4948 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Parrish et al.
(DMSO-d6): δ 8.31 (d, 1H, J ) 2.3 Hz), 7.89-7.84 (m, 3H), 7.80-
7.75 (m, 2H), 7.65 (s, 2H), 7.15 (d, 1H, J ) 8.8 Hz). MS m/z 283.2
[M + H]+. The intermediate N-[3-nitro-4′-(trifluoromethyl)-4-
biphenylyl]sulfamide was prepared from the aniline following
Hz), 7.62 (d, 2H, J ) 8.8 Hz), 7.07 (s, 2H). MS m/z 353.2 [M +
H]+. Analytical HPLC 95.4% purity, tR ) 8.80.
N-(4′-Chloro-4-biphenylyl)methanesulfonamide (40). The title
compound was prepared as a yellow solid (82%) from N-(4-
bromophenyl)methanesulfonamide47 and (4-chlorophenyl)boronic
1
Method D (69%). H NMR (DMSO-d6): δ 9.62 (s, 1H), 8.44 (d,
1
1H, J ) 2.3 Hz), 8.19 (dd, 1H, J ) 8.8, 2.3 Hz), 8.00 (d, 2H, J )
8.1 Hz), 7.86 (dd, 3H, J ) 8.5, 2.6 Hz), 7.76 (s, 2H). MS m/z
362.0 [M + H]+. A solution of the sulfamide (0.73 mmol) in ethanol
(10 mL) was reduced in a Parr shaker at 50 psi H2 with platinum-
(IV) oxide (0.01 mmol). After 15 min, the reaction mixture was
filtered through celite and concentrated in vacuo. Purification by
reverse phase HPLC afforded the title product as a white solid
acid following Method A. H NMR (DMSO-d6): δ 9.91 (s, 1H),
7.67 (m, 4H), 7.51 (d, 2H, J ) 8.5 Hz), 7.30 (d, 2H, J ) 8.6 Hz),
3.03 (s, 3H). MS m/z 282.0 [M + H]+. Anal. (C13H12ClNO2S) H,
N. Analytical HPLC 95.4% purity, tR ) 7.36.
N-[4′-(2,2,2-Trifluoroethyl)-4-biphenylyl]methanesulfon-
amide (41). To a solution of 4-bromobenzyl bromide (20 mmol)
in 1-methyl-2-pyrrolidinone (25 mL) was added copper(I) iodide
(5.2 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (39
mmol). The reaction mixture was purged with nitrogen and heated
at 80 °C for 24 h. After cooling, the reaction mixture was diluted
with water, and the organics were extracted with hexanes, filtered
through a pad of celite, and concentrated in vacuo. Purification of
the residue by silica gel chromatography (hexanes) gave the
intermediate 4-(2,2,2-trifluoroethyl)bromobenzene as a white solid
(61%, contained ∼15% 4-bromobenzyl bromide). 1H NMR
(CDCl3): δ 7.51 (d, 2H, J ) 8.3 Hz), 7.19 (d, 2H, J ) 8.3 Hz),
3.35 (q, 2H, J ) 10.7 Hz). Intermediate 4-[4′-(2,2,2-trifluoroethyl)-
4-biphenylyl]amine was prepared as a yellow solid from this
bromide and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
following Method A (100%). 1H NMR (CDCl3): δ 7.54 (d, 2H, J
) 8.4 Hz), 7.37 (d, 2H, J ) 8.5 Hz), 7.34 (d, 2H, J ) 8.5 Hz),
6.64 (d, 2H, J ) 8.4 Hz), 5.26 (s, 2H), 3.63 (q, 2H, J ) 11.6 Hz).
MS m/z 252.0 [M + H]+. The title compound was prepared from
4-[4′-(2,2,2-trifluoroethyl)-4-biphenylyl]amine following Method B.
Purification of the residue by silica gel chromatography (35% ethyl
acetate/hexanes), trituration with hexanes, filtration, and concentra-
tion in vacuo afforded the title product as a white solid (94%). 1H
NMR (CDCl3): δ 9.88 (s, 1H), 7.67 (d, 2H, J ) 8.6 Hz), 7.65 (d,
2H, J ) 8.1 Hz), 7.44 (d, 2H, J ) 8.1 Hz), 7.30 (d, 2H, J ) 8.6
Hz), 3.68 (m, 2H, J ) 11.6 Hz), 3.03 (s, 3H). MS m/z 330.2 [M +
H]+. Anal. (C15H14F3NO2S) C, H, N.
