4618 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 23
Kuo et al.
peracetic acid (25 mL of 32% solution in acetic acid, 105 mmol)
was added. The reaction mixture was stirred overnight at
room temperature, and water (250 mL) was added. The
precipitate was filtered, washed with water, and dried in
vacuo. Crystallization from ethyl acetate/hexane afforded (4.6
g, 51%) of a white solid: mp 199-201 °C; IR (KBr) 3250, 2930,
2220, 1630, 1570; 1H NMR (DMSO-d6) δ 11.42 (1H, s), 7.84
(4H, m), 3.21 (3H, s), 2.23 (1H, m), 1.02 (4H, m). Anal. C, H,
N, S.
Meth od I. N-(4′-Am in op h en yl)-2-cya n o-3-cyclop r op yl-
3-h yd r oxyp r op en a m id e Hyd r och lor id e (50). 2-Cyano-3-
cyclopropyl-3-hydroxy-N-(4′-nitrophenyl)propenamide (49) (4.3
g, 15.7 mmol) was dissolved in ethanol/0.5 N sodium hydroxide
(1:1, 150 mL) and treated with hydrogen (1 atm) for 6 h in the
presence of 10% palladium/carbon (150 mg). The reaction
mixture was filtered through Celite, and the solution was
acidified to pH 1 with concentrated hydrochloric acid. The
product was filtered, washed with water, and dried in vacuo
to afford the title compound (3.7 g, 84%): mp >300 °C; IR
(KBr) 3300, 2840, 2590, 2200 (CN), 1630, 1570. 1H NMR
(DMSO-d6) δ 11.16 (1H, s), 7.66 (2H, m), 7.35 (2H, m), 2.21
(1H, m), 1.04 (4H, m). Anal. C, H, N.
Syn th esis of An ilin es. P r ep a r a tion of 1-Iod o-2-m eth -
yl-4-n itr oben zen e. 2-Methyl-4-nitroaniline (230 g, 1.51 mmol)
was suspended in dilute sulfuric acid (concentrated H2SO4 (189
mL)/H2O (1.38 L)) and cooled to below 5° using an ice/salt bath.
A solution of sodium nitrite (109.6 g, 1.59 mmol in 345 mL of
H2O) was added at a rate to maintain a temperature of 0-5
°C. This diazonium salt solution was added to a solution of
potassium iodide (422.1 g, 2.54 mmol in 1.27 L of H2O)
maintaining a temperature of 0-5 °C during the addition. The
mixture was stirred at ambient temperature for 2 h and then
heated to 50-60 °C for 1 h. The mixture was cooled and
filtered and the solid washed with water. Solid was dissolved
in dichloromethane (4 L) and washed with sodium met-
abisulfite solution (2 × 2 L). The solution was passed down a
column of silica gel to remove the majority of the dark brown
coloration. The solvent was concentrated in vacuo and the
orange crystalline solid triturated with ether, filtered, and
dried to afford the title compound (327 g, 82%): 1H NMR
(CDCl3) δ 8.07 (2H, m), 7.72 (1H, dd, J ) 8.7, 2.8 Hz), 2.55
(3H, s).
(CDCl3) δ 150.05, 145.54, 133.71 (q, J ) 30.5 Hz, C-1), 127.32
(q, J ) 5.5 Hz, C-6), 125.05, 123.48 (q, J ) 273.0 Hz, CF3),
120.72, 25.58, 15.08. Anal. C, H, N. F.
P r ep a r a tion of 1-(Br om od iflu or om eth oxy)-2-m eth yl-
4-n itr oben zen e. 2-Methyl-4-nitrophenol (6 g, 43.13 mmol)
was added to sodium (0.92 g, 40 mmol) dissolved in ethanol
(30 mL). The solvent was evaporated in vacuo, and benzene
(20 mL) was added and reevaporated. The sodium salt was
added to DMF (24 mL), dibromodifluoromethane (30 mL), and
ethanethiol (3 drops; catalyst). The reaction mixture was
heated at 70 °C for 10 h, poured onto ice/water, and extracted
with ethyl acetate. The organic phase was washed with
aqueous sodium hydroxide (0.5 M) and water, dried (MgSO4),
and concentrated in vacuo. The product was purified by flash
chromatography (4% ethyl acetate in hexane) to afford 1-(bro-
modifluoromethoxy)-2-methyl-4-nitrobenzene (3.35 g, 29%)
which was used without further purification: IR (film) 1591,
1
1529, 1490, 1351, 1310, 1237; H NMR (CDCl3) δ 8.15 (2 H,
m), 7.46 (1H, d, J ) 8.9 Hz), 2.43 (3H, s).
