Enantioselective synthesis of planar chiral ferrocenes via Pd(0)-catalyzed intramolecular direct C-H bond arylation

Article abstract of DOI:10.1021/ja500444v

A highly efficient synthesis of planar chiral ferrocenes by enantioselective Pd(0)-catalyzed direct C-H arylation from readily available starting materials under mild reaction conditions was developed (up to 99% yield, 99% ee). The products can be easily transformed to the highly efficient planar ferrocene ligands, which have demonstrated high efficiency in Pd-catalyzed asymmetric allylic alkylation and amination reactions.

Full text of DOI:10.1021/ja500444v

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of Planar Chiral Ferrocenes via Pd(0)-
Catalyzed Intramolecular Direct C−H Bond Arylation
De-Wei Gao, Qin Yin, Qing Gu,* and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. China
S
* Supporting Information
both cases, the required oxidative conditions would cause the
ABSTRACT: A highly efficient synthesis of planar chiral
ferrocenes by enantioselective Pd(0)-catalyzed direct C−H
arylation from readily available starting materials under
mild reaction conditions was developed (up to 99% yield,
99% ee). The products can be easily transformed to the
highly efficient planar ferrocene ligands, which have
demonstrated high efficiency in Pd-catalyzed asymmetric
allylic alkylation and amination reactions.
decomposition of ferrocene, leading to undesired side products.
Aside from these studies, the catalytic enantioselective synthesis
of planar chiral ferrocenes remains sporadic. In the light of their
wide application in both academia and industry mentioned
above, development of efficient syntheses of planar chiral
ferrocenes under mild reaction conditions is extremely
desirable. We envisioned that Pd(0)-catalyzed intramolecular
C−H arylation may be an effective way to synthesize planar
chiral ferrocenes (Figure 1). Particularly, eliminating external
oxidant would avoid the side products due to the oxidation of
ferrocene. In this Communication, we report such a direct
access to enantiopure planar chiral ferrocene derivatives via
Pd(0)-catalyzed intramolecular C−H arylation.
o-Bromobenzoylferrocene 2a, readily prepared from ferro-
cene via Friedel−Crafts acylation, was chosen as the model
substrate. In the presence of 5 mol % of Pd(OAc)2 and 5.5
mol % of (Ra)-BINAP, gratifyingly, our preliminary attempt at
80 °C afforded the arylative product 3a in 99% yield and 95%
ee (Table 1, entry 1). Increasing the loading of ligand to 10
mol % gave even higher enantioselectivity (98% ee, Table 1,
entry 2). By lowering the temperature to 60 °C, the
enantioselectivity could be further improved to 99% ee without
affecting the yield (99% yield, Table 1, entry 3). However, the
reaction at room temperature did not afford any desired
product, even after 24 h. Next, different chiral ligands were
systematically examined. As shown in Table 1, the mono-
phosphine ligand L2 could also be used to catalyze the reaction
with moderate ee but low conversion. The phosphoramidite
ligands L3−L5 had no catalytic activity (Table 1, entries 7−9).
As expected, the reactions with the diphosphine ligands L6 and
L7 also proceeded in excellent yields and enantioselectivity
(>99% ee, Table 1, entries 10 and 11). Given its relatively low
cost and ready availability, (Ra)-BINAP was chosen for further
studies. Screening of bases, acids, and solvents led to the
following optimal reaction conditions: 2.5 mol % of Pd(OAc)2,
5.0 mol % of (Ra)-BINAP, 30 mol % of pivalic acid, and 1.5
equiv of Cs2CO3 in p-xylene at 60 °C (see the Supporting
Information for details).
errocene now serves as a widely applicable organometallic
F
scaffold for the preparation of functional molecules in
catalysis, material science, and, more recently, biomedicinal
chemistry.1 Particularly, ferrocenes with planar chirality have
been widely employed as ligands or catalysts in asymmetric
catalysis.2 Some of them have found industrial applications in
the production of pharmaceuticals and agrochemicals (Josiphos
and PPFA, Figure 1). Therefore, considerable efforts have been
Figure 1. Chiral ferrocene ligands and newly designed enantioselective
C−H arylation.
devoted to the synthesis of planar chiral ferrocenes.3,4 In this
regard, the methods employed extensively involve diastereose-
lective directed ortho-metalation (DoM),5 enantioselective
DoM,6 and resolution.7 Although these approaches have been
well developed and widely applied, in most cases preinstalled
chiral auxiliaries and external stoichiometric chiral bases have
been required.
Under the above optimized reaction conditions, the substrate
scope was then explored. As summarized in Table 2, various
substituents on the different positions of the phenyl ring (4-Me,
5-Me, 6-Me, 7-Me, 6-MeO, 6-F, 6-Cl), regardless of their
electronic nature, were well tolerated. Their corresponding
Recently, Ogasawara and co-workers8 reported an elegant
method to prepare planar chiral ferrocenes through ring-closing
metathesis reactions. We developed a facile introduction of
planar chirality into the ferrocene backbone via enantioselective
C−H functionalization.9,10 Employing a similar strategy, Cui,
Wu, and their co-workers11 reported the synthesis of planar
chiral ferrocenes via Pd-catalyzed oxidative Heck reaction. In
Received: January 15, 2014
