From simple to complex: Rhodium(III)-catalyzed C-C bond cleavage and C-H bond functionalization for the synthesis of 3a, 8b- dihydro-1H-cyclopenta[b]benzofuran-1-ones

Article abstract of DOI:10.1021/acs.orglett.7b02052

A rhodium(III)-catalyzed strategy for the onestep synthesis of polysubstituted cis-3a, 8b-dihydro-1Hcyclopenta[ b]benzofuran-1-ones from simple 2′-hydroxychalcones and alkynes is developed. This novel transformation involves a sequential C-C bond cleavage and dehydrogenative annulation, leading to the product bearing a quaternary and a tertiary carbon center. 13C labeling experiments revealed that C-C bond cleavage takes place not only at the C-C(C-O) bond but also at the C-C bond. This study provides an alternative strategy using C-C bond cleavage thus demonstrating the power of this strategy combined with C-H bond functionalization for assembling complex structures from simple starting materials.

Full text of DOI:10.1021/acs.orglett.7b02052

Letter
pubs.acs.org/OrgLett
From Simple to Complex: Rhodium(III)-Catalyzed C−C Bond Cleavage
and C−H Bond Functionalization for the Synthesis of 3a,8b-
Dihydro‑1H‑cyclopenta[b]benzofuran-1-ones
Guiyu Guo,§ Saihong Wan,§ Xiaodong Si, Qijian Jiang, Yuanyuan Jia, Luo Yang, and Wang Zhou*,†,‡
†College of Chemical Engineering, Xiangtan University, Xiangtan 411105, China
‡State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Road 38, Beijing 100191, China
S
* Supporting Information
ABSTRACT: A rhodium(III)-catalyzed strategy for the one-
step synthesis of polysubstituted cis-3a,8b-dihydro-1H-
cyclopenta[b]benzofuran-1-ones from simple 2′-hydroxychal-
cones and alkynes is developed. This novel transformation
involves a sequential C−C bond cleavage and dehydrogenative
annulation, leading to the product bearing a quaternary and a
tertiary carbon center. 13C labeling experiments revealed that C−C bond cleavage takes place not only at the C−C(CO) bond
but also at the CC bond. This study provides an alternative strategy using C−C bond cleavage thus demonstrating the power
of this strategy combined with C−H bond functionalization for assembling complex structures from simple starting materials.
2,3,3a,8b-Tetrahydro-1H-cyclopenta[b]benzofurans are preva-
lent structural motifs found in numerous natural products such
as Aplysin, Rocaglamide, Silvestrol, and their derivatives. Some
of them exhibit a broad range of interesting and unique
bioactivities (Figure 1).1 To assemble this particular molecular
which the 2-pyridinyl group serves as a directing group.5
Considering the dual catalytic activities of rhodium(III) for C−
C bond activation and dehydrogenative annulation, we
envisioned that a rhodium(III) catalyzed reaction of readily
available 2′-hydroxychalcones and alkynes would enable a direct
approach toward dihydro-1H-cyclopenta[b]benzofuran-1-ones.
In our design (Scheme 1), the buildup of the desired
molecular skeleton could be achieved by the incorporation of
Scheme 1. Strategy for Constructing Ploysubstitued cis-
3a,8b-Dihydro-1H-cyclopenta[b]benzofuran-1-ones
Figure 1. Representative natural products possessing tetrahydro-1H-
cyclopenta[b]benzofuran core.
the alkyne moiety into the carbon skeleton of 2′-hydrox-
ychalcones along with the formation of four new bonds via a
rhodium-catalyzed sequential C−C(CO) bond cleavage and
dehydrogenative annulation. A valuable product bearing both a
quaternary and a tertiary carbon center will be generated in a
single step manipulation. As part of our continuous efforts to
develop methods for the cleavage of unstrained C−C bonds,6
we disclose herein a rhodium(III) catalyzed one-step synthesis
of polysubstituted cis-3a,8b-dihydro-1H-cyclopenta[b]-
benzofuran-1-ones from simple starting materials.
To test our hypothesis (Scheme 1), the reaction of 2′-
hydroxychalcone 1a with diphenyl acetylene 2a was conducted
in the presence of Cp*Rh(III), silver salt, and an oxidant.
Gratifyingly, the reaction was successful, giving cis-3,3a,8b-
architecture, some elegant methods have been developed such
as [3 + 2] photocycloadditions,2a Nazarov cyclization,2b radical
cyclization,2c,d and others,2e−g but in many of these cases
several steps are required. In fact, the rapid construction of
complex molecules from inexpensive and simple starting
materials represents one of the greatest challenges in synthetic
chemistry.
