7812 J . Org. Chem., Vol. 65, No. 23, 2000
Kim et al.
6.4 mmol) at 5-10°C, and then the resulting mixture was
heated to 100-110 °C for 17 h. After being cooled to room
temperature, the reaction mixture was diluted with ether and
sequentially washed with 5% aqueous Na2S2O3 solution, 10%
citric acid solution, and saturated NaHCO3 solution. The
organic layer was dried, filtered, and concentrated. The residue
was purified by column chromatography (hexane:EtOAc, 9:1)
to afford methyl 2-diphenylphosphanylbenzoate (975 mg, 76%)
as a white solid: Rf ) 0.30 (hexane:EtOAc, 9:1); 1H NMR (300
MHz, CDCl3) δ 3.75 (s, 3H), 6.93-6.96 (m, 1H), 7.25-7.41 (m,
1H), 8.05-8.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 167.6,
141.1, 140.7, 138.4, 138.2, 134.8, 134.7, 134.4, 134.2, 132.4,
131.1, 129.1, 129.0, 128.9, 128.6, 52.5.
1.11-1.35 (m, 3H), 1.39 (s, 9H), 1.58-1.74 (m, 2H), 1.83-2.01
(m, 2H), 3.25-3.40 (m, 1H), 3.61-3.73 (m, 1H), 4.81 (d, J )
8.5 Hz, 1H), 6.42 (d, J ) 7.9 Hz, 1H), 6.90-6.94 (m, 1H), 7.24-
7.33 (m, 12H), 7.55-7.59 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 169.6, 157.3, 141.7, 141.3, 138.5, 137.7, 137.4, 134.9, 134.7,
134.4, 130.8, 129.2, 129.1, 129.0, 128.0, 80.1, 55.5, 54.7, 33.4,
32.8, 29.1, 25.6, 25.2; HRMS (FAB) calcd for C30H35N2O3P (M
+ H)+ 503.2464, found 503.2448.
(1R,2R)-N-(2-Am in o)cycloh exyl-2-(dim eth ylam in o)ben z-
a m id e (12a ). To a stirred solution of 10a (275 mg, 0.76 mmol)
in CH2Cl2 (2 mL) at 0 °C was added trifluoroacetic acid (1.2
mL, 15.2 mmol) under argon atmosphere. The reaction mixture
was allowed to warm to room temperature for 12 h, and it was
diluted with CH2Cl2 and poured into saturated NaHCO3
solution. Extractive workup with CH2Cl2 and purification by
column chromatography (CH2Cl2:MeOH, 9:1) afforded 12a (201
mg, 100%) as a white solid: Rf ) 0.15 (CH2Cl2:MeOH, 9:1); 1H
NMR (300 MHz, CDCl3) δ 1.21-1.53 (m, 4H), 1.70-1.79 (m,
2H), 2.02-2.16 (m, 2H), 2.69 (s, 6H), 2.90-2.95 (m, 1H), 3.95-
3.98 (m, 1H), 5.88 (br s, 2H), 7.09-7.26 (m, 2H), 7.36-7.42
(m, 1H), 8.00 (dd, J ) 1.3, 7.8 Hz, 1H), 10.17 (d, J ) 7.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 168.2, 152.8, 132.7, 131.8,
127.2, 125.0, 120.6, 56.4, 53.4, 45.7, 32.2, 32.0, 24.8, 24.6.
(1R,2R)-N-(2-Am in o)cycloh exyl-2-(diph en ylam in o)ben z-
a m id e (12c). Similarly, deprotection of 10c (640 mg, 1.32
mmol) with trifluoroacetic acid (2.03 mL, 26.4 mmol) gave 12c
in a quantitative yield (518 mg) as a pale yellow solid: Rf )
To a stirred solution of methyl 2-diphenylphosphanylben-
zoate (1.45 g, 4.53 mmol) in THF-water (1:1, 16 mL) at room
temperature was added lithium hydroxide hydrate (4.0 g, 90
mmol), and the resulting mixture was heated to 70 °C for 12
h. After being cooled to room temperature, the reaction mixture
was diluted with EtOAc and poured into 10% citric acid
solution. Extractive workup with EtOAc and purification by
column chromatography (CH2Cl2:MeOH, 9:1) afforded 9 (1.6
g, 100%) as a white solid: Rf ) 0.1 (hexane:EtOAc, 8:2); mp
165-167 °C; 1H NMR (300 MHz, CDCl3) δ 6.96-6.99 (m, 1H),
7.25-7.43 (m, 12H), 8.15-8.17 (m 1H), 11.0-11.8 (br, 1H); 13
C
NMR (75 MHz, CDCl3) δ 172.1, 142.6, 142.3, 138.2, 138.0,
134.7, 134.6, 134.3, 133.1, 132.9, 132.2, 129.1, 128.9, 128.8,
128.6.
