Copper-catalyzed olefinic C-H difluoroacetylation of enamides

Article abstract of DOI:10.1039/c4cc01994f

Copper-catalyzed olefinic difluoroacetylation of enamides via direct C-H bond functionalization using BrCF₂CO₂Et is reported for the first time. It constitutes an efficient radical-free method for the regioselective synthesis of β-di

Full text of DOI:10.1039/c4cc01994f

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Copper-catalyzed olefinic C–H
difluoroacetylation of enamides†
Cite this: Chem. Commun., 2014,
50, 5887
Gilles Caillot,a Jeremy Dufour,a Marie-Charlotte Belhomme,b Thomas Poisson,b
´ ´
Laurence Grimaud,c Xavier Pannecoucke*b and Isabelle Gillaizeau*a
Received 17th March 2014,
Accepted 10th April 2014
DOI: 10.1039/c4cc01994f
www.rsc.org/chemcomm
Copper-catalyzed olefinic difluoroacetylation of enamides via direct
C–H bond functionalization using BrCF2CO2Et is reported for the
first time. It constitutes an efficient radical-free method for the
regioselective synthesis of b-difluoroester substituted enamides
which exhibits broad substrate scope, and thus demonstrates its
potent application in a late stage fluorination strategy.
Scheme 1 Present work.
Organofluorine chemistry is a rapidly expanding field. The ubiquity the copper-catalyzed direct b-arylation of enamides13 and on the
of fluorinated compounds has been particularly highlighted in dihydropyran series,11b herein, we would like to report the regio-
the fields of pharmaceutical research and agrochemistry.1,2 selective synthesis of b-difluoroester substituted enamides by
Recently, fluorinated compounds and particularly those containing using the commercially available BrCF2CO2Et (Scheme 1).
a fluorinated methyl group (CF3, CF2R) have attracted much
Within this protocol and as an extension of our interest in
attention, spurring research groups to discover new access to alkene functionalization, copper catalysis, which is a field of
fluorine containing molecules.3–7 These remarkable efforts gave tremendous expansion due to its abundance, low cost and low
birth to efficient and selective methods towards the introduction toxicity, was adopted to perform carbon–carbon bond formation.
of CF3 and CF2R groups particularly by means of direct C–H Moreover, enamides have been widely used as valuable building
bond functionalization which recently became one of the most blocks to introduce nitrogen based functionalities into various
attractive research fields in organic synthesis.8–10 Rather surprisingly, aromatic or non-aromatic heterocycles.14 In the present case, the
less attention has been paid to the direct introduction of pre- resulting difluoroester substituted enamides are thus of immediate
functionalized fluorinated building blocks (i.e. CF2SO2Ph, CF2CO2Et) relevance for the target-oriented synthesis of derivatives comprising
that can be used in further transformations.11 The CF2CO2Et moiety a fluorinated heterocyclic subunit. To the best of our knowledge,
appeared notably as an interesting manifold to access a wide range the Cu-catalyzed olefinic difluoroacetylation of non-aromatic
of fluorinated substituents. Noteworthily, its introduction mainly enamides via direct C–H bond functionalization is unprecedented
focused on the use of radical processes or transition metal and would constitute a powerful, selective and atom-economic
catalyzed cross-coupling reactions between a halo-derivative and strategy to reach the fluorinated p-electron-rich olefin, which is
an organometallic partner.12 Stimulated by our recent findings on still in great demand.
At the outset of our study, the reaction condition was
optimized using six-membered cyclic enamide 1a as a model
substrate. Standard screening of solvents, catalysts, temperature,
a Institut de Chimie Organique et Analytique, UMR 7311 CNRS,
´
´
´
and the ratio of reagents established that the optimized conditions15
were Cu2O (10 mol%) and 1,10-phenanthroline (12 mol%) as a
ligand in the presence of BrCF2CO2Et (2 equiv.), K2CO3 (2 equiv.) in
CH3CN at 80 1C (Table 1). Accordingly, we were pleased to isolate 2a
in 91% yield along with a complete b-regioselectivity (entry 1).
Modification of the BrCF2CO2Et stoichiometry did not provide
further improvements and the reaction was ineffective in the
presence of 1 equiv. of BrCF2CO2Et (entries 2 and 3). A catalyst
screening showed that Cu(OTf)2, CuI, Cu[MeCN]4ꢀPF6 were less
Universite d’Orleans, rue de Chartres, 45067 Orleans cedex 2, France.
