Tunable Synthesis of Indeno[1,2- c]furans and 3-Benzoylindenones via FeCl3-Catalyzed Carbene/Alkyne Metathesis Reaction of o-Alkynylbenzoyl Diazoacetates

Article abstract of DOI:10.1021/acs.orglett.0c03882

An efficient synthesis of indeno[1,2-c]furan and 3-benzoylindenone derivatives through a FeCl3-catalyzed carbene/alkyne metathesis reaction of o-alkynylbenzoyl diazoacetates is presented. Mechanistically, the key intermediate, vinyl iron carbene, is formed by 5-exo-dig carbocyclization and terminated with a formal [3 + 2] cycloaddition or carbonylation. To the best of our knowledge, this is the first example in which FeCl3 is used as a catalyst for a carbene/alkyne metathesis reaction. Finally, derivatization reactions were carried out to showcase the value of the products.

Full text of DOI:10.1021/acs.orglett.0c03882

pubs.acs.org/OrgLett
Letter
Tunable Synthesis of Indeno[1,2‑c]furans and 3‑Benzoylindenones
via FeCl3‑Catalyzed Carbene/Alkyne Metathesis Reaction of
o‑Alkynylbenzoyl Diazoacetates
Bin Li,* Nana Shen, Yujie Yang, Xinying Zhang, and Xuesen Fan*
Cite This: Org. Lett. 2021, 23, 388−393
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An efficient synthesis of indeno[1,2-c]furan and 3-
benzoylindenone derivatives through a FeCl3-catalyzed carbene/
alkyne metathesis reaction of o-alkynylbenzoyl diazoacetates is
presented. Mechanistically, the key intermediate, vinyl iron
carbene, is formed by 5-exo-dig carbocyclization and terminated
with a formal [3 + 2] cycloaddition or carbonylation. To the best
of our knowledge, this is the first example in which FeCl3 is used as
a catalyst for a carbene/alkyne metathesis reaction. Finally, derivatization reactions were carried out to showcase the value of the
products.
ndanones and indenones are important structural motifs
found in a number of natural products and synthetically
indanone and indenone derivatives,1,9,10 conventional ap-
proaches still suffer from tedious multiple steps, harsh reaction
conditions, and limited substrate scopes. Therefore, it is
currently highly desirable to develop novel method to
construct the indanone and indenone skeletons in a more
convenient, sustainable, and green manner.
I
bioactive molecules.1 For example, compound A (pauciflorol F,
Figure 1), isolated from the stem bark of Vatica pauciflora,
On the other hand, metal−carbene insertion serves as a
powerful and useful method for C−X bond formation.11
Among them, transition-metal-catalyzed carbene/alkyne meta-
thesis (CAM) turns out to be a straightforward tool for the
construction of complex polycyclic skeletons in one pot.12 In
this regard, CAM reactions using diazo compounds as the
carbene precursors have attracted widespread attention due to
its easy accessibility and high reactivity.13−17 However, it was
also noticed that most of these methods have to be
accomplished in the presence of noble metal catalysts such
as gold,14 rhodium,15 ruthenium,16 and copper,17 and the
toxicity and scarcity of these catalysts could be the main
restrictive factors for the sustainability of these methods,
especially in large-scale applications. Therefore, finding low-
cost yet still effective catalysts to promote the CAM reactions
is urgently needed.
Figure 1. Biologically interesting indanones and indenones.
possesses diverse biological activities such as antibacterial,
antiviral, and anti-HIV.2 Compound B has been used for the
treatment of Alzheimer’s disease.3 Compound C, isolated from
the filamentous marine cyanobacterium Lyngbya majuscula, is a
promising anticancer drug candidate.4 Compound D is known
for its applications as antiviral and antibacterial agents.5
Compound E is isolated from the fruits of Verola sebifera
and has unique biological activity.6 Compound F was
discovered as a unique template for the activation of
peroxisome proliferator-activated receptor γ (PPAR γ).7
Compound G and its derivatives are a novel class of anticancer
agents with two of them in clinical trials8 (Figure 1). In
addition, a large number of indanone and indenone derivatives
were used as organic functional materials.9 While a variety of
synthetic methods have been developed for the preparation of
o-Alkynylaryl α-diazoester is a reactive substrate that is used
to synthesize various functional molecules via metal-catalyzed
carbocyclization. For example, in 2016, Zhang et al. reported a
gold-catalyzed concise synthesis of functional indenes via
Received: November 23, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03882
© 2020 American Chemical Society
Org. Lett. 2021, 23, 388−393
388

Organic Letters
pubs.acs.org/OrgLett
Letter
sequential C−H bond functionalization and 5-endo-dig
carbocyclization of o-alkynylaryl α-diazoester and electron-
rich aromatics18 (Scheme 1a). More recently, Xu and co-
synthesis of 2, and the results are listed in Scheme 2.
