Difluoroisoxazolacetophenone: A Difluoroalkylation Reagent for Organocatalytic Vinylogous Nitroaldol Reactions of 1,2-Diketones

Article abstract of DOI:10.1021/acs.orglett.0c02873

Difluoroisoxazolacetophenone (DFIO) is developed as a new difluoroalkylation reagent that can be easily prepared from inexpensive starting materials. In situ remote C-C bond cleavage of DFIO affords γ,γ-difluoroisoxazole nitronate that undergoes base-catalyzed vinylogous nitroaldol additions to isatins, benzothiophene-2,3-dione, unsaturated-α-ketoesters, and cyclic 1,2-diketones. This organocatalytic debenzoate vinylogous nitroaldol reaction provides a new and mild approach for the preparation of various difluoroisoxazole-substituted 3-hydroxy-2-oxindoles.

Full text of DOI:10.1021/acs.orglett.0c02873

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Letter
Difluoroisoxazolacetophenone: A Difluoroalkylation Reagent for
Organocatalytic Vinylogous Nitroaldol Reactions of 1,2-Diketones
Yong Zhang,* Jin Ge, Liang Luo, Su-Qiong Yan, Guo-Wei Lai, Zu-Qin Mei, Hai-Qing Luo,
and Xiao-Lin Fan
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ABSTRACT: Difluoroisoxazolacetophenone (DFIO) is devel-
oped as a new difluoroalkylation reagent that can be easily
prepared from inexpensive starting materials. In situ remote C−C
bond cleavage of DFIO affords γ,γ-difluoroisoxazole nitronate that
undergoes base-catalyzed vinylogous nitroaldol additions to isatins,
benzothiophene-2,3-dione, unsaturated-α-ketoesters, and cyclic
1,2-diketones. This organocatalytic debenzoate vinylogous nitro-
aldol reaction provides a new and mild approach for the
preparation of various difluoroisoxazole-substituted 3-hydroxy-2-
oxindoles.
luorine-containing compounds are now widespread in
ketones (V)13 have been developed for the in situ generation
of α,α-difluoroenolates and α,α-difluoronitronates. As part of
our research interest in the development of vinylogous
reactions,14 we envisioned that the deacylative fluoroalkylation
can be extended in its vinylogous terms15 by exploiting the
cleavage of remote C−C bonds.16 Herein, we describe the
development of difluoroisoxazolacetophenone (DFIO) as a
new vinylogous difluoroalkylation reagent. DFIO can be used
to in situ generate γ,γ-difluoroisoxazole nitronates from the
release of benzoate under mild conditions (Scheme 1b). The
synthetic potency of DFIO is demonstrated by its vinylogous
nitroaldol reactions in the presence of catalytic amounts of
organic base.
Initially, DFIO (2) was designed and synthesized according
to the procedure illustrated in Scheme 2.17 The direct
vinylogous Henry reaction of benzaldehyde with 3,5-
dimethyl-4-nitroisoxazole gave the nitroaldol adduct,14e
which was easily transformed to the corresponding nitro-
ketone18 in the presence of o-iodoxybenzoic acid (IBX).
Subsequent electrophilic fluorination of nitroketone with
selectfluor produced DFIO (2) in high yield. Isatin 1a and
DFIO (2) were then chosen as model substrates to study the
debenzoate vinylogous nitroaldol reaction. As shown in Table
F
medicinal chemistry and material sciences.1 It is well
established that the introduction of fluorine into bioactive
compounds can significantly alter their lipophilicity, bioavail-
ability, and metabolic stability.2 Consequently, great efforts
have been made to develop efficient strategies, methods,
reagents, and catalysts for the preparation of various fluorine-
containing compounds.3 Recently, the introduction of a
difluoromethylene group has been particularly interesting
because it can serve as a bioisostere for an oxygen atom, an
isopropyl group, or a carbonyl group.4 Significant progress has
been witnessed in the studies on transition-metal-catalyzed5 or
radical-mediated6 difluoroalkylation for the formation of C−
CF2 bonds. However, reliable methods for the introduction of
functionalized α,α-difluoroalkyl groups onto heteroarenes are
limited. Therefore, the development of novel alternative
methods for the preparation of heterocyclic compounds with
a difluoromethylene group would be highly desirable.
