Catalytic enantioselective synthesis of diarylmethanols from Aryl bromides and aldehydes by using organolithium reagents

Article abstract of DOI:10.1002/ejoc.201001254

A general method has been developed for preparing enantioenriched secondary alcohols by starting from aryl bromides and aldehydes. Aryl bromides were first treated with BuLi, and the resulting aryllithium reagents were mixed with titanium tetraisopropoxide and magnesium bromide. The reaction of aldehydes with the resulting mixed titanium reagents, in the presence of 3-(3,5- diphenylphenyl)-H₈-BINOL (2 mol-%) and titanium tetraisopropoxide, furnished the corresponding alcohols in high enantioselectivities and in high yields. Copyright

Full text of DOI:10.1002/ejoc.201001254

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001254
Catalytic Enantioselective Synthesis of Diarylmethanols from Aryl Bromides
and Aldehydes by Using Organolithium Reagents
Yuya Nakagawa,[a] Yusuke Muramatsu,[a] and Toshiro Harada*[a]
Keywords: Alcohols / Aldehydes / Asymmetric catalysis / Lithium / Titanium
A general method has been developed for preparing enantio-
enriched secondary alcohols by starting from aryl bromides
and aldehydes. Aryl bromides were first treated with BuLi,
and the resulting aryllithium reagents were mixed with tita-
nium tetraisopropoxide and magnesium bromide. The reac-
tion of aldehydes with the resulting mixed titanium reagents,
in the presence of 3-(3,5-diphenylphenyl)-H8-BINOL (2 mol-
%) and titanium tetraisopropoxide, furnished the corre-
sponding alcohols in high enantioselectivities and in high
yields.
Introduction
Enantiomerically enriched diarylmethanols are impor-
tant constituents and precursors of biologically active com-
pounds. In recent years, the catalytic enantioselective aryl-
ation of aldehydes has attracted great attention as a
straightforward method for the synthesis of these alcohols
by which a carbon–carbon bond and a stereogenic center
are produced simultaneously.[1] Several efficient catalytic
arylation methods have been developed by using phenyllith-
ium,[2] diphenylzinc,[3] arylboronic acids,[4,5] arylaluminium
reagents,[6] arylzinc bromides,[7] and aryl Grignard rea-
gents,[8,9] as aryl sources. However, additional reaction steps
are required to prepare these arylation reagents. Some of
them are commercially available but often quite expensive.
The enantioselective arylation of aldehydes by employing
aryllithium reagents generated in situ from common aryl
bromides by Br/Li exchange serves as a more practical and
versatile method (Scheme 1). Recently, Walsh and co-
workers clearly demonstrated the utility and practicality of
the approach by developing a chiral amino alcohol cata-
lyzed highly enantioselective, one-pot arylation method in
which aryl butylzinc reagents [ArZn(nBu)] were generated
from aryl bromides (ArBr) by successive treatment with
nBuLi, ZnCl2, and additional nBuLi.[10,11]
Scheme 1. Catalytic enantioselective arylation of aldehydes by
using aryl bromides as aryl source.
enantioselectivity by the reaction of aldehydes with the
mixed titanium reagents in the presence of DPP-H8-BINOL
1 (2 mol-%) and titanium tetraisopropoxide.
Results and Discussion
A recent report from this laboratory showed that Grig-
nard reagents can be used in the enantioselective arylation
of aldehydes by using a titanium(IV) catalyst derived from
DPP-H8-BINOL 1 (2 mol-%) in the presence of excess tita-
nium tetraisopropoxide [Equation (1)].[8b,8c] The reaction
protocol involves the slow addition of a ca. 1:2 mixture of
an aryl Grignard reagent (Et2O solution) and titanium
tetraisopropoxide to a solution of an aldehyde, ligand 1
(2 mol-%), and titanium tetraisopropoxide in CH2Cl2 at
0 °C. When a mixed titanium reagent derived from PhLi
(cyclohexane/Et2O solution) was used in the reaction of 1-
naphthaldehyde under these conditions, the corresponding
phenylation product was obtained only in 50% ee. However,
a high selectivity (95% ee) was obtained by using PhLi after
treatment with magnesium bromide.[8b,8c] The order of mix-
ing was not critical; treatment of PhLi first with titanium
tetraisopropoxide and then with magnesium bromide also
afforded the product in 94% ee and in 94% yield.