Compound 1 bearing either an electron-donating group
a b
,
Scheme 2. Substrate Scope for the Synthesis of 2
Scheme 1. Metal-Catalyzed Carbocyclization Reaction
workers reported a gold-catalyzed CAM reaction of o-
alkynylaryl diazoacetates and protic nucleophiles for the
synthesis of indenol derivatives with a tertiary center14c
(Scheme 1b). As a continuation of our recent interest in
using diazo compounds as carbene precursors to construct
organic functional molecular skeletons via transition-metal-
catalyzed C−H bond activation,19 we have used o-alkynylben-
zoyl diazoacetates (1) as coupling partners to synthesize
naphthol compounds.14d During our study, we were surprised
to find that under the promotion of [Ir(cod)Cl]2 and NaOAc
in dichloroethane (DCE) ethyl 2-diazo-3-oxo-3-(2-
(phenylethynyl)phenyl)propanoate (1a) could be transformed
into 1-ethoxy-3-phenyl-8H-indeno[1,2-c]furan-8-one (2a) in
an excellent yield of 95%, and the structure of 2a was
confirmed by X-ray crystallography (see the Supporting
Information). Considering that iron carbene has been
frequently used for C−C or C−X bond (X = C, N, O, Si, S,
etc.) formation and iron catalyst has advantages such as low
price and environmental friendliness,20 and in conjunction
with our recent studies on iron-catalyzed reaction,21 we tried to
us FeCl3 (0.2 equiv) to replace [Ir(cod)Cl]2 as the catalyst for
this interesting transformation. To our pleasure, 2a could be
obtained in a yield of 53%. In the absence of NaOAc, the yield
of 2a decreased to 22%. Meanwhile, ethyl 3-benzoyl-1-oxo-1H-
indene-2-carboxylate (3a) was obtained in 28% yield (Scheme
1c). Bearing in mind the importance of products 2 and 3 and
the fact that there is still no report on Fe-catalyzed CAM
reaction, we realized that this reaction deserved a systematic
study to explore its intriguing mechanism and its application
scope on the synthesis related compounds. Herein, we report
the detailed results obtained in this direction.
a
Conditions: 0.2 mmol of 1, 0.1 mmol of FeCl3, 0.2 mmol of NaOAc,
b
c
1 mL of DCM, air, sealed tube, 15 h. Isolated yield. 4 mmol of 1a
was used.
(EDG) such as methoxy and methyl or an electron-
withdrawing group (EWG) including fluoro, chloro, or
trifluoromethyl as the R1 unit attached on different sites of
the connecting benzene ring readily underwent this CAM
reaction to afford 2b−2h in excellent yields. Interestingly, the
reactions of ethyl 2-diazo-3-oxo-3-(6-(phenylethynyl)benzo-
[d][1,3]dioxol-5-yl)propanoate (1i) and ethyl 2-diazo-3-oxo-3-
(1-(phenylethynyl)naphthalen-2-yl)propanoate (1j) also pro-
ceeded smoothly to generate 2i and 2j in 87% and 82% yields,
respectively. In addition, 1 bearing a phenyl unit attached a
phenyl unit attached with either EDGs (methoxy, phenyl,
methyl, ethyl, and tert-butyl) or EWGs (fluoro, chloro, bromo,
and trifluoromethyl) on its para-, meta-, or ortho-position as
the R2 moiety took part in this reaction to give 2k−2w in 85−
94% yields. When o-alkynylbenzoyl diazoacetate 1 contained a
sterically hindered 2,6-dimethyl-tethered alkyne group, the
reaction could also take place smoothly to give 2x in 90% yield.
Delightfully, 1 bearing a thiophen-2-yl-tethered alkyne unit was
also suitable for this cascade reaction to give 2y in good yield.
It is worth mentioning that 1 bearing a linear or cyclic alkane-
tethered alkyne unit was found to be well tolerated, giving the
corresponding products 2z and 2aa in 86% and 83% yields.
Notably, 1 containing a TMS-tethered alkyne unit was found
to be also suitable for the Fe(III)-catalyzed CAM reaction to
give product 2ab bearing no substituent at the 3-position.
