Nickel-Catalyzed Coupling Reaction of α-Bromo-α-fluoroketones with Arylboronic Acids toward the Synthesis of α-Fluoroketones

Article abstract of DOI:10.1021/acs.orglett.9b02474

A nickel-catalyzed coupling reaction of α-bromo-α-fluoroketones with arylboronic acids was reported, which provides an efficient pathway to access 2-fluoro-1,2-diarylethanones in high yields. We also disclosed the synthesis of the monofluorination agents

Full text of DOI:10.1021/acs.orglett.9b02474

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Coupling Reaction of α‑Bromo-α-fluoroketones
with Arylboronic Acids toward the Synthesis of α‑Fluoroketones
Junqing Liang,† Jie Han,† Jingjing Wu,* Pingjie Wu, Jian Hu, Feng Hu, and Fanhong Wu*
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, People’s Republic of
China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed coupling reaction of α-bromo-
α-fluoroketones with arylboronic acids was reported, which
provides an efficient pathway to access 2-fluoro-1,2-diary-
lethanones in high yields. We also disclosed the synthesis of the
monofluorination agents α-bromo-α-fluoroketones by using a
trifluoroacetate release protocol. Mechanistic investigation
indicated that a monofluoroalkyl radical is involved in the catalytic circle. Moreover, an important medical intermediate of
flindokalner was synthesized via a nickel-catalyzed coupling reaction of α-bromo-α-fluoro-2-indolone and boronic ester.
he introduction of fluorine or fluorine-containing func-
tional groups into organic molecules can significantly
Wu, respectively.13a−c Fu and co-workers reported the
enantioselective synthesis of tertiary alkyl fluorides through
nickel-catalyzed Negishi reactions of racemic α-halo-α-
fluoroketone.13d Ando also disclosed the stereoselective Suzuki
reaction of α-bromo-α-fluoro-β-lactam with aryl-(9-BBN)
reagents to generate α-aryl-α-fluoro-β-lactams.13e Therefore,
we could find that α-halo-α-fluoroketones have great
importance as bifunctional intermediates, which could undergo
a vast array of useful transformations to construct valuable
fluorinated molecules but remain underutilized. Herein, we
describe a novel and efficient nickel-catalyzed coupling
reaction of α-bromo-α-fluoroketones with arylboronic acids,
giving a series of 2-fluoro-1,2-diarylethanones in high yields
(Scheme 1).
T
change their lipophilicity, bioavailability, and metabolic
stability. Hence, different classes of fluorine-containing organic
compounds have been developed and used as pharmaceuticals
and agrochemicals.1 Over the past decades, significant progress
has been made on the construction of trifluoromethyl
compounds2 and difluoroalkyl compounds.3 In contrast, the
monofluoroalkylation reactions for the synthesis of diverse
fluorine-containing molecules have been less intensively
investigated. There are only a few monofluorinating agents,
such as BrCFHCOOEt, (EtO)2P(O)CFHBr, 1-halo-1-fluo-
roalkanes, PhSO2CHFI, CH2FI, CH2FBr, and monofluoromal-
onate, that have served as building blocks to incorporate
monofluoroalkylated groups or monofluoromethyl groups.4
Therefore, the development of novel monofluorinating agents
as well as their utility in the diversity-oriented synthesis of
monofluorinated compounds, which might have potential use
in drug synthesis and drug discovery, is in high demand.
Ketones are ubiquitous structural motifs in synthetic
chemistry and life science related fields. The literature showed
that α-fluorination to a carbonyl group could increase the
electrophilicity of the carbonyl carbon, making it very
susceptible toward attack by nucleophiles.5 Hence, they
could serve as fluorinated synthons (or intermediate)6 in the
construction of fluorinated heterocycles as well as chiral
catalysts for epoxidation reactions.7 Moreover, fluorinated
ketones have been widely used in new drug designs as enzyme
inhibitors,8 potential antibacterial agents,9 potassium channel
inhibitors,10 and potential antimalarial agents.11 During the
past decades, methods for the synthesis of fluorinated ketones
have been rapidly developed, especially those for α,α-
difluoroketones.12 However, the synthesis of α-fluoroketones
was rarely reported.13 α-Fluorocarbonyl compounds were
successfully used as building blocks in palladium-catalyzed
coupling reactions with phenylboronic acids or bromoben-
zenes to access α-fluoro-α-arylketones by Qing, Shreeve, and
Scheme 1. Nickel-Catalyzed Coupling Reaction of α-Bromo-
α-fluoroketones with Arylboronic Acids
Despite the importance of α-halo-α-fluoroketones, very few
synthetic methods for their preparation have been reported.14
Except for the halogenation of α-fluoroenoxysilanes,14b
Burtoloso reported a direct synthesis of α-halo-α-fluoroketones
using sulfoxonium ylides as intermediates through dihaloge-
nation in moderate yields.14c Therefore, we are interested in
developing an alternative method to assemble α-halo-α-
fluoroketones with structure diversity in more mild conditions.
