Practical enantioselective arylation and heteroarylation of aldehydes with in situ prepared organotitanium reagents catalyzed by 3-aryl-H 8-BINOL-derived titanium complexes

Article abstract of DOI:10.1002/chem.201203946

A highly efficient and practical method for the catalytic enantioselective arylation and heteroarylation of aldehydes with organotitanium reagents, prepared in situ by the reaction of aryl- and heteroaryllithium reagents with ClTi(OiPr)₃, is described. Titanium complexes derived from DPP-H ₈-BINOL (3 d; DPP=3,5-diphenylphenyl) and DTBP-H₈-BINOL (3 e; DTBP=3,5-di-tert-butylphenyl) exhibit excellent catalytic activity in terms of enantioselectivity and turnover efficiency for the transformation, providing diaryl-, aryl heteroaryl-, and diheteroarylmethanol derivatives in high enantioselectivity at low catalyst loading (0.2-2 mol %). The reaction begins with a variety of aryl and heteroaryl bromides through their conversion into organolithium intermediates by Br/Li exchange with nBuLi, thus providing straightforward access to a range of enantioenriched alcohols from commercially available starting materials. Various 2-thienylmethanols can be synthesized enantioselectively by using commercially available 2-thienyllithium in THF. The reaction can be carried out on a 10 mmol scale at 0.5 mol % catalyst loading, demonstrating its preparative utility. Titanium does it! Titanium complexes derived from 3-aryl-H₈-BINOLs exhibit excellent catalytic activity in terms of enantioselectivity and turnover efficiency, providing diaryl-, aryl heteroaryl-, and diheteroarylmethanol derivatives in high enantioselectivity at low catalyst loading (0.2-2 mol %; see scheme). Copyright

Full text of DOI:10.1002/chem.201203946

DOI: 10.1002/chem.201203946
Practical Enantioselective Arylation and Heteroarylation of Aldehydes with
In Situ Prepared Organotitanium Reagents Catalyzed by 3-Aryl-H8-BINOL-
Derived Titanium Complexes
Ami Uenishi, Yuya Nakagawa, Hironobu Osumi, and Toshiro Harada*[a]
Abstract: A highly efficient and practi-
cal method for the catalytic enantiose-
lective arylation and heteroarylation of
aldehydes with organotitanium re-
agents, prepared in situ by the reaction
of aryl- and heteroaryllithium reagents
with ClTiACHTUNGTRENNUNG(OiPr)3, is described. Titani-
um complexes derived from DPP-H8-
BINOL (3d; DPP=3,5-diphenylphen-
ciency for the transformation, provid-
ing diaryl-, aryl heteroaryl-, and dihe-
teroarylmethanol derivatives in high
enantioselectivity at low catalyst load-
ing (0.2–2 mol%). The reaction begins
with a variety of aryl and heteroaryl
bromides through their conversion into
organolithium intermediates by Br/Li
exchange with nBuLi, thus providing
straightforward access to a range of
enantioenriched alcohols from com-
mercially available starting materials.
Various 2-thienylmethanols can be syn-
thesized enantioselectively by using
commercially available 2-thienyllithium
in THF. The reaction can be carried
out on a 10 mmol scale at 0.5 mol%
catalyst loading, demonstrating its
preparative utility.
yl)
and
DTBP-H8-BINOL
(3e;
Keywords: alcohols · aldehydes ·
asymmetric catalysis · lithium · tita-
nium
DTBP=3,5-di-tert-butylphenyl) exhibit
excellent catalytic activity in terms of
enantioselectivity and turnover effi-
Introduction
simultaneously.[2,5] Several efficient catalytic methods have
been developed that involve phenyllithium,[6] diphenylzinc,[7]
arylboronic acids,[8,9] arylaluminium reagents,[10] arylzinc bro-
mides,[11] aryl Grignard reagents,[12,13] and aryltitanium re-
agents[14] as aryl sources, expanding significantly the scope
of diarylmethanols that are available in enantiomerically en-
riched form. However, the preparation of the aryl–metal re-
agents entails additional reaction steps. Some reagents are
commercially available but are often quite expensive. There-
fore, the availability of the aryl sources is an important issue
for the practical applications of this approach.
Enantioenriched diaryl-, aryl heteroaryl-, and diheteroaryl-
methanol derivatives are important structural motifs and
precursors in the synthesis of pharmaceutically important
molecules including antihistaminic, anaesthetic, diuretic, an-
tidepressive, antiarrhythmic, and anticholinergic com-
pounds.[1] Accordingly, there are substantial demands for
their practical enantioselective synthesis and the catalytic
enantioselective synthesis of diarylmethanol derivatives has
been the focus of many recent studies.[2]
The enantioselective reduction of inexpensive prochiral
diaryl ketones is an attractive practical approach. Indeed,
highly efficient methods have been developed with chemi-
cal[3] and enzymatic catalysis.[4] However, the limitation of
this approach lies in the fact that two aryl groups of the sub-
strates must be either electronically or sterically dissymmet-
ric to achieve good selectivity.
Aryllithium reagents 1 are attractive aryl sources for the
enantioselective addition to aldehydes (Scheme 1) and can
be generated cleanly from common aryl bromides by Br/Li
exchange reactions. In addition, heteroaryllithium reagents
1’, such as 2-thienyl- and 2-furyllithium, are readily prepared
by lithiation of the parent heteroaromatics.[15] Recently,
Walsh and co-workers demonstrated the utility and practi-
cality of the approach by developing a chiral amino alcohol
catalyzed enantioselective, one-pot arylation method in
which aryl butylzinc reagents 2 (M=ZnBu) were generated
from aryl bromides by successive treatment with nBuLi,
ZnCl2, and additional nBuLi.[16] The reaction was carried
out in the presence of a chelating diamine to inhibit a back-
ground racemic reaction promoted by concurrently formed
LiCl. It was also shown that the method could be applied
with some modification to the heteroarylation of aldehydes
starting from heteroaryl bromides, such as 3-bromothio-
phene and -furan.[16b] A recent report[17] from this laboratory
revealed that the mixed titanium reagent formed from an in
An alternative approach involves the catalytic enantiose-
lective addition of aryl-metal reagents to the prochiral car-
bonyl group of aromatic aldehydes, through which
a
carbon–carbon bond and a stereogenic center are produced
[a] A. Uenishi, Y. Nakagawa, H. Osumi, Prof. Dr. T. Harada
Department of Chemistry and Materials Technology
Kyoto Institute of Technology
Matsugasaki, Sakyo-ku
Kyoto 606-8585 (Japan)
Fax : (+81)75-724-7581
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203946.
situ generated aryllithium reagent, TiACTHNURGTNEUNG(OiPr)4, and MgBr2 un-
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FULL PAPER
(10 mol%).[6] To achieve high enantioselectivity, the rigor-
ous removal of concurrently formed LiCl by centrifugation
was required, otherwise the enantioselectivity was severely
degraded by a racemic background reaction promoted by
the salt. Some aryltitanium reagents ArTi
lated by recrystallization from the hexane extracts of the re-
action of ArMgX with ClTi
(OiPr)3.[20] Very recently, Gau
ACHTUNGTERN(NGNU OiPr)3 can be iso-
AHCTUNGTRENNUNG
and co-workers reported that such salt-free aryltitanium re-
agents underwent enantioselective addition to aldehydes in
the presence of a titanium catalyst of H8-BINOL (3a; 5–
10 mol%).[14] We envisaged that the superior catalytic activi-
ty of the titanium complex of DPP-H8-BINOL (3d) would
allow highly enantioselective addition of the aryltitanium re-
agents without the removal LiCl even at the lower catalyst
loadings, thus providing a practical protocol for the enantio-
selective synthesis of diarylmethanol derivatives from aryl
bromides and aromatic aldehydes.
