Oxidative C?H/C?H Cross-Coupling Reactions between N-Acylanilines and Benzamides Enabled by a Cp*-Free RhCl3/TFA Catalytic System

Article abstract of DOI:10.1002/anie.201804528

By making use of a dual-chelation-assisted strategy, a completely regiocontrolled oxidative C?H/C?H cross-coupling reaction between an N-acylaniline and a benzamide has been accomplished for the first time. This process constitutes a step-economic and highly efficient pathway to 2-amino-2′-carboxybiaryl scaffolds from readily available substrates. A Cp*-free RhCl₃/TFA catalytic system was developed to replace the [Cp*RhCl₂]₂/AgSbF₆ system generally used in oxidative C?H/C?H cross-coupling reactions between two (hetero)arenes (Cp=pentamethylcyclopentadienyl, TFA=trifluoroacetic acid). The RhCl₃/TFA system avoids the use of the expensive Cp* ligand and AgSbF₆. As an illustrative example, the procedure developed herein greatly streamlines the total synthesis of the naturally occurring benzo[c]phenanthridine alkaloid oxynitidine, which was accomplished in excellent overall yield.

Full text of DOI:10.1002/anie.201804528

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
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Accepted Article
Title: Oxidative C−H/C−H Cross-Coupling Reactions between N-
Acylanilines and Benzamides Enabled by a Cp*-Free RhCl3/TFA
Catalytic System
Authors: Jingsong You, Yang Shi, Luoqiang Zhang, Jingbo Lan, Min
Zhang, Fulin Zhou, and Wenlong Wei
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804528
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10.1002/anie.201804528
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Oxidative C−H/C−H Cross-Coupling Reactions between N-
Acylanilines and Benzamides Enabled by a Cp*-Free RhCl3/TFA
Catalytic System
Yang Shi, Luoqiang Zhang, Jingbo Lan*, Min Zhang, Fulin Zhou, Wenlong Wei, and Jingsong You*
Abstract: Using the dual chelation-assisted strategy, a completely
regiocontrolled oxidative C−H/C−H cross-coupling reaction between
an N-acylaniline and a benzamide has been accomplished for the first
time, which enables a step-economical and highly efficient pathway to
2-amino-2'-carboxybiaryl scaffolds from readily available substrates. A
Cp*-free RhCl3/TFA catalytic system has been developed to replace
substrates. Despite practical usefulness, such a dual chelation-
assisted strategy is rarely reported and appeared until 2015.[10]
Manipulating this strategy to access unsymmetrical 2,2'-
difunctional biaryls is still a challenging task due to consistent
obstacles associated with the chemoselectivity of cross-ccoupling
over homo-coupling. In those pioneering works, significant
substrate excess is required (usually 3 to 8 equivalents) to
increase the amount of the cross-coupled product,[10a,b,d] which
restrains the practicality of strategy. Herein, we wish to present
the first example of completely regiocontrolled oxidative
C−H/C−H cross-coupling reactions between N-acylanilines and
benzamides via a Cp*-free RhCl3/TFA catalytic system to forge 2-
amino-2'-carboxybiaryl scaffolds even with a low molar ratio of
coupling partners (Scheme 2b).
the generally used [Cp*RhCl2]2/AgSbF6 (Cp*
=
pentamethyl
cyclopentadienyl) in oxidative C−H/C−H cross-coupling reactions
between two (hetero)arenes. The RhCl3/TFA system avoids the use
of expensive Cp* ligand and AgSbF6. As an illustrative example, the
protocol developed herein greatly streamlines access to naturally
occurring benzo[c]phenanthridine alkaloid oxynitidine in an excellent
overall yield.
2,2'-Difunctional biaryls are important structure motifs in natural
products, pharmaceuticals, organic functional materials and
ligands for transition metal catalysts.[1] Among various 2,2'-
difunctional biaryls, 2-amino-2'-carboxybiaryl scaffolds show
versatile biological activities and medicinal properties (Scheme
1).[2] Traditional routes to 2-amino-2'-carboxybiaryls are mainly
dependent on the Suzuki coupling reaction after prior ortho-
halogenation or ortho-borylation of benzoic acid and aniline.[2b,3,4]
However, ortho-prefunctionalization of both substrates typically
requires multi-step synthesis and purification procedures.