The selective cleavage of carbon−carbon (C−C) bonds is
quite challenging due to the inherent robustness of the C−C
bond.7 One of the most powerful of these methods is
deacylation because of its efficiency in generating reaction
intermediates under mild conditions.8 In 2011, Colby and co-
workers demonstrated that the trifluoroacetate release strategy
was also applicable in furnishing α,α-difluoroenolates with the
use of α,α-difluoro-β-ketone-gem-diols (I) as precursors
(Scheme 1a).9 Since then, the deacylative fluoroalkylation
has been extensively studied for the synthesis of various
organofluorine compounds.10 Several new difluoroalkylation
reagents including α,α-difluorodiaroylmethane (II),11 α,α-
difluoro-β-ketoesters (III and IV),12 and difluoronitromethyl
Received: August 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02873
© XXXX American Chemical Society
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A

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a
Scheme 1. Strategies for the in Situ Generation of Difluoro-
Table 1. Optimization of Reaction Conditions
enolate and Nitronate
b
entry
catalyst
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
THF
MeCN
DMF
DMSO
DCM
toluene
MeOH
EtOH
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
48
48
48
48
48
48
24
24
48
24
10
24
24
24
72
24
10
48
31
20
26
20
10
<10
99
75
74
0
83
85
99
90
75
72
78
98
9
Et3N
10
11
12
13
none
DBU
DMAP
DABCO
QD
imidazole
K2CO3
KOH
Et3N
c
14
15
16
17
d
18
a
Unless otherwise noted, the reaction was performed with 0.15 mmol
of 1a, 0.20 mmol of 2 and 10 mol % of catalyst in 0.75 mL solvent.
Isolated yield. No enantioselectivity. 5 mol % of catalyst was used.
b
c
d
Scheme 2. Synthesis of Difluoroisoxazolacetophenone 2a
Under the optimal reaction conditions, a wide range of
isatins were subsequently investigated (Scheme 3). Isatins
bearing electron-withdrawing (5-F, 5-Cl, 5-Br, 5-I, 5-NO2, and
5-OCF3) or electron-donating (5-OMe and 5-Me) groups on
the phenyl ring were well tolerated, and their reactions with
DFIO (2) smoothly afforded the corresponding vinylogous
products with good to excellent yields (3b−3i). Moreover,
substitution was viable at the 4-position, 6-position, and 7-
position of the isatin, and their corresponding products were
formed in good to excellent yields (3j−3p). Furthermore,
disubstituted isatins (3,5-dimethylisatin and 4,7-dichloroisatin)
were also applicable for this reaction, affording the desired
products in good yields. The scope of this debenzoate
vinylogous procedure was further extended to N-protected
isatins. It is shown that N-methylisatin, N-ethylisatin, N-
benzylisatin, N-phenylisatin, and N-allylisatin were also
compatible substrates with the formation of the desired
products 3s−3w in 85−99% yields. The structure of 3i was
confirmed by X-ray crystallographic analysis.
The scope of the difluoroisoxazolacetophenones was also
briefly examined (Scheme 4). The reaction proceeded
smoothly when the 3-position of isoxazole was substituted
with a phenyl group, affording the desired product 4a in good
yield. Both electron-donating and electron-withdrawing groups
on the benzene ring were tolerated, and their corresponding
products 4b−4e were formed in good to excellent yields.
To further demonstrate the synthetic utility of DFIO (2a),
we applied it to the vinylogous nitroaldol reactions with several
other electrophiles (Scheme 5). In the presence of DBU at 50
°C, the reaction of β,γ-unsaturated-α-ketoesters with 2a
proceeded smoothly to afford the desired products 5a and
5b in 62% yield and 93% yield, respectively. A heterocyclic
electrophile such as benzothiophene-2,3-dione worked as well
1, using THF as a solvent at room temperature for the reaction
catalyzed with 10 mol % Et3N gave product 3a in 31% yield
after 48 h. Other solvents such as MeCN, DMF, DMSO,
DCM, and toluene gave inferior results (entries 1−6). To our
delight, the formation of vinylogous nitroaldol product 3a was
almost quantitative when MeOH was used as the reaction
solvent (entry 7). It is worth mentioning that the reaction can
easily be monitored by the color change from dark reddish to
pale orange. Methyl benzoate was detected as a byproduct in
this reaction, which indicated that MeOH may serve as a
nucleophile to facilitate the debenzoate process. Using other
protic solvents such as EtOH and i-PrOH did not improve the
reaction efficiency. These results promoted us to further
investigate the role of base catalyst with MeOH as the solvent.
