Iron-catalyzed trifluoromethylation of enamide

Article abstract of DOI:10.1002/chem.201406333

Herein the first example of the iron(II)-catalyzed trifluoromethylation of enamide using mild and simple reaction conditions is reported. The method is cost-effective and uses the easy-to-handle Togni's reagent as the electrophilic CF₃ source. This transformation is totally regioselective at the C₃ position of enamides and exhibits broad substrate scope, good functional group tolerance and thus demonstrates its useful application in a late-stage fluorination strategy.

Full text of DOI:10.1002/chem.201406333

DOI: 10.1002/chem.201406333
Communication
&
Synthetic Methods
Iron-Catalyzed Trifluoromethylation of Enamide
Romain Rey-Rodriguez,[a] Pascal Retailleau,[b] Pascal Bonnet,[a] and Isabelle Gillaizeau*[a]
Abstract: Herein the first example of the iron(II)-catalyzed
trifluoromethylation of enamide using mild and simple re-
action conditions is reported. The method is cost-effective
and uses the easy-to-handle Togni’s reagent as the elec-
trophilic CF3 source. This transformation is totally regiose-
lective at the C3 position of enamides and exhibits broad
Figure 1. Metal-catalyzed fluorofunctionalization of enamide.
substrate scope, good functional group tolerance and
thus demonstrates its useful application in a late-stage flu-
membered cyclic enamide 1a as a model substrate. Standard
screening of solvents, catalysts, temperature, and ratio of re-
agents established that the optimized conditions were FeCl2
(10 mol%) as a catalyst in the presence of Togni’s reagent 2
(1.2 equiv) in CH2Cl2 at only 358C (Table 1). Accordingly, we
were pleased to isolate enamide 3a in 84% yield along with
a complete b-regioselectivity (entry 1). b-Trifluoromethylated
enamides are polyvalent building blocks for bioactive com-
pounds bearing a trifluoromethyl moiety.
orination strategy.
Among molecular substituents containing fluorinated moieties,
the trifluoromethyl group has unique physical, chemical and
biological properties with many applications in the pharma-
ceutical and agrochemical industries.[1] Consequently, the de-
velopment of a new method to form C(sp3)ÀCF3 bonds has re-
cently attracted great attention. Transition-metal-catalyzed tri-
fluoromethylation reactions of alkenes using electrophilic fluo-
roalkylating reagents have been extensively explored due to
the versatility and large scope of this method.[2,3] The develop-
ment of a reaction for direct trifluoromethylation in late-stage
of synthetic routes is still a great challenge, however. As part
of our ongoing research towards developing a new methodol-
ogy to functionalize CÀH bonds of non-aromatic enamide,[4]
we focused on iron-catalyzed trifluoromethylation reactions
(Figure 1). Iron-catalyzed reactions have recently emerged as
a greener alternative to traditional cross-coupling reactions
and have been intensively studied due to the high abundance,
low cost and low toxicity of iron.[5] While iron salts have al-
ready been identified to perform the trifluoromethylation of
alkene,[6] to our knowledge, the Fe-catalyzed olefinic trifluoro-
methylation of non-aromatic enamide remains undeveloped[7]
and would constitute a powerful, selective and atom-economic
strategy to reach fluorinated aromatic or non-aromatic azahe-
terocycles, which are still highly required.
Table 1. Optimization of the iron-catalyzed trifluoromethylation of 1a.
Entry
Catalyst
CF3 source
Solvent
Yield [%][a]
1
2
3
4[b]
5
6
7
8
9[c]
10[d]
11[e]
12
13
14
15
16
17
18
19
20
21
22[f]
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
none
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl3
ferrocene
Cu(OAc)2
Cu2O
CuCl
2
2
2
2
2
2
2
2
DCM
ACN
84
81
0
11
21
43
29
0
77
58
77
59
0
39
55
58
0
PEG-200
TPGS-750
glycerol
[BMIM][PF6]
NMP
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
2
2
2
CF3SO2Cl
