Iodonium Ylides as Carbene Precursors in Rh(III)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/acs.orglett.0c02618

The rhodium(III)-catalyzed coupling of C-H substrates with iodonium ylides has been realized for the efficient synthesis of diverse cyclic skeletons, where the iodonium ylides have been identified as efficient and outstanding carbene precursors. The reaction systems are applicable to both sp2 and sp3 C-H substrates under mild and redox-neutral conditions. The catalyst loading can be as low as 0.5 mol % in a gram-scale reaction. Representative products exhibit cytotoxicity toward human cancer cells at nanomolar levels.

Full text of DOI:10.1021/acs.orglett.0c02618

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Letter
Iodonium Ylides as Carbene Precursors in Rh(III)-Catalyzed C−H
Activation
Yuqin Jiang, Pengfei Li, Jie Zhao, Bingxian Liu,* and Xingwei Li*
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ABSTRACT: The rhodium(III)-catalyzed coupling of C−H substrates
with iodonium ylides has been realized for the efficient synthesis of diverse
cyclic skeletons, where the iodonium ylides have been identified as efficient
and outstanding carbene precursors. The reaction systems are applicable to
both sp2 and sp3 C−H substrates under mild and redox-neutral conditions.
The catalyst loading can be as low as 0.5 mol % in a gram-scale reaction.
Representative products exhibit cytotoxicity toward human cancer cells at
nanomolar levels.
Scheme 1. Reaction Modes of Iodonium Ylides with C−H
ypervalent iodine compounds, which are versatile and
Henvironmental friendly, are known as important reagents
in organic synthesis.1 Among them, iodonium ylides are known
to show good stability as singlet carbene reagents or metal
carbene species for synthetic purposes.2 Furthermore,
iodonium ylides can be applied as both nucleophiles and
electrophiles,1b,2d,3 and their applications in single-electron-
transfer (SET) processes have also be reported.4 On the
contrary, the abundance and ready availability of C−H bonds
has inspired tremendous endeavors in C−H activation studies.
Despite important advances in iodonium ylide chemistry, only
limited examples of C−H insertion into iodonium-ylide-
derived carbenoid species have been reported (Scheme
1a,b).2,5,6 Thus the synthetic potential of iodonium ylides is
far from being fully exploited. In contrast, other carbene
precursors such as diazo compounds,7 hydrazones,8 and
sulfoxonium ylides,9 among others,10 have been extensively
used as efficient coupling partners in rhodium-catalyzed C−H
activation for constructions of various complex skeletons
(Scheme 1c).11 Given the ready availability, stability, and
relatively high reactivity of iodonium ylides, it is necessary to
fully explore the fundamental carbene properties of iodonium
ylides in transition-metal-catalyzed C−H activation.
Substrates
with carbene precursors via a C−H activation pathway are rare,
likely due to the high tendency of olefins to undergo
cyclopropanation.1,2 By treating 2-benzylacrylic acid (1a)
We now report the application of hypervalent iodonium
ylides in the Rh(III)-catalyzed C−H activation of arenes. A
diverse scope of sp2 C−H and sp3 C−H bonds in arenes has
been defined. Meanwhile, the catalyst loading can be decreased
to 0.5 mol % in gram-scale synthesis, which showcases the high
reactivity of iodonium ylides as carbene precursors in C−H
functionalization.
Received: August 5, 2020
We initially examined the reactivity of iodonium ylide in
olefinic C−H activation.12 Although olefinic C−H functional-
ization has been widely investigated, the couplings of olefins
https://dx.doi.org/10.1021/acs.orglett.0c02618
© XXXX American Chemical Society
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a
with iodonium ylide cyclohexane-1,3-dione (2a) in the
presence of [Cp*RhCl2]2 (2 mol %) and NaOAc (25 mol
%) in HFIP, a lactone product, 3-benzyl-7,8-dihydro-2H-
chromene-2,5(6H)-dione, was obtained in almost quantitative
yield (Table 1, entry 1). Cp*Rh(OAc)2 was also a workable
Scheme 2. Scope of Acrylic Acids
Table 1. Optimizations of the Model Reaction
entry
changes from optimal conditions
yield (%)
1
2
no changes
Cp*Rh(OAc)2 (4 mol %) instead of
[Cp*RhCl2]2/NaOAc
99
69
3
4
5
H2O instead of HFIP
EtOH instead of HFIP
cyclohexanedione (0.24 mmol) and PhI(OAc)2
(0.24 mmol) instead of 2a
65
22
63
a
Reaction conditions: acrylic acids (0.2 mmol), 2a (0.24 mmol),
[Cp*RhCl2]2 (2 mol %), NaOAc (25 mol %), HFIP (2 mL), 80 °C,
6
7
8
9
2-diazocyclohexane-1,3-dione instead of 2a
60 °C
40 °C
without [Cp*RhCl2]2
without NaOAc
14
90
28
n.d.