In recent years, our group has used a trifluoroacetate release/
Received: July 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
halogenation protocol of Colby to prepare diverse α-iodo-α,α-
difluoroketones, which were served as difluorinating building
blocks, from available α,α-difluorinated gem-diols.12a Further-
more, we have previously reported the synthesis of
trifluoromethyl α-fluorinated gem-diols from Selectfluor and
trifluoro-1,3-diones obtained by trifluoroacetylation of methyl
ketones.15 Thus, we envisioned that Colby’s protocol could be
used to give α-halo-α-fluoroketones directly through a
trifluoroacetate release/halogenation process. Initially, aceto-
phenone 1a was used as the starting material to produce
trifluoromethyl α-fluorinated gem-diols according to our
previously reported procedure.15 The gem-diol intermediates
were then used without purification in the next trifluoroacetate
release/halogenation reaction according to the procedure
reported by Colby.12a Gratifyingly, the reaction proceeded
smoothly to afford the desired product 2-bromo-2-fluoro-1-
phenylethan-1-one 2a in relatively high total yield. Next,
different ketones 1a−t were employed in this protocol,
routinely giving the desirable α-bromo-α-fluoroketones 2a−t
in good yields (Table 1). The structures of compounds 2d and
It is worth mentioning that α-bromo-α-fluoro-2-indolones
2q−2s have been first synthesized through this strategy in
good yields since α-fluoro-2-indolones are key structures found
in numerous nature products and pharmaceuticals (Figure 1),
Figure 1. Examples of bioactive compounds containing a 3-
fluorooxindole unit.
such as F-convolutamydine A, corticotropin-releasing factor
receptor, antipsychotic drug candidate, and flindokalner (BMS
204352, MaxiPost).16 The product 2s could be used as
building block to prepare the potassium channel activator
flindokalner via coupling reaction. Furthermore, we have
synthesized bromofluorinated paeonol derivative 2t. Paeonol is
a compound found in some traditional Chinese medicine
remedies and shows some biological activity.17 The fluorinated
agent 2t could serve as a fluorinated synthon for the
modification of the paeonol structure.
a
Table 1. Synthesis of α-Bromo-α-monofluoroketones
With the monofluorinating agents 2 in hand, we sought to
explore their application in organic synthesis. Therefore, 2-
bromo-2-fluoro-1-phenylethan-1-one 2a and phenylboronic
acid 3a were selected as model substrates to optimize the
Suzuki coupling reaction conditions. Initially, the reaction was
performed in the presence of 5 mol % of Ni(OTf)2 without
any ligand, leading to no formation of the desired coupling
product (Table 2, entry 1). Then a variety of diamine ligands
were examined in the model reaction. We observed that 1,10-
phenanthroline (L6) showed highest activity, providing the
desired coupling product 4a in 92% yield (Table 2, entry 7).
Other bipyridine (bpy) and bpy-based ligands L1−L5 also
could afford the product 4a, but in relatively lower yields
(Table 2, entries 2−6). Furthermore, a careful survey of nickel
catalysts (Table 2, entries 8−11) and solvents (entries 12−15)
was then performed, which showed the combination of
Ni(OTf)2 and 1,4-dioxane was the best choice (Table 2,
entry 7). Decreasing the reaction temperature from 80 to 70
°C resulted in a lower yield (Table 2, 57%; entry 16). The
control experiment indicated that the yield of 4a was greatly
reduced under air atmosphere (Table 2, 43%, entry 17).
