1,4,2-Benzodiazaphosphepin-5-one 2-Oxide Analogues
J . Org. Chem., Vol. 64, No. 22, 1999 8159
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hexanes): mp 98-99 °C; H NMR (CDCl3) δ 8.10 (d, J ) 8.7,
ature, the solution was poured into H2O, acidified to pH 5-6
using HCl, and then extracted with two portions of EtOAc.
The organic layer was washed successively with H2O (two to
three portions) and then brine. The organic phases were dried
and concentrated, and the products were purified by the
method indicated.
1H), 7.61 (d, J ) 2.1, 1H), 7.46 (dd, J ) 2.1, 8.7, 1H), 4.10-
4.00 (m, 4H), 3.71 (dd, J ) 8.4, 17.1, 1H), 3.43 (br s, 1H), 1.59
(s, 9H), 1.25 (m, 6H); 31P NMR (CDCl3) δ +21.2; MS 407 (MH+).
Anal. Calcd for C16H24ClN2O6P: C, 47.24; H, 5.95; N, 6.89; P,
7.61. Found: C, 47.20; H, 6.15; N, 6.76; P, 7.68.
Dieth yl [(5-Ch lor o-N-m eth yl-2-n itr oben za m id o)m eth -
yl]p h osp h on a t e (5b ). Reaction of 3 (24.3 mmol), 4b (22.1
mmol), and triethylamine (27.6 mmol) gave, after chromatog-
raphy (EtOAc/hexanes, 50-60%), 5.56 g of 5b as a yellow oil
(69%): 1H NMR (CDCl3, rotamers, 4:1) δ (major) 8.11 (d, J )
8.8, 1H), 7.50 (dd, J ) 2.4, 8.7, 1H), 7.31 (d, J ) 2.2, 1H), 4.18
4-ter t-Bu tyl-7-ch lor o-2-eth oxy-2,3-dih ydr o-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (7a ). Treatment of
a solution of 6a (10.3 g, 27.4 mmol) in DMF (100 mL) with
NaH (1.37 g, 34.2 mmol) followed by heating at 60 °C for 5 h
gave, after workup, a solid. Trituration of the crude product
in EtOAc/hexanes (1/3) afforded 6.45 g (71%) of 7a as a white
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1
(dq, J ) 7.0, J HP )7.0, 4H), 3.98 (br s, 2H), 2.94 (s, 3H), 1.33
solid: mp 225-227 °C; H NMR (CDCl3) δ 7.58 (d, J ) 2.4,
(t, J ) 7.2, 6H), (minor, partial) 8.10 (d, J ) 9.6, 1H), 4.07
(dq, J ) 7.2, 8.2, 4H), 3.43-3.38 (m, 2H), 3.23 (s, 3H), 1.28 (t,
J ) 7.2, 1H); 31P NMR (CDCl3) δ +20.5 (major), +19.3 (minor);
MS 365 (MH+). Anal. Calcd for C13H18ClN2O6P: C, 42.85; H,
4.97; N, 7.68; P, 8.49. Found: C, 42.62; H, 4.97; N, 7.61; P,
8.44.
1H), 7.37 (br s, 1H), 7.25 (dd, J ) 2.1, 8.4, 1H), 6.93 (d, J )
2
8.7, 1H), 4.12-4.04 (m, 2H), 3.76 (dd, J ) 17.1, J HP)12.3,
2
1H), 3.49 (dd, J ) 17.1, J HP)6.0, 1H), 1.55 (s, 9H), 1.25 (t, J
) 7.2, 3H); 31P NMR (CDCl3) δ +34.7; 13C NMR (CDCl3) δ
167.8, 134.6, 134.4, 130.8, 130.1 (d, J CP ) 3.5), 130.0, 125.6
2
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(d, J CP ) 5.6), 61.0 (d, J CP ) 7.6), 58.5, 39.5 (d, J CP ) 144),
Dieth yl [(N-Ben zyl-5-ch lor o-2-n itr oben za m id o)m eth -
yl]p h osp h on a te (5c). Reaction of 3 (200 mmol), 4c12b (174
mmol), and triethylamine (400 mmol) gave 44.4 g (58%) of 5c
as an off-white solid after recrystallization (EtOAc/hexanes):
28.1, 16.1 (d, 3J CP ) 6.0); MS 331 (MH+). Anal. Calcd for C14H20
-
ClN2O3P: C, 50.84; H, 6.09; N, 8.47; P, 9.36. Found: C, 51.10;
H, 6.14; N, 8.45; P, 9.43.
7-Ch lor o-2-eth oxy-2,3-d ih yd r o-4-m eth yl-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (7b). Treatment of
a solution of 6b (4.00 g, 13.9 mmol) in DMF (30 mL) with NaH
(0.72 g, 18.0 mmol) was followed by heating at 60 °C for 1 h.
After the usual workup, the crude product was applied to C18
reversed-phase silica gel and eluted with CH3CN/H2O (15/85).
