Palladium-catalyzed intramolecular asymmetric C-H functionalization/ cyclization reaction of metallocenes: An efficient approach toward the synthesis of planar chiral metallocene compounds

Article abstract of DOI:10.1021/ja500699x

A palladium-catalyzed asymmetric synthesis of planar chiral metallocene compounds is reported. The reaction stereoselectively functionalized one of the ortho C-H bonds of Cp rings by intramolecular cyclization to form indenone derivatives in high yields w

Full text of DOI:10.1021/ja500699x

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Intramolecular Asymmetric C−H
Functionalization/Cyclization Reaction of Metallocenes: An Efficient
Approach toward the Synthesis of Planar Chiral Metallocene
Compounds
Ruixian Deng,† Yunze Huang,† Xinna Ma, Gencheng Li, Rui Zhu, Bin Wang, Yan-Biao Kang,*
and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
S
* Supporting Information
(−)-sparteine/lithium complex or chiral lithium amide,
ABSTRACT: A palladium-catalyzed asymmetric synthesis
of planar chiral metallocene compounds is reported. The
reaction stereoselectively functionalized one of the ortho
C−H bonds of Cp rings by intramolecular cyclization to
form indenone derivatives in high yields with excellent
enantioselectivity. The mild set of reaction conditions
allowed a wide variety of chiral metallocene compounds to
be synthesized with broad functional group tolerance. The
influences of preinstalled chiralities on the other Cp-ring
were also investigated.
respectively.
Catalytic asymmetric approaches to the synthesis of chiral
planar molecules are a desirable alternative to using chiral
starting materials and/or stoichimetric amounts of chiral
reagents or auxiliaries. Currently studies on the catalytic
asymmetric construction of planar chiral compounds mostly
focus on the desymmetrization of prochiral compounds. The
groups of Uemura,9 Schmalz,10 Kundig,11 and Richards12 have
̈
developed palladium-catalyzed desymmetric cross-couplings of
prechiral dihalogenated metallocenes with chiral ligands to
discriminate between these two halogen atoms with moderate
to excellent enantioselectivities. Very recently You and Gu have
reported a direct oxidative Pd(II)/amino acid-catalyzed
asymmetric C−H functionalization reaction that couples
aminomethylferrocenes with organic boronic acids.13 Gold(I)-
catalyzed desymmetric cyclizations of 1,3-dihydroxymethyl-2-
alkynylbenzene chromium complexes have also been demon-
strated to generate planar chiral molecules with high
enantioselectivities.14 Additionally the Ogasawara and Takaha-
shi group described a synthesis of planar chiral phosphaferro-
cenes via chiral molybdenum carbene-catalyzed ring-closing
metathesis.15 However, the development of new efficient
methods for the synthesis of scaffold-different planar chiral
metallocenes with good functional group tolerance is still
challenging and necessary.
lanar chiral molecules have attracted great attention these
P
past decades since they were first predicted by Cahn,
Ingold, and Prelog in 1966.1 This class of compounds
represents the most successful scaffolds for chiral ligands and
catalysts for asymmetric catalysis. Examples of such planar
ligands and catalysts include Josiphos and Fu’s catalysts etc.
(Figure 1).2 Additionally, applications which incorporate planar
Catalytic direct arylation of arenes is a powerful and atom
economic method16 for the construction of biaryl compounds,
which has caught significant attention in recent years.17,18
Despite tremendous advances and great efforts that have been
made for enantioselective C−H activation by the groups of Yu,
Cramer, and others,19 there are still only very limited studies
that focused on the Pd(0)-initiated asymmetric arylation of
arenes.19i−m The deficit in the area reflects the great challenges
in controlling both the reactivity and stereoselectivity for these
transformations.
Here we report a palladium(0)-initiated catalytic asymmetric
intramolecular C−H functionalization/arylation reaction to
synthesize planar chiral metallocenes with high enantioselectiv-
ities. We anticipate that during the C−H functionalization step
Figure 1. Representative ferrocene-based planar chiral ligands and
catalyst.
chiral molecules have also appeared in biochemistry and
material sciences.3 Ligands or catalysts that contain planar
chiralities, in some cases combining with other chiral moieties,
usually showed very unique characters.
