Silver-Catalyzed C-H Aryloxydifluoromethylation and Arylthiodifluoromethylation of Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.0c01826

The oxidative C-H aryloxydifluoromethylation and arylthiodifluoromethylation of heteroaromatic compounds through the decarboxylation of easily accessible aryloxydifluoroacetic acids and arylthiodifluoroacetic acids, respectively, are disclosed. These reac

Full text of DOI:10.1021/acs.orglett.0c01826

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Letter
Silver-Catalyzed C−H Aryloxydifluoromethylation and
Arylthiodifluoromethylation of Heteroarenes
Xiao-Lei Zhu, Yangen Huang, Xiu-Hua Xu, and Feng-Ling Qing*
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ABSTRACT: The oxidative C−H aryloxydifluoromethylation and
arylthiodifluoromethylation of heteroaromatic compounds through
the decarboxylation of easily accessible aryloxydifluoroacetic acids
and arylthiodifluoroacetic acids, respectively, are disclosed. These
reactions are promoted by the combination of catalytic AgNO3 and
Selectfluor or K2S2O8 to give ArOCF2- and ArSCF2-substituted
heteroaromatic compounds in moderate to high yields.
Scheme 1. Preparation of ArOCF2- and ArSCF2-Substituted
Aromatic Compounds
ecent years have witnessed a growing interest in the
synthesis of CF2-containing compounds. The incorpo-
1
R
ration of a difluoromethylene (CF2) group into organic
compounds could lead to increased dipole moments, enhanced
metabolic stability, and conformational changes.2 Furthermore,
the presence of oxygen and sulfur would improve the
lipophilicity of parent molecules. Thus, the CF2OAr and
CF2SAr motifs have garnered increasing attention with the
realm of drug discovery. For instance, ArOCF2- and ArSCF2-
substituted aromatic compounds have found applications as
TRPV1 inhibitors,3a apoB-100 inhibitors,3b and HIV-1 reverse
transcriptase inhibitors3c (see Figure 1).
derivatives (see Scheme 1b).6 However, the aryldifluorome-
thylating reagents are not easily available. An attractive strategy
would be the direct functionalization of aromatic compounds
with ArOCF2- and ArSCF2-containing reagents. In 2016, the
Cho group reported a visible-light-induced arylthiodifluor-
omethylation of heteroaromatics with BrCF2SAr (see Scheme
Figure 1. Bioactive ArOCF2- and ArSCF2-substituted aromatic
compounds.
Traditional approaches to ArOCF2-substituted aromatic
compounds include desulfurization−fluorination of thionoest-
ers4 and fluorination−rearrangement of ketones5 (see Scheme
1a). These methods suffer from the use of toxic and/or
expensive fluorinating reagents. Alternatively, ArOCF2- and
ArSCF2-substituted aromatic compounds can be prepared
using the aryldifluoromethylation of phenol and thiophenol
Received: May 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01826
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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1c).7 However, this method is limited to the electron-rich
heteroarenes including pyrrole, furan, indole, benzofuran, and
benzothiophene. Hence, the development of new methods for
efficient incorporation of CF2OAr or CF2SAr motifs into
aromatic compounds is still of high demand.
either (Table 1, entry 2). In contrast, the use of Selectfluor
furnished 3a in 56% yield (Table 1, entry 3). The Ag(I)
catalyst is also crucial to this reaction. AgOTf and Ag2CO3 led
to inferior results (Table 1, entries 4 and 5), whereas no 3a was
detected in the absence of Ag(I) catalyst (Table 1, entry 6).
Further screening of the temperature revealed that 90 °C was
optimal, resulting in slightly higher yield (Table 1, entry 8). On
the other hand, the exploration of other solvents and solvent
mixture gave inferior results (see the Supporting Information).
Finally, the yield of 3a was improved to 78% by increasing the
amount of 2a to 3.0 equiv (Table 1, entry 10). Notably, no bis-
aryloxydifluoromethylated product was detected.11a Further-
more, lower yield was obtained when the amount of AgNO3
was reduced (Table 1, entry 11). 3a was formed in 44% yield
when 2a was employed as the limiting reagent (Table 1, entry
12).
Having optimized the aryloxydifluoromethylation condi-
tions, we then explored the scope of heteroaromatic
compounds and aryloxydifluoroacetic acids. As shown in
Scheme 2, a series of common heteroaromatic scaffolds
including pyridine (1a−1g), pyrazine (1h), pyridazine (1i),
1,5-naphthyridine (1j), phenanthridine (1k), 2H-chromen-2-
one (1l), and naphthoquinone (1m) all underwent this
In 1971, Minisci initially reported the silver-catalyzed C−H
functionalization of heteroarenes using alkyl carboxylic acids as
the radical precursors and persulfates as oxidants.8 Following
this pioneering work, the radical functionalization of
heteroarenes has been studied extensively.9 Recently, the
Minisci-type fluoroalkylation of heteroarenes with fluorine-
containing carboxylic acids, such as CF3CO2H,10
CF2HCO2H,11 and ArCF2CO2H,12 have been reported.
