Rh(III)-Catalyzed C-H Activation/[3 + 2] Annulation of N-Phenoxyacetamides via Carbooxygenation of 1,3-Dienes

Article abstract of DOI:10.1021/acs.orglett.1c00945

A unique Rh(III)-catalyzed C-H activation/[3 + 2] annulation of N-phenoxyacetamides has been developed for the construction of dihydrobenzofurans via carbooxygenation of 1,3-dienes. This transformation features a redox-neutral process with specific chemoselectivity, good substrate/functional group compatibility, and profound synthetic potentials. A preliminary exploration to realize their asymmetric synthesis have been also successfully demonstrated, which further strengthens the practicality of this approach.

Full text of DOI:10.1021/acs.orglett.1c00945

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Letter
Rh(III)-Catalyzed C−H Activation/[3 + 2] Annulation of
N‑Phenoxyacetamides via Carbooxygenation of 1,3-Dienes
Liexin Wu, Liping Li, Haiman Zhang, Hui Gao, Zhi Zhou,* and Wei Yi*
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ABSTRACT: A unique Rh(III)-catalyzed C−H activation/[3 + 2]
annulation of N-phenoxyacetamides has been developed for the
construction of dihydrobenzofurans via carbooxygenation of 1,3-
dienes. This transformation features a redox-neutral process with
specific chemoselectivity, good substrate/functional group compat-
ibility, and profound synthetic potentials. A preliminary exploration
to realize their asymmetric synthesis have been also successfully
demonstrated, which further strengthens the practicality of this approach.
Scheme 1. Diversified C−H Functionalization of N-Phenoxy
Amides with Alkenes
he construction of privileged heterocyclic motifs from
readily available raw materials has received continuous
T
interest in medicinal chemistry and organic synthesis. Due to
the high efficiency and good atom-/step-economy, transition
metal (TM)-catalyzed C−H functionalization represents a
powerful strategy for fulfilling the assembly of complex
heterocycles over the past decades.1 Various directing groups
(DGs) and coupling partners (CPs) had been developed in
this field to enrich the reaction diversity, complexity and
practicality, among which the −ONHR moiety was identified
as a versatile oxidizing directing group (ODG) in assembling
different oxygen- or nitrogen-containing skeletons via TM-
catalyzed redox-neutral C−H couplings of N-phenoxy amides.2
Despite these remarkable advances, further development of
−ONHR-mediated novel reaction modes and practical trans-
formations to afford intriguing molecules is still highly
desirable.
By virtue of the −ONHR as ODGs and the easily accessible
alkenes as CPs, a variety of distinctive reaction modes
including C−H alkenylation,3 alkylation,4 and carboamination5
have been efficiently established under Rh(III)- or Co(III)-
catalyzed conditions (Scheme 1a).6 Compared with alkenes,
the conjugated 1,3-dienes are less explored in C−H
functionalization, especially in mild Rh(III)-catalyzed trans-
formations.7 The main reason might be that it would bring a
great challenge in the control of chemoselectivity and
regioselectivity because of the existence of the conjugated
diene moiety. However, the additional coordination affinity to
the metal center enabled by the extra double bond in 1,3-
dienes or facile π-allylation process from η1-allyl metal species
provides good efficiency in suppressing the fast β-H
elimination of carbon−metal bond,7a,8 thereby delivering
unconventional transformations. By taking advantage of the
distinct reactivity of 1,3-dienes, very recently we have
developed a Rh(III)-catalyzed carboamination reaction for
the synthesis of chiral allylic amines, in which N-phenox-
yisobutyramides acted as both the C−H activation substrates
and amidating reagents (Scheme 1b).9 Mechanistic studies
revealed that the η3 π-allyl rhodium species was involved,
followed by an intramolecular amide transfer to give the allylic
amine frameworks. In continuation of our interest in
developing −ONHR-directed C−H functionalization, we
envisioned that an alternative carbooxygenation might be
achieved by appropriately tuning the reaction conditions and
the −ONHR ODGs. Herein, we disclose the Rh(III)-catalyzed
redox-neutral C−H activation/[3 + 2] annulation of N-
phenoxyacetamides with 1,3-dienes to afford dihydrobenzofur-
Received: March 19, 2021
https://doi.org/10.1021/acs.orglett.1c00945
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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an derivatives with the embedment of a chiral carbon center
(Scheme 1c). Moreover, synthetic utilities for late stage C−H
modification, the derivatization of the obtained products, as
well as a preliminary attempt to access the asymmetric
synthesis of dihydrobenzofuran products have been success-
fully demonstrated.
