Rh(III)-Catalyzed meta-C-H Alkenylation with Alkynes

Article abstract of DOI:10.1021/jacs.8b11038

Rh(III)-catalyzed meta-C-H functionalization reactions are still rare. Herein, we report the first example of Rh(III)-catalyzed meta-C-H alkenylation with disubstituted alkynes directed by a U-shaped nitrile template. Exclusive regio-selectivity has been achieved using unsymmetrical aryl and alkyl-disubstituted alkynes to afford synthetically valuable trisubstituted olefins. Propargyl alcohols are also compatible, affording complex allylic alcohols. Notably, transition metal-catalyzed meta-alkenylation with alkynes has not been successful with Pd catalysts.

Full text of DOI:10.1021/jacs.8b11038

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Communication
Rh(III)-Catalyzed meta-C–H Alkenylation with Alkynes
Hua-Jin Xu, Yan-Shang Kang, Hang Shi, Ping Zhang, You-Ke Chen, Bing
Zhang, Zhi-Qiang Liu, Jing Zhao, Wei-Yin Sun, Jin-Quan Yu, and Yi Lu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Dec 2018
Downloaded from http://pubs.acs.org on December 26, 2018
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Rh(III)-Catalyzed meta-C–H Alkenylation with Alkynes
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Hua-Jin Xu,† Yan-Shang Kang,† Hang Shi,‡ Ping Zhang,† You-Ke Chen,† Bing Zhang,†
Zhi-Qiang Liu,† Jing Zhao,† Wei-Yin Sun,*,† Jin-Quan Yu,*,‡ Yi Lu*,†
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† Coordination Chemistry Institute, State Key Laboratory of Coordination Chemistry, School of Chemistry
and Chemical Engineering, Nanjing National Laboratory of Microstructures, Collaborative Innovation
Center of Advanced Microstructures, Nanjing University, Nanjing 210023, China
‡ Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, USA
RECEIVED DATE (automatically inserted by publisher); sunwy@nju.edu.cn, yu200@scripps.edu, luyi@nju.edu.cn
Scheme 1. Directed meta-C–H Functionalization
Abstract: Rh(III)-catalyzed meta-C–H functionalization reactions
are still rare. Herein, we report the first example of Rh(III)-
catalyzed meta-C–H alkenylation with di-substituted alkynes
directed by a U-shaped nitrile template. Exclusive regio-selectivity
has been achieved using unsymmetrical aryl and alkyl-disubstituted
alkynes to afford synthetically valuable tri-substituted olefins.
Propargyl alcohols are also compatible, affording complex allylic
alcohols. Notably, transition metal-catalyzed meta-alkenylation
with alkynes has not been successful with Pd catalysts.
In the last decade, diverse C–H activation transformations
have been developed to introduce various functional groups at the
ortho-position of arenes via five or six-membered cyclopalladation
directed by various coordinating groups,[1] including weakly
In a preliminary study, [RhCp*Cl2]2 was selected as the catalyst,
coordinating functional groups.[2] Rhodium(III) complexes have
Cu(OAc)2 and AcOH as additives for the reaction. Dry DCE was
also emerged as effective catalysts that are complementary to Pd(II)
used as the solvent under a nitrogen atmosphere at 120 °C.
catalysts.[3] However, directed remote meta- or para-C–H bond
Regrettably, no desired product was obtained under these
activation using Rh(III) catalysts has been difficult, because of the
conditions. Considering the importance of counter-ions in Rh
ring strain of the macrocyclic transition states.[4] Following the Pd-
catalysts,[9] we screened a series of Rh catalysts, and fortunately,
catalyzed meta-C–H activation using U-shaped templates,[5] we
reported the first example of Rh-catalyzed meta-C–H olefination of
acrylates via a macrocyclic cyclophane-like transition state
(Scheme 1).[6] Meta-selective C–H olefination with a different class
we obtained the desired product in 14% yield in the presence of
[Cp*Rh(MeCN)3](SbF6)2 (entry 1). This result indicates that the
cationic Rh(III) species are more effective for the electrophilic C–
H activation step or the alkyne insertion step. Solvent screening
of arene substrates using the nitrile template under rhodium(I)
demonstrated that only DCE and DCM gave the desired product,
catalysis has also been reported.[7] However, both examples were
with DCE proving more effective than DCM (See Supporting
limited to the coupling with acrylate derivatives. Herein, we report
the first example of Rh(III)-catalyzed meta-selective C–H
activation with di-substituted alkynes which are significantly less
reactive than the polarized and reactive Michael acceptor acrylate.
