SONOPO ET AL.
7
was added. The mixture was thoroughly degassed with nitro-
gen for 15 minutes. Pd(PPh3)4Cl2 (0.59 g, 0.84 mmol) was
then added to the degassed solution under a nitrogen atmo-
sphere, followed by aqueous K2CO3 (1 M, 6.9 mL). The reac-
tion mixture was stirred at 90°C for 14 hours, poured into
H2O, and extracted with EtOAc (3 X 50 mL). The combined
organic layers were washed with brine (20 mL), dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel 20% (EtOAc/Hex-
ane) to give the desired product 6 as solid (3.85 g, 72%).
extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by column chro-
matography on silica gel Hexane/EtOAc (6/4) to give the
product (151.88 mg, 0.386 mmol, 90%). The HPLC analysis
showed the chemical purity to be 99.5%, and it eluted at RT
8.97 minutes. M.P:224‐225°C, 1H‐NMR (400 MHz, CDCl3):
δ 8.92 (1H, d, J = 2.3 Hz), 8.51 (1H, d, J = 2.3 Hz), 8.24
(1H, dd, J = 2.3, 8.1 Hz), 7.99 (1H, d, J = 8.1 Hz), 7.95‐7.92
(4H, m), 7.90 (1H, d, J = 2.3 Hz), 6.34, (2H, br s), 3.23 (3H,
s). 13C‐NMR (100 MHz, CDCl3): δ 157.1, 150.2, 147.2,
145.1, 142.5, 138.5, 138.4, 137.3, 136.9, 127.6 (2 X C),
126.1 (2 X C), 123.1, 120.8, 115.8, 43.6. HRMS calculated
for C18H14F3N3O2S (M + H) 394.0821, found 394.0833.
1
M.P:120‐123°C; H‐NMR (400 MHz, CDCl3): δ 8.81 (1H,
d, J = 2.3 Hz), 8.18 (1H, dd, J = 2.3 Hz, 8.1 Hz), 7.79
(1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 8.1 Hz), 7.47 (1H, d,
J = 2.3 Hz), 4.55 (2H, brs); 13C‐NMR (100 MHz, CDCl3):
δ 154.4, 149.9, 149.6, 147.8, 140.3, 139.1, 137.6, 135.7,
120.8, 118.3, 109.0.
5.7 | Synthesis of 4‐bromophenyl [14C]methyl sulfide
([14C]‐9)
5.5 | 3‐(6‐(trifluoromethyl)pyridin‐3‐yl)‐5‐(4,4,5,5‐
tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridin‐2‐amine (7)
Triethylamine (5.93 mg, 0.0556 mmol) and methyl iodide
(5.00 mg, 0.0352 mmol, 92.5 MBq) were added to a stirred
solution of bromothiophenol (5.50 mg, 0.0293 mmol) in
dry acetonitrile (20 mL) at room temperature. The reaction
mixture was stirred for 12 hours after which TLC showed
no starting material remaining. The reaction mixture was
acidified with HCl (3 mL, 2 M) and extracted with ethyl ace-
tate (3 × 10 mL). The combined ethyl acetate layer was
washed with water (10 mL), dried under anhydrous Na2SO4,
and purified on silica gel column using hexane to EtOAc ratio
(8:2) solvent mixture. The product was obtained as a white
solid (5.35 mg, 0.0264 mmol, 85.1 MBq, 90%). The product
was analyzed by HPLC, UV detector 254 nm, 99% pure, RT
17.98 min, β‐Ram detector (99.5% pure), and the isolated
product co‐eluted with an authentic sample of unlabeled 2
using the HPLC method described earlier.
To a round bottom flask (25 mL), fitted with a condenser
under argon were added 5‐bromo‐6’‐(trifluoromethyl)‐3‐3’‐
bipyridin‐2‐amine (6) (0.40 g, 1.20 mmol) and dry DMF
(20 mL). To the mixture were added bis (pinacolato)diboron
(0.366 g, 1.44 mmol) and sodium acetate (0.295 g,
3.60 mmol), and argon was bubbled into the mixture for
20 minutes. To the degassed mixture was added PdCl2(dppf)
(97.99 mg, 0.12 mmol,10 mol%) under argon atmosphere,
and the mixture was heated to 60°C in an oil bath for
24 hours. The reaction mixture was cooled to room tempera-
ture then dilute with water and extracted with ethyl acetate
(3 × 30 mL). The combined extracts were washed with water,
then brine and dried over MgSO4, filtered, and evaporated.
The crude mixture was isolated as
a brown solid
(219.09 mg, 0.60 mmol) by silica gel chromatography
using DCM:EtOAc:MeOH (20:4:1) as the eluent. M.P:
1
248‐250°C; H‐NMR (400 MHz, CDCl3): δ 8.82 (1H, d,
5.8 | 4‐bromophenyl [14C]methyl sulfoxide ([14C]‐10)
J = 2.3 Hz), 8.46 (1H, dd, J = 2.3 Hz, 8.1 Hz), 7.99
(1H, d, J = 8.1 Hz), 7.79 (2H, overlapping), 5.30 (2H, brs),
1.33 (12H, s); 13C‐NMR (100 MHz, CDCl3): δ 156.8,
153.5, 149.9, 147.7, 145.3, 137.7, 136.1, 122.7, 120.7,
119.9, 116.8, 84.1, 24.8. HRMS calculated for
C17H18BF3N3O2 (M + H) 366.1513, found 366.1605.
To a solution of oxone (5 equiv) in water (3 mL) at 5°C was
added a solution of phenyl sulfide [14C]‐9 (5.35 mg,
0.0264 mmol, 85.1 MBq) in methanol (3 mL), and the reac-
tion mixture stirred at room temperature for 5 hours. When
the reaction was completed methanol was removed on a
rotary evaporator at 40°C, and the remaining aqueous layer
was extracted with dichloromethane (3 × 10 mL). The com-
bined organic layers were dried over Na2SO4, concentrated
to ca 3 mL, filtered through a plug of silica gel, and the silica
gel was washed with dichloromethane (30 mL). The filtrate
was concentrated, and the resulting solid was dried under
vacuum at room temperature to provide (5.46 mg,
0.0232 mmol, 68.1 MBq, 80%) of the desired product. The
product was analyzed by HPLC, UV detector 254 nm, 99%
pure, RT 11.90 min, β‐Ram detector (99.9% pure), and the
isolated product co‐eluted with an authentic sample of
unlabeled 3 using the HPLC method described earlier.
5.6 | 3‐(6‐(trifluoromethyl)pyridin‐3‐yl)‐5‐(4‐
(methylsulfonyl)phenyl)pyridin‐2‐amine (8)
To a solution of aryl 3 (100 mg, 0.429 mmol) in dioxane/H2O
(3:1) (10 mL) was added boronate ester 7 (172.32 mg,
0.472 mmol, 1.1 equiv), and the mixture was thoroughly
degassed with nitrogen for 15 minutes. To the degassed mix-
ture was added PdCl2(dppf) (175.17 mg, 0.214 mmol,0.5
equiv) under nitrogen atmosphere, followed by K2CO3
(177.87 mg, 1.29 mmol, 3. 0 equiv). The reaction mixture
was stirred at 110°C for 16 hours, poured into H2O, and