Leroux et al.
(22 g, 0.25 mol) was added to the alcohol 17 (20 g, 50 mmol)
in ethyl acetate (0.30 L). The slurry was stirred for 20 h at 25
°C, then filtered. The clear solution was evaporated and the
residue crystallized from pentanes to give colorless needles;
mp 77-78 °C; yield 16.4 g (82%). 1H NMR: δ 10.47 (s, 1 H),
8.57 (d, J ) 9.2 Hz, 1 H), 7.6 (m, 1 H), 7.47 (t, J ) 7.3 Hz, 1
H), 7.41 (dd, J ) 9.1, 2.2 Hz, 1 H), 7.3 (m, 2 H), 7.18 (d, J )
9.1 Hz, 1 H), 1.55 (s, 9 H). 13C NMR: δ 195.2, 159.6 (d, J )
255.2 Hz), 152.8, 142.1, 140.7, 133.6 (d, J ) 9.5 Hz), 130.3,
128.0, 126.8 (d, J ) 14.3 Hz), 126.1, 124.4 (d, J ) 3.6 Hz),
122.6, 120.8, 120.4 (d, J ) 258.4 Hz), 116.5 (d, J ) 22.0 Hz),
81.2, 28.2 (3 C). MS: m/z (%) 417 (100, M+ + NH4), 400 (86,
M+ + 1), 344 (73), 299 (77).
2-Am in o-5-(tr iflu or om eth oxy)p h en yl 2-F lu or op h en yl
Keton e (18b). Carbamate 18a (16 g, 40 mmol) and trifluoro-
acetic acid (3.8 mL, 5.7 g, 50 mmol) were dissolved in
dichloromethane (80 mL) and kept for 2 h at 25 °C. When the
solvent was evaporated and the residue crystallized from
hexanes (at -75 °C), pale yellow microneedles were obtained;
mp 55-56 °C; yield 10.9 g (91%). 1H NMR: δ 7.5 (m, 1 H),
7.42 (td, J ) 7.2, 1.6 Hz, 1 H), 7.27 (td, J ) 7.4, 0.9 Hz, 1 H),
7.2 (m, 3 H), 6.71 (d, J ) 9.2 Hz, 1 H), 6.43 (s, br, 2 H). 13C
NMR: δ 194.3, 159.0 (d, J ) 251.9 Hz), 149.7, 138.3, 132.4 (d,
J ) 9.0 Hz), 129.8, 128.9, 127.2 (d, J ) 15.7 Hz), 126.6, 124.3
(d, J ) 3.8 Hz), 120.4 (q, J ) 257.6 Hz), 117.9, 117.5, 116.2 (d,
J ) 21.7 Hz). MS: m/z (%) 299 (100, M+), 280 (12), 204 (7),
177 (3), 123 (31). Anal. Calcd for C14H9F4O2 (299.23): C 56.20,
H 3.03. Found: C 56.23, H 3.19.
N-[2-(2-F lu or oben zoyl)-4-(tr iflu or om eth oxy)p h en yl]-r-
br om oa ceta m id e (18c). The aminobenzophenone 18b (7.5
g, 25 mmol) was dissolved in ethyl acetate (50 mL) and treated
with bromoacetyl bromide (2.2 mL, 5.0 g, 25 mmol). After 2 h
at 25 °C, the homogeneous mixture was washed with a 1.0 M
aqueous solution (50 mL) of sodium hydroxide. The organic
layer was decanted, dried, and evaporated. Crystallization
from hexanes afforded colorless needles; mp 96-97 °C; yield
9.0 g (86%). 1H NMR: δ 8.77 (d, J ) 9.2 Hz, 1 H), 7.6 (m, 1 H),
7.54 (td, J ) 7.4, 1.8 Hz, 1 H), 7.48 (dd, J ) 9.2, 1.5 Hz, 1 H),
7.4 (m, 1 H), 7.32 (td, J ) 7.6, 1.0 Hz, 1 H), 7.20 (ddd, J ) 9.3,
8.4, 1.0 Hz, 1 H), 4.05 (s, 2 H). 13C NMR: δ 195.4, 165.4, 160.7
(d, J ) 253.3 Hz), 143.9, 138.5, 134.2 (d, J ) 8.0 Hz), 130.6,
127.8, 126.3 (d, J ) 14.3 Hz), 126.1, 124.7 (d, J ) 3.2 Hz),
124.5, 122.6, 120.5 (q, J ) 258.1 Hz), 116.6 (d, J ) 22.2 Hz),
29.3. MS: m/z (%) 421 (52, M+ + 1), 340 (7), 298 (24), 228 (100),
214 (36), 177 (10), 123 (35). Anal. Calcd for C16H10BrF4NO3
(420.16): C 45.74, H 2.40. Found: C 45.92, H 2.44.
