The Journal of Organic Chemistry
Article
(dd, J = 2.4, 1.5 Hz, 1H), 7.46−7.40 (m, 2H), 7.29 (dd, J = 15.3,
7.8 Hz, 2H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.7,
149.8, 147.3, 145.8, 143.8, 138.4, 136.4, 131.7, 131.6, 130.5, 125.9, 20.7.
Typical Procedure for the Preparation 2-(2-Bromo-4-
chlorobenzoyl)pyridine (3f).25 In a 250 mL round-bottomed
flask, 2-bromo-4-chlorobenzoyl chloride (5.0 g, 19.7 mmol) and
18.0 mL of THF were placed. Next, a solution of 2-pyridylzinc bromide
(5.3 g, 23.6 mmol) in THF (15.0 mmol) was added into the reaction
flask via a syringe. The resulting mixture was stirred at 0 °C for 4 h and
quenched with saturated NH4Cl solution, then extracted with ether
(13.0 mL × 3). The combined organic layers were washed with
saturated NaHCO3 solution and brine and then dried with anhydrous
Na2SO4. The crude product was purified by column chromatography
(PE/EA = 5:1) to give 3f as yellow oil: 4.8 g (82.2%); 1H NMR (400
MHz, CDCl3) δ 8.68−8.65 (m, 1H), 8.16 (td, J = 7.9, 1.0 Hz, 1H), 7.91
(td, J = 7.7, 1.7 Hz, 1H), 7.65 (t, J = 1.1 Hz, 1H), 7.49 (ddd, J = 7.6,
4.8, 1.2 Hz, 1H), 7.41 (d, J = 1.1 Hz, 2H); 13C NMR (101 MHz,
CDCl3) δ 194.7, 153.1, 149.2, 138.6, 137.1, 136.8, 132.8, 130.8, 127.4,
127.4, 123.9, 120.8.
1H), 7.41 (td, J = 7.5, 1.7 Hz, 1H), 7.25−7.16 (m, 3H), 7.13−7.01 (m,
2H), 6.13 (s, 1H), 5.51 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
160.0, 148.1, 142.1, 137.6, 133.0, 129.8, 129.9, 128.3, 123.3, 122.9,
121.6, 73.2; HPLC (Chiralcel AD-H column, hexane/i-PrOH: 96/4,
0.7 mL min−1, 220 nm) t1 = 25.6 min, t2 = 28.6 min.
o-(2-Bromo-4-chlorophenyl)-2-pyridinemethanol (4f). 1H
NMR (400 MHz, CDCl3) δ 8.60−8.55 (m, 1H), 7.64 (td, J = 7.7,
1.7 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.27−
7.26 (m, 1H), 7.25−7.22 (m, 2H), 6.19 (s, 1H), 5.52 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 159.4, 148.3, 141.3, 137.6, 134.3, 132.4,
130.1, 128.3, 123.3, 123.3, 121.4, 72.7; HPLC (Chiralcel OD-H
column, hexane/i-PrOH: 96/4, 0.8 mL min−1, 220 nm) t1 = 14.4 min,
t2 = 22.8 min; HRMS calcd for C12H9BrClNO (M + H)+ 297.9630,
found 297.9631.
m-Tolyl-2-pyridylmethanol29 (4g): 1H NMR (400 MHz,
CDCl3) δ 8.59−8.54 (m, 1H), 7.62 (td, J = 7.7, 1.7 Hz, 1H), 7.25−
7.14 (m, 5H), 7.09 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 5.27 (s, 1H), 2.33
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.2, 147.1, 143.7, 138.4,
136.9, 128.7, 128.8, 127.8, 124.3, 122.5, 121.9, 75.9, 21.8; HPLC
(Chiralcel AD-H column, hexane/i-PrOH: 92/8, 0.7 mL min−1,
220 nm) t1 = 16.3 min, t2 = 24.7 min.
Typical Procedure for the Asymmetric Hydrogenation. To a
20 mL Schlenk tube were added [RuCl2(benzene)]2 (5.0 mg,
0.01 mmol) and (S)-Xyl-SunPhos (17.2 mg, 0.02 mmol). The tube
was vacuumed and purged with nitrogen three times before addition
of freshly distilled and freeze-and-thaw degassed DMF (1.5 mL). The
resulting mixture was heated at 100 °C for 10 min to form a reddish
brown solution. After the solution was cooed to room temperature,
(S)-Daipen (6.9 mg, 0.02 mmol) was added and the mixture was
stirred for 3 h at 25 °C; the solvent was then removed under reduced
pressure (1 Torr) to give the catalyst as a brownish yellow solid. The
catalyst was dissolved in degassed i-PrOH (8.0 mL), and then the
solution was equally divided into four vials which contained 1 mmol of
substrate, and the base (t-C4H9OK) was added. Then the vials were
transferred into an autoclave. The autoclave was purged five times with
H2, and the required pressure of H2 was set. The autoclave was stirred
under specified reaction conditions. After being cooled to ambient
temperature and careful release of the hydrogen, the autoclave was
opened and the solvent was evaporated. The enantiomeric excess was
determined by HPLC after passing the residue through a short pad of
silica gel column with petroleum ether and ethyl acetate.
