH =7.1,
12H, CH2CH3), 3.34 (t, JHP =21.45, 1H, PCHP), 4.16–4.28 (m, 8H,
CH2CH3), 7.40–7.48 ppm (m, 4H, aromatics); GC-MS: m/z (%): 476
[M+2]+ (97), 474 [M]+ (91), 201 (100).
(4-Bromo-phenylsulfonylamino)methyl-1,1-bisphosphonic acid
(3): 60% yield; mp: 234–2358C; 1H NMR ([D6]DMSO): d=3.79 (td,
J
HH =9.9, JHP =21.7, 1H, PCHP), 6.83 (br, 4H, OH), 7.64–7.66, 7.71–
7.74 (m, 2H, 2H, aromatics), 8.07 ppm (d, JHH =9.3, 1H, NH);
31P NMR ([D6]DMSO): d=14.94 ppm (d, JPH =24.4, 2P, PCHP); MS
(ESI): m/z: 410 [M+2ꢀH]ꢀ, 408 [MꢀH]ꢀ; MS2: m/z (%): 392 [M+2]+
+
(100), 390 [M] (90); Anal. calcd for C7H10BrNO8P2S: C 20.50%, H
2.46%, N 3.42%, found: C 20.75%, H 2.56%, N 3.36%.
(4-Methyl-phenylsulfonylamino)methyl-1,1-bisphosphonic acid
(7): 90% yield; mp: 218–2228C (dec); H NMR ([D6]DMSO): d=2.33
1
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ChemMedChem 2011, 6, 1258 – 1268