10.1002/chem.201701395
Chemistry - A European Journal
COMMUNICATION
In summary, we have developed an efficient and practical
method for the catalytic enantioselective arylation and
heteroarylation of ketones with organotitanium reagents, which
are prepared by the reaction of aryl- and heteroaryllithiums with
ClTi(OiPr)4. The titanium complex derived from (R)-BTFP-BINOL
(6e) was demonstrated to be an excellent catalyst in terms of
enantioselectivity and activity, providing tertiary diaryl-, aryl
heteroaryl-, and diheteroaryl carbinols in good to high
Keywords: alcohols • ketones • asymmetric catalysis • lithium•
titanium
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enantioselectivity at
2
mol% catalyst loading. As the
organolithium intermediates can be generated by the Br/Li
exchange of bromides or by the lithiation of heteroarenes, the
present reaction permits a straightforward access to a range of
enantioenriched tertiary alcohols from commercially available
low-cost starting materials. The preparative utility of the present
reaction has been shown by the fact that the reaction is
operationally simple and can be conducted on a 10-mmol scale
without any difficulties.
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Experimental Section
General Procedure for Enantioselective Arylation (10 mmol-scale,
Scheme 4). In a glove box, Ti(OiPr)4 (3.20 g, 11.25 mmol) and TiCl4
(0.711 g, 3.75 mmol) were weighed in a flask. The flask was removed
from the glove box and the resulting mixture was dissolved in anhydrous
Et2O (13.7 mL) at 0 °C under argon atmosphere to prepare a Et2O
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mL, 15.0 mmol) for 15 min. After being stirred at room temperature for 15
min, the reaction mixture was cooled again at 0 °C. To this was added
the solution of ClTi(OiPr)3 for 5 min and the reaction mixture was stirred
for 10 min at 0 °C. The stirring was stopped and LiCl was allowed to
almost settle for 5 min. Thus prepared aryltitanium reagent was added to
a solution of ketone 9 (10 mmol) and ligand (R)-6e (100 mg, 0.2 mmol) in
anhydrous Et2O (22 mL) at 0 °C for 3 h using a syringe pump.
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addition. After being stirred further at 0 °C for 18–24 h, the reaction
mixture was poured into aqueous 5% NH4Cl. The resulting mixture was
filtered through a pad of Celite and washed with ethyl acetate (50 mL).
The filtrate was extracted with ethyl acetate (50 mL x 3). The combined
organic layers were washed with aqueous 5% NaHCO3 and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was passed through a
short silica gel column (10% ethyl acetate in hexane) and concentrated
filtrate was purified by Kugelrohr distillation at reduced pressure in the
presence of Na2CO3 (10aa; 150–160 °C/0.2 mmHg, ent-10ab; 130–
140 °C/0.2 mmHg, 10eb; 170 °C/0.2 mmHg, 11b; 110 °C/0.2 mmHg) or
by recrystallization from hexane (13a; mp 74–77 °C, 14a; mp 53–57 °C).
The filtered titanium salts and Celite were washed with 1 N aqueous HCl
(50 mL) and Et2O (50 mL). After filtration, the washing was extracted with
ethyl acetate (50 mL x 2). The combined organic layers were washed
with aqueous 5% NaHCO3 and brine, dried (Na2SO4), and concentrated
in vacuo. The residue was combined with the residue of Kugelrohr
distillation or recrystallization and subjected to silica gel flash
chromatography (toluene) to recover ligand (R)-6e in >85% yield.
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Acknowledgements
This work was supported by KAKENHI (No. 15K05500) from
Ministry of Education, Culture, Sports, Science, and Technology
(MEXT), Japan.
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