As expected, formation of product 3a was not observed in the
absence of base catalyst (entry 10). The reaction with DABCO
gave a similar result as Et3N, while other bases led to lower
yields (entries 11−17). Hence, the most available and
inexpensive Et3N was considered as the best catalyst for this
reaction. Additional experimentation showed that the catalyst
loading could be reduced to 5 mol % with only a slight effect
on reaction efficiency (entry 18).
B
https://dx.doi.org/10.1021/acs.orglett.0c02873
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a
,b
a,b
Scheme 3. Scope of Reaction of Isatins 1 and 2a
Scheme 4. Scope of Reaction of Isatin 1a and 2
a
Unless otherwise noted, the reaction was performed with 0.15 mmol
of 1a, 0.20 mmol of 2, and 10 mol % of catalyst in 0.75 mL of MeOH.
b
Isolated yield.
a
Scheme 5. Scope of Other Electrophiles
a
Unless otherwise noted, the reaction was performed with 0.15 mmol
of the corresponding electrophiles, 0.20 mmol of 2a, and 10 mol % of
b
Et3N in 0.75 mL of MeOH at room temperature. Isolated yield. The
reaction was performed at 50 °C using DBU as the catalyst.
a
Unless otherwise noted, the reaction was performed with 0.15 mmol
of 1, 0.20 mmol of 2a and 10 mol % of catalyst in 0.75 mL of MeOH.
b
Isolated yield.
Scheme 6. Substrate Scope and Limitation
to afford 5c in 81% yield. In addition, cyclic 1,2-diketones such
as phenanthrenequinone and acenaphthenequinone also
underwent efficient vinylogous nitroaldol reactions to furnish
5d in 88% yield and 5e in 95% yield. Disappointingly,
aldehydes, trifluoromethyl ketones, and unactive ketones were
not suitable for this reaction under the optimized conditions
(Scheme S1).
Inspired by the success with the catalysis summarized in
Schemes 3−5, we wondered if this method can be extended to
monofluoroisoxazolacetophenone 6 or other dihaloisoxazola-
cetophenones 7. As shown in Scheme 6, the reaction of
monofluoroisoxazolacetophenone 6 with isatin 1a proceeded
C
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smoothly to afford the corresponding monofluoro substituted
product 8 in moderate yield with excellent dr value, while no
desired products were obtained when dichloroisoxazolaceto-
phenone 7a or dibromoisoxazolacetophenone 7b were used,
presumably due to steric hindrance. These experimental results
indicate that the fluoro atom plays a significant role in this
debenzoate vinylogous nitroaldol reaction.
Scheme 8. Gram-Scale Synthesis of 3a and Its
Transformations
To gain insight into the mechanism of the debenzoate
vinylogous nitroaldol reaction, we performed several control
reactions to verify that the vinylogous nitroaldol reaction is not
a stepwise process in which release of benzoate occurs first,
followed by deprotonation of 5-(difluoromethyl)-3-methyl-4-
nitroisoxazole, and then addition to the isatin. In fact,
treatment of DFIO (2a) with Et3N in MeOH (or CD3OD)
at room temperature produced smoothly the benzoate 9 as
well as the difluoroisoxazole 10, which was confirmed by GC−
MS analysis (see the Supporting Information for details).
Although we failed to isolate the difluoroisoxazole 10a, a step
by step experiment resulted only small amount of product. On
the basis of the above results, we propose a plausible reaction
mechanism, which is shown in Scheme 7b for the vinylogous
of 3a could be conveniently converted to acid 12 in high yield
(Scheme 8b).
In conclusion, we have developed difluoroisoxazolacetophe-
none (DFIO) as a new and practical reagent for vinylogous
difluoroalkylation reactions of isatins, benzothiophene-2,3-
dione, unsaturated α-ketoesters, and cyclic 1,2-diketones.
The key step of these vinylogous difluoroalkylation reactions
is the release of benzoate for the cleavage of remote C−C bond
by making use of DFIO as a synthetic equivalent of γ,γ-
difluoroisoxazole nitronate. The resulting medicinally impor-
tant difluoroisoxazole19 substituted 3-hydroxy-2-oxindoles20
were obtained in good to excellent yields. Further application
of a debenzoate process for other (asymmetric) vinylogous
fluoroalkylation reactions is currently underway in our
laboratory.
