Molecular Diversity
tert-butoxide and anhydrous DMF at 100 °C for 3 h. The
reaction cocktail was poured into cool water, extracted by
dichloromethane, filtered, concentrated and purified by sil-
ica gel column chromatography to give a white solid in 61%
yield. Finally, the white solid (4a–d, 1 eq) was dissolved
in dichloromethane (10 mL), which was cooled to 0 °C.
The desired compounds (6a–h) were obtained by slowly
adding deuterated 4-chloro-3-(trifluoromethyl) phenyl iso-
cyanate (5a–b, 1 eq) into the stirred cooling solution and
then reacting at room temperature for 12 h. The structure of
compounds 6a–h was identified by MS and NMR.
1H), 9.23 (s,1H); 13C NMR (125 MHz, DMSO-d6) (ppm):
δ 109.07, 114.46, 120.83, 123.56, 132.46, 137.49, 139.78,
148.15, 150.82, 152.89, 152.91, 164.24, 166.41; HRMS
+
calculated for C21H12D O3N4ClF3 [M+H] 470.1250,
5
found 470.1236.
4
-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl-2, 6-d2) ure-
ido) phenoxy)-N-methylpicolinamide (6c) White solid
1
(
3.4 g, yield 84%); H NMR (500 MHz, DMSO-d6) (ppm):
δ 2.75 (d, 3H, J ꢀ3.6 Hz), 7.11–7.14 (m, 3H), 7.15 (s, 1H),
.56–7.59(m, 3H), 8.47(d, 1H, J ꢀ4.4Hz), 8.73(s, 1H), 8.97
s, 1H), 9.18(s, 1H);13CNMR(125MHz, DMSO-d6)(ppm):
δ 26.44, 109.10, 114.45, 120.96, 121.89, 132.33, 137.49,
39.62, 148.28, 150.81, 152.90, 164.22, 166.39; ESI–MS:
7
(
Spectral data
1
(
+
m/z)ꢀ467.11 [M+H] .
4
-(4-aminophenoxy)-N-(methyl-d3) picolinamide (4a)
1
Yellow oil liquid (yield 65%); H NMR (500 MHz, CDCl3)
ppm): δ 3.69 (s, 2H), 6.70–6.71 (d, 2H), 6.87–6.92 (m, 3H),
4
-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl-2, 6-d2) ure-
(
ido) phenoxy)-N-(methyl-d3)-picolinamide (6d) White
7
.67 (s, 1H), 8.32–8.34 (d, 1H); ESI–MS: (m/z)ꢀ247.12
1
solid (3.0 g, yield 74%); H NMR (500 MHz, DMSO-d6)
+
[
M+H] .
(
3
ppm): δ 7.14–7.18 (m, 3H), 7.37 (s, 1H), 7.58–7.60 (m,
H), 8.50 (d, 1H, J ꢀ4.4 Hz), 8.73 (s, 1H), 9.00 (s, 1H),
9.22 (s, 1H); C NMR (125 MHz, DMSO-d6) (ppm): δ
4
-(4-aminophenoxy-2, 6-d2)-N-(methyl-d3) picolinamide
1
3
1
(4b) Yellow oil liquid (yield 58%); H NMR (500 MHz,
108.65, 114.00, 120.51, 121.43, 131.87, 137.03, 139.17,
CDCl3) (ppm): δ 3.70 (s, 2H), 6.71 (s, 2H), 6.91–6.92 (m,
1
47.83, 150.35, 152.44, 163.80, 165.94; ESI–MS: (m/z)ꢀ
1
H), 7.66–7.67 (d, 1H), 8.32–8.34 (d, 1H); ESI–MS: (m/z)ꢀ
+
+
470.12 [M+H] .
249.13 [M+H] .
4
-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl-2, 6-d2) ure-
4
-(4-aminophenoxy)-N-methylpicolinamide Yellow oil
1
ido) phenoxy-2, 6-d2)-N-(methyl-d3)-picolinamide (6e)
White solid (3.0 g, yield 74%); H NMR (500 MHz, DMSO-
liquid (yield 56%); H NMR (500 MHz, DMSO-d ) (ppm):
δ 2.93 (s, 3H), 6.79–6.81 (d, 2H), 6.87–6.89 (d, 2H),
6
1
d6) (ppm): δ 7.12–7.13 (m, 1H), 7.36 (d, 1H, J ꢀ1.6 Hz),
6.98–6.99 (d, 1H), 7.52 (s, 1H), 8.40–8.41 (d, 1H); ESI–MS:
+
7.57–7.60 (m, 3H), 8.48 (d, 1H, J ꢀ4.4 Hz), 8.71 (s, 1H),
(
m/z)ꢀ244.10 [M+H] .
