508 J . Org. Chem., Vol. 63, No. 3, 1998
Chen and Coward
) 6), 7.00 (d, 1H, J ) 501), 7.23 (d, 2H, J ) 8), 7.62 (d, 2H, J
) 8), 7.65-7.77 (m, 2H), 7.88-7.85 (m, 2H); 13C NMR (CDCl3)
δ 168.5, 143.3, 136.8, 134.2, 132.2, 129.9, 127.3, 123.4, 48.3,
48.1, 37.5, 31.3 (d, J ) 91), 30.0 (d, J ) 15), 26.1, 25.9, 21.6,
19.2; 31P NMR (CDCl3) δ 28.3; MS (FAB) m/z 493 (MH+, 100),
479 (30), 160 (40), 337 (40); HRMS (FAB) calcd for C23H29N2O6-
PSH 493.1562, found 493.1562.
To a suspension of the mixture containing 13 and 16a (1.1
g) in MeOH (15 mL) was added a solution of diazomethane in
ether until a yellow color persisted for 5 min. The resultant
solution was stirred at rt for 1.5 h. Removal of the solvent
afforded the crude products 14 and 16b. Column chromatog-
raphy on silica gel eluting with EtOAc/MeOH (10:1) afforded
0.96 g of 14 (99% based on 13) and 0.16 g of 16b (78% based
on 16a ) as white solids. 14: Rf 0.57 (EtOAc); mp 101-102
O-Eth yl [4-[N-(Tr iflu or oa cetyl)-N-(4-p h th a lim id obu -
tyl)a m in o]bu tyl]p h osp h on ite (11a ). To a stirred solution
of 10a (1.21 g, 2.8 mmol) in THF (25 mL) and ethanol (3.0
mL) was added DMAP (36 mg) followed by DCC (0.75 g, 3.6
mmol). The mixture was stirred overnight at rt, the resultant
precipitated material was removed by filtration, and the
filtrate was concentrated under reduced pressure. After usual
workup and column chromatography on silica gel using EtOAc
as eluant, 1.0 g (76%) of the product 11a was obtained as a
syrup: 1H NMR (CDCl3) δ 1.34-1.40 (m, 3H), 1.57-1.83 (m,
10 H), 3.30-3.42 (m, 4H), 3.72 (t, 2H, J ) 6.5), 4.04-4.22 (m,
2H), 7.12 (dm, 1H, J ) 533), 7.68-7.74 (m, 2H), 7.76-7.88
(m, 2H); 13C NMR (CDCl3) δ 168.1, 156.6 (q, J ) 35.4), 134.0,
1
°C; H NMR (CDCl3) δ 3.84 (d, 3H, J ) 11.7), 4.11 (dd, 2H, J
) 2.2, 9.8), 7.4 (d, 1H, J ) 583), 7.75-7.81 (m, 2H), 7.86-7.95
(m, 2H); 13C NMR (CDCl3) δ 167.2, 134.5, 131.9, 123.8, 52.9
(d, J ) 7), 36.2 (d, J ) 99); 31P NMR (CDCl3) δ 28.1. 16b: Rf
0.47 (EtOAc); mp 198-200 °C; 1H NMR (CDCl3) δ 3.83 (dd,
3H, J ) 2, 11), 4.21-4.40 (m, 2H), 7.75-7.81 (m, 2H), 7.86-
7.93 (m, 2H); 13C NMR δ 167.4, 134.3, 132.2, 123.8, 52.5, 36.9
(d, J ) 98); 31P NMR (CDCl3) δ 39.7; MS (CI/NH3) m/z 399
(MH+, 100), 238 (28); HRMS (CI/NH3) calcd for C19H15N2O6-
PH 399.0746, found 399.0741. Anal. Calcd for C19H15N2O6P‚
0.3H2O: C, 56.52; H, 3.90; N, 6.94. Found: C, 56.80; H, 4.09;
N, 6.69.
133.9, 131.9, 123.1, 123.0, 116.5 (q, J ) 288), 62.4, 62.2, 46.9,
O-Eth yl (P h th a lim id om eth yl)p h osp h on ite (15). A so-
lution of 13 (0.30 g, 1.6 mmol), ethanol (0.5 mL), EDC (0.28 g,
1.6 mmol), and DMAP (10 mg) in CH2Cl2 (10 mL) was stirred
at rt for 12 h. After removal of the volatile components, the
crude product was purified by column chromatography on
silica gel (EtOAc) to afford 0.26 g (78%) of 15 as a powder: Rf
1
46.3, 46.2, 37.0, 36.9, 29.2 (d, J ) 14.1 Hz), 28.1 (d, J CP
)
93.6 Hz), 27.4 (d, J ) 14.6 Hz), 25.8, 25.7, 23.9, 18.0, 17.8,
16.1, 16.0; 19F NMR (CDCl3) δ 4.86; 31P NMR (CDCl3) δ 38.1,
37.4; MS (CI/CH4) m/z 463 (MH+, 100), 427 (7), 365 (13), 301
(10); HRMS (CI/CH4) calcd for C20H26F3N2O5PH 463.1610,
found 463.1600. Anal. Calcd for C20H26F3N2O5P: C, 51.95;
H, 5.68; N, 6.06. Found: C, 51.84; H, 5.66; N, 6.18.
