PdII-Catalyzed Regio- and Enantioselective Oxidative C?H/C?H Cross-Coupling Reaction between Ferrocenes and Azoles

Article abstract of DOI:10.1002/anie.201813887

Asymmetric C?H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein we disclose an asymmetric C?H/C?H cross-coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA) catalytic system which exhibits excellent reactivity and regioselectivity for oxazoles and thiazoles. This method offers a powerful strategy for constructing planar chiral ferrocenes. Mechanistic studies suggest that the C?H bond cleavage of azoles is likely proceeding through a S_EAr process and may not be a turnover limiting step.

Full text of DOI:10.1002/anie.201813887

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Accepted Article
Title: Pd(II)-Catalyzed Regio- and Enantioselective Oxidative C-H/C-H
Cross-Coupling Reaction between Ferrocenes and Azoles
Authors: Zhong-Jian Cai, Chen-Xu Liu, Qing Gu, Chao Zheng, and
Shuli You
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813887
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10.1002/anie.201813887
Angewandte Chemie International Edition
COMMUNICATION
Pd(II)-Catalyzed Regio- and Enantioselective Oxidative C-H/C-H
Cross-Coupling Reaction between Ferrocenes and Azoles
Zhong-Jian Cai,† Chen-Xu Liu,† Qing Gu*,† Chao Zheng,† and Shu-Li You*,†,‡
Abstract: Asymmetric C-H bond functionalization reaction is one of
the most efficient and straightforward methods for the synthesis of
optically active molecules. Herein we disclose an asymmetric C-H/C-
cross-coupling reaction of ferrocenes with oxazoles and
thiazoles. Although this approach was conceptually attractive,
the reactivity and the regioselectivity between C2-, C4- and C5-
H bonds of azoles remain challenging. More importantly,
experimental studies will be crucial to gain insights into the
mechanisms and important elementary steps of such
enantioselective dual C-H bond functionalization reactions.
Herein, we report our results from this study.
H
cross-coupling reaction of ferrocenes with azoles such as
oxazoles and thiazoles. Palladium(II)/monoprotected amino acid
(MPAA) catalytic system exhibits excellent reactivity and
regioselectivity for oxazoles and thiazoles. This method offers a
powerful strategy for constructing planar chiral ferrocenes.
Mechanistic studies suggest that the C-H bond cleavage of azoles is
likely proceeding via a SEAr process and may not be a turnover
limiting step.
Transition-metal-catalyzed C-H functionalization reaction
has tremendously contributed to the improvement of molecular
complexity from simple and readily available chemical
feedstocks.[1,2] In recent years, extensive efforts have been
made on the enantioselective C-H bond functionalization
reaction, which offers a highly atom- and step-economic method
towards the facile synthesis of high-value-added optically active
molecules.[3,4] From the viewpoint of atom and step economy, the
Scheme 1. Asymmetric C-H Arylation of Ferrocene.
We initially hypothesized that the more electrophilic C5-H of
oxazole might be a plausible reactive position that participates in
the cross-coupling reaction. Based on this proposal, we started
direct
asymmetric
cross-coupling
reaction
of
two
our attempt by allowing
a model substrate 2-methyl-4-
unfunctionalized arenes (Ar-H) would undoubtedly be an
attractive pathway to construct chiral compounds.[5] Our group
has been interested in developing asymmetric C-H bond
functionalization reaction to construct different types of
stereogenic elements.[6] For instance, we and others[7] have
developed several asymmetric C-H functionalization reactions of
ferrocenes to introduce planar chirality. In general, the
asymmetric C-H arylation reactions utilize functionalized arenes
such as aryl halides and aryl organometallic reagents (Scheme
1, a). We next turn our attention to develop enantioselective
oxidative C-H/C-H cross-coupling reaction of arenes (Scheme 1,
b).[8] Notably, oxazoles and thiazoles are fundamental ring
systems widely utilized in organic synthesis,[9] agrochemicals,[10]
pharmaceuticals[11] and organic functional materials such as
fluorescent dyes,[12] light emitting and liquid crystalline
materials[13]. The importance of oxazoles and thiazoles in
biologically active compounds and advanced materials
continues to inspire the development of synthetic application to
introduce them into novel frameworks. Inspired by the rapidly
growing area of transition-metal-catalyzed direct arylation
reaction of oxazoles and thiazoles with functionalized arenes,[14]
we began to explore the capability of enantioselective C-H/C-H
phenyloxazole 2a to react with dimethylaminomethylferrocene
1a.[15] To our delight, the desired product 3a was obtained in
83% yield and 98% ee in the presence of 10 mol% Pd(OAc)2, 20
mol% Boc-L-Ile-OH,[16] 2.0 equiv. K2CO3, 0.1 equiv. BQ, 4.0
equiv. H2O in DMA at 80 oC (Table 1). We then sought to
employ an O2 balloon to improve the reaction efficiency;
however, no obvious improvement was observed (entry 2). In
the absence of excessive H2O, the reaction proceeded smoothly
to give 3a in 81% yield without decreasing the ee value (entry 3).
