9556
H. Hikawa, Y. Yokoyama / Tetrahedron 66 (2010) 9552e9559
(10 mg, 0.0125 mmol), methylboronic acid (30 mg, 0.5 mmol), and KF
(58mg,1.0mmol) inTHF(1mL)wasstirredatroom temperaturefor 1
day. The reaction mixture was poured into water and extracted with
EtOAc. The organic layer was washed with brine and concentrated in
vacuo. The residue was purified by preparative TLC (silica gel, hex-
anes/EtOAc)togive3a(69mg, 71%)asanoff-whitesolidand5a(6mg,
7%) as a colorless oil.
brine and concentrated in vacuo. The residue was purified by pre-
parative TLC (silica gel, hexanes/EtOAc) to give 3c (137 mg, 60%) as
a white solid and 5c (52 mg, 23%) as an off-white solid.
4.4.1. Benzyl 4-(5-bromo-3,30-bipyridin-2-yl)piperazine-1-carboxyl-
ate (3c). Mp 138e140 ꢀC; IR (KBr) (cmꢁ1) 1707 (CO); 1H NMR
(400 MHz, CDCl3):
d 2.90e3.20 (m, 4H), 3.30e3.50 (m, 4H), 5.11 (s,
2H), 7.27e7.40 (m, 6H), 7.59 (d, J¼2.2 Hz, 1H), 7.88e7.94 (m, 1H),
4.2.1. Benzyl
boxylate (3a). Mp 64e65 ꢀC; IR (KBr) (cmꢁ1) 1703 (CO); 1H NMR
(400 MHz, CDCl3): 2.26 (s, 3H), 3.00e3.20 (m, 4H), 3.50e3.70 (m,
4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-car-
8.30 (d, J¼2.2 Hz, 1H), 8.59e8.62 (m, 1H), 8.80e8.82 (m, 1H); 13C
NMR (400 MHz, CDCl3):
d 43.1, 48.7, 67.0, 112.8, 123.4, 125.3, 127.7,
d
127.9, 128.3, 134.0, 134.9, 136.4, 141.4, 147.8, 148.7, 149.2, 155.1,
158.2; MS-EI: m/z 452 (Mþ, 30%), 454 (Mþþ2, 30%), 91 (BP); HRMS-
EI: m/z (Mþ) calcd for C22H21BrN4O2 452.0848, found 452.0848.
4H), 5.17 (s, 2H), 7.27e7.40 (m, 5H), 7.53 (d, J¼2.2 Hz, 1H), 8.17 (d,
J¼2.2 Hz, 1H); 13C NMR (400 MHz, CDCl3):
d 18.0, 43.7, 49.1, 67.0,
113.5, 126.6, 127.7, 127.8, 128.3, 136.5, 141.3, 145.7, 155.1, 159.8; MS-
EI: m/z 389 (Mþ, 20%), 391 (Mþþ2, 20%), 91 (BP); HRMS-EI: m/z
(Mþ) calcd for C18H20BrN3O2 389.0739, found 389.0739.
4.4.2. Benzyl 4-(3,5-bis(3-pyridyl)pyridin-2-yl)piperazine-1-carbox-
ylate (5c). Mp 131e133 ꢀC; IR (KBr) (cmꢁ1) 1700 (CO); 1H NMR
(400 MHz, CDCl3):
d 3.00e3.30 (m, 4H), 3.30e3.50 (m, 4H), 5.12
4.2.2. Benzyl 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylate
(s, 2H), 7.27e7.50 (m, 7H), 7.68 (d, J¼2.2 Hz, 1H), 7.86 (d, J¼7.8 Hz,
(5a). IR (neat) (cmꢁ1) 1697 (CO); 1H NMR (400 MHz, CDCl3):
d 2.22
1H), 7.98 (d, J¼7.8 Hz, 1H), 8.50 (d, J¼2.2 Hz, 1H), 8.62 (s, 2H), 8.84
(s, 3H), 2.25 (s, 3H), 3.00e3.10 (m, 4H), 3.60e3.70 (m, 4H), 5.17 (s,
2H), 7.25 (d, J¼1.4 Hz, 1H), 7.30e7.40 (m, 5H), 7.97 (d, J¼2.2 Hz, 1H);
(s, 1H), 8.88 (s, 1H); 13C NMR (400 MHz, CDCl3):
d 43.3, 48.8, 67.1,
123.5, 123.7, 123.8, 127.4, 127.8, 128.0, 128.4, 133.0, 133.7, 135.1,
136.4, 138.0, 145.4, 147.6, 148.7,148.9,149.0,155.2, 159.2; MS-EI: m/z
451 (Mþ, 28%), 261 (BP); HRMS-EI: m/z (Mþ) calcd for C27H25N5O2
451.2008, found 451.2010.