P r ep a r a tion of 2-Meth yl-4-n itr o-1-(tr iflu or om eth oxy)-
ben zen e. 1-(Bromodifluoromethoxy)-2-methyl-4-nitrobenzene
(0.3 g, 1.06 mmol), antimony trifluoride (0.12 g, 0.67 mmol),
and antimony pentachloride (0.02 g; catalyst) were heated in
a sealed flask at 175 °C for 4 h. The reaction mixture was
cooled, diluted with ether, washed with water, dried (MgSO4),
and concentrated in vacuo. This afforded the title compound
(0.13 g, 83%) which was used without further purification: IR
(film) 3413, 2928, 1593, 1529, 1494, 1350, 1339; 1H NMR
(CDCl3) δ 8.15 (2H, m), 7.44 (1H, d, J ) 8.9 Hz), 2.43 (3H, s);
13C NMR (CDCl3) δ 120.34 (CF3, J CF ) 260 Hz).
P r ep a r a tion of 4-(Tr iflu or om eth yl)-3-tolu id in e. 2-(Tri-
fluoromethyl)-5-nitrotoluene (145 g, 0.759 mmol) in methanol
(1.7 L) was hydrogenated at 1250 mbar using 5% palladium
on charcoal (14.5 g) as catalyst. When hydrogen uptake had
ceased, the catalyst was filtered off and the solvent removed
under reduced pressure to leave the product as a pale yellow
oil (123 g, 93%): IR (film) 3500, 3400, 3240, 1630, 1590, 1520,
1
1465, 1445, 1320, 1280, 1195, 1163, 1115, 1045, 865, 825; H
NMR (CDCl3) δ 7.36 (1H, d, J ) 8.2 Hz), 6.50 (2H, m), 3.86
(2H, brs), 2.37 (3H, m). Anal. C, H, N, F.
1-Am in o-3-m eth yl-4-(p en ta flu or oeth yl)ben zen e: pre-
pared by the same method, 94% yield; IR (KBr) 3391, 3331,
1
2-E t h yl-1-iod o-4-n it r ob en zen e: prepared by the above
method starting from 4-amino-3-ethyl-1-nitrobenzene,28 60%
yield; mp 32-3 °C; 1H NMR (CDCl3) δ 8.05 (1H, d, J ) 2.7
Hz, H-3), 8.01 (1H, d, J ) 8.6 Hz, H-6), 7.73 (1H, dd, J ) 2.7,
8.6 Hz, H-5), 2.83 (2H, q, J ) 7.5 Hz, -CH2), 1.28 (3H, t, J )
7.5 Hz, -CH3); MS (70 eV) m/e 277 (M+, 100), 262, 204, 133,
104, 103, 78, 77.
3227, 1676, 1650, 1599, 1554, 1342; H NMR (CDCl3) δ 7.30
(1H, s), 6.53 (2H, m), 3.80 (2H, brs), 2.37 (3H, t, J ) 3 Hz).
