Catalytic enantioselective arylation of aldehydes by using functionalized grignard reagents generated from aryl bromides

Article abstract of DOI:10.1055/s-0031-1289854

An efficient catalytic method has been developed for the enantioselective synthesis of functionalized diarylmethanols starting from aryl bromides and aldehydes. In the presence of (R)-3-(3,5-diphenylphenyl)BINOL (2 mol%) and titanium tetraisopropoxide, fu

Full text of DOI:10.1055/s-0031-1289854

LETTER
2875
Catalytic Enantioselective Arylation of Aldehydes by Using Functionalized
Grignard Reagents Generated from Aryl Bromides
Catalytic
E
nantios
a
elective
A
ry
i
lationsuke Itakura, Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Fax +81(75)7247514; E-mail: harada@chem.kit.ac.jp
Received 21 September 2011
I
i-PrMgCl
Abstract: An efficient catalytic method has been developed for the
enantioselective synthesis of functionalized diarylmethanols start-
FG
ing from aryl bromides and aldehydes. In the presence of (R)-3-
(3,5-diphenylphenyl)BINOL (2 mol%) and titanium tetraisopro-
O
MgCl
poxide, functionalized aryl Grignard reagents (FGArMgCl; FG = 3-
+
H
FG
+ Ti(Oi-Pr)4
R
F3C, 4-F3C, 3-Br, 3-CN, 4-CN), prepared in situ by treatment of the
bromides with i-PrMgCl·LiCl, undergo addition to aldehydes to
give the corresponding functionalized diarylmethanols in high
enantioselectivities.
Ph
Key words: aldehydes, arylation, asymmetric catalysis, magne-
sium, titanium
Ph
OH
OH
Catalytic methods allowing the enantioselective transfer
of functionalized aryl groups to aromatic aldehydes has
attracted considerable attention in recent years because
the resulting functionalized diarylmethanols are in de-
mand as precursors to many biologically active com-
pounds.1 Because of superior functional-group tolerance
and wide commercial availability, arylboronic acids and
their derivatives are most often employed as nucleophilic
reagents in this transformation directly through chiral
transition-metal catalysis2 or via transmetalation to orga-
nozinc derivatives.3 A variety of functionalized arylzinc
halides are commercially available. Catalytic enantio-
selective aldehyde arylation has also been developed by
using the functionalized arylzinc reagents in the presence
of Me3Al.4
OH
1 (2 mol%)
R1
FG
Ti(Oi-Pr)4, CH2Cl2
FG = CN, CO2R2, CONR2
2
Scheme 1
Aryl bromides would be preferable precursors for the
preparation of functionalized Grignard reagents in light of
their stability, good availability, and low price in compar-
ison to the corresponding iodides. Therefore, it is desir-
able to develop a method for the enantioselective
synthesis of functionalized diarylmethanols starting from
functionalized aryl bromides and aromatic aldehydes.
Functionalized arylzinc bromides prepared in situ by
CoBr2-catalyzed oxidative addition of zinc metal to aryl
bromides8 were successfully employed in the enantio-
selective arylation.4b Unfortunately, however, good re-
sults were reported mostly for a-branched aliphatic
aldehydes.
Recently, we have reported a catalytic enantioselective
arylation of aldehydes using Grignard reagents.5 In the
presence of a titanium catalyst derived from DPP-H8-
BINOL (1, 2 mol%), mixed titanium reagents derived
from aryl Grignard reagents, and titanium tetraisopro-
poxide undergo addition to aldehydes to give secondary