E-mail: isabelle.gillaizeau@univ-orleans.fr
b Normandie Univ, COBRA, UMR 6014 and FR 3038, Univ Rouen, INSA Rouen,
`
CNRS, IRCOF, 1 rue Tesniere, 76821 Mont Saint-Aignan Cedex, France.
E-mail: xavier.pannecoucke@insa-rouen.fr
c
´
´
Ecole Normale Superieure-PSL Research University, Departement de Chimie,
´
Sorbonne Universites - UPMC Univ Paris 06, CNRS UMR 8640 PASTEUR,
24, rue Lhomond, 75005 Paris, France
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra of products. See
DOI: 10.1039/c4cc01994f
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Table 1 Optimization of the copper-catalyzed difluoroacetylation of
enamide 1aa
Table 2 Scope of the Cu-catalyzed difluoroacetylation reaction by varying
enamides 1
Entry Catalyst
Ligand
Base
Yieldb (%)
1
Cu2O
Cu2O
Cu2O
Cu(OTf)2
CuI
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3 88
Et3N
dtbpy
91
88
Traces
25
26
2c
3d
4
5
6
7
Cu[MeCN]4ꢀPF6 1,10-Phenanthroline
24
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
—
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
8c
9c
10
11
12
13
14c
15
Traces
0
38
Traces
41
0
0
Bathophenanthroline K2CO3
Neocuproine
K2CO3
K2CO3
K2CO3
—
2,20-Bipyridine
1,10-Phenanthroline
1,10-Phenanthroline
—
Cu2O
Cu2O
K2CO3
0
a
Reaction conditions unless otherwise specified: BrCF2CO2Et (2 equiv.),
copper catalyst (10 mol%), ligand (12 mol%), base (2 equiv.), CH3CN,
b
80 1C, 6 h. Isolated yield after purification by flash chromatography.
c
d
4 equiv. of BrCF2CO2Et were used. 1 equiv. of BrCF2CO2Et was used.
dtbpy = 4,40-di-tert-butyl-2,20-bipyridine.
a
With 4 equiv. of BrCF2CO2Et.
active, furnishing the desired product 2a in lower yield (entries 4–6).16
An examination of the nature of the base revealed that K2CO3 gave trifluoromethylpyridone derivative has been reported in the
the best results (entry 7). Organic bases did not allow the formation of literature.22 Furthermore, experiments were also carried out on the
2a (entries 8 and 9). Other ligands, such as bathophenanthroline, valuable acyclic substrates affording the desired b-difluoroester enam-
neocuproine and 2,20-bipyridine, were tested, but no enhance- ides 2n–r with complete regio- and stereoselectivity, as only one
ment of the reaction yield was measured (entries 10–12). It is diastereoisomer (E or Z) could be detected.21,23 Evans oxazolidinone
worth mentioning that no reaction occurred in the absence of a was also a suitable substrate; 2o was isolated in 56% isolated yield.24
copper catalyst, base or a ligand (entries 13–15).
Importantly, acyclic b-difluoroester enamides were readily available
Having established the reaction conditions, a wide range of cyclic via Cu-catalyzed C–H functionalization, setting up the possibility of
and acyclic enamides 1 were examined, as depicted in Table 2. The developing new unprecedented access to either non-natural fluorine
scope, site selectivity, and functional group tolerance are notable containing amino acids or fluorinated heterocycles.25 Our method
aspects of this original methodology. We were delighted to note that also proved applicable to aromatic enamides such as indole 1s. The
all transformations worked well and afforded the corres- corresponding a-fluorinated derivative 2s was isolated albeit with low
ponding b-difluoroester substituted enamides 2 with complete yield.26 The a-selectivity is a result of the higher acidity of the hydrogen
regioselectivity. Modifications concerning both the protecting at the C-1 position (cf. Scheme 3) and extends the scope of our
group on the nitrogen atom and the size of the heterocycle were reaction beyond existing other methods.27
envisaged. While enecarbamate 1a, 1d and enamide 1b gave
Then, in order to showcase the versatility of these difluoroester
very satisfying results, sulfonamide 1c proved not to be acti- enamides 2, further transformations were carried out (Scheme 2).
vated enough to react. The desired fluorinated endo-enamides First, aminolysis of enamide 2e worked smoothly which generated
2e and 2f17 were isolated, respectively, in good and low yields. the corresponding fluorinated amide 3 with an excellent 93%
Furthermore, the reaction turned out to be compatible with a yield. Hydrogenation of 2e at room temperature and atmospheric
variety of functional groups, which were amenable to further pressure afforded the difluoroacetylated lactam 4 in 62% yield.
useful transformations (2g, 2h, 2i). Uracil and uridine deriva-
tives, giving, respectively, 2j18 and 2k, were also proved to be
applicable in this reaction. This result points out the functional
group tolerance of our process and its potent application in a
late stage fluorination strategy.19 Expectedly, when a thymine
derivative20 was used as a substrate, no coupling product was
obtained, ruling out the possibility of a coupling at the a-position.