4-Am in o-2-eth yl-1-(tr iflu or om eth yl)ben zen e: prepared
by the same method, 93% yield, colorless liquid; 1H NMR
(CDCl3) δ 7.37 (1H, d, J ) 8.4 Hz), 6.58 (1H, d, J ) 2.0 Hz),
6.50 (1H, dd, J ) 8.4, 2.0 Hz), 3.88 (2H, brs), 2.72 (2H, q, J )
7.5 Hz), 1.22 (3H, t, J ) 7.5 Hz).
P r ep a r a tion of 2-(Tr iflu or om eth yl)-5-n itr otolu en e. A
450 mL Parr pressure reactor was charged with 2-iodo-5-
nitrotoluene (81.0 g, 0.308 mmol), active copper powder14,15
(62.3 g, 0.98 mol), and dimethylformamide (200 mL). The
reactor was purged with argon and cooled to ca. -25 °C, and
trifluoromethyl iodide (93 g, 0.475 mmol) was introduced via
the dip-tube inlet valve. The reactor was then heated gradu-
ally to 150 °C, with stirring, and maintained at 150 °C for 5
h. The cooled reaction mixture was poured onto ice/water (1.0
L), washing out the reactor with ethyl acetate. The copper
salt was filtered off and washed with ethyl acetate. The
aqueous layer was separated and extracted with ethyl acetate.
All extracts were combined, washed with water, and dried over
magnesium sulfate. The solvent was concentrated in vacuo
and the crude product purified by distillation at ca. 10 mbar,
bp 89-92 °C. The title product was obtained (54.5 g, 95%):
IR (film) 1536, 1355, 1314, 1273, 1178, 1127, 1047, 925, 899,
843, 807; 1H NMR (CDCl3) δ 8.13 (2H, m), 7.81 (1H, d, J ) 8.3
Hz), 2.61 (3 H, m). Anal. C, H, N.
P r epar ation of 4-Am in o-2-m eth yl-1-(tr iflu or om eth oxy)-
ben zen e. 5-Nitro-2-(trifluoromethoxy)toluene (2.5 g, 0.0113
mol) in toluene (100 mL) was treated with iron powder (13 g)
and concentrated HCl (3 drops) and stirred vigorously under
reflux. Water (2.0 mL) was added over 2 h; the mixture was
filtered and concentrated to a low volume. The product was
used in the next step without further purification.
P r ep a r a tion of 4-Am in o-2-m eth yl-1-[(tr iflu or om eth yl)-
th io]ben zen e. 2-Fluoro-5-nitrotoluene (15.5 g, 0.1 mmol) and
sodium sulfide nonahydrate (30 g, 0.125 mmol) in DMSO (50
mL) were heated at 50 °C under a nitrogen atmosphere for 2
h. The reaction mixture was poured onto ice/water and
extracted with dichloromethane. The organic phase was
washed with water, dried (MgSO4), and concentrated in vacuo
to afford 4-mercapto-3-methyl-1-nitrobenzene (12 g, 71%)
which was used without further purification. The product (9
g, 0.053 mmol) was added to sodium (1.22 g, 0.053 mmol) in
ethanol (120 mL) and evaporated to dryness. The residue was
azeotroped with benzene and evaporated to dryness. The
residue was then dissolved in DMF (30 mL) in a Fischer Porter
apparatus, flushed with argon, and cooled to -78 °C and the
flask charged with trifluoromethyl iodide (21 g). The reaction
mixture was stirred for 48 h at room temperature followed by
heating at 75 °C for 24 h. The reaction mixture was cooled,
poured onto ice/water/ether, and filtered. The aqueous phase
was separated and reextracted with ether. The combined
organic phases were dried (MgSO4), evaporated, and purified
3-Met h yl-1-n it r o-4-(p en t a flu or oet h yl)b en zen e: pre-
pared by the same method using pentafluoroethyl iodide, 68%
yield; IR (film) 1536, 1350, 1334, 1304; 1H NMR (CDCl3) δ 8.14
(2H, m), 7.75 (1H, d, J ) 8.4 Hz), 2.65 (3H, t, J ) 3.1 Hz).
3-Eth yl-1-n itr o-4-(tr iflu or om eth yl)ben zen e: prepared
by the same method, 71% yield; IR (film) 2977, 2942, 1535,
1
1352, 1310; H NMR (CDCl3) δ 8.22 (1H, d, J ) 1.5 Hz), 8.14
(1H, dd, J ) 8.6, 1.5 Hz), 7.81 (1H, d, J ) 8.6 Hz); 13C NMR