Next, the substrate scope for the preparation of 3 was
investigated. Thus, a range of 1 bearing various R1 groups were
all tolerated and gave the corresponding products 3b−3f in
good yields (Scheme 3). Notably, the structure of 3f was
unambiguously confirmed by single-crystal X-ray diffraction
analysis (see the Supporting Information). On the pendant
alkyne, both electron-neutral and electron-rich aryl groups
were subjected to the optimal reaction conditions to give the
Initially, the reaction parameters, including the solvent, base,
catalyst, and temperature, were screened by using 1a as model
substrates. As shown in Table S1, we found that when 1a was
treated with FeCl3 and NaOAc in dichloromethane (DCM) at
50 °C product 2a was obtained in a higher 88% yield (Table
S1, entry 17). In addition, the optimized reaction conditions
for 3a were found to be as follows: FeCl3 (0.5 equiv) as a
catalyst and 5 equiv of water in DCE at 80 °C under air (Table
S1, entry 22). With the optimal reaction conditions in hand,
we first focused on screening the substrate scope for the
389
https://dx.doi.org/10.1021/acs.orglett.0c03882
Org. Lett. 2021, 23, 388−393

Organic Letters
pubs.acs.org/OrgLett
Letter
a b
,
or without FeCl3, revealing that the transition from 2a to 3a is
a possible pathway (Scheme 4c). Fourth, to determine the
source of oxygen atom on the benzoyl group, 18O-labeling
experiments with H218O for the formation of 3a were carried
out (Scheme 4d). From this reaction, [16O4]-3a vs [16O318O1]-
3a vs [16O218O2]-3a vs [16O118O3]-3a were obtained in a ratio
of 0.09:0.64:1:0.24 as determined by HRMS analysis (see
Figures S3 and S4 for details), revealing that the oxygen atom
on the benzoyl group comes from water and there is a
reversible reaction before forming of final product 3a.
Scheme 3. Substrate Scope for the Synthesis of 3
On the basis of the above control experiment results and
related literature reports, two possible pathways for the
preparation of 2a and 3a are described in Scheme 5. First,
Scheme 5. Proposed Mechanism Accounting for the
Formation of 2a and 3a
a
Conditions: 0.2 mmol of 1, 0.1 mmol of FeCl3, 1 mmol of H2O, 1
b
c
mL of DCE, air, sealed tube, 15 h. Isolated yield. 4 mmol of 1a was
used. The reaction became messy.
d
desired products 3g−3r in 69−82% yields. Unfortunately, the
reactions of substrates containing linear alkane- or cyclic
alkane- or TMS-tethered alkyne failed to give the desired
products 3s−3u under the standard conditions.
To gain insight into the mechanism of this reaction, a series
of control experiments were carried out. First, ethyl 3-oxo-3-
(2-(phenylethynyl)phenyl)propanoate (4) was subjected to
the standard reaction conditions for the formation of 2. It
turned out that no reaction occurred and 96% of 4 was
recovered (Scheme 4a), indicating that the reaction should be
iron carbene I is formed through iron-catalyzed dinitrogen
expulsion of o-alkynylbenzoyl diazoacetate 1a.22 This is
followed by 5-exo-dig carbocyclization to afford vinyl iron
carbene II.14−17 Next, II is terminated with a formal [3 + 2]
cycloaddition to give product 2a.10d,23 On the other hand, II is
terminated with O−H insertion to form the intermediate
III,14c,16a which undergoes an oxidant dehydrogenation to
afford product 3a (Scheme 5, path a). As an alternative
pathway, 2a might undergo a furan ring opening under the
assistance of water to afford intermediate IV. Proton transfer of
IV gives intermediate V. Subsequently, keto−enol tautomeri-
zation of V occurs to give intermediate VI or VI′, which
undergoes an oxidation by air to afford product 3a (Scheme 5,
path b). Additionally, an intramolecular O-nucleophilic
addition occurs with VI′ to give 2a by losing one molecule
of water. Moreover, vinyl iron carbene II might be direct
oxidized under the reaction conditions to give the product 3a
(Scheme 5, path c).24
Scheme 4. Control Experiments
The synthetic utility of the products have been demon-
strated in several derivatization reactions (Scheme 6).
Treatment of 2a with N-methylmaleimide in toluene/DCE at
80 °C for 12 h afforded maleimide-related polycyclic
compound 5 in 52% yield via [4 + 2] cycloaddition and the
following dehydration aromatization. In the presence of 3-
chloroperbenzoic acid (m-CPBA), 3a was oxidized to epoxide
product 7 in 68% yield and its structural confirmation by X-ray
crystallography (see the Supporting Information).