Moreover, an ortho-directing group or blocking group at para-
position is commonly necessary to achieve ortho-selectivity,[5]
which renders the difficulty in the preparation of substrates. Given
that benzoic acids and anilines are both readily available raw
materials,[6] from the perspective of starting material availability
and step economy, transition metal-catalyzed oxidative cross-
coupling between two different ortho-C−H bonds of N-acylaniline
and benzamide is doubtless one of the most attractive
approaches to access 2-amino-2'-carboxybiaryls.
Scheme 1. Selected examples of 2-amino-2'-carboxybiaryls.
Recently, transition metal-catalyzed oxidative C−H/C−H cross-
coupling reactions between two arenes have made significant
advance.[7] However, controlling the regioselectivity of C−H
activation for each coupling partner remains challenging. Besides
the chelation-assisted strategy, the regioselectivity of arenes
mainly relies on steric and electronic effects.[8] The substrate
without distinct electronic effect or steric hindrance inevitably
leads to an intractable mixture of regioisomers (Scheme 2a).[9]
Thus, the dual chelation-assisted strategy would be an ideal tool
to simultaneously accomplish the regioseclective control for both
Scheme 2. Evolution of the chelation-assisted oxidative C−H/C−H cross-
coupling reactions between two arenes.
Given that [Cp*RhCl2]2/AgSbF6 is most frequently used in
rhodium-catalyzed chelation-assisted C−H activation to access
bi(hetero)aryls.[11] An initial investigation of the coupling reaction
was conducted in the [Cp*RhCl2]2/AgSbF6 catalytic system using
N-(tert-butyl)benzamide (1a) and N-phenylpivalamide (2a) as the
model substrates (Table S1). To our delight, the desired biaryl 3a
was obtained in 10% yield (Table S1, entry 1). Using 1.0 equiv of
TFA as an additive, the yield increased to 26% (Table S1, entry
2). In addition to the yield, the chemoselectivity of cross-coupling
over homo-coupling could be efficiently improved with an
increasing amount of TFA. Considering that CF3COO- (OTFA-) as
[]
Y. Shi, L. Zhang, Prof. Dr. J. Lan, M. Zhang, F. Zhou, W. Wei, and
Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry
Sichuan University
29 Wangjiang Road, Chengdu 610064, PR China
E-mail: jsyou@scu.edu.cn; jingbolan@scu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804528
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the anion enables to enhance the electrophilicity of the Rh(III)
center,[12] the intermediates were next investigated via NMR and
HRMS (Figure 1 and Section IX, SI). ESI-HRMS analysis of a
mixture of [Cp*RhCl2]2, AgSbF6, Ag2CO3 and TFA in toluene
implies the formation of [Cp*Rh(OTFA)]+ (I) (calcd: 351.0079,
found 351.0074) [Eq. (S8)], indicative of the presence of OTFA-
groups were screened in the RhCl3/TFA system. As a result, the
more sterically hindered pivalamido (DG2b) and N-(tert-butyl)
carbamoyl (DG1d) groups were designated as a matched
directing group pair for anilines and benzoic acids, respectively
(Scheme 3). After screening of various oxidants, additives and
solvents (Tables S3-S6), the optimized result was obtained in
toluene at 150 ºC for 24 h using 5 mol% of RhCl3•3H2O as a
catalyst, Ag2CO3 as an oxidant, TFA and CuF2 as additives
(Table S6, entry 1).
1
coordinated to the Rh center. H NMR analysis indicates that the
methyl hydrogen of [Cp*RhCl2]2 shifts from 1.26 to 5.52 ppm. The
remarkable downfield chemical shift demonstrates
electron-deficient rhodium core, suggesting
electrophilicity. To our surprise, in the presence of both coupling
substrates, [RhAr1Ar2]+ (II) (Ar1 PhCONHtBu; Ar2
p-
a
more
a
greater
=
=
CH3PhNHPiv) (calcd: 469.1362, found 469.1359) was detected
rather than [Cp*RhAr1Ar2] (III) in ESI-HRMS [Eq. (S9)], implying
that Cp* could not be essential in this reaction. Thus, we replaced
the [Cp*RhCl2]2/AgSbF6 system with lower-cost RhCl3/TFA. As
expected, the yield of the cross-coupled product 3a remained
basically unchanged (Table S1, entry 6).