1
(1R,2R)-2-[N-(2-Dim et h yla m in o)ben zoyla m in o]cyclo-
h exylca r ba m ic Acid ter t-Bu tyl Ester (10a ). To a stirred
solution of 2-dimethylaminobenzoic acid 8a (18 mg, 0.11 mmol)
and triethylamine (0.018 mL, 0.143 mmol) in THF (0.5 mL)
at -25 °C was added ethyl chloroformate (0.012 mL, 0.143
mmol) slowly under argon atmosphere. After being stirred for
30 min, the reaction mixture was treated with monoprotected
amine 4 (21.4 mg, 0.10 mmol), and it was allowed to warm to
room temperature over 12 h. The reaction mixture was diluted
with EtOAc and poured into a saturated NH4Cl solution.
Extractive workup with EtOAc and purification by column
chromatography (hexane:EtOAc, 9:1) afforded 10a (22.2 mg,
61%) as a white solid: Rf ) 0.2 (hexane:EtOAc, 8:2); mp 135-
0.2 (CH2Cl2:MeOH, 9:1); H NMR (300 MHz, CDCl3) δ 0.84-
0.96 (m, 1H), 1.11-1.30 (m, 3H), 1.55-1.80 (m, 3H), 1.89 (br
s, 1H), 1.23 (br s, 1H), 2.48 (br s, 2H), 3.51-3.62 (m, 1H), 6.94-
7.14 (m, 7H), 7.22-7.33 (m, 6H), 7.41-7.47 (m, 1H), 8.03 (dd,
J ) 0.9, 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 147.4,
144.4, 132.4, 131.3, 130.3, 129.4, 126.2, 123.8, 122.9, 122.1,
55.6, 55.5, 33.9, 32.0, 24.8 (coincided two peaks).
(1R,2R)-N-(2-Am in o)cycloh exyl-2-(d ip h en ylp h osp h a -
n yl)ben za m id e (13). Similarly, deprotection of 11 (326 mg,
0.65 mmol) with trifluoroacetic acid (0.5 mL, 6.48 mmol) gave
13 in a quantitative yield (260 mg) as a white solid: Rf ) 0.3
(CH2Cl2:MeOH, 9:1); 1H NMR (300 MHz, CDCl3) δ 0.82-0.95
(m, 1H), 1.07-1.23 (m, 3H), 1.57-1.64 (m, 2H), 1.77-1.92 (m,
2H), 2.29-2.36 (m, 1H), 2.85 (br s, 2H), 3.56-3.68 (m, 1H),
6.09 (br s, 1H), 6.87-6.91 (m, 1H), 7.17-7.34 (m, 12H), 7.59-
7.63 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 169.5, 141.3, 136.9,
134.2, 134.0, 133.9, 133.7, 133.6, 130.2, 129.0, 128.9, 128.8,
128.7, 128.6, 128.2, 56.0, 55.3, 33.9, 32.0, 24.8 (coincided two
peaks).
1
136 °C; H NMR (300 MHz, CDCl3) δ 1.26 (s, 9H), 1.20-1.38
(m, 4H), 1.64-1.75 (m, 2H), 2.03-2.15 (m, 2H), 2.71 (s, 6H),
3.36-3.40 (m, 1H), 3.90-3.94 (m, 1H), 5.06 (d, J ) 8.1 Hz,
1H), 7.11-7.18 (m, 2H), 7.35-7.41 (m, 1H), 8.05 (dd, J ) 1.6,
7.6 Hz, 1H), 9.57 (d, J ) 8.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 167.6, 152.7, 147.5, 132.2, 131.7, 127.8, 124.2, 119.8,
79.3, 56.0, 52.5, 45.5, 33.7, 33.1, 28.6, 25.3, 25.2; HRMS (FAB)-
calcd for C20H31N3O3 (M + H)+ 362.2444, found 362.2443.
