3960 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Selvakumar et al.
respective acid chloride (1.2 equiv) dropwise. After it was
stirred at room temperature for 1-6 h (TLC control), the
reaction mixture was diluted with dichloromethane and
washed with water twice followed by brine. The organic extract
was dried, was evaporated, and was passed through a column
to afford the acylated product.
Com p ou n d 36. mp 149 °C. IR (KBr): 3296, 1743, 1511,
1241 cm-1 1H NMR (CDCl3): δ 8.11 (bs, 1H), 7.01 (dd, J )
.
13.2, 2.0 Hz, 1H), 6.74 (s, 1H), 5.05-4.85 (m, 1H), 4.40-2.90
(m, 9H), 2.62 (s, 3H), 2.30-1.90 (m, 3H), 1.60-1.40 (m, 1H).
HPLC (system 2) 95.2% purity.
P r ep a r a tion of Isoth iocya n a te 40. Thiophosgene (200
mg, 1.8 mmol) was added dropwise to a solution of the amine
18 (450 mg, 1.5 mmol) and Et3N (0.5 mL, 3.7 mmol) in dry
dichloromethane at ice bath temperature under argon. The
reaction mixture was warmed to room temperature over 3 h,
and then, the volatiles were removed. The residue obtained
was directly charged on to a column of silica gel to afford the
product 40 (350 mg, 68% yield); mp 164 °C. IR (KBr): 2117,
1748, 1512, 1247 cm-1. 1H NMR (CDCl3): δ 7.04 (dd, J ) 13.7,
2.4 Hz, 1H), 6.77 (s, 1H), 4.90-4.70 (m, 1H), 4.35-3.25 (m,
8H), 3.10-2.90 (m, 1H), 2.30-1.90 (m, 3H), 1.60-1.35 (m, 1H).
MS (CI method) 350 (M + 1)+.
P r ep a r a tion of Th ioca r ba m a tes 41-44. A solution of the
isothiocyanate 40 in the respective alcohol was heated to 80-
100 °C while monitoring by TLC. At the complete consumption
of starting material, the reaction mixture was allowed to cool
to room temperature. The crystals formed were separated,
washed with ether, and dried at vacuum to yield the pure
product.
Com p ou n d 20. mp 171 °C. IR (KBr): 3329, 1724, 1673,
1
1520 cm-1. H NMR (CDCl3): δ 7.00-6.85 (m, 2H), 6.50 (d, J
) 8.3, 1H), 6.40-6.00 (m, 3H), 5.75-5.60 (m, 1H), 4.90-4.65
(m, 1H), 4.39 (dd, J ) 9.5, 2.4 Hz, 1H), 4.10-2.90 (m, 8H),
2.20-1.85 (m, 3H), 1.60-1.35 (m, 1H). 13C NMR (DMSO-d6):
δ 165.2, 154.2, 142.4, 132.0, 131.2, 127.7, 125.7, 112.7, 112.3,
107.5, 71.2, 68.0, 55.0, 48.0, 41.6, 27.7, 23.2. MS 343 (M+), 299,
227, 203.
Com p ou n d 21. mp 158 °C. IR (KBr): 3326, 2930, 1732,
1
1628 cm-1. H NMR (CDCl3): δ 7.00-6.85 (m, 2H), 6.52 (d, J
) 9.7, 1H), 6.05-5.90 (bt, 1H), 4.80-4.65 (m, 1H), 4.45-4.35
(m, 1H), 3.97 (t, J ) 9.0 Hz, 1H), 3.75-3.10 (m, 7H), 2.45-
1.85 (m, 4H), 1.60-1.10 (m, 7H). MS 359 (M+), 315, 224, 143,
99.
Com p ou n d 22. mp 148 °C. IR (KBr): 3314, 1734, 1679,
1
1520 cm-1. H NMR (CDCl3): δ 7.15-6.85 (m, 3H), 6.52 (d, J
) 8.8, 1H), 4.80-4.65 (m, 1H), 4.39 (dd, J ) 9.5, 2.4 Hz, 1H),
4.15-3.10 (m, 10H), 2.20-1.80 (m, 3H), 1.60-1.35 (m, 1H).
13C NMR (DMSO-d6): δ 166.8, 154.2, 142.5, 132.1, 127.8, 112.8,
112.4, 107.6, 70.9, 68.0, 55.1, 48.0, 47. 9, 42.5, 41.9, 27.7, 23.2.
MS 367 (M + 2)+, 365 (M+), 228, 203, 185.