Finally, an optimization of the amount of phenylboronic acid
(Table 2, entries 18 and 19) revealed that product 4a could be
obtained in the highest yield when the reaction of 2a was
conducted with 1.5 equiv of phenylboronic acid 3a catalyzed
by 5 mol % of Ni(OTf)2 and 1,10-phenanthroline (phen) in
1,4-dioxane at 80 °C under N2 atmosphere (Table 2, entry 7).
With the optimized reaction conditions in hand (Table 2,
entry 7), we next examined the scope of this nickel-catalyzed
monofluoroacylation of phenylboronic acid 3a by using
structurally diverse α-bromo-α-fluoroketones 2 (Table 3).
Overall, the monofluorinating building blocks bearing electron-
donating or electron-withdrawing groups on the benzene ring
are compatible with the reaction conditions, thus providing the
products 4a−4i in high yields. 2-Bromo-2-fluoro-1-(naphtha-
len-2-yl) ethanone 2k and 2-bromo-2-fluoro-1-(thiophene-2-
yl)ethanone 2l were also suitable monofluorinating agents for
a
Reaction conditions: (1) 1 (10 mmol), trifluoromethyl ethyl acetate
(1.78 g, 12.5 mmol), NaH (1 g, 25 mmol), THF (25 mL), rt; (2) for
compounds 2a−2m and 2t: Cu(NO3)2·3H2O (483.2 mg, 2.0 mmol),
Selectfluor (4.25 g, 12 mmol), CH3CN/H2O = 50/4, −20 °C, 6 h; for
compounds 2n−2s: Selectfluor (4.25 g, 12 mmol), CH3CN (50 mL),
rt, N2; (3) LiBr (5.21 g, 60 mmol), Selectfluor (7.08 g, 20 mmol),
Et3N (2.02 g, 20 mmol), dry THF (30 mL), 30 min. Isolated yields.
2s were confirmed by X-ray diffraction analysis (see the SI).
The reaction was revealed to be compatible with a broad range
of ketones, including aryl ketones with various substituents on
the aryl ring, as well as aliphatic and cyclic ketones. The
method provides an alternative method for the facile synthesis
of α-halo-α-fluoroketones in high yields (Table 1).
B
DOI: 10.1021/acs.orglett.9b02474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
when the monofluorinating agent 2o was subjected to the
reaction, no coupling product was observed and the reduction
product 5 was obtained instead. Meanwhile, we also carried
out a gram-scale reaction which gave product 4a in a high yield
of 90%. This result could be achieved by reducing the amount
of nickel catalyst to 2 mol % of substrate 2a.
Table 2. Nickel-Catalyzed Monofluoromethylation of
Phenylboronic Acid: Optimization of Reaction Conditions
a
Encouraged by the excellent radical reactivity of α-bromo-α-
fluoroketones 2, we then investigated the scope of the
monofluoroacylation by testing various aryl boronic acids in
reaction with 2a. As shown in Table 4, aryl boronic acids with
a
Table 4. Scope of Substituted Aryl Boric Acid Substrates
b
entry
Ni source
Ni(OTf)2
ligand
solvent
yield (%)
1
2
3
4
5
6
7
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
Toluene
DME
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
NR
45
79
87
85
73
92
68
74
78
trace
46
67
83
trace
73
37
81
86
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
NiBr2·DME
Ni(acac)2
Ni(NO3)2·6H2O
NiCl2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
9
10
11
12
13
14
15
c
16
d
17
18
e
f
19
a
Reaction conditions: 2a (0.6 mmol, 1.0 equiv), 3a (1.5 equiv),
b
c
K2CO3 (2.0 quiv), 80 °C, 8 h, under N2. GC yields. Performed at 70
°C. Under air. 3a (1.2 equiv). 3a (2.0 equiv).
d
e
f
a
Table 3. Scope of α-Bromo-α-monofluoroketones
a
Reaction conditions: 2a (0.6 mmol, 1.0 equiv), 3 (1.5 equiv),
Ni(OTf)2 (5 mol %), phen (5 mol %), K2CO3 (2.0 equiv), 1,4-
dioxane (2.0 mL), 80 °C, 8 h, under N2. Isolated yields.
various substituents on the aryl ring, both electron-donating
and electron-withdrawing groups, are all suitable cross-
coupling partners for the transformation, no matter where
the substituent is located, affording the corresponding
fluoromethylated arenes 6a−6r in good yields. The structure
of compound 6k was confirmed by X-ray diffraction analysis
(see the SI). Additionally, boronic acids derived from
polycyclic and heterocyclic arenes, such as p-biphenyl, m-
biphenyl, 2-naphthyl, and thiophene, reacted smoothly with 2a
to give the compounds 6s, 6t, 6u, and 6v in satisfactory yields.