Scheme 1. Catalytic enantioselective synthesis of diaryl-, aryl heteroaryl-,
and diheteroarylmethanol derivatives starting from aryl bromides and
heteroaromatic compounds.
Herein, we report a practical and efficient method for the
enantioselective arylation and heteroarylation of aldehydes
with organotitanium reagents catalyzed by 3-substituted H8-
BINOL-based chiral titanium complexes. The titanium re-
agents are generated in situ from readily available aryl and
heteroaryl bromides via organolithium intermediates. A va-
riety of diaryl-, aryl heteroaryl-, and diheteroarylmethanol
derivatives were synthesized in high enantioselectivity at
low catalyst loadings (2–0.2 mol%). The practicality of the
method is demonstrated in the successful application to
gram-scale asymmetric syntheses.
dergoes enantioselective arylation of aldehydes in the pres-
ence of a titanium catalyst derived from 3,5-diphenylphenyl
(DPP)-H8-BINOL (3d; Figure 1).[18,19]
Results and Discussion
Catalytic enantioselective arylation of aldehydes: The phe-
Figure 1. 3-Substituted BINOL derivatives 3a–e and 4a and b.
nylation of 1-naphthaldehyde (6a) was first carried out with
[20]
separately prepared salt-free PhTi
G
(Scheme 2).
In addition to the availability of aryl sources, key issues
concerning the practicality of the aldehyde arylation involve
the reduction of catalyst loadings. Previously reported enan-
tioselective arylation reactions were carried out, in most
cases at 5 mol% catalyst loadings or higher, making them
less practical for scale-up applications. To date, few methods
are available that function satisfactorily at lower catalyst
loadings.[9b,d,e,g,h] Yamamoto, Miyaura, and co-workers re-
ported highly efficient arylation reactions with arylboronic
acids catalyzed by a chiral phosporamidite-RuII complex at
2 mol%.[9d,h] The titanium catalyst derived from 3d exhibit-
ed high enantioselectivity even at 2 mol% loadings in the
arylation of aldehydes with the mixed titanium reagent of a
Scheme 2. Enantioselective phenylation of 1-naphthaldehyde (6a) with
PhTi(OiPr)3 catalyzed by a titanium complex derived from 3d.
AHCTUNGTRENNUNG
Grignard reagent and TiACHTNUTGRNEUNG
(OiPr)4.[12,17,19b]
With this background in mind, we aimed to develop a
practical, cost-effective, and scalable protocol for the enan-
tioselective arylation of aldehydes. We focused our attention
on the transmetalation of aryllithium reagents to titanium to
Slow addition of a solution of PhTi
CH2Cl2 and Et2O over 2 h to a solution of the aldehyde,
DPP-H8-BINOL (3d; 2 mol%), and Ti(OiPr)4 (0.2 equiv) in
CH2Cl2 at 08C and an additional 1 h stirring afforded diary-
lmethanol 7aa in 95% yield and in 98% ee (Table 1,
entry 1). We then examined the reaction of 6a with PhTi-
ACHTUNGTERN(NNUG OiPr)3 (1.2 equiv) in
AHCTUNGTRENNUNG
generate 2 {M=Ti
lytic enantioselective arylation, Seebach and co-workers em-
ployed PhTi(OiPr)3, prepared from PhLi and ClTi(OiPr)3, in
combination with TADDOL-based chiral titanium catalysts
ACHTUNGTRENNUNG(OiPr)3}. In the early studies of the cata-
A
U
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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T. Harada et al.
Table 1. Enantioselective phenylation of 1-naphthaldehyde (6a) with
PhTi
(OiPr)3 catalyzed by a titanium complex derived from 3d.[a]
entry 10). Gratifyingly, however, a high enantioselectivity
(93% ee) could be obtained even at such low catalyst load-
ing by carrying out the reaction by slow addition of PhTi-
ACHTUNGTERN(NNUG OiPr)3 (1.5 equiv) over 3 h under dilute conditions (Table 1,
entry 11).
The performance of a series of H8-BINOL derivatives 3a–
e and BINOL derivatives 4a and b was evaluated in the
phenylation of 6a (Table 2). Parent BINOL 4a and H8-
ACHTUNGTRENNUNG
Entry
3d [mol%]
Ti
(OiPr)4 [equiv]
Yield [%]
ee [%]
1[b]
2
2
2
2
2
2
2
2
1
0.5
0.2
0.2
0
0.2
0.2
0.2
0.2
0.2
0.2
0
0.2
0.2
0.2
0.2
0
95
97
98
85
77
93
75
89
72
77
84
88
98
97
77
88
90
94
97
97
96
88
93
–
3[c]
4[d]
5[e]
6[f]
7
8[g]
9[g]
10[g]
11[g,h]
12
Table 2. Enantioselectivity of chiral ligands 3a–e and 4a and b in the
phenylation of 6a.[a]
Entry
Ligand
[mol%]
Yield [%]
ee [%]
1
2
3
4a
4b
3a
3b
3b
3c
3c
3d
3d
3e
3e
2
2
2
2
0.5
2
0.5
2
0.5
2
0.5
68
72
69
77
76
81
73
97
72
82
82
60
80
77
97
61
94
90
97
96
99
95
[a] Unless otherwise noted, reactions were carried out by adding in situ
prepared PhTi(OiPr)3 (1.2 equiv) in CH2Cl2 (8 mL) and Et2O (0.5 mL)
dropwise over 2 h by using a syringe pump to a solution of 6a (1 mmol),
3b, and Ti(OiPr)4 in CH2Cl2 (4 mL) at 08C. The reaction mixture was
stirred for a further 1 h before workup. [b] LiCl-free PhTi(OiPr)3 was
used. [c] PhTi(OiPr)3 was added in one portion. [d] A solution of 6a in
ACHTUNGTRENNUNG
4[b]
5[b]
6[b]
7[b]
8
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
CH2Cl2 (4 mL) was added. [e] The reaction was carried out without using
Et2O as a co-solvent. [f] THF (2.6 mL) was employed as a co-solvent.
9[b]
10[b]
11[b]
[g] PhTi
the reaction mixture. [h] The reactions were carried out by adding in situ
prepared PhTi(OiPr)3 (1.5 equiv) in CH2Cl2 (15 mL) and Et2O (0.5 mL)
ACHTUNGTRENNUNG(OiPr)3 was added steadily by immersing the syringe needle into
ACHTUNGTRENNUNG
[a] Unless otherwise noted, reactions were carried out by adding in situ
prepared PhTi(OiPr)3 (1.2 equiv) in CH2Cl2 (8 mL) and Et2O (0.5 mL)
dropwise over 2 h by using a syringe pump to a solution of 6a (1 mmol),
ligand, and Ti(OiPr)4 (0.2 equiv) in CH2Cl2 (4 mL) at 08C. The reaction
mixture was stirred for a further 1 h before workup. [b] PhTi(OiPr)3 was
to a solution of 6a (1 mmol), 3d, and Ti
3 h at 08C.
