A R T I C L E S
Liao et al.
then cooled to room temperature, and the reaction was quenched with
ice water. The resulting solution was then diluted with ethyl acetate
(15 mL) and washed with brine. The organic phase with dried over
Na2SO4, filtered, and concentrated at reduced pressure. The residue
was then purified by preparative TLC (hexane/ether ) 97:3) to provide
19.1 mg (81% yield) of product. 1H NMR (CDCl3, 500 MHz): δ 1.45
(s, 3H), 2.12-2.22 (m, 1H), 2.51-2.57 (m, 1H), 2.71-2.77 (m, 2H),
7.03 (d, J ) 7.6 Hz, 1H), 7.09-7.26 (m, 6H), 7.33 (td, J ) 7.3, 1.4
Hz, 1H), 8.08 (dd, J ) 7.8, 1.0 Hz, 1H). 13C NMR (CDCl3, 125
MHz): δ 26.3, 27.3, 36.5, 50.7, 126.6, 126.8, 126.9, 128.2, 128.8, 128.9,
132.9, 133.3, 142.3, 143.8, 201.6. Chiral HPLC conditions: Chiralcel
AD-H column; solvent, hexane/isopropyl alcohol (96.5/3.5); flow rate,
the smaller dihedral angle of segphos and difluorphos appears
to create complexes that react with higher enantioselectivity than
complexes of related ligands with larger dihedral angles. This
effect has been attributed in previous studies to enhanced steric
effects. It has been proposed that the smaller dihedral angle
causes the aryl groups of the phosphine to project closer to the
incoming substrates.11 Second, the faster reactions of aryl
triflates versus aryl bromides allows the reactions to be
conducted at lower temperature, and this lower temperature leads
to higher enantioselectivity. Third, the identity of the halide or
pseudohalide can affect enantioselectivity by altering the ability
of the complex to undergo transmetalation and by affecting the
stability of the catalyst. Fourth, an appropriate pairing of the
catalyst with the electronic properties of the aryl group, although
empirical, leads to a set of R-arylation processes that encompass
reactions of electron-rich, electron-neutral, and electron-poor
aryl triflates. Fifth, the stability of the ligand toward P-C bond
cleavage affects reaction yield and might affect the stability of
the catalyst toward formation of achiral or less selective chiral
catalysts. Ultimately, the identification and control of a com-
bination factors that dictate enantioselectivity has led to reac-
tions that are selective enough for applications in complex mole-
cule synthesis. Studies on the applications of this reaction are
ongoing.
0.5 mL/min; UV lamp, 254 nm. [R]26 ) +179 (c ) 0.24, CHCl3).
D
Representative Procedure for the Asymmetric Arylation of
Ketones with Aryl Triflates Using Ni(0)/Difluorphos (Table 3, Entry
1). To a screw-capped vial containing difluorphos (10.3 mg, 0.0150
mmol), Ni(COD)2 (3.5 mg, 0.016mmol), NaOtBu (48.0 mg, 0.500mmol),
and 2-methylindanone (36.5 mg, 0.250 mmol) in toluene (2.0 mL) was
added 4-cyanophenyl trifluoromethanesulfonate (188 mg, 0.750 mmol).
The vial was sealed with a cap containing a PTFE septum and removed
from the drybox. The reaction mixture was stirred at 80 °C for 60 h.
The crude reaction mixture was then cooled to room temperature, and
the reaction was quenched with ice water. The resulting solution was
then diluted with ethyl acetate (20 mL) and washed with brine. The
organic phase was dried over Na2SO4, filtered, and concentrated at
reduced pressure. The residue was then purified by chromatography
on silica gel, eluting with hexane/ether (80:20) to provide the 54.6 mg
(84% yield) of the product. 1H NMR (CDCl3, 500 MHz): δ 1.59 (3H,
s), 3.27 (1H, d, J ) 17.4 Hz), 3.48 (1H, d, J ) 17.4 Hz), 7.35-7.39
(3H, m), 7.43 (1H, d, J ) 7.9 Hz), 7.51 (2H, d, J ) 8.4 Hz), 7.60 (1H,
t, J ) 7.4 Hz), 7.74 (1H, d, J ) 7.8 Hz). 13CNMR (CDCl3, 125 MHz):
δ 23.5, 43.3, 52.2, 109.5, 117.7, 124.1, 125.5, 126.1, 127.1, 131.3,
134.0, 134.6, 148.2, 151.0, 206.3. Anal. Calcd. For C17H13NO: C,
82.57; H, 5.30; N, 5.66. Found: C, 82.27; H, 5.28; N, 5.65. Chiral
HPLC conditions: Chiralcel OB-H column; solvent, hexane/isopropyl
Experimental Section
General Methods. Reactions were conducted using standard drybox
1
techniques. H and 13C NMR spectra were recorded in CDCl3 on a
400 or 500 MHz spectrometer with tetramethylsilane or residual
protiated solvent used as a reference, and coupling constants are reported
in hertz (Hz). Chromatographic purifications were performed by flash
chromatography using silica gel (200-400 mesh) or preparative TLC.
The yields of the coupled products included in all tables refer to isolated
yields. Products that had been reported previously were isolated in
greater than 95% purity, as determined by 1H and 13C NMR, and copies
of spectra are provided in the Supporting Information. All 13C NMR
spectra were proton decoupled. Enantioselectivities were measured by
HPLC using the indicated columns and conditions.
Representative Procedure for the Asymmetric Arylation of
Ketones with Aryl Triflates Using Pd(0)/Difluorphos (Table 2, Entry
1). To a screw-capped vial containing difluorphos (8.2 mg, 0.012mmol),
Pd(dba)2 (5.8 mg, 0.010mmol), NaOtBu (19.2 mg, 0.200 mmol), and
2-methyltetralone (16.0 mg, 0.100 mmol) in toluene (2.0 mL) was added
phenyl triflate (31.4 mg, 0.200 mmol). The vial was sealed with a cap
containing a PTFE septum and removed from the drybox. The reaction
mixture was stirred at 60 °C for 48 h. The crude reaction mixture was
alcohol (80/20); flow rate, 1.0 mL/min; UV lamp, 254 nm. [R]26
-56.7 (c ) 0.22, CHCl3).
)
D
Acknowledgment. We thank the NIH (NIGMS GM-58108)
for support of this work. We also thank Takasago Int. Co. for
gifts of segphos and Johnson-Matthey for a gift of palladium
salts.
Supporting Information Available: All experimental proce-
dures and spectroscopic data of new compounds. This material
JA074453G
9
200 J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008