1
(81%). H NMR (DMSO-d6): δ 8.40 (s, 1H), 7.80-7.74 (m, 4H),
7.24 (d, 1H, J ) 8.1 Hz), 7.03 (d, 1H, J ) 2.0 Hz), 6.91 (s, 2H),
6.88 (dd, 1H, J ) 8.2, 2.2 Hz), 5.21 (s, 2H). MS m/z 332.2 [M +
H]+. Anal. (C13H12F3N3O2S) C, H, N.
N-[3-(Methylamino)-4′-(trifluoromethyl)-4-biphenylyl]sul-
famide (36). N-Methyl-4-nitro-4′-(trifluoromethyl)-3-biphenylamine
was prepared following Method A using 5-chloro-N-methyl-2-
1
nitroaniline (68%). H NMR (DMSO-d6): δ 8.31 (d, 1H, J ) 4.8
Hz), 8.19 (d, 1H, J ) 9.1 Hz), 8.01 (d, 2H, J ) 8.1 Hz), 7.88 (d,
2H, J ) 8.3 Hz), 7.22 (d, 1H, J ) 1.5 Hz), 7.03 (dd, 1H, J ) 8.8,
1.8 Hz), 3.07 (d, 3H, J ) 5.0 Hz). MS m/z 297.2 [M + H]+. To a
solution of this biphenyl (1.09 mmol) in acetic acid (7 mL) was
added zinc dust (7.63 mmol). The reaction mixure was stirred at
room temperature for 2 h, filtered through celite, and the filter pad
was washed with acetic acid (10 mL) and ethanol (10 mL). The
filtrate was concentrated in vacuo, and the residue was taken up in
ethyl acetate (10 mL) and washed with saturated aqueous sodium
bicarbonate solution (10 mL). The organic layer was dried over
magnesium sulfate and concentrated in vacuo to give the intermedi-
ate 4-amino-4′-(trifluoromethyl)-3-biphenylyl]methylamine as an
1
off-white solid (77%). H NMR (DMSO-d6): δ 7.77 (d, 2H, J )
8.3 Hz), 7.69 (d, 2H, J ) 8.4 Hz), 6.85 (dd, 1H, J ) 7.8, 2.0 Hz),
6.71 (d, 1H, J ) 1.8 Hz), 6.63 (d, 1H, J ) 8.1 Hz), 4.82 (s, 2H),
4.79 (d, 1H, J ) 4.8 Hz), 2.80 (d, 3H, J ) 5.0 Hz). MS m/z 267.0
[M + H]+. A solution of the aniline (0.38 mmol) and sulfamide
(1.9 mmol) in 1,4-dioxane (1.0 mL) was irradiated in the microwave
at 150 °C for 10 min. The reaction mixture was concentrated in
vacuo. Purification of the residue by reverse phase HPLC afforded
the title compound as a pink solid (5%). 1H NMR (DMSO-d6): δ
8.40 (s, 1H), 7.86 (d, 2H, J ) 8.3 Hz), 7.78 (d, 2H, J ) 8.6 Hz),
7.26 (d, 1H, J ) 8.1 Hz), 6.93-6.85 (m, 3H), 6.82 (d, 1H, J ) 1.5
Hz), 5.41 (br s, 1H), 2.80 (s, 3H). MS m/z 346.2 [M + H]+.
Analytical HPLC 97.3% purity, tR ) 6.18.
N-[4′-(Trifluoromethoxy)-4-biphenylyl]methanesulfon-
amide (42). The title compound was prepared from N-(4-bro-
mophenyl)methanesulfonamide47 and 4-(trifluoromethoxy)phenyl
boronic acid following Method A. Purification by reverse phase
HPLC provided the title product as a white powder (25%). 1H NMR
(DMSO-d6): δ 10.10 (s, 1H), 8.16 (d, 2H, J ) 8.6 Hz), 8.13 (d,
2H, J ) 8.6 Hz), 7.85 (d, 2H, J ) 8.4 Hz), 7.36 (d, 2H, J ) 8.3
Hz), 3.08 (s, 3H). MS m/z 332.4 [M + H]+. Anal. (C14H12F3NO3S)
C, H, N.
N-[3-Chloro-4′-(trifluoromethyl)-4-biphenylyl]sulfamide (37).
Crude intermediate 3-chloro-4′-(trifluoromethyl)-4-biphenylamine
was prepared following Method A using 4-bromo-2-chloroaniline.