ACHTUNGTREN(GNUN OiPr)4 in CH2Cl2 (8 mL) over
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
added steadily by immersing the syringe needle into the reaction mix-
ture.
action afforded 7aa in 97% yield and in 97% ee, demon-
strating that the enantioselectivity was not affected by LiCl
contamination.
As anticipated from previous studies,[21] the phenyltitani-
um reagent underwent facile addition to the aldehyde in the
absence of the catalyst, giving rise to the racemic product
(Table 1, entry 12). Judging from the high enantioselectivi-
ties detailed in Table 1, entries 1 and 2, potential racemic
background reaction was almost completely overridden by
the enantioselective catalytic reaction when the titanium re-
agent was slowly introduced into the reaction mixture over
2 h. Even when the titanium reagent was added at once, 7aa
was obtained in 77% ee, indicating the high activity of the
titanium catalyst (Table 1, entry 3). Slow addition of the al-
dehyde also improved the enantioselectivity (Table 1,
entry 4) although not as much as the slow addition of the
phenyltitanium reagent. Without Et2O as a co-solvent, the
reaction resulted in slightly lower selectivity (Table 1,
entry 5). The use of THF as a co-solvent also provided high
enantioselectivity (Table 1, entry 6). It should be noted that
BINOL 3a exhibited only moderate enantioselectivity at
2 mol% catalyst loading (Table 2, entries 1 and 3). Introduc-
tion of the 3,5-diphenylphenyl group at the 3-position result-
ed in enhanced selectivity of the reaction with DPP-BINOL
(4b; 80% ee) and DPP-H8-BINOL (3d; 97% ee; Table 2,
entries 2 and 8). BINOL derivatives 4a and b are inferior li-
gands compared with H8-BINOL derivatives 3a and d.
To clarify the effect of substituents at the 3-position, reac-
tions were also carried out with 3-aryl-H8-BINOLs 3b, c and
e. At 2 mol% catalyst loading, all these ligands showed high
selectivity (94–99% ee) similar to 3d (Table 2, entries 4, 6
and 10). However, at 0.5 mol% loading, the enantioselectiv-
ity was increased in the order of phenyl derivative 3b
(61% ee), 3,5-dimethylphenyl derivative 3c (90% ee), 3,5-
di-tert-butylphenyl (DTBP) derivative 3e (95% ee), and
DPP derivative 3d (96% ee), indicating that the selectivity
is increased by increasing the size of the 3-aryl substituents
(Table 2, entries 5, 7, 9 and 11). It is most probable that the
inherent enantioselectivity is equally high for 3-aryl-H8-
BINOLs 3b–e, judging from the result at 0.5 mol% loading.
Sterically demanding substituents at the 3-position might ac-
celerate the turnover of the titanium catalyst to minimize
the participation of noncatalyzed background reaction and
exhibit high selectivity at lower catalyst loadings.
additional TiACHTUNGTRENNUNG(OiPr)4 was not necessary for the formation of
the titanium catalyst. When the phenyltitanium reagent was
added to the solution of 6a and ligand 3d (2 mol%), 7aa
was obtained with essentially the same efficiency (Table 1,
entry 7). In the absence of Ti
BINOLate)Ti(OiPr)2, a plausible titanium catalyst, might be
formed by the reaction of 3d with PhTi(OiPr)3.
ACHTUNGRTENN(NUG OiPr)4, (DPP-H8-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
The amount of chiral ligand 3d could be reduced to
0.5 mol% without erosion of enantioselectivity (Table 1, en-
tries 8 and 9). At 0.2 mol% catalyst loading, the reaction re-
The high activity of the titanium catalysts derived from
DPP-H8-BINOL 3d and DTBP-H8-BINOL 3e prompted us
to examine the enantioselective catalytic arylation of alde-
hydes starting from aryl bromides 5 (Scheme 3). Thus, suc-
sulted in
a
decreased selectivity of 88% ee (Table 1,
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ACHTUNGTRENNUNG(Hetero)arylation of Aldehydes
FULL PAPER
agent (Table 3, entries 1 and 2) and (p-chlorophenyl)titani-
um reagent (Table 3, entries 4–9). The results showed that
the present reaction is applicable to ortho-substituted aro-
matic aldehyde 6d, heteroaromatic aldehyde 6e, and a,b-un-
saturated aldehyde 6 f. Enantioselectivity was low to moder-
ate for aliphatic aldehydes 6g and h.
The reaction could also be carried out successfully by
using an aryllithium reagent prepared from aryl bromides
and metallic lithium. m-Tolyllithium was prepared by the re-
action of bromide 5 f and lithium in Et2O [Eq. (1)].[22] With-
out rigorous removal of co-produced LiBr,[23] this reagent
was employed in the catalytic addition to 6b to give diary-
lmethanol 7 fb (97% ee) in quantitative yield.
Scheme 3. Enantioselective arylation of aldehydes 6 starting from aryl
bromides 5 catalyzed by a titanium complex derived from H8-BINOL de-
rivative 3d.
cessive treatment of bromobenzene (5a; 1.5 equiv) with
nBuLi (1.5 equiv) in Et2O and ClTiACTHNUTRGNEUNG(OiPr)3 (1.5 equiv) in
CH2Cl2, followed by slow addition of the resulting phenylti-
tanium reagent over 2 h to a CH2Cl2 solution of 1-napthal-
dehyde (6a) and 3d (2 mol%), afforded diarylmethanol 7aa
in high yield (96%) and high selectivity (98% ee), compara-
ble to those obtained in the reaction employing commercial-
ly available PhLi (Table 3, entry 1).
Under similar conditions, the (p-chlorophenyl)titanium re-
agent was prepared from p-bromochlorobenzene (5c). The
titanium reagent underwent enantioselective addition to
benzaldehyde (6b) to give the corresponding adduct 7cb
(98% ee) in quantitative yield (Table 3, entry 4). The reac-
tion of p- and m-substituted phenyl bromides 5b–f and 2-
naphthyl bromide (5i) afforded the corresponding benzalde-
hyde adduct 7 uniformly in high yields (75–100%) and in
high selectivities (90–98% ee; Table 3, entries 3, 4, 10–12,
and 15). On the other hand, reactions employing aryltitani-
um reagents derived from o-substituted bromides 5g and h
resulted in low enantioselectivities (Table 3, entries 13 and
14). The scope of the reaction was also examined with rep-
resentative aldehydes in the reaction of phenyl titanium re-
It is also worth noting that the arylation reaction could be
carried out even at 0.5 mol% catalyst loading while keeping
high enantioselectivity [Eq. (2)]. The reaction of 5c and 6b
using DTBP-H8-BINOL (3e; 0.5 mol%) provided diarylme-
thanol 7cb in 97% ee and in 94% yield. Under similar con-
ditions, diarylmethanol 7eb was obtained in 90% ee starting
from 5e and 6b.