In summary, we have developed the first iron-catalyzed
CAM reaction of o-alkynylbenzoyl diazoacetates, which
provided an efficient and facile method to access indeno[1,2-
c]furans and 3-benzoylindenones. Mechanistically, the in situ
initiated with a iron carbene. Second, 2a and 3a were obtained
in 62% and 14% yields, respectively, by treating substrate 1a
with FeCl3 and H2O in DCE under Ar at 80 °C for 15 h
(Scheme 4b). Meanwhile, the unoxidized intermediate, ethyl 3-
(hydroxy(phenyl)methyl)-1-oxo-1H-indene-2-carboxylate
+
(HRMS (ESI) calcd for C19H15O3 : 291.1027 [M − OH]+,
found: 291.0997) was not obtained but was detected in the
reaction mixture by HRMS analysis (for details, see Figures S1
and S2). These results indicate that air as an oxidant is
indispensable for the efficient transformation of 3a. Third, 2a
could be partially converted to 3a in the presence of H2O, with
390
https://dx.doi.org/10.1021/acs.orglett.0c03882
Org. Lett. 2021, 23, 388−393

Organic Letters
pubs.acs.org/OrgLett
Letter
Authors
Scheme 6. Derivatization of 2a and 3a
Nana Shen − School of Environment, School of Chemistry and
Chemical Engineering, Key Laboratory for Yellow River and
Huai River Water Environmental Pollution Control and Key
Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Collaborative
Innovation Center of Henan Province for
GreenManufacturing of Fine Chemicals, Henan Normal
University, Xinxiang, Henan 453007, China
Yujie Yang − School of Environment, School of Chemistry and
Chemical Engineering, Key Laboratory for Yellow River and
Huai River Water Environmental Pollution Control and Key
Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Collaborative
Innovation Center of Henan Province for
formed vinyl iron carbene as a key intermediate is terminated
with a formal [3 + 2] cycloaddition to afford indeno[1,2-
c]furans in the absence of water. On the other hand, vinyl iron
carbene would undergo carbonylation in the presence of water
and air to afford 3-benzoylindenones. Compared with
literature protocols, these novel methods have notable features
such use of cheap and green catalyst, mild reaction conditions,
and an environmentally friendly nature. Further studies are
currently underway to elucidate the mechanism and to develop
more iron-catalyzed CAM reactions in our laboratory.
GreenManufacturing of Fine Chemicals, Henan Normal
University, Xinxiang, Henan 453007, China
Xinying Zhang − School of Environment, School of Chemistry
and Chemical Engineering, Key Laboratory for Yellow River
and Huai River Water Environmental Pollution Control and
Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Collaborative
Innovation Center of Henan Province for
GreenManufacturing of Fine Chemicals, Henan Normal
University, Xinxiang, Henan 453007, China; orcid.org/
0000-0002-3416-4623
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03882.
Experimental procedures, mechanism studies, data and
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03882
1
spectra of the H, 13C and 19F NMR of all products
(PDF)
Accession Codes
Notes
CCDC 2043433−2043435 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant No. U2004189), the Scientific Research Starting
Foundation of Henan Normal University (5101219170128),
Program for Innovative Research Team in Science and
Technology in Universities of Henan Province
(20IRTSTHN005), and 111 Project (D17007) for financial
support.
AUTHOR INFORMATION
Corresponding Authors
■
Bin Li − School of Environment, School of Chemistry and
Chemical Engineering, Key Laboratory for Yellow River and
Huai River Water Environmental Pollution Control and Key
Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Collaborative
Innovation Center of Henan Province for
GreenManufacturing of Fine Chemicals, Henan Normal
University, Xinxiang, Henan 453007, China; orcid.org/
0000-0002-0145-5926; Email: libin@htu.edu.cn
REFERENCES
■
(1) (a) Ahmed, N. Synthetic Advances in the Indane Natural
Product Scaffolds as Drug Candidates: A Review. Stud. Nat. Prod.
Chem. 2016, 51, 383−434. See also references cited therein.
(b) Turek, M.; Szczęsna, D.; Koprowski, M.; Bałczewski, P. Synthesis
of 1-Indanones with a Broad Range of Biological Activity. Beilstein J.
Org. Chem. 2017, 13, 451−494.
(2) (a) Dai, J. R.; Hallock, Y. F.; Cardellina, J. H.; Boyd, M. R. HIV-
Inhibitory and Cytotoxic Oligostilbenes from the Leaves of Hopea
malibato1. J. Nat. Prod. 1998, 61, 351−353. (b) Nitta, T.; Arai, T.;
Takamatsu, H.; Inatomi, Y.; Murata, H.; Iinuma, M.; Tanaka, T.; Ito,
T.; Asai, F.; Ibrahim, I.; Nakanishi, T.; Watabe, K. Antibacterial
Activity of Extracts Prepared from Tropical and Subtropical Plants on
Methicillin-Resistant Staphylococcus aureus. J. Health Sci. 2002, 48,
273−276. (c) Ito, T.; Tanaka, T.; Iinuma, M.; Nakaya, K.; Takahashi,
Y.; Sawa, R.; Murata, J.; Darnaedi, D. Three New Resveratrol
Oligomers from the Stem Bark of Vatica pauciflora. J. Nat. Prod. 2004,
67, 932−937.