MS m/z 272.0 [M + H]+. The title compound was prepared as a
white solid from this aniline following Method D with purification
N-{4′-[(Trifluoromethyl)sulfonyl]-4-biphenylyl}methanesul-
fonamide (43). N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]methanesulfonamide was prepared in 30% yield with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following
Method B with purification by flash chromatography (50-100%
ethyl acetate/hexanes). 1H NMR (DMSO-d6): δ 10.05 (s, 1H), 7.62
(d, 2H, J ) 8.5 Hz), 7.20 (d, 2H, J ) 8.5 Hz), 3.03 (s, 3H), 1.28
(s, 12H). MS m/z 298.2 [M + H]+. The title compound was
prepared from this boronate and 1-bromo-4-[(trifluoromethyl)-
sulfonyl]benzene following Method A with purification by reverse
1
by reverse phase HPLC (35%). H NMR (DMSO-d6): δ 9.96 (s,
1H), 7.82 (d, 2H, J ) 8.1 Hz), 7.65 (d, 2H, J ) 8.1 Hz), 7.40-7.36
(m, 4H), 7.20 (dd, 1H, J ) 8.4, 2.2 Hz). MS m/z 351.2 [M + H]+.
Anal. (C13H10ClF3N2O2S) C, H, N.
N-[2-Fluoro-4′-(trifluoromethyl)-4-biphenylyl]sulfamide (38).
Crude intermediate 2-fluoro-4′-(trifluoromethyl)-4-biphenylamine
was prepared following Method A using 4-bromo-3-fluoroaniline.
MS m/z 256.2 [M + H]+. The title compound was prepared as a
white solid from this aniline following Method D with purification
by reverse phase HPLC (35%). 1H NMR (DMSO-d6): δ 10.04 (s,
1H), 7.82 (d, 2H, J ) 8.3 Hz), 7.75 (d, 2H, J ) 8.1 Hz), 7.53 (t,
1H, J ) 8.7 Hz), 7.38 (s, 2H), 7.12 (dd, 1H, J ) 13.2, 2.2 Hz),
7.06 (dd, 1H, J ) 8.5, 2.2 Hz). MS m/z 335.2 [M + H]+. Anal.
(C13H10F4N2O2S) C, H, N.
N-[3,5-Difluoro-4′-(trifluoromethyl)-4-biphenylyl]sulfamide
(39). Crude intermediate 3,5-difluoro-4′-(trifluoromethyl)-4-biphen-
ylamine was prepared following Method A using 4-bromo-2,6-
difluoroaniline. MS m/z 274.0 [M + H]+. The title compound was
prepared as a white solid from this aniline following Method D
with purification by reverse phase HPLC (16%). 1H NMR (DMSO-
d6): δ 8.95 (s, 1H), 7.99 (d, 2H, J ) 8.3 Hz), 7.85 (d, 2H, J ) 8.3
1
phase HPLC (61%). H NMR (DMSO-d6): δ 10.13 (s, 1H), 8.18
(d, 2H, J ) 8.6 Hz), 8.12 (d, 2H, J ) 8.7 Hz), 7.85 (d, 2H, J ) 8.7
Hz), 7.36 (d, 2H, J ) 8.7 Hz), 3.09 (s, 3H). MS m/z 380.2 [M +
H]+. Anal. (C14H12F3NO4S2) C, H, N.
N-4-Biphenylylurea (44). The title compound was prepared as
a white powder from 4-biphenylamine following Method C (27%).
1H NMR (DMSO-d6): δ 8.64 (s, 1H), 7.62 (d, 2H, J ) 8.4 Hz),
7.55 (d, 2H, J ) 8.8 Hz), 7.49 (d, 2H, J ) 8.8 Hz), 7.43 (t, 2H, J
) 7.7 Hz), 7.30 (m, 1H), 5.90 (s, 2H). MS m/z 213.2 [M + H]+.
Analytical HPLC 95.0% purity, tR ) 5.23.
N-[3′-(Trifluoromethyl)-4-biphenylyl]urea (45). The intermedi-
ate 3′-(trifluoromethyl)-4-biphenylamine was prepared as a brown
solid following Method A using 3-trifluoromethylphenyl boronic
acid (48%). 1H NMR (CDCl3): δ 7.76 (s, 1H), 7.69 (m, 1H), 7.50
(m, 2H), 7.41 (d, 2H, J ) 8.6 Hz), 6.76 (d, 2H, J ) 8.5 Hz), 3.60
(br s, 2H). MS m/z 238.0 [M + H]+. The title compound was