Functionalized BINOL-mono-PHOS for multinuclear Cu-catalysts in asymmetric conjugate addition of organozinc reagents

Article abstract of DOI:10.1246/cl.130080

Functionalization of BINOL-mono-PHOS achieved the Cucatalyzed highly asymmetric conjugate addition of organozinc reagents to enones. The incorporation of a bulky hydroxy group at the 3'-position of BINOL-mono-PHOS dramatically improved the yield and enantioselectivity. The present novel BINOL-mono-PHOS ligands are effective in the Cu-catalyzed asymmetric conjugate addition of organozinc reagents in both acyclic enones and cyclohexenone.

Full text of DOI:10.1246/cl.130080

doi:10.1246/cl.130080
Published on the web April 24, 2013
547
Functionalized BINOL-mono-PHOS for Multinuclear Cu-Catalysts
in Asymmetric Conjugate Addition of Organozinc Reagents
Kohei Endo,*1,2 Sayuri Yakeishi,3 Daisuke Hamada,3 and Takanori Shibata*3
1Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa 920-1192
2PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012
3Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University,
Shinjuku-ku, Tokyo 169-8555
(Received January 31, 2013; CL-130080; E-mail: kendo@se.kanazawa-u.ac.jp)
Previous Concept of Multinuclear Complexes
Functionalization of BINOL-mono-PHOS achieved the Cu-
catalyzed highly asymmetric conjugate addition of organozinc
reagents to enones. The incorporation of a bulky hydroxy group
at the 3¤-position of BINOL-mono-PHOS dramatically improved
the yield and enantioselectivity. The present novel BINOL-
mono-PHOS ligands are effective in the Cu-catalyzed asym-
metric conjugate addition of organozinc reagents in both acyclic
enones and cyclohexenone.
M1
P
X
X
P
P
X
X
P
P
M2
RnM2
M1
XH
XH
M2
M1
P
n
We previously reported that BINOL or SPINOL bearing
bisphosphorous moieties at the ortho-positions of hydroxy
moieties, named BINOL-PHOS and SPINOL-PHOS, generated
multinuclear Cu/Zn, Pd/Zn, or Cu/Al complexes for highly
efficient asymmetric alkylation reactions.1 In some cases, the use
of BINOL bearing monophosphorous moiety at the 3-position,
named BINOL-mono-PHOS, gave improved catalytic perform-
ance. The use of BINOL-mono-PHOS achieved excellent
catalytic performance in the Cu-catalyzed asymmetric conjugate
addition of organoaluminum reagents to ¢,¢-disubstituted
enones to create chiral quaternary carbon centers, although
BINOL-PHOS gave lower enantioselectivity; the simple mod-
ification of a diarylphosphino moiety in BINOL-mono-PHOS
could improve the yield and enantioselectivity.1d However,
typical BINOL-mono-PHOS derivatives did not improve the
yield and enantioselectivity in the Cu-catalyzed asymmetric
conjugate addition of organozinc reagents. Since ligands that can
realize high asymmetric induction for both acyclic and cyclic
enones are rare, facile approaches to the design of ligands should
be important in the Cu-catalyzed conjugate addition.2,3 Herein,
we describe the novel design of phosphorous ligands with a
peripheral substituent at the 3¤-position of BINOL (Figure 1).
The ligands were easily prepared from the commercially
available BINOL (Scheme 1). The mono-lithiation of MOM-
protected (R)-BINOL B1 using tert-BuLi and the nucleophilic
addition to ClPPh2, followed by the acidic deprotection of MOM
groups gave BmP1. The lithiation of 3-phenyl-MOM-protected
(R)-BINOL B2 using n-BuLi, the subsequent nucleophilic
addition to ClPPh2, and the following acidic deprotection gave
BmP2. The lithiation of MOM-protected BINOL-mono-PHOS
B3, formylation using DMF, and the reduction using NaBH4,
followed by the acidic deprotection gave BmP3. The lithiation
of B3, nucleophilic addition to benzophenone, and the following
acidic deprotection gave BmP4.
PAr2
PAr2
OH
OH
OH
OH
PAr2
R
Previous Work
Present Work
Figure 1. Influence of substituent at 3¤-position of BINOL-
mono-PHOS.
long reaction time (23 h) and gave the desired product 2a in 81%
yield with 80% ee (Entry 1). In sharp contrast, the use of BmP2
bearing a phenyl group at the 3¤-position completed the reaction
within 1 h and gave the product 2a in 98% yield albeit with 64%
ee (Entry 2). The bulky substituent at the peripheral 3¤-position
seems to promote the reaction. Furthermore, the incorporation of
hydroxymethyl group at the 3¤-position improved the enantio-