However, in the absence of BQ, this operation gave 3a in a
diminished yield, and an enhanced yield of 72% was resulted in
combination with an O2 balloon (entries 4-5). These results
Table 1. Optimization of the reaction conditions. [a]
entry
deviation from standard conditions
yield (%)[b]
ee (%)[c]
98
1
2
3
4
5
6
7
8
none
O2
83
80
81
51
72
80
75
42
99
no H2O
99
[*]
Z.-J. Cai, C.-X. Liu, Dr. Q. Gu, Dr. C. Zheng, Prof. Dr. S.-L. You
† State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
‡ Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin 300072, China
no BQ
99
No BQ, under O2 atmosphere, no H2O
Pd(OAc)2 (5 mol%), no H2O
Pd(OAc)2 (2.5 mol%), no H2O
Pd(OAc)2 (1 mol%), no H2O
99
99
99
97
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2 (10 mol%),
Boc-L-Ile-OH (20 mol%), K2CO3 (0.6 mmol), H2O (1.2 mmol) and BQ (10
mol%) in DMA (2 mL) at 80 oC. [b] Yield of isolated product. [c] Determined by
HPLC analysis.
E-mail: slyou@sioc.ac.cn; qinggu@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813887
Angewandte Chemie International Edition
COMMUNICATION
highlight the critical role of BQ in promoting the enantioselective
cross-coupling reaction. Reducing Pd(OAc)2 to 5 mol% had
minimal deleterious effects (entry 6), whereas further lowering
the loading of palladium catalyst to 2.5 mol% decreased the
yield slightly (entry 7). A switch of the loading to 1 mol% further
reduced the yield of product 3a to 42%.
cases, a variety of 2-aryl-substituted thiazoles proved to be good
coupling partners, yielding the desired products 5a-e in
moderate yields with excellent ee. Meanwhile, the absolute
configuration of product 5e was confirmed by X-ray
crystallographic diffraction and found to be Rp (see the SI for
details). 2-Ethyl-4-methylthiazole, 2-ethyl-4-phenylthiazole and
ethyl 2-ethylthiazole-4-carboxylate are also suitable substrates.
Products 5f-h were isolated in 32-38% yields with excellent level
of enantioselectivity (95-96% ee).
Then, we investigated the scope of oxazole substrates
(Scheme 2). The introduction of electron-donating groups (Me,
MeO), halogen substituents (F, Cl) and electron-withdrawing
groups (CN, NO2) on the phenyl ring of 4-aryloxazole proved
acceptable, providing planar chiral ferrocenes in good to
excellent yields and excellent enantioselectivity (3b-i, 71-90%
yields, 98-99% ee). The 2-isopropyl and phenyl substituted
oxazoles reacted smoothly, generating the desired products 3j
and 3k respectively, in 81% and 84% yield with excellent ee.
Notably, this protocol was also applicable to 2,4-dimethyloxazole,
although the corresponding product 3l was obtained in a lower
yield (36% yield, 98% ee). In order to study the regioselectivity
of oxazoles, 4-phenyloxazole 2m was used as the cross-
coupling partner in our catalytic system. Interestingly, the
reaction proceeded smoothly to product (3m) with exclusive C5
regioselectivity in 61% yield and 94% ee. The moderate yield
was caused by the relatively low conversion of 2m. Furthermore,
2-aryloxazoles 2n-p are also suitable substrates for this process,
leading to the C5-oxazole products 3n-p regioselectivity in 69-
71% yields with excellent ee values (97-99%).
Reaction conditions: 1a (0.3 mmol), 4 (0.6 mmol), Pd(OAc)2 (10 mol%), Boc-L
-Ile-OH (20 mol%), K2CO3 (0.6 mmol), and BQ (10 mol%) in DMA (2 mL) at 80
oC for 24 h. Isolated yield is reported. Ee was determined by HPLC analysis.
Scheme 3. Scope of the thiazoles.
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Pd(OAc)2 (5 mol%), Boc-L-
Ile-OH (10mol%), K2CO3 (0.6 mmol), and BQ (10 mol%) in DMA (2 mL) at 80
oC for 14 h. Isolated yield is reported. Ee was determined by HPLC analysis.
