DHDMBFs as Antiinflammatory and Analgesic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3523
7.42 (d, J ) 1.7 Hz, 1 H), 7.53 (d, J ) 1.7 Hz, 1 H); 13C NMR
δ 3.5, 10.9, 27.5, 29.2, 34.2, 41.3, 44.9, 84.4, 119.3, 124.4, 127.2,
133.0, 137.5, 160.0, 167.9; IR 3267, 2956, 1628 cm-1; MS m/z
302 (MH+). Anal. (C19H27NO2) C, H, N.
with 2-methoxyethylamine, and the resulting compound 20
was chromatographed with 1:6 and then with 2:3 EtOAc/
hexanes: 1H NMR δ 7.54 (d, J ) 1.8 Hz, 1 H), 7.41 (d, J ) 1.8
Hz, 1 H), 6.48 (br, 1 H), 4.28 (s, 2 H), 3.64 (dt, J ) 4.9 Hz, 2
H), 3.56 (t, J ) 4.9 Hz, 2 H), 3.39 (s, 3 H), 1.36 (s, 9 H), 1.33
(s, 6 H); 13C NMR δ 167.9, 160.1, 137.5, 133.0, 126.9, 124.5,
119.3, 84.4, 71.5, 58.8, 41.3, 39.7, 34.2, 29.2, 27.5; IR 3271,
7-ter t-Bu tyl-N-(2-cyclop r op yleth yl)-2,3-d ih yd r o-3,3-d i-
m eth yl-5-ben zofu r a n ca r boxa m id e (15). Step 1. 2-Cy-
clop r op yleth yla m in e. Concentrated sulfuric acid (1.09 mL,
20.0 mmol) was added dropwise to a vigorously stirred solution
of lithium aluminum hydride (1.53 g, 40.0 mmol) in 40 mL of
ether at 0 °C. The reaction mixture was warmed to room
temperature and stirred for 1 h, and a solution of cyclopropyl-
acetonitrile (1.06 g, 13.0 mmol, Lancaster) in 5 mL of ether
was added dropwise. The resulting mixture was heated at
reflux for 2 h, cooled to 0 °C, and slowly quenched with water.
A solution of sodium hydroxide (2 g) in 18 mL of water was
added, and the organic phase was decanted from the resulting
aluminum hydroxide precipitate which was rinsed with three
20-mL portions of ether. All ethereal portions were combined,
and the solvent was distilled off to leave 1.10 g (99%) of
2-cyclopropylethylamine as a colorless liquid: 1H NMR δ 2.77
(t, J ) 6.9 Hz, 2 H), 1.34 (q, J ) 6.9 Hz, 2 H), 0.67 (m, 1 H),
0.42 (m, 2 H), 0.04 (m, 2 H).
2955, 1630, 1548 cm-1; MS m/z 306 (MH+). Anal. (C18H27
-
NO3) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-N-(2,3-d ih yd r oxyp r op yl)-3,3-
d im eth yl-5-ben zofu r a n ca r boxa m id e (21). Method A was
used with 2,3-dihydroxypropylamine, and the resulting com-
pound 21 was chromatographed without workup with EtOAc
and then with 10:1 EtOAc/MeOH, followed by recrystallization
from EtOAc: 1H NMR (CD3OD) δ 7.65 (d, J ) 1.9 Hz, 1 H),
7.54 (d, J ) 1.9 Hz, 1 H), 4.90 (s, 2 H), 4.30 (s, 1 H), 3.83 (m,
1 H), 3.58-3.38 (m, 4 H), 1.36 (s, 9 H), 1.34 (s, 6 H); 13C NMR
(CDCl3/CD3OD) δ 170.1, 160.8, 137.9, 133.4, 126.1, 125.3,
119.8, 84.8, 71.4, 63.8, 42.8, 41.5, 34.5, 29.4, 27.7; IR 3442,
3324, 2959, 1649, 1545 cm-1; MS m/z 322 (MH+), 248. Anal.
(C18H27NO4) C, H, N.
7-t er t -Bu t yl-2,3-d ih yd r o-3,3-d im e t h yl-N -(2-d im e t h -
yla m in oeth yl)-5-ben zofu r a n ca r boxa m id e (22). Method A
was used with N,N-dimethyethylenediamine, and the resulting
compound 22 was chromatographed with 10:1 CH2Cl2/MeOH:
1H NMR δ 7.53 (d, J ) 1.9 Hz, 1 H), 7.41 (d, J ) 1.9 Hz, 1 H),
6.66 (br, 1 H), 4.27 (s, 2 H), 3.54 (q, J ) 5.8 Hz, 2 H), 2.54 (t,
J ) 6.0 Hz, 2 H), 2.28 (s, 6 H), 1.37 (s, 9 H), 1.34 (s, 6 H); 13C
NMR δ 168.0, 160.0, 137.4, 132.9, 127.2, 124.5, 119.3, 84.4,
58.1, 45.3, 41.3, 37.3, 34.2, 29.1, 27.5; IR 3297, 2961, 1630,
1547 cm-1; MS m/z 319 (MH+). Anal. (C19H30N2O2) C, H, N.
