2700
M.G. Kamau et al. / Tetrahedron 68 (2012) 2696e2703
98.3%, tR¼5.706 min (method B). HRMS (ESI) calcd for C17H23N2
(MþH)þ¼255.1856, found 255.1856.
(method A); 96.0%, tR¼7.126 min (method B). HRMS (ESI) calcd for
C20H15ClF5N2 (MþH)þ¼413.0838, found 413.0843.
4.2. General procedure 2 in the Radley’s Cooled Carousel 12
ReactionStationÔ for preparation of tertiarycarbinamines 5dei
4.2.5. 2-(2-Chloro-4-fluorophenyl)-1-(5-chloropyridin-2-yl)-1-(3-
fluoro-5-(trifluoromethyl)phenyl)ethanamine (5h). Free based to
yield 5h (872 mg, 49%) as a yellow oil. 1H NMR (500 MHz, CD3OD)
Aryl or heteroaryl bromide (4 mmol) was charged in oven dried
Radley’s synthesis tube that was equipped with a stir bar under
a stream of nitrogen. Anhydrous diethyl ether was added and the
reaction mixture was cooled to ꢀ78 ꢁC. n-BuLi (1.6 M in hexanes,
2.5 mL, 4.00 mmol) was added dropwise and the reaction mixture
was stirred at ꢀ78 ꢁC for 10 min. A solution of aryl or heteroaryl
nitrile in THF (4 mmol) was added dropwise and the reaction
mixture was stirred at ꢀ78 ꢁC for 2 h. TMSCl (0.550 mL, 4.00 mmol)
was added to the reaction mixture at ꢀ78 ꢁC and the reaction
mixture was allowed to warm up to 0 ꢁC. The reaction mixture was
cooled to ꢀ78 ꢁC, benzylmagnesium chloride in either THF or ether
(2 mmol) or benzyl zinc(II) bromide in ether (2 mmol), was added
dropwise, stirred at ꢀ78 ꢁC for 2 h, and then stirred at rt for 12 h.
The reaction mixture was worked up and purified as in general
procedure 1.
d
8.55 (d, J¼2.2 Hz, 1H), 7.76 (dd, J¼8.5, 2.6 Hz, 1H), 7.54e7.49 (m,
2H), 7.44e7.40 (m,1H), 7.28 (d, J¼8.0 Hz,1H), 7.06 (dd, J¼8.7, 2.6 Hz,
1H), 6.92e6.87 (m, 1H), 6.85e6.80 (m, 1H), 3.87 (d, J¼13.9 Hz, 1H),
3.84 (d, J¼13.9 Hz, 1H). 13C NMR (126 MHz, CD3OD)
d 164.3, 163.8
(d, J¼247.0 Hz), 162.9 (d, J¼248.0 Hz), 151.9 (d, J¼6.7 Hz), 148.5,
138.0, 137.5 (d, J¼10.5 Hz), 134.9 (d, J¼8.6 Hz), 133.1 (qd, J¼33.4,
7.6 Hz), 132.1, 131.7 (d, J¼2.9 Hz), 124.0, 124.9 (qd, J¼271.8, 2.9 Hz),
121.4e121.0 (m), 119.4 (d, J¼22.9 Hz), 117.6 (d, J¼25.7 Hz), 114.6 (d,
J¼21.0 Hz), 112.2 (dq, J¼24.8, 3.8 Hz), 64.9, 43.7. HPLC purity: 91.9%,
tR¼8.839 min (method A); 94.3%, tR¼7.731 min (method B). HRMS
(ESI) calcd for C20H14Cl2F5N2 (MþH)þ¼447.0449, found 447.0455.
4.2.6. 3-(2-Amino-2-(5-chloropyridin-2-yl)-2-(3-fluoro-5-(tri-
fluoromethyl)phenyl)ethyl)benzonitrile (5i). Yielded TFA salt of 5i
(1110 mg, 66%) as a pale yellow oil. 1H NMR (500 MHz, CD3OD)
d
8.56 (dd, J¼2.5, 0.6 Hz,1H), 7.74 (dd, J¼8.5, 2.6 Hz,1H), 7.59 (s,1H),
4.2.1. 1-(3,5-Bis(trifluoromethyl)phenyl)-1-(5-chloropyridin-2-yl)-2-
phenylethanamine (5d). Yielded TFA salt of 5d (760 mg, 43%) as
7.54 (dd, J¼8.6, 0.6 Hz, 1H), 7.51e7.45 (m, 2H), 7.30e7.24 (m, 3H),
7.14 (d, J¼8.3 Hz,1H), 3.85 (d, J¼13.3 Hz,1H), 3.61 (d, J¼13.3 Hz,1H).
