Design of chiral sulfoxide-Schiff base hybrids and their application in Cu-catalyzed asymmetric Henry reactions

Article abstract of DOI:10.1039/c2cc31907a

A new class of chiral sulfoxide-Schiff base ligands has been developed by the rational combination of two privileged chiral backbones. These sulfoxide-Schiff base ligands were found to be highly efficient for Cu-catalyzed asymmetric Henry reactions (up to

Full text of DOI:10.1039/c2cc31907a

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Design of chiral sulfoxide–Schiff base hybrids and their application in
Cu-catalyzed asymmetric Henry reactionsw
Hong-Gang Cheng, Liang-Qiu Lu, Tao Wang, Jia-Rong Chen* and Wen-Jing Xiao*
Received 15th March 2012, Accepted 16th April 2012
DOI: 10.1039/c2cc31907a
A new class of chiral sulfoxide–Schiff base ligands has been
developed by the rational combination of two privileged chiral
backbones. These sulfoxide–Schiff base ligands were found to be
highly efficient for Cu-catalyzed asymmetric Henry reactions
(up to 98% yield and 96% ee).
impressive advances, there is still great room for the development
of new sulfoxide-based ligands with high stereoselectivity and
broad reaction scope.
On the other hand, catalytic asymmetric reactions employing
Schiff base derivatives, such as privileged salen ligands, have
been intensively investigated in recent years.11 However, to the
best of our knowledge, the Schiff base moiety has never been
incorporated into the sulfoxide scaffold as an additional
binding site. Moreover, as a further application of our
previously developed concept of catalyst development,12
the combination of two privileged chiral backbones into
one molecule for the design of new types of ligands and
catalysts,13 we envision that a rational assembly of the sulf-
oxide and Schiff base moieties with a suitable chiral backbone
may provide a new type of ligand (Fig. 1). Herein, we describe
the design and synthesis of such sulfoxide–Schiff hybrids as
efficient chiral ligands for highly enantioselective Henry
reactions.
Asymmetric metal catalysis as an efficient and powerful
method for obtaining enantiopure compounds has seen
tremendous advances in the past decades, and a great number
of chiral ligands have been successfully developed.1 A literature
survey reveals that the overwhelming majority are still limited
to phosphorus and nitrogen ligands, which usually involve
multistep synthesis or tedious separation procedures. Therefore,
the design of highly efficient and selective ligands and catalytic
systems for metal-catalyzed asymmetric reactions remains an
intriguing but challenging research topic in the chemical
community.1 Recently, sulfoxides have emerged as potentially
ideal ligand candidates for catalytic asymmetric transforma-
tions due to their ready availability, moisture and air stability,
and well-defined coordination features.2 Since the pioneering
work from the Dorta group on the successful application of a
new sulfur-based p-tol-BINASO ligand to the Rh-catalyzed
1,4-addition of boronic acids to a,b-unsaturated ketones,3 the
development of novel and efficient sulfoxide ligands has received
intensive research interest. For example, Liao and co-workers
developed a C2-symmetric chiral bis-sulfoxide ligand and also
successfully applied it to Rh-catalyzed asymmetric 1,4-addition
reactions.4 Inspired by these works, Zhou and Li et al. recently
described an efficient oxidative coupling reaction for the synthesis
of a series of bis-sulfoxide ligands containing a stereogenic axis.5
In addition to these chiral bis-sulfoxide ligands, other types of
hybrid ligands based on chiral sulfoxide have also been elegantly
developed. Representative examples include olefin-sulfoxide,6
phosphine sulfoxide,7 oxazoline sulfoxide,8 hydroxysulfoxide,9
and ferrocenyl sulfoxide ligands.10 Nevertheless, despite these
Starting from commercially available (1R,2S)-2-amino-1,2-
diphenylethanol, the target chiral sulfoxide–Schiff base ligand
1a could be synthesized in four steps in good overall yield
(see ESIw). We then evaluated its performances in the benchmark
asymmetric Henry reaction of 4-nitrobenzaldehyde with nitro-
methane.14,15 To our delight, with 10 mol% of Cu(OAc)2ꢀH2O
and 1a in t-BuOH, the reaction proceeded smoothly to provide
the corresponding product in 94% yield and 85% ee (Scheme 1).
To examine the roles of the sulfoxide group and Schiff
base moiety on the catalytic efficiency, we designed analogous
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China.
E-mail: jiarongchen2003@yahoo.com.cn, wxiao@mail.ccnu.edu.cn;