The exclusive regio- and stereoselectivity obtained using
unsymmetrical alkynes bearing alkyl and aryl substituents is
appealing for the synthesis of tri-substituted alkenes. Notably,
efforts to develop this meta-C–H activation reaction using Pd(II)
catalysts have not been successful.
Information (SI) for more details). A brief temperature study was
carried out, showing that decreasing the temperature to 100 °C
reduced the yield, while increasing of the temperature to 140 °C did
not provide a higher yield. Thus, 120 °C was selected as the
reaction temperature. The yield was slightly increased when the
reaction time was extended to 48 hours. Subsequently, a wide
variety of additives were evaluated and Ag3PO4 was found to be
superior, enhancing the yield to 36% (entry 7). Surprisingly, when
we exchanged the [Cp*Rh(MeCN)3](SbF6)2 catalyst to the
ensemble of [RhCp*Cl2]2 and AgSbF6, the total yield increased to
70%, including 21% di-substituted product (Entry 10). It is possible
that three acetonitrile molecules on the Rh center in the cationic
precursor outcompete the coordination of the nitrile group of the
directing template, while the in situ generated Cp*Rh(III) species
coordinates with the nitrile template effectively. We also evaluated
different acids as additives. When propionic acid was added to the
reaction mixture, the total yield was increased to 82% which could
be attributed to the enhanced protonation of the carbon-rhodium
bond (entry 12). A brief evaluation of templates revealed that the
use of T3 (which contains a single nitrile group) could slightly
improve the yield and the mono:di ratio (entry 16).
Our initial experimental design was guided by the Rh(III)-
catalyzed ortho-C–H alkenylation with alkynes[8] and the meta-C–
H olefination of hydrocinnamic acid derivatives with acrylate.[6]
We selected hydrocinnamic acid derived compound 1’ (Table 1) as
our initial substrate for optimization.
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Substrates bearing substituents at the ortho-, meta-, or para-
1
positions provided only mono-substituted products. For ortho-
substituted substrates, both electron-donating groups (1c, 1d) and
halogens (1e – 1g) were tolerated, providing the desired products
in good yield, while the ortho-trifluoromethyl-substituted substrate
1h provided the desired product in a modest yield of 45%. For
meta-substituted substrates, electron-donating groups at the meta-
position (1i, 1j) worked well to give the desired products in good
yields of 83% (3i) and 85% (3j). Substitution at the meta-position
with halogens (entries 1k – 1m, Table 2) provided lower yields.
Meta-trifluoromethyl substituted substrate 1n gave the desired
product 3n in a modest yield of 50%. Methoxy or fluoride
substitution at the para-position is also well tolerated (1o, 1p). All
substrates maintained high meta-selectivity.
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Table 1. Optimization of reaction conditions.a
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Table 3. Scope of alkyne coupling partners.a
aReaction conditions: 1’ (0.1 mmol), 2a (0.3 mmol), [Cp*Rh(MeCN)3](SbF6)2 (5
mol %), additives (0.1 mmol), acid (0.4 mmol), dry DCE (2 mL), N2, 48 h, 120 °C.
Isolated yield. bThe ensemble of [RhCp*Cl2]2 (5 mol %) and AgSbF6 (20 mol %) was
used instead of [Cp*Rh(MeCN)3](SbF6)2. cUsing T3 as template.
Table 2. Rh(III)-catalyzed meta-C–H alkenylation of
hydrocinnamic acid derivatives.a,b
b
aIsolated yield. Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), [RhCp*Cl2]2 (5
mol %), AgSbF6 (20 mol %), Ag3PO4 (0.1 mmol), propionic acid (0.4 mmol), dry DCE
(2 mL), N2, 48 h, 120 °C. cReaction conditions: 1 (0.1 mmol), 2a (0.3 mmol),
[Cp*Rh(MeCN)3](SbF6)2 (5 mol %), propionic acid (0.4 mmol), dry DCE (2 mL), N2,
48 h, 120 °C.
