Palladium-catalyzed C-H ethoxycarbonyldifluoromethylation of electron-rich heteroarenes

Article abstract of DOI:10.1021/acs.orglett.5b01024

The first Pd-catalyzed C-H ethoxycarbonyldifluoromethylation with BrCF₂CO₂Et has been developed. The use of a bidentate phosphine ligand (Xantphos) is critical for the reaction to occur. A variety of electron-rich heteroarenes, including indoles, furans, thiophenes, and pyrroles, can be ethoxycarbonyldifluoromethylated in moderate to excellent yields. The reactions take place at the C-H bonds adjacent to the heteroatoms with high regioselectivity. This method provides a new protocol for the introduction of difuoroalkyl groups into electron-rich heteroarenes.

Full text of DOI:10.1021/acs.orglett.5b01024

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C−H Ethoxycarbonyldifluoromethylation of
Electron-Rich Heteroarenes
Changdong Shao,† Guangfa Shi,† Yanghui Zhang,*,† Shulei Pan,† and Xiaohong Guan‡
†Shanghai Key Laboratory of Chemical Assessment and Sustainability, Department of Chemistry, and UNEP-Tongji Institute of
Environment for Sustainable Development, Tongji University, 1239 Siping Road, Shanghai 200092, P. R. China
‡College of Environmental Science and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, P. R. China
S
* Supporting Information
ABSTRACT: The first Pd-catalyzed C−H ethoxycarbonyldi-
fluoromethylation with BrCF2CO2Et has been developed. The
use of a bidentate phosphine ligand (Xantphos) is critical for
the reaction to occur. A variety of electron-rich heteroarenes,
including indoles, furans, thiophenes, and pyrroles, can be
ethoxycarbonyldifluoromethylated in moderate to excellent yields. The reactions take place at the C−H bonds adjacent to the
heteroatoms with high regioselectivity. This method provides a new protocol for the introduction of difuoroalkyl groups into
electron-rich heteroarenes.
Scheme 1. Direct C−H Ethoxycarbonyldifluoromethylation
Reactions
s fluoroalkyl groups can endow organic molecules with
Anovel and useful physical and biological properties; they
are widely present in functional materials, pharmaceuticals,
agrochemicals, and fine chemicals.1 In particular, the difluoro-
methylene group, a bio-isostere for an ethereal oxygen atom, is
an appealing functionality due to their unique properties.2
While a number of trifluoromethylation reactions have been
developed,3 efficient and general difluoroalkylation methods are
comparatively rare.4 Traditionally, difluoroalkylated molecules
are synthesized via the deoxyfluorination of aldehydes or
ketones with DAST, PPHF, SF4, ClFO3, or XeF2.5 However,
these methodologies generally suffer from harsh conditions,
poor functional group tolerance, and the use of highly toxic
regents. Recently, the direct installation of difluoroalkyl groups
by using reagents containing difluoromethylene groups has
gained great interest.6 In particular, a variety of transition metal-
catalyzed reactions have been developed.7
The CF2CO2Et moiety is extremely appealing because it can
be transformed into a variety of other difluoromethylene-
containing functional groups.8 It is of great importance to
develop efficient methods for incorporating this significant
structural motif into organic molecules. Notably, several
significant methods for the introduction of CF2CO2Et
employing aryl iodides or arylboronic acids have been
developed.9 While these methods rely on the use of
prefunctionalized substrates, a new strategy via direct C−H
functionalization has attracted considerable attention recently,
and some interesting reactions have been reported (Scheme 1).
The current C−H ethoxycarbonyldifluoromethylation reactions
can be classified into three categories according to the methods
of generation of CF2CO2Et species and the mechanism of the
difluoromethylation: (1) radical addition followed by the
dehydrogenation of electron-rich (hetero)arenes with electro-
philic CF2 radicals, which are generated from halogenated or
selenium-based CF2CO2Et reagent;10 (2) copper-catalyzed
direct C−H functionalization of electron-rich olefins involving
Cu(I)/Cu(III) redox cycle process;11 and (3) visible light-
induced C−H difluoromethylation of electron-rich (hetero)-
arenes catalyzed by Ru(II) or Ir(III).12 However, to the best of
Received: April 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01024
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
our knowledge, palladium has not been developed as the
catalyst in this type of reactions. Herein, we present the first
example of Pd-catalyzed introduction of the CF2CO2Et moiety
onto heteroarenes with ethyl 2-bromo-2,2-difluoroacetate
(BrCF2CO2Et) by means of C−H functionalization.
Our initial investigation focused on the reaction of 3-