We have recently reported enantioselective arylation of
aldehydes catalyzed by the DPP-H8-BINOL-based titanium
complex with mixed reagents
Table 3. Catalytic enantioselective arylation of aldehydes by using bromides as aryl source.[a]
of aryl Grignard reagents and
[12b,c]
Ti
reagents of aryllithiums, Ti-
AHCTUNGTRENNUNG
(OiPr)4, and MgBr2.[17] Al-
A
and with mixed
Entry
Bromide 5
Aldehyde 6
Product
Yield [%]
ee [%][b]
1
2
3
PhBr (5a)
PhBr (5a)
1-NaphCHO (6a)
p-ClC6H4CHO (6c)
PhCHO (6b)
7aa
7ac
7bb
ent-7ac
7cd
96
92
98
99
88
96
88
82
97
85
75
95
92
93
90
98
95
93
98
96
94
98
72
39
92
94
92
12
27
90
(95)
(94)
(91) {92}
(91)
(90)
{82}
{96}
{96}
–
(97) {93}
{89}
{92}
–
though being carried out under
similar conditions, the present
reaction employing aryltitani-
um reagents exhibited general-
ly higher enantioselectivities
(Table 3). A notable exception
is a lower selectivity observed
for aliphatic aldehydes 6g and
h (Table 3, entries 8 and 9);
with these substrates the
p-MeC6H4Br (5b)
p-ClC6H4Br (5c)
p-ClC6H4Br (5c)
p-ClC6H4Br (5c)
p-ClC6H4Br (5c)
p-ClC6H4Br (5c)
p-ClC6H4Br (5c)
p-FC6H4Br (5d)
p-MeOC6H4Br (5e)
m-MeC6H4Br (5 f)
o-MeC6H4Br (5g)
o-MeOC6H4Br (5h)
2-NaphBr (5i)
4
PhCHO (6b)
5[c]
6
o-ClC6H4CHO (6d)
2-ThiCHO (6e)
CH2=C(Me)CHO (6 f)
BuCHO (6g)
c-C6H11CHO (6h)
PhCHO (6b)
PhCHO (6b)
PhCHO (6b)
PhCHO (6b)
PhCHO (6b)
7ce
7cf
7cg
7ch
7db
7eb
7 fb
7gb
7hb
7ib
7
8
9[c]
10
11
12[c]
13[d]
14
15
{9}
{86}
PhCHO (6b)
mixed
reagent
of
p-
ClC6H4MgBr and TiACHTUNGTRENNUNG(OiPr)4
[a] Unless otherwise noted, reactions were carried out by adding aryltitanium reagents ArTi
ACHTUNGTERN(NUNG OiPr)3 prepared
from aryl bromides 6 (1.5 equiv), nBuLi (1.5 equiv), and ClTi(OiPr)3 (1.5 equiv) in CH2Cl2 (3 mL) and Et2O
AHCTUNGTRENNUNG
underwent highly enantioselec-
tive addition to 6g.[12b,c] The
results imply that the mixed ti-
tanium reagents participated in
the catalytic reaction not in
(3 mL) dropwise over 2 h to a solution of aldehydes 6 (1 mmol) and 3d (2 mol%) in CH2Cl2 (4 mL) at 08C.
The reaction mixture was stirred for a further 1 h before workup. [b] The ee values reported for reactions with
[12c]
[17]
ArMgBr-Ti
G
and with ArLi-MgBr2-TiACTHNGUTERNN(UG OiPr)4 are shown in round and curly brackets, respectively.
[c] The aryltitanium reagent was added steadily by immersing the syringe needle into the reaction mixture.
[d] o-MeC6H4Li (1.5 equiv) was prepared from 5g and Li in Et2O and used after titration.
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T. Harada et al.
Table 4. Catalytic enantioselective 2-thienylation of benzaldehyde (6b).[a]
Entry Slow addition
Concentration [m]
Yield ee
[%] [%]
Mode[b] Time [h][c] Titanium reagent 6b
1
2
3
4
A
B
B
B
B
B
2
2
3
2
3
3
0.16
0.16
0.16
0.08
0.08
0.08
0.25 90
62
76
87
90
93
95
0.25 89
0.25 92
0.13 79
0.13 97
0.13 95
5
6[d]
the form of ArTi
(OiPr)4·MgX.
ACHTUNGTRENNUNG(OiPr)3 but in the form of titanates, ArTi-
[a] Unless otherwise noted, reactions were carried out on a 1 mmol-scale
by using 3d (2 mol%). After the slow addition of the 2-thienyltitanium
reagent, the reaction mixture was stirred for a further 1 h before workup.
[b] Mode A: dropwise addition, mode B: steady addition by immersing a
syringe needle into the reaction mixture. [c] Time for slow addition.
[d] 3e (2 mol%) was used.
ACHTUNGTRENNUNG
Catalytic enantioselective heteroarylation of aldehydes by
organolithium reagents: Despite the importance of heteroar-
yl groups in medicinal chemistry, the enantioselective addi-
tion of heteroaryl groups to aldehydes has been relatively
less developed.[16b,24,25] Indeed, to the best of our knowledge,
the only examples of highly enantioselective heteroaryl ad-
dition to heteroaryl aldehydes giving rise to enantioenriched
diheteroarylmethanols were reported by Walsh and co-
workers.[16b] The method involved the transmetalation of
heteroaryllithiums, such as 2- and 3-thiophenyl and 3-furyl,
with EtZnCl to generate (heteroaryl)ZnEt species. To
expand the scope of the present enantioselective arylation,
we examined the reactions employing heteroaryltitanium re-
agents prepared in situ.
Under these optimized conditions employing 3d or e
(2 mol%), a variety of aldehydes, including aryl, heteroaryl,
and a,b-unsaturated derivatives, underwent 2-thienylation to
give the corresponding adducts 8 in high enantioselectivities
(86–95% ee) and in high yields (Scheme 5). The reaction of
When the protocol for the enantioselective arylation was
applied to (2-thienyl)TiACTHNUTRGNE(NUG OiPr)3, prepared in situ from com-
mercially available 2-thienyllithium (1m in THF), the corre-
sponding benzaldehyde adduct 8b was obtained in high
yield but with moderate selectivity (62% ee; Scheme 4,
Scheme 5. Enantioselective 2-thienylation of aldehydes
6 with (2-
thienyl)Ti(OiPr)3 catalyzed by a titanium complex derived from 3d or e.
AHCTUNGTRENNUNG
Unless otherwise noted, DPP-H8-BINOL (3d) was used. [a] DTBP-H8-
BINOL (3e) was used.
Scheme 4. Enantioselective 2-thienylation of benzaldehyde (6b) with (2-
thienyl)-TiACHTUNGTRENNUNG(OiPr)3 catalyzed by a titanium complex derived from 3d or e.
cyclohexanecarboxaldehyde (6h) resulted in poor selectivity,
as observed in the arylation (Table 3, entry 8). Ligand 3e ex-
hibited slightly higher selectivities than 3d, as illustrated in
the formation of 8b and c.
The enantioselective addition of the 2-benzothienyl group
was also achievable (Scheme 6). Thus, lithiation of benzo-
Table 4, entry 1). It was found that the manner of slow addi-
tion is influential to the enantioselectivity. In mode A
(Table 4, entry 1), the 2-thienyltitanium reagent was added
dropwise over 2 h by using a syringe pump. On the other
hand, when the titanium reagent was added steadily for 2 h
by immersing a syringe needle in the reaction mixture
(mode B), the selectivity of 8b was improved to 76% ee
(Table 4, entry 2). Further improvement was achieved either
by extending the addition times (Table 4, entry 3) or by em-
ploying dilute conditions (Table 4, entry 4). Finally, the com-
bination of the two modifications brought about the optimal
enantioselectivities of 93 and 95% ee with 2 mol% of ligand
3d and e, respectively (Table 4, entries 5 and 6).
thiophene with nBuLi and transmetalation with ClTiACHTUNGTRENNUNG(OiPr)3
followed by the slow addition of the resulting (2-benzothie-
nyl)titanium reagent to aldehydes 6a and b in the presence
of 3e (5 mol%) afforded the corresponding adducts 9a and
b in high enantioselectivities. For 2-benzothienylation, enan-
tioselectivities were less satisfactory at 2 mol% catalyst
loading.