Scheme 7. Control Reactions and a Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02873.
Experimental details and spectroscopic data (PDF)
Accession Codes
CCDC 1941387 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
addition of 2a to 1a in the presence of Et3N. The deacylation
of 2a in the presence of Et3N and MeOH results in γ,γ-
difluoroisoxazole nitronate I, which is in situ stablized by Et3N.
The vinylogous addition is activated by the hydrogen bond
between protonated Et3N and two carbonyls in isatin.
Nucleophilic addition of γ,γ-difluoroisoxazole nitronate I to
isatin affords the desired vinylogous nitroaldol addition
product 3a (Scheme 7a).
AUTHOR INFORMATION
Corresponding Author
■
Yong Zhang − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China; orcid.org/0000-0001-8911-4650;
To demonstrated the synthetic utility of this debenzoate
process, a gram-scale reaction of isatin 1a (0.736 g, 5.0 mmol)
and DFIO 2a (1.693 g, 6.0 mmol) was conducted in the
presence of 5 mol % of Et3N in 10 mL of MeOH (Scheme 8a).
Gratifyingly, the reaction proceeded smoothly to afford 3a
(1.615 g) in 99% yield. It should be pointed out that in order
to achieve excellent reactivity with 5 mol % of catalyst and only
a slight excess of 2a (1.2 equiv) a high concentration was
required. In the presence of Zn dust and acetic acid, the nitro
group of 3a could be smoothly reduced, affording product 11
in almost quantitative yield. In addition, the isoxazole moiety
Email: yong_zhanggnnu@126.com
Authors
Jin Ge − Key Laboratory of Organo-pharmaceutical Chemistry,
Gannan Normal University, Ganzhou 341000, P.R. China
Liang Luo − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China
Su-Qiong Yan − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China
D
https://dx.doi.org/10.1021/acs.orglett.0c02873
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Ed. 2015, 54, 1270−1274. (e) Doi, R.; Ohashi, M.; Ogoshi, S. Angew.
Chem., Int. Ed. 2016, 55, 341−344. (f) Arlow, S. I.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2016, 55, 4567−4572. (g) Nie, X.; Cheng, C.;
Zhu, G. Angew. Chem., Int. Ed. 2017, 56, 1898−1902. (h) Yin, H.;
Kumke, J. J.; Domino, K.; Skrydstrup, T. ACS Catal. 2018, 8, 3853−
3858. (i) Zhu, S.-Q.; Liu, Y.-L.; Li, H.; Xu, X.-H.; Qing, F.-L. J. Am.
Chem. Soc. 2018, 140, 11613−11617. (j) Zhao, H.; Ma, G.; Xie, X.;
Wang, Y.; Hao, J.; Wan, W. Chem. Commun. 2019, 55, 3927−3930.
(k) Zhao, H.-Y.; Gao, X.; Zhang, S.; Zhang, X. Org. Lett. 2019, 21,
1031−1036. (l) Xu, C.; Yang, Z.-F.; An, L.; Zhang, X. ACS Catal.
2019, 9, 8224−8229. (m) Guo, W.-H.; Zhao, H.-Y.; Luo, Z.-J.; Zhang,
S.; Zhang, X. ACS Catal. 2019, 9, 38−43. (n) Luo, C.; Bandar, J. S. J.
Am. Chem. Soc. 2019, 141, 14120−14125. (o) Zhu, X.-L.; Huang, Y.;
Xu, X.-H.; Qiang, F.-L. Org. Lett. 2020, 22, 5451−5455.
Guo-Wei Lai − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China
Zu-Qin Mei − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China
Hai-Qing Luo − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China
Xiao-Lin Fan − Key Laboratory of Organo-pharmaceutical
Chemistry, Gannan Normal University, Ganzhou 341000, P.R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02873
(6) For selected reviews, see: (a) Chatterjee, T.; Iqbal, N.; You, Y.;
Cho, E. J. Acc. Chem. Res. 2016, 49, 2284−2294. (b) Koike, T.; Akita,
M. Org. Biomol. Chem. 2019, 17, 5413−5419. (c) Lemos, A.; Lemaire,
C.; Luxen, A. Adv. Synth. Catal. 2019, 361, 1500−1537. For selected
examples, see: (d) Yu, C.; Iqbal, N.; Park, S.; Cho, E. J. Chem.
