Difluorocarbene-triggered cyclization: Synthesis of (hetero)arene-fused 2,2-difluoro-2,3-dihydrothiophenes

Article abstract of DOI:10.1021/acs.orglett.0c02688

An efficient method for the synthesis of (hetero)arene-fused 2,2-difluoro-2,3-dihydrothiophene derivatives using readily available sodium chlorodifluoroacetate (ClCF2CO2Na) has been developed. This transformation is achieved through a combination of a thi

Full text of DOI:10.1021/acs.orglett.0c02688

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Letter
Difluorocarbene-Triggered Cyclization: Synthesis of (Hetero)arene-
Fused 2,2-Difluoro-2,3-dihydrothiophenes
Huamin Liang, Ran Liu, Min Zhou, Yue Fu, Chuanfa Ni,* and Jinbo Hu*
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ABSTRACT: An efficient method for the synthesis of (hetero)-
arene-fused 2,2-difluoro-2,3-dihydrothiophene derivatives using
readily available sodium chlorodifluoroacetate (ClCF2CO2Na)
has been developed. This transformation is achieved through a
combination of a thiolate with difluorocarbene, followed by
intramolecular nucleophilic addition to a ketone, cyano, or ester
functional group.
rganofluorine compounds make up a fascinating class of
molecules, which have shown wide applications in the
through its sequential reaction with a nucleophile and an
electrophile (rather than a proton).6 However, this approach
has witnessed limited success in bridging a heteroatom
nucleophile and a ketone7 (Scheme 1a) because of the poor
stability of the newly generated gem-difluorinated carbanion
species, with only two examples being reported (Scheme 1b).8
One is the three-component reaction of triphenylphosphine,
difluorocarbene, and a ketone, which requires the action of a
silyl cation to trap the in situ-formed gem-difluorinated
alcoholate intermediate;8a the other is the cyclization of o-
hydroxyaryl ketones with difluorocarbene, which was demon-
strated with only chalcones.8b
O
fields of pharmaceuticals, agrochemicals, and material
sciences.1 Selective introduction of fluorine atoms or
fluorinated moieties has become a routine strategy for
imparting significant properties on organic molecules, partic-
ularly in terms of reactivity and biological activity.2 Among
various fluorinated moieties, the sp3-hybridized difluoro-
methylene (-CF2-) can be regarded as the bioisostere of the
oxygen atom and has been applied to mimic the metabolically
labile oxygen atom in ether, phosphonate, and sulfate.3
Moreover, substitution of a methylene group with CF2 can
alter the conformation and reactivity of an organic molecule,
thus bringing about a dramatic improvement in biological
activity.3a,f,4 For instance (Figure 1),5 compared to non-
Previously, we reported the nucleophilic difluoro-
(phenylthio)methylation of a series of electrophiles with
PhSCF2H using t-BuOK or KOH as the base and found that
PhSCF2 can readily react with ketones.9 In view of this, we
−
envisioned that the combination of an aromatic thiolate anion
(ArS−) and difluorocarbene (to in situ generate ArSCF2 )
−
would provide a novel method for nucleophilic difluoro-
(arylthio)methylations. However, our initial attempt to
−
difluoromethylate ketones using 2-PySCF2 generated in situ
from 2-PyS− and a difluorocarbene source such as sodium
chlorodifluoroacetate (SCDA) failed to afford the desired
product (Scheme 1c). Instead, the protonation of the 2-
Figure 1. Dramatic effect of fluorine substituents on the HIF-2α
activity of benzo-cyclic sulfone compounds.
−
PySCF2 anion proceeded much faster than the ketone
addition reaction. In this context, we speculated that the
combination of the thiolate nucleophile and the ketone
electrophile within the same molecule might facilitate the
addition step. Herein, we report the cyclization of o-
fluorinated benzo-cyclic sulfone A, gem-difluorinated benzo-
cyclic sulfone B showed an at least 100-fold higher HIF-2α
activity due to the enhancement of the electron-withdrawing
ability of the sulfonyl group, as well as the change of the
environment of the hydroxyl group by the two geminal fluorine
substituents.
