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LETTER
C.; Wang, Y. Angew. Chem. Int. Ed. 2007, 46, 5554.
(b) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1473.
ethane were heated in a sealed reaction tube at 130 °C for 24
h.23 Dichloromethane (10 mL) and Na2S (aq sat., 10 mL)
were added. The mixture was filtered over Celite and the
filtrate was washed with brine (2 × 10 mL). The combined
organic layers were dried over MgSO4 and the volatiles were
removed under reduced pressure. The residue was purified
by flash chromatography (pentane–MTBE, 20:1).
(11) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 12634. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang,
D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. (c) Wang, D.-H.; Wasa, M.;
Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(12) Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129.
(13) Vogler, T.; Studer, A. Synthesis 2008, 1979.
(14) Shi and Yu used Cu(II) salts as stoichiometric oxidants, see
refs. 10 and 11.
(15) (a) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439.
(b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.;
Inoue, Y. Org. Lett. 2001, 3, 2579. (c) Kalyani, D.; Deprez,
N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 7330. (d) Shabashov, D.; Daugulis, O. Org. Lett. 2005,
7, 3657. (e) Ackermann, L.; Althammer, A.; Born, R.
Angew. Chem. Int. Ed. 2006, 45, 2619. (f) Ackermann, L.;
Born, R.; Álvarez-Bercedo, P. Angew. Chem. Int. Ed. 2007,
46, 6364.
2-(2-Bromo-6-deuterophenyl)pyridine
To a solution of 2-(2,6-dibromophenyl)pyridine (313 mg,
1.0 mmol) in THF (20 mL) at –78 °C was added dropwise
n-BuLi (1.68 M solution in hexanes, 0.60 mL, 1.00 mmol).23
The mixture was stirred for 30 min. Then, D2O (2.0 mL) was
added and stirring was continued for additional 30 min. The
mixture was allowed to warm to r.t., and EtOAc (10 mL) and
brine (20 mL) were added. The mixture was extracted with
EtOAc (3 × 20 mL), dried over MgSO4, and the volatiles
were removed under reduced pressure. The residue was
purified by flash chromatography (pentane–MTBE, 50:1)
and the product was obtained as a yellow oil (0.181 g, 0.68
mmol, 77%). The product was used without any further
characterization.
(16) General Experimental Procedure
2-(2,6-Dideuterophenyl)pyridine (D2-1)
The corresponding boronic acid (1.00 mmol), TEMPO (156
mg, 1.00 mmol), KF (58 mg, 1.0 mmol), Pd(OAc)2 (5.6 mg,
25 mmol), the pyridine derivative (0.25 mmol), and AcOH (1
mL) were stirred in a sealed tube at 50 °C for 24 h or 72 h,
respectively. Water (3 mL) and brine (1 mL) were added and
the mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried over MgSO4 and the
volatiles were removed under reduced pressure. The residue
was purified by flash chromatography.
To a solution of 2-(2-bromo-6-deuterophenyl)pyridine (160
mg, 0.68 mmol) in THF (10 mL) at –78 °C was added
dropwise n-BuLi (1.68 M solution in hexanes, 0.4 mL, 0.68
mmol).23 The mixture was stirred for 30 min. Then, D2O (1.0
mL) was added and stirring was continued for additional 30
min. The mixture was allowed to warm to r.t., and EtOAc
(5 mL) and brine (10 mL) were added. The mixture was
extracted with EtOAc (3 × 10 mL), dried over MgSO4, and
the volatiles were removed under reduced pressure. The
residue was purified by flash chromatography (pentane–
MTBE, 50:1) and the product was obtained as a colorless oil
(0.104 g, 0.66 mmol, 97%, 88 atom% D). 1H NMR (300
MHz, CDCl3): d = 8.68 (d, J = 4.78 Hz, 1 H, aryl-H), 7.69
(d, J = 3.52 Hz, 2 H, aryl-H), 7.42 (m, 3 H, aryl-H), 7.19 (m,
1 H, aryl-H). 13C NMR (75 MHz, CDCl3): d = 157.4 (C),
149.7 (C-H), 139.3 (C), 136.7 (CH), 129.0 (CH), 128.7
(CH), 126.6 (J = 23 Hz, CD), 122.1 (CH), 120.5 (CH). ESI-
HRMS: m/z calcd for C11H7D2N [M + H]+: 157.0933; found:
157.0939.
