Copper-catalyzed direct C-H fluoroalkenylation of heteroarenes

Article abstract of DOI:10.1039/c5ob02213d

Copper-catalyzed direct C-H fluoroalkenylation of heterocycles using various gem-bromofluoroalkenes as electrophiles is reported. This efficient method offers step-economical, low-cost and stereocontrolled access to relevant heteroarylated monofluoroalkenes. The synthesis of fluorinated analogues of biomolecules and therapeutic agents for the treatment of Duchenne muscular dystrophy as application is reported.

Full text of DOI:10.1039/c5ob02213d

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Copper-catalyzed direct C–H fluoroalkenylation
of heteroarenes†
Cite this: DOI: 10.1039/c5ob02213d
Kevin Rousée, Cédric Schneider, Jean-Philippe Bouillon, Vincent Levacher,
Christophe Hoarau,* Samuel Couve-Bonnaire* and Xavier Pannecoucke
Received 26th October 2015,
Accepted 13th November 2015
Copper-catalyzed direct C–H fluoroalkenylation of heterocycles using various gem-bromofluoroalkenes as
electrophiles is reported. This efficient method offers step-economical, low-cost and stereocontrolled access
to relevant heteroarylated monofluoroalkenes. The synthesis of fluorinated analogues of biomolecules and
therapeutic agents for the treatment of Duchenne muscular dystrophy as application is reported.
DOI: 10.1039/c5ob02213d
www.rsc.org/obc
logenoalkenes. Indeed, the latter have been used only for
copper-catalyzed C–H alkynylation of heterocycles, the non-
Introduction
The importance of fluorinated compounds in agrochemicals,1,2 coupled second halogen being eliminated during the catalytic
pharmaceuticals/medicinals,1,3 and materials science1,4 has trig- process (Fig. 1, eqn (3)).19 Recently, Cao has described an
gered an explosion of research efforts in developing new and elegant metal-free base mediated nucleophilic vinylic substi-
efficient methods to introduce a fluorinated functional group tution reaction between tetrasubstituted gem-difluoroalkenes
into organic molecules. Of particular relevance is the emergence and azoles (Fig. 1, eqn (4)).20a In this case, only tetrasubsti-
of fluoroalkenes,5 versatile compounds that have found many tuted gem-difluoroalkenes can be used as substrates, and the
applications as, for example, peptidomimetics,6 drugs7 and trisubstituted ones would directly lead to the dehydrofluorina-
materials.8 In peptide synthesis and fine organic chemistry, tion process. This year, Loh have successfully engaged
fluoroalkenes are widely looked upon as stable isosteric and iso-
electronic mimics of the amide bond,6 and bioisosteres in the
structure/activity relationship studies.
Within the readily available fluorinated building blocks for
the construction of fluoroolefins, gem-bromofluoroalkenes are
easily accessible9 and versatile reagents for the achievement of
highly useful cross-coupling reactions.10 The development of
catalytic direct C–H bond functionalization methodologies
using transition metals as catalysts has received considerable
attention avoiding thus the preparation of organometallic
intermediates as coupling partners.11 For a realistic catalyst
loading of these precious metals, less expensive transition
elements such as copper have received significant attention.
Indeed, since the breakthroughs made by Daugulis,12 Miura13
and Piguel,14 remarkable advances have been made in copper-
catalyzed direct arylation,15 alkynylation16 and alkenyla-
tion17,18 of azoles from monohalogenoalkenes (Fig. 1, eqn (1)
and (2)). However, no example of copper-catalyzed direct C–H
halogenoalkenylation so far has been reported from gem-diha-
Normandie Univ, COBRA, UMR 6014 & FR 3038, Univ Rouen, INSA Rouen, CNRS,
IRCOF, 1 rue Tesnière 76821, Mont-Saint-Aignan Cedex, France.