Received: August 11, 2020
Among various methods for the construction of gem-
difluorinated compounds, difluorocarbene-involved reactions
have attracted a great deal of attenton.6 Since 2013,
difluorocarbene has been exploited as a versatile C1 building
block for the synthesis of gem-difluorinated compounds
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the desired cyclization product 2g was slightly increased, with
inhibition of S- and N-difluoromethylation to some extent.
We next explored the substrate scope of o-mercapto-
(hetero)aryl ketones by using SCDA as the difluorocarbene
precursor, K2CO3 as the base, and 4 Å MS as the additive
(Scheme 3). The reaction tolerated 2-mercaptopyridin-3-yl
Scheme 1. Nucleophilic Difluoroalkylation of Ketones with
Difluorocarbene
a
Scheme 3. Scope of o-Mercapto(hetero)aryl Ketones 1
mercapto(hetero)aryl ketones with difluorocarbene derived
from sodium chlorodifluoroacetate (Scheme 1d), which
provides a concise method for the construction of novel
(hetero)arene-fused 2,2-difluoro-2,3-dihydrothiophene deriva-
tives.10
Our study began with the reaction of o-mercaptoheteroaryl
ketone 1g with sodium chlorodifluoroacetate (SCDA)
(Scheme 2). We chose SCDA as the difluorocarbene reagent
Scheme 2. Cyclization Reaction of 2-Mercaptopyridin-3-yl
Ketone 1g with Difluorocarbene
a
The reactions were conducted on a 0.35−1.0 mmol scale; for
experimental details, see the Supporting Information. Unless
b
otherwise noted, isolated yields are given. The yield was calculated
a
The yield and product ratio were determined by 19F NMR
according to the 19F NMR spectroscopy analysis of the isolated crude
product. An analytically pure sample was obtained through HPLC
separation.
spectroscopy with benzotrifluoride as the internal standard.
for two reasons. (1) It is readily available, and (2) it can
generate difluorocarbene and react with aromatic thiols under
non-aqueous conditions,11 thus minimizing the competitive
protonation of the arylthiodifluoromethyl anion intermediate.
To our delight, when 1g was treated with 2.0 equiv of SCDA in
the presence of 2.0 equiv of K2CO3 as the base in DMF at 100
°C, the reaction proceeded smoothly to provide the desired
product 2g in 68% 19F NMR yield. Meanwhile, difluoromethyl
compounds 2g′ and 2g″ were formed as side products. When 4
Å molecular sieves (MS) were used as an additive, the yield of
ketones with various substitution patterns. Both alkyl and aryl
substituents led to the formation of the expected cyclization
products 2a−2l in 62−89% yields. It is noteworthy that the
alkyl-substituted ketones took part in the reaction to afford the
products (2a−2f) in yields that were significantly higher than
those of the aryl-substituted ketones (products 2g−2l) due to
the decreased steric hindrance. In the cases of aryl-substituted
ketones, the electronic nature of the aryl substituents had little
influence on the yields of the desired products 2g−2l. The
B
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electron-rich and electron-deficient aryl-substituted ketones
underwent the reaction to afford the products in similar yields.
A variety of substituents on the pyridyl ring of the substrates,
such as methyl, chloro, phenyl, and naphthyl, were also
tolerated and produced the corresponding cyclization products
2m−2r in similar yields (63−75%). In addition to the pyridyl
ring, the reaction is also amenable to other heteroaromatic
rings such as the quinolinyl ring. For example, the reaction of
(2-mercaptoquinolin-3-yl)(phenyl)methanone (1s) gave the
desired product 2s in 66% yield. The cyclization reaction was
also examined using aryl- and alkyl-substituted 2-mercapto-
phenyl ketones, which proceeded smoothly to furnish benzo-
fused 2,2-difluoro-2,3-dihydrothiophen-3-ols 2t−2v in 72−
84% yields.