Inspired by these works, we envisioned that the similar
aryloxydifluoromethylation and arylthiodifluoromethylation of
heteroarenes with ArOCF2CO2H and ArSCF2CO2H might
allow the efficient synthesis of ArOCF2- and ArSCF2-
substituted aromatic compounds. ArOCF2CO2H and
ArSCF2CO2H are easily prepared from the reaction of phenols
or thiophenols and sodium bromodifluoroacetates.13a The
fluorodecarboxylation13 and protodecarboxylation14 of Ar-
OCF2CO2H and/or ArSCF2CO2H were reported by the
groups of Hartwig, Hu, Sammis, Prakash, and Gouverneur. In
continuation of our recent research interest in the direct
fluoroalkylation of aromatic compounds,15 herein we disclose
the silver-catalyzed aryloxydifluoromethylation and arylthiodi-
fluoromethylation of heteroarenes with ArOCF2CO2H and
ArSCF2CO2H, respectively (see Scheme 1d).
Scheme 2. Substrate Scope of Aryloxydifluoromethylation of
a
Heteroaromatic Compounds
Initially, we investigated the aryloxydifluoromethylation
reaction using ethyl isonicotinate (1a) as the model substrate
and phenoxydifluoroacetic acid (2a) as the ArOCF2 source
(Table 1). However, the reaction in the presence of catalytic
amount of AgNO3 (20 mol %) and 2.0 equiv of K2S2O8 failed
to afford the desired product 3a (Table 1, entry 1). The 19F
NMR spectrum of the reaction mixture showed that most of 2a
was consumed, and no major byproducts were evident. When
PhI(OAc)2 was employed as the oxidant, 3a was not formed
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
oxidant
K2S2O8
temperature (°C)
yield (%)
1
2
3
4
5
6
7
8
9
AgNO3
AgNO3
AgNO3
AgOTf
Ag2CO3

80
80
80
80
80
80
70
90
100
90
90
90
0
0
56
15
33
0
45
68
63
78
45
44
PhI(OAc)2
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
c
10
c d
,
11
12
e
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.04
mmol), oxidant (0.4 mmol), DCE/H2O (1:1, 2.0 mL), N2,
b
a
temperature, 20 h. Yields determined by 19F NMR spectroscopy,
Reaction conditions: 1 (0.6 mmol), 2 (1.8 mmol), AgNO3 (0.12
c
using trifluoromethoxybenzene as an internal standard. 2a (0.6
mmol), selectfluor (1.2 mmol), DCE/H2O (1:1, 6.0 mL), N2, 90 °C,
20 h, isolated yields. Reaction was performed on a 1.2 mmol scale.
d
e
b
mmol). AgNO3 (0.02 mmol). 1a (0.6 mmol), 2a (0.2 mmol).
B
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pubs.acs.org/OrgLett
Letter
transformation smoothly, affording the aryloxydifluoromethy-
lated products 3a−3m in moderate to good yields. For the
products formed in low yields, the reaction efficiency was not
improved by increasing the reaction temperature or prolonging
the reaction time. In most cases, excellent regioselectivities
were observed when heterocyclic scaffold contained multiple
potentially reactive positions. The reaction of unsubstituted
pyridine gave a mixture of two isomers in low yields.
Aryloxydifluoroacetic acids (2a−2e) bearing different sub-
stituents on the aromatic ring were also suitable for this
reaction to deliver products 3ma−3me in high yields.
Functional groups such as alkyl, aryl, ester, cyano, acyl, fluoro,
chloro, and bromo were all compatible with the reaction
conditions. Furthermore, when the reaction of 1a was
performed on a 1.2 mmol scale, the yield was comparable to
that observed on a 0.6 mmol scale.
Scheme 3. Substrate Scope of Arylthiodifluoromethylation
of Heteroaromatic Compounds
a
Encouraged by the above results, we subsequently examined
the arylthiodifluoromethylation of 1a with phenylthiodifluoro-
acetic acid (4a), under the standard aryloxydifluoromethyla-
tion conditions. To our disappointment, the arylthiodifluor-
omethylated product 5a was not observed (see Table 2, entry
a
Table 2. Optimization of Reaction Conditions
b
entry
oxidant
temperature (°C)
yield (%)
c
1
2
3
4
5
6
7
Selectfluor
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
90
90
90
90
70
50
30
0
52
43
40
79
87
32
a
Reaction conditions 1 (0.6 mmol), 4 (1.8 mmol), AgNO3 (0.12
mmol), K2S2O8 (1.2 mmol), DCE/H2O (1:1, 6.0 mL), N2, 50 °C, 20
K2S2O8
K2S2O8
b
h, isolated yields. Reaction was performed on a 1.2 mmol scale.
a
Reaction conditions: 1a (0.2 mmol), 4a (0.6 mmol), AgNO3 (0.04
mmol), oxidant (0.4 mmol), DCE/H2O (1:1, 2.0 mL), N2,
b
although the exact reason is not clear. The structure of product
5kc was confirmed by X-ray crystallographic analysis. When
the reaction of 1a was scaled up to 1.2 mmol, the desired
product 5a was obtained in comparable yield. Regarding the
arylthiodifluoroacetic acids (4b−4f), the electron-donating or
electron-withdrawing substituent at ortho-, meta-, and para-
positions were well-tolerated, furnishing products 5ab−5af in
high yields.