Herein, we wish to report an alternative method in which
in situ generated aryllithium reagents are used after mixing
with titanium tetraisopropoxide and magnesium bromide.
Starting from aryl bromides, a variety of diarylmethanols
as well as other benzylic alcohols can be obtained in high
[a] Department of Chemistry and Materials Technology, Kyoto
Institute of Technology,
Matsugasaki, Sakyo-ku, 606-8585 Kyoto, Japan
Fax: +81-75-724-7580
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001254.
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Y. Nakagawa, Y. Muramatsu, T. Harada
SHORT COMMUNICATION
Table 1. Enantioselective arylation of benzaldehyde starting with
aryl bromides 2a,b.[a]
Entry Aryl bromide
1
Time Product Yield
ee
[%]
[mol-%] [h][b]
[%]
1[c]
2
3
4
5
2a
2a
2b
2b
2b
2b
2
2
2
4
2
2
2
2
2
2
3
4
5a
5a
5b
5b
5b
5b
88
95
78
77
93
87
75
92
86
90
88
92
6
(1)
[a] Unless otherwise noted, reactions were carried out by treatment
of 2a,b (1.5 equiv.) with nBuLi (1.5 equiv.) in THF at –78 °C fol-
lowed by mixing the resulting aryllithium reagents 3 successively
with Ti(OiPr)4 (2.5 equiv.) and MgBr2 (1.5 equiv.) and subsequent
removal of solvents in vacuo. After dissolution in CH2Cl2 and Et2O
with additional Ti(OiPr)4 (1.5 equiv.), the resulting mixed titanium
reagents were slowly added to a CH2Cl2 solution of benzaldehyde
(1 mmol), 1, and Ti(OiPr)4 (1.5 equiv.). The reaction mixture was
stirred further for 1 h before workup. [b] Time for slow addition.
[c] The reaction was carried out without removal of THF in vacuo.
Based on these results, we examined the arylation of
benzaldehyde (4a) starting with p-bromotoluene (2a) [Equa-
tion (2)]. Treatment of 2a (1.5 equiv.) with nBuLi
(1.5 equiv.) in THF at –78 °C afforded aryllithium 3a. To
avoid an undesirable alkylation of 3a with concurrently pro-
duced butyl bromide, it was mixed successively with tita-
nium tetraisopropoxide (2.5 equiv.) in CH2Cl2 and magne-
sium bromide (1.5 equiv.) in Et2O at –78 °C. Addition of
the resulting mixed titanium reagent to a CH2Cl2 solution
of 4a, ligand 1 (2 mol-%), and titanium tetraisopropoxide
(1 equiv.) at 0 °C for 2 h followed by additional 1 h of stir-
ring afforded diarylmethanol 5a in high yield but with a
moderate enantioselectivity (75% ee) (Table 1, Entry 1). In
our previous study, the use of Grignard reagents in Et2O
was necessary to obtain a high enantioselectivity; the use of
the reagents in THF caused a significant decrease in
enantioselectivity.[8] To circumvent the detrimental effect of
THF, the solvent system was modified. Thus, when the
mixed titanium reagent derived from aryllithium 3a was
employed after the removal of THF in vacuo and dissol-
ution in CH2Cl2 and Et2O with additional titanium tetra-
isopropoxide (to replace its partial loss in evacuation of
THF), 5a was obtained with increased enantioselectivity
(92% ee) and in high yield (Entry 2). Application of this
protocol to the reaction of m-bromotoluene (2b) and 4a re-
sulted in a slightly lower selectivity (86% ee) of the corre-
sponding diarylmethanol 5b (Entry 3). However, a higher
selectivity (up to 92% ee) could be attained either by using
4 mol-% of ligand 1 (Entry 4) or by elongation of the time
for the slow addition (Entries 5 and 6).
