The Journal of Organic Chemistry
Note
General Procedure B: Synthesis of β-Ketophosphonates
Using Lithiated Dimethyl Methylphosphonate Reagent 7. To a
solution of n-BuLi (0.26 mL, 2.5 M in hexanes, 0.66 mmol, 2.2 equiv)
in THF (1.5 mL) at −78 °C was added dimethyl methylphosphonate
(75 μL, 0.69 mmol, 2.3 equiv). After 30 min at −78 °C, a solution of
activated ester (0.30 mmol, 1 equiv) in THF (1.5 mL) was added
dropwise. The reaction mixture was stirred for 30 min at −78 °C, and
a saturated solution of NH4Cl was added. The mixture was extracted
with EtOAc, and the combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography to afford the desired
phosphonate.
2H), 2.84 (t, J = 7.3 Hz, 2H), 2.58−2.51 (m, 2H), 2.42−2.32 (m, 1H),
2.03 (m, 1H), 1.94−1.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
2
2
200.6 (d, JC−P = 6.4 Hz), 176.8, 79.5, 53.1 (d, JC−P = 6.8 Hz, 2C),
1
37.5 (d, JC−P = 128.6 Hz), 39.8, 29.1, 28.7, 27.9; HRMS calcd for
C10H17O6PNa (M + Na+): 287.06550. Found: 287.06531.
8-(Dimethoxyphosphoryl)-7-oxooctyl Acetate (6f). Yield 71.5 mg
(81%) with procedure A and 38.1 mg (43%) with procedure B
(pentane/acetone = 65:35 then 50:50); yellow oil. IR 1733, 1715,
1
1462, 1367, 1239, 1184, 1023 cm−1; H NMR (400 MHz, CDCl3) δ
4.04 (t, J = 6.7 Hz, 2H), 3.79 (d, 3JH−P = 11.2 Hz, 6H), 3.09 (d, 2JH−P
= 22.7 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.05 (s, 3H), 1.67−1.54 (m,
4H), 1.41−127 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 201.8 (d,
2JC−P = 6.0 Hz), 171.1, 64.3, 53.0 (d, 2JC−P = 6.8 Hz, 2C), 43.9, 41.2 (d,
1JC−P = 127.8 Hz), 28.4, 28.3, 25.6, 23.1, 20.9; EI−MS m/z (relative
intensity) 235 (M − OAc+, 2), 234 (2), 221 (1), 207 (1), 193 (2), 179
Dimethyl (2-Oxo-2-phenylethyl)phosphonate (4).9a Yield 68.2 mg
(99%) with procedure A (pentane/acetone = 75:25 then 60:40);
yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.04−7.98 (m, 2H), 7.64−
3
+
+
7.57 (m, 1H), 7.53−7.46 (tapp, J = 7.4 Hz, 2H), 3.79 (d, JH−P = 11.2
(M − C6H11O2 , 19), 166 (M − C7H12O2 , 100), 151 (M −
2
+
Hz, 6H), 3.65 (d, JH−P = 22.6 Hz, 2H).
C8H15O2 , 79), 147 (8), 124 (100), 119 (9), 109 (43). HRMS calcd
Methyl 6-(Dimethoxyphosphoryl)-5-oxohexanoate (6a).30 Yield
for C12H23O6PNa (M + Na+): 317.11245. Found: 317.11184.
8-(Dimethoxyphosphoryl)-7-oxooctyl Benzoate (6g). Yield 101.3
mg (95%) with procedure A and 74.4 mg (70%) with procedure B
(petroleum ether/acetone = 60:40 then 50:50); yellow oil. IR 1713,
1601, 1452, 1399, 1315, 1271, 1177, 1113, 1024 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.07−8.01 (m, 2H), 7.56 (m, 1H), 7.48−7.41 (br t, J
= 7.3 Hz, 2H), 4.31 (t, J = 6.7 Hz, 2H), 3.79 (d, 3JH−P = 11.2 Hz, 6H),
73.6 mg (97%) with procedure A and 33.8 mg (45%) with procedure
1
B (pentane/acetone = 60:40 then 40:60); pale yellow oil. H NMR
(400 MHz, CDCl3) δ 3.79 (d, 3JH−P = 11.2 Hz, 6H), 3.67 (s, 3H), 3.09
(d, 2JH−P = 22.7 Hz, 2H), 2.71 (t, J = 7.1 Hz, 2H), 2.35 (t, J = 7.1 Hz,
2H), 1.91 (quintet, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
2
2
201.0 (d, JC−P = 6.4 Hz), 173.4, 53.0 (d, JC−P = 6.4 Hz, 2C), 51.5,
1
2
42.8, 41.3 (d, JC−P = 128.2 Hz), 32.6, 18.5.