line), electron-withdrawing (CF3, OCF3, CO2Me, and NO2),
and halogen groups into different positions of the phenyl ring
resulted in smooth formation of the corresponding products in
moderate to good yields (3ab−au). In addition, other 1,3-
dienes with the equipment of naphthyl or heteroaryl groups
including thiophene, benzothiophene, and indole skeleton
were also compatible to deliver the desired dihydrobenzofur-
ans, 3av−3az, smoothly. Nevertheless, the 1,1-disubstituted,
1,2-disubstituted, and alkyl-substituted 1,3-dienes were not
compatible, demonstrating the limitation of this reaction.
Delightfully, ferrocenyl-substituted diene was found to
participate in the developed [3 + 2] annulation swimmingly,
affording desired product 3aa′ in 61% isolated yield, which
illustrated the profound potential of this protocol in
constructing such complexes. Of note, further investigation
revealed that Z-type 1,3-dienes were also good reactants to
carry out the Rh(III)-catalyzed C−H coupling of N-
phenoxyacetamide, affording the desired dihydrobenzofurans
with the retention of the Z-configuration.
We commenced our investigation by testing the C−H
coupling of N-phenoxyacetamide (1a) with (E)-buta-1,3-dien-
1-ylbenzene (2a) under the Rh(III)-catalyzed conditions in
MeOH, the reaction proceeded smoothly to afford dihydro-
benzofuran derivative 3aa in 51% yield via C−H activation/[3
+ 2] annulation (Table S1, entry 1). Interestingly, the C−H
alkenylation and carboamination processes of N-phenoxy
amides reported in literature precedents were not observed
under the tested conditions, leading to the specific assembly of
dihydrobenzofuran skeleton with the retention of the
configuration of the diene substrate. Further experimental
parameters screening identified the optimized conditions (see
Table S1 for details). It should be noted that the trace amount
of the carboamination product could be detected as a side
product among part of the examined reaction conditions,
suggesting the two competitive reaction mechanisms for the
formation of dihydrobenzofuran or allylic amine frameworks.
With the optimal conditions in hand, we next investigated
the compatibility of this methodology for the assembly of
dihydrobenzofuran derivatives. A range of 1,3-dienes were first
examined systematically to react with N-phenoxyacetamide
and showed good functional group tolerance with exclusively
chemo- and perfect E-selectivity (Scheme 2). As expected,
diverse aryl-substituted dienes proved viable CPs for this
transformation and showed broad applicability. Introduction of
various electron-donating (alkyl, OMe, NMe2, and morpho-
Subsequently, the scope of this transformation was further
extended with regard to diverse N-phenoxyacetamides. As
shown in Scheme 3, a series of N-phenoxyacetamides bearing
a
Scheme 3. Scope of N-Phenoxyacetamides
a
Scheme 2. Substrate Scope of 1,3-Dienes
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [Cp*RhCl2]2
(2.5 mol %), NaOAc (1 equiv) in MeOH (0.1 M) at 60 °C for 14 h
under air; isolated yields were reported.
various commonly encountered functional groups at either
ortho-, meta-, and para-position were all tolerated in coupling
with 2a efficiently regardless of the electronic properties of the
substituents. Of note, when meta-methyl-substituted N-
phenoxyacetamides were employed, the C−H metalation
occurred in a regioselective manner toward the less hindered
site (3pa, 3qa, and 3sa), while meta-methoxyl-substituted N-
phenoxyacetamide led to the formation of two regioisomers
(3ra and 3ra′). Naphthalene substrate was also tolerated under
the standard conditions to furnish an inseparable mixture of
two regioisomers with the ratio of 6.5:1 (3ta and 3ta′). Taken
together, the developed Rh(III)-catalyzed [3 + 2] annulation
showed good compatibility with both 1,3-dienes and N-
phenoxyacetamides, providing a reliable synthetic approach for
the assembly of diverse dihydrobenzofuran derivatives.