5-(2-F lu or op h en yl)-1,3-d ih yd r o-7-t r iflu or om et h oxy-
2H-1,4-ben zod ia zep in -2-on e (19). At 0 °C, gaseous ammonia
was introduced for 45 min into a solution containing acetamide
18c (4.2 g, 10 mmol) in methanol (20 mL). After having been
heated to reflux for 2 h, the mixture was evaporated. The oily
residue crystallized from a 1:9 (v/v) mixture of diethyl ether
and hexanes as colorless needles; mp 165 166 °C; 3.2 g (92%).
1H NMR: δ 9.12 (s, br, 1 H), 7.65 (td, J ) 7.5, 1.7 Hz, 1 H), 7.5
(m, 1 H), 7.39 (d, J ) 8.1 Hz, 1 H), 7.3 (m, 1 H), 7.22 (d, J )
8.9 Hz, 1 H), 7.1 (m, 2 H), 4.42 (s, br, 2 H). 13C NMR: δ 171.1,
166.4, 159.5 (d, J ) 252.5 Hz), 144.5, 136.1, 132.4 (d, J ) 9.5
Hz), 131.4, 129.2, 127.0 (d, J ) 12.8 Hz), 124.8, 124.4 (d, J )
3.2 Hz), 120.2 (q, J ) 259.6 Hz), 116.3 (d, J ) 21.5 Hz), 56.6.
MS: m/z (%) 338 (60, M+), 337 (62), 310 (98), 299 (100), 282
(45), 123 (18). Anal. Calcd for C16H10F4N2O2 (338.26): C 56.81,
H 2.96. Found: C 56.65, H 3.06.
hexanes in the form of colorless cubes; mp 115-116 °C; yield
1
22.1 g (53%). H NMR: δ 7.6 (m, 2 H), 7.4 (m, 2 H), 7.3 (m, 2
H), 7.09 (d, J ) 2.4 Hz, 1 H), 6.17 (d, J ) 3.4 Hz, 1 H), 3.21 (s,
br, 1 H), 1.50 (s, 9 H). 13C NMR: δ 158.3, 146.2, 134.7, 134.3,
133.2, 129.6, 129.4, 128.7, 128.2, 128.1, 126.9, 124.4, 120.4 (q,
J ) 263.4 Hz), 119.6, 80.9, 68.2, 28.2 (3 C). MS: m/z (%) 435
(13, M+ + NH4), 381 (19), 344 (44), 281 (100), 127 (39). Anal.
Calcd for C19H19ClF3NO4 (417.81): C 54.62, H 4.58. Found: C
54.55, H 4.63.
ter t-Bu tyl N-[4-Ch lor o-2-[2-(tr iflu or om eth oxy)p h en -yl-
]]ca r ba m a te (21a ). Commercial manganese dioxide (22 g,
0.25 mol) was added to alcohol 20 (21 g, 50 mmol) dissolved
in ethyl acetate (0.30 L). The slurry was stirred for 20 h at 25
°C, then filtered. The clear solution was evaporated. Crystal-
lization of the residue from pentanes gave colorless needles;
mp 102-104 °C; yield 15.6 g (75%). 1H NMR: δ 8.52 (d, J )
9.2 Hz, 1 H), 7.60 (ddd, J ) 9.2, 6.5, 2.8 Hz, 1 H), 7.50 (dd, J
) 9.1, 2.6 Hz, 1 H), 7.4 (m, 3 H), 7.28 (d, J ) 2.6 Hz, 1 H),
1.54 (s, 9 H). 13C NMR: δ 195.9, 152.8, 141.0, 138.2, 135.2,
133.0, 132.5, 132.2, 129.7, 126.8, 125.7, 122.4, 121.2, 120.7,
120.5 (q, J ) 262.1 Hz), 81.2, 28.2 (3 C). MS: m/z (%) 415 (4,
M+), 315 (100), 230 (20), 189 (9), 154 (13). Anal. Calcd for
C
19H17ClF3NO4 (415.80): C 54.88, H 4.12. Found: C 54.87, H
4.32.
2-Am in o-4-ch lor op h en yl 2-(Tr iflu or om eth oxy)p h en yl
Keton e (21b). The carbamate 21a (15 g, 35 mmol) and
trifluoroacetic acid (3.8 mL, 5.7 g, 50 mmol) were dissolved in
dichloromethane (70 mL) and kept for 2 h at 25 °C. Upon
distillation, a yellow oil was collected; bp 183-185 °C/3 mmHg;
nD 1.5915; yield 9.8 g (89%). 1H NMR: δ 7.5 (m, 1 H), 7.4 (m,
20
3 H), 7.21 (dd, J ) 8.9, 2.5 Hz, 1 H), 7.14 (d, J ) 2.4 Hz, 1 H),
6.66 (d, J ) 8.8 Hz, 1 H), 6.4 (s, br, 2 H). 13C NMR: δ 194.7,
149.7, 145.6, 135.1, 133.3, 132.9, 131.3, 129.2, 126.7, 121.0,
120.3 (q, J ) 259.3 Hz), 119.9, 118.5, 118.2. MS: m/z (%) 315
(100, M+), 246 (14), 230 (13), 189 (9), 154 (15). Anal. Calcd for
C
14H9ClF3NO2 (315.16): C 53.26, H 2.88. Found: C 53.13, H
2.83.