3.09 (d, JH−P = 22.7 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 1.77
Benzyl 6-(Dimethoxyphosphoryl)-5-oxohexanoate (6b). Yield
90.8 mg (92%) with procedure A and 49.0 mg (50%) with procedure
B (petroleum ether/acetone = 70:30 then 50:50); pale yellow oil. IR
1714, 1497, 1455, 1386, 1253, 1168, 1022 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.40−7.30 (m, 5H), 5.11 (s, 2H), 3.77 (d, 3JH−P = 11.3 Hz,
6H), 3.07 (d, 2JH−P = 22.7 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.40 (t, J
= 7.2 Hz, 2H), 1.93 (quintet, J = 7.2 Hz, 2H); 13C NMR (100 MHz,
(quintetapp, J = 6.7 Hz, 2H), 1.62 (quintet, J = 7.3 Hz, 2H), 1.51−1.42
(m, 2H), 1.41−1.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.8
(d, 2JC−P = 6.0 Hz), 166.6, 132.8, 130.4, 129.5 (2C), 128.3 (2C), 64.8,
53.0 (d, JC−P = 6.4 Hz, 2C), 43.9, 41.2 (d, JC−P = 128.2 Hz), 28.5
(2C), 25.8, 23.1. HRMS calcd for C17H25O6PNa (M + Na+):
379.12810. Found: 379.12770.
2
1
Dimethyl [5-(Oxiran-2-yl)-2-oxopentyl]phosphonate (6h). Yield
68.0 mg (96%) with procedure A and 68.4 mg (98%) with procedure
B (petroleum ether/acetone = 60:40 then 40:60); yellow oil. IR 1713,
2
CDCl3) δ 201.0 (d, JC−P = 6.4 Hz), 172.8, 135.8, 128.5 (2C), 128.2
2
1
(3C), 66.2, 53.0 (d, JC−P = 6.4 Hz, 2C), 42.8, 41.3 (d, JC−P = 128.2
Hz), 32.8, 18.5; EI−MS m/z (relative intensity) 221 (M − BnO+, 31),
194 (26), 179 (23), 166 (36), 151 (51), 91 (100). HRMS calcd for
C15H21O6PNa (M + Na+): 351.09680. Found: 351.09624.
1
1457, 1406, 1374, 1253, 1020 cm−1; H NMR (400 MHz, CDCl3) δ
3
2
3.79 (d, JH−P = 11.2 Hz, 6H), 3.10 (d, JH−P = 22.7 Hz, 2H), 2.91
(dtd, J = 6.8 Hz, J = 4.3 Hz and J = 2.8 Hz, 1H), 2.75 (dd, J = 4.9 Hz
and J = 4.3 Hz, 1H), 2.71 (t, J = 6.9 Hz, 2H), 2.47 (dd, J = 4.9 Hz and
J = 2.8 Hz, 1H), 1.82−1.71 (m, 2H), 1.68−1.58 (m, 1H), 1.48
(quintetapp, J = 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 201.3 (d,
2JC−P = 6.4 Hz), 53.0 (d, 2JC−P = 6.4 Hz, 2C), 51.8, 46.7, 43.4, 41.3 (d,
1JC−P = 128.2 Hz), 31.4, 19.7; EI−MS m/z (relative intensity) 166 (M
− C4H6O+, 14), 151 (M − C5H9O+, 100), 124 (84), 109 (94). HRMS
calcd for C9H17O5PNa (M + Na+): 259.07058. Found: 259.06989.
Dimethyl (6-Bromo-2-oxohexyl)phosphonate (6i). Yield 79.7 mg
(93%) with procedure A and 69.4 mg (81%) with procedure B
(petroleum ether/acetone = 60:40 then 40:60); yellow oil. IR 1713,
1449, 1403, 1373, 1253, 1183, 1021 cm−1; 1H NMR (400 MHz,
CDCl3) δ 3.79 (d, 3JH−P = 11.2 Hz, 6H), 3.41 (t, J = 6.6 Hz, 2H), 3.10
(d, 2JH−P = 22.9 Hz, 2H), 2.67 (t, J = 6.9 Hz, 2H), 1.91−1.83 (m, 2H),
Methyl 4-[2-(Dimethoxyphosphoryl)acetyl]benzoate (6c). Yield
83.2 mg (97%) with procedure A and 34.3 mg (40%) with procedure
B (petroleum ether/acetone = 70:30 then 60:40); colorless solid: mp
57−60 °C; IR 2955, 2911, 2849, 1717, 1673, 1572, 1503, 1435, 1420,
1
1405, 1260, 1209, 1189, 1140, 1109, 1043, 1019, 1002, 959 cm−1; H
NMR (400 MHz, CDCl3) δ 8.15 (br d, J = 8.7 Hz, 2H), 8.06 (br d, J =
3
8.7 Hz, 2H), 3.96 (s, 3H), 3.79 (d, JH−P = 11.3 Hz, 6H), 3.67 (d,
2JH−P = 22.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 191.3 (d, 2JC−P
2
= 6.4 Hz), 166.0, 139.4, 134.3, 129.8 (2C), 128.8 (2C), 53.2 (d, JC−P
= 6.8 Hz, 2C), 52.5, 37.8 (d, 1JC−P = 131.4 Hz); EI−MS m/z (relative
intensity) 286 (M+, 10), 255 (M − MeO+, 8), 226 (6), 198 (6), 190
(7), 163 (100), 151 (19), 135 (23), 109 (18). HRMS calcd for
C12H15O6PNa (M + Na+): 309.04985. Found: 309.04940.