The modified protocol developed in the 2-thienylation
were not effective in the 2-furylation of aldehydes
4900
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Chem. Eur. J. 2013, 19, 4896 – 4905

ACHTUNGTRENNUNG(Hetero)arylation of Aldehydes
FULL PAPER
Scheme 6. Enantioselective addition of a 2-benzothienyl group to alde-
hydes 6a and b catalyzed by a titanium complex derived from 3e.
(Scheme 7). Thus, in the presence of 3d (5 mol%), (2-
furyl)TiACHTUNGTRENNUNG(OiPr)3, prepared in situ from furan via 2-furyllithi-
um, gave benzaldehyde adduct 10b in 45% ee and in 66%
yield. The enantioselectivity was slightly improved by the
use of 3e, although still unsatisfactory.
Scheme 8. Enantioselective 3-thienylation and 3-furylation of aldehydes 6
catalyzed by a titanium complex derived from 3d or e. Unless otherwise
noted, DPP-H8-BINOL (3d, 2 mol%) was used with slow addition over
2h. [a] DTBP-H8-BINOL (3e, 0.5 mol%) was used with slow addition
over 3h.
(10 mmol) and bromide 5c (15 mmol) provided 2.05 g (94%
yield) of diarylmethanol 7cb in 97% ee [Eq. (3)]. Likewise,
a 10 mmol-scale reaction of 6b employing m-tolyllithium af-
forded 1.97 g (99% yield) of diarylmethanol 7 fd in 93% ee
[Eq. (4)]. The enantiopurity of 7 fb was enhanced to 97% ee
by recrystallization from hexane. As shown in [Eq. (5)], het-
eroarylation could also be carried out on a 10 mmol scale
without difficulty.
Scheme 7. Enantioselective 2-furylation of benzaldehyde (6b) catalyzed
by a titanium complex derived from 3d or e.
In comparison with 2-thienylation and 2-furylation, the
enantioselective addition of 3-thienyl and 3-furyl groups to
aldehydes proceeded in
a
more efficient manner
(Scheme 8). The 3-thienyltitanium reagent was prepared in
situ from bromide 11 via a 3-thienyllithium intermediate.
Reactions were carried out with aldehydes 6 in the presence
of ligand 3d (2 mol%) by adding the titanium reagent
(1.5 equiv) over 2 h. Under these conditions, not only aro-
matic aldehyde 6b but also heteroaromatic aldehyde 6e and
a,b-unsaturated aldehyde 6j underwent highly enantioselec-
tive 3-thienylation to give the corresponding adducts 13b, e,
and j (94–99% ee) in high yields. Under similar conditions,
3-furylation of aldehydes starting from 3-bromofuran (12)
also proceeded efficiently to furnish adducts 14b and k in
high selectivities (91–95% ee). Remarkably, further reduc-
tion in the amount of catalyst did not result in an erosion of
enantioselectivity. Thus, even with 0.5 mol% 3e, 3-thienyl
adduct 13b and 3-furyl adducts 14b and k were obtained in
high selectivities (89–95% ee) comparable to those obtained
in reactions with 2 mol% 3e.
Application to gram-scale synthesis: To demonstrate the
preparative utility of the present enantioselective arylation,
gram-scale syntheses of diarylmethanol and aryl heteroaryl-
methanol derivatives were examined. Even with 24 mg
(0.5 mol%) of chiral ligand 3e, the reaction of aldehyde 6b
Chem. Eur. J. 2013, 19, 4896 – 4905
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4901

T. Harada et al.
under an argon atmosphere and the solution was stirred at this tempera-
ture for 2 h. The reaction mixture was poured into water, and extracted
twice with ethyl acetate. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (5% ethyl acetate in hexane) to give 3e
(411 mg, 73%) as an amorphous solid. [a]2D3 =+63.3 (c=1.03, CHCl3);
1H NMR (400 MHz, CDCl3): d=1.37 (s, 18H), 1.64–1.82 (m, 8H), 2.17–
2.29 (m, 2H), 2.31–2.45 (m, 2H), 2.73–2.85 (m, 4H), 4.69 (br, 1H), 5.00
(br, 1H), 6.85 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.16 (s, 1H),
7.38–7.44 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=22.9, 23.0 (3C),
23.1, 27.1, 27.2, 29.3, 31.5, 34.9, 112.8, 119.6, 120.1, 121.4, 123.5, 127.1,
129.9, 130.1, 130.7, 131.7, 136.5, 136.7, 136.8, 148.3, 150.9, 151.0 ppm;
HRMS (FAB): m/z calcd for C34H42O2: 482.3185; found: 482.3177.
Conclusion
We have developed a highly efficient and practical method
for the catalytic enantioselective arylation and heteroaryla-
tion of aldehydes with organotitanium reagents, prepared in
situ by the reaction of aryl- and heteroaryllithiums with
ClTiACHTUNGTRENNUNG(OiPr)4. Titanium complexes derived from DPP-H8-
BINOL (3d) and DTBP-H8-BINOL (3e) were shown to be
excellent catalysts in terms of enantioselectivity and turn-
over efficiency for this transformation, providing diaryl-,
aryl heteroaryl-, and diheteroarylmethanol derivatives in
high enantioselectivity at low catalyst loading (0.2–2 mol%).
Because the organolithium intermediates can be generated
by Br/Li exchange of aryl bromides 5 and heteroaryl bro-
mides 11 and 12 with nBuLi, the present reaction permits
access to a wide range of enantioenriched secondary alco-
hols starting from commercially available bromides and al-
dehydes in a most straightforward manner. In addition, com-
mercially available 2-thienyllithium in THF has been em-
ployed, for the first time, in enantioselective addition to al-
dehydes. The preparative utility of the present reaction has
Typical procedure for the catalytic enantioselective arylation of alde-
hydes with aryl bromides at 2 mol% catalyst loading—(S)-phenyl-p-tolyl-
methanol (7bb; Table 3, entry 3):[11b] nBuLi (1.4m in hexane, 1.07 mL,
1.5 mmol) was added over 10 min to a solution of p-bromotoluene (5b;
257 mg, 1.5 mmol) in Et2O (3 mL) at À308C under argon. After stirring
at RT for 30 min, the resulting solution of p-tolyllithium was cooled to
À788C. To this was added ClTi
ACHTNUGRTEN(NNUG OiPr)3 (0.5m in CH2Cl2, 3.0 mL,
1.5 mmol) and the mixture was allowed to warm to RT for 15 min. The
resulting suspension was added dropwise over 2 h, by using a syringe
pump, to a solution of ligand 3d (10.5 mg, 0.020 mmol) and benzaldehyde
(6b; 106 mg, 1.0 mmol) in CH2Cl2 (4 mL) at 08C. After stirring further at
08C for 1 h, the reaction mixture was quenched by the addition of aque-
ous HCl (1n) and extracted three times with ethyl acetate. The organic
layers were washed successively with aqueous NaHCO3 (5%) and with
brine, dried (Na2SO4), and concentrated in vacuo. Purification of the resi-
due by flash chromatography (silica gel; 1% ethyl acetate in toluene)
gave 7bb (193 mg, 98% yield). 1H NMR (500 MHz, CDCl3): d=2.22
(brs, 1H), 2.35 (s, 3H), 5.80 (s, 1H), 7.16 (m, 2H), 7.27–7.29 (m, 3H),
7.33–7.40 ppm (m, 4H); HPLC (Chiralcel OD-H, 5% iPrOH in n-
hexane, 0.5 mLminÀ1): tR =30.5 (major S enantiomer), 34.0 min (minor R
enantiomer); ee: 93%. The retention times were concordant with pub-
lished values.[11b]
been demonstrated by conducting the reaction on
10 mmol scale without any difficulty at 0.5 mol% catalyst
loading.
