Rational design of sulfoxide-phosphine ligands for Pd-catalyzed enantioselective allylic alkylation reactions

Article abstract of DOI:10.1039/c3cc49488h

A new type of chiral sulfoxide-phosphine ligands have been developed by a rational combination of two privileged scaffolds for Pd-catalyzed asymmetric allylic alkylation reactions. Under optimized conditions, generally high yields (up to 97%) and excellent enantioselectivities (up to >99% ee) were obtained.

Full text of DOI:10.1039/c3cc49488h

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Rational design of sulfoxide–phosphine ligands
for Pd-catalyzed enantioselective allylic alkylation
reactions†
Cite this: Chem. Commun., 2014,
50, 2873
Received 14th December 2013,
Accepted 24th January 2014
Hong-Gang Cheng,ab Bin Feng,ab Li-Yan Chen,ab Wei Guo,ab Xiao-Ye Yu,ab
Liang-Qiu Lu,ab Jia-Rong Chen*ab and Wen-Jing Xiao*ab
DOI: 10.1039/c3cc49488h
www.rsc.org/chemcomm
A new type of chiral sulfoxide–phosphine ligands have been developed
by a rational combination of two privileged scaffolds for Pd-catalyzed
asymmetric allylic alkylation reactions. Under optimized conditions,
generally high yields (up to 97%) and excellent enantioselectivities
(up to >99% ee) were obtained.
The increasing demand for enantiopure compounds for pharma-
ceuticals, agrochemicals, and materials has catapulted asymmetric
catalysis to be one of the most important frontiers in chemical
Scheme 1 Design of chiral sulfoxide–phosphine ligands.
sciences.1 Not surprisingly, the search for high synthetic efficiency units for transition-metal catalyzed asymmetric carbon–carbon
and enantioselectivity continues to stimulate the development bond formation processes (Scheme 1).
of innovative strategies and concepts for catalyst and ligand
Palladium-catalyzed asymmetric allylic alkylation (AAA; also
design. New chiral catalysts and ligands are usually prepared named as the Tsuji–Trost reaction) represents one of the most
from natural chiral sources or through the modification of powerful synthetic methods for the construction of various
existing chiral scaffolds. In this regard, the latter provides a carbon–carbon and carbon–heteroatom bonds.5 As a result,
promising platform for the design of new efficient ligands since numerous efficient chiral ligands have been developed for this
a wealth of powerful ligands have been identified and employed transformation. However, the use of the S-chiral sulfoxide
in asymmetric transition-metal catalysis over the past several ligands has not yet been extensively explored for this reaction.6
decades.2 Recently, a new strategy involving rational combination Since the pioneering work by Shibasaki,7 a wide range of chiral
of two privileged backbones into one molecule was adopted in our sulfoxide ligands have thereafter been designed for Tsuji–Trost
laboratory for the design of novel organocatalysts.3 Along this reactions, such as bis-sulfoxide,8 sulfoxide-phosphine,9 sulfoxide-
line, we recently developed a new type of sulfoxide-Schiff base oxazoline,10 sulfoxide-amine11 and sulfoxide-sulfide.12 In spite of
ligands, which exhibited excellent efficiency and stereoselectivities these impressive contributions, the development of more efficient
in the Cu-catalyzed asymmetric Henry reaction (Scheme 1).4 sulfoxide-based ligands for the Pd-catalyzed AAA reactions remains
More importantly, the chiral sulfoxide-amino unit has proved highly desirable. Herein, we wish to communicate the develop-
to be critical to the stereoinduction. Encouraged by these results, ment of a new type of sulfoxide–phosphine ligands by combining
we attempted to design other new sulfoxide-containing ligands sulfoxide-amino with a soft base element, aryl phosphine unit, and
by merging such sulfoxide-amino units with aryl phosphine their application in the Pd-catalyzed AAA reactions.
Initially, the sulfoxide ligand 2 containing imino-phosphine
motif was successfully synthesized by the condensation of
a Key Laboratory of Pesticide & Chemical Biology of Education, Ministry College of
2-(diphenylphosphino)benzaldehyde with our key intermediate
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
chiral sulfoxide amine4 (see ESI† for details). Compared with
Hubei 430079, China. E-mail: chenjiarong@mail.ccnu.edu.cn,
wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041; Tel: +86 27 67862041
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
China
the previous chiral sulfoxide-Schiff base 1 (48 h, trace), greatly
improved reaction efficiency was observed in the model reaction
of rac-(E)-1,3-diphenylallyl acetate 4a and dimethyl malonate 5a
(95% yield) (Scheme 2). Unfortunately, a poor enantioselectivity
was obtained (37% ee). We expected that replacing the basic
imine linker between the sulfoxide-amino and phosphine units
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterisation data, including X-ray crystal data for 3d. CCDC
971186. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc49488h
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Table 1 Ligand screeninga
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3
3
3
3
3
3
12
12
99
99
99
99
99
99
98
97
98.8
98.8
99.0
98.6
98.7
98.4
87.0
84.0
3g
3h
a
Unless otherwise noted, reactions were carried out with 4a (0.3 mmol),
5a (0.9 mmol), [Pd(C3H5)Cl]2 (2 mol%), 3 (4 mol%), K2CO3 (0.75 mmol)
Scheme 2 Initial attempts and control experiments.