Scheme 4. Gram-scale reaction and transformation.
Scheme 2. Scope of the oxazoles.
To further investigate the potential application of this
asymmetric dual C-H bonds functionalization, we conducted a
gram-scale reaction of 1a with 2k. To our delight, the cross-
coupling product 3k was obtained in 1.11 grams in 80% yield
and 99% ee (Scheme 4, a). In addition, the dimethylamino group
could be easily converted into an acetoxy group by a simple
nucleophilic substitution (Scheme 4, b).
We next examined the suitability of thiazoles as substrates
in the asymmetric cross-coupling reaction. Gratifyingly, a range
of thiazoles could be converted into the corresponding planar
chiral ferrocenes smoothly, although an increased catalyst
loading and a longer reaction time were necessary. In these
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10.1002/anie.201813887
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COMMUNICATION
To shed lights on the mechanism of this cross-coupling
reaction, we conducted a competitive experiment of 2c and 2i,
and it was found that products 3c and 3i were obtained in a
1.38:1 ratio (Scheme 5). This indicated that the relative rate of
C-H functionalization is slightly larger for electron-rich oxazole.
Scheme 5. Competitive experiment.
Scheme 7. Proposed catalytic cycle.
Next, we carried out the H/D exchange experiments of
oxazole and dimethylaminomethylferrocene under the standard
conditions. It was found that oxazole 2k could be deuterated
easily and 2k-[D] was obtained with high deuterium
incorporation in a short time (Scheme 6, a). However, product
1a-[D] was obtained in only 30% deuterium although the
reaction time was extended to 30 h (Scheme 6, b). In addition,
the kinetic isotope effect of the dual C-H bond functionalization
reaction was studied. It was found that the kinetic isotope effect
of oxazole was only 1.17 and a significant intermolecular kinetic
isotope effect (3.33) was obtained for ferrocene (Supporting
Information, S25-26). These above results suggested that the C-
H bond cleavage of oxazole likely proceeds via a SEAr process
and may not be a turnover limiting step. The C-H bond cleavage
of dimethylaminomethylferrocene 1a likely proceeds via a
concerted metalation deprotonation (CMD) pathway which may
be the rate-limiting step.
In summary, we have developed an efficient and
straightforward asymmetric C-H/C-H cross-coupling reaction of
ferrocenes with azoles such as oxazoles and thiazoles. The
reaction shows excellent regioselectivity toward C5-H bond of
various oxazoles and thiazoles and offers a powerful tool to
synthesize
planar
chiral
ferrocenes.
The
excellent
enantioselectivity and regioselectivity of this methodology are
derived from the combination of palladium acetate and a
monoprotected amino acid (MPAA) ligand. Competitive
experiments, H/D scrambling experiments, and kinetic studies
gave further insights into the mechanism. It is indicated that the
C-H bond cleavage of heteroarenes proceeds likely via a SEAr
process and may not be a turnover limiting step, and the C-H
bond cleavage of dimethylaminomethylferrocene 1a proceeds
likely via a concerted metalation deprotonation (CMD) pathway
which may be the rate-limiting step.
Acknowledgements
We thank the National Key R&D Program of China
(2016YFA0202900), the National Basic Research Program of
China (2015CB856600), NSFC (91856201, 21572250,
21821002), Program of Shanghai Subject Chief Scientist
(16XD1404300), and the CAS (XDB20000000, QYZDY-SSW-
SLH012) for generous financial support.
Keywords: azole • asymmetric catalysis • C-H activation •
ferrocene • regioselectivity
Scheme 6. Deuteration experiments.
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10.1002/anie.201813887
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Zhong-Jian Cai, Chen-Xu Liu, Qing Gu*,
Chao Zheng, and Shu-Li You*
Page No. – Page No.
Pd(II)-Catalyzed Regio- and
Enantioselective Oxidative C-H/C-H
Cross-Coupling Reaction between
Ferrocenes and Azoles
Asymmetric C-H bond functionalization reaction is one of the most efficient and
straightforward methods for the synthesis of optically active molecules. Herein we
disclose an asymmetric C-H/C-H cross-coupling reaction of ferrocenes with azoles
such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA)
catalytic system exhibits excellent reactivity and regioselectivity for oxazoles and
thiazoles. This method offers a powerful strategy for constructing planar chiral
ferrocenes. Mechanistic studies suggest that the C-H bond cleavage of azoles is
likely proceeding via a SEAr process and may not be a turnover limiting step.
This article is protected by copyright. All rights reserved.