13C NMR (400 MHz, CDCl3):
d 17.5, 17.8, 44.1, 49.7, 67.1, 124.6, 127.6,
127.8, 128.0, 128.5, 136.8, 140.3, 145.3, 155.4, 159.4; MS-EI: m/z 325
(Mþ, 28%), 135 (BP); HRMS-EI: m/z (Mþ) calcd for C19H23N3O2
325.1790, found 325.1792.
4.5. Procedure for the synthesis of 3d and 5d (Table 3, entry 4)
4.3. Procedure for the synthesis of 3b and 5b (Table 3, entry 3)
A mixture of 2a (228 mg, 0.5 mmol), [1,10-bis(diphenylphos-
phino)ferrocene]palladium(II) dichloride dichloromethane com-
plex (20 mg, 0.025 mmol), 4-methoxyphenylboronic acid (91 mg,
0.6 mmol), and Na2CO3 (159 mg, 1.5 mmol) in THF (1.5 mL) and H2O
(0.75 mL) was reflux for 3 h. After cooling, the reaction mixture was
poured into water and extracted with EtOAc. The organic layer was
washed with brine and concentrated in vacuo. The residue was
purified by preparative TLC (silica gel, hexanes/EtOAc) to give 3d
(140 mg, 58%) as a white solid and 5d (63 mg, 25%) as a pale yellow
oil.
A mixture of 2b (105 mg, 0.25 mmol), [1,10-bis(diphenylphos-
phino)ferrocene]palladium(II) dichloride dichloromethane com-
plex (10 mg, 0.0125 mmol), phenylboronic acid (40 mg,
0.325 mmol), and KF (38 mg, 0.65 mmol) in THF (1 mL) was stirred
for 1 day. The reaction mixture was poured into water and
extracted with EtOAc. The organic layer was washed with brine and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, hexanes/EtOAc) to give 3b (86 mg, 82%) as
a white solid and 5b (16 mg, 15%) as a white solid.
4.3.1. tert-Butyl 4-(5-bromo-3-phenylpyridin-2-yl)piperazine-1-car-
4.5.1. Benzyl 4-(5-bromo-3-(4-methoxyphenyl)pyridin-2-yl)pipera-
boxylate (3b). Mp 98e100 ꢀC; IR (KBr) (cmꢁ1) 1692 (CO); 1H NMR
zine-1-carboxylate (3d). Mp 119e120 ꢀC; 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
d
1.43 (s, 9H), 3.00e3.20 (m, 4H), 3.30e3.50 (m,
IR (KBr) (cmꢁ1) 1702 (CO);
d 3.00e3.10 (m, 4H), 3.30e3.50 (m, 4H),
4H), 7.32e7.38 (m, 1H), 7.40e7.46 (m, 2H), 7.52e7.57 (m, 2H), 7.57
3.85 (s, 3H), 5.11 (s, 2H), 6.95 (d, J¼9.0 Hz, 2H), 7.28e7.40 (m, 5H),
(d, J¼2.2 Hz, 1H), 8.23 (d, J¼2.2 Hz, 1H); 13C NMR (400 MHz, CDCl3):
7.48 (d, J¼9.0 Hz, 2H), 7.55 (d, J¼2.4 Hz,1H), 8.21 (d, J¼2.4 Hz,1H); 13C
d
28.3, 48.5, 79.6, 112.3, 127.6, 127.9, 128.5, 128.9, 138.4, 141.4, 146.8,
NMR (400 MHz, CDCl3): d 43.4, 48.4, 55.2, 67.0, 112.5, 114.2, 127.8,
154.7, 158.0; MS-EI: m/z 417 (Mþ, 51%), 419 (Mþþ2, 51%), 261 (BP);
HRMS-EI: m/z (Mþ) calcd for C20H24BrN3O2 417.1052, found
417.1045.