selectivity (Entry 3). Finally, the use of BmP4 bearing a bulky
diphenylhydroxymethyl group gave the product 2a in 94% yield
with 97% ee (Entry 4).
The scope of enones is described (Table 2). The reaction of
chalcone derivatives 1a-1g bearing an electron-withdrawing or
-donating group can give the desired products 2a-2g in high to
excellent yields with high ee (Entries 1-7). The enones 1h-1j
bearing an electron-rich aromatic substituent were available
(Entries 8-10). Aliphatic substituents instead of aryl substituents
did not decrease the yields and enantioselectivities (Entries 11
and 12). However, enones 1m and 1n bearing an acetyl moiety
diminished the yields and enantioselectivities (Entries 13 and
14).
We further examined the use of cyclohexenone as a model
cyclic enone (Table 3). The screening of Cu-salts with BmP1
showed that the use of CuBr¢SMe2 was suitable to achieve high
yield with high ee (Entries 1-9).5 The screening of BINOL-
We initially examined the ligands for the Cu-catalyzed
asymmetric conjugate addition of Et2Zn (3 equiv) to chalcone in
THF at ¹20 °C (Table 1). The reaction using BmP1 required a
Chem. Lett. 2013, 42, 547-549
© 2013 The Chemical Society of Japan
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548
Table 2. Scope of acyclic enones4
1) t-BuLi (1.1 equiv)
THF, –78 °C, 3 h
ClPPh2 (1.5 equiv)
–78 °C–rt, 1 h
PPh2
Et2Zn (3 equiv)
CuCl2·2H2O (5 mol %)
OH
OH
OMOM
OMOM
BmP4 (10 mol %)
O
Et
O
2) HCl aq. MeOH, reflux
R1
R2
R1
R2
THF, –20 °C, time
1a–n
2a–n
BmP1, 54%
B1
Entry R1, R2
Time/h
Yield, ee/%a
1) n-BuLi (1.5 equiv)
ether, rt, 3 h
then THF, rt, 1 h
ClPPh2 (1.5 equiv)
rt, 0.5 h
PPh2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a, Ph, Ph
3
3
2
1
7
2
5
9
5
6
2
1
2
1
2a, 94, 97 (S)
2b, 95, 96 (+)
2c, 97, 96 (S)
2d, 94, 95 (S)
2e, 92, 94 (+)
2f, 88, 96 (¹)
2g, 76, 97 (S)
2h, 89, 95 (¹)
2i, 76, 97 (¹)
2j, 85, 93 (+)
2k, 94, 96 (R)
2l, 80, 94 (+)
2m, 82, 88 (S)
2n, 80, 77 (¹)
1b, 4-F-Ph, Ph
1c, 4-Cl-Ph, Ph
1d, 4-F3C-Ph, Ph
1e, 4-Me-Ph, Ph
1f, 4-biphenylyl, Ph
1g, 4-MeO-Ph, Ph
1h, 2-Np, Ph
OH
OH
OMOM
OMOM
2) HCl aq. EtOH
reflux, 16 h
Ph
Ph
B2
BmP2, 30%
1) n-BuLi (1.5 equiv)
ether, rt, 3 h
then THF, rt, 1 h
DMF (10 equiv)
–94 °C–rt, 10 min
PPh2
PPh2
1i, 2-furyl, Ph
OH
OH
1j, 2-thienyl, Ph
1k, cyclohexyl, Ph
1l, n-pentyl, Ph
1m, Ph, Me
OMOM
OMOM
2) NaBH4 (3 equiv)
CH2Cl2 /MeOH
0 °C, 30 min
3) HCl aq. MeOH
reflux, 16 h
OH
BmP3, 46%
B3
B3
1n, n-butyl, Me
aIsolated yields. ee was determined by chiral HPLC analysis or
chiral GC analysis.
1) n-BuLi (1.3 equiv)
ether, rt, 3 h
PPh2
then THF, rt, 1 h
benzophenone (3 equiv)
rt, 12 h
Table 3. Addition of Et2Zn to cyclohexenone
OH
OH
Et2Zn (3 equiv)
3) HCl aq. THF, reflux, 2 d
Cu-salt (5 mol %)
ligand (10 mol %)
O
O
OH
Ph Ph
BmP4, 54%
THF, –20 °C, time
Et
1o
2o
Scheme 1. Synthesis of representative ligands.4
PAr2
Table 1. Screening of ligands
BmP5; Ar = 4-MeC6H4-
BmP6; Ar = 2-MeC6H4-
BmP7; Ar = 3,5-Me2C6H3-
BmP8; Ar = 3,5-(F3C)2C6H3-
OH
OH
Et2Zn (3 equiv)
CuCl2·2H2O (5 mol %)
ligand (10 mol %)
O
Et
O
Ph
Ph
Ph
Ph
THF, –20 °C, time
Entry Cu-salt
Ligand Time/h Yield, ee/%a
1a
2a
1
2
3
CuCl2¢2H2O
BmP1
BmP1
BmP1
BmP1
4
5
24
5
98, 58
NDb, 55
91, 76
97, 83
88, 23
88, 94
25, 33
90, 68
98, 83
>98, 90
87, 71
>98, >98
>98, 94
75, 46
78, 89
>98, 98
b
Entry
Ligand
BmP1
BmP2
BmP3
BmP4
Time/h
Yield, ee/%a
Cu(OAc)2
[Cu(acac)2]
Cu(OTf)2
1
2
3
4
23
1
6
81, 80
98, 64
97, 89
94, 97
4
5
Cu(NO3)2¢3H2O BmP1
24
8
24
20
3
1
22
1
3
6
7
CuBr¢SMe2
CuOAc
BmP1
BmP1
BmP1
BmP1
BmP2
BmP3
BmP4
BmP5
BmP6
BmP7
BmP8
aIsolated yields. ee was determined by chiral HPLC analysis.
8
CuTC
9
CuI¢0.75SMe2
CuBr¢SMe2
CuBr¢SMe2
CuBr¢SMe2
CuBr¢SMe2
CuBr¢SMe2
CuBr¢SMe2
CuBr¢SMe2
10
11
12
13
14
15
16
mono-PHOS derivatives in the presence of CuBr¢SMe2 achieved
more than 98% yield with more than 98% ee (Entry 12).
Furthermore, BINOL-mono-PHOS derivatives BmP5-BmP8
were examined;1d BmP8 bearing electron-withdrawing substitu-
ents on a phosphorous moiety showed an excellent perform-
ance.6
The methylation reaction using Me2Zn for asymmetric
conjugate addition to cyclohexenone was examined (Table 4).
Although the use of BmP4 as a ligand gave a poor result
2
24
2
1
aNMR yields. ee was determined by chiral GC analysis. Not
determined, due to the complicated spectrum.
Chem. Lett. 2013, 42, 547-549
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