Figure 1. (a) Rh(III) intermediates. 1H NMR analysis of (b) [Cp*RhCl2]2 and (c)
[Cp*RhCl2]2, AgSbF6, Ag2CO3 and TFA-d1 in toluene-d8.
Scheme 4. Scopes of benzamides and N-acylanilines. Reaction conditions: 1
(0.2 mmol) and 2 (2.0 equiv) in toluene at 150 oC under N2 for 24 h. [a] 1a (5.0
mmol) and 2a (1.5 equiv). [b] 1 (0.2 mmol) and 2 (1.2 equiv). [c] 1 (0.2 mmol)
and 2 (1.5 equiv). [d] AgOTFA (4.0 equiv) instead of Ag2CO3 and TFA.
With the optimized reaction conditions in hand, we embarked
on exploring substrate scope of benzamides. The benzamides
with various electron-withdrawing groups such as halogen,
aldehyde, acetyl and ester could smoothly couple with 2a to
deliver the corresponding biaryls (Scheme 4, 3b-3h). Electron-
donating groups including alkyl, methoxyl, and even hydroxyl
could also be tolerated (Scheme 4, 3j-3m and 3s). Gratefully, a
series of heteroaromatic amides including thiophene, furan and
quinoline could also couple with 2a. The reaction of 1a (5.0 mmol)
with 2a (7.5 mmol) was carried out on a gram-scale, delivering 3a
in 66% yield (1.16 g), suggesting a potential for mass preparation.
It is worthy of note that 1.2 equiv of N-acylanilines could give the
Scheme 3. Directing group screening. nd = not detected; nr = no reaction; Q =
quinolin-8-yl.
The directing group is known to have a distinct impact on the
substrate reactivity associated with electronic nature and steric
hindrance. Thus, the oxidative C−H/C−H cross-coupling reactions
between benzoic acids and anilines could be conducted by
judicious choice of the directing group pair to match the
reactivities of both substrates. Subsequently, various directing
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corresponding products in slightly decreased yields (3b, 3c, 3j, 3l
and 3n).
not detected in the above experiments, suggesting that 1a could
coordinate to the rhodium center through the carbonyl oxygen
atom rather than the nitrogen atom in the formation of
cyclometallic complex. Next, kinetic isotope effect (KIE)
experiments were performed for both coupling partners. The
competition reactions between 1a or [D5]-1a with 2a were carried
out, and the KIE value was found to be 2.21 [Eq. (S6)], indicating
the probable involvement of the C–H bond cleavage of 1a in the
rate-determining step. A KIE value of 1.10 was observed for
parallel competition reactions between 2a or [D5]-2a with 1a [Eq.
(S7)], suggesting that the C–H activation of 2a might not be
involved in the rate-determining step. Finally, the intermolecular
competition experiments of electronically differentiated 2f and 2p
with 1a as well as 1c and 1l with 2a indicate an electrophilic
aromatic substitution (SEAr) process for the C−H activation of N-
acylanilines and a concerted metalation-deprotonation (CMD)
pathway for the C−H activation of benzamides [Eqs. (1) and (2)].
The scope of N-phenylpivalamide derivatives was also
investigated (Scheme 4). The substituents at ortho-, meta- or
para-position of anilines showed a negligible effect on the
coupling yields. A wide range of substituents from electron-
withdrawing groups (Scheme 4, 4a-4e, 4g) to electron-donating
groups (Scheme 4, 4i-4j, 4l-4q) were compatible with this
RhCl3/TFA catalytic system. The nitro and diphenylamino groups
could be tolerated using AgOTFA instead of Ag2CO3 and TFA
(Scheme 4, 4f and 4m). The readily oxidizable methene in 4r
could survive from this oxidative catalytic system. Moreover, the
natural product coumarin-120 was also modified by this protocol
without obstacle (Scheme 4, 4s).
Scheme 5. Total synthesis of oxynitidine.