1
0.5 (EtOAc); mp 90-92 °C; H NMR (CDCl3) δ 1.35 (t, 3H, J
) 7), 4.09 (dd, 2H, J ) 8, 11), 4.12-4.28 (m, 2H), 7.38 (dt, 1H,
J ) 2, 580), 7.75-7.84 (m, 2H), 7.87-7.95 (m, 2H); 13C NMR
δ 166.9, 135.7, 134.2, 131.5, 123.5, 62.9, 36.3 (d, J ) 100), 16.3;
31P NMR (CDCl3) δ 26.2; MS (DCI/NH3) m/z 254 (MH+, 100),
160 (5), 134 (8); HRMS (CI/NH3) calcd for C11H12NO4PH
254.0582, found 254.0590. Anal. Calcd for C11H12NO4P: C,
52.17; H, 4.79; N, 5.53. Found: C, 52.17; H, 4.88; N, 5.67.
O-Eth yl P h en yl [(N-Tr ityla m in o)m eth yl]p h osp h in a te
(19). A solution of ethyl phenylphosphonite 18 (18 mg, 0.11
mmol), 17 (29 mg, 0.11 mmol), and a drop of BF3‚Et2O in dry
toluene (8 mL) was stirred and heated to reflux for 8 h.
Removal of the volatile components followed by silica gel
column chromatography (EtOAc) afforded 39 mg (82%) of 19
O-Eth yl [4-[N-Tosyl-N-(4-p h th a lim id obu tyl)a m in o]bu -
tyl]p h osp h on ite (11c). To a stirred solution of 10c (0.3 g,
0.62 mmol), ethanol (29 mg), and DMAP (8 mg) in THF (6 mL)
was added DCC at 0 °C. The mixture was stirred at rt
overnight. Precipitate DCU was filtered off, and the filtrate
was concentrated and dissolved in EtOAc (40 mL). Some more
precipitated DCU was filtered off again, and the EtOAc
solution was washed with 5% NaHCO3 (2 × 30 mL) and brine
(30 mL). After being dried over sodium sulfate, the solvent
was removed. The resultant solid product was then recrystal-
lized from CHCl3/hexane to afford 0.26 g (81%) of the product
1
as a white powder: mp 102-105 °C; H NMR (CDCl3) δ 1.35
1
(t, 3H, J ) 7), 1.55-1.75 (m, 10H), 2.40 (s, 3H), 3.08-3.15 (m,
4H), 3.67 (t, 2H, J ) 7), 4.08-4.18 (m, 2H), 7.10 (d, 1H, J )
530), 7.28 (d, 2H, J ) 8), 7.66 (d, 2H, J ) 8), 7.70-7.75 (m,
2H), 7.82-7.89 (m, 2H); 13C NMR (CDCl3) δ 168.5, 143.4, 136.7,
134.2, 132.2, 131.4, 129.8, 128.2, 127.3, 123.7, 123.4, 122.9,
62.5 (d, J ) 6), 48.2, 48.1, 37.4, 29.7, (d, J ) 15), 28.3 (d, J )
94), 26.2, 25.9, 21.6, 18.2, 16.4 (d, J ) 6); 31P NMR (CDCl3) δ
38.6. Anal. Calcd for C25H33N2O6PS: C, 57.68; H, 6.40; N,
5.38. Found: C, 57.86; H, 6.64; N, 5.51.
as a solid: mp 114-116 °C; H NMR (CDCl3) δ 1.32 (m, 3H),
2.20 (t, 1H, J ) 7.8), 2.48-2.72 (m, 2H), 3.88-4.20 (m 2H),
7.11-7.42 (m, 15H), 7.55-7.82 (m, 2H), 7.94-8.07 (m, 2H);
13C NMR (CDCl3) δ 145.2, 132.9, 132.8, 132.7, 129.8, 129.0,
128.9, 128.4, 126.9, 71.9, 42.4 (d, J ) 117), 17.0; 31P NMR
(CDCl3) δ 41.4; MS (FAB) m/z 442 (MH+, 3.4), 243 (100), 91
(11); HRMS (FAB) calcd for C28H28NO2PH 442.1936, found
442.1913. Anal. Calcd for C28H28NO2P‚0.3H2O: C, 75.23; H,
6.46; N, 3.13. Found: C, 75.17; H, 6.56; N, 3.10.