549
Table 4. Addition of Me2Zn to cyclohexenone
Me2Zn (x equiv)
This work was supported by JST PRESTO program, Grant-
in-Aid for Young Scientists (B) (Nos. 21750108 and 23750049)
from the Japan Society for the Promotion of Science, and
Hokuriku Bank.
CuBr·SMe2 (5 mol %)
ligand (10 mol %)
O
O
THF, 0 °C, time
Me
References and Notes
1o
3o
1
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D. Hamada, S. Yakeishi, T. Shibata, Angew. Chem., Int. Ed.
2013, 52, 606.
Entry
Ligand
BmP4
BmP8
BmP8
BmP8
x
Time/h
Yield, ee/%a
1
2
3
4
3
3
1.5
5
7
7
21
2
23, 19
49, >98
15, >98
84, >98
2
3
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(Entry 1), the use of BmP8 as a ligand realized an excellent
enantioselectivity (Entry 2). The use of excess amount of Me2Zn
was required to obtain a high yield of product (Entry 4).
We further examined the reaction using chalcone (1a) and
Me2Zn. The reaction proceeded in the presence of BmP4, but the
desired product was not obtained (eq 1).7 The use of BmP8 gave
the desired product in poor yield with moderate enantioselec-
tivity, because of the generation of various amount of
unidentified by-products.
Me2Zn (3 equiv)
CuCl2·2H2O (5 mol %)
ligand (10 mol %)
THF, 0 C–rt, 24 h
O
Me
O
ð1Þ
Ph
Ph
R1
R2
°
1a
3a
not obtained
14%, 56% ee
BmP4
BmP8
To elucidate the structure of Cu/Zn complexes, the ESI-
TOF-MS analyses of Zn and Cu/Zn complexes derived from
BINOL-mono-PHOS were performed. Various unidentified
peaks were observed, but the structure of the complexes is
unclear. The isotope pattern indicated that Zn and Cu atoms
could be incorporated in the complexes. We deduced that the
deprotonation reaction of triol moieties seems to be essential,
and led to the generation of oligomeric complexes in situ.
In conclusion, we developed a new approach to the
improvement of catalytic performance based on functionalized
BINOL-mono-PHOS derivatives in the Cu-catalyzed asymmet-
ric conjugate addition of organozinc reagents. The bulky
substituent at the peripheral 3¤-position of BINOL-mono-PHOS
promoted the reaction, and the incorporation of hydroxy moiety
improved the enantioselectivity. The reaction of cyclohexenone
took place with excellent enantioselectivity in the presence of
BINOL-mono-PHOS ligands, which is one of the superior
characteristics of BINOL-mono-PHOS to BINOL-PHOS deriv-
atives bearing bisphosphorous moieties. The influence of the
steric repulsion around the 3¤-position of BINOL architecture as
well as the effect of metal atoms should be examined further.
The present paper could show the new approach to the
improvement of catalytic performance based on our multinuclear
system. Therefore, further functionalization of BINOL-mono-
PHOS derivatives is ongoing to develop metal-linked complexes
for catalytic reactions and will be reported in the future.
4
5
6
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
A dramatic influence of Cu-salts, see: A. Alexakis, C.
Benhaim, S. Rosset, M. Humam, J. Am. Chem. Soc. 2002,
124, 5262.
The reaction of (E)-chalcone (1a) and Et2Zn (3 equiv) in the
presence of CuCl2¢2H2O (5 mol %) and BmP8 (10 mol %) in
THF at ¹20 °C for 2 h gave the product 2a in 75% yield with
96% ee (S).
7
K. Endo, T. Shibata, Synthesis 2012, 44, 1427.
Chem. Lett. 2013, 42, 547-549
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/