-(4-aminophenoxy-2, 6-d2)-N-methylpicolinamide (4d)
8
.98 (s, 1H), 9.20 (s, 1H); 13C NMR (125 MHz, DMSO-d6)
4
(ppm): δ 109.10, 114.45, 120.84, 132.33, 137.48, 139.62,
148.18, 150.80, 152.90, 164.25, 166.39; ESI–MS: (m/z)ꢀ
1
Yellow oil liquid (yield 61%); H NMR (500 MHz, CDCl3)
ppm): δ 2.99–3.00 (d, 3H), 6.75 (s, 2H), 6.92–6.93 (dd,
+
(
472.14 [M+H] .
1
H), 7.67–7.68 (d, 1H), 8.33–8.34 (d, 1H); ESI–MS: (m/z)ꢀ
+
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phe-
noxy-2, 6-d2)-N-methylpicolinamide (6f) White solid
(1.4 g, yield 36%); H NMR (500 MHz, DMSO-d6) (ppm):
246.11 [M+H] .
1
4
-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phe-
noxy)-N-(methyl-d3)-picolinamide (6a) (CM4307) White
solid (1.4 g, yield 36%); H NMR (500 MHz, DMSO-d6)
δ 2.76 (d, 3H, J=4.0 Hz), 7.12–7.16 (m, 1H), 7.36 (d, 1H,
J=2.0 Hz), 7.57–7.65 (m, 4H), 8.09 (d, 1H, J=2.0 Hz), 8.48
(d, 1H, J=4.8 Hz), 8.72–8.74 (m, 1H), 8.98 (s, 1H), 9.20
(s, 1H); 13C NMR (125 MHz, DMSO-d6) (ppm): δ 25.97,
108.63, 113.99, 120.37, 123.09, 131.98, 137.01, 139.31,
1
(
7
ppm): δ 7.13–7.17 (m, 3H), 7.36 (d, 1H, J ꢀ2.0 Hz),
.57–7.66 (m, 4H), 8.11 (d, 1H, J ꢀ4.8 Hz), 8.49 (d, 1H,
J=4.4Hz), 8.74(d, 1H, J ꢀ4.4Hz), 9.01(s, 1H), 9.23(s, 1H);
1
3
C NMR (125 MHz, DMSO-d6) (ppm): δ 109.07, 114.47,
147.71, 150.34, 152.42, 152.44, 163.74, 165.93; HRMS cal-
+
117.23, 120.94, 122.76, 127.26, 132.46, 137.51, 139.78,
culated for C21H D2O3N4ClF3 [M+H] 467.1061, found
1
5
1
48.24, 150.83, 152.89, 152.92, 164.24, 166.41; HRMS cal-
467.1048.
+
culated for C21H14D3O3N4ClF3 [M+H] 468.1124, found
4
-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl-2, 6-d2) ure-
468.1113.
ido) phenoxy-2, 6-d2)-N- methylpicolinamide (6g) White
solid (3.5 g, yield 87%); H NMR (500 MHz, DMSO-
1
4
-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phe-
noxy-2, 6-d2)-N-(methyl-d3)-picolinamide (6b) White
solid (3.2 g, yield 79%); H NMR (500 MHz, DMSO-d6)
d6) (ppm): δ 2.76 (d, 3H, J=4.0 Hz), 7.12–7.16 (m, 1H),
7.36 (d, 1H, J=2.0 Hz), 7.57–7.63 (m, 3H), 8.48 (d, 1H,
1
1
3
(
8
ppm): δ 7.14–7.15 (m, 1H), 7.37 (s, 1H), 7.59–7.67 (m, 4H),
.12 (s, 1H), 8.50 (d, 1H, J ꢀ4.4 Hz), 8.75 (s, 1H), 9.01 (s,
J=4.4 Hz), 8.73–8.74 (m, 1H), 8.98 (s, 1H), 9.20 (s, 1H);
C
NMR (125 MHz, DMSO-d6) (ppm): δ 25.99, 108.66, 114.00,
1
23