64
b
12 h, under air, isolated yield. [Cp*RhCl2]2 (5 mol ‰).
c
[Cp*RhCl2]2 (3 mol ‰).
a
10
Scheme 3. Scope of Iodonium Ylides
catalyst for this coupling reaction, with a slightly dropped yield
(entry 2, 69%). A moderate yield of 65% was achieved by using
H2O as the solvent (entry 3), whereas a poor yield was
obtained when EtOH was used as a solvent (entry 4, 22%). In
situ generation of 2a in this catalytic system was found to be
possible but with decreased yield (entry 5, 63%). For
comparisons, 2-diazocyclohexane-1,3-dione was also tested
but with quite a low yield of the same product (entry 6). The
reaction system seemed to be sensitive to the reaction
temperature (entries 7 and 8). Control experiments were
conducted; no corresponding product was detected without
the Cp*Rh catalyst, and only a moderate yield was achieved in
the absence of NaOAc (entries 9 and 10).
The scope of acrylic acids in the coupling with 2a for the
construction of 7,8-dihydro-2H-chromene-2,5(6H)-diones was
explored (Scheme 2). As shown in Scheme 2, alkyl-group-
substituted acrylic acids at the α-position all reacted with 2a to
deliver the corresponding products in good to excellent yields
(3a−3e, 65−99%). Cyclic acrylic acids such as 1-cyclo-
pentenecarboxylic acid (1f) and 1-cyclohexenecarboxylic acid
(1g) also reacted to give the corresponding products (3f and
3g, 20 and 30%, respectively). Slightly decreased yields of the
products were detected when aryl-substituted acrylic acids
bearing an electron-donating group were used (3h−3j, 54−
67%). The introduction of halogens is tolerated in the system,
and good to excellent yields were isolated (3k−3m, 57−91%).
Substrates with an electron-withdrawing group (NO2) and 2-
naphthyl group substituted acrylicacid were also tolerated (3n
and 3o). However, no product was detected when simple
acrylic acid and β-ethyl acrylic acid were used.
The scope of iodonium ylides was next investigated (Scheme
3). As shown in Scheme 3, different substituted cyclohexane-
1,3-diones generally provided the desired products in good to
excellent yields. Functional groups such as methyl and phenyl
in the cyclohexa-2,5-dienone ring were tolerated, affording the
desired products 3p−3r (90−99%). The structure of 3s was
confirmed by NOESY spectroscopy of the corresponding
a
Reaction conditions: 2-benzylacrylic acid (0.2 mmol), 2 (0.24
mmol), [Cp*RhCl2]2 (2 mol %), NaOAc (25 mol %), HFIP (2 mL),
80 °C, 12 h, under air, isolated yield.
derivative by treatment with MeNH2−HCl. (See the SI). We
also applied this protocol to iodonium ylides such as
cyclopentane-1,3-dione and cycloheptane-1,3-dione, and the
desired products (3t and 3u) were isolated in diminished
yields (16 and 41% yield). These results indicate that the
reaction system is sensitive to the size of the dione rings. To
further investigate the scope of the protocol, coumarin-derived
fused iodonium ylides (2v−2z) were also explored, affording
the desired tricyclic compounds in moderate to good yields
(3v−3z, 41−85%). In contrast with the above success, several
prepared or in-situ-generated acyclic iodonium ylides all failed
to undergo the desired coupling under the standard conditions.