Fax: +86 27 67862041; Tel: +86 27 67862041
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterisation data, including X-ray
crystal data for 1g (CCDC 852993). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc31907a
Fig. 1 Design of chiral sulfoxide–Schiff base ligand.
c
5596 Chem. Commun., 2012, 48, 5596–5598
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Table 1 Ligand screeninga
Entry
Ligand
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
24
24
24
24
108
20
32
24
48
24
30
95
92
91
94
53
96
92
93
90
94
94
88
88
87
80
24
90
90
86
90
80
93
9
10
11d
1j
1f
a
Unless otherwise noted, reactions were carried out with 2a
(0.4 mmol), 3a (1.0 mL), Cu(OAc)2ꢀH2O (10 mol%) and
Scheme 1 Control experiments.
1
b
c
(12 mol%) in t-BuOH (4.0 mL) at 25 1C. Isolated yield. Determined
by chiral HPLC, the absolute configuration was established as R by
ligands 5–9 for control experiments. Comparison studies
using ligands 1a and 5–7 revealed that the presence of chiral
sulfoxide groups is critical for the reaction efficiency and
enantioselectivity. Notably, either protection of the hydroxyl
group or reduction of the imine group resulted in diminished
yield and ee, which indeed highlighted the importance of these
two binding sites.
d
comparison with literature data. 2.5 mol% of Cu(OAc)2ꢀH2O and
3 mol% of 1f were used.
and enantioselectivity (entry 6, 90% ee). Importantly, when
the catalyst loading of 1f was reduced to 2.5 mol%, a slight
increase in enantioselectivity was observed (Table 1, entry 11,
93% ee).
These results have shown that both the sulfoxide group and
the Schiff base moiety are indispensable for the high catalytic
efficiency and enantioselectivity.
Experiments to probe the scope of the asymmetric Henry
reaction were performed under optimal reaction conditions.
As highlighted in Table 2, a wide range of aldehydes bearing
electron-withdrawing (Table 2, entries 1–9), electron-donating
(Table 2, entries 11–12), and electron-neutral (Table 2, entry 10)
groups can be readily tolerated for the aromatic aldehydes,
providing the corresponding products in excellent enantio-
selectivities (91%–96% ee) and high yields. Moreover, the
condensed aromatic aldehyde (2-naphthaldehyde) (Table 2,
entry 13), heteroaromatic aldehydes (Table 2, entries 14–15)
and cinnamaldehyde (Table 2, entry 16) were also suitable for
this reaction, giving the desired products in 61–91% yields and
91–95% ee. Notably, aliphatic aldehydes were also success-
fully utilized and high enantioselectivities and good yields were
obtained (Table 2, entries 17–19). Finally, nitroethane was
also investigated and the corresponding adduct 4t was
obtained in good yield and enantioselectivity, albeit with
moderate diastereoselectivity (Table 2, entry 20).
Encouraged by these preliminary results, we prepared an
array of other chiral sulfoxide–Schiff base ligands bearing
different substituents (Fig. 2) and explored their catalytic
efficiency in the Henry reaction. As summarized in Table 1,
all the sulfoxide–Schiff base ligands were effective for the
model reaction (90–96% yield, 80–90% ee), except for the
sterically bulky ligand 1e (53% yield, 24% ee) (Table 1, entry 5).
Moreover, it was found that the electronic properties of the
sulfoxide group had little influence on this reaction (Table 1,
entries 1–3, 6). Then, we continued to investigate the effect of
substituents on the benzene ring of the Schiff-base moiety
(Table 1, entries 7–10). Generally, electron-withdrawing
groups resulted in higher enantioselectivity but with longer
reaction time, while electron-donating ones displayed better
catalytic reactivity with lower enantioselectivity. Finally, 1f
was found to be the ligand of choice with respect to the yield
In summary, we have developed a new class of chiral
sulfoxide–Schiff base ligand by the rational combination of
two privileged chiral architectures. These sulfoxide–Schiff base
hybrids were found to be highly efficient for the Cu-catalyzed
asymmetric Henry reaction, furnishing the corresponding
products with excellent yields and enantioselectivities. Studies
into the precise reaction mechanism and further applications
of this type of ligands in other transition-metal catalyzed
asymmetric transformations are currently underway in our
laboratory.
We are grateful to the National Science Foundation of
China (NO. 21002036) and the National Basic Research
Program of China (2011CB808603) for support of this
research.
Fig. 2 Chiral sulfoxide–Schiff base ligands explored in this study and
X-ray structure of ligand 1g.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5596–5598 5597