Considering that dihydrobenzofuran represents a common
structural motif involved in pharmaceuticals and many
biologically active molecules,10 we were next intrigued to
explore the application of this versatile methodology for the
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2
(2.5 mol %), NaOAc (1 equiv) in MeOH (0.1 M) at 60 °C for 14 h
under air; isolated yields were reported.
B
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late stage C−H modification of complex nature products. As
listed in Scheme 4a, the N-phenoxyacetamides incorporated
Experiments were then carried out to gain more insight into
the reaction mechanism (Scheme 5). Deuterium-labeling
Scheme 4. Synthetic Application and Asymmetric Synthesis
Scheme 5. Experimental Mechanistic Studies
experiments were first conducted in CD3OD, and the results
showed obvious deuteration at the ortho-position of the DG in
both recovered 1a and dihydrobenzofuran product 3aa,
suggesting a reversible and fast C−H metalation process
(Scheme 5a). In addition, five-membered rhodacycle A was
rationally synthesized and subjected to the developed [3 + 2]
annulation reaction, the corresponding dihydrobenzofuran
derivative was isolated in 66% yield, thus demonstrating that
rhodacycle A should be an active intermediate for this
transformation (Scheme 5b). Control experiment using 2-
vinylnaphthalene as the CP led to the formation of ortho-
alkenylation product 12 instead of the dihydrobenzofuran
derivative, suggesting that the 1,3-diene moiety was crucial in
realizing the observed [3 + 2] annulation process. Moreover,
further investigation disclosed the effect of external Lewis acid
additives in tuning the chemoselectivity between [3 + 2]
annulation and carboamination, which was in line with our
previous observation9 (Scheme 5c).
a
Reaction conditions: 10 (0.15 mmol, 1.5 equiv), 2a (0.1 mmol),
(R)-Rh1 (5 mol %), AgSbF6 (20 mol %) and NaOPiv (1 equiv) in
EtOH (0.1 M) at room temperature for 36 h without exclusion of air
or moisture; isolated yields were reported. The er values were
determined by HPLC analysis with a chiral stationary phase.
with an L-tyrosine, dopamine, or estrone moiety showed good
reactivity and provided highly functionalized heterocyclic
frameworks 4−6 with decent yields. Moreover, the next
derivatizations of compound 3aa have been demonstrated,
which further strengthens the application potentials of this
transformation (Scheme 4b). For example, the treatment of
3aa with m-CPBA resulted in the generation of product 7
bearing three contiguous stereogenic centers in moderate yield
and good diastereoselectivity via epoxidation. Exposure of 3aa
to diiodomethane in the presence of diethylzinc afforded
cyclopropane skeleton 8 in 78% yield. Additionally, 3aa could
also be converted into dihydrobenzofuran tethered ketone
derivative 9 under Co(acac)2-catalyzed conditions in the
presence of O2. Inspired by the elegant advances in asymmetric
C−H functionalization mediated by chiral rhodium(III)
catalysts recently,11,12 we were intrigued to test the feasibility
for the construction of chiral dihydrobenzofurans. Preliminary
investigation implied that the asymmetric synthesis of
dihydrobenzofuran skeleton could be realized in the presence
of chiral CpXRh(III) catalyst (R)-Rh1 starting from N-
phenoxypivalamide (see Table S2 for details). Further
substrate scope examination revealed that the enantioselective
[3 + 2] annulation was quite applicable with different N-
phenoxypivalamides and 1,3-dienes, delivering diverse enan-
tioenriched dihydrobenzofuran derivatives smoothly albeit
with relatively less satisfactory yield and enantioselectivity
(Scheme 4c).
