syringe at 0 ЊC, the reaction stirred overnight at rt, then
quenched by dropwise addition of aqueous NaHCO3. The reac-
tion was worked up as usual and the crude product purified by
flash column chromatography (DCM–MeOH, 98:2) to give the
title compound as a pale orange oil (1.55 g, 76%); Rf 0.36
(DCM–MeOH, 95:5) (Found: Mϩ 313.057. C12H17ClFO3P
34.2 (d, JCP 139), 70.6, 73.7, 117.9 (dt, JCP 221, JCF 263), 126.5,
129.7, 133.0 (ddt, 2JCP 13.8, 2JCF 22.1, 4JCP 3.8), 134.9; m/z (EIϩ)
470 (44%, Mϩ), 428 (7, M Ϫ C3H6), 386 (10, M Ϫ C3H6), 306
(97, M Ϫ PO3Pri2), 264 (62, M Ϫ PO3Pri2 Ϫ C3H6), 222 (87
M Ϫ PO3Pri2 Ϫ 2C3H6), 140 (88, M Ϫ 2PO3Pri2).
requires M 313.057); νmax/cmϪ1 (film) 2985 (C–H), 1611 (C᎐C),
3-(Phosphonomethylphenyl)hydroxymethylphosphonic acid (37a)
᎐
1265 (P᎐O), 1183 (C–F), 1023 (P–O–C); δH (CDCl3) 1.25 (6 H,
᎐
Diethyl 3-[(diethoxyphosphoryl)methylphenyl]hydroxymethyl-
phosphonate 32a (0.19 g, 0.48 mmol) was deprotected as for 2
with TMSBr (0.59 g, 3.82 mmol, 8 eq., 0.50 ml) and the free
acid was isolated as usual (0.11 g). Salt formation and purifi-
cation as for 2 gave the biscyclohexylammonium salt of the title
compound as a white solid (0.18 g, 56%, mp >275 ЊC) (Found:
C 49.9, H 8.2, N 5.5. C20H38N2O7P2 (salt) requires C 50.0, H
8.0, N 5.8%; Found: Mϩ 382.118. C14H26NO7P2 requires M
382.118); δH (D2O) 1.10–2.00 (22 H, m, cyclohexyl-H), 2.90
(2 H, d, JHP 16.4, PCH2–), 4.60 (1 H, d, JHP 14.0, PCH(OH)–),
7.05–7.25 (4 H, m, ArH); δP (D2O) 15.8, 19.6 (2 s); δC (D2O)
23.8, 24.2, 30.3, 36.5 (d, JCP 124), 50.2, 73.5 (d, JCP 144), 124.4,
127.8, 128.0, 131.4, 136.5, 140.7; m/z (FABϩ) 283 (25%, MHϩ),
382 (29, M ϩ C6H11NH3ϩ).
t, 2 CH3CH2–), 3.95–4.10 (4 H, m, 2 CH3CH2–), 4.55 (2 H, s,
CH2Cl), 7.40–7.50 (4 H, m, ArH); δP (CDCl3) 6.41 (t, JPF 111.9);
δF (CDCl3) Ϫ109.5 (d, JFP 112); δC (CDCl3) 16.2. 16.3, 45.5,
64.8, 64.9, 117.8 (dt, JCP 218, JCF 263), 126.3, 127.7, 128.9,
129.2, 133.0, 137.9; m/z (FABϩ) 313 (30%, MHϩ), 175 (27,
M Ϫ PO3Et2), 137 (25, PO3Et2).
Diisopropyl 4-(chloromethylphenyl)difluoromethylphosphonate
(35c)
Diisopropyl 4-chloromethylbenzoylphosphonate 30c (0.85 g,
2.67 mmol) and DAST (1.29 g, 8.01 mmol, 3 eq., 1.06 ml) were
reacted under the same conditions as for 35a. The product was
purified by flash column chromatography (DCM–MeOH,
98:2), affording the title compound as a yellow oil (0.67 g,
73%) (Found: Mϩ 340.080. C14H20F2O3P requires M 340.081);
δH (CDCl3) 1.15, 1.20 (6 H each, 2 s, (CH3)2CH– each), 4.60
(2 H, s, CH2Cl), 4.70–4.80, 4.85–4.90 (1 H each, 2 m, (CH3)2-
CH– each), 7.45 (2 H, d, J 7.7, ArH), 7.55 (2 H, d, J 7.7, ArH);
δP (CDCl3) 4.81 (t, JFP 116); δF (CDCl3) Ϫ109.3 (d, JPF 117);
δC (CDCl3) 23.5, 23.6, 24.1, 24.2, 45.4, 73.8, 74.0, 118.2 (dt, JCP
220, JCF 263), 126.7, 128.5, 133.0, 140.0; m/z (EIϩ) 340 (9%,
Mϩ), 256 (18, M Ϫ 2C3H6), 175 (67, M Ϫ PO3Pri2), 140 (100,
M Ϫ Cl Ϫ PO3Pri2).