Several approaches have been developed to access these
types of chiral scaffolds. Diastereoselective synthesis is one of
the most frequently used methods for preparation of planar
chiral compounds. This preparation includes the use of Ugi’s
amine4 as well as the introduction and use of various of chiral
auxiliaries.5,6 Additionally, the groups of Snieckus7 and
Simpkins8 have demonstrated that “traceless” enantioselective
ortho-directed metalation reactions of ferrocene compounds
can be accomplished by using a stoichimetric amount of a
Received: January 22, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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Communication
a chiral palladium(II)/phosphine complex would discriminate
between two ortho C−H bonds on the Cp ring. This strategy
has several advantages: (1) a variety of commercially available
or readily prepared phosphine ligands are suitable for screening
for Pd(0)-initiated reactions; (2) over-reacted byproducts
(double cross-couplings products) could be avoided by the
intramolecular cyclization process, and as a result usually high
yields could be achieved.
Our initial studies commenced with the reaction of the
model compound 4a, which was readily prepared by a Friedel−
Crafts acylation reaction from 2-iodobenzoyl chloride and
ferrocene. With monodentate phosphine ligand (R)-MOP the
reaction did not take place at all and starting material was
recovered (Table 1, entry 1).20 By the use of P,N-ligand Ph-
dioxane provided 5a in moderate yield and good enantiose-
lectivity (entries 7−10). Finally considering the cost and easy
accessibility, BINAP was chosen as the optimal ligand. The
reaction at an elevated reaction temperature (100 °C) with (R)-
BINAP gave an increased isolated yield (85%) without loss in
enantioselectivity (entry 11).21
On the basis of these results, the generality of this reaction
was tested by the subjection of various substituted acyl
metallocene compounds to the optimized reaction conditions.
The reactions work well for 5-methyl or 4,5-dimethoxyl
substituted iodobenzenes, affording excellent yields and
enantioselectivities (Table 2, 5b and 5c). The aryl chloride
a
Table 2. Substrate Scope
a
Table 1. Reaction Condition Optimization
b
c
entry
ligand
solvent
yield /%
NR
ee/%
1
2
3
4
5
6
7
8
9
(R)-MOP
toluene
toluene
toluene
toluene
toluene
toluene
DMF
−
d
Ph-Phox
10
<5
98
98
80
−
−
−
−
93
(R)-BINAP
(R)-tolBINAP
(R)-Segphos
(R,R)-DIOP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
74
74
85
<5
NR
NR
NR
77
(ClCH2)2
CH3CN
dioxane
toluene
e
10
e
11
85
99
a
The reaction was conducted with 4 (0.10 mmol), Pd(OAc)2 (5 mol
a
The reaction was conducted with 4a (0.10 mmol), Pd(OAc)2 (5 mol
%), ligand (6.5 mol %) [for (R)-MOP, 13 mol %], Cs2CO3 (2.0 equiv)
%), (R)- or (S)-BINAP (6.5 mol %), Cs2CO3 (2.0 equiv) at 100 °C for
5−12 h.
b
c
at 80 °C. Isolated yields. The ee% was determined by HPLC analysis
on chiral columns. The absolute configuration of the product was not
determined. There was 17% of conversion after 12 h at 100 °C. The
reactions were conducted at 100 °C for 10 h.
d
e
bond is well tolerated, which provided opportunities for further
functionalization (5d). With 2-iodonaphthalene derivatives, the
reaction performance was equally efficient, affording the
corresponding product in 89% yield with 97% ee (5e).
Notably, bis(cyclopentadienyl) ruthenium (ruthenocene) de-
rivatives are suitable substrates, and the corresponding
cyclization products are yellow or light red solids and stable
enough for chromatography. For instance, under standard
conditions the reactions with ruthenocenes proceeded
uneventfully and gave the products with excellent enantiose-
lectivities, albeit with relatively low yields (5f−h).
Compared to the traditional lithium reagent-mediated
transformations, the relatively mild conditions of palladium
catalysis allow a wide range of functional groups. As depicted in
Table 3, substitutions on the second Cp ring could include
aldehyde, ketones, carboxyl ester, and amides (Table 3, 5i−m).