It is worth noting that many naturally occurring
benzo[c]phenanthridine alkaloids are of significant biological and
drug activities.[2d,13] For example, oxynitidine can effectively inhibit
DNA replication in hepatitis B virus.[14] The precedent synthetic
routes typically require multistep procedures and complex starting
materials and suffered from relatively low yields.[14] To our delight,
the current protocol provided a more step-economical and highly
efficient pathway to oxynitidine from readily available materials in
an excellent overall yield of about 80% (Scheme 5).
Scheme 6. Plausible mechanistic pathway.
Based on the above mechanistic studies,[11] a plausible
pathway is proposed (scheme 6). Firstly, RhCl3 is transformed to
a cationic Rh(III) species in the presence of Ag2CO3 and TFA,
further increasing the electrophilicity of rhodium core. The more
electron-rich aniline substrate 2p is activated preferentially to
form intermediate IM1 through a SEAr process,[15] confirmed by
ESI-HRMS analysis [Eq. (S10)]. Then, 1a coordinates with IM1
and undergoes the second C−H activation via a CMD pathway to
generate IM2, detected by ESI-HRMS [Eq. (S11)]. Next, the
reductive elimination of diarylrhodium complex delivers the cross-
coupled product 4o. The generated Rh(I) is re-oxidized to Rh(III)
species by Ag(I) to accomplish the catalytic cycle.
To get some insights into the reaction mechanism, a series of
experiments were conducted. When N-phenylpivalamide (2a) was
treated with 20.0 equiv of D2O and 4.0 equiv of TFA-d1 under the
standrad condition for 2 h, the H/D exchange ratio of 2a was 35%
[Eq. (S3)]. This result illustrates that the C−H activation of 2a is
reversible. In contrast, no deuterated [Dn]-1a was observed while
N-(tert-butyl)benzamide (1a) reacted with 20.0 equiv of D2O and
4.0 equiv of TFA-d1 [Eq. (S4)]. However, treatment of 1a and 2a
in one pot with 20.0 equiv of D2O and and 4.0 equiv of TFA-d1
resulted in 10% H/D exchange ratio of 1a [Eq. (S5)], indicating
that the C−H cleavage of 1a became reversible in the presence of
2a. Furthermore, the H/D exchange of the amido group of 1a was
In conclusion, we have developed a RhCl3/TFA catalytic
system instead of [Cp*RhCl2]2/AgSbF6 and have accomplished for
the first time the completely regiocontrolled oxidative C−H/C−H
cross-coupling reactions between benzamides and N-acylanilines
through the dual chelation-assisted strategy. This protocol
enables a step-economical and highly efficient pathway to 2-
amino-2'-carboxybiaryl scaffolds from readily available substrates.
The RhCl3/TFA catalytic system exhibits high catalytic activity and
excellent tolerance of reactive functional groups. This strategy
has been successfully applied in the total synthesis of natural
product, which greatly shortens the synthetic route to oxynitidine.
This work represents a new perspective for the study of the
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oxidative C–H/C–H cross-coupling reaction between two
functionality-containing arenes to access unsymmetrical 2,2'-
difunctional biaryls.
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Acknowledgements
This work was supported by grants from the National NSF of
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Keywords: oxidative C−H/C−H cross-coupling • 2-amino-2'-
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carboxybiaryls
•
dual chelation-assisted strategy
•
high
regioselectivity • synthesis of oxynitidine
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Yang Shi, Luoqiang Zhang, Jingbo Lan*,
Min Zhang, Fulin Zhou, Wenlong Wei,
and Jingsong You*
Page No. – Page No.
Oxidative C−H/C−H Cross-Coupling
Reactions between N-Acylanilines
and Benzamides Enabled by a Cp*-
Free RhCl3/TFA Catalytic System
Dual chelation-assisted strategy:
A completely regiocontrolled oxidative
C−H/C−H cross-coupling reaction between benzamide and N-acylaniline has been
accomplished for the first time through a Cp*-free RhCl3/TFA catalytic system
instead of expensive Cp* ligand and AgSbF6. The strategy greatly streamlines
access to naturally occurring benzo[c]phenanthridine alkaloid oxynitidine in an
excellent overall yield.
This article is protected by copyright. All rights reserved.