3298
H. Miyabe et al.
SPECIAL TOPIC
Anal. Calcd for C19H26F3N3O2S: C, 54.66; H, 6.28; N, 10.06.
Found: C, 54.87; H, 6.41; N, 9.81.
13C NMR (125 MHz, CDCl3): d = 163.9, 139.6, 133.3, 133.2, 132.6
(q, J = 33 Hz), 129.6, 126.2, 124.5, 122.7 (q, J = 273 Hz), 66.1,
62.7, 32.2, 28.3, 25.8, 22.3, 18.2, –5.5.
5-(tert-Butyldimethylsilyloxy)pent-1-yl 5-(Trifluoromethyl)-3-
nitrobenzoate (11)
MS (FAB+): m/z (%) = 448 (8, M + H+), 73 (100).
HRMS (FAB+): m/z calcd for C20H29F3NO3SSi (M + H+): 448.1590;
To a solution of 5-(trifluoromethyl)-3-nitrobenzoic acid (3; 2.0 g,
8.6 mmol) in anhyd CH2Cl2 (50 mL) were added oxalyl chloride
(3.3 mL, 38 mmol) and anhyd DMF (4 drops) under argon at 0 °C.
After stirring for 18 h at r.t., the mixture was concentrated under re-
duced pressure. The resulting oil was dissolved in anhyd THF (30
mL) under argon. To this solution were added 5-(tert-butyldimeth-
ylsilyloxy)pentan-1-ol (2.3 g, 11 mmol) and Et3N (6 mL) under ar-
gon at 0 °C. After stirring for 12 h at r.t., the mixture was
concentrated under reduced pressure. The residue was dissolved in
EtOAc, and then the organic layer was washed with H2O and brine,
dried (MgSO4), and concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography (hexane–EtOAc, 12:1)
afforded ester 11 (3.1 g, 83%) as a colorless oil.
found: 448.1585.
Thiourea 13
To a solution of isothiocyanate 12 (12.9 g, 28.9 mmol) in anhyd
benzene (110 mL) was added (1R,2R)-N,N-dimethylcyclohexanedi-
amine (6.1 g, 43.0 mmol) under argon at 0 °C. After stirring for 3 h
at r.t., the mixture was concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (CHCl3–
MeOH, 20:1) afforded the silylated thiourea (12.3 g, 73%) as a col-
orless oil; [a]D27 –9.2 (c = 1.0, CHCl3).
IR (CHCl3): 1721 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.09 (1 H, s), 7.80 (1 H, s), 7.86
(1 H, s), 4.29 (2 H, t, J = 6.7 Hz), 3.90 (1 H, br s), 3.59 (2 H, t,
J = 6.4 Hz), 2.57 (1 H, br s), 2.42 (1 H, dt, J = 11.0, 3.1 Hz), 2.22 (6
H, s), 1.88–1.05 (15 H, m), 0.84 (9 H, s), 0.00 (6 H, s).
13C NMR (125 MHz, CDCl3): d = 179.7, 164.5, 139.3, 132.2, 131.4
(q, J = 33 Hz), 127.8, 124.5, 123.1 (q, J = 273 Hz), 122.5, 66.5,
65.5, 62.5, 55.8, 39.6, 32.5, 32.0, 28.1, 25.6, 24.6, 24.3, 22.0, 21.1,
17.9, –5.7.
IR (CHCl3): 1729 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.03 (1 H, s), 8.68 (1 H, s), 8.61
(1 H, s), 4.44 (2 H, t, J = 6.7 Hz), 3.65 (2 H, t, J = 6.7 Hz), 1.85 (2
H, m), 1.60 (2 H, m), 1.54 (2 H, m), 0.88 (9 H, s), 0.05 (6 H, s).
13C NMR (125 MHz, CDCl3): d = 163.2, 148.6, 133.6, 132.8 (q,
J = 34 Hz), 131.8, 127.4, 124.3, 122.4 (q, J = 273 Hz), 66.6, 62.7,
32.2, 28.3, 25.8, 22.3, 18.2, –5.5.
MS (FAB+): m/z (%) = 436 (21, M + H+), 69 (100).
HRMS (FAB+): m/z calcd for C19H29F3NO5Si (M + H+): 436.1776;
MS (FAB+): m/z (%) = 590 (100, M + H+).
HRMS (FAB+): m/z calcd for C28H47F3N3O3SSi (M + H+):
590.3060; found: 590.3063.
found: 436.1767.
To a solution of the above silylated thiourea (3.2 g, 5.4 mmol) in
THF (16 mL) was added Bu4NF (1 mol/L in THF, 11 mL, 11 mmol)
under argon at r.t. After stirring for 12 h at r.t., the mixture was con-
centrated under reduced pressure. The residue was dissolved in
EtOAc, and then the organic layer was washed with H2O and brine,
dried (MgSO4), and concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography (CHCl3–MeOH, 7:1)
afforded the desilylated thiourea 13 (1.4 g, 54%); white solid; [a]D
–0.2 (c = 0.1, CHCl3).