Over the past few decades, transition-metal-catalyzed C−C
bond activation has emerged as an active research topic because
its straightforward means to restructure the carbon framework
of organic compounds would provide a shortcut to molecular
complexity.3 Rhodium(III) catalysis has been shown to be
highly efficient in the dehydrogenative cyclization reactions,
allowing the construction of cyclic/heterocyclic compounds in
an atom-efficient manner.4 However, until recently, Shi and co-
workers have reported the pioneering works on rhodium(III)-
catalyzed C−C bond cleavage of second-arylmethanols, in
Received: July 5, 2017
© XXXX American Chemical Society
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Letter
triphenyl-3a,8b-dihydro-1H-cyclopenta[b]benzofuran-1-one
(3aa) as product (Scheme 2). Its structure was later further
phenomena were also observed when chalcone 1a was reacted
with a set of symmetric diaryl acetylenes (Scheme 4). The X-
a b
,
Scheme 2. Scope of 2′-Hydroxychalcones Bearing Different
Scheme 4. Scope of Alkynes
ab
,
Aromatic Substituents Groups
a
Standard reaction conditions: 1 (0.30 mmol), 2 (0.20 mmol),
[(Cp*RhCl2)2] (5.0 mol %), AgSbF6 (20 mol %), Cu(OAc)2·H2O
b
(2.0 equiv), DCE (1.5 mL) at 100 °C for 12 h under N2. Isolated
yields based on alkyne 2. The numbers in parentheses refer to the
result through slow dropwise addition of the alkyne.
a
b
Using standard reaction conditions shown in Scheme 2. Isolated
confirmed by single crystal X-ray crystallography. After
extensive screening of reaction parameters including solvent,
oxidant, additive, catalyst, and reaction temperature (Tables
S1−S9 in the Supporting Information), the isolated yield of
product 3aa was improved to 66% under the current optimum
reaction conditions (see footnote of Scheme 2). With the
optimized conditions in hand, 2′-hydroxychalcones bearing
different aromatic substituent groups were explored, affording
the corresponding dihydro-1H-cyclopenta[b]benzofuran-1-
ones 3 in moderate to good yields (Scheme 2). Notably, the
yield in some instances could be improved slightly by slow
dropwise addition of an alkyne. Importantly many of the
chosen substituents offer a handle for further synthetic
manipulation. Encouraged by these results, we next targeted
chalcones with a variety of substituents on the ring fused
aromatic ring to explore the versatility of this reaction. To our
surprise, a mixture of two regioisomers were obtained as
products (Scheme 3), with one isomer seemingly undergoing a
C−C aryl shift. These results suggest a unique arrangement
might be involved in this reaction. Moreover, similar
1
yield based on 2. Ratio of the isomers was determined by H NMR.
ray crystal structure of the mixture of ( )-3ab and ( )-3′ab
further confirmed that the two isomers differ from each other
with the exchanged aromatic ring on carbon atom C3a and
C8b. Unusually, it appeard as if the ratio of the two isomers is
not significantly related to the electronic nature of the
substituents on the substrate phenyl ring. It is worth noting
that the reaction predominately gave ( )-3ah as the product
when 1-phenyl-1-propyne was used. It is expected other alkyl
phenyl acetylenes could give similar results (( )-3ai to
( )-3ak). In addition, some chalcones and alkynes were not
compatible in this transformation (Schemes 3 and 4).
To obtain insight into the reaction mechanism, isotopic
labeling experiments were carried out. In 13C labeling
experiments, when the carbonyl carbon C1 and alkenyl C2 of
2′-hydroxychalcone 1a were labeled, the reaction provided 3aa
with labeled carbon at the C1 and C2 positions, respectively
(Scheme 5, eqs 1 and 2). When chalcone 1a, with alkenyl C3
labeling, was subjected to the standard reaction conditions, a
mixture of two isomers with a labeled carbon at C3 and C8b
Scheme 3. Scope with Respect to the 2′-Hydroxychalcones
ab
,
Component
Scheme 5. Isotopic Labelling Experiments
a
b
Using standard reaction conditions shown in Scheme 2. Isolated
1
yield based on 2. Ratio of the isomers were determined by H NMR.
B
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Letter
were obtained (eq 3). By taking into account the aforemen-
tioned formation of a mixture of products, these results indicate
that not only the aromatic ring but also the carbon atom
connected to the aromatic ring undergo rearrangement
simultaneously during the reaction, suggesting a C−C shift
and not the formation of a cationic intermediate. In a
deuterium labeling experiment, the reaction of the α-deuterated
chalcone (1a-d) with 2a affords 3aa-d with 98% deuterium
retention at the C2 position (eq 4).
Then, 0.5 equiv of Rh(III) catalyst, that is equal to the
stoichiometric amount of monomer Rh(III) catalyst, was used
in the absence of copper acetate. The desired product was
formed only in trace amount (Scheme 6). However, a 38%
species would not further cyclize to give trans product due to
the large strain of a 5−5 trans-fused bicyclic system.
Alternatively, the oxygen atom would facilitate the isomer-
ization of IV to VI via η-3 rhodium enolate V,10 allowing the
subsequent intermolecular alkene insertion and annulation4,11
in the presence of an oxidant to furnish the final product and
liberate the catalyst.
Alternatively, in catalytic cycle B, intermediate II provides
intermediate IX presumably via intramolecular thermal [2 +
2]12 and retro-[2 + 2]13 cycloadditions,14 followed by alkene
insertion, carbonyl insertion, β-carbon elimination,15 and
ketone α-C−H functionalization16 to give the isomer 3′.