hydes 4a–d [Equation (3), Table 2]. Not only tolyl bromides
2a,b but also phenyl bromides, bearing a halogen atom
(2c,d) or a methoxy group (2e), or 2-naphthyl bromide (2h)
could be employed in the arylation of 4a to give the corre-
sponding diarylmethanols 5a–e,h in high yields and high
enantioselectivities (86–95% ee) (Entries 1–5 and 8). Al-
though aryllithium intermediates bearing a cyano group are
thermally unstable, mixed titanium reagents derived from
bromobenzonitriles 2f,g were stable at room temperature
during the slow addition, successfully employed in the reac-
tion of 4a to furnish functionalized diarylmethanols 5f,g
with high enantioselectivity (Entries 6 and 7). The reaction
using nBuLi in hexane afforded butylation product 5i with
relatively high selectivity (Entry 9). The mixed titanium rea-
gent prepared from 2c also underwent a highly enantio-
selective addition to α,β-unsaturated aldehyde 4c and ali-
phatic aldehyde 4d to give allylic alcohol 5k (96% ee) and
benzylic alcohol 5l (96% ee), respectively (Entries 11 and
12), whereas a lower selectivity was observed in the reaction
of the heterocyclic aldehyde 4b (Entry 10).
(3)
Conclusions
We have developed a versatile method for the enantio-
selective arylation of aldehydes starting from readily avail-
able aryl bromides. Mixed titanium reagents, derived from
(2)
Under the optimized conditions with 2 mol-% of ligand aryllithium intermediates, titanium tetraisopropoxide, and
1 (i.e., Entry 2 or 6 in Table 1), reactions were carried out magnesium bromide, underwent highly enantioselective ad-
for various combinations of aryl bromides 2a–h and alde- dition to aldehydes. The reactions could be carried out at
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Diarylmethanols from Aryl Bromides and Aldehydes
Table 2. Enantioselective arylation of aldehydes 4a–d by using bro-
mides 2a–h as aryl sources.[a]
Experimental Section
(S)-Phenyl(p-tolyl)methanol (5a). Typical Procedure for the Enantio-
selective Arylation of Aldehydes by Using Aryl Bromides as Aryl
Source: Table 1, Entry 2. To a solution of p-bromotoluene (2a)
(0.257 g, 1.5 mmol) in THF (3 mL) at –78 °C under argon was
added nBuLi (1.6 m in hexane, 0.955 mL, 1.5 mmol). The resulting
solution was stirred at this temperature for 0.5 h. To the resulting
solution of p-tolyllithium was then added titanium tetraisopropox-
ide (0.74 mL, 2.5 mmol). The resulting mixed titanium reagent was
added with a syringe to a two-layer mixture of MgBr2 in Et2O
(2.5 mL), which was prepared by the reaction of magnesium turn-
ings (36.5 mg, 1.5 mmol) with 1,2-dibromoethane (1.5 mmol,
0.13 mL) at 0 °C under argon. After stirring for 30 min, the sol-
vents were removed under vacuum (0.1 Torr, room temp., 10 min),
and the residue was dissolved with Et2O (3.8 mL) and CH2Cl2
(10 mL). After addition of titanium tetraisopropoxide (0.44 mL,
1.5 mmol), the resulting mixture was slowly added by using a sy-
ringe pump to a CH2Cl2 (4 mL) solution of ligand 1 (10.5 mg,
0.020 mmol), benzaldehyde (4a) (0.106 mg, 1.0 mmol), and tita-
nium tetraisopropoxide (0.30 mL, 1.0 mmol) at 0 °C under argon
over a period of 2 h. After additional stirring for 1 h, the reaction
was quenched by the addition of aqueous 1 n HCl and the mixture
extracted three times with ethyl acetate. The combined organic lay-
ers were washed successively with aqueous 5% NaHCO3 and brine,
dried (MgSO4), and concentrated in vacuo. Flash chromatography
(silica gel; 1% ethyl acetate in toluene) of the residue gave 0.186 g
(94% yield) of 5a[12] (92% ee): HPLC analysis: Chiralcel OD col-
umn, 0.5 mL/min, 5% iPrOH in hexane; retention times: 30.9 min
[major (S) enantiomer], 34.6 min [minor (R) enantiomer]. This data
is in agreement with published values.[12]
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR spectra and determination of the ee values of aryl-
ation products 5.
Acknowledgments
This work was supported by the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT), Japan, through a Grant-
in-Aid for Scientific Research (No. 20550095) and by the Kyoto
Institute of Technology Research Fund.
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SHORT COMMUNICATION
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Received: September 6, 2010
Published Online: October 26, 2010
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Eur. J. Org. Chem. 2010, 6535–6538