Xuesen Fan − School of Environment, School of Chemistry and
Chemical Engineering, Key Laboratory for Yellow River and
Huai River Water Environmental Pollution Control and Key
Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory of Organic
Functional Molecules and Drug Innovation, Collaborative
Innovation Center of Henan Province for
GreenManufacturing of Fine Chemicals, Henan Normal
University, Xinxiang, Henan 453007, China; orcid.org/
0000-0002-2040-6919; Email: xuesen.fan@htu.cn
391
https://dx.doi.org/10.1021/acs.orglett.0c03882
Org. Lett. 2021, 23, 388−393

Organic Letters
pubs.acs.org/OrgLett
Letter
(3) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. Synthesis
and Structure-Activity Relationships of Acetylcholinesterase Inhib-
itors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine
Hydrochloride and Related Compounds. J. Med. Chem. 1995, 38,
4821−4829.
(4) Nagle, D. G.; Zhou, Y. D.; Park, P. U.; Paul, V. J.; Rajbhandari,
I.; Duncan, C. J. G.; Pasco, D. S. A New Indanone From the Marine
Cyanobacterium Lyngbya majuscula that Inhibits Hypoxia-Induced
Activation of the VEGF Promoter in Hep3B Cells. J. Nat. Prod. 2000,
63, 1431−1433.
(5) Wessig, P.; Teubner, J. Total Synthesis of Pterosines B and C via
a Photochemical Key Step. Synlett 2006, 1543−1546. See also
references therein.
Guiding Principles for Site Selective and Stereoselective Intermo-
lecular C−H Functionalization by Donor/Acceptor Rhodium
Carbenes. Chem. Soc. Rev. 2011, 40, 1857−1869. (c) Wang, B.;
Qiu, D.; Zhang, Y.; Wang, J. B. Recent Advances in C(sp3)−H Bond
Functionalization via Metal−Carbene Insertions. Beilstein J. Org.
Chem. 2016, 12, 796−804.
(12) (a) For selected reviews, see: Harvey, D. F.; Sigano, D. M.
Carbene-Alkyne-Alkene Cyclization Reactions. Chem. Rev. 1996, 96,
́
271−288. (b) Gomez-Gallego, M.; Mancheno, M. J.; Sierra, M.
̃
Catalytic Transmetalation from Group 6 Fischer Carbene Complexes:
An Emerging Powerful Tool in Organic Synthesis. Acc. Chem. Res.
̈
2005, 38, 44−53. (c) Dotz, K. H.; Stendel, J., Jr Fischer Carbene
Complexes in Organic Synthesis: Metal-Assisted and Metal-
(6) Lopes, L. M. X.; Yoshida, M.; Gottlieb, O. R. Aryltetralone and
Arylindanone Neolignans From Virola sebifera. Phytochemistry 1984,
23, 2021−2024.
(7) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kang, S. K.; Kim, K. R.;
Rhee, S. D.; Jung, W. H.; Yang, S. D.; Kim, S. J.; Woo, J. R.; Lee, J. H.;
Cheon, H. G.; Kim, S. S. Indenone Derivatives: A Novel Template for
Peroxisome Proliferator-Activated Receptor γ (PPARγ) Agonists. J.
Med. Chem. 2006, 49, 4781−4784.
Templated Reactions. Chem. Rev. 2009, 109, 3227−3274. (d) Bar-
́
luenga, J.; Valdes, C. Tosylhydrazones: New Uses for Classic Reagents
in Palladium-Catalyzed Cross-Coupling and Metal-Free Reactions.
Angew. Chem., Int. Ed. 2011, 50, 7486−7500.
(13) Pei, C.; Zhang, C.; Qian, Y.; Xu, X. F. Catalytic Carbene/
Alkyne Metathesis (CAM): A Versatile Strategy for Alkyne
Bifunctionalization. Org. Biomol. Chem. 2018, 16, 8677−8685 and
references cited therein.
(8) (a) Nagarajan, M.; Morrell, A.; Ioanoviciu, A.; Antony, S.;
Kohlhagen, G.; Agama, K.; Hollingshead, M.; Pommier, Y.; Cushman,
M. Synthesis and Evaluation of Indenoisoquinoline Topoisomerase I
Inhibitors Substituted with Nitrogen Heterocycles. J. Med. Chem.
2006, 49, 6283−6289. (b) Morrell, A.; Placzek, M.; Parmley, S.;
Grella, B.; Antony, S.; Pommier, Y.; Cushman, M. Optimization of the
Indenone Ring of Indenoisoquinoline Topoisomerase I Inhibitors. J.
Med. Chem. 2007, 50, 4388−4404. (c) Lv, P. C.; Elsayed, M. S. A.;
Agama, K.; Marchand, C.; Pommier, Y.; Cushman, M. Design,
Synthesis, and Biological Evaluation of Potential Prodrugs Related to
the Experimental Anticancer Agent Indotecan (LMP400). J. Med.
Chem. 2016, 59, 4890−4899.
(9) (a) For selected examples, see: McCubbin, J. A.; Tong, X.;
Wang, R. Y.; Zhao, Y.; Snieckus, V.; Lemieux, R. P. Directed
Metalation Route to Ferroelectric Liquid Crystals with a Chiral
Fluorenol Core: The Effect of Restricted Rotation on Polar Order. J.