benzylic alcohols with high enantioselectivities.5b,c The
pioneering work of Knochel and co-workers on the prep-
aration of functionalized Grignard reagents made them
available for the catalytic enantioselective addition to al-
dehydes.6,7 Indeed, the catalytic aldehyde arylation reac-
tion was successfully applied to the enantioselective
synthesis of functionalized diarylmethanols by employing
functionalized aryl Grignard reagents prepared in situ by
iodine–magnesium exchange of the corresponding aryl
iodides with i-PrMgCl (Scheme 1).5c
Although bromine–magnesium exchange of aryl bro-
mides is a less efficient process with i-PrMgCl, it was re-
cently demonstrated that the exchange reaction becomes
feasible when using i-PrMgCl·LiCl with enhanced reac-
tivity by virtue of LiCl complexation.7b,c In the present
study, we were attracted to the possibility of using func-
tionalized Grignard reagents prepared in situ from bro-
mide precursors in the enantioselective arylation of
aldehydes catalyzed by a titanium complex of DPP-H8-
BINOL (1). Herein, we report the results of our study to
probe the scope and limitations of this approach.
We first examined the reaction of 4-bromo(trifluorometh-
yl)benzene (2a) and 1-naphthaldehyde (3a) by modifying
our previous protocol developed for the enantioselective
SYNLETT 2011, No. 19, pp 2875–2879
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289854; Art ID: U07011ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2876
D. Itakura, T. Harada
LETTER
arylation starting from aryl iodides (Scheme 2).5c Thus, 4-
F3CC6H4MgCl·LiCl was prepared by treatment of 2a (1.5
equiv) with i-PrMgCl·LiCl (1.7 equiv) in THF at room
temperature for three hours7b and then treated with titani-
um tetraisopropoxide (2.5 equiv). After the removal of
THF in vacuo and dissolution in CH2Cl2 and Et2O with
additional titanium tetraisopropoxide (1.5 equiv; to re-
place its partial loss during evacuation of THF), the result-
ing mixed titanium reagent was slowly added within two
hours to a CH2Cl2 solution of aldehyde 3a, 1 (2 mol%),
and titanium tetraisopropoxide (1 equiv) at 0 °C. Addi-
tional stirring for one hour afforded the corresponding di-
arylmethanol 4aa in 97% ee but in moderate yield. When
the amount of bromide 2a and i-PrMgCl·LiCl was in-
creased to 2 and 2.2 equivalents, respectively, the chemi-
cal yield of 4aa was improved to 95% while maintaining
high enantioselectivity.
MgCl⋅LiCl
Br
i-PrMgCl⋅LiCl
THF
F3C
F3C
2a
CHO
OH
1) Ti(Oi-Pr)4
2) in vacuo
3a
3) Et2O, CH2Cl2,
Ti(Oi-Pr)4
1 (2 mol%), Ti(Oi-Pr)4,
CH2Cl2, 0 °C
CF3
4) slow addition to
4aa
2a
i-PrMgCl⋅LiCl yield
ee
1.5 equiv 1.7 equiv
2.0 equiv 2.2 equuiv
50%
95%
97%
96%
Scheme 2
Table 1 Enantioselective Arylation of Aldehydes 3a–f by Using Bromides 2a–g as Aryl Sourcesa
O
2a; FG = 4-CF3 3a; R = 1-naphthyl
2b; FG = 3-CF3 3b; R = 4-ClC6H4
OH
R
H
1) i-PrMgCl⋅LiCl
Br
2c; FG = 3-Br
2d; FG = 2-Br
2e; FG = 3-CN
2f; FG = 4-CN
2g; FG = 2-CN
3c; R = 4-(CN)C6H4
3d; R = Ph
3e; R = 1-furyl
3f; R = c-hexyl
2) Ti(Oi-Pr)4
3a–f
R
FG
FG
1 (2 mol%), Ti(Oi-Pr)4,
CH2Cl2, 0 °C, 1 h
3) slow addition for 2 h
2a–g
4
Entry
Bromide 2
Aldehyde 3
Product 4
Yield (%)
ee (%)
OH
1
50
95
97
96
2a
3a
2b
CF3
4aa
OH
3b
4b
5b
6
2a
2a
2b
2c
3b
3c
3a
3a
85
94
86
71
86
99
87
94
Cl
CF3
4ab
OH
NC
CF3
4ac
OH
CF3
4ba
4ca
OH
Br
Synlett 2011, No. 19, 2875–2879 © Thieme Stuttgart · New York