127.9, 128.4, 128.8, 130.4, 136.5, 141.1, 146.3, 155.2, 157.9, 159.2; MS-
EI: m/z 481 (Mþ, 47%), 483 (Mþþ2, 48%), 291 (BP); HRMS-EI: m/z
(Mþ) calcd for C24H24BrN3O3 481.1001, found 481.0996.
4.3.2. tert-Butyl 4-(3,5-diphenylpyridin-2-yl)piperazine-1-carboxyl-
4.5.2. Benzyl 4-[3,5-bis(4-methoxyphenyl)pyridin-2-yl]piperazine-1-
ate (5b). Mp 190e192 ꢀC; IR (KBr) (cmꢁ1) 1686 (CO); 1H NMR
carboxylate (5d). IR (neat) (cmꢁ1) 1701 (CO); 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
1.44 (s, 9H), 3.00e3.20 (m, 4H), 3.30e3.40 (m,
CDCl3): d 3.00e3.20 (m, 4H), 3.40e3.60 (m, 4H), 3.85 (s, 3H), 3.86 (s,
4H), 7.30e7.40 (m, 2H), 7.40e7.50 (m, 4H), 7.56 (d, J¼7.8 Hz, 2H),
3H), 5.12 (s, 2H), 6.90e7.00 (m, 4H), 7.26e7.34 (m, 5H), 7.48 (d,
J¼8.8 Hz, 2H), 7.55 (d, J¼8.8 Hz, 2H), 7.63 (d, J¼2.4 Hz, 1H), 8.39 (d,
7.63 (d, J¼7.8 Hz, 2H), 7.71 (s, 1H), 8.46 (d, J¼2.4 Hz, 1H); 13C NMR
(400 MHz, CDCl3):
d
28.3, 48.7, 79.5, 126.4, 126.8, 127.2, 127.5, 127.9,
J¼2.4Hz,1H);13CNMR(400MHz,CDCl3):
d43.6, 48.6,55.2, 67.0,114.1,
128.8, 128.9, 130.2, 137.7, 138.1, 139.7, 144.4, 154.8, 158.5; MS-EI: m/z
415 (Mþ, 39%), 259 (BP); HRMS-EI: m/z (Mþ) calcd for C26H29N3O2
415.2260, found 415.2261.
114.4, 126.8, 127.5, 127.8, 127.9, 128.4, 129.1, 130.2, 131.8, 136.6, 137.6,
143.6, 155.3, 158.1, 159.0, 159.1; MS-EI: m/z 509 (Mþ, 50%), 319 (BP);
HRMS-EI: m/z (Mþ) calcd for C31H31N3O4 509.2315, found 509.2312.
4.4. Procedure for the synthesis of 3c and 5c (Table 3, entry 3)
4.5.3. Benzyl 4-[5-bromo-3-(4-cyanophenyl)pyridin-2-yl]piperazine-
1-carboxylate (3e) (Table 3, entry 5). A mixture of 2a (228 mg,
0.5 mmol), [1,10-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride dichloromethane complex (20 mg, 0.025 mmol), 4-cya-
nophenylboronic acid (88 mg, 0.6 mmol), and Na2CO3 (159 mg,
1.5 mmol) in THF (1.5 mL) and H2O (0.75 mL) was reflux for 3 h. After
cooling, the reaction mixture was poured into water and extracted
with EtOAc. The organic layer was washed with brine and
A mixture of 2a (228 mg, 0.5 mmol), [1,10-bis(diphenylphosphino)
ferrocene]palladium(II) dichloride dichloromethane complex
(20 mg, 0.025 mmol), pyridin-3-ylboronic acid (74 mg, 0.6 mmol),
andNa2CO3 (159mg,1.5mmol)inTHF(1.5mL)andH2O(0.75mL)was
reflux for 3 h. After cooling, the reaction mixture was poured into
water and extracted with EtOAc. The organic layer was washed with