a
Experimental Section
General: CH2Cl2 was dried and distilled over CaH2. Et2O and THF were
Typical procedure for the catalytic enantioselective arylation of alde-
distilled from sodium benzophenone ketyl. Aldehydes, Ti
TiCl4 were used after distillation. A stock solution of ClTi
CH2Cl2 (0.5m) was prepared by mixing Ti(OiPr)4 and TiCl4 in a molar
ACHTUNGTRENNUNG
hydes with aryllithium reagents [Eq. (1)]—(S)-phenyl-m-tolylmethanol
AHCTUNGTRENNUNG
(7 fb):[11b] ClTi
ACHTNUTRGNE(UGN OiPr)3 (0.5m in CH2Cl2, 3.0 mL, 1.5 mmol) was diluted
AHCTUNGTRENNUNG
ratio of 3:1 in CH2Cl2 at 08C. Ligands 3d[12c] and 4b[26] were prepared ac-
cording to a reported procedure. The reagents m- and o-tolyllithium
were prepared by reaction of m- and o-bromotoluene with lithium in
Et2O, respectively, according to a reported procedure[22] and used after
filtration and titration. nBuLi in hexane and PhLi in cyclohexane and
Et2O were obtained from Kanto Chemicals Co. Ltd. and used after titra-
tion.[27] 2-Thienyllithium (1m in THF) was purchased from Aldrich and
used without titration.
with CH2Cl2 (7 mL) and cooled to À788C under an argon atmosphere
and m-tolyllithium (0.56m in Et2O, 2.7 mL, 1.5 mmol) was added. The
mixture was allowed to warm to RT for 15 min and the resulting suspen-
sion was added with a syringe pump over 2 h to a solution of ligand 3d
(10.5 mg, 0.020 mmol) and benzaldehyde (6b; 106 mg, 1.0 mmol) in
CH2Cl2 (4 mL) at 08C. During the addition, the syringe needle was im-
mersed in the solution so that the titanium reagent was introduced stead-
ily. After stirring further at 08C for 1 h, the reaction mixture was
quenched by the addition of aqueous HCl (1n) and extracted three times
with ethyl acetate. The organic layers were washed successively with
aqueous NaHCO3 (5%) and with brine, dried (Na2SO4), and concentrat-
ed in vacuo. Purification of the residue by flash chromatography (silica
gel; 1% ethyl acetate in toluene) gave 7 fb (196 mg, 99% yield).
1H NMR (500 MHz, CDCl3): d=2.22 (brs, 1H), 2.35 (s, 3H), 5.81 (s,
1H), 7.10 (d, J=7.4 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.22–7.31 (m, 3H),
7.34–7.42 ppm (m, 4H); HPLC (Chiralcel OB-H, 10% iPrOH in n-
hexane, 1 mLminÀ1): tR =27.1 (major S enantiomer), 12.7 min (minor R
enantiomer); ee: 98%. The retention times were concordant with pub-
lished values.[11b]
(R)-3-(3,5-Di-tert-butylphenyl)-2,2’-dihydroxy-5,5’,6,6’,7,7’,8,8’-octahydro-
1,1’-binaphthyl (3e):
5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-binaphthyl[12c] (0.503 g, 1.25 mmol), (3,5-
di-tert-butyl)phenylboronic acid (0.323 g, 1.38 mmol),[28] [Pd
(PPh3)4]
A
mixture of (R)-3-bromo-2,2’-dimethoxy-
AHCTUNGTRENNUNG
(36 mg, 0.031 mmol), and Ba(OH)2·8H2O (0.435 g, 1.38 mmol) in water
(4 mL) and 1,4-dioxane (12.5 mL) was heated to reflux for 19 h under an
argon atmosphere. The reaction mixture was passed through a plug of
Celite and the filtrate was extracted twice with ethyl acetate. The com-
bined organic layers were dried (Na2SO4) and concentrated in vacuo. The
residue was purified by flash column chromatography (3% ethyl acetate
in hexane) to give (R)-3-(3,5-di-tert-butylphenyl)-2,2’-dimethoxy-
5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-binaphthyl (0.594 g, 93%) as an amor-
Typical procedure for the catalytic enantioselective arylation of alde-
hydes with aryl bromides at 0.5 mol% catalyst loading [Eq. (2)]—(S)-(4-
chlorophenyl)phenylmethanol (ent-7ac):[29] nBuLi (1.54m in hexane,
0.97 mL, 1.5 mmol) was added over 5 min to a solution of 4-bromo-1-
chlorobenzene (5c; 287 mg, 1.5 mmol) in Et2O (3 mL) at 08C under
argon. After stirring at RT for 20 min, the resulting solution of 4-chloro-
1
phous solid. H NMR (500 MHz, CDCl3): d=1.38 (s, 18H), 1.62–1.87 (m,
8H), 2.11–2.21 (m, 2H), 2.35 (m, 1H), 2.48 (m, 1H), 2.78–2.91 (m, 4H),
3.22 (s, 3H), 3.76 (s, 3H), 6.82 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz,
1H), 7.14 (s, 1H), 7.38 (s, 1H), 7.44 ppm (s, 2H); 13C NMR (126 MHz,
CDCl3): d=23.1 (2C), 23.2 (2C), 27.0, 27.4, 29.4, 29.6, 31.6, 34.9, 55.3,
60.3, 107.9, 120.3, 123.5, 126.0, 128.7, 129.6, 130.8, 131.0, 132.3, 133.0,
135.9, 136.7. 138.3, 150.1, 153.0, 154.8 ppm; HRMS (FAB): m/z calcd for
C36H46O2: 510.3498; found: 510.3495.
phenyllithium was cooled to À788C, and ClTi
ACHTUNGTRENUN(GN OiPr)3 (0.5m in CH2Cl2,
2.86 mL, 1.43 mmol) was added. After diluting with CH2Cl2 (12.2 mL),
the mixture was allowed to warm to RT for 15 min. The resulting suspen-
sion was added by using a syringe pump over 3 h to a solution of ligand
3e (2.5 mg, 0.005 mmol) and benzaldehyde (6b; 106 mg, 1.0 mmol) in
Boron tribromide (0.55 mL, 5.8 mmol) was added to a solution of the
above dimethyl ether (594 mg, 1.16 mmol) in CH2Cl2 (7.5 mL) at À108C
4902
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ACHTUNGTRENNUNG(Hetero)arylation of Aldehydes
FULL PAPER
CH2Cl2 (8 mL) at 08C. During the addition, the syringe needle was im-
mersed in the solution so that the titanium reagent was introduced stead-
ily. After stirring further at 08C for 1 h, the reaction mixture was
quenched by the addition of aqueous HCl (1n) and extracted three times
with ethyl acetate. The organic layers were washed successively with
aqueous NaHCO3 (5%) and with brine, dried (Na2SO4), and concentrat-
ed in vacuo. Purification of the residue by flash chromatography (silica
gel; 1% ethyl acetate in toluene) gave ent-7ac (205 mg, 94% yield).