Most remarkably, cyclohexene-1-boronic acid was also
compatible with the reaction condition, giving the product
6w in a high yield (91%).
a
Reaction conditions: 2 (0.6 mmol, 1.0 equiv), 3a (1.5 equiv),
Ni(OTf)2 (5 mol %), phen (5 mol %), K2CO3 (2.0 equiv), 1,4-
dioxane (2.0 mL), 80 °C, 8 h, under N2. Isolated yields. Ni(OTf)2 (2
mol %), phen (2 mol %), reaction carried out on a gram scale.
b
To further probe the generality of the new reaction, the
treatments of several α-bromo-α-monofluoroketones 2 with
different boronic acids 3 were performed under the same
reaction conditions (Table 5). Gratifyingly, all reactions
this transformation, and 2l was less effective in the coupling
reaction, affording the product 4k in 69% yield. However,
C
DOI: 10.1021/acs.orglett.9b02474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 5. Scope of α-Bromo-α-monofluoroketones and
Substituted Aryl Boric Acid Substrates
Scheme 3. Proposed Reaction Mechanism
a
reaction by using compound 2s as a monofluorinated building
block. First, the amino group in the agent 2s was protected
with a benzyl group to afford the intermediate 10, which then
reacted with 5-chloro-2-methoxybenzeneboronic acid under
the standard reaction conditions. However, only a trace yield
of the target compound 12 was observed (Scheme 4a). Next,
a
Reaction conditions: 2 (0.6 mmol, 1.0 equiv), 3 (1.5 equiv),
Ni(OTf)2 (5 mol %), phen (5 mol %), K2CO3 (2.0 equiv), 1,4-
dioxane (2.0 mL), 80 °C, 8 h, under N2. Isolated yields.
Scheme 4. Synthesis of Benzyl-Protected BMS-204352
(Racemate)
proceeded smoothly to give the target compounds 7a−7i in
high yields, which proved the universal applicability of the
reaction in the preparation of diverse monofluoroketones.
In order to gain some insight into the reaction mechanism,
two control experiments were then carried out (Scheme 2).
Scheme 2. Radical-Trapping Experiment
2-(5-chloro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane 11 was used to react with 2s under the same reaction
conditions. Gratifyingly, the desired compound 12 was
obtained in 47% yield, which could be used as an important
medical intermediate to further prepare flindokalner (Scheme
4b). This method is more efficient and easier compared with
the traditional synthetic route for flindokalner.16d
In summary, we have developed a novel method for the
preparation of α-bromo-α-fluoroketones by a trifluoroacetate
release protocol. A series of α-bromo-α-fluoroketones includ-
ing α-bromo-α-fluoro-2-indolones were synthesized in good
yields. The coupling reactions between α-bromo-α-fluoroke-
tones and arylboronic acids occurred efficiently in the presence
of Ni(OTf)2, phen, and K2CO3 with high yields. This method
demonstrated broad scope and high efficiency. Mechanistic
investigation indicated that a monofluoroalkyl radical is
involved in the coupling reaction pathway. Moreover, an
important medical intermediate of flindokalner 12 was
obtained via a nickel-catalyzed coupling reaction of 3-bromo-
3-fluoro-6-(trifluoromethyl)indolin-2-one 2s and 2-(5-chloro-
2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 11.
Further studies of the application of the monofluorinated
agents 2 and the coupling reaction are still ongoing in our
laboratory.
The reaction was completely suppressed when 1.0 equiv of
TEMPO (2,2,6,6-tetramethyl-1-oxylpiperidine) was added into
the reaction system (Scheme 2a), which shows that a radical
may be involved in the reaction pathway. We were able to trap
the PhCOCHF• radical using (1S)-(−)-β-Pinene 8 under our
standard conditions, giving the ring-opened diene 9 in 40%
yield accompanied by 51% yield of the coupling product 4a
(Scheme 2b), which further implicated the generation of the
PhCOCHF• radical in the reaction process. On the basis of the
control experiment and literature data, we proposed a plausible
reaction mechanism shown in Scheme 3. As depicted, the NiI
species A may be produced through the comproportionation
reaction of in situ generated Ni0 and the remaining NiII
species.4h,18 The transmetalation between species A and aryl
boronic acid 3 could afford NiI−Ar species B, which
subsequently reacted with 2 to form monoaluoroalkyl radical
and NiII intermediate C through an bromine atom transfer
process. The intermediate C is then went through an oxidative
radical addition to give NiIII species D followed by reductive
elimination to form the final monofluorinated product 4 while
regenerating NiI species A.