On the basis of the mechanistic studies and literature
precedents,3a,4a,8,9,13 we propose the reaction mechanism for
the developed C−H activation/[3 + 2] annulation reaction
(Scheme 6). Initially, the active catalyst was generated via
anion exchange, which coordinated with N-phenoxyacetamide
followed by the N−H/C-H bond cleavage to yield rhodacycle
Scheme 6. Proposed Mechanism
C
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A. The following regioselective alkene insertion afforded seven-
membered intermediate B, in which we proposed the
coordination affinity between the alkene moiety and the
rhodium metal center played a crucial role in inhibiting the
classic β-H elimination; thus, such an interaction promoted the
oxidative addition process to give intermediate C. From
intermediate C, the direct C−O bond reductive elimination
delivered the dihydrobenzofuran skeleton along with the
release of active Rh(III) catalyst in the presence of HOAc
(path I). Alternatively, a facile π-allylation might occur to give
the η3 π-allyl rhodium species D, which was trapped by an
internal phenolate oxygen to form the final dihydrobenzofuran
derivative, 3aa (path II). The C−N bond reductive elimination
or intramolecular amide transfer process leading to the
formation of carboamination product was inhibited in this
reaction, thus providing a specific approach for the assembly of
dihydrobenzofuran skeleton.
Pharmaceutical Sciences, Guangzhou Medical University,
Guangzhou, Guangdong 511436, China
Haiman Zhang − The Fifth Affiliated Hospital, Key
Laboratory of Molecular Target & Clinical Pharmacology
and the State Key Laboratory of Respiratory Disease, School
of Pharmaceutical Sciences, Guangzhou Medical University,
Guangzhou, Guangdong 511436, China
Hui Gao − The Fifth Affiliated Hospital, Key Laboratory of
Molecular Target & Clinical Pharmacology and the State
Key Laboratory of Respiratory Disease, School of
Pharmaceutical Sciences, Guangzhou Medical University,
Guangzhou, Guangdong 511436, China; orcid.org/
0000-0002-8736-4485
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00945
Notes
In summary, we have developed the efficient and redox-
neutral Rh(III)-catalyzed C−H activation/[3 + 2] annulation
of N-phenoxyacetamides with 1,3-dienes for direct construc-
tion of dihydrobenzofuran frameworks. This transformation
features specific regioselectivity, good tolerance of substrates/
functional groups, and profound synthetic utility. Preliminary
asymmetric synthesis enabled by the chiral CpXRh(III) catalyst
further straightened the potential of this approach. Further
exploration of novel reaction modes of 1,3-dienes in the C−H
functionalization field and detailed mechanistic studies are in
progress.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (21877020, 22007020), the Guangdong
Natural Science Funds for Distinguished Young Scholar
(2017A030306031), and the Natural Science Foundation of
Guangdong Province (2019A1515010935) for financial
support on this study.
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00945.
Experimental procedures, characterization of products,
1
HPLC details and copies of H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhi Zhou − The Fifth Affiliated Hospital, Key Laboratory of
Molecular Target & Clinical Pharmacology and the State
Key Laboratory of Respiratory Disease, School of
Pharmaceutical Sciences, Guangzhou Medical University,
Guangzhou, Guangdong 511436, China; orcid.org/0000-
0002-6521-8946; Email: zhouzhi@gzhmu.edu.cn
Wei Yi − The Fifth Affiliated Hospital, Key Laboratory of
Molecular Target & Clinical Pharmacology and the State
Key Laboratory of Respiratory Disease, School of
Pharmaceutical Sciences, Guangzhou Medical University,
Guangzhou, Guangdong 511436, China; orcid.org/0000-
0001-7936-9326; Email: yiwei@gzhmu.edu.cn
Authors
Liexin Wu − The Fifth Affiliated Hospital, Key Laboratory of
Molecular Target & Clinical Pharmacology and the State
Key Laboratory of Respiratory Disease, School of
Pharmaceutical Sciences, Guangzhou Medical University,
Guangzhou, Guangdong 511436, China
Liping Li − The Fifth Affiliated Hospital, Key Laboratory of
Molecular Target & Clinical Pharmacology and the State
Key Laboratory of Respiratory Disease, School of
D
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́
see (a) Velasco-Rubio, A.; Varela, J. A.; Saá, C. Palladium-Catalyzed
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Catalyzed Asymmetric Oxidative Annulation of N-Alkoxyheteroaryl
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(e) Chen, S.-S.; Wu, M.-S.; Han, Z.-Y. Palladium-Catalyzed Cascade
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(13) (a) Liu, S.; Qi, X.; Qu, L.-B.; Bai, R.; Lan, Y. C-H Bond
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Org. Chem. 2015, 80, 10686. (c) Guo, W.; Xia, Y. Mechanistic
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