1H NMR (500 MHz, CDCl3): d=2.35 (brs, 1H), 5.83 (s, 1H), 7.26–
7.35 ppm (m, 9H); HPLC (Chiralcel OB-H, 9% iPrOH in n-hexane,
1 mLminÀ1): tR =25.9 (major S enantiomer), 17.4 min (minor R enan-
tiomer); ee: 97%. The retention times were concordant with published
values.[29]
was allowed to warm to RT for 15 min and the resulting suspension was
added by using a syringe pump over 3 h to a solution of ligand 3e
(24.9 mg, 0.05 mmol) and benzaldehyde (6b; 106 mg, 1.0 mmol) in
CH2Cl2 (8 mL) at 08C. During the addition, the syringe needle was im-
mersed in the solution so that the titanium reagent was introduced stead-
ily. After stirring further at 08C for 1 h, the reaction mixture was
quenched by the addition of aqueous HCl (1n) and extracted three times
with ethyl acetate. The organic layers were washed successively with
aqueous NaHCO3 (5%) and with brine, dried (Na2SO4), and concentrat-
ed in vacuo. Purification of the residue by flash chromatography (silica
gel; 1% ethyl acetate in toluene) gave 10b (118 mg, 68% yield).
1H NMR (500 MHz, CDCl3): d=2.40 (brs, 1H), 5.84 (s, 1H), 6.12 (d, J=
4.1 Hz, 1H), 6.32 (dd, J=2.3, 4.1 Hz, 1H), 7.31–7.46 ppm (m, 6H);
HPLC: (Chiralcel OD-H, 5% iPrOH in n-hexane, 1.0 mLminÀ1): tR =
16.2 (major R enantiomer), 20.1 min (minor S enantiomer); ee: 55%.
The retention times were concordant with published values.[7c]
Typical procedure for the catalytic enantioselective 2-thienylation of al-
dehydes (Scheme 5)—(S)-phenylthiophen-2-ylmethanol (8b):[9d] ClTi-
ACHTUNGTRENNUNG(OiPr)3 (0.5m in CH2Cl2, 3.0 mL, 1.5 mmol) was diluted with CH2Cl2
(14.5 mL) and cooled to À788C. 2-Thienyllithium (1m in THF, 1.5 mL,
1.5 mmol) was added and the mixture was allowed to warm to RT for
15 min. The resulting suspension was added by using a syringe pump
over 3 h to a solution of ligand 3d (10.5 mg, 0.02 mmol) and benzalde-
hyde (6b) (106 mg, 1.0 mmol) CH2Cl2 (8 mL) at 08C. During the addi-
tion, the syringe needle was immersed in the solution so that the titanium
reagent was introduced steadily. After stirring further at 08C for 1 h, the
reaction mixture was quenched by the addition of aqueous HCl (1n) and
extracted three times with ethyl acetate. The organic layers were washed
successively with aqueous NaHCO3 (5%) and with brine, dried
(Na2SO4), and concentrated in vacuo. Purification of the residue by flash
chromatography (silica gel; 1% ethyl acetate in toluene) gave 8b
(185 mg, 97% yield). 1H NMR (500 MHz, CDCl3): d=2.43 (brs, 1H),
6.06 (1H, s), 6.89 (d, J=3.5 Hz, 1H), 6.95 (m, 1H), 7.27 (d, J=5.8 Hz,
1H), 7.32 (m, 1H), 7.38 (m, 2H), 7.45 ppm (m, 2H); HPLC (Chiralcel
OD-H, 2% iPrOH in n-hexane, 1 mLminÀ1): tR =40.6 min (major S enan-
tiomer), 46.0 min (minor R enantiomer); ee: 93%. The retention times
were concordant with published values.[9d]
Typical procedure for the catalytic enantioselective 3-thienylation and 3-
furylation of aldehydes at 2 mol% catalyst loading (Scheme 8)—(R)-thi-
ophen-3-ylthiophen-2-ylmethanol (13e):[16b] 3-Bromothiophene (0.14 mL,
1.5 mmol) was added over 15 min to a solution of nBuLi (1.41m in
hexane, 1.17 mL, 1.65 mmol) in Et2O (1.2 mL) at À708C under argon.
After stirring at À308C for 30 min, the resulting solution of 3-thienyllithi-
um was cooled to À788C, then ClTi
ACHTNUGRTEN(NNUG OiPr)3 (0.5m in CH2Cl2, 3.0 mL,
1.5 mmol) was added. After diluting with CH2Cl2 (14 mL), the mixture
was allowed to warm to RT for 15 min. The resulting suspension was
added by using a syringe pump over 2 h to a solution of ligand 3d
(105 mg, 0.02 mmol) and thiophene-2-carbaldehyde (6e; 112 mg,
1.0 mmol) in CH2Cl2 (8 mL) at 08C. During the addition, the syringe
needle was immersed in the solution so that the titanium reagent was in-
troduced steadily. After being stirred further at 08C for 1 h, the reaction
mixture was quenched by the addition of aqueous HCl (1n) and extract-
ed three times with ethyl acetate. The organic layers were washed succes-
sively with aqueous NaHCO3 (5%) and with brine, dried (Na2SO4), and
concentrated in vacuo. Purification of the residue by flash chromatogra-
phy (silica gel; 1% ethyl acetate in toluene) gave 13d (184 mg, 94%
yield). [a]2D5 =À8.5 (c 1.01, CHCl3) {Lit.[16b] [a]D = +5.0 (c 0.015, CHCl3)
for S isomer (93% ee)}; 1H NMR (500 MHz, CDCl3): d=2.44 (brs, 1H),
6.14 (s, 1H), 6.97 (m, 2H) 7.10 (m, 1H) 7.27–7.32 ppm (m, 3H);
13C NMR (126 MHz, CDCl3): d=68.8, 121.9, 124.8, 125.4, 126.2, 126.3,
126.7, 144.5, 147.5 ppm; HPLC (Chiralcel OD-H, 5% iPrOH in n-
hexane, 1.0 mLminÀ1): tR =21.2 (major R enantiomer), 23.2 min (minor S
enantiomer); ee: 94%.