As reported, compounds containing a 2H-pyran-2-one motif,
such as isocoumarins, are known to possess anticancer
bioactivity.6b,13 Thus the bioactivities of selected products
B
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a
Scheme 6. Scope of the sp3 C−H Substrates
were evaluated toward MCF-7 cells, REC-1 cells, and A549
cells. Impressive results have been achieved in that the 50%
inhibitory concentration (IC50) of the selected compounds is
calculated to be at the nanomolar level toward the MCF-7 cell
line and at the micromolar level toward the A549 cell line and
REC-1 cell line (Scheme 4), which indicates that our products
may exhibit the potential to be a kind of anticancer agent
precursor.
Scheme 4. Antitumor Bioactivities of Selected Compounds
a
Reaction conditions: 10 (0.2 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
(4 mol %), AgOAc (20 mol %), HFIP (2 mL), 80 °C, 12 h, under air,
isolated yield.
Scheme 7. Gram-Scale Synthesis and Derivatization of the
Products
Encouraged by the above results, we next explored the
generality of iodonium ylides in arene C−H activation−
annulation reactions. More than six types of arenes bearing a
nucleophilic directing group (NH, oxime, or OH) or an
electrophilic directing group (imine) have been examined. In
all cases, the reaction proceeded via C−H activation, carbene
insertion, and nucleophilic cyclization, leading to the efficient
synthesis of a diverse heterocyclic scaffold as well as spiro-
heterocycles in moderate to excellent yields (Scheme 5,
products 4−9, 42−99% yield).
a
Scheme 5. Scope of the Arenes
methylmaleimide led to a diastereomeric mixture of products
13a and 13a′ (31 and 49% yield, respectively). The products
were delivered via a Diels−Alder reaction of 3a with 1 equiv of
N-methylmaleimide, a retro-Diels−Alder reaction with the
concomitant extrusion of carbon dioxide, and a second Diels−
Alder reaction.15 The 2H-pyran-2-one skeletons can also be
transformed to be pyridin-2(1H)-ones in good yields when
treated with a primary amine (14a and 15a).
To gain some insight into the mechanism, deuterium
labeling experiments were performed. By using D2O as the
reaction solvent, H/D exchange was observed at the vinyl
reactive site of 1a in the presence of iodonium ylide 2a,
indicating the reversibility of the olefinic C−H activation
(Scheme 8a). An intermolecular kinetic isotope effect (KIE)
a
Reaction conditions: (a) standard conditions with AgOAc instead of
NaOAc. (b) Arenes (0.2 mmol), 2a (0.24 mmol), [Cp*RhCl2]2 (4
mol %), AgSbF6 (16 mol %), NaOAc (50 mol %), DCE (2 mL), 80
°C, 12 h, under air, isolated yield.
Scheme 8. Mechanistic Studies
In addition to sp2 C−H activation, the utilization of
iodonium ylides in 8-methylquinoline benzylic C(sp3)−H
functionalization was also investigated.14 After simple opti-
mization, an efficient reaction system was realized using 8-
methylquinolines as the substrates (Scheme 6). The scope is
quite decent with mostly excellent yields (11a−11k, 75−99%).
Different substituents at the five-, six-, and seven-positions all
exhibit marginal influence on the reaction efficiency.
To showcase the synthetic utility, the gram-scale synthesis of
3a was conducted (Scheme 7), which proceeded smoothly
even with a catalyst loading as low as 0.5 mol % (87% yield).
Furthermore, several derivatization reactions were conducted.
The selective iodization of 3a with NIS gave product 12a
(73%). The treatment of 3a with an excess of N-
value of 1.9 was determined using 1h and 1h-d2 by parallel
reactions (Scheme 8b). This result indicates that the cleavage
of the C−H bond might not be involved in the turnover-
limiting step.
A catalytic cycle is proposed in Scheme 9 on the basis of the
above reaction results and reported reports on related carbene
C
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Letter
Authors
Scheme 9. Proposed Reaction Pathway
Yuqin Jiang − Henan Key Laboratory of Organic Functional
Molecule and Drug Innovation, Collaborative Innovation Center
of Henan Province for Green Manufacturing of Fine Chemicals,
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, China
Pengfei Li − Henan Key Laboratory of Organic Functional
Molecule and Drug Innovation, Collaborative Innovation Center
of Henan Province for Green Manufacturing of Fine Chemicals,
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, China
Jie Zhao − Henan Key Laboratory of Organic Functional
Molecule and Drug Innovation, Collaborative Innovation Center
of Henan Province for Green Manufacturing of Fine Chemicals,
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, China
migration insertions.11,16 Intermediate A is achieved by ligand
exchange between acetate and acrylate, which follows the vinyl
C−H activation and subsequent coordination of the ylide via
the elimination of PhI to give a carbene species B. Migratory
insertion of the carbene unit is proposed to give the
intermediate C, which undergoes protonation to give the C−
C-coupled intermediate D together with regeneration of the
active Rh(III) catalyst. Intermediate D eventually undergoes
nucleophilic cyclization−dehydration to yield the final product.