LETTER
Catalytic Enantioselective Arylation
2877
Table 1 Enantioselective Arylation of Aldehydes 3a–f by Using Bromides 2a–g as Aryl Sourcesa (continued)
O
2a; FG = 4-CF3 3a; R = 1-naphthyl
2b; FG = 3-CF3 3b; R = 4-ClC6H4
OH
R
H
1) i-PrMgCl⋅LiCl
Br
2c; FG = 3-Br
2d; FG = 2-Br
2e; FG = 3-CN
2f; FG = 4-CN
2g; FG = 2-CN
3c; R = 4-(CN)C6H4
3d; R = Ph
3e; R = 1-furyl
3f; R = c-hexyl
2) Ti(Oi-Pr)4
3a–f
R
FG
FG
1 (2 mol%), Ti(Oi-Pr)4,
CH2Cl2, 0 °C, 1 h
3) slow addition for 2 h
2a–g
4
Entry
7
Bromide 2
Aldehyde 3
Product 4
Yield (%)
ee (%)
OH Br
2d
3a
50
0
4da
4ea
OH
CN
8
9
2e
2e
2e
3a
3d
3c
72
68
94
90
93
95
OH
CN
4ed
OH
CN
10
NC
4ec
OH
OH
CN
CN
O
11
12
2e
2e
3e
3f
87
54
87
63
4ee
4ef
OH
13b
2f
3a
80
84
CN
4fa
4fd
4gd
OH
14b
15
2f
3d
3d
61
23
86
78
CN
OH CN
2g
a Unless otherwise noted, reactions were carried out by using Grignard reagents generated by the reaction of bromides 2 (1.5 equiv) with
i-PrMgCl·LiCl (1.7 equiv, 1.3 M in THF) at r.t. (for 2a,b), at –15 °C for 2c,d, and at 0 °C for 2e–g.
b Bromides 2 (2 equiv) and i-PrMgCl·LiCl (2.2 equiv) were used in generation of Grignard reagents.
Synlett 2011, No. 19, 2875–2879 © Thieme Stuttgart · New York