p-Tolyl-2-pyridylmethanol29 (4h): 1H NMR (400 MHz,
CDCl3) δ 8.57−8.54 (m, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.28−7.24
(m, 2H), 7.21−7.08 (m, 5H), 5.73 (s, 1H), 2.33 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 161.4, 147.9, 140.4, 137.6, 136.9, 129.3, 127.1,
122.4, 121.4, 77.4, 77.1, 76.8, 74.9, 21.2; HPLC (Chiralcel AD-H
column, hexane/i-PrOH: 92/8, 0.7 mL min−1, 220 nm) t1 = 19.3 min,
t2 = 23.4 min.
o-(4-Methoxyphenyl)-2-pyridinemethanol6b (4i): 1H NMR
(400 MHz, CDCl3) δ 8.56 (d, J = 4.6 Hz, 1H), 7.65−7.57 (m, 1H),
7.30−7.24 (m, 2H), 7.16 (ddd, J = 8.4, 7.4, 2.7 Hz, 2H), 6.89−6.83
(m, 2H), 5.71 (d, J = 3.1 Hz, 1H), 5.22 (d, J = 3.8 Hz, 1H), 3.78 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 161.2, 159.3, 147.8, 136.9,
135.6, 128.5, 122.4, 121.4, 114.0, 74.6, 55.4; HPLC (Chiralcel AD-H
column, hexane/i-PrOH: 92/8, 0.8 mL min−1, 220 nm) t1 = 25.4 min,
t2 = 30.8 min.
o-(4-Trifuoromethylphenyl)-2-pyridinemethanol23 (4j): 1H
NMR (400 MHz, CDCl3) δ 8.56 (d, J = 4.8 Hz, 1H), 7.68−7.48
(m, 5H), 7.25−7.11 (m, 2H), 5.80 (s, 1H), 5.43 (s, 1H); 13C NMR
(101 MHz, CDCl3) δ 160.1, 148.2, 147.3, 137.3, 130.0, 127.4, 125.6,
125.2, 123.0, 121.4, 74.6; HPLC (Chiralcel AD-H column, hexane/
i-PrOH: 95/5, 0.8 mL min−1, 220 nm) t1 = 16.3 min, t2 = 23.9 min.
o-Tolyl-3-pyridylmethanol9 (4k): 1H NMR (400 MHz, CDCl3)
δ 8.40 (d, J = 1.9 Hz, 1H), 8.31 (dd, J = 4.8, 1.4 Hz, 1H), 7.61 (d, J =
7.9 Hz, 1H), 7.49−7.45 (m, 1H), 7.23−7.16 (m, 3H), 7.15−7.11 (m,
1H), 5.96 (s, 1H), 4.50 (s, 1H), 2.20 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 148.4, 148.0, 141.0, 139.6, 135.5, 135.7, 130.7, 127.8, 126.8,
126.6, 123.5, 70.5, 19.4; HPLC (Chiralcel AD-H column, hexane/
i-PrOH: 92/8, 0.7 mL min−1, 220 nm) t1 = 21.7 min, t2 = 27.3 min.
o-Tolyl-4-pyridylmethanol30 (4l): 1H NMR (400 MHz, CDCl3)
δ 8.39 (dd, J = 4.6, 1.6 Hz, 2H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (ddd,
J = 4.5, 1.3, 0.7 Hz, 2H), 7.22−7.12 (m, 3H), 5.97 (s, 1H), 2.29 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 152.7, 149.6, 140.6, 135.5,
131.1, 128.3, 127.7, 126.3, 121.9, 72.2, 19.6; HPLC (Chiralcel AD-H
column, hexane/i-PrOH: 96/4, 0.7 mL min−1, 220 nm) t1 = 55.7 min,
t2 = 60.1 min.