The fractions containing the product were combined and
concentrated and then diluted with CHCl3 and dried. Concen-
tration of the solution gave 2.35 g (68%) of 7b as a yellow
foam: mp 86-94 °C; 1H NMR (CDCl3) δ 7.54 (d, J ) 2.5, 1H),
7.48 (br s, 1H), 7.24 (dd, J ) 2.5, 8.5, 1H), 6.94 (dd, J ) 8.5,
1
mp 108-109 °C; H NMR (CDCl3, rotamers, 3:1) δ 8.14 (d, J
) 8.7, 1H, major), 8.13 (d, J ) 9.0, 1H, minor), 7.64-7.18 (m,
3
7H), 4.60-4.40 (m, 2H), 4.20 (dq, J ) 7.2, J HP ) 7.2, 4H,
3
major), 4.08 (dq, J ) 7.3, J HP ) 7.3, 4H, minor), 4.20-3.75
(m, 2H), 1.36 (t, J ) 6.9, 3H, major), 1.31 (t, J ) 6.6, 3H,
minor); 31P NMR (CDCl3) δ +21.0 (major), +19.9 (minor); MS
440 (M+). Anal. Calcd for C19H22ClN2O6P: C, 51.77; H, 5.03;
N, 6.35; P, 7.03. Found: C, 52.03; H, 4.87; N, 6.32; P, 7.00.
2-Am in oben za m id op h osp h on a tes. Gen er a l P r oced u r e.
A solution of the 2-nitrobenzamidophosphonates 5a -c was
hydrogenated over 5% Pt-C (30 wt %) in a Parr shaker at 50
psi until hydrogen uptake ceased. The catalyst was filtered,
and the filtrate was concentrated. The crude product was
purified by the method indicated.
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4J HP ) 1.1, 1H), 4.10 (dq, J ) 7.3, J HP ) 7.3, 2H), 3.69-3.50
(m, 2H), 3.20 (s, 3H), 1.26 (t, J ) 7.1, 3H); 31P NMR (CDCl3)
δ +32.7; 13C NMR (CDCl3) δ 167.9, 135.5, 132.0, 131.6, 130.8,
2
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130.7, 126.2 (d, J CP ) 5.0), 62.5 (d, J CP ) 7.1), 45.0 (d, J CP
)
3
Dieth yl [(2-Am in o-N-ter t-bu tyl-5-ch lor oben za m id o)-
m eth yl]p h osp h on a te (6a ). A solution of 5a (24.0 g, 59.0
mmol) in EtOH (600 mL) was hydrogenated for 24 h. Recrys-
tallization (EtOAc/hexanes) gave 15.8 g (71%) of 6a as an off-
white solid: mp 123.5-125 °C; 1H NMR (CDCl3) δ 7.04 (m,
2H), 6.52 (d, J ) 8.7, 1H), 4.27 (br s, 2H), 4.04-3.94 (m, 4H),
3.85-3.80 (m, 2H), 1.47 (s, 9H), 1.23 (t, J ) 7.2, 3H); 31P NMR
139), 36.7, 16.7 (d, J CP ) 5.1); MS 288 (M+); HRMS calcd for
C
11H14ClN2O3P (M+) 288.0431, found 288.0430.
4-Ben zyl-7-ch lor o-2-et h oxy-2,3-d ih yd r o-1H -1,4,2-b en -
zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (7c). Treatment of
a solution of 6c (2.10 g, 5.10 mmol) in DMF (20 mL) with NaH
(0.27 g, 6.62 mmol) followed by heating at 60 °C for 2 h gave,
after workup and trituration with hexanes, 1.06 g (57%) of 7c
as a yellow glass: 1H NMR (CDCl3) δ 7.72 (d, J ) 2.5, 1H),
7.40 (br s, 1H), 7.37-7.25 (m, 6H), 7.01 (dd, J ) 8.1, 4J HP)1.1,
1H), 5.18 (d, J ) 14.7, 1H), 4.56 (d, J ) 14.7, 1H), 4.18-4.04
(m, 2H), 3.46 (d, J ) 9.0, 2H), 1.28 (t, J ) 7.2, 3H); 31P NMR
(CDCl3) δ +32.8; 13C NMR (CDCl3) δ 168.2, 136.0, 135.5, 132.3,
131.8, 131.1, 131.0, 129.1, 128.6, 128.3, 126.5 (d, J CP ) 5.5),
(CDCl3) δ +23.3; MS 377 (MH+). Anal. Calcd for C16H26
-
ClN2O4P: C, 51.00; H, 6.95; N, 7.43; P, 8.22. Found: C, 51.15;
H, 7.05; N, 7.43; P, 8.14.