(17) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (b) Garcia-Cuadrado, D.; de Mendoza, P.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc.
2007, 129, 6880.
(18) Gómez, M.; Granell, J.; Martinez, M. J. Chem. Soc., Dalton
Trans. 1998, 37.
(19) Determination of the Kinetic Isotope Effects
According to the general experimental procedure with 2-(2-
deuterophenyl)pyridine (D-1, 39 mg, 0.25 mmol) and
phenylboronic acid (122 mg, 1.00 mmol) for 72 h. Flash
chromatography (pentane–EtOAc, 20:1 → 10:1) gave a
mixture of 2a and D-2a as a yellow oil (17 mg, 65%). The
isotope effect was determined by integration of the ESI-
HRMS data in consideration of the isotope pattern of 2a. The
deuterated species D-2a and compound 2a were obtained in
a ratio of 4.5:1. According to GP 1 with 2-ethoxy-2-
phenylpyridine (6, 10 mg, 50 mmol), 2-(2-ethoxy-6-
deuterophenyl)pyridine (D-6, 10 mg, 50 mmol) and
phenylboronic acid (24 mg, 0.2 mmol) for 4 h. The ratios of
D-6 to 6 (0.87:1) were determined before the reaction (0 h)
and after a reaction time of 4 h (1.05:1) by integration of the
corresponding ESI-HRMS data in consideration of the
isotope pattern of 6. The kinetic isotope effect was
calculated to be 1.21.
2-(2-Ethoxy-6-deuterophenyl)pyridine (D-6)
2-(2-Ethoxyphenyl)pyridine (6, 93 mg, 0.47 mmol), NBS
(0.10 g, 0.56 mmol) and Pd(OAc)2 (5.4 mg, 24 mol) in
MeCN (10 mL) were heated in a reaction tube at 120 °C for
10 h.22 The solvent was removed under reduced pressure,
and the residue was purified by flash chromatography
(pentane–MTBE, 10:1). Crude 2-(2-bromo-6-ethoxy-
phenyl)pyridine was obtained as a pale yellow oil (96 mg)
and used for the next reaction without any further
characterization. To a solution of crude 2-(2-bromo-6-
ethoxyphenyl)pyridine (86 mg, 0.31 mmol) in THF (10 mL)
at –78 °C was added dropwise n-BuLi (1.3 M solution in
hexanes, 0.48 mL, 0.62 mmol).23 The mixture was allowed
to warm to –40 °C and stirred for 30 min. Then, D2O (0.5
mL) was added and stirring was continued for additional 30
min. The mixture was allowed to warm to r.t., and EtOAc (5
mL) was added. The organic layer was washed with brine,
dried over MgSO4, and the volatiles were removed under
reduced pressure. The crude product was purified by flash
chromatography (pentane–MTBE, 20:1) and D-6 was
obtained as a pale yellow oil (43 mg, 46% over two steps, 94
atom% D determined via ESI-MS). IR (neat): 3036, 2980,
2933, 2881, 2363, 2341, 1578, 1474, 1452, 1421, 1391,
1285, 1250, 1190, 1138, 1111, 1088, 1040, 1026, 990, 924,
874, 812, 795, 746, 733, 679, 611, 552 cm–1. 1H NMR (300
MHz, CDCl3): d = 8.68 (m, 1 H, aryl-H), 7.88 (m, 1 H, aryl-
(20) As a side product the doubly arylated product is always
formed (<15% with respect to the monoarylated compound).
We assume that the primary kinetic isotope effect for the
second arylation and the first arylation should be similar.
Therefore, the measured value of 4.5 is slightly too high
since 2a is consumed faster than D-2a. However, the error
should be smaller than 12%. Hence the primary kinetic
isotope effect for the first arylation is about 4.0–4.5 to 1.
(21) 2-(2,6-Dideuterophenyl)pyridine (D2-1) and 2-(2,6-
Dibromophenyl)pyridine
2-(2-Bromophenyl)pyridine22 (466 mg, 2.0 mmol),
Cu(OAc)2 (363 mg, 2.0 mmol), and 1,1,2,2-tetra-bromo-
Synlett 2008, No. 18, 2841–2845 © Thieme Stuttgart · New York