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Table 2 Substrate scope examinationa
76, 7256; (g) T.-S. Zhu, S.-S. Jin and M.-H. Xu, Angew. Chem.,
Int. Ed., 2012, 51, 780.
7 For selected examples, see: (a) K. Hiroi, Y. Suzuki and R. Kawagishi,
Tetrahedron Lett., 1999, 40, 715; (b) K. Hiroi, Y. Suzuki, I. Abe and
R. Kawagishi, Tetrahedron, 2000, 56, 4701; (c) K. Hiroi, I. Izawa,
T. Takizawa and K. Kawai, Tetrahedron, 2004, 60, 2155; (d) J. Sola,
M. Reves, A. Riera and X. Verdaguer, Angew. Chem., Int. Ed., 2007,
´
46, 5020; (e) F. Lang, D. Li, J.-M. Chen, J. Chen, L.-C. Li, L.-F. Cun,
J. Zhu, J.-G. Deng and J. Liao, Adv. Synth. Catal., 2010, 352, 843;
(f) F. Lang, G.-H. Chen, L.-C. Li, J.-W. Xing, F.-Z. Han, L.-F. Cun
and J. Liao, Chem.–Eur. J., 2011, 17, 5242.
Entry
R
R0
Product Yield (%)b Ee (%)c
1
2
3
4
5
6
7
8
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CF3Ph
4-ClPh
4-BrPh
2-FPh
2,4-Cl2Ph
3,4-F2Ph
Ph
2-OCH3Ph
2-CH3Ph
2-Naphthyl
2-Furyl
2-Thiophenyl
PhCHQCH
PhCH2CH2
CH3(CH2)3CH2
(CH3)2CH
4-ClPh
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
94
94
95
96
91
94
93
98
90
85
92
84
75
91
61
72
90
90
66
87e
93
94
96
94
92
92
93
95
94
93
94
91
93
95
92
91
92
92
92
68/81f
8 For selected examples, see: (a) K. Hiroi, K. Watanabe, I. Abe and
M. Koseki, Tetrahedron Lett., 2001, 42, 7617; (b) K. Watanabe,
T. Hirasawa and K. Hiroi, Chem. Pharm. Bull., 2002, 50, 372; (c) K.
Watanabe, T. Hirasawa and K. Hiroi, Heterocycles, 2002, 58, 93;
(d) G. J. Rowlands and W. K. Barnes, Chem. Commun., 2003, 2712.
9 For selected examples, see: (a) M. Ordofiez, G. Rosa, V. Labastida
and J. M. Llera, Tetrahedron: Asymmetry, 1996, 7, 2675;
(b) K. Hiroi and M. Ishii, Tetrahedron Lett., 2000, 41, 7071.
10 For selected examples, see: (a) J. Priego, O. G. Mancheno,
S. Carretero and J. C. Carretero, Chem. Commun., 2001, 2026;
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11 For recent reviews, see: (a) P. G. Cozzi, Chem. Soc. Rev., 2004,
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(c) C. Baleizao and H. Garcia, Chem. Rev., 2006, 106, 3987;
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(f) W. Zhang, J. L. Loebach, S. R. Wilson and E. N. Jacobsen,
J. Am. Chem. Soc., 1990, 112, 2801; (g) R. Irie, K. Noda, Y. Ito,
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9
10
11
12
13
14
15
16
17d
18d
19d
20
CH3 4t
a
Unless otherwise noted, reactions were carried out with 2 (0.4 mmol),
3 (1.0 mL), Cu(OAc)2ꢀH2O (2.5 mol%) and 1f (3 mol%) in t-BuOH
b
c
(4.0 mL) at 25 1C for 30–132 h. Isolated yield. Determined by
chiral HPLC. 1.0 mmol of 2 and 2.0 mL of 3 were used. The ratio
d
e
f
of anti/syn was 3 : 2, as determined by chiral HPLC. Ee of anti and
12 (a) J.-R. Chen, H.-H. Lu, X.-Y. Li, L. Cheng, J. Wan and
W.-J. Xiao, Org. Lett., 2005, 7, 4543; (b) J.-R. Chen, X.-Y. Li,
X.-N. Xing and W.-J. Xiao, J. Org. Chem., 2006, 71, 8198;
(c) J.-R. Chen, X.-L. An, X.-Y. Zhu, X.-F. Wang and
W.-J. Xiao, J. Org. Chem., 2008, 73, 6006.
syn isomers.
Notes and references
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14 For recent reviews, see: (a) J. Boruwa, N. Gogoi, P. P. Saikia and
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c
5598 Chem. Commun., 2012, 48, 5596–5598
This journal is The Royal Society of Chemistry 2012