Finally, we anticipated that the potassium channel activator
flindokalner would be prepared via this reported coupling
D
DOI: 10.1021/acs.orglett.9b02474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
F.-H. Tetrahedron 2017, 73, 3478. (i) Liang, J.-Q.; Huang, G.-Z.;
Peng, P.; Zhang, T.-Y.; Wu, J.-J.; Wu, F.-H. Adv. Synth. Catal. 2018,
360, 2221.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02474.
■
S
(4) (a) Zhao, Y.-C.; Gao, B.; Ni, C.-F.; Hu, J.-B. Org. Lett. 2012, 14,
6080. (b) Guo, C.; Yue, X.-Y.; Qing, F.-L. Synthesis 2010, 1837.
(c) Zhang, X.; Qiu, W.-M.; Burton, D. J. Tetrahedron Lett. 1999, 40,
2681. (d) Tang, W.-K.; Xu, Z.-W.; Xu, J.; Tang, F.; Li, X.-Y.; Dai, J.-J.;
Xu, H.-J.; Feng, Y.-S. Org. Lett. 2019, 21, 196. (e) Zhao, Y.-C.; Ni, C.-
F.; Jiang, F.-Z.; Gao, B.; Shen, X.; Hu, J.-B. ACS Catal. 2013, 3, 631.
(f) Jiang, X. J.; Sekarpandi, S.; Kulbitski, K.; Nisnevich, G.;
Gandelman, M. J. Am. Chem. Soc. 2014, 136, 9548. (g) Hu, J.-Y.;
Gao, B.; Li, L.-C.; Ni, C.-F.; Hu, J.-B. Org. Lett. 2015, 17, 3086.
(h) Su, Y.-M.; Feng, G.-S.; Wang, Z.-Y.; Lan, Q.; Wang, X.-S. Angew.
Chem., Int. Ed. 2015, 54, 6003. (i) An, L.; Xiao, Y.-L.; Min, Q.-Q.;
Zhang, X.-G. Angew. Chem., Int. Ed. 2015, 54, 9079. (j) Wu, Y.;
Zhang, H.-R.; Cao, Y.-X.; Lan, Q.; Wang, X.-S. Org. Lett. 2016, 18,
5564. (k) Sheng, J.; Ni, H.-Q.; Liu, G.; Li, Y.; Wang, X.-S. Org. Lett.
2017, 19, 4480. (l) Wu, N.-Y.; Xu, X.-H.; Qing, F.-L. ACS Catal.
2019, 9, 5726. (m) Yin, H.; Sheng, J.; Zhang, K.-F.; Zhang, Z.-Q.;
Bian, K.-J.; Wang, X.-S. Chem. Commun. 2019, 55, 7635. (n) Beare, N.
A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541. (o) Cosimi, E.; Saadi, J.;
Wennemers, H. Org. Lett. 2016, 18, 6014.
Experimental procedures, NMR spectra, and X-ray
crystal data (PDF)
Accession Codes
CCDC 1897634, 1901373, and 1922967 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wujj@sit.edu.cn.
*E-mail: wfh@sit.edu.cn.
ORCID
(5) (a) Dobson, L. S.; Pattison, G. Chem. Commun. 2016, 52, 11116.
(b) Pattison, G. Beilstein J. Org. Chem. 2017, 13, 2915.
́
́
(6) Fernandez, R.; Martín-Zamora, E.; Pareja, C.; Vazquez, J.; Díez,
E.; Monge, A.; Lassaletta, J. M. Angew. Chem., Int. Ed. 1998, 37, 3428.
(7) (a) Mello, R.; Fiorentino, M.; Fusco, F.; Curci, R. J. Am. Chem.
Soc. 1989, 111, 6749. (b) Yang, D.; Yip, Y. C.; Chen, J.; Cheung, K. K.