Scheme 5. Further Transformation of 2
Furthermore, other functional groups such as cyano and
ester functionalities could also serve as acceptors of the in situ-
−
formed ArSCF2 (Scheme 4). Thus, treatment of 2-
Scheme 4. Cyclization Reaction of 2-
Mercaptonicotinonitrile and 2-Mercaptobenzoate with
Difluorocarbene
a plausible reaction mechanism for a reaction in which sulfur
participates was proposed (Scheme 6). Deprotonation of 1
Scheme 6. Proposed Reaction Mechanism
mercaptonicotinonitrile 3a with SCDA and K2CO3 at 100
°C delivered the pyridine-fused 2,2-difluorothiophen-3(2H)-
imine 4a in 43% isolated yield. The difluorinated cyclic imines
could be transformed into the corresponding cyclic ketones
under acidic hydrolysis. The one-pot reaction of 2-
mercaptonicotinonitrile 3a and 3b with SCDA followed by
hydrolysis with concentrated hydrochloric acid gave 5a and 5b
in 56% and 53% yields, respectively. When 2-mercaptoben-
zoate 6 was subjected to the reaction with SCDA, the
employment of NaH instead of K2CO3 was required to
promote the cyclization reaction, providing benzo-fused
difluorinated cyclic ketone 7 in 53% yield.
Finally, to demonstrate the synthetic utility of the obtained
cyclization products, we explored the transformation of
products 2 (Scheme 5). Oxidation of cyclic sulfide 2c with
NaIO4 at room temperature generated the desired cyclic
sulfone 8 in 60% yield. It is worth mentioning that the
difluorinated five-membered cyclic sulfone scaffold in 8 has
found application in the design of specific HIF-2α inhibitors.5
In addition, selective O-methylation of 2g with CH3I followed
by oxidation produced the corresponding sulfone product 9 in
81% yield. The structure of 9 has been unambiguously
confirmed by single-crystal X-ray analysis.
with K2CO3 would generate thiolate nucleophile 10, and the
latter would react with difluorocarbene to generate difluori-
nated carbanion 11. The fate of 11 is determined by the type
of proton source. When K2CO3 is used as the base under
anhydrous conditions, KHCO3 would serve as a proton source,
and the intramolecular cyclization of carbanion 11 followed by
protonation by KHCO3 (path a) would proceed much faster
than the direct protonation of carbanion 11 by KHCO3 (path
b). Thus, the formation of the desired cyclization product
would predominate. When K2CO3 was used in the presence of
water, water quenched carbanion 11 preferentially to give the
S-CF2H product (path b).
In conclusion, we report a new entry of tandem cyclization
reactions of o-acyl-, aroyl-, alkoxycarbonyl-, and cyano-
substituted (hetero)aromatic thiols with difluorocarbene
derived from sodium chlorodifluoroacetate.12 The reaction
proceeds via the trapping of difluorocarbene by the thiolate
anion followed by intramolecular addition. This method allows
the synthesis of a series of novel (hetero)arene-fused 2,2-
difluoro-2,3-dihydrothiophene derivatives, which promises to
On the basis of our experimental results and in combination
with a previous report on S-difluoromethylation with SCDA,11
C
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find applications in drug design and agrochemical develop-
ment.
ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (2016YFB0101200), the
National Natural Science Foundation of China (21632009
and 21421002), the Key Programs of the Chinese Academy of
Sciences (KGZD-EW-T08), the Key Research Program of
Frontier Sciences of CAS (QYZDJ-SSW-SLH049), and the
Shanghai Science and Technology Program (18JC1410601).
H.L. thanks Jie Sun (SIOC) for assistance with the X-ray
crystallographic analysis.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02688.
Detailed experimental procedures, characterization data,
1
and copies of H, 19F, and 13C NMR spectra of new
compounds (PDF)
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Jinbo Hu − Key Laboratory of Organofluorine Chemistry, Center
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Chuanfa Ni − Key Laboratory of Organofluorine Chemistry,
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of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032,
China; Email: nichuanfa@sioc.ac.cn
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Authors
Huamin Liang − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032,
China; School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
Ran Liu − Key Laboratory of Organofluorine Chemistry, Center
for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, Shanghai 200032, China
Min Zhou − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Yue Fu − Key Laboratory of Organofluorine Chemistry, Center
for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, Shanghai 200032, China
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Complete contact information is available at:
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Notes
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E
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