In summary, a diverse scope of cyclic skeletons has been
readily assembled via Rh(III)-catalyzed C−H activation of
arenes using iodonium ylides as a coupling reagent. The
reaction system exhibits relatively high efficiency with wide
substrate compatibility. Besides olefinic C−H substrates,
arenes and sp3 C−H substrates are also applicable. The
utilization of iodonium ylides provides an alternative carbene
procedure in Rh-catalyzed C−H activation. Meanwhile, the
reaction products showed cytotoxicity toward some human
cancer cell lines at the nanomolar or micromolar level, which
may constitute a potential skeleton for the further development
of anticancer agents. Subsequent research to extend the
application and overcome the limitation of iodonium ylides in
this field may make the versatile and environmentally benign
reagent more useful in the synthesis of organic intermediates
and drug-related compounds.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02618
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NSFC (nos. 21801066, 21525208, U1804283, and
21801067), research fund from Henan Educational Committee
(19A150028 and 20B350001), the Central Plains Scholars and
Scientists Studio Fund (2018002), fund from Henan Normal
University (2019QK04), and Natural Science Foundation of
Henan Province (182300410131) are acknowledged.
REFERENCES
■
(1) For selected reviews on hypervalent iodine chemistry, see:
(a) Yang, R.-Y.; Dai, L.-X. Chin. J. Org. Chem. 1994, 14 (2), 113.
(b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(c) Duan, Y.; Jiang, S.; Han, Y.; Sun, B.; Zhang, C. Youji Huaxue
2016, 36, 1973. (d) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016,
116, 3328.
(2) (a) Muller, P.; Fernandez, D.; Nury, P.; Rossier, J.-C. J. Phys.
Org. Chem. 1998, 11, 321. (b) Muller, P. Acc. Chem. Res. 2004, 37,
243. (c) Muller, P.; Allenbach, Y. F.; Chappellet, S.; Ghanem, A.
Synthesis 2006, 2006, 1689. (d) Malamidou-Xenikaki, E.; Spyroudis,
S. Synlett 2008, 2008, 2725. (e) Jia, M.; Ma, S. Angew. Chem., Int. Ed.
2016, 55, 9134.
(3) (a) Antos, A.; Elemes, Y.; Michaelides, A.; Nyxas, J. A.; Skoulika,
S.; Hadjiarapoglou, L. P. J. Org. Chem. 2012, 77, 10949. (b) Huang,
H.; Yang, Y.; Zhang, X.; Zeng, W.; Liang, Y. Tetrahedron Lett. 2013,
54, 6049. (c) Chelli, S.; Troshin, K.; Mayer, P.; Lakhdar, S.; Ofial, A.
R.; Mayr, H. J. Am. Chem. Soc. 2016, 138, 10304.
(4) (a) Zhao, Z.; Luo, Y.; Liu, S.; Zhang, L.; Feng, L.; Wang, Y.
Angew. Chem., Int. Ed. 2018, 57, 3792. (b) Zhao, Z.; Kong, X.; Wang,
W.; Hao, J.; Wang, Y. Org. Lett. 2020, 22, 230.
(5) Gomes, L. F. R.; Veiros, L. F.; Maulide, N.; Afonso, C. A. M.
Chem. - Eur. J. 2015, 21, 1449.
́
̈
(6) (a) Muller, P.; Bolea, C. Molecules 2001, 6, 258. (b) Batsila, C.;
Gogonas, E. P.; Kostakis, G.; Hadjiarapoglou, L. P. Org. Lett. 2003, 5,
1511.
(7) For selected papers, see: (a) Chan, W.-W.; Lo, S.-F.; Zhou, Z.;
Yu, W.-Y. J. Am. Chem. Soc. 2012, 134, 13565. (b) Shi, Z.; Koester, D.