N-(2-Am in ot h ia zolyl)-7-ter t-b u t yl-2,3-d ih yd r o-3,3-d i-
m eth yl-5-ben zofu r a n ca r boxa m id e (23). Method A was
used with 2-aminothiazole, and the resulting compound 23 was
chromatographed with 1:7 EtOAc/hexanes and then washed
with hot hexane: 1H NMR δ 12.6 (br, 1 H), 7.81 (d, J ) 1.8
Hz, 1 H), 7.68 (d, J ) 1.8 Hz, 1 H), 7.09 (d, J ) 3.6 Hz, 1 H),
6.91 (d, J ) 3.6 Hz, 1 H), 4.34 (s, 2 H), 1.34 (s, 15 H); 13C NMR
δ 166.1, 161.4, 160.7, 137.9, 137.2, 133.5, 126.2, 124.8, 120.6,
113.2, 84.7, 41.3, 34.3, 29.0, 27.6; IR 3235, 2961, 1640, 1547
cm-1; MS m/z 331 (MH+), 231. Anal. (C18H22N2O2S) C, H, N,
S.
Step 2. 7-ter t-Bu tyl-N-(2-cyclop r op yleth yl)-2,3-d ih y-
d r o-3,3-d im eth yl-5-ben zofu r a n ca r boxa m id e (15). Method
A was used with 2-cyclopropylethylamine, and the resulting
compound 15 was chromatographed with 10 f 20% EtOAc/
hexanes: 1H NMR δ 7.49 (d, J ) 1.8 Hz, 1 H), 7.40 (d, J ) 1.8
Hz, 1 H), 6.16 (br s,1 H), 4.26 (s, 2 H), 3.53 (q, J ) 7.4 Hz, 2
H), 1.52 (q, J ) 7.4 Hz, 2 H), 1.35 (s, 9 H), 1.32 (s, 6 H), 0.74
(m, 1 H), 0.50 (m, 2 H), 0.12 (m, 2 H); 13C NMR δ 167.7, 160.0,
137.4, 132.8, 127.2, 124.0, 119.2, 84.3, 41.2, 40.2, 34.4, 34.1,
29.0, 27.4, 8.63, 4.08; IR 3266, 3079, 2956, 2869, 1630 cm-1
;
MS m/z 316 (MH+). Anal. (C20H29NO2) C, H, N.
7-ter t-Bu tyl-N-cyclobu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (16). Method A was used with
cyclobutylamine, and the resulting compound 16 was recrys-
tallized from EtOAc: 1H NMR δ 1.33 (s, 6 H), 1.35 (s, 9 H),
1.75 (m, 2 H), 1.96 (m, 2 H), 2.42 (m, 2 H), 4.27 (s, 2 H), 4.59
(m, 1 H), 5.99 (br s, 1 H), 7.39 (d, J ) 1.5 Hz, 1 H), 7.50 (d, J
) 1.5 Hz, 1 H); 13C NMR δ 15.2, 27.5, 29.2, 31.4, 34.2, 41.3,
45.3, 84.5, 119.3, 124.5, 126.9, 133.1, 137.5, 160.1, 167.1; IR
3243, 2955, 1627 cm-1; MS m/z 302 (MH+). Anal. (C19H27
-
NO2) C, H, N.
N-(2-Am in o-2-th ia zolin yl)-7-ter t-bu tyl-2,3-d ih yd r o-3,3-
d im eth yl-5-ben zofu r a n ca r boxa m id e (24). Method A was
used with 2-aminothiazoline, and the resulting compound 24
was chromatographed with 2:3 EtOAc/hexanes and then
triturated with hot ether: 1H NMR δ 7.93 (d, J ) 1.8 Hz, 1
H), 7.77 (d, J ) 1.8 Hz, 1 H), 4.28 (s, 2 H), 3.68 (t, J ) 7.6 Hz,
2 H), 3.22 (t, J ) 7.6 Hz, 2 H), 1.35 (s, 9 H), 1.32 (s, 6 H); 13C
NMR δ 174.1, 173.1, 161.1, 137.3, 132.7, 128.0, 127.2, 121.6,
84.6, 47.4, 41.2, 34.2, 30.0, 29.2, 27.6; IR 3356, 2959, 1620,
1599 cm-1; MS m/z 333 (MH+) 247. Anal. (C18H24N2O2S) C,
H, N, S.