Notably, the vinylogous b-difluoroester pyridones 2l and 2m were
isolated in good yields.21 It is worth noting that to date only the
Scheme 2 Transformations from fluorinated enamide 2e or 2m.
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Fig. 1 CV performed in CH3CN containing nBu4NBF4 (0.3 M) at
a
steady glassy disk electrode (d = 1 mm), at a scan rate of 0.5 V sꢁ1, at
20 1C. (a) Oxidation of the enamide 1a (2 mM) (in black); (b) oxidation of the
enamide 1a in the presence of CuI(phen)S3 (1 equiv.) (in blue).
+
Scheme 3 Plausible reaction mechanism.
involving a complexation of the nucleophile to Cu(I) prior to
deprotonation (Scheme 3).32
It should be noted that, under the conditions used, only the double
bond of the enamide was reduced, while the benzyl group was not
removed and no fluorine abstraction occurred. Noteworthily, this
reduction gave unique access to b-CF2CO2Et-piperidones, which are
key scaffolds in the quest for new pharmaceuticals.22 Finally,
hydrolysis of the ester function of 2m under basic conditions led
to the corresponding carboxylic acid 5 with good yield.
In an effort to understand the mechanism of the reaction,
we initiated an investigation in the presence of a catalytic
amount (20 mol%) of radical inhibitors or scavengers: TEMPO,
benzoquinone and TBHT. In all cases, no inhibition of the
coupling reaction was observed. Although the reaction required
a longer reaction time, the fluorinated product was formed in
similar yield when one equivalent of TEMPO was added to the
reaction mixture. These observations prompted us to do not
consider a radical mechanism as a plausible pathway for this
transformation.
In summary, we have developed a mild, simple and efficient
Cu-catalyzed radical free synthesis of the b-difluoroester substituted
enamide. This original transformation is completely regioselective
and exhibits broad substrate scope, good functional group tolerance
and thus demonstrates its potent application in a late stage
fluorination strategy. Beyond this elegant method, the resulting
original difluoroester enamides could be versatile building
blocks for the synthesis of various N-containing aromatic or
non-aromatic heterocycles. Moreover, mechanistic studies were
carried out to elucidate the reaction pathway. Cyclic voltammetry
along with MS-ESI experiments led us to propose a Cu(I)/Cu(III)
catalytic cycle. Further investigations of the mechanism, scope
and applications of this method are underway.
´
´
This work has been partially supported by Universite d’Orleans,
´
INSA de Rouen, Universite de Rouen, CNRS, and LABEX SynOrg
(ANR-11-LABX-0029). G.C. thanks LABEX SynOrg for a postdoctoral
fellowship. M.-C.B. thanks the MESR for a doctoral fellowship. The
authors thank A. Jutand for fruitful discussions.
Then, to gain further insight into the reaction mechanism,
studies were undertaken via electrochemical techniques. Cyclic
voltammetry (CV) was performed with the tꢁetrakisacetonitrile
copper(I) hexafluorophosphate CuIS4 PF6 as the copper
+
+ 28
source to analyze a homogeneous mixture. CuI(phen)S3 ,
Notes and references
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(S), did not react with the BrCF2CO2Et.29 However, the CV of the
enamide, characterized by its oxidation peak at +1.42 V (O1),
evolved after addition of CuI(phen)S3+ (1 equiv.) and a pre-wave
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´
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30
appeared at O2 before O1 (Fig. 1). This pre-wave indicates that a
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the free enamide. The plateau shape of the new wave typically
characterizes a CE mechanism, in which the equilibrium is shifted
+
in the diffusion layer by the first oxidation of CuI(phen)(enamide)S2
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+
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´
´
˜
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+
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.
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`
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5890 | Chem. Commun., 2014, 50, 5887--5890
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