2-Am in o-4-ch lor op h en yl 2-(Tr iflu or om eth oxy)p h en yl
Keton e Oxim e (21c). Hydroxylamine hydrochloride (8.6 g,
9.12 mol) was added to a solution of ketone 21b (7.9 g, 25
mmol) and pyridine (25 mL) in ethanol (25 mL). The suspen-
sion was heated to reflux for 60 h under stirring. After
filtration, the volatiles were evaporated to leave behind a
colorless crude product; yield 7.8 g (94%). 1H NMR: δ 7.53 (td,
J ) 7.6, 1.8 Hz, 1 H), 7.4 (m, 2 H), 7.28 (dd, J ) 7.8, 1.7 Hz,
1 H), 7.09 (dd, J ) 8.2, 2.1 Hz, 1 H), 6.68 (d, J ) 8.3 Hz, 1 H),
6.60 (d, J ) 2.2 Hz, 1 H), 4.70 (s, br, 2 H). MS: m/z (%) )331
(65, M+ + 1), 316 (100), 246 (11), 230 (16), 189 (10), 154 (12).
N-[4-Ch lor o-2-(r-h ydr oxyim in o-r-2-(tr iflu or om eth oxy)-
p h en yl]-r-ch lor oa ceta m id e (21d ). The (hydroxyimino)ben-
zophenone 21c (5.0 g, 15 mmol) and chloroacetyl chloride (1.2
mL, 1.8 g, 15 mmol) were conjointly dissolved in ethyl acetate
(30 mL). The homogeneous mixture was allowed to stand for
2 h at 25 °C before being shaken with a 2.0 M aqueous solution
(30 mL) of sodium hydroxide. The organic layer was decanted,
dried, and evaporated. Upon crystallization of the residue from
ethanol, pale yellow needles were obtained; mp 146-149 °C;
yield 5.5 g (90%). 1H NMR: δ 11.37 (s, br, 1 H), 8.67 (d, J )
9.0 Hz, 1 H), 7.65 (td, J ) 7.8, 1.9 Hz, 1 H), 7.5 (m, 3 H), 7.25
(dd, J ) 8.1, 1.9 Hz, 1 H), 4.03 (s, 2 H). 13C NMR: δ 165.6,
163.7, 161.8, 145.9, 136.2, 132.2 (2 C), 131.2, 129.6, 129.0,
127.0, 123.3, 121.9, 120.7 (q, J ) 259.8 Hz), 120.5, 43.7. MS:
m/z (%) 407 (6, M+), 391 (43), 373 (55), 341 (80), 312 (100).
Anal. Calcd for C16H11Cl2F3N2O3 (407.18): C 47.20, H 2.72.
Found: C 46.88, H 2.90.
ter t-Bu tyl N-[4-Ch lor o-2-[r-h ydr oxy-r-2-(tr iflu or om eth -
oxy)p h en yl]]ca r ba m a te (20). At -75 °C, tert-butyl N-(4-
chlorophenyl)carbamate24 (23 g, 0.10 mol) in tetrahydrofuran
(0.20 L) was treated with tert-butyllithium (0.20 L) in pentanes
(0.13 L). After the addition of 2-(trifluoromethoxy)benzalde-
hyde (19 g, 0.10 mol), the mixture was kept 1 h more at -75
°C before being washed with brine (0.10 L). The organic phase
was dried and evaporated. The residue crystallized from
7-Ch lor o-1,3-d ih yd r o-3-h yd r oxy-5-[2-(t r iflu or om et h -
oxy)p h en yl]-2H-1,4-b en zod ia zep in -2-on e (22). The acet-
amide 21d (4.1 g, 10 mmol) and sodium hydroxide (0.80 g, 20
mmol) were conjointly dissolved in 50% aqueous dioxane (20
mL). The homogeneous mixture was kept for 20 h at 25 °C
before being acidified (to pH 2) with concentrated hydrochloric
acid. The precipitate formed was removed by filtration and
(24) Frank, K. E.; Aube, J . J . Org. Chem. 2000, 65, 655-666.
4698 J . Org. Chem., Vol. 68, No. 12, 2003