J. Am. Chem. Soc. 1998, 120, 7659.
Jingjing Wu: 0000-0002-5733-7670
Author Contributions
†J.L. and J.H. contributed equally.
Notes
(8) (a) Bernstein, P. R.; Gomes, B. C.; Kosmider, B. J.; Vacek, E. P.;
Williams, J. C. J. Med. Chem. 1995, 38, 212. (b) Chatterjee, S.; Ator,
M. A.; Bozyczko-Coyne, D.; Josef, K.; Wells, G.; Tripathy, R.; Iqbal,
M.; Bihovsky, R.; Senadhi, S. E.; Mallya, S.; O’Kane, T. M.; McKenna,
B. A.; Siman, R.; Mallamo, J. P. J. Med. Chem. 1997, 40, 3820.
(c) Zhang, J.-M.; Huitema, C.; Niu, C.-Y.; Yin, J.; James, M. N. G.;
Eltis, L. D.; Vederas, J. C. Bioorg. Chem. 2008, 36, 229.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21672151 and 21602136).
■
(9) Riber, D.; Venkataramana, M.; Sanyal, S.; Duvold, T. J. Med.
Chem. 2006, 49, 1503.
REFERENCES
(1) Recent reviews: (a) Wang, J.; Sanchez-Rosello, M.; Acen
del Pozo, C. D.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.;
Liu, H. Chem. Rev. 2014, 114, 2432. (b) O’Hagan, D. Chem. Soc. Rev.
(10) Sarantakis, D.; Bicksler, J. J.; Wu, J.-C. PAT. Appl. Pub. US
2006/0014826A1, 2006.
(11) Abad, A.; Agullo, C.; Cunat, A. C.; Gonzalez-Coloma, A.;
Pardo, D. Eur. J. Org. Chem. 2010, 2010, 2182.
(12) (a) John, J. P.; Colby, D. A. J. Org. Chem. 2011, 76, 9163.
(b) Li, Y.-L.; Liu, J.; Zhao, S.; Du, X.-Z.; Guo, M.-J.; Zhao, W.-T.;
Tang, X.-Y.; Wang, G.-W. Org. Lett. 2018, 20, 917.
(13) (a) Guo, C.; Wang, R.-W.; Guo, Y.; Qing, F.-L. J. Fluorine
Chem. 2012, 133, 86. (b) Guo, Y.; Twamley, B.; Shreeve, J. M. Org.
Biomol. Chem. 2009, 7, 1716. (c) Zhou, J.; Fang, X.; Shao, T.-L.; Yang,
X.-Y.; Wu, F.-H. J. Fluorine Chem. 2016, 191, 54. (d) Liang, Y.-F.; Fu,
G. C. J. Am. Chem. Soc. 2014, 136, 5520. (e) Tarui, A.; Miyata, E.;
Tanaka, A.; Sato, K.; Omote, M.; Ando, A. Synlett 2014, 26, 55.
■
́
́
̃
a, J. L.;
2008, 37, 308. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007,
̈
317, 1881. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (e) Hagmann, W. K. J. Med. Chem.
2008, 51, 4359.
(2) (a) Cheng, Y.-Z.; Yuan, X.-G.; Jiang, H.; Wang, R.-Z.; Ma, J.;
Zhang, Y.; Yu, S.-Y. Adv. Synth. Catal. 2014, 356, 2859. (b) Li, L.;
Chen, Q.-Y.; Guo, Y. J. Fluorine Chem. 2014, 167, 79. (c) Yu, Y.-Y.;
Ranade, A. R.; Georg, G. I. Adv. Synth. Catal. 2014, 356, 3510.
(d) Sahoo, B.; Li, J.-L.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54,
11577. (e) Tomita, R.; Koike, T.; Akita, M. Angew. Chem., Int. Ed.
2015, 54, 12923. (f) Noto, N.; Koike, T.; Akita, M. J. Org. Chem.
2016, 81, 7064. (g) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.;
Tan, B.; Liu, X.-Y. J. Am. Chem. Soc. 2016, 138, 9357. (h) Bao, X.;
Wang, Q.; Zhu, J.-P. Nat. Commun. 2019, 10, 1. (i) Xiao, H.-W.; Liu,
Z.-L.; Shen, H.-G.; Zhang, B.-X.; Zhu, L.; Li, C.-Z. Chem. 2019, 5,
940.