The competition experiments of 1a with 2a and 4a were
conducted to compare the relative reactivity of ArOCF2CO2H
and ArSCF2CO2H. Surprisingly, neither aryloxydifluoromethy-
lated product 3a nor arylthiodifluoromethylated product 5a
was generated under the AgNO3/Selectfluor reaction system
(Scheme 4a). In contrast, the AgNO3/K2S2O8 reaction system
afforded product 5a in 72% yield (Scheme 4b). These results
indicated that the oxidative decarboxylation of PhSCF2CO2H
was faster than that of PhOCF2CO2H.
To gain insights into the reaction mechanism, a radical
scavenger, TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), was
added to into standard aryloxydifluoromethylation and
arylthiodifluoromethylation conditions (see the Supporting
Information). No desired product was observed, indicating the
involvement of a radical pathway. Based on the above results
and previous reports,9−14,16 a silver-catalyzed Minisci-type
reaction mechanism was proposed in Scheme 5. First,
temperature, 20 h. Yields determined by 19F NMR spectroscopy,
c
using trifluoromethoxybenzene as an internal standard. PhSCF3 and
an unknown byproduct were formed.
1). Instead, PhSCF3 and an unknown byproduct were formed.
Fortunately, switching the oxidant to persulfates, including
K2S2O8, Na2S2O8, and (NH4)2S2O8, gave the desired product
5a in moderate yields (Table 2, entries 2−4). Among them,
K2S2O8 was most effective, affording 5a in 52% yield. Similar to
the aryloxydifluoromethylation of 1a shown in Table 1, the
reaction temperature also affected the arylthiodifluoromethy-
lation reaction (Table 2, entries 5−7). The yield of 5a was
improved to 87% when the reaction was performed at 50 °C.
We next set out to explore the scope of arylthiodifluor-
omethylation reaction (Scheme 3). With respect to hetero-
aromatic compounds, pyridines (1a−1c,1n), quinoline (1o),
pyrazine (1h), pyridazine (1i), phenanthridine (1k), and
acridine (1p) were efficiently converted to the corresponding
products in moderate to high yields. Consistent with the
aryloxydifluoromethylation reaction, the CF2SAr group was
regioselectively attached the position next to the N atom of
heteroarenes to give products 5a−5kc. In the cases of
substrates 1b and 1c, the regioselectivities in products 5b
and 5c were much better than those in products 3b and 3c,
C
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Scheme 4. Competition Experiments
AUTHOR INFORMATION
Corresponding Author
■
Feng-Ling Qing − College of Chemistry, Chemical Engineering
and Biotechnology, Donghua University, Shanghai 201620,
China; Key Laboratory of Organofluorine Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Science, Chinese
Academy of Science, Shanghai 200032, China; orcid.org/
0000-0002-7082-756X; Email: flq@mail.sioc.ac.cn
Authors
Scheme 5. Proposed Reaction Mechanism
Xiao-Lei Zhu − College of Chemistry, Chemical Engineering and
Biotechnology, Donghua University, Shanghai 201620, China
Yangen Huang − College of Chemistry, Chemical Engineering
and Biotechnology, Donghua University, Shanghai 201620,
China
Xiu-Hua Xu − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of Science,
Chinese Academy of Science, Shanghai 200032, China;
orcid.org/0000-0002-0759-2286
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01826
Notes
The authors declare no competing financial interest.
aryloxydifluoroacetic or arylthiodifluoroacetic acids (2/4)
undergo oxidative decarboxylation in the presence of silver(I)
catalyst and oxidant to give the corresponding radical A.
Subsequently, the addition of radical A to protonated
heteroarenes B affords radical cation C. Finally, the radical
cation C is converted to the desired products (3/5) through
oxidation and deprotonation.
In conclusion, we have developed an operationally simple
methodology for the direct incorporation of CF2OAr and
CF2SAr groups into heteroarenes through silver-catalyzed
decarboxylation of ArOCF2CO2H and ArSCF2CO2H. The
employment of proper oxidants is crucial for the success of
these reactions. This protocol exhibits broad substrate,
enabling the efficient synthesis of various ArOCF2- and
ArSCF2-substituted heteroaromatic compounds. Most of the
resulting products are previously unknown and potentially
useful in the field of medicinal chemistry. Intensive studies to
identify fundamental reactivity differences among different
fluorine-containing groups in radical C−H functionalization
reactions are in progress.
ACKNOWLEDGMENTS
■
The National Natural Science Foundation of China (Nos.
21421002 and 21991211) and the Strategic Priority Research
Program of the Chinese Academy of Sciences (No.
XDB20000000) are greatly acknowledged for funding this
work.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01826.
Experimental procedures; characterization data; copies
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