Am. Chem. Soc. 2004, 126, 1161−1167. (b) Morinaka, K.; Ubukata,
T.; Yokoyama, Y. Structurally Versatile Novel Photochromic
Bisarylindenone and Its Acetal: Achievement of Large Cyclization
Quantum Yield. Org. Lett. 2009, 11, 3890−3893. (c) Estrada, L. A.;
Yarnell, J. E.; Neckers, D. C. Revisiting Fluorenone Photophysics via
Dipolar Fluorenone Derivatives. J. Phys. Chem. A 2011, 115, 6366−
6375. (d) Xia, J. B.; Zhu, C.; Chen, C. Visible Light-Promoted Metal-
Free C−H Activation: Diarylketone-Catalyzed Selective Benzylic
Mono- and Difluorination. J. Am. Chem. Soc. 2013, 135, 17494−
17500. (e) Capodilupo, A. L.; Vergaro, V.; Fabiano, E.; Giorgi, M. D.;
Baldassarre, F.; Cardone, A.; Maggiore, A.; Maiorano, V.; Sanvitto, D.;
Gigli, G.; Ciccarella, G. Design and Synthesis of Fluorenone-Based
Dyes: Two-Photon Excited Fluorescent Probes for Imaging of
Lysosomes and Mitochondria in Living Cells. J. Mater. Chem. B
2015, 3, 3315−3323.
(14) (a) Bao, M.; Qian, Y.; Su, H.; Wu, B.; Qiu, L. H.; Hu, W. H.;
Xu, X. F. Gold(I)-Catalyzed and H2O-Mediated Carbene Cascade
Reaction of Propargyl Diazoacetates: Furan Synthesis and Mecha-
nistic Insights. Org. Lett. 2018, 20, 5332−5335. (b) Bao, M.; Wang,
X.; Qiu, L. H.; Hu, W. H.; Chan, P. W. H.; Xu, X. F. Gold-Catalyzed
1,2-Acyloxy Migration/Coupling Cascade of Propargyl Diazoacetates:
Synthesis of Isomycin Derivatives. Org. Lett. 2019, 21, 1813−1817.
(c) Zhang, C.; Li, H. L.; Pei, C.; Qiu, L. H.; Hu, W. H.; Bao, X. G.;
Xu, X. F. Selective Vinylogous Reactivity of Carbene Intermediate in
Gold-Catalyzed Alkyne Carbocyclization: Synthesis of Indenols. ACS
Catal. 2019, 9, 2440−2447. (d) Zhang, C.; Hong, K. M.; Dong, S. L.;
Pei, C.; Zhang, X. L.; He, C. W.; Hu, W. H.; Xu, X. F. Gold(I)-
Catalyzed Aromatization: Expeditious Synthesis of Polyfunctionalized
Naphthalenes. iScience 2019, 21, 499−508.
(15) (a) Jansone-Popova, S.; May, J. A. Synthesis of Bridged
Polycyclic Ring Systems via Carbene Cascades Terminating in C−H
Bond Insertion. J. Am. Chem. Soc. 2012, 134, 17877−17880.
(b) Wang, X. B.; Zhou, Y. F.; Qiu, L. H.; Yao, R. E.; Zheng, Y.;
Zhang, C.; Bao, X. G.; Xu, X. F. Enantioselective Carbene Cascade:
An Effective Approach to Cyclopentadienes and Applications in Diels-
Alder Reactions. Adv. Synth. Catal. 2016, 358, 1571−1576. (c) Jia, S.
K.; Dong, G. Z.; Ao, C. Q.; Jiang, X. X.; Hu, W. H. Rhodium-
Catalyzed Formal C−O Insertion in Carbene/Alkyne Metathesis
Reactions: Synthesis of 3-Substituted 3H-Indol-3-ols. Org. Lett. 2019,
21, 4322−4326. (d) Dong, K. Y.; Pei, C.; Zeng, Q.; Wei, H. L.; Doyle,
M. P.; Xu, X. F. Selective C(sp3)−H Bond Insertion in Carbene/
Alkyne Metathesis Reactions. Enantioselective Construction of
Dihydroindoles. ACS Catal. 2018, 8, 9543−9549. (e) Dong, K. Y.;
Fan, X.; Pei, C.; Zheng, Y.; Chang, S. L.; Cai, J.; Qiu, L. H.; Yu, Z. X.;
Xu, X. F. Transient-Axial-Chirality Controlled Asymmetric Rhodium-
Carbene C(sp2)−H Functionalization for the Synthesis of Chiral
Fluorenes. Nat. Commun. 2020, 11, 2363−2373.
(10) (a) For selected examples, see: Zhao, P.; Liu, Y.; Xi, C.