Commun. 2014, 50, 12884−12887. (e) Xie, J.; Zhang, T.; Chen, F.;
Mehrkens, N.; Rominger, F.; Rudolph, M.; Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2016, 55, 2934−2938. (f) Xu, P.; Wang, G.; Zhu, Y.;
Li, W.; Cheng, Y.; Li, S.; Zhu, C. Angew. Chem., Int. Ed. 2016, 55,
2939−2943. (g) Rong, J.; Deng, L.; Tan, P.; Ni, C.; Gu, Y.; Hu, J.
Angew. Chem., Int. Ed. 2016, 55, 2743−2747. (h) Xiao, P.; Rong, J.;
Ni, C.; Guo, J.; Li, X.; Chen, D.; Hu, J. Org. Lett. 2016, 18, 5912−
5915. (i) Wan, Y.; Shang, T.; Lu, Z.; Zhu, G. Org. Lett. 2019, 21,
4187−4191. (j) Liu, D.; Jiao, M.-J.; Wang, X.-Z.; Xu, P.-F. Org. Lett.
2019, 21, 4745−4749. (k) Zhao, L.; Huang, Y.; Wang, Z.; Zhu, E.;
Mao, T.; Jia, J.; Gu, J.; Li, X.-F.; He, C.-Y. Org. Lett. 2019, 21, 6705−
6709. (l) Zeng, X.; Yan, W.; Zacate, S. S.; Chao, T.-H.; Sun, X.; Cao,
Z.; Bradford, K. G. E.; Paeth, M.; Tyndall, S. B.; Yang, K.; Kuo, T.-C.;
Cheng, M.-J.; Liu, W. J. Am. Chem. Soc. 2019, 141, 11398−11403.
(m) Li, K.; Chen, J.; Yang, C.; Zhang, K.; Pan, C.; Fan, B. Org. Lett.
2020, 22, 4261−4265. (n) Liu, J.; Yu, D.; Yang, Y.; You, H.; Sun, M.;
Wang, Y.; Liu, Z.-Q. Org. Lett. 2020, 22, 4844−4847.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21865003, 21562003), the Jiangxi
Provincial Department of Science and Technology Fund
(20192BAB213007), and the Gannan Normal University
Innovation Fund (CX180050).
REFERENCES
■
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−
1886. (b) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger,
J. Chem. Soc. Rev. 2011, 40, 3496−3508. (c) Wang, J.; Sanchez-
Rosello, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432−2506.
(d) Gouverneur, V.; Seppelt, K. Chem. Rev. 2015, 115, 563−565.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320−330. (b) Cametti, M.; Crousse, B.;
Metrangolo, P.; Milani, R.; Resnati, G. Chem. Soc. Rev. 2012, 41,
(7) (a) Ho, T. L. Heterolytic Fragmentation of Organic Molecules;
Wiley: New York, 1993. (b) Sattler, A.; Parkin, G. Nature 2010, 463,
̈
523−526. (c) Roque, J. B.; Kuroda, Y.; Gottemann, L. T.; Sarpong, R.
31−42. (c) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J.
̃
L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422−
518.
Nature 2018, 564, 244−248.
(8) (a) Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A.
Chem. Rev. 2011, 111, 1846−1913. (b) Ortega-Martínez, A.; Molina,
C.; Moreno-Cabrerizo, C.; Sansano, J. M.; Najera, C. Eur. J. Org.
(3) For selected reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter,
T. Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (b) Gouverneur, V.;
Seppelt, K. Chem. Rev. 2015, 115, 563−565. (c) Ni, C.; Hu, M.; Hu, J.
Chem. Rev. 2015, 115, 765−825. (d) Yang, X.; Wu, T.; Phipps, R. J.;
Toste, F. D. Chem. Rev. 2015, 115, 826−870. (e) Alonso, C.; de
Marigorta, E. M.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115,
1847−1935. (f) Liu, Q.; Ni, C.; Hu, J. Natl. Sci. Rev. 2017, 4, 303−
325. (g) Yerien, D. E.; Barata-Vallejo, S.; Postigo, A. Chem. - Eur. J.
2017, 23, 14676−14701. (h) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.;
Sodeoka, M.; Soloshonok, V. A.; Coelho, J. A. S.; Toste, F. D. Chem.
Rev. 2018, 118, 3887−3964. (i) Hu, X.-S.; Yu, J.-S.; Zhou, J. Chem.