Com p ou n d 41. mp 201 °C. IR (KBr): 3247, 1752, 1512
cm-1 1H NMR (CDCl3): δ 7.03 (d, J ) 12.7 Hz, 1H), 6.85-
.
6.70 (m, 2H), 4.95-4.60 (m, 1H), 4.30-2.90 (m, 12H), 2.30-
1.40 (m, 3H), 1.60-1.40 (m, 1H). 13C NMR (DMSO-d6): δ 161.9,
152.9 (d, J ) 237.9 Hz, 1C), 154.0, 146.1 (d, J ) 8.7 Hz, 1C),
130.0 (d, J ) 13.3 Hz, 1C), 120.0 (d, J ) 14.4 Hz, 1C), 102.7,
99.2 (d, J ) 25.8 Hz, 1C), 71.2, 65.8, 54.2, 51.8 (d, J ) 6.5 Hz,
1C), 47.4, 26.1, 23.2. MS 381 (M)+, 349, 337, 221. HPLC
(system 1) 97.5% purity. Anal. (C17H20N3O4FS) C, N; H: calcd,
5.29; found, 5.62.
Com p ou n d 23. mp 194 °C. IR (KBr): 3327, 2930, 1627
1
cm-1. H NMR (CDCl3): δ 7.10-6.90(m, 3H), 6.52 (d, J ) 8.6
Hz, 1H), 5.95(s, 1H), 4.85-4.70(m, 1H), 4.41(dd, J ) 9.5, 2.7
Hz, 1H), 4.20-3.10 (m, 8H), 2.10-1.95 (m, 3H), 1.60-1.35 (m,
1H). MS 399 (M - 1)+, 224, 143, 99. HPLC (system 1) 95.6%
purity.
Com p ou n d 31. mp 192 °C. IR (KBr): 3323, 1742, 1663,
1512 cm-1 1H NMR (CDCl3): δ 7.02 (dd, J ) 13.7, 2.4 Hz,
.
P r ep a r a tion of Th iou r ea 45. Ammonia gas was bubbled
to a solution of isothiocyanate 40 in THF at -10 °C over 20
min. The resultant mixture was stirred at room temperature
for 1 h and then diluted with ethyl acetate. The organic layer
was washed with water (two times) and brine and dried. The
residue obtained upon evaporation of the solvent was passed
through a column of silica gel to afford the thiourea 45; mp
1H), 6.73 (s, 1H), 6.40-6.00 (m, 4H), 5.71 (d, J ) 9.8 Hz, 1H),
4.85-4.70 (m, 1H), 4.22 (dd, J ) 9.8, 2.4 Hz, 1H), 4.05-2.90
(m, 8H), 2.30-1.80 (m, 3H), 1.60-1.40 (m, 1H). MS 361 (M+),
317, 246, 221. HPLC (system 1) 99.2% purity.
Com p ou n d 32. mp 152 °C. IR (KBr): 3319, 1740, 1681,
1512 cm-1 1H NMR (CDCl3): δ 7.10-6.95 (m, 2H), 6.70 (s,
.
157 °C. IR (KBr): 3357, 1752, 1511, 1246 cm-1 1H NMR
.
(CDCl3): δ 7.60 (bs, 1H), 6.95-6.80 (m, 2H), 6.24 (bs, 2H),
5.00-4.80 (m, 1H), 4.30-2.90 (m, 11H), 2.35-1.90 (m, 3H),
1.60-1.20 (m, 1H). MS 409.
P r ep a r a tion of Th iou r ea 46-49. A neat solution of
isothiocyanate 40 in the appropriate amine (1 mL for 100 mg
isothiocyanate) was stirred at room temperature over 4 h, and
water was added to the reaction mixture followed by extraction
with ethyl acetate. The residue obtained upon evaporation of
the solvent was passed through a column of silica gel to afford
the respective thiourea.
1H), 4.85-4.65 (m, 1H), 4.20 (dd, J ) 9.8, 2.4 Hz, 1H), 4.05 (s,
2H), 3.99-2.90 (m, 8H), 2.30-1.80 (m, 3H), 1.60-1.40 (m, 1H).