MeOTf-Induced Carboannulation of Isothiocyanates and Aryl
Alkynes with C−S Bond Cleavage: Access to Indenones. Org. Lett.
2015, 17, 4388−4391. (b) Dethe, D. H.; Murhade, G. M. FeCl3
Mediated Synthesis of Substituted Indenones by a Formal [2 + 2]
Cycloaddition/Ring Opening Cascade of o-Keto-cinnamates. Chem.
Commun. 2015, 51, 10891−10894. (c) Pan, C.; Huang, B.; Hu, W.;
Feng, X.; Yu, J. T. Metal-Free Radical Oxidative Annulation of Ynones
with Alkanes to Access Indenones. J. Org. Chem. 2016, 81, 2087−
2093. (d) Rode, N.; Marinelli, F.; Arcadi, A.; Adak, T.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. Sequential Gold-Catalyzed Carbene
Transfer/Ring Closure: Oxidative Cyclization of beta-(2-Alkynyl-
phenyl)-alpha, betaynones to Indenofuranones. Adv. Synth. Catal.
2018, 360, 4790−4794.
́
́
(16) (a) Cambeiro, F.; Lopez, S.; Varela, J. A.; Saa, C. Vinyl
Dihydropyrans and Dihydrooxazines: Cyclizations of Catalytic
Ruthenium Carbenes Derived from Alkynals and Alkynones. Angew.
́
Chem., Int. Ed. 2014, 53, 5959−5963. (b) Gonzalez-Rodríguez, C.;
́
́
Suarez, J. R.; Varela, J. A.; Saa, C. Nucleophilic Addition of Amines to
Ruthenium Carbenes: ortho-(Alkynyloxy)benzylamine Cyclizations
towards 1,3-Benzoxazines. Angew. Chem., Int. Ed. 2015, 54, 2724−
́
2728. (c) Padín, D.; Cambeiro, F.; Fananas-Mastral, M.; Varela, J. A.;
̃
́
Saa, C. [2 + 1] Cycloaddition of Catalytic Ruthenium Vinyl Carbenes:
A Stereoselective Controlled Access to (Z)- and (E)-Vinyl
Epoxypyrrolidines. ACS Catal. 2017, 7, 992−996. (d) Padín, D.;
́
Varela, J. A.; Saa, C. Ruthenium-Catalyzed Tandem Carbene/Alkyne
Metathesis/N−H Insertion: Synthesis of Benzofused Six-Membered
(11) (a) For selected reviews, see: Doyle, M. P.; Duffy, R.;
Ratnikov, M.; Zhou, L. Catalytic Carbene Insertion into C−H Bonds.
Chem. Rev. 2010, 110, 704−724. (b) Davies, H. M. L.; Morton, D.
Azaheterocycles. Org. Lett. 2020, 22, 2621−2625.
(17) (a) Yao, R. W.; Rong, G. W.; Yan, B.; Qiu, L. H.; Xu, X. F.
Dual-Functionalization of Alkynes via Copper-Catalyzed Carbene/
392
https://dx.doi.org/10.1021/acs.orglett.0c03882
Org. Lett. 2021, 23, 388−393

Organic Letters
pubs.acs.org/OrgLett
Letter
Alkyne Metathesis: A Direct Access to the 4-Carboxyl Quinolines.
ACS Catal. 2016, 6, 1024−1027. (b) Zhang, C.; Chang, S. L.; Qiu, L.
H.; Xu, X. F. Chemodivergent Synthesis of Multi-substituted/Fused
Pyrroles via Copper-Catalyzed Carbene Cascade Reaction of
Propargyl α-Iminodiazoacetates. Chem. Commun. 2016, 52, 12470−
12473.
Alkynes: One-Pot Synthesis of Quinoxalines. Chem. - Eur. J. 2013, 19,
6576−6580.
(18) Ma, B.; Wu, Z.; Huang, B.; Liu, L.; Zhang, J. L. Gold-catalyzed
Facile Access to Indene Scaffolds via Sequential C−H Functionaliza-
tion and 5-endo-dig Carbocyclization. Chem. Commun. 2016, 52,
9351−9354.
(19) (a) Li, B.; Zhang, B. B.; Zhang, X. Y.; Fan, X. S. Regioselective
Synthesis of Diversely Substituted Benzo[a]carbazoles through
Rh(iii)-Catalyzed Annulation of 2-Arylindoles with α-Diazo Carbonyl
Compounds. Chem. Commun. 2017, 53, 1297−1300. (b) Zhang, B.
B.; Li, B.; Zhang, X. Y.; Fan, X. S. Synthesis of Naphthoquinolizinones
through Rh(III)-Catalyzed Double C(sp2)−H Bond Carbenoid
Insertion and Annulation of 2-Aryl-3-cyanopyridines with α-Diazo
Carbonyl Compounds. Org. Lett. 2017, 19, 2294−2297. (c) Zhang, B.