4-(Phosphonomethylphenyl)hydroxymethylphosphonic acid (37c)
Diisopropyl
4-[(diisopropoxyphosphoryl)methylphenyl]-
hydroxymethylphosphonate 32c (0.62 g, 1.36 mmol) was
de-esterified as for 2 with TMSBr (1.67 g, 10.90 mmol, 8 eq.,
1.45 ml) and the free acid was isolated as usual (0.42 g). Salt
formation and purification as for 2 gave the biscyclohexyl-
ammonium salt of the title compound as a white solid (0.57 g,
66%, mp >275 ЊC) (Found: C 49.7, H 8.25, N 5.8. C20H38N2-
O7P2 (salt) requires C 50.0, H 8.0, N 5.8%); δH (D2O) 1.20–2.00
(22 H, m, cyclohexyl-H), 2.90 (2 H, d, JHP 20.8, PCH2–), 4.80
(1 H, d, JHP 9.7, PCH(OH)–), 7.15–7.30 (4 H, m, ArH); δP
(D2O) 21.2, 17.1 (2 s); δC (D2O) 23.8, 24.2, 30.3, 35.7 (d, JCP
137), 50.3, 72.0 (d, JCP 128), 126.9, 129.2, 131.0, 134.4; m/z
(FABϩ) 283 (100%, MHϩ), 201 (87, M Ϫ PO3H2).
Diethyl 3-[(diethoxyphosphoryl)methylphenyl]difluoromethyl-
phosphonate (36a)
Sodium hydride (0.08 g, 2.80 mmol, 90% powder) was sus-
pended in dry THF under nitrogen and diethyl phosphonate
(0.43 g, 3.08 mmol, 1.1 eq., 0.40 ml) added dropwise at 0 ЊC
then diethyl 3-(chloromethylphenyl)difluoromethylphosphon-
ate 35a (1.00 g, 2.80 mmol) in dry THF (15 ml) was added
dropwise over 5 min. The reaction was stirred overnight at rt
then quenched with ethanol. After standard work-up the crude
product was purified (~50%) by flash column chromatography
(DCM–MeOH, 98:2) to yield the title compound as a pale yel-
low oil (0.62 g, 94%, 50% conversion); Rf 0.23 (DCM–MeOH,
3-(Phosphonomethylphenyl)fluoromethylphosphonic acid (38a)
Diethyl
3-[(diethoxyphosphoryl)methylphenyl]fluoromethyl-
phosphonate 33a (0.07 g, 0.18 mmol) was deprotected as for 2
with TMSBr (0.19 g, 1.24 mmol, 7 eq., 0.17 ml) and the free
acid isolated as usual (0.05 g). Salt formation and purification
as for 2 gave the biscyclohexylammonium salt of the title com-
pound as a white solid (0.05 g, 62%, mp >300 ЊC) (Found: C
50.0, H 7.4, N 6.1. C20H37FN2O6P2 (salt) requires C 49.8, H
7.4, N 6.1%. Found: Mϩ 384.114. C14H25FNO6P2 requires M
384.114); δH (D2O) 1.10–2.00 (22 H, m, cyclohexyl-H), 3.00
(2 H, d, JHP 16.4, PCH2–), 5.50 (1 H, dd, JHP 7.0, JHF 39.1,
PCHF–), 7.15–7.40 (4 H, m, ArH); δP (D2O) 11.1 (d, JPF 73.0),
20.3 (s); δF (D2O) Ϫ193.4 (d); H-coupled Ϫ193.6 (dd, JHF 34.2,
JPF 73.0); δC (D2O) 23.8, 24.3, 30.3, 35.9 (d, JCP 127), 50.2, 91.6
(dd, JCP 169, JCF 184), 124.2, 127.5, 128.2, 129.1, 134.1, 135.9;
m/z (FABϩ) 285 (27%, Mϩ), 384 (92, M ϩ C6H11NH3ϩ).