13C NMR (DMSO-d6): δ 201.4, 153.3 (d, J ) 237.4 Hz, 1C),
153.8, 146.0 (d, J ) 8.8 Hz, 1C), 129.9 (d, J ) 13.2 Hz, 1C),
120.0 (d, J ) 14.6 Hz, 1C), 102.7, 99.3 (d, J ) 25.7 Hz, 1C),
70.1, 65.8, 54.2, 51.7 (d, J ) 6.4 Hz, 1C), 48.1, 47.5, 32.8, 26.1,
23.2. MS 383 (M+), 339, 246, 221. HPLC (system 1) 96.7%
purity.
Com p ou n d 33. mp 182 °C. IR (KBr): 3323, 1742, 1663,
1512 cm-1 1H NMR (CDCl3): δ 7.02 (dd, J ) 13.7, 2.4 Hz,
.
1H), 6.73 (s, 1H), 6.40-6.00 (m, 4H), 5.71 (d, J ) 9.8 Hz, 1H),
4.85-4.70 (m, 1H), 4.22 (dd, J ) 9.8, 2.4 Hz, 1H), 4.05-2.90
(m, 8H), 2.30-1.80 (m, 3H), 1.60-1.40 (m, 1H). 13C NMR
(DMSO-d6): δ 165.2, 153.3 (d, J ) 237.4 Hz, 1C), 153.9, 145.9
(d, J ) 8.3 Hz, 1C), 131.2, 129.9 (d, J ) 13.2 Hz, 1C), 125.7,
119.8 (d, J ) 14.6 Hz, 1C), 102.6, 99.2 (d, J ) 26.0 Hz, 1C),
71.3, 65.8, 54.1, 51.7 (d, J ) 5.9 Hz, 1C), 47.4, 26.1, 23.2. MS
361 (M+), 317, 246, 221. HPLC (system 1) 99.2% purity.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ioa m id es
35-39. A solution of the amide (1 equiv) and Lawesson’s
reagent (0.6 equiv) in dry dioxane was heated to 55-90 °C
over 3-10 h (TLC control). The reaction mixture was allowed
to cool to room temperature and diluted with ethyl acetate.
The resultant mixture was washed with water (four times)
followed by brine and dried. The residue obtained upon
evaporation of solvent was passed through a column of silica
gel to afford the respective thioamide.
Com p ou n d 46. mp 148 °C. IR (KBr): 3376, 1731, 1512,
1240 cm-1 1H NMR (CDCl3): δ 6.94 (d, J ) 13.2 Hz, 1H),
.
6.80-6.40 (m, 2H), 5.00-4.90 (m, 1H), 4.35-2.90 (m, 12H),
2.30-1.80 (m, 3H), 1.60-1.40 (m, 1H).
Com p ou n d 47. mp 158 °C. IR (KBr): 3348, 1746, 1510,
1246 cm-1 1H NMR (CDCl3): δ 7.01 (dd, J ) 13.7, 2.4 Hz,
.
1H), 6.75 (s, 1H), 6.30-6.10 (bs, 1H), 4.40-2.90 (m, 13H), 2.68
(t, J ) 5.4 Hz, 4H), 2.30-1.80 (m, 3H), 1.60-1.40 (m, 1H).
HPLC (system 1) 98.1% purity.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r ba m -
a tes 50 a n d 51. To a solution of the amine 18 (1 equiv) and
Et3N (2.2 equiv) in dry dichloromethane was added alkyl
chloroformate (1.2 equiv) under argon atmosphere at 0 °C. The
reaction mixture was stirred at room temperature overnight
and worked up by diluting with dichloromethane followed by
washing with water and brine. The residue obtained after
evaporation of the dried organic layer was passed through a
column to afford the carbamate.
Com p ou n d 35. mp 149 °C. IR (KBr): 3440, 1746, 1511
cm-1 1H NMR (CDCl3): δ 9.54 (d, J ) 6.2 Hz, 1H), 8.42 (s,
.
1H), 6.95 (dd, J ) 13.4, 2.4 Hz, 1H), 6.72 (s, 1H), 5.05-4.95
(m, 1H), 4.26-4.18 (m, 3H), 4.06-3.73 (m, 3H), 3.48-3.28 (m,
2H), 3.07-2.94 (m, 1H), 2.30-1.90 (m, 3H), 1.60-1.40 (m, 1H).
HPLC (system 2) 95.0% purity.
Com p ou n d 50. mp 204 °C. IR (KBr): 1754, 1708, 1511,
1246 cm-1 1H NMR (CDCl3): δ 7.04 (dd, J ) 13.7, 2.4 Hz,
.
1H), 6.73 (s, 1H), 5.30-5.10 (bs, 1H), 4.80-4.65 (m, 1H), 4.30-