methylindole 1a with (BrCF2CO2Et) to access the difluor-
oalkylated product 2a (Table 1). When the reaction mixture in
the difluoromethylation reaction efficiently, giving the desired
products in moderate to excellent yields (Figure 1). Notably,
a
Table 1. Optimization of Reaction Conditions.
b
entry
base
solvent
ligand
yield (%)
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
Cs2CO3
KOH
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
THF
-
-
2
PCy3·HBF4
Sphos
12
17
23
67
64
65
11
-
3
4
DPEphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
5
6
7
8
9
-
10
11
12
13
14
15
16
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
56
48
25
24
87
CH3CN
DMSO
DMA
c
c
c
1,4-dioxane
1,4-dioxane
1,4-dioxane
,
,
d
d
e
91(88)
,
f
-
a
Reaction conditions: 3-Methylindole (0.2 mmol, 1.0 equiv),
BrCF2CO2Et (0.4 mmol, 2.0 equiv), Pd(PPh3)4 (0.01 mmol, 5 mol
%), ligand (0.02 mmol, 10 mol %), base (0.4 mmol, 2.0 equiv), solvent
b
1
(2.0 mL), Ar, 110 °C, 1 h. Yields were determined by H NMR
c
Figure 1. Palldium-catalyzed C−H ethoxycarbonyldifluoromethylation
of indoles. (a) Isolated yields of major products. (b) The ratios of
isomers were determined by GC−MS.
analysis of crude product using CH2Br2 as the internal standard. 1,4-
d
e
f
Dioxane 4.0 mL. 2 h. Isolated yield. No Pd(PPh3)4. Sphos = 2-
Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; DPEphos = Bis[(2-
diphenylphosphino)phenyl] ether; Xantphos = 4,5-Bis(diphenylphos-
phino)-9,9-dimethylxanthene.
the reaction took place at C2-position with high selectivity for
the substrates without 3-substituents. A range of functional
groups, such as ester, nitrile, and amide, were well-tolerated. It
is noted that reactive chloro and bromo group survived the
reaction conditions. In general, the reactions of the substrates
bearing a 3-alkyl group were a little higher yielding.
The reactivity of other electron-rich heteroarenes such as
furans, thiophenes, and pyrroles were also examined.
Unsurprisingly, the desired difluoromethylation products were
obtained under the same reaction conditions with moderate to
good yields (Figure 2). The C−H bonds adjacent to the
heteroatoms were functionalized with excellent selectivity for all
of the heteroarenes examined. Both electron-withdrawing and
donating substituents were compatible with the protocol.
Interestingly, difunctionalized product (4d′) was obtained in
26% yield for 3,4-ethylenedioxythiophene (3d) .
In summary, an efficient and convenient method for the
synthesis of ethoxycarbonyldifluoromethylated electron-rich
heteroarenes with BrCF2CO2Et has been developed by means
of C−H functionalization. Palladium is used to catalyze this
type of reaction for the first time, and ligand Xantphos plays a
crucial role in the reaction. Compared to the current C−H
ethoxycarbonyldifluoromethylation reactions, this new trans-
1,4-dioxane was stirred at 110 °C under an argon atmosphere
for 1 h by using Pd(PPh3)4 as the catalyst and K2CO3 as the
base, no desired product was observed (entry 1). Fortunately,
the addition of ligand PCy3·HBF4 gave rise to product 2a in
12% yield (entry 2). Ligand screening revealed that bidentate
phosphine ligand Xantphos was the optimal one and the yield
was improved to 67%. The other bidentate ligand DPEphos
and sterically hindered monodentate phosphine ligand Sphos
(entries 3 and 4) were far less efficient. While bases such as
KOAc, Cs2CO3, and K2CO3 gave similar yields, the reaction
was low yielding in the presence of strong base KOH (entries
6−8). 1,4-Dioxane proved to be the optimal solvent as the
other solvents were less productive (entries 10−13). Gratify-
ingly, the yield was improved significantly just by decreasing the
concentration of the reaction mixture, and it further increased
to 91% in 2 h (entries 14 and 15). Control experiments
demonstrated that no desired product was generated in the
absence of a base or Pd catalyst (entries 9 and 16).
With the optimized reaction conditions in hand, we next
investigated the substrate scope of this new difluoromethylation
protocol. Gratifyingly, various substituted indoles underwent
B
DOI: 10.1021/acs.orglett.5b01024
Org. Lett. XXXX, XXX, XXX−XXX

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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, spectroscopic data of
authentic compounds, and characterization of products. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01024.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhangyanghui@tongji.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by the National Natural Science
Foundation of China (No. 21372176), Tongji University 985
Phase III funds, and the Program for Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions of
Higher Learning.
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