E-mail: samuel.couve-bonnaire@insa-rouen.fr, christophe.hoarau@insa-rouen.fr
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, optimization tables, characterization data and NMR spectra of new
compounds. See DOI: 10.1039/c5ob02213d
Fig. 1 Direct functionalization of ubiquitous C–H bonds using halo-
genoaryls/alkenes and gem-dihalogenoalkenes.
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Table 1 Optimization of the fluoroalkenylation reactiona
gem-difluoroalkenes in an innovative Rh(III)-catalyzed ortho-
directed C–H activation, migratory insertion into the double
bond and a defluorination sequence to produce fluoroalkeny-
lated (hetero)aromatics.20b Our group has previously reported
the first Pd-catalyzed direct C–H halogenoalkenylation of het-
erocycles demonstrating that gem-bromofluoroalkenes are suit-
able building blocks for this transformation (Fig. 1, eqn (5)).21
During this study, a combination of copper salt with a palla-
dium catalyst led to a cooperative Pd(0)/Cu(I) catalysis which
was found highly performant to achieve the direct C–H alkeny-
lation of a broad range of 1,3-diazoles with any gem-bromo-
fluoroalkenes as electrophiles. This efficiency was based upon
the catalytic generation of an heteroaryl copper intermediate
reacting as a transmetallating agent.22 In our ongoing project
devoted to the production of fluorinated biomolecule ana-
logues, we have recently turned our attention to the evaluation
of the reactivity of the heteroaryl copper intermediate towards
gem-bromofluoroalkenes in view of developing a novel palla-
dium free copper-catalyzed direct C–H fluoroalkenylation of
heterocycles offering step-economical, low-cost and stereocon-
trolled access to heteroarylated monofluoroalkenes (Fig. 1, eqn
(6)). Moreover, taking into account that the direct fluoroalkeny-
lation is very scarce in the literature, it could represent an
efficient alternative to produce fluorinated fine chemicals. We
reported herein this methodology giving access to a wide
variety of trisubstituted monofluoroalkene5,23 derivatives
including fluorinated analogues of therapeutic agents.
Entry
[Cu]
Ligand
Base
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
CuBr
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
—
CuBr
CuCl2
Cu(OTf)2
—
—
—
Phen
Phen
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
K2CO3
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
75
63
65
51
—
51
81
83
51
96
—
66
73
65
d
L1 e
L2
PPh3
PCy3·HBF4
dppe
dppe
dppe
dppe
dppe
a All reactions were performed using 1A (1.1 equiv.), 2a (0.2 mmol,
1.0 equiv.), copper source (10 mol%), ligand (20 mol%), and base
(3 equiv.) in 1,4-dioxane (0.25 M) at 110 °C. b Yield based on the
isolated product after flash chromatography. c In the presence of
PdCl2(PPh3)2 (5 mol%). d L1 = 3,4,7,8-(Me)4-1,10-Phen. e L2 = trans-N,N′-
dimethylcyclohexane-1,2-diamine.
Under these optimized reaction conditions, the hetero-
arylated fluoroalkene 3Aa was produced in 96% isolated yield
as a pure (Z)-isomer, demonstrating that the reaction proceeds
with complete retention of the stereochemistry.
With the optimized conditions in hand, the establishment
of the scope of the direct C–H fluoroalkenylation was under-
taken on 5-phenyloxazole (2a) with various readily accessible
(E)-gem-bromofluoroalkenes9 (Table 2). The latter flanked
indifferently with electron-donating or electron-withdrawing
groups on the aromatic unit at the ortho, meta and para posi-
tions, reacted at the C-2 position of the 5-phenyloxazole produ-
cing the desired product in moderate to excellent yields.