1.79−1.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.2 (d, 2JC−P
=
Methyl 3-[2-(Dimethoxyphosphoryl)acetyl]benzoate (6d). Yield
78.1 mg (91%) with procedure A and 38.7 mg (45%) with procedure
B (petroleum ether/acetone = 60:40); pale yellow oil. IR 2973, 2955,
2926, 2854, 1722, 1679, 1602, 1467, 1434, 1417, 1287, 1238, 1216,
1182, 1138, 1113, 1057, 1024, 978 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.64 (t, J = 1.8 Hz, 1H), 8.27 (dt, J = 7.8 Hz and J = 1.8 Hz,
1H), 8.21 (dt, J = 7.8 Hz and J = 1.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H),
3.97 (s, 3H), 3.80 (d, 3JH−P = 11.3 Hz, 6H), 3.70 (d, 2JH−P = 22.7 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 191.0 (d, 2JC−P = 6.8 Hz), 166.0,
6.0 Hz), 53.0 (d, 2JC−P = 6.4 Hz, 2C), 42.8, 41.3 (d, 1JC−P = 128.2 Hz),
33.1, 31.6, 21.8; EI−MS m/z (relative intensity) 207 (M − Br+, 41),
179 (26), 151 (M − C4H8Br+, 96), 124 (52), 119 (17), 109 (100), 94
(64), 79 (69). HRMS calcd for C8H16O4BrPNa (M79[Br]+Na+):
308.98618. Found: 308.98630; calcd for C8H16O4BrPNa
(M81[Br]+Na+), 310.98413. Found: 310.98348.
Dimethyl (2-Oxohept-6-yn-1-yl)phosphonate (6j).31 Yield 58.9
mg (90%) with procedure A and 53.7 mg (82%) with procedure B
2
1
136.5, 134.5, 133.0, 130.8, 130.0, 129.0, 53.2 (d, JC−P = 6.8 Hz, 2C),
(petroleum ether/acetone = 60:40); pale yellow oil. H NMR (400
1
3
2
52.4, 37.5 (d, JC−P = 131.4 Hz); EI−MS m/z (relative intensity) 255
MHz, CDCl3) δ 3.80 (d, JH−P = 11.3 Hz, 6H), 3.11 (d, JH−P = 22.7
Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.24 (td, J = 6.9 Hz and J = 2.6 Hz,
2H), 1.97 (t, J = 2.6 Hz, 1H), 1.81 (quintet, J = 6.9 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 201.2 (d, 2JC−P = 6.8 Hz), 83.4, 69.1, 53.1
(M − MeO+, 3), 226 (13), 190 (3), 163 (100), 151 (12), 135 (26),
119 (14), 109 (21). HRMS calcd for C12H15O6PNa (M + Na+):
309.04985. Found: 309.04926.
2
1
Dimethyl [2-Oxo-4-(5-oxotetrahydrofuran-2-yl)butyl]phos-
phonate (6e). Yield 49.4 mg (62%) with procedure A and 22.5 mg
(28%) with procedure B (petroleum ether/acetone = 70:30 then
60:40); pale yellow oil. IR 2957, 2922, 2853, 1765, 1713, 1517, 1460,
(d, JC−P = 6.4 Hz, 2C), 42.5, 41.4 (d, JC−P = 128.2 Hz), 22.0, 17.5.
Dimethyl {4-[(4-Methoxyphenyl)methoxy]-2-oxopentyl}phos-
phonate (6k). Yield 89.7 mg (91%) with procedure A and 84.0 mg
(82%) with procedure B (petroleum ether/acetone = 70:30 then
50:50); pale yellow oil. IR 1713, 1613, 1514, 1462, 1374, 1301, 1246,
1177, 1137, 1111, 1022 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.23 (br
1
1409, 1350, 1250, 1178, 1018 cm−1; H NMR (400 MHz, CDCl3) δ
4.51 (m, 1H), 3.80 (d, 3JH−P = 11.2 Hz, 6H), 3.12 (d, 2JH−P = 22.7 Hz,
3307
J. Org. Chem. 2015, 80, 3302−3308