b
and Cs2CO3 (0.15 mmol) in CH2Cl2 (3.0 mL) at 40 1C. GC yield.
c
Determined by chiral HPLC; the absolute configuration was estab-
lished as S by comparison with literature data.
with an amide group would result in good enantioselectivity
preserving the high yield. Similarly, the target ligand 3a can be
easily prepared in a high yield from commercially available
2-(diphenylphosphino)benzoic acid and our key intermediate,
enantiopure sulfoxide amine (see ESI† for details). To our
delight, the use of ligand 3a resulted in the formation of the
corresponding product with 97% ee, albeit in moderate yield
(46%), which suggested that the absolute configurations of
diamine and sulfoxide moieties in 3a matched well with each
other (Scheme 2). Replacement of the imine linker in 2 with
amide group was beneficial for the coordination of Pd species
with both phosphine and sulfoxide groups, and therefore provided
a better steric environment for asymmetric induction.6 To evaluate
the effects of the sulfoxide group and phosphine moiety on the
catalytic performance, we have designed analogous ligands 7–9
for control experiments. The poor results with ligands 7–9
revealed that both chiral sulfoxide group and phosphine moiety
were essential for the high efficiency and enantioselectivity of
the model reaction.
To further improve the chemical yield and enantioselectiv-
ity, we continued to optimize reaction conditions. Screening of
various bases13 and temperature indicated that a mixture of
K2CO3 and Cs2CO3 at 40 1C gave optimal results (Table S1 in the
ESI†). In addition, investigation of the catalyst loading showed
that 2 mol% of [Pd(C3H5)Cl]2 was enough for reaching high
reaction efficiency and stereoselectivity (Table S4 in the ESI†).
Encouraged by these preliminary results, we have synthesized
a small library of chiral sulfoxide–phosphine ligands with
different substituents on the sulfoxide moiety (Scheme 3) and
examined their catalytic efficiency in the model AAA reaction.
As highlighted in Table 1, most of the sulfoxide–phosphine
ligands proved to be effective for the model reaction, giving 6a
in good yields with high enantioselectivities (97–99% yields,
84.0–99.0% ee). It was found that the electronic properties
of the sulfoxide group had little influence on this reaction
(Table 1, entries 1–6). In the case of ligand 3g, the reaction
became sluggish and the enantiomeric excess dramatically
decreased to 87.0% (Table 1, entry 7), suggesting that a
sterically bulky R group would disfavour the coordination
and stereoinduction. Moreover, incorporation of the aliphatic
group into the ligand, such as 3h, also resulted in an obvious
decrease in catalytic efficiency and enantioselectivity (Table 1,
entry 8, 84.0% ee).
With optimal chiral sulfoxide–phosphine ligand 3c in hand,
we then investigated the substrate scope in these Pd-catalyzed
AAA reactions under optimized reaction conditions. As shown
in Table 2, a variety of symmetric 1,3-dicarbonyl compounds
5a–5g can react with rac-(E)-1,3-diphenylallyl acetate 4a efficiently
to afford the corresponding products 6a–6g with excellent
yields and enantioselectivities (Table 2, entries 1–7, 93–97%
yields, 97.4–99.3% ee). The unsymmetric 1,3-dicarbonyl com-
pounds, such as 5h–5j, can also participate in this transforma-
tion; however, diastereoselectivities are not good (Table 2,
entries 8–10). Notably, this reaction exhibited a high tolerance
of the 1,3-diphenylallyl acetate components. For example,
substrates bearing either the electron-donating or electron-
withdrawing substituents on the aromatic ring underwent the
reaction smoothly to give the desired products in good yields
with high levels of enantioselectivities (Table 2, entries 11–14,
86–95% yields, 98.0–98.5% ee).
To demonstrate the synthetic potential of the AAA products,
we removed the ester groups of products 6h and 6i under
the basic conditions in refluxing MeOH–H2O.14 After 1 h,
the corresponding products 10a and 10b can be obtained in
high yields without any loss of enantiomeric excess (eqn (1)).
More importantly, product 6g has been successfully applied for
Scheme 3 Chiral sulfoxide–phosphines and the X-ray structure of 3d.
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Table 2 Substrate scopea
Notes and references
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1994; (b) E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Comprehensive
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Entry
4
5
Product
Yieldb (%)
eec (%)
3 (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;
(d) H.-H. Lu, X.-F. Wang, C.-J. Yao, J.-M. Zhang, H. Wu and
W.-J. Xiao, Chem. Commun., 2009, 4251; (e) J.-R. Chen, Y.-J. Cao,
Y.-Q. Zou, F. Tan, L. Fu, X.-Y. Zhu and W.-J. Xiao, Org. Biomol. Chem.,
2010, 8, 1275.