a colorless viscous oil. 1H NMR (500 MHz, CD3OD)
d
8.62 (dd, J¼2.4,
13C NMR (126 MHz, CD3OD)
d
164.0, 163.8 (d, J¼247.0 Hz), 152.2 (d,
0.7 Hz, 1H), 8.17e8.11 (m, 3H), 8.04 (dd, J¼8.6, 2.5 Hz, 1H), 7.65 (dd,
J¼8.6, 0.6 Hz, 1H), 7.33e7.23 (m, 3H), 6.93e6.86 (m, 2H), 4.12 (d,
J¼13.9 Hz, 1H), 4.00 (d, J¼13.9 Hz, 1H). 13C NMR (126 MHz, CD3OD)
J¼6.7 Hz), 148.5, 139.7, 138.0, 136.7, 135.6, 133.2 (qd, J¼32.4, 8.6 Hz),
132.0, 131.5, 129.9, 123.8, 124.9 (qd, J¼271.8, 2.9 Hz), 121.0e120.6
(m), 119.8, 119.1 (d, J¼22.9 Hz), 112.9, 112.2 (dq, J¼24.8, 3.8 Hz), 64.4
(d, J¼1.9 Hz), 47.9. HPLC purity: 93.3%, tR¼8.239 min (method A);
97.1%, tR¼7.031 min (method B). HRMS (ESI) calcd for C21H15ClF4N3
(MþH)þ¼420.0885, found 420.0889.
d
156.7, 149.0, 143.4, 139.2, 134.2, 133.6, 133.8 (q, J¼33.4 Hz, 2C),
132.0, 130.1, 129.4, 129.3e129.2 (m, J¼2.9 Hz, 2C), 125.0e124.8 (m),
124.7e124.3 (m, J¼7.6, 3.8, 3.8 Hz), 124.6 (q, J¼272.8 Hz, 2C), 66.7,
44.6. HPLC purity: 93.7%, tR¼9.191 min (method A); 95.4%,
tR¼7.839 min (method B). HRMS (ESI) calcd for C21H16ClF6N2
(MþH)þ¼445.0901, found 445.0904.
Compounds 5jem were prepared similarly following general
procedure 2 but the reactions were run in a round-bottomed flask
instead of using Radley’s Cooled Carousel 12 Reaction StationÔ.
4.2.2. 1-(5-Chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phe-
nyl)-2-phenylethanamine (5e). Yielded TFA salt of 5e (462 mg, 29%)
as a white amorphous solid with analytical data as for compound
9e. HPLC purity: 95.2%, tR¼8.793 min (method A); 97.1%,
tR¼7.208 min (method B). HRMS (ESI) calcd for C20H16ClF4N2
(MþH)þ¼395.0933, found 395.0936.
4.2.7. 1-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(thiazol-2-
yl)ethanamine (5j). Yielded TFA salt of 5j (24%). 1H NMR (600 MHz,
CD3OD)
d
7.93 (d, J¼3.2 Hz, 1H), 7.80 (d, J¼3.2 Hz, 1H), 7.64 (m, 3H),
7.29 (t, J¼7.3 Hz, 1H), 7.25 (t, J¼7.4 Hz, 2H), 6.95 (d, J¼7.2 Hz, 2H),
4.05 (d, J¼14.3 Hz, 1H), 3.94 (d, J¼14.3 Hz, 1H). 13C NMR (151 MHz,
CD3OD)
d
170.6, 164.2 (d, J¼249 Hz), 144.3 (d, J¼5.9 Hz), 144.1, 134.4
(qd, J¼33.7, 8.3 Hz), 133.7, 132.1, 130.0, 129.5, 124.5 (q, J¼271.0 Hz).
123.9, 120.8 (m), 119.5 (d, J¼24.4 Hz), 115.0 (dd, J¼24.9, 2.9 Hz),
65.6, 46.9. HPLC purity: 98.9%, tR¼7.061 min (method C17); 99.1%,
tR¼8.789 min (method D17). HRMS (ESI) calcd for C18H15F4N2S
(MþH)þ¼367.0887, found 367.0880.
4.2.3. 1-(5-Chloropyridin-2-yl)-2-phenyl-1-(3-(trifluoromethoxy)
phenyl)ethanamine (5f). Yielded TFA salt of 5f (364 mg, 23%) as
a colorless viscous oil. 1H NMR (500 MHz, CD3OD)
d
8.56 (dd, J¼2.4,
0.7 Hz,1H), 7.96 (dd, J¼8.5, 2.4 Hz,1H), 7.64e7.58 (m,1H), 7.54e7.50
(m, 2H), 7.45 (s, 1H), 7.41 (dt, J¼8.3, 1.0 Hz, 1H), 7.31e7.17 (m, 3H),
6.93e6.82 (m, 2H), 3.98 (d, J¼14.4 Hz, 1H), 3.92 (d, J¼14.4 Hz, 1H).