Commun. 2019, 55, 13638−13648. For selected examples, see:
(j) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon,
D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc.
2012, 134, 1494−1497. (k) Tang, H.-J.; Lin, L.-Z.; Feng, C.; Loh, T.-
P. Angew. Chem., Int. Ed. 2017, 56, 9872−9876. (l) Sheng, J.; Ni, H.-
Q.; Zhang, H.-R.; Zhang, K.-F.; Wang, Y.-N.; Wang, X.-S. Angew.
Chem., Int. Ed. 2018, 57, 7634−7639. (m) Zhou, M.; Ni, C.; Zeng, Y.;
Hu, J. J. Am. Chem. Soc. 2018, 140, 6801−6805. (n) Huang, X.;
Zhang, Y.; Zhang, C.; Zhang, L.; Xu, Y.; Kong, L.; Wang, Z.-X.; Peng,
B. Angew. Chem., Int. Ed. 2019, 58, 5956−5961. (o) Wang, Z.; Guo,
C.-Y.; Yang, C.; Chen, J.-P. J. Am. Chem. Soc. 2019, 141, 5617−5622.
(4) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529−2591.
́
Chem. 2018, 2018, 2394−2405.
(9) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133,
5802−5805.
(10) (a) Zhang, P.; Wolf, C. Angew. Chem., Int. Ed. 2013, 52, 7869−
7873. (b) Xie, C.; Wu, L.; Han, J.; Soloshonok, V. A.; Pan, Y. Angew.
Chem., Int. Ed. 2015, 54, 6019−6023. (c) Nguyen, A. L.; Khatri, H.
R.; Woods, J. R.; Baldwin, C. S.; Fronczek, F. R.; Colby, D. A. J. Org.
Chem. 2018, 83, 3109−3118. (d) Reddy, M. K.; Ramakrishna, I.;
Baidya, M. Org. Lett. 2018, 20, 4610−4613. (e) Khatri, H. R.; Han,
C.; Luong, E.; Pan, X.; Adam, A. T.; Alshammari, M. D.; Shao, Y.;
Colby, D. A. J. Org. Chem. 2019, 84, 11665−11675. (f) Mei, H.; Liu,
́
J.; Fustero, S.; Roman, R.; Ruzziconi, R.; Soloshonok, V. A.; Han, J.
Org. Biomol. Chem. 2019, 17, 762−775. See also references cited
therein.
(11) (a) Lin, Y.; Yi, W.; Shen, W.; Lu, G. Org. Lett. 2016, 18, 592−
595. (b) Qian, J.; Yi, W.; Huang, X.; Jasinski, J. P.; Zhang, W. Adv.
Synth. Catal. 2016, 358, 2811−2816.
(12) (a) Yang, M.-H.; Orsi, D. L.; Altman, R. A. Angew. Chem., Int.
Ed. 2015, 54, 2361−2365. (b) Yang, M.-H.; Hunt, J. R.; Sharifi, N.;
Altman, R. A. Angew. Chem., Int. Ed. 2016, 55, 9080−9083.
(13) (a) Ding, R.; Wolf, C. Chem. Commun. 2016, 52, 3576−3579.
(b) Ding, R.; Bakhshi, P. R.; Wolf, C. J. Org. Chem. 2017, 82, 1273−
1278.
(5) (a) Feng, Z.; Xiao, Y.-L.; Zhang, X. Acc. Chem. Res. 2018, 51,
2264−2278. (b) Ge, S.; Chaladaj, W.; Hartwig, J. F. J. Am. Chem. Soc.
2014, 136, 4149−4152. (c) Ge, S.; Arlow, S. I.; Mormino, M. G.;
Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 14401−14404. (d) Feng,
Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.; Zhang, X. Angew. Chem., Int.
(14) (a) Zhang, Y.; Shao, Y.-L.; Xu, H.-S.; Wang, W. J. Org. Chem.
2011, 76, 1472−1474. (b) Zhu, J.-L.; Zhang, Y.; Liu, C.; Zhang, A.-
M.; Wang, W. J. Org. Chem. 2012, 77, 9813−9825. (c) Zhang, Y.;
E
https://dx.doi.org/10.1021/acs.orglett.0c02873
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Wei, B.-W.; Lin, H.; Cui, W.; Zeng, X.; Fan, X. Adv. Synth. Catal.