Interestingly, (E)-gem-bromofluoroalkenes bearing the
cyano group (1D) or the chlorine atom (1F) on the aromatic
ring, both valuable functional groups for further post-functio-
nalizations, displayed good reactivity, even if, in the case of
3Da, the reaction yield was lower than that obtained under Pd/
Cu catalysis.21
Alkylated or tetrasubstituted gem-bromofluoroalkenes
proved to be unreactive under Cu-catalysis whereas the reac-
tion occurred under Pd/Cu catalysis.21,25 The aromatic ring
bearing an electron-withdrawing group at the ortho position
proved to be unstable under these reaction conditions.25
We next examined the substrate scope of various aryl-
oxazoles (2b–e) with a panel of gem-bromofluoroalkenes in this
transformation (Table 3). The reaction was efficient whatever
the electronic nature of the substituents on the benzene ring
of the 5-phenyloxazole 2b–d. It is noteworthy that the use of
Phen instead of dppe as a ligand with 4-phenyloxazole 2e as
the substrate was crucial to obtain trisubstituted Z-fluoro-
alkenes 3Ae, 3Ce and 3Ee in good yields.25
Results and discussion
We initiated our investigation by probing various reaction con-
ditions for the direct C–H fluoroalkenylation of 5-phenyl-
oxazole (2a) with easily accessible (E)-gem-bromofluoroalkene9
1A (Table 1). Indeed, whereas a set of experiments with our
model substrate, phenyloxadiazole, under an optimized pre-
viously reported procedure was found unsuccessful without
the palladium catalyst,24 2a proved to be a suitable substrate
for direct fluoroalkenylation without a palladium source, pro-
viding 3Aa in 63% yield compared to 75% yield under bi-
metallic Pd/Cu catalysis (entries 1 and 2). Switching the nature
of the copper source for CuI led to a slight enhancement of
the yield (entry 3). Among the bases, t-BuOLi proved to be the
most effective without formation of the alkynylated side-
product via a dehydrofluorination process (entries 4 and 5).
Subsequently, common ligands of copper have been screened,
such as Phen and derivatives, diamine ligands or mono- and
bidendate phosphines (entries 4–10), and surprisingly, dppe
revealed considerable efficiency affording the desired product
in almost quantitative yield (entry 10). Crucially, formation of
3Aa was not observed when copper was omitted from the reac-
tion mixture (entry 11). We then performed the reaction with
different copper sources (entries 12–14). The best performance
of the reaction was thus attained by using CuI as the catalyst;
however, we observed that the monofluoroalkenylation was
slightly insensitive to the copper source (Cu(I) or Cu(II)).
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Table 2 Copper-catalyzed C–H fluoroalkenylation of 5-phenyloxazole
with various gem-bromofluoroalkenesa
Table 4 Extension of the reaction to various heterocyclesa
a All reactions were performed using 1 (1.1 equiv.), 2a (0.2 mmol,
1.0 equiv.), CuI (10 mol%), dppe (20 mol%), t-BuOLi (3 equiv.) in
1,4-dioxane (0.25 M) at 110 °C. Yields are based on the isolated
product after flash chromatography. b Yield obtained under bimetallic
Pd/Cu catalysis.
a All reactions were performed using
1 (1.1 equiv.), heterocycle
(0.2 mmol, 1.0 equiv.), CuI (10 mol%), ligand (20 mol%), and t-BuOLi
(3 equiv.) in 1,4-dioxane (0.25 M) at 110 °C. Yields are based on the
isolated product after flash chromatography. b Yield obtained under
bimetallic Pd/Cu catalysis. c Reaction performed at 130 °C. d Reaction
performed on a 1 mmol scale. e L2 = trans-N,N′-dimethylcyclohexane-
1,2-diamine. f Reaction performed at 90 °C. g CuI (20 mol%) and Phen
(40 mol%) were used.
Table 3 Copper-catalyzed C–H fluoroalkenylation of various aryloxazolesa
coupling partners was addressed. Through the expected mono-
fluoroalkenes, 4Aa was obtained in good (82%) yield whereas
the chlorinated benzoxazolylfluoroalkene 4Fa was produced in
poor (20%) yield (19F NMR yield). Nevertheless, when the
temperature was increased from 110 to 130 °C, full completion
of benzoxazole 4a was attained to provide product 4Fa in
74% yield. The reaction performed with chlorinated benzoxa-
zole 4b at the same 130 °C temperature delivered the expected
benzoxazolylfluoroalkene 4Ab in good (70%) yield and impor-
tantly, the reaction could be scaled up from 0.2 mmol to 1 mmol
without any loss of efficiency.