o-Tolyl-2-pyridylmethanol6b (4a): 1H NMR (400 MHz,
CDCl3) δ 8.59 (d, J = 4.9 Hz, 1H), 7.60 (td, J = 7.7, 1.7 Hz, 1H),
7.25−7.15 (m, 5H), 7.03 (d, J = 7.9 Hz, 1H), 5.97 (s, 1H), 5.18 (s,
1H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.1, 147.9,
140.8, 136.9, 136.4, 131.0, 128.5, 127.9, 126.3, 122.5, 121.5, 72.3, 19.0;
HPLC (Chiralcel AD-H column, hexane/i-PrOH: 96/4, 0.7 mL min−1,
220 nm) t1 = 22.6 min, t2 = 29.8 min.
o-(2-Methoxyphenyl)-2-pyridinemethanol20 (4b): 1H NMR
(400 MHz, CDCl3) δ 8.52 (dd, J = 4.6, 1.1 Hz, 1H), 7.57 (dd, J = 7.6,
1.7 Hz, 1H), 7.33−7.27 (m, 2H), 7.23 (dd, J = 8.0, 1.7 Hz, 1H), 7.16−
7.12 (m, 1H), 6.97−6.87 (m, 2H), 6.22 (s, 1H), 5.30 (s, 1H), 3.84 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 161.6, 156.6, 147.7, 136.7,
131.9, 128.7, 127.8, 122.2, 121.5, 120.9, 110.7, 69.9, 55.5; HPLC
(Chiralcel AD-H column, hexane/i-PrOH: 92/8, 0.8 mL min−1, 220 nm)
t1 = 17.7 min, t2 = 21.9 min.
o-(2-Fulorophenyl)-2-pyridinemethanol26 (4c): 1H NMR
(400 MHz, CDCl3) δ 8.57−8.49 (m, 1H), 7.63 (td, J = 7.7, 1.7 Hz,
1H), 7.41 (td, J = 7.5, 1.7 Hz, 1H), 7.25−7.16 (m, 3H), 7.13−7.01 (m,
2H), 6.13 (s, 1H), 5.51 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
147.9, 137.6, 129.9, 129.1, 128.6, 128.2, 124.5, 122.7, 121.2, 115.6,
115.4, 68.3; HPLC (Chiralcel AD-H column, hexane/i-PrOH: 96/4,
0.7 mL min−1, 220 nm) t1 = 22.9 min, t2 = 28.5 min.
o-Tolyl-4-pyrazylmethanol31 (4m): 1H NMR (400 MHz,
CDCl3) δ 8.68 (d, J = 14.9 Hz, 1H), 8.58−8.44 (m, 2H), 7.44−7.32
(m, 2H), 7.21 (d, J = 5.7 Hz, 2H), 6.08 (s, 1H), 2.39 (d, J = 9.9 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 148.4, 148.0, 141.0, 139.2,
135.0, 130.8, 127.8, 126.6, 126.4, 123.6, 70.8, 19.5; HPLC (Chiralcel
AD-H column, hexane/i-PrOH: 92/8, 0.7 mL min−1, 220 nm) t1 =
21.4 min, t2 = 22.2 min.
o-(2-Chlorophenyl)-2-pyridinemethanol27 (4d): 1H NMR
(400 MHz, CDCl3) δ 8.62−8.49 (m, 1H), 7.61 (td, J = 7.8, 1.7 Hz,
1H), 7.46−7.35 (m, 2H), 7.28−7.07 (m, 4H), 6.28 (d, J = 3.8 Hz,
1H), 5.64 (d, J = 3.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 159.8,
147.9, 140.7, 137.4, 132.8, 129.6, 128.9, 128.8, 127.3, 122.8, 121.4,
70.9; HPLC (Chiralcel AD-H column, hexane/i-PrOH: 96/4, 0.7 mL
min−1, 220 nm) t1 = 23.7 min, t2 = 27.9 min.
o-(4-Chlorophenyl)-2-pyridinemethanol32 (5): 1H NMR
(400 MHz, CDCl3) δ 8.54 (dd, J = 6.2, 2.4 Hz, 1H), 7.62 (td, J =
7.7, 3.8 Hz, 1H), 7.33−7.27 (m, 4H), 7.22−7.17 (m, 1H), 7.15−7.11
(m, 1H), 5.72 (s, 1H), 5.38 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
160.6, 148.0, 141.8, 137.1, 133.8, 128.8, 128.5, 122.7, 121.3, 74.4;
HPLC (Chiralcel AD-H column, hexane/i-PrOH: 95/5, 0.8 mL min−1,
220 nm) t1 = 20.0 min, t2 = 26.6 min.
o-(2-Bromophenyl)-2-pyridinemethanol28 (4e): 1H NMR
(400 MHz, CDCl3) δ 8.57−8.49 (m, 1H), 7.63 (td, J = 7.7, 1.7 Hz,
615
dx.doi.org/10.1021/jo202204j | J. Org. Chem. 2012, 77, 612−616