IR (CHCl3): 1721 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.15 (1 H, s), 8.04 (1 H, s), 7.89
(1 H, s), 4.34 (2 H, t, J = 6.7 Hz), 3.94 (1 H, br s), 3.67 (2 H, t,
J = 6.4 Hz), 2.58 (1 H, br s), 2.46 (1 H, dt, J = 10.9, 3.0 Hz), 2.28 (6
H, s), 1.95–1.00 (16 H, m).
13C NMR (125 MHz, CDCl3): d = 179.5, 164.6, 139.5, 131.9, 131.2
(q, J = 32 Hz), 127.4, 124.1, 123.1 (q, J = 273 Hz), 122.2, 66.3,
65.4, 61.9, 55.6, 39.6, 32.4, 31.9, 28.0, 24.5, 24.2, 21.9, 20.9.
5-(tert-Butyldimethylsilyloxy)pent-1-yl 3-Amino-5-(trifluoro-
methyl)benzoate
To a solution of ester 11 (4.0 g, 9.2 mmol) in EtOAc (200 mL) was
added 10% Pd/C (500 mg) at r.t. After stirring for 5 h under a H2 at-
mosphere at r.t., the mixture was filtered through a Celite pad and
concentrated under reduced pressure. Purification of the residue by
flash chromatography (hexane–EtOAc, 1:1) afforded 5-(tert-butyl-
dimethylsilyloxy)pent-1-yl 3-amino-5-(trifluoromethyl)benzoate
(3.7 g, quant) as a colorless oil.
26
IR (CHCl3): 1717 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.60 (1 H, s), 7.46 (1 H, s), 7.02
(1 H, s), 4.30 (2 H, t, J = 6.7 Hz), 4.05 (2 H, br s), 3.61 (2 H, t,
J = 6.4 Hz), 1.76 (2 H, m), 1.56 (2 H, m), 1.46 (2 H, m), 0.86 (9 H,
s), 0.02 (6 H, s).
13C NMR (125 MHz, CDCl3): d = 165.7, 147.2, 132.3, 131.9 (q,
J = 32 Hz), 123.7 (q, J = 272 Hz), 118.5, 115.8, 115.0, 65.4, 62.8,
32.3, 28.4, 25.8, 22.3, 18.2, –5.5.
MS (FAB+): m/z (%) = 476 (58, M + H+), 125 (100).
HRMS (FAB+): m/z calcd for C22H33F3N3O3S (M + H+): 476.2195;
MS (FAB+): m/z (%) = 406 (30, M + H+), 73 (100).
HRMS (FAB+): m/z calcd for C19H31F3NO3Si (M + H+): 406.2026;
found: 476.2202.
found: 406.2016.
Attachment of Thiourea 13 to Resin
5-(tert-Butyldimethylsilyloxy)pent-1-yl 3-Isothiocyanato-5-(tri-
fluoromethyl)benzoate (12)
To a suspension of carboxypolystyrene HL resin (1.10 mmol/g, 1.0
g, 1.10 mmol) in CH2Cl2 (20 mL) were added thiourea 13 (1.36 g,
2.9 mmol), EDC (0.56 g, 2.9 mmol) and DMAP (0.21 mg, 1.7
mmol) under argon at r.t. After stirring for 1 h at r.t. for 1 h, the mix-
ture was kept for 11 h. The resin was then filtered, washed well with
CH2Cl2, EtOAc followed by MeOH and then dried in vacuo to give
the catalyst 9. Following the same procedure as for 9, catalyst 10
was obtained from TentaGel carboxy resin (0.26 mmol/g). Loading
level of catalyst 9: ca. 0.79 mmol/g (Anal. Calcd: F, 4.17. Found: F,
3.00). Loading level of catalyst 10: ca. 0.19 mmol/g (Anal. Calcd:
F, 1.33. Found: F, 0.97).
To a solution of 5-(tert-butyldimethylsilyloxy)pent-1-yl 3-amino-5-
(trifluoromethyl)benzoate (7.8 g, 19 mmol) in anhyd MeCN (74
mL) were added imidazole (375 mg, 5.5 mmol) and 1,1-thiocarbo-
nyldiimidazole (4.9 g, 28 mmol) under argon at 0 °C. After stirring
for 2 h at r.t. for 2 h, the mixture was concentrated under reduced
pressure. Purification of the residue by flash chromatography (hex-
ane–EtOAc, 10:1) afforded isothiocyanate 12 (8.0 g, 93%) as a col-
orless oil. IR (CHCl3): 1724 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.16 (1 H, s), 8.03 (1 H, s), 7.63
(1 H, s), 4.38 (2 H, t, J = 6.7 Hz), 3.64 (2 H, t, J = 6.1 Hz), 1.81 (2
H, m), 1.58 (2 H, m), 1.51 (2 H, m), 0.88 (9 H, s), 0.05 (6 H, s).
Synthesis 2006, No. 19, 3295–3300 © Thieme Stuttgart · New York