Typical procedure for the catalytic enantioselective 2-benzothienylation
of aldehydes (Scheme 6)—(S)-benzo[b]thiophen-2-yl-naphthalen-1-yl-
methanol (9a):[30] nBuLi (1.41m in hexane, 1.06 mL, 1.5 mmol) was
added to a solution of benzo[b]thiophene (287 mg, 2.14 mmol) in Et2O
(4.7 mL) at 08C under argon over 5 min. After stirring at RT for 30 min,
the resulting solution of 2-benzothienyllithium was cooled at À788C and
ClTiACHTUNGTRENNUNG(OiPr)3 (0.5m in CH2Cl2, 3.0 mL, 1.5 mmol) was added. After dilut-
ing with CH2Cl2 (10.3 mL), the mixture was allowed to warm to RT for
15 min and the resulting suspension was added by using a syringe pump
over 3 h to a solution of ligand 3e (24.9 mg, 0.05 mmol) and 1-naphthal-
dehyde (6a) (156 mg, 1.0 mmol) in CH2Cl2 (8 mL) at 08C. During the ad-
dition, the syringe needle was immersed in the solution so that the titani-
um reagent was introduced steadily. After stirring further at 08C for 1 h,
the reaction mixture was quenched by the addition of aqueous HCl (1n)
and extracted three times with ethyl acetate. The organic layers were
washed successively with aqueous NaHCO3 (5%) and with brine, dried
(Na2SO4), and concentrated in vacuo. Purification of the residue by flash
chromatography (silica gel; 1% ethyl acetate in toluene) gave 9a
(253 mg, 87% yield). [a]D30 = +97.0 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d=2.66 (brs, 1H), 6.80 (s, 1H), 7.08 (s, 1H), 7.27–7.32 (m, 2H),
7.44–7.50 (m, 2H), 7.53 (dd, J=7.3, 8.1 Hz, 1H), 7.63 (m, 1H), 7.77–7.82
(m, 2H), 7.86–7.92 (m, 2H), 8.12 ppm (m, 1H); 13C NMR (126 MHz,
CDCl3): d=70.5, 122.8, 122.4, 123.6, 123.8, 124.2 (2C), 124.4, 125.4, 125.8,
126.4, 128.8, 129.1, 130.5, 133.9, 137.8, 139.5, 139.9, 148.1 ppm; HPLC
(Chiralcel OD-H, 10% iPrOH in n-hexane, 1 mLminÀ1): tR =42.5 (major
S enantiomer), 20.7 min (minor R enantiomer); ee: 90%. The absolute
structure was assumed by analogy.
Typical procedure for the catalytic enantioselective 3-thienylation and 3-
furylation of aldehydes at 0.5 mol% catalyst loading (Scheme 8)—(R)-
furan-3-yl-furan-2-yl-methanol
(14k):[16b]
3-Bromofuran
(0.14 mL,
1.5 mmol) was added over 15 min to a solution of nBuLi (1.54m in
hexane, 1.07 mL, 1.65 mmol) in Et2O (1.2 mL) at À708C under argon.
After stirring at À408C for 30 min, the resulting solution of 3-furyllithium
was cooled at À788C and ClTi
ACHTNUGRTEN(NNUG OiPr)3 (0.5m in CH2Cl2, 3.0 mL,
1.5 mmol) was added. After diluting with CH2Cl2 (14 mL), the mixture
was allowed to warm to RT for 15 min. The resulting suspension was
added by using a syringe pump over 3 h to a solution of ligand 3e
(2.5 mg, 0.005 mmol) and furan-2-carbaldehyde (6e; 96 mg, 1.0 mmol) in
CH2Cl2 (8 mL) at 08C. During the addition, the syringe needle was im-
mersed in the solution so that the titanium reagent was introduced stead-
ily. After being stirred further at 08C for 1 h, the reaction mixture was
quenched by the addition of aqueous HCl (1n) and extracted three times
with ethyl acetate. The organic layers were washed successively with
aqueous NaHCO3 (5%) and with brine, dried (Na2SO4), and concentrat-
ed in vacuo. Purification of the residue by flash chromatography (silica
gel; 1% ethyl acetate in toluene) gave 14k (140 mg, 86% yield). [a]D25
=
1
À3.6 (c 1.1, CHCl3); H NMR (500 MHz, CDCl3): d=2.82 (brs, 1H), 5.74
(brs, 1H), 6.22 (brd, J=3.3 Hz, 1H), 6.33 (dd, J=1.9, 3.3 Hz, 1H), 4.44
(brs, 1H), 7.39 (m, 2H), 7.43 ppm (brs, 1H); 13C NMR (126 MHz,
CDCl3): d=63.0, 107.0, 108.2, 110.2, 125.9, 140.0, 142.4, 143.2, 155.2 ppm;
HPLC (Chiralcel OB-H, 3% iPrOH in n-hexane, 1.0 mLminÀ1): tR =28.8
(minor S enantiomer), 30.8 min (major R enantiomer); ee: 89%. The ab-
solute structure was assumed by analogy.
Typical procedure for the catalytic enantioselective 2-furylation of ben-
zaldehyde (6b; Scheme 7)—(S)-furan-2-ylphenylmethanol (10b):[7c]
nBuLi (1.41m in hexane, 1.06 mL, 1.5 mmol) was added to a solution of
furan (0.13 mL, 1.8 mmol) in Et2O (1 mL) at 108C under argon over
5 min. After stirring at RT for 1.5 h, the resulting solution of 2-furyllithi-
um was cooled at À788C and ClTi
ACHTNUGRTEN(NNUG OiPr)3 (0.5m in CH2Cl2, 3.0 mL,
1.5 mmol) was added. After diluting with CH2Cl2 (14 mL), the mixture
Chem. Eur. J. 2013, 19, 4896 – 4905
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T. Harada et al.
Typical procedure for the gram-scale synthesis of enantioenriched diary-
lmethanols [Eq. (3–5)]—(S)-(4-chlorophenyl)phenylmethanol (ent-7ac):
nBuLi (1.54m in hexane, 9.7 mL, 15 mmol) was added over 10 min to a
solution of 4-bromo-1-chlorobenzene (5c; 2.87 g, 15.0 mmol) in Et2O
(30 mL) at 08C under argon. After stirring at RT for 20 min, the resulting
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solution of 4-chlorophenyllithium was cooled to À788C and ClTi
ACHTUNGERTN(NUNG OiPr)3
(0.5m in CH2Cl2, 28.6 mL, 14.3 mmol) was added. After diluting with
CH2Cl2 (122 mL), the mixture was allowed to warm to RT for 15 min.
The resulting suspension was added by using a cannula (Teflon needle)
over 3 h to a solution of ligand 3e (25 mg, 0.050 mmol) and benzaldehyde
(6b) (1.06 g, 10.0 mmol) in CH2Cl2 (80 mL) at 08C. During the addition,
the needle was immersed in the solution so that the titanium reagent was
introduced steadily. After stirring at 08C for 1 h, the reaction mixture
was quenched by the addition of aqueous HCl (1n, 150 mL) and extract-
ed three times with CH2Cl2. The organic layers were washed successively
with aqueous NaHCO3 (5%) and with brine, dried (Na2SO4), and con-
centrated in vacuo. Purification of the residue by flash chromatography
(silica gel; 1% ethyl acetate in toluene) gave ent-7ac (1.94 g, 89% yield;
97% ee).
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Acknowledgements
We thank Professor Adam R. Johnson of Harvey Mudd College for help-
ful discussion. This work was supported by KAKENHI (No. 20550095
and 24550118) from Ministry of Education, Culture, Sports, Science, and
Technology (MEXT), Japan and by Kyoto Institute of Technology Re-
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Received: November 5, 2012
Published online: February 21, 2013
Chem. Eur. J. 2013, 19, 4896 – 4905
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4905