́
(f) Belanger, E.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J. F. J.
Am. Chem. Soc. 2007, 129, 1034. (g) Stavber, S.; Jereb, M.; Zupan, M.
Synthesis 2002, 17, 2609.
(14) (a) Bergmann, F.; Kalmus, A.; Vromen, S. J. Am. Chem. Soc.
1955, 77, 2494. (b) Shibatomi, K.; Yamamoto, H. Angew. Chem., Int.
Ed. 2008, 47, 5796. (c) Gallo, R. D. C.; Ahmad, A.; Metzker, G.;
Burtoloso, A. C. B. Chem. - Eur. J. 2017, 23, 16980.
(15) (a) Saidalimu, I.; Fang, X.; He, X.-P.; Liang, J.; Yang, X.-Y.; Wu,
F.-H. Angew. Chem., Int. Ed. 2013, 52, 5566. (b) Saidalimu, I.; Fang,
X.; Lv, W.-W.; Yang, X.-Y.; He, X.-P.; Zhang, J.-Y.; Wu, F.-H. Adv.
Synth. Catal. 2013, 355, 857.
(16) (a) Atkinson, B.; Beattie, D.; Culshaw, A. J.; Dale, J.; Devereux,
N. J.; Mckenna, J. Pat. Appl. Pub. WO 2011/0922293A2, 2011.
(b) Fernandes, P. D.; Zardo, R. S.; Figueiredo, G. S.; Silva, B. V.;
Pinto, A. C. Life Sci. 2014, 116, 16. (c) Spear, K. L.; Campbell, U. Pat.
Appl. Pub. WO2014/106238 A1, 2014. (d) Gribkoff, V. K.; Post-
Munson, D. J.; Yeola, S. W.; Boissard, C. G.; Hewawasam, P. Pat.
Appl. Pub. WO2002/030868A1, 2002. (e) Hewawasam, P.; Gribkoff,
(3) (a) Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X.
Angew. Chem., Int. Ed. 2014, 53, 1669. (b) Schwaebe, M. K.;
McCarthy, J. R.; Whitten, J. P. Tetrahedron Lett. 2000, 41, 791.
(c) Chen, Y.-J.; Li, L.-K.; Ma, Y.-Y.; Li, Z.-P. J. Org. Chem. 2019, 84,
5328. (d) Huang, X.; Zhang, Y.-G.; Zhang, C.-S.; Zhang, L.; Xu, Y.;
Kong, L.-C.; Wang, Z.-X. Angew. Chem., Int. Ed. 2019, 58, 5956.
(e) Zhao, H.-Y.; Gao, X.; Zhang, S.; Zhang, X. Org. Lett. 2019, 21,
1031. (f) Chen, H.; Wang, J.-X.; Wu, J.-J.; Kuang, Y.-J.; Wu, F.-H. J.
Fluorine Chem. 2017, 200, 41. (g) Wang, J.-X.; Wu, J.-J.; Chen, H.;
Zhang, S.-W.; Wu, F.-H. Chin. Chem. Lett. 2015, 26, 1381. (h) Wang,
D.-F.; Wu, J.-J.; Huang, J.-W.; Liang, J.-Q.; Peng, P.; Chen, H.; Wu,
E
DOI: 10.1021/acs.orglett.9b02474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
V. K.; Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.; Martinez, E.;
Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram, K.;
Pajor, L. M.; Knipe, J.; Gao, Q.; Perrone, R.; Starrett, J. E. Bioorg. Med.
Chem. Lett. 2002, 12, 1023.
(17) (a) Zhang, L.; Chen, Z.-Q.; Gong, W.-Y.; Zou, Y.-Z.; Xu, F.-T.;
Chen, L.-H.; Huang, H.-Q. Front. Pharmacol. 2018, 9, 512. (b) Wu, J.;
Xu, L.-L.; Sun, C.; Zhang, B.; Li, J.; Sun, J.; Zhang, Y.; Sun, D.-Q. Eur.
J. Pharmacol. 2017, 795, 84.
(18) (a) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.;
Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers,
P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175.
́
(b) Cornella, J.; Gomez-Bengoa, E.; Martin, R. J. Am. Chem. Soc.
2013, 135, 1997.
F
DOI: 10.1021/acs.orglett.9b02474
Org. Lett. XXXX, XXX, XXX−XXX