We then examined the selective C–H monofluoroalkenyla-
tion with N-methyl-benzimidazole 5 as a heterocycle under our
optimized conditions and, unfortunately no desired product
was obtained. A careful screening of bases, solvents and
ligands at different reaction temperatures25 led to select trans-
N,N′-dimethylcyclohexane-1,2-diamine as a ligand and a reac-
tion temperature of 130 °C to produce fluoroalkenes 5A and
5H in optimized 54 and 55% yields, respectively.
a All reactions were performed using 1 (1.1 equiv.), 2 (0.2 mmol,
1.0 equiv.), CuI (10 mol%), dppe (20 mol%), and t-BuOLi (3 equiv.) in
1,4-dioxane (0.25 M) at 110 °C. Yields are based on the isolated
product after flash chromatography. b Phen (20 mol%) has been used
as a ligand instead of dppe.
Finally, the reaction was investigated in a thiazole series.
In this case, the phenanthroline ligand was found highly per-
We then applied our reaction conditions to various relevant formant to achieve the cross-coupling at 110 °C of para-, ortho-
1,3-diazoles (Table 4). A first set of experiments engaging benz- or disubstituted gem-bromofluoroalkenes 1A, 1G and 1H
oxazole 4a with the (E)-gem-bromofluoroalkenes 1A and 1F, as with benzothiazole 6 and 4,5-dimethythiazole 7 giving the
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fair to excellent yields. It was finally applied to the synthesis of
valuable benzoxazolylfluoroalkenes 4Ba, a fluorinated ana-
logue of an antiasthmatic agent, and 4Bc which is potentially
active in the treatment of Duchenne muscular dystrophy.
Acknowledgements
Scheme 1 Synthesis of fluorinated therapeutic agents. a Yields based
on the isolated product after flash chromatography.
This work has been partially supported by INSA Rouen, Rouen
University, CNRS EFRD, Labex SynOrg (ANR-11-LABX-0029).
Notes and references
fluoroalkenes in fair 54% to excellent 91% yields. However, the
reaction performed with the trifluoromethylated (E)-gem-
bromofluoroalkenes 1E provided the desired product 6E in poor
20% isolated yield mainly due to the degradation of the coup-
ling partner 1E. Fortunately, the yield was significantly
improved to 41% when operating at lower temperature, 90 °C.
It has to be noted that the yields obtained for 4Aa and 6A
under these experimental conditions were better than the
yields obtained under bimetallic catalysis.21
Finally, we applied this copper-catalyzed fluoroalkenylation
to the synthesis of relevant biomolecules as depicted in
Scheme 1. Taking into account the similarities between the
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fluoroalkene 1B (Scheme 1). Interestingly, a library of com-
pounds may be readily produced for further SAR study
introducing various substituents on both aromatic rings
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In summary, an efficient Cu(I)/t-BuOLi catalyst has been
employed for direct C–H fluoroalkenylation of 1,3-diazoles
with readily available gem-bromofluoroalkenes as coupling
partners. Although phenyloxadiazole remained unreactive as
well as the use of alkylated gem-bromofluoroalkenes as electro-
philes were unsuitable under these experimental conditions
compared to the bimetallic Pd/Cu catalysis, the palladium free
copper catalyzed fluoroalkenylation proved to be very efficient
with gem-bromofluorostyrenes. Remarkably, a broad scope of
1,3-diazoles was accomplished modulating the nature of the
ligand. Notably, the (benzo)oxazole, (benzo)thiazole and benz-
imidazole series were successfully coupled with various gem-
bromofluoroalkenes using diarylphosphine, phenanthroline
and diamine ligands. The methodology gave access to innova-
tive and valuable heteroarylated fluoroalkenes 3–7 produced in
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