Published: March 13, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Optimization of C−H Arylation
Table 2. Pd(0)-Catalyzed Enantioselective Synthesis of
Planar Chiral Ferrocenes
a
b
c
entry
R1, R2 (3)
temp (°C) time (h) yield (%)
ee (%)
1
2
3
4
5
6
7
8
H, H (3a)
60
80
60
60
80
60
80
60
24
35
24
24
24
19
18
42
99
95
99
99
98
99
99
97
98
98
98
99
99
99
98
99
4-Me, H (3b)
5-Me, H (3c)
6-Me, H (3d)
7-Me, H (3e)
6-MeO, H (3f)
6-F, H (3g)
6-Cl, H (3h)
b
c
entry
ligand
temp (°C)
time (h)
yield (%)
ee (%)
d
1
L1
L1
L1
L1
L2
L2
L3
L4
L5
L6
L7
80
80
60
rt
10
10
18
24
18
18
18
18
18
22
22
99
99
99
tr
95
98
2
3
4
5
99
nd
60
60
60
60
60
60
60
21
26
tr
53
e
6
55
a
7
nd
Reaction conditions: 2a (0.3 mmol), Pd(OAc)2 (2.5 mol %), (Ra)-
BINAP (5.0 mol %), Cs2CO3 (1.5 equiv), pivalic acid (0.3 equiv) in p-
8
tr
nd
b
c
xylene (1.5 mL) at 60 or 80 °C. Isolated yield. Determined by
9
tr
nd
HPLC analysis.
10
11
99
87
>99
>99
Scheme 1. Gram-Scale Synthesis of 3a
a
Reaction conditions: 2a (0.2 mmol), Pd(OAc)2 (5 mol %), ligand
(10 mol %), Cs2CO3 (1.5 equiv), pivalic acid (0.3 equiv) in p-xylene
b
(1.5 mL) unless noted otherwise. Isolated yield (tr = trace).
c
d
Determined by HPLC analysis (nd = not detected). 5.5 mol % L1
e
was used. With 20 mol % of ligand.
planar chiral ferrocenyl products were obtained in excellent
yields and enantioselectivity (95−99% yield, 98−99% ee, Table
2). The reaction of substrate 2i, bearing a naphthyl substituent,
proceeded smoothly to afford the desired product 3i in 82%
yield and 98% ee. Notably, ferrocenes possessing a pentamethyl
Cp ring, which could not be tolerated previously,9a were
suitable substrates under the same conditions, giving the
arylative products 3j and 3k in excellent yields and
enantiocontrol (96% yield, 99% ee and 91% yield, 99% ee,
respectively). Interestingly, introduction of an aryl bromide on
each Cp ring was also tolerated for the double C−H arylation
process: C2-symmetric planar chiral ferrocene 3l was obtained
in 97% yield and >99% ee. The stereochemistry of the products
was confirmed unambiguously by X-ray crystallographic
analysis of a crystal of enantiopure 3a. The absolute
configuration was assigned as Rp (see the Supporting
Information for details).
As a further demonstration of the utility of the current
methodology, we developed an efficient synthesis of planar
chiral P,N ligand 7, in which planar chirality was previously
introduced by the DoM strategy.12 As shown in Scheme 2,
ferrocene 6 was readily prepared from arylative product 3a
through oximation, reduction (dr = 1:1), and subsequent
Scheme 2. Synthesis of Planar Chiral P,N Ligand 7
To test the practicality of the methodology, a gram-scale
reaction was carried out. The intramolecular arylation of 2a on
a 4.0 mmol scale gave the desired product in 99% yield and
97% ee without any erosion on both yield and enantiose-
lectivity (Scheme 1). Furthermore, when the catalyst loading
was reduced to 0.5 mol %, the arylative product 3a was
obtained in a quantitative yield and excellent ee (99% yield,
96% ee).
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Journal of the American Chemical Society
Communication
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reductive amination in 36% yield over three steps. The two
diastereoisomers of 6 could be easily separated by silica gel
column chromatography. The chiral P,N ligand 7 was
accomplished by lithiation of (S, Rp)-6 and subsequent trapping
with diphenylphosphanyl chloride in 68% yield. Ligand 7 has
been demonstrated to be highly efficient in Pd-catalyzed
asymmetric allylic alkylation and amination reactions.12
In summary, we have developed a highly efficient synthesis of
planar chiral ferrocenes by enantioselective Pd(0)-catalyzed
direct C−H arylation from readily available starting materials
under mild reaction conditions. Compared with the previous
oxidative C−H arylation,9a such an overall redox-neutral
process (Pd0/PdII catalysis) does not require an external
stoichiometric oxidant, which avoids ferrocenium generation
and is also crucial for compatibility with various commercially
available chiral phosphine ligands. It is noteworthy that a
straightforward transformation of the products provides a
concise access to the highly efficient planar ferrocene ligands.
Synthesis of ligands and catalysts from these enantiopure
ferrocenes and development of new catalytic systems are
currently ongoing in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analysis data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
́
A.-N.; Gomez-Sal, P.; Rios, R.; Moyano, A. Tetrahedron: Asymmetry
2009, 20, 1314.
AUTHOR INFORMATION
Corresponding Authors
qinggu@sioc.ac.cn
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review: (f) Ogasawara, M.; Watanabe, S. Synthesis 2009, 1761.
(9) (a) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J. Am.
Chem. Soc. 2013, 135, 86. (b) Shi, Y.-C.; Yang, R.-F.; Gao, D.-W.; You,
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■
slyou@sioc.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (973
Program 2010CB833300) and National Natural Science
Foundation of China (21025209, 21121062, 21272253,
21332009), and the Science and Technology Commission of
Shanghai Municipality (13JC1406900) for generous financial
support. This paper is dedicated to Professor Li-Xin Dai on the
occasion of his 90th birthday.
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