95:5); νmax/cmϪ1 (film) 2986, 2913 (C–H), 1653 (C᎐C), 1273
᎐
(P᎐O), 1024 (P–O–C); δ (CDCl ) 1.18, 1.25 (6 H each, 2 t, J 7.1,
᎐
H
3
2 CH3CH2– each), 3.15 (2 H, d, JHP 21.6, PCH2–), 3.80–4.00,
4.10–4.15 (4 H each, 2 m, 2 CH3CH2– each), 7.30–7.45 (4 H, m,
ArH); δP (CDCl3) 6.65 (t, JPF 116), 25.9; δF (CDCl3) Ϫ108.9 (d,
JFP 114.9); δC (CDCl3) 16.2. 16.3, 33.1 (d, JCP 138), 62.1, 62.2,
64.7, 64.8, 117.9 (dt, JCP 217, JCF 263), 127.4, 127.5, 128.6,
132.1, 132.4, 132.9.
Diisopropyl 4-[(diisopropoxyphosphoryl)methylphenyl]difluoro-
methylphosphonate (36c)
4-(Phosphonomethylphenyl)fluoromethylphosphonic acid (38c)
Diisopropyl 4-(chloromethylphenyl)difluoromethylphosphon-
ate 35c (0.53 g, 1.57 mmol) and diisopropyl phosphonate (0.29
g, 1.72 mmol, 1.1 eq., 0.29 ml) and sodium hydride (0.04 g, 1.72
mmol, 90% powder) were reacted as for 36a. The title compound
was isolated by flash column chromatography (DCM–MeOH,
98:2) as a colourless oil (0.34 g, 90%, 52% conversion); Rf 0.14
(DCM–MeOH, 98:2) (Found: Mϩ 470.181. C20H34F2O6P2
Diisopropyl 4-[(diisopropoxyphosphoryl)methylphenyl]fluoro-
methylphosphonate 33c (0.26 g, 0.56 mmol) was deesterified as
for 2 with TMSBr (0.61 g, 3.95 mmol, 7 eq., 0.52 ml) and the
free acid isolated as usual (0.18 g). Salt formation and purifi-
cation as for 2 gave the biscyclohexylammonium salt of the title
compound as a white solid (0.12 g, 63%, mp >300 ЊC) (Found:
C 49.5, H 8.1, N 5.8. C20H37FNO6P2 (salt) requires C 49.8, H
7.4, N 6.1%); δH (D2O) 1.20–2.00 (22 H, m, cyclohexyl-H), 3.00
(2 H, d, JHP 21.3, PCH2–), 5.80 (1 H, d, JHP 6.8, JHF 42.0,
PCHF–), 7.30, 7.40 (2 H each, 2 d, J 7.1, 2 ArH each); δP (D2O)
11.5 (d, JFP 72.6), 20.9 (s); δF (D2O) Ϫ195.2 (d); H-coupled
Ϫ195.3 (dd, JPF 74.1, JHF 42.6); δC (D2O) 23.8, 24.3, 30.2, 50.2,
128.3, 130.6, 134.0, 135.9.
requires M 470.180); νmax/cmϪ1 (film) 2923 (C–H), 1618 (C᎐C),
᎐
1265 (P᎐O), 1024 (P–O–C); δ (CDCl3) 1.05–1.25 (24 H, m,
᎐
H
4 (CH3)2CH–), 3.05 (2 H, d, JHP 22.0, PCH2–), 4.50–4.55, 4.60–
4.65 (2 H each, 2 m, 2 (CH3)2CH– each), 7.25 (2 H, d, J 7.9,
ArH), 7.45 (2 H, d, J 7.7, ArH); δP (CDCl3) 4.93 (t, JFP 119),
24.1 (s); δF (CDCl3) Ϫ109.1 (d, JPF 118); δC (CDCl3) 23.7, 23.9,
J. Chem. Soc., Perkin Trans. 1, 2000, 421–437
433