(1R,2R)-2-[N-(2-Dip h en yla m in o)b en zoyla m in o]cyclo-
h exylca r ba m ic Acid ter t-Bu tyl Ester (10c). To a stirred
solution of 2-diphenylaminobenzoic acid 8c (32 mg, 0.11 mmol)
in CH2Cl2 (1.0 mL) were added dicyclohexylcarbodiimide (DCC,
23 mg, 0.11 mmol), monoprotected amine 4 (21.4 mg, 0.10
mmol), and DMAP (1.2 mg, 0.01 mmol) at 0 °C. The resulting
mixture was allowed to warm to room temperature over 2 h,
and it was diluted with CH2Cl2 and poured into saturated NH4-
Cl solution. Extractive workup with CH2Cl2 and purification
by column chromatography (hexane:EtOAc, 8:2) afforded 10c
(47 mg, 97%) as a white solid: Rf ) 0.2 (hexane:EtOAc, 8:2);
mp 73-74 °C; 1H NMR (300 MHz, CDCl3) δ 0.62-0.73 (m, 1H),
1.08-1.25 (m, 3H), 1.33 (s, 9H), 1.31-1.63 (m, 3H), 1.94-1.98
(m, 1H), 3.20-3.25 (m, 1H), 3.49-3.54 (m, 1H), 4.72 (d, J )
8.5 Hz, 1H), 6.88-7.06 (m, 7H), 7.16-7.26 (m, 6H), 7.33-7.39
(m, 1H), 7.75 (d, J ) 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 167.0, 156.3, 147.7, 144.7, 133.1, 131.7, 130.4, 129.4, 129.1,
125.1, 122.7, 122.5, 79.1, 54.2, 33.9, 32.6, 31.8, 28.2, 24.8, 24.4;
HRMS (FAB) calcd for C30H35N3O3 (M + H)+ 486.2757, found
486.2676.
(1R,2R)-N-{2-[2-(Dim eth yla m in o)ben zoyl]a m in o}cyclo-
h exyl-2-(d ip h en ylp h osp h a n yl)ben za m id e (3a ). According
to the procedure of the synthesis of 10c, 3a was synthesized
by DCC-mediated coupling of 12a (24.7 mg, 0.10 mmol) with
2-diphenylphosphanylbenzoic acid 9 (32 mg, 0.11 mmol) in 85%
yield (47 mg) as a white solid: Rf ) 0.2 (hexane:EtOAc, 8:2);
[R]28D +12.0 (c 1.17, CHCl3); mp 90-92 °C; 1H NMR (300 MHz,
CDCl3) δ 0.99-1.11 (m, 1H), 1.22-1.43 (m, 3H), 1.65-1.77 (m,
2H), 1.87-2.08 (m, 2H), 2.68 (s, 6H), 3.72-3.84 (m, 1H), 3.95-
4.05 (m, 1H), 6.84-6.92 (m, 2H), 7.12-7.31 (m, 14H), 7.37-
7.44 (m, 1H), 8.07 (dd, J ) 1.7, 7.8 Hz, 1H), 9.87 (d, J ) 8.4
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.2, 167.0, 152.1,
137.8, 137.6, 136.9, 136.5, 133.7, 133.5, 133.2, 131.6, 130.8,
129.5, 128.1, 128.0, 127.8, 127.7, 126.6, 126.6, 126.5, 123.7,
119.4, 55.1, 51.2, 44.8, 31.9, 31.7, 24.5, 24.0; 31P NMR (121
MHz, CDCl3) δ -6.267; HRMS (FAB) calcd for C34H36N3O2P
(M + H)+ 550.2623, found 550.2615. Anal. Calcd for C34H36
-
N3O2P: C, 74.30; H, 6.60; N, 7.65. Found: C, 74.06; H, 6.99;
N, 7.69.
(1R,2R)-N-{2-[2-(Di-n -bu tylam in o)ben zoyl]am in o}cyclo-
h exyl-2-(diph en ylph osph an yl)ben zam ide (3b). To a stirred
solution of 2-di-n-butylaminobenzoic acid 8b (27 mg, 0.11
mmol) and triethylamine (0.018 mL, 0.14 mmol) in THF (0.5
mL) at -10 °C was added ethyl chloroformate (0.013 mL, 0.14
mmol) slowly under argon atmosphere. After being stirred for
30 min, phosphino-acid 13 (40 mg, 0.10 mmol) was added to
the reaction mixture at 0 °C, and then the resulting mixture
was allowed to warm to room temperature over 12 h. The
reaction mixture was subjected to a standard extraction with
(1R,2R)-2-[N-(2-Dip h en ylp h osp h a n yl)ben zoyla m in o]-
cycloh exylca r ba m ic Acid ter t-Bu t yl E st er (11). 9c was
similarly synthesized as above by DCC-mediated coupling of
monoprotected amine 4 (42.9 mg, 0.2 mmol) with 2-diphen-
ylphosphanyl benzoic acid 9 (61.3 mg, 0.2 mmol) in 78% yield
(78 mg) as a white solid: Rf ) 0.15 (hexane:EtOAc, 8:2); mp
1
95-97 °C; H NMR (300 MHz, CDCl3) δ 0.88-1.01 (m, 1H),