Notably, the amide bearing a free N−H bond is tolerant, which
did not affect the palladium catalyst by chelation (5n). In
addition, under the current reaction conditions the terminal
Phox the reaction afforded 10% of isolated product 5a, which
was essentially racemic (entry 2). Fortunately, in the presence
of 5 mol % Pd(OAc)2 and 6.5 mol % of (R)-BINAP full
conversion was achieved and product 5a was isolated in 74%
yield with 98% ee (entry 3). Encouraged by these results, other
bidentate phosphine ligands were further screened: (R)-
tolBINAP showed promising results for this transformation in
both yield and enantioselectivity (entry 4). The reaction with
(R)-segphos delivered 5a in decent enantioselectivity albeit the
yield was increased to 85% (entry 5). It is interesting to find
that tartaric acid derived bidentate phosphine (R,R)-DIOP was
not suitable for this cyclization reaction, giving a very poor
conversion (entry 6). A brief screening of the solvents revealed
that DMF, 1,2-dichloroethane, and CH3CN were not good
solvents for this transformation, while the reaction in 1,4-
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Communication
a
Table 3. Substrate Scope
Scheme 1. Effects of the Preinstalled Chiral Moieties
Scheme 2. Plausible Catalytic Cycle
phosphine ligand could discriminate between two ortho
C(Cp)−H bonds to selectively form II, which ultimately
delivered the cyclization product 5a via reductive elimination.
In summary, the present results demonstrated an efficient
synthesis of planar chiral metallocenes by the strategy of a
palladium-catalyzed intramolecular C−H functionalization/
cyclization reaction. Generally good to excellent yields with
high enantioselectivities could be achieved. This method
provided a new and efficient way to synthesize structurally
different planar chiral metallocenes with a wide range of
functional group tolerance. Studies on the mechanistic aspects
and applications of these structurally new metallocene
compounds in organic synthesis are underway in our
laboratories.
a
The reaction was conducted with 4 (0.10−0.15 mmol), Pd(OAc)2 (5
mol %), (R)- or (S)-BINAP (6.5 mol %), Cs2CO3 (2.0 equiv) at 100
°C for 5−12 h.
CC double bond and α,β-unsaturated ester are compatible,
which are conventional substrates for Pd-catalyzed Heck
reactions. For instance, the reactions afforded 5o and 5p in
excellent yields and enantiomeric excesses, and no intra- or
intermolecular Heck product was detected. Forrecenes bearing
an electron-rich group, such as CH2OTBS and tert-butyl, on the
second Cp ring are also good substrates, which could be
efficiently advanced to the desired cyclization products in
excellent selectivity and yields (5q and 5r).
In order to discover the effects of the preinstalled chiral
moieties (center and planar chiralities) on this transformation,
two additional reactions were conducted (Scheme 1). The
chiral amide 4s derived from (R)-α-methylbenzylamine was
subjected to the optimized reaction conditions in the presence
of (S)-BINAP giving 5sa in 91% yield and >25:1
diastereoselectivity, while with (R)-BINAP the reaction favored
the formation of the other diastereomer with a dr of <1:25. It is
worth noting that the double cyclization of 4t also worked well,
delivering the desired product 5t with excellent diastereo- and
enantioselectivity, indicating the “preformed” planar chirality
does not affect the second cyclization reaction.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, HPLC traces,
1H and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
zhgu@ustc.edu.cn
■
ybkang@ustc.edu.cn
Author Contributions
†R.D. and Y.H. contributed equally.
Notes
The authors declare no competing financial interest.
A brief catalytic cycle with 4a as the representative substrate
was proposed in Scheme 2. The oxidative addition of Pd(0)
with 4a gave the anticipated palladium species I, which would
undergo C−H palladation to afford II.22 The Pd with a chiral
ACKNOWLEDGMENTS
This work was financially supported by the National Natural
Science Foundation of China (21272221), the Recruitment
■
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Journal of the American Chemical Society
Communication
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Program of Global Experts, the Fundamental Research Funds
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rative Teams Program for Science, Technology and Innovation
(2014-2016) from the Chinese Academy of Sciences. We thank
Dr. C. E. Stivala (Stanford University) for his assistance with
the manuscript preparation.
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