O-Meth yl (P h th a lim id om eth yl)p h osp h on ite (14) a n d
O-Meth yl Bis(p h th a lim id om eth yl)p h osp h in a te (16b). A
mixture of ammonium hypophosphite (3.15 g, 38 mmol) and
HMDS (6.16 g, 38 mmol) was stirred and heated to 120 °C
under dry N2 for 2 h. After being cooled to rt, CH2Cl2 (30 mL)
was added, and the reaction flask was then chilled in an ice
bath. A solution of bromomethyl phthalimide (2.28 g, 9.5
mmol) in dry CH2Cl2 (15 mL) was then added. The mixture
was stirred at 0 °C for 1 h and then at rt for 12 h. The mixture
was filtered through a layer of Celite into a mixture of MeOH
(6 mL) and CH2Cl2 (100 mL), and the filtrate was washed with
6 N HCl (20 mL). The aqueous layer was separated and back-
extracted with CH2Cl2 (2 × 40 mL). The combined CH2Cl2
solution was then dried (Na2SO4). Removal of solvents af-
forded 1.74 g (78% conversion) of a mixture of 13 and 16a (41:
9) as a light yellow solid. This material was used directly for
the reaction with diazomethane described below. An analyti-
cal sample of (phthalimidomethyl)phosphonous acid (13) was
obtained by precipitation from EtoAc: mp 209-211 °C; 1H
NMR (D2O) δ 3.83 (d, 2H, J ) 11), 7.17 (d, 1H, J ) 580), 7.70-
7.84 (m, 4H); 13C NMR (CDCl3) δ 166.8, 134.4, 134.3, 131.2,
123.0, 38.2 (d, J ) 97); 31P NMR (D2O) δ 16.4 (ammonium salt;
free acid δ 24 ppm vs 16a δ 38 ppm); MS (FAB) m/z 226 (MH+,
100), 153 (35), 103 (34); HRMS (DCI/NH3) calcd for C9H8NO4P
226.0269, found 226.0262. Anal. Calcd for C9H8NO4P: C,
48.01; H, 3.59; N, 6.22. Found: C, 47.99; H, 3.77; N, 6.27.
O-Eth yl [(N-(p h th a lim id om eth yl-N′-tr ityla m in o)m eth -
yl]p h osp h in a te (20) was obtained in a similar manner in
86% yield as an oil: Rf 0.7 (EtOAc); H NMR (CDCl3) δ 1.35
1
(t, 3H, J ) 7), 2.40-2.85 (m, 3H), 4.05-4.38 (m, 4H), 7.10-
7.29 (m, 9H), 7.45-7.65 (m, 6H), 7.70-7.81 (m, 2H), 7.84-
7.93 (m, 2H); 13C NMR (CDCl3) δ 167.7, 145.2, 134.6, 132.3,
62.1 (d, J ) 109), 35.0 (d, J ) 95), 16.9 (d, J ) 6); 31P NMR
(CDCl3) δ 41.2; MS (DCI/NH3) m/z 525 (MH+, 0.5), 447 (3),
243 (100); HRMS (CI/NH3) calcd for C31H29N2O4PH 525.1943,
found 525.1926.
O-Eth yl [N-(Tr iflu or oa cetyl)-N-(4-p h th a lim id obu tyl)-
4-a m in obu tyl]-[(N′-tr ityla m in o)m eth yl]p h osp h in a te (21).
To a stirred solution of 11a (1.0 g, 2.3 mmol) and 17 (0.58 g,
2.3 mmol) in dry toluene (50 mL) was added BF3‚Et2O (30 µL,
0.24 mmol), and the reaction solution was heated overnight
at reflux temperature under N2. The mixture was cooled to
rt and diluted with EtOAc (150 mL). After usual workup, the
crude product was purified by column chromatography on
silica gel (CHCl3/MeOH, 100:0 to 99:1) to afford 1.29 g (81%)
of the product as a syrup: 1H NMR (CDCl3) δ 1.26 (t, 3H, J )
7), 1.55-1.86 (m, 8H), 1.95-2.00 (m, 3H), 2.43-2.62 (m, 2H),
3.38-3.49 (m, 4H), 3.72 (t, 2H, J ) 6.2), 3.42-4.08 (m, 2H),
7.15-7.35 (m, 9H), 7.44 (d, 6H, J ) 7.5), 7.67-7.75 (m, 2H),
7.82-7.87 (m, 2H); 13C NMR (CDCl3) δ 168.43, 156.7 (q, J )
41 Hz), 144.8, 144.75, 134.2, 134.1, 134.0, 132.1, 132.0, 128.6,
128.3, 128.1, 126.8, 126.7, 123.4, 123.3, 116.6 (q, J ) 290 Hz),