C.; Boultadakis-Arapinis, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135,
12204. (c) Tang, G.-D.; Pan, C.-L.; Li, X. Org. Chem. Front. 2016, 3,
87. (d) Zhao, D.; Kim, J. H.; Stegemann, L.; Strassert, C. A.; Glorius,
F. Angew. Chem., Int. Ed. 2015, 54, 4508. (e) Chen, R.; Cui, S. Org.
Lett. 2017, 19, 4002.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02618.
Experimental procedures, characterization of new
compounds, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xingwei Li − Henan Key Laboratory of Organic Functional
Molecule and Drug Innovation, Collaborative Innovation Center
of Henan Province for Green Manufacturing of Fine Chemicals,
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, China; School of Chemistry and
Chemical Engineering, Shaanxi Normal University (SNNU),
Xi’an 710062, China; orcid.org/0000-0002-1153-1558;
Email: lixw@snnu.edu.cn
Bingxian Liu − Henan Key Laboratory of Organic Functional
Molecule and Drug Innovation, Collaborative Innovation Center
of Henan Province for Green Manufacturing of Fine Chemicals,
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, China; orcid.org/0000-0001-
9872-9876; Email: liubx1120@163.com
(8) For selected papers, see: Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 1364.
D
https://dx.doi.org/10.1021/acs.orglett.0c02618
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Organic Letters
pubs.acs.org/OrgLett
Letter
(9) For selected papers, see: (a) Barday, M.; Janot, C.; Halcovitch,
N. R.; Muir, J.; Aissa, C. Angew. Chem., Int. Ed. 2017, 56, 13117.
(b) Xu, Y.-W.; Zhou, X.-K.; Zheng, G.-F.; Li, X.-W. Org. Lett. 2017,
19, 5256.
(10) For other carbene precursors, see: (a) Zhang, H.; Wang, K.;
Wang, B.; Yi, H.; Hu, F.; Li, C.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2014, 53, 13234. (b) Hong, S. Y.; Jeong, J.; Chang, S. Angew.
Chem., Int. Ed. 2017, 56, 2408. (c) Kim, J. H.; Gensch, T.; Zhao, D.;
Stegemann, L.; Strassert, C. A.; Glorius, F. Angew. Chem., Int. Ed.
2015, 54, 10975.
(11) For selected reviews of carbene precursors on C−H activation,
see: (a) Xia, Y.; Qiu, D.; Wang, J. Chem. Rev. 2017, 117, 13810.
(b) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. Chem. Commun. 2015,
51, 7986−7995.
(12) For selected reviews of alkene C−H activation, see:
(a) Maraswami, M.; Loh, T.-P. Synthesis 2019, 51, 1049. (b) Wang,
K.; Hu, F.; Zhang, Y.; Wang, J. Sci. China: Chem. 2015, 58, 1252.
(c) Shang, X.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42, 3253.
(13) (a) Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187.
(b) Tutov, A.; Bakulina, O.; Dar’in, D.; Krasavin, M. Tetrahedron Lett.
2018, 59, 1511. (c) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.;
Nakajima, S. Chem. Pharm. Bull. 1981, 29, 2689. (d) Whyte, A. C.;
Gloer, J. B.; Scott, J. A.; Malloch, D. J. Nat. Prod. 1996, 59, 765.
(14) For selected papers of Rh-catalyzed sp3 C−H activation, see:
(a) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc.
2014, 136, 4141. (b) Liu, B.; Zhou, T.; Li, B.; Xu, S.; Song, H.; Wang,
B. Angew. Chem., Int. Ed. 2014, 53, 4191. (c) Huang, X.; Wang, Y.;
Lan, J.; You, J. Angew. Chem., Int. Ed. 2015, 54, 9404. (d) Wang, X.;
Yu, D.-G.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 10280.
(e) Hou, W.; Yang, Y.; Wu, Y.; Feng, H.; Li, Y.; Zhou, B. Chem.
Commun. 2016, 52, 9672.
(15) Fernandez, D. F.; Casanova, N.; Mascarenas, J.; Gulías, M. ACS
Omega 2019, 4, 6257.
(16) Li, Y.; Wang, Q.; Yang, X.; Xie, F.; Li, X. Org. Lett. 2017, 19,
3410.
E
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