Key words
fluorine - cross-coupling - palladium - copper - radicals
1
Introduction
The difluoromethyl group has received a great deal of attention in medicinal chemistry
because it is isosteric and isopolar with the hydroxyl group and is found in various
biologically active compounds (Figure [1]).[1] Generally, methods for the synthesis of difluoromethylated arenes through deoxyfluorination
of aldehydes or ketones suffer from poor functional-group compatibility and require
the use of expensive and toxic fluorinated reagents.[2] Recent developments in organo- and transition-metal catalysis have allowed new methods
to prepare difluoromethylated arenes.[3] Herein we highlight recent progress in the synthesis of difluoromethylated arenes.
Figure 1 Representative drug and drug candidate containing CF2H functional group
Peng Xu(left) was born in Jiangsu Province, P. R. of China in 1990. He obtained his BSc degree
from Jiangnan University in 2012 and then joined Professor Pingping Tang’s research
group in Nankai University to pursue his PhD degree. His current research interests
focus on fluorine chemistry.
Shuo Guo (middle left) was born in Hebei Province, P. R. of China in 1986. He received his
BSc degree from Hebei Normal University in 2010 and MSc degree from Zhengzhou University
in 2013, under the supervision of Professor Yangjie Wu. Since 2013 he joined Professor
Pingping Tang’s research group in Nankai University to pursue his PhD degree. He is
currently interested in carbon–fluorine bond-formation reactions based on C–H activation.
Liyan Wang (middle right) was born in Shandong Province, P. R. of China in 1990. She obtained
her BSc degree from Shandong University of Science and Technology in 2013 and then
joined Professor Pingping Tang’s research group in Nankai University to pursue her
MSc degree. Her current research interests focus on fluorine chemistry.
Pingping Tang (right) received his BSc degree from Nankai University in 2002. After obtaining his
PhD degree in 2007 working with Professor Biao Yu at Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, he worked as a postdoctoral fellow with Professor
Tobias Ritter at Harvard University (2008–2012). Since 2012, he joined the State Key
Laboratory and Institute of Elemento-Organic Chemistry at Nankai University as a professor.
His research interests include fluorine chemistry and total synthesis of biologically
important small molecules.
Cross-Coupling with Copper
2
Cross-Coupling with Copper
Recently, Amii and co-workers reported a copper-catalyzed cross-coupling and decarboxylation
from aryl iodides to prepare difluoromethylated arenes (Scheme [1, a]).[4] Although cross-coupling with α-silyldifluoroacetates was achieved under mild conditions,
the decarboxylation step is limited to electron-deficient aryl iodides and requires
high temperature (>170 °C). The copper-catalyzed cross-coupling of ethyl ortho-iodobenzoates with bromozinc-difluorophosphonates was reported by Zhang and co-workers.[5] The benzoate ester directing group plays important roles, and the features of this
reaction are the high reaction efficiency, excellent functional-group compatibility,
and operational simplicity. Hartwig and co-workers presented a one-step copper-mediated
cross-coupling between iodoarenes and TMSCF2H (Scheme [1, b]).[6] Although the reaction proceeds in high yields with good functional-group compatibility,
the reaction requires a large excess amount of TMSCF2H (5 equiv) and is limited to electron-rich and electron-neutral iodoarenes. These
problems were addressed successfully by Surya Prakash with n-Bu3SnCF2H as the difluoromethyl pronucleophile (Scheme [1, c]).[7] The disadvantages of the method are that the reaction requires high temperature
and n-Bu3SnCF2H is toxic. Shen and Lu developed a copper-mediated ligandless aerobic fluoroalkylation
of arylboronic acids under mild conditions to prepare difluoromethylated arenes.[8] The reaction tolerates a wide range of functional groups and can be easily scaled
up. Recently, Qing’s group reported a copper-mediated direct difluoromethylation of
electron-deficient aryl iodides using 2.4 equivalents of TMSCF2H at room temperature (Scheme [1, d]).[9] The mild reaction conditions make this method attractive for the synthesis of difluoromethylated
arenes.