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
96
95
94
97
95
93
93
96
94
93
86
93
92
95
99.0 (S)
99.0 (S)
98.8 (S)
97.4 (S)
99.1 (R)
98.7 (R)
99.3 (R)
98.6/98.4d
98.5/98.3e
98.6/96.0 f
98.2 (S)
98.5 (S)
98.0 (S)
98.3 (S)
4 H.-G. Cheng, L.-Q. Lu, T. Wang, J.-R. Chen and W.-J. Xiao, Chem.
Commun., 2012, 48, 5596.
9
10
11
12
13
14
5j
5 For selected reviews, see: (a) B. M. Trost and D. L. VanVranken,
Chem. Rev., 1996, 96, 395; (b) Z. Lu and S. Ma, Angew. Chem., Int. Ed.,
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and A. C. Burns, Angew. Chem., Int. Ed., 2013, 52, 2260.
6 For selected reviews on S-chiral sulfoxide ligands, see: (a) M. Mellah,
A. Voituriez and E. Schulz, Chem. Rev., 2007, 107, 5133;
(b) H. Pellissier, Tetrahedron, 2007, 63, 1297; (c) T. Toru and
C. Bolm, Organosulfur Chemistry in Asymmetric Synthesis, Wiley-VCH,
Weinheim, 2008; (d) H. Pellissier, Chiral Sulfur Ligands: Asymmetric
Catalysis, Royal Society of Chemistry, Cambridge, U.K., 2009.
7 R. Tokunoh, M. Sodeoka, K. Aoe and M. Shibasaki, Tetrahedron Lett.,
1995, 36, 8035.
5a
5a
5a
5a
a
Unless otherwise noted, reactions were carried out with 4 (0.3 mmol),
5 (0.9 mmol), [Pd(C3H5)Cl]2 (2 mol%), 3c (4 mol%), K2CO3 (0.75 mmol)
and Cs2CO3 (0.15 mmol) in CH2Cl2 (3.0 mL) at 40 1C for 3 h. Isolated
yield. Determined by chiral HPLC, the absolute configuration was
b
c
d
established by comparison with literature data. The d.r. was 52 : 48 as
determined using chiral HPLC and 1H NMR. The d.r. was 55 : 45 as
e
determined using chiral HPLC and 1H NMR. The d.r. was 55 : 45
f
as determined using chiral HPLC and 1H NMR.
a convenient synthesis of the cyclopentene 11 by ring-closing
metathesis (eqn (2)).15
(1)
(2)
8 R. Siedlecka, E. Wojaczynka and J. Skarzewski, Tetrahedron: Asym-
metry, 2004, 15, 1437.
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Lett., 1998, 39, 6499; (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) S. Nakamura, T. Fukuzumi
and T. Toru, Chirality, 2004, 16, 10; (e) J. Chen, F. Lang, D. Li, L. Cun,
J. Zhu, J. Deng and J. Liao, Tetrahedron: Asymmetry, 2009, 20, 1953;
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Tetrahedron: Asymmetry, 1994, 5, 1895; (b) J. F. Bower, C. J. Martin,
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1996, 333.
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Tetrahedron: Asymmetry, 1998, 9, 3797.
12 J. Liu, G. Chen, J. Xing and J. Liao, Tetrahedron: Asymmetry, 2011,
22, 575.
In summary, we have developed a new class of chiral sulfoxide–
phosphine ligands by a rational combination of chiral sulfoxide-
amino scaffold and soft basic phosphine groups. These new ligands
were found to be highly efficient for Pd-catalyzed AAA reactions,
affording the corresponding products in excellent yields (up to 97%)
and enantioselectivities (up to >99% ee). Studies on possible
coordination mode between the metal and the ligand, and
further applications of this type of ligands to other transforma-
tions are currently ongoing in our laboratory.16
We are grateful to the National Science Foundation of China
(No. 21272087, 21002036, and 21202053) and the National
13 K. Ouyang and Z. Xi, Acta Chim. Sin., 2013, 71, 13.
´ˇ ´
´ ˇ
´
ˇ ´
Basic Research Program of China (2011CB808603) for support 14 M. Paˇzick´y, V. Semak, B. Gaspar, A. Bılesova, M. Salisova and
´˘
A. Bohac, ARKIVOC, 2008, 8, 225.
of this research. H.-G. Cheng is thankful for the Excellent
Doctoral Dissertation Cultivation Grant from Central China
Normal University (CCNU13T04060, 2013YBYB54).
15 J. Dugal-Tessier, G. R. Dake and D. P. Gates, Org. Lett., 2010, 12, 4667.
16 Currently, attempts to get the X-ray crystal structure of Pd–3c
complex were unsuccessful.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 2873--2875 | 2875