Dieth yl [(2-Am in o-5-ch lor o-N-m eth ylben za m id o)m eth -
yl]p h osp h on a te (6b). A solution of 5b (4.54 g, 12.5 mmol)
in 100 mL of THF/EtOH (1/1, v/v) was hydrogenated for 25 h
to afford 4.08 g (98%) of an off-white waxy solid. A small
sample (0.6 g) recrystallized from EtOAc/hexanes gave 0.42 g
of 6b as beige needles: mp 110-111.5 °C; 1H NMR (CDCl3) δ
7.11-7.08 (m, 2H), 6.60 (d, J ) 9.1, 1H), 4.50-4.25 (m, 2H),
2
1
3
62.5 (d, J CP ) 7.0), 51.6, 42.1 (d, J CP ) 141), 16.8 (d, J CP
)
6.0); MS 365 (MH+); HRMS calcd for C17H18ClN2O3P (M+)
364.0743, found 364.0760.
4-ter t-Bu tyl-7-ch lor o-2-eth oxy-2,3-dih ydr o-1H-1,4,2-ben -
zod ia za p h osp h ep in -5(4H)-on e 2-Th ioxid e (8). To a sus-
pension of 7a (1.00 g, 3.03 mmol) in toluene (20 mL) was added
Lawesson’s reagent (0.67 g, 1.67 mmol, 55 mol %) in one
portion. The reaction was heated to reflux for 5 h and then
cooled to room temperature. The yellow reaction mixture was
then concentrated and chromatographed (EtOAc/hexanes, 15/
85) to afford 8 (0.98 g, 93%) as a white solid: mp 150-153 °C;
1H NMR (CDCl3) δ 7.59 (d, J ) 2.5, 1H), 7.30 (dd, J ) 2.5, 8.2,
1H), 6.87 (dd, J ) 2.6, 8.4, 1H), 5.27 (d, J ) 4.8, 1H), 4.22-
4.08 (m, 2H), 3.94 (dd, J ) 17.0, 2J HP ) 7.1, 1H), 3.73 (dd, J )
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2
4.17 (dq, J ) 7.1, J HP ) 7.1, 4H), 3.94 (d, J HP ) 11.3, 2H),
3.11 (s, 3H), 1.34 (t, J ) 7.2, 3H); 31P NMR (CDCl3) δ +22.5;
MS 335 (MH+). Anal. Calcd for C13H20ClN2O4P: C, 46.65; H,
6.02; N, 8.37; P, 9.25. Found: C, 46.49; H, 6.12; N, 8.28; P,
9.23.
Dieth yl [(2-Am in o-N-ben zyl-5-ch lor oben za m id o)m eth -
yl]p h osp h on a te (6c). A solution of 5c (46.6 g, 105 mmol) in
500 mL of THF/EtOH (1/1, v/v) was hydrogenated for 22 h to
afford 40.1 g (92%) of a pale yellow oil that was essentially
pure: 1H NMR (CDCl3) δ 7.36-7.08 (m, 7H), 6.61 (d, J ) 8.5,
1H), 4.65 (br s, 2H), 4.70-4.30 (br s, 2H), 4.23-4.11 (m, 4H),
3.80 (d, 2J HP ) 10.7, 2H), 1.34 (t, J ) 7.1, 3H); 31P NMR (CDCl3)
δ +23.4; MS 410 (M+). Anal. Calcd for C19H24ClN2O4P: C,
55.55; H, 5.89; N, 6.82; P, 7.54. Found: C, 55.16; H, 5.98; N,
6.67; P, 7.58.
1,4,2-Ben zod ia za p h osp h ep in -5-on e 2-oxid es. Gen er a l
P r oced u r e. A solution of the aminobenzamidophosphonates
6a -c in DMF (0.25-0.50 M) was treated with NaH (120-130
mol %, 60% oil dispersion) and then warmed to 60 °C and held
at this temperature until TLC or HPLC indicated the reaction
was complete (ca. 1-5 h). After being cooled to room temper-
2
17.0, J HP ) 8.2, 1H), 1.64 (s, 9H), 1.28 (t, J ) 7.1, 3H); 31P
NMR (CDCl3) δ +84.4; 13C NMR (CDCl3) δ 167.5, 135.9, 133.1
(d, J CP ) 6.0), 131.3, 130.5, 126.2 (d, J CP ) 3.5), 126.1, 61.1 (d,
1
3
2J CP ) 7.0), 58.6, 45.4 (d, J CP ) 118), 28.3, 15.5 (d, J CP
)
6.6); MS 347 (MH+); HRMS calcd for C14H20ClN2O2PS (M+)
346.0672, found 346.0662.
7-Ch lor o-1,4-d im et h yl-2-et h oxy-2,3-d ih yd r o-1H -1,4,2-
ben zod ia za p h osp h ep in -5(4H)-on e 2-Oxid e (9). To a solu-
tion of 7b (1.20 g, 4.16 mmol) in DMF (15 mL) was added NaH
(0.25 g, 6.24 mmol, 60% oil dispersion). After the mixture was
stirred for 20 min at room temperature, methyl iodide (0.39