B.; Li, B.; Guo, C. H.; Zhang, X. Y.; Fan, X. S. Cascade C−H Bond
Functionalizations of Benzoyl Acetonitriles/ Methylsulfones with
Cyclic 2-Diazo-1,3-Dicarbonyl Compounds: An Efficient Access to
Diversely Functionalized Naphtho[1,8-bc]pyrans. Tetrahedron Lett.
2018, 59, 3094−3099. (d) Guo, S. H.; Sun, L. C.; Liu, Y. F.; Ma, N.
N.; Zhang, X. Y.; Fan, X. S. Rh(III)-Catalyzed Oxidative
Spirocyclization of Isoquinolones with α-Diazo-1,3-indandiones.
Org. Lett. 2019, 21, 4082−4086. (e) Gao, C.; Li, B.; Geng, X. Y.;
Zhou, Q. T.; Zhang, X. Y.; Fan, X. S. Two Birds with One Stone:
One-Pot Simultaneous Synthesis of 2,2,2-Trifluoroethylphenanthri-
dines and Benzochromenones Featuring the Utilization of the
Byproduct of Togni’s Reagent. Green Chem. 2019, 21, 5113−5117.
(20) (a) For selected reviews, see: Bolm, C.; Legros, J.; Paih, J. L.;
Zani, L. Iron-Catalyzed Reactions in Organic Synthesis. Chem. Rev.
2004, 104, 6217−6254. (b) Zhu, S. F.; Zhou, Q. L. Iron-Catalyzed
Transformations of Diazo Compounds. Natl. Sci. Rev. 2014, 1, 580−
̈
603. (c) Bauer, I.; Knolker, H. J. Iron Catalysis in Organic Synthesis.
Chem. Rev. 2015, 115, 3170−3387. (d) Carreras, V.; Tanbouza, N.;
Ollevier, T. The Power of Iron Catalysis in Diazo Chemistry. Synthesis
2021, 53, 79.
(21) (a) Shi, X. N.; He, Y.; Zhang, X. Y.; Fan, X. S. FeCl3-Catalyzed
Cascade Reactions of Cyclic Amines with 2-Oxo-2-arylacetic Acids
toward Furan-2(5H)-one Fused N,O-Bicyclic Compounds. Adv.
Synth. Catal. 2018, 360, 261−266. (b) Chen, G.; Li, B.; Hu, B.;
Zhang, X. Y.; Fan, X. S. FeCl3-Catalyzed C-3 Functionalization of
Imidazo[1,2-a]pyridines with Diazoacetonitrile under Oxidant- and
Ligand-free Conditions. Tetrahedron Lett. 2020, 61, 151774.
(22) (a) Cai, Y.; Zhu, S. F.; Wang, G. P.; Zhou, Q. L. Iron-Catalyzed
C−H Fuctionalization of Indoles. Adv. Synth. Catal. 2011, 353, 2939−
2944. (b) Wang, Z. J.; Peck, N. E.; Renata, H.; Arnold, F. H.
Cytochrome P450-Catalyzed Insertion of Carbenoids into N−H
Bonds. Chem. Sci. 2014, 5, 598−601. (c) Keipour, H.; Ollevier, T.
Iron-Catalyzed Carbene Insertion Reactions of α-Diazoesters into Si−
H Bonds. Org. Lett. 2017, 19, 5736−5739. (d) Li, C. C.; Dai, X. J.;
Wang, H. N.; Zhu, D. H.; Gao, J.; Li, C. J. Iron-Catalyzed
Nucleophilic Addition Reaction of Organic Carbanion Equivalents
via Hydrazones. Org. Lett. 2018, 20, 3801−3805.
(23) (a) Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. Stereo and
Electronic Effects in the Rhodium(II)-Mediated Synthesis of
Polycyclic Lactones and Lactams from -Diazo Ester and Amide
Precursors. J. Org. Chem. 1993, 58, 4646−4655. (b) Zhang, C.;
Huang, J. J.; Qiu, L. H.; Xu, X. F. Thermally Induced [3 + 2]
Cycloaddition of Alkynyl-Tethered Diazoamides: Synthetic and
Mechanistic Insights. Org. Lett. 2016, 18, 6208−6211. (c) Zheng,
Y.; Bao, M.; Yao, R. W.; Qiu, L. H.; Xu, X. F. Palladium-Catalyzed
Carbene/Alkyne Metathesis with Enynones as Carbene Precursors:
Synthesis of Fused Polyheterocycles. Chem. Commun. 2018, 54, 350−
353.
(24) Shi, S.; Wang, T.; Yang, W. B.; Rudolph, M.; Hashmi, S. K.
Gold-Catalyzed Synthesis of Glyoxals by Oxidation of Terminal
393
https://dx.doi.org/10.1021/acs.orglett.0c03882
Org. Lett. 2021, 23, 388−393