Even though we do not have direct evidence to verify the
speculated catalytic cycles, given that the proposed mechanism
is reasonable, a single product should be obtained when the
aromatic ring on C3 of chalcones 1 and the aromatic rings on
alkyne 2 are the same. The experimental results shown in
Scheme 8 are nicely consistent with the expected outcomes.
Scheme 6. Control Experiments
a
Scheme 8. Substrates Leading to Single Products
yield of ( )-3aa was obtained when 2.0 equiv of sodium acetate
were added. Moreover, triethylamine failed to show a similar
effect (for more control experiments, see Scheme S1 in the
Supporting Information).
a
The numbers in parentheses refer to the result through slow
dropwise addition of alkyne.
Based on these preliminary results and previous studies,4 a
mechanism with two catalytic cycles is proposed to rationalize
the formation of the mixture of products (Scheme 7). Initially,
an active Rh(III) species is generated by the reaction of
[(Cp*RhCl2)2] with a silver salt and copper salt,7 followed by
ligand exchange with the phenol of the chalcones and alkynes
insertion to give alkenyl rhodium intermediate II.8 At this stage,
two possible pathways exist concurrently. In catalytic cycle A,
intermediate II undergoes an intramolecular carbonyl insertion9
and subsequent β-carbon elimination5 to afford aryl rhodium
intermediate IV. Although a reversible intramolecular alkene
insertion would produce intermediates VII′, in principle, this
Subjecting the product 3aa to two reductions further showed
the utility of these cyclopenta[b]dihydrobenzofuran-1-ones.
Pd/C and H2 reduction of product 3aa gave 4 in 55% yield
while Luche reduction afforded the corresponding alcohol 5 in
73% yield (Scheme 9).
In summary, we have developed a rhodium(III)-catalyzed
strategy for the one-step synthesis of polysubstituted cis-3a,8b-
dihydro-1H-cyclopenta[b]benzofuran-1-ones from simple 2′-
hydroxychalcones and alkynes. This chemistry involves a
tandem C−C bond cleavage and dehydrogenative annulation.
To rationalize the formation of the observed products, β-carbon
Scheme 7. Proposed Mechanism
C
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(4) For selected recent reviews on rhodium(III)-catalyzed C−H
bond fuctionalization reactions, see: (a) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (b) Satoh, T.; Miura, M.
Chem. - Eur. J. 2010, 16, 11212. (c) Patureau, F. W.; Wencel-Delord,
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Chem. Res. 2015, 48, 1007. (e) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 10578. (f) Gulías, M.;
Scheme 9. Further Transformations of ( )-3aa
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2015, 80, 8782. (b) Zhou, W.; Fan, W.; Jiang, Q.; Liang, Y.-F.; Jiao, N.
Org. Lett. 2015, 17, 2542. (c) Zhou, W.; Yang, Y.; Liu, Y.; Deng, G.-J.
Green Chem. 2013, 15, 76.
elimination of rhodium alkoxide, alkene isomerization, and
intramolecular thermal [2 + 2]/retro-[2 + 2] cycloadditions of
alkenyl rhodium species were proposed as the key steps.
Although the efficiency and selectivity are still not satisfactory,
this chemistry demonstrates the power of the concept based on
merging C−C bond cleavage and C−H bond functionalization
for assembling complex structures from simple starting
materials. Further studies on substrate scope and mechanistic
details are ongoing in our group.
(7) Yang, Y.; Zhou, M.-B.; Ouyang, X.-H.; Pi, R.; Song, R.-J.; Li, J.-H.
Angew. Chem., Int. Ed. 2015, 54, 6595.
(8) (a) Mochida, S.; Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02052.
■
Chem. - Asian J. 2010, 5, 847. (b) Seoane, A.; Casanova, N.; Quinones,
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S
N.; Mascarenas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 834.
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(9) (a) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 2154. (b) Muralirajan, K.; Parthasarathy, K.; Cheng,
C.-H. Angew. Chem., Int. Ed. 2011, 50, 4169.
(10) (a) Shi, X.-Y.; Li, C.-J. Org. Lett. 2013, 15, 1476. (b) Dateer, R.
B.; Chang, S. J. Am. Chem. Soc. 2015, 137, 4908. A base-promoted
isomerization is also possible.
Experimental procedures, analytical data for products,
NMR spectra of products (PDF)
Crystallographic data (CIF, CIF, CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wzhou@xtu.edu.cn.
ORCID
(11) For some representative examples of Rh(III)-catalyzed C−H
activation, see: (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407. (b) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
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(12) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev.
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Wang Zhou: 0000-0001-8629-086X
Author Contributions
§G.G. and S.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from NSFC (21372188) and the State Key
Laboratory of Natural and Biomimetic Drugs are greatly
appreciated. We thank Prof. Qingjiang Li at Sun Yat-sen
University, Prof. Zhuangzhi Shi at Nanjing University, and Prof.
Scott Stewart at the University of Western Australia for helpful
discussions and suggestions.
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