Subsequently, we investigated the scope of alkyne coupling
partners (Table 3). A wide range of symmetrical alkyne coupling
partners can be employed in this transformation. Alkynes with
aromatic methyl substituents afforded the desired products in good
yields (3q). Halogen and cyanide substituents on the alkynes could
also be tolerated and gave modest yields (3r – 3u). Gratifyingly,
unsymmetrical alkynes with alkyl groups on one side of the alkyne
could be coupled in good yields with excellent selectivity (3v – 3x).
Encouraged by these results, we evaluated propargyl alcohols using
our optimized conditions (3y – 3bb). However, no desired product
was obtained in the presence of Ag3PO4 or AgSbF6. We speculated
that the silver salt might be impeding the progress of the reaction.
Surprisingly, we obtained the desired allylic alcohols in satisfactory
yields using [Cp*Rh(MeCN)3](SbF6)2 as the catalyst without using
silver salt additives. To our delight, the dialkyl-substituted alkyne
2-butyne also provided the desired product in moderate yield (3cc).
aReaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6
(20 mol %), Ag3PO4 (0.1 mmol), propionic acid (0.4 mmol), dry DCE (2 mL), N2, 48
h, 120 °C. bIsolated yield.
With the optimized conditions in hand, we evaluated the scope
of hydrocinnamic acid derivatives using phenylacetylene (2a) as
the coupling partner (Table 2). Unsubstituted compounds 1a and
1b provided the highest total yields of 85% and 87% respectively.
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However, t-Butyl-substituted alkyne gave low yields (<20%).
*luyi@nju.edu.cn
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Finally, this reaction was scaled up, using a standard round-bottom
flask, to 1 mmol with substrate 1a, and the desired products was
obtained in 70% yield (56% mono, 14% di) (Scheme 2).
ORCID
Wei-Yin Sun: 0000-0001-8966-9728
Jin-Quan Yu: 0000-0003-3560-5774
Yi Lu: 0000-0002-8767-7801
Scheme 2. Gram-Scale Synthesis
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We gratefully acknowledge the National Natural Science
Foundation of China (grant no. 21671097 and 21331002), National
Science Foundation (CHE-1465292) and the Fundamental
Research Funds for the Central Universities for financial support.
A plausible reaction mechanism is shown in Scheme 3. The
active catalytic species [Cp*Rh](SbF6)2 was generated in situ from
[RhCp*Cl2]2 by noncoordinating AgSbF6. Subsequent
coordination of the nitrile to the [Rh(III)] catalyst is followed by
meta-C–H bond activation to give the corresponding 12-membered
rhodacyclic intermediate 2. Subsequently, alkyne insertion into the
C-Rh bond yields intermediate 3. Protonation of intermediate 3 by
propionic acid releases the desired product accompanied by
regeneration of active Rh(III) species.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and spectral data for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
*sunwy@nju.edu.cn
*yu200@scripps.edu
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(5) For selected examples of Pd-catalyzed meta-C–H functionalization
using nitrile-based templates: (a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-
Q. Activation of Remote Meta-C–H Bonds Assisted by an End-On
Template. Nature 2012, 486, 518; (b) Dai, H.-X.; Li, G.; Zhang, X.-
G.; Stepan, A. F.; Yu, J.-Q. Pd(II)-Catalyzed Ortho- Or Meta-C–H
Olefination of Phenol Derivatives. J. Am. Chem. Soc. 2013, 135, 7567;
(c) Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. Cross-Coupling of
Remote Meta-C–H Bonds Directed by a U-Shaped Template. J. Am.
Chem. Soc. 2013, 135, 18056; (d) Lee, S.; Lee, H.; Tan, K. L. Meta-
Selective C–H Functionalization Using a Nitrile-Based Directing
Group and Cleavable Si-Tether. J. Am. Chem. Soc. 2013, 135, 18778;
(e) Tang, R.-Y.; Li, G.; Yu, J.-Q. Conformation-Induced Remote
Meta-C–H Activation of Amines. Nature 2014, 507, 215; (f) Yang, G.;
Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.; Tang, R.-Y.; Movassaghi,
M.; Yu, J.-Q. Pd(II)-Catalyzed Meta-C–H Olefination, Arylation, and
Acetoxylation of Indolines Using a U-Shaped Template. J. Am. Chem.
(9) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. Diverse Strategies
toward Indenol and Fulvene Derivatives: Rh-Catalyzed C–H
Activation of Aryl Ketones Followed by Coupling with Internal
Alkynes. J. Am. Chem. Soc. 2011, 133, 2154.
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