2015, 357, 1299−1304. (d) Zhang, Y.; Wei, B.-W.; Lin, H.; Zhang, L.;
Liu, J.-X.; Luo, H.-Q.; Fan, X.-L. Green Chem. 2015, 17, 3266−3270.
(e) Zhang, Y.; Wei, B.-W.; Zou, L.-N.; Kang, M.-L.; Luo, H.-Q.; Fan,
X.-L. Tetrahedron 2016, 72, 2472−2475. (f) Zhang, Y.; Wei, B.-W.;
Wang, W.-X.; Deng, L.-L.; Nie, L.-J.; Luo, H.-Q.; Fan, X.-L. RSC Adv.
2017, 7, 1229−1232.
(15) For selected reviews, see: (a) Fuson, R. C. Chem. Rev. 1935, 16,
1−27. (b) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F.
Chem. Rev. 2011, 111, 3076−3154. (c) Yin, Y.; Jiang, Z.
ChemCatChem 2017, 9, 4306−4318. (d) Curti, C.; Battistini, L.;
Sartori, A.; Zanardi, F. Chem. Rev. 2020, 120, 2448−2612. For
selected examples, see: (e) Bai, X.; Zeng, G.; Shao, T.; Jiang, Z.
Angew. Chem., Int. Ed. 2017, 56, 3684−3688. (f) Zhu, B.; Lee, R.; Yin,
Y.; Li, F.; Coote, M. L.; Jiang, Z. Org. Lett. 2018, 20, 429−432.
(g) Zhu, B.; Li, F.; Lu, B.; Chang, J.; Jiang, Z. J. Org. Chem. 2018, 83,
11350−11358. (h) Xia, X.; Zhu, Q.; Wang, J.; Chen, J.; Cao, W.; Zhu,
B.; Wu, X. J. Org. Chem. 2018, 83, 14617−14625. (i) Zhang, H.-J.;
Schuppe, A. W.; Pan, S.-T.; Chen, J.-X.; Wang, B.-R.; Newhouse, T.
R.; Yin, L. J. Am. Chem. Soc. 2018, 140, 5300−5310. (j) Zhang, H.-J.;
Yin, L. J. Am. Chem. Soc. 2018, 140, 12270−12279. (k) Ding, X.-F.;
Yang, W.-L.; Mao, J.; Cao, C.-X.; Deng, W.-P. Org. Lett. 2019, 21,
5514−5518. (l) Ran, G.-Y.; Yang, X.-X.; Yue, J.-F.; Du, W.; Chen, Y.-
C. Angew. Chem., Int. Ed. 2019, 58, 9210−9214. See also references
cited therein.
(16) (a) Tran, V. T.; Gurak, J. A.; Yang, K. S.; Engle, K. M. Nat.
Chem. 2018, 10, 1126−1133. (b) Ye, J.; Shi, Z.; Sperger, T.;
Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Nat. Chem.
2017, 9, 361−368. (c) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.;
Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed. 2018, 57, 744−748.
́
(d) Azizollahi, H.; Mehta, V. P.; García-Lopez, J.-A. Chem. Commun.
2019, 55, 10281−10284.
(17) See the Supporting Information for details.
(18) Rajanarendar, E.; Krishna, S. R.; Nagaraju, D.; Reddy, K. G.;
Kishore, B.; Reddy, Y. N. Bioorg. Med. Chem. Lett. 2015, 25, 1630−
1634.
́
(19) (a) Sysak, A.; Obminska-Mrukowicz, B. Eur. J. Med. Chem.
2017, 137, 292−309. (b) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro,
M.; Shibata, N. Angew. Chem., Int. Ed. 2011, 50, 7803−7806.
(c) Bonacorso, H. G.; Ketzer, A.; Garcia, F. D.; Rosa, W. C.; Calheiro,
T. P.; Feitosa, S. C.; Dal Forno, G. M.; Zanatta, N.; Martins, M. A. P.;
Frizzo, C. P. J. Fluorine Chem. 2017, 197, 6−14.
(20) (a) Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug
Discovery Dev. 2010, 13, 758−776. (b) Zhou, F.; Liu, Y.-L.; Zhou, J.
Adv. Synth. Catal. 2010, 352, 1381−1407. (c) Cao, Z.-Y.; Zhou, F.;
Zhou, J. Acc. Chem. Res. 2018, 51, 1443−1454.
F
https://dx.doi.org/10.1021/acs.orglett.0c02873
Org. Lett. XXXX, XXX, XXX−XXX