2878
D. Itakura, T. Harada
LETTER
Typical Procedure for the Synthesis of (S)-3-[4-Cyanophe-
Under similar conditions, the reaction of p-substituted
benzaldehydes 3b,c with the mixed titanium reagent de-
rived from 2a provided the corresponding diarylmetha-
nols in high yields and high enantioselectivities (Table 1,
entries 3 and 4). Furthermore, the Grignard reagent pre-
pared from m-bromo(trifluoromethyl)benzene (2b) also
underwent enantioselective addition to aldehyde 3a to
give diarylmethanol 4ba in an efficient manner (Table 1,
entry 5). It has been reported that the preparation of (tri-
fluoromethyl)phenyl Grignard reagents by magnesium in-
sertion is dangerous owing to possible runaway
reactions.9,7d The successful use of this Grignard reagent
prepared by bromine–magnesium exchange is of synthet-
nyl(hydroxy)methyl]benzonitrile (4ec, Table 1, Entry 10)
To a 1.3 M THF solution of i-PrMgCl·LiCl (1.27 mL, 1.65 mmol)
at 0 °C, under an argon atmosphere, was added bromide 2e (0.273
g, 1.5 mmol). After being stirred for 3 h, the resulting solution of
m-cyanophenyl Grignard reagent was diluted with CH2Cl2 (4 mL)
at –78 °C. After addition of Ti(Oi-Pr)4 (0.74 mL, 2.5 mmol), the sol-
vents were removed under vacuum (1.3·10–4 bar, 0 °C), and the res-
idue was dissolved with Et2O (3.8 mL) and CH2Cl2 (10 mL). After
addition of Ti(Oi-Pr)4 (0.44 mL, 1.5 mmol), the resulting mixture
was slowly added over a period of 2 h by using a syringe pump to a
CH2Cl2 (4 mL) solution of ligand 1 (10.5 mg, 0.020 mmol), alde-
hyde 3c (0.131 g, 1.0 mmol), and Ti(Oi-Pr)4 (0.30 mL, 1.0 mmol)
at 0 °C. After being stirred for an additional hour, the reaction mix-
ture was quenched by the addition of aq 1 N HCl and extracted three
ic value in light of the fact that the (trifluoromethyl)phe- times with EtOAc. The organic layers were washed successively
with aq NaHCO3 (5% soln) and with brine, dried (Na2SO4), and
nyl moiety is frequently encountered in pharmaceutical
drugs.10
concentrated in vacuo. Flash chromatography (silica gel, 5–10%
EtOAc in toluene) of the residue gave 0.219 g (94% yield) of 4ec:
[a]D30 –9.8 (c 1.04, CHCl3; 95% ee). 1H NMR (500 MHz, CDCl3):
d = 2.8 (1 H, br), 5.89 (1 H, s), 7.44–7.51 (3 H, m), 7.56–7.58 (2 H,
m), 7.65 (2 H, d, J = 9.0 Hz). 13C NMR (125.8 MHz, CDCl3): d =
74.5, 111.8, 112.7, 118.4 (2 C), 127.1, 129.6, 130, 130.9, 131.6,
132.6, 144.2, 147.8. HRMS–FAB: m/z calcd for C15H11N2O [MH+]:
235.00871; found: 235.0871. The ee value was determined by
HPLC analysis using a Chiralpak AS-H column (1 mL/min, 1% i-
PrOH in hexane); retention times: 14.5 min (major S enantiomer)
and 11.7 min (minor R enantiomer).
Dibromobenzenes undergo selective monoexchange with
i-PrMgCl·LiCl to give bromophenyl Grignard reagents.7
3-Bromophenyl Grignard reagent prepared from 1,4-di-
bromobenzene (2c) could be successfully employed in
enantioselective addition to 1-naphthaldehyde 3a to give
4ca in high enantioselectivity (Table 1, entry 6). On the
other hand, the reaction starting from 1,2-dibromoben-
zene (2d) resulted in nonselective formation of the corre-
sponding adduct 4da (Table 1, entry 7).11
Starting from bromobenzonitriles 2e,f, a variety of diaryl-
methanol possessing a cyano group could be synthesized
in an enantiomerically enriched form. Thus, for example,
starting from 3-cyano derivative 2e (1.5 equiv) and alde-
hyde 3a, functionalized diarylmethanol 4ea was synthe-
sized in 72% and in 90% ee (Table 1, entry 8). Under
similar conditions, the mixed titanium reagent underwent
enantioselective addition to aromatic aldehydes 3d,c and
furfural (3e, Table 1, entries 9–11). On the other hand, the
reaction of aliphatic aldehyde 3f resulted in the formation
of the corresponding adduct 4ef in only moderate yield
and enantioselectivity (Table 1, entry 12). A mixed titani-
um reagent derived from 4-bromobenzonitrile (2f) also
underwent enantioselective addition to aldehyde 3a,d
(Table 1, entries 13 and 14) while, on the other hand, that
derived from 2-bromobenzonitrile (2g) exhibited a re-
duced product yield and enantioselectivity (Table 1, entry
15). Finally, the attempted reaction of 3a with a mixed ti-
tanium reagent derived from tert-butyl 4-bromobenzoate
resulted in the formation of complex mixtures of uniden-
tified products.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by Grant-in-Aid for Scientific Research
(No. 20550095) from Ministry of Education, Culture, Sports, Sci-
ence, and Technology (MEXT), Japan and by Kyoto Institute of
Technology Research Fund.
References and Notes
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In summary, we have developed a catatlytic enantioselec-
tive arylation of aldehydes using Grignard reagents gener-
ated in situ from functionalized aryl bromides. The
method is applicable to aryl bromides bearing a CF3, Br,
and CN group at the meta and para positions, affording
enantiomerically enriched functionalized diarylmethanols
of synthetic importance at a low catalyst loading (2
mol%).
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Synlett 2011, No. 19, 2875–2879 © Thieme Stuttgart · New York

LETTER
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