Scheme 1 Difluoromethylation of (hetero)aryl iodides with copper
Cross-Coupling with Palladium
3
Cross-Coupling with Palladium
Early this year, Zhang and co-workers described a palladium-catalyzed difluoroallylation
of aryl boronic acid using 3-bromo-3,3-difluoropropene (Scheme [2, a]).[10] The reaction proceeds with low catalyst loading, high regioselectivity, and excellent
functional-group compatibility. At the same time, the authors also reported another
palladium-catalyzed difluoroalkylation of aryl boronic acid with bromodifluoromethylphosphonate,
bromodifluoroacetate, and further derivatives, which provides a facile and useful
access to a series of functionalized difluoromethylated arenes.[11] Qing and co-workers reported a palladium-catalyzed directed α-arylation of α,α-difluoro
ketones with aryl bromides.[12] The method provides an efficient and straightforward access to a variety of difluoromethylated
arenes with broad substrate scope. The disadvantage of the method is that the reaction
required high temperature and high catalyst loading. This problem was addressed successfully
by Hartwig and co-workers with an air- and moisture-stable palladacyclic complex as
a catalyst, a broad range of electronically varied aryl bromides and chlorides was
used to provide difluoromethylated arenes in high yields with low catalyst loading
and lower temperature (Scheme [2, b]).[13]
Scheme 2 Formation of difluoromethylated arenes with palladium
Scheme 3 Formation of difluoromethylated arenes with other metals
Cross-Coupling with Other Metals
4
Cross-Coupling with Other Metals
In 2012, Li and co-workers reported a silver-catalyzed decarboxylative fluorination
of aliphatic carboxylic acids with Selectfluor under mild conditions.[14] Using Li’s method, the transformation of α-fluoroarylacetic acids into difluoromethylated
arenes was achieved by Gouverneur and co-workers (Scheme [3, a]).[15] This method allows for the preparation of [18F]-labeled difluoromethylarenes using [18F]-Selectfluor bistriflate. Inoue and co-workers reported a cobalt-catalyzed cross-coupling
reaction of arylzinc reagents with ethyl bromodifluoroacetate to form difluoromethylated
arenes (Scheme [3, b]).[16] The reaction proceeds under mild conditions and is applicable to various arylzinc
reagents to afford the corresponding ethyl aryldifluoroacetates.
5
C(sp2)–H Activation
Recently, directed ethoxycarbonyldifluoromethylation of aromatic compounds with BrCF2CO2Et was reported using Cp2Fe by Testu Yamakawa and co-workers.[17] Moreover, the one-pot synthesis of 3,3-difluoro-2,3-dihydroindole-2-one derivatives
was achieved with para-substituted aniline derivatives using this method. Baran and co-workers reported
a directed difluoromethylation of C–H bonds in heteroarenes with benchtop-stable Zn(SO2CF2H)2 (Scheme [4, a]).[18] Shortly after, the authors developed other new reagents, such as sodium difluoroethylsulfinate,
for the synthesis of fluorinated heteroarenes.[19] Early this year, Wang and co-workers developed a new method for visible-light photoredox
difluoromethylation of electron-rich heteroarenes under mild conditions (Scheme [4, b]).[20] Mechanistic investigation indicated that the reaction proceeds through an electrophilic
radical-type pathway.
Scheme 4 Formation of difluoromethylated arenes via C(sp2)–H activation
6
C(sp3)–H Activation
In 2013, Chen and co-workers reported a visible-light-promoted metal-free C–H activation
for the synthesis of difluoromethylated arenes (Scheme [5, a]).[21] This is the first report of selective C–H gem-difluorination. Shortly after, we reported a silver-catalyzed oxidative activation
of benzylic C–H bonds to synthesize difluoromethylated arenes (Scheme [5, b]).[22] With AgNO3 as the catalyst, the reaction of a variety of methylated arenes with Selectfluor
and Na2S2O8 in acetonitrile–water (v/v = 1:1) at 80 °C under nitrogen atmosphere led to the formation
of the corresponding difluoromethylated arenes in 42–93% isolated yield.
Some representative examples are shown in Scheme [6]. The mild reaction conditions generally tolerate diverse functional groups on the
aryl rings. Notably, the reaction is amenable to gram-scale synthesis, proving the
practicality of our method. The preliminary mechanism studies indicate that a radical-chain
mechanism or single-electron transfer (SET) may be involved in this transformation.
Scheme 5 Formation of difluoromethylated arenes via C(sp3)–H activation
Scheme 6 Silver-catalyzed benzylic C–H activation for the synthesis of difluoromethylated
arenes by Tang and Xu (representative examples)
7
Conclusion
To summarize, significant advances have been made in the synthesis of difluoromethylated
arenes. Particularly, recent advances have allowed innovative approaches for benzylic
C–H fluorination to prepare difluoromethylatd arenes. However, some challenges still
remain. Such as directed introduction of the difluoromethyl group to arene through
C–H activation is still not efficient. New metal catalysts such as iron are still
required. These challenges are expected to stimulate further development in the synthesis
of difluromethylated arenes.