4.2.8. 1-(3-Fluoro-5-(trifluoromethyl)phenyl)-1-(5-methylfuran-2-
yl)-2-phenylethanamine (5k). Yield of 5k (71%). 1H NMR (400 MHz,
13C NMR (126 MHz, CD3OD)
d
157.4, 151.0 (d, J¼1.9 Hz), 148.5, 142.9,
138.8, 134.0, 133.8, 132.3, 132.0, 129.9, 129.2, 127.4, 125.0, 122.9,
121.6, 122.0 (q, J¼255.6 Hz), 66.6, 44.8. HPLC purity: 92.7%,
tR¼8.844 min (method A); 97.9%, tR¼7.213 min (method B). HRMS
(ESI) calcd for C20H17ClF3N2O (MþH)þ¼393.0976, found 393.0979.
CDCl3)
d
7.42 (br s, 1H), 7.25 (d, J¼10.0 Hz, 1H), 7.14e7.04 (m, 4H),
6.77e6.70 (m, 2H), 5.97 (d, J¼3.0 Hz, 1H), 5.86e5.80 (m, 1H), 3.41 (d,
J¼13.2 Hz, 1H), 3.09 (d, J¼13.2 Hz, 1H), 2.21 (s, 3H). 13C NMR
(101 MHz, CDCl3)
d
162.5 (d, J¼247.6 Hz), 157.1, 152.0, 150.2 (d,
J¼6.6 Hz), 135.8, 132.0 (qd, J¼32.9, 8.0 Hz), 130.8, 128.2, 127.1, 123.6
(d, J¼272.7 Hz), 119.5, 117.7 (d, J¼22.7 Hz), 111.4 (d, J¼24.8 Hz), 107.7,
106.4, 59.4, 48.1,13.8. LCeMS (ESI), tR¼3.16 min, 347.13 (MꢀNH2þH).
HRMS (ESI) calcd for C20H15F4O (MꢀNH2þH)þ¼347.1054, found
347.1064.
4.2.4. 1-(5-Chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phe-
nyl)-2-(2-fluorophenyl)ethanamine (5g). Free based to yield 5g
(660 mg, 40%) as
a
brown oil. 1H NMR (500 MHz, CD3OD)
d
8.55e8.52 (m, 1H), 7.75 (dd, J¼8.6, 2.5 Hz, 1H), 7.56 (s, 1H), 7.52 (d,
J¼8.6 Hz, 1H), 7.49e7.44 (m, 1H), 7.28 (d, J¼8.3 Hz, 1H), 7.21e7.14
(m, 1H), 6.97e6.88 (m, 2H), 6.83 (td, J¼7.6, 1.5 Hz, 1H), 3.75 (s, 2H).
4.2.9. 1-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(4-(tri-
fluoromethyl)pyridin-2-yl)ethanamine (5l). Yielded TFA salt of 5l
13C NMR (126 MHz, CD3OD)
d
164.0, 163.8 (d, J¼247.0 Hz), 164.1 (d,
J¼245.1 Hz), 151.8 (d, J¼6.7 Hz), 148.5, 138.0, 134.0 (d, J¼3.8 Hz),
133.1 (qd, J¼33.4, 8.6 Hz), 132.1, 130.1 (d, J¼8.6 Hz), 124.9 (d,
J¼3.8 Hz), 124.4 (d, J¼15.3 Hz), 123.8, 124.9 (qd, J¼271.8, 2.9 Hz),
121.2e120.9 (m), 119.3 (d, J¼22.9 Hz), 116.3 (d, J¼22.9 Hz), 112.2
(dq, J¼24.8, 3.8 Hz), 64.5, 41.1. HPLC purity: 91.9%, tR¼8.434 min
(67%). 1H NMR (500 MHz, CD3OD)
d
8.84 (d, J¼5.1 Hz, 1H), 7.91 (s,
1H), 7.78 (d, J¼5.1 Hz, 1H), 7.67 (t, J¼5.1 Hz, 2H), 7.64 (d, J¼8.0 Hz,
1H), 7.27e7.25 (m, 1H), 7.24e7.19 (m, 2H), 6.95e6.75 (m, 2H), 4.08
(d, J¼14.3 Hz, 1H), 4.04 (d, J¼14.3 Hz, 1H). 13C NMR (126 MHz,
CD3OD)
d
164.2 (d, J¼249.9 Hz), 160.2, 151.6, 144.1 (d, J¼7.1 Hz),