7-ter t-Bu tyl-N-cyclop en tyl-2,3-d ih yd r o-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (17). Method A was used with
cyclopentylamine, and the resulting compound 17 was recrys-
tallized from EtOAc: 1H NMR δ 1.33 (s, 6 H), 1.36 (s, 9 H),
1.50 (m, 2 H), 1.70 (m, 4 H), 2.10 (m, 2 H), 4.27 (s, 2 H), 4.37
(m, 1 H), 5.99 (br s, 1 H), 7.36 (d, J ) 1.8 Hz, 1 H), 7.49 (d, J
) 1.8 Hz, 1 H); 13C NMR δ 23.8, 27.4, 29.0, 33.1, 34.1, 41.2,
51.5, 84.3, 119.0, 124.2, 127.3, 132.9, 137.3, 160.1, 167.3; IR
3265, 2954, 1624 cm-1; MS m/z 316 (MH+). Anal. (C20H29
NO2) C, H, N.,
-
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-p h en yl-5-ben -
zofu r a n ca r boxa m id e (18). Method A was used with aniline,
and the resulting compound 18 was recrystallized from
EtOAc: 1H NMR δ 1.35 (s, 6 H), 1.38 (s, 9 H), 4.30 (s, 2 H),
7.12 (t, J ) 7.4 Hz, 1 H), 7.35 (t, J ) 8.4 Hz, 2 H), 7.66-7.56
(m, 3 H), 7.85 (s, 1 H); 13C NMR δ 27.5, 29.0, 34.2, 41.2, 84.5,
119.4, 120.1, 124.1, 124.6, 127.2, 128.9, 133.2, 137.7, 138.2,
160.1, 166.1; IR 3278, 2959, 1645 cm-1; MS m/z 324 (MH+).
Anal. (C21H25NO2) C, H, N.
7-ter t-Bu tyl-2,3-d ih yd r o-N,N-d im eth yl-3,3-d im eth yl-5-
ben zofu r a n ca r boxa m id e (25). Method A was used with
dimethylamine, and the resulting compound 25 was chromato-
graphed with 1:1 EtOAc/hexanes: 1H NMR (CD3OD) δ 7.17
(d, J ) 1.8 Hz, 1 H), 7.11 (d, J ) 1.8 Hz, 1 H), 4.26 (s, 2 H),
3.04 (s, 6 H), 1.34 (s, 9 H), 1.31 (s, 6 H); 13C NMR (CD3OD) δ
174.5, 160.0, 138.8, 134.1, 129.1, 125.9, 121.0, 85.4, 42.5, 40.5,
30.2, 29.8, 27.9; IR 2957, 1629, 1496 cm-1; MS m/z 276 (MH+),
275, 231. Anal. (C17H25NO2) C, H, N.
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-N-(2-h yd r oxy-
eth yl)-5-ben zofu r a n ca r boxa m id e (19). Method A was used
with ethanolamine, and the resulting compound 19 was
chromatographed with 3:2 EtOAc/hexanes: 1H NMR δ 7.53
(d, J ) 1.8 Hz, 1 H), 7.42 (d, J ) 1.8 Hz, 1 H), 6.58 (s, 1 H),
4.32 (s, 2 H), 3.84 (t, J ) 6.9 Hz, 2 H), 3.65 (q, J ) 6.9 Hz, 2
H), 1.38 (s, 9 H), 1.33 (s, 6 H); 13C NMR δ 169.2, 160.2, 137.5,
132.0, 126.2, 124.5, 119.3, 84.4, 62.6, 43.0, 41.1, 34.1, 29.0, 27.4;
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-eth yl-N-m eth -
yl-5-ben zofu r a n ca r boxa m id e (26). Method A was used
with ethylmethylamine, and the resulting compound 26 was
recrystallized from hexane: 1H NMR δ 7.13 (d, J ) 1.8 Hz, 1
H), 7.03 (d, J ) 1.8 Hz, 1 H), 4.24 (s, 2 H), 3.42 (br s, 2 H),
3.01 (s, 3 H), 1.45 (s, 9 H) 1.41 (s, 6 H), 1.18 (t, J ) 8.6 Hz, 3
H); 13C NMR δ 172.2, 157.9, 136.7, 132.4, 128.4, 123.9, 118.9,
83.8, 45.8, 42.4, 41.1, 33.9, 29.3, 27.3, 13.4; IR 2964, 1620 cm-1
;
MS m/z 292 (MH+), 215, 140; IR 3410, 3275, 2958, 1610 cm-1
.
MS m/z 290 (MH+), 231. Anal. (C18H27NO2) C, H, N.
Anal. (C17H25NO3) C, H, N.,
7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-N-(2-m et h oxy-
eth yl)-5-ben zofu r a n ca r boxa m id e (20). Method A was used
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-N-m eth yl-N-p r o-
p yl-5-ben zofu r a n ca r boxa m id e (27). Method A was used
with methylpropylamine, and the resulting compound 27 was