CF3SO2Na
At the outset of our study, it was unclear which catalyst or
reagent would enable the desired sequence of bond-forming
processes. The reaction condition was optimized using six-
2
2
2
2
2
2
2
2
2
32
38
0
65
54
[a] R. Rey-Rodriguez, Prof. P. Bonnet, Prof. I. Gillaizeau
Institut de Chimie Organique et Analytique, UMR 7311 CNRS
Universitꢀ d’Orlꢀans, rue de Chartres, 45067 Orlꢀans Cedex 2 (France)
E-mail: isabelle.gillaizeau@univ-orleans.fr
AlCl3
Sc(OTf)3
SnCl2
FeCl2
DCM
DCM
DCM
[b] P. Retailleau
[a] Isolated yield after purification by flash chromatography; [b] 2 wt% of
TPGS-750M was used; [c] ultrapure FeCl2 (99.998% based on trace metals,
Sigma–Aldrich) was used; [d] 0.9 equiv of Togni’s reagent 2 was used;
[e] reaction conducted at RT; [f] 2 equiv of K2CO3 was used.
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406333.
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Recently, efforts have been made to perform reactions in
greener or more environmentally acceptable media.[8] Due to
their low toxicity and recyclability, polyethylene glycols
(PEGs)[9] or glycerol[10] have been used as green media for vari-
ous transformations including homogenous catalysis. Since
2008, Lipshutz et al. have also demonstrated the viability of
surfactants to promote transition-metal-catalyzed chemistry in
water.[11] They have shown that polyoxyethanyl-a-tocopheryl
succinate (TPGS-750M), a non-ionic amphiphile, allows cross-
coupling reactions to be carried out in water by forming nano-
micellar reactors. Unfortunately, in our case, the process was
ineffective in PEG-200 (entry 3) and led to lower conversion in
TPGS-750M (entry 4). Interestingly, [BMIM][PF6][9] was shown to
be fully suitable for CÀH bond functionalization of enamide
using iron catalysis (entry 6). Glycerol (entry 5) and NMP
(entry 7), which are both polar protic solvents, were less effec-
tive. In addition, no detectable amounts of b-trifluoromethylat-
ed product 3a was observed in the absence of metal catalyst
(entry 8). The use of ultrapure FeCl2 resulted in an equally effi-
cient trifluoromethylation of 1, thus suggesting that the cata-
lyst system is iron based (entry 9). Moreover, yield decreased
by using a lower amount of the CF3 electrophilic source
(entry 10), by performing the reaction at room temperature
(entry 11) or by using ClSO2CF3 or NaSO2CF3 as economic and
stable CF3 sources (entries 12 and 13). Modifying the nature of
the iron source was also unsatisfactory (entries 14 and 15). In
contrast to Loh’s work,[6] copper salts worked as catalyst but
with low to moderate yields (entries 16–18). Considering the
Lewis acid character of FeCl2, we investigated whether product
formation may be achieved by using Lewis acid catalysis
through the direct formation of a cationic intermediate
(Scheme 2, B). To validate this hypothesis, AlCl3 and Sc(OTf)3
were thus tested without any satisfactory yields (entries 19 and
20). However, an interesting result was obtained by using a cat-
alytic amount of SnCl2. It is worth noting that to the best of
our knowledge, this is the first example of tin(II)-catalyzed tri-
fluoromethylation reaction onto C(sp2).[12] As an elimination
step may be involved for the formation of enamide 3a, the ad-
dition of an inorganic base (K2CO3) was studied, however it did
not lead to a significantly improved yield (entry 22). It is note-
worthy that in addition to the benefits of cost and the possible
use of green solvent, the ortho-iodobenzoic acid residue re-
leased during the reaction was easily recycled in a one-pot
procedure for preparing again Togni’s reagent.[13]
2 h. This product results from the nucleophilic addition of the
À
released ArCO2 (Scheme 2).
A lower yield was observed starting with the seven-mem-
bered ring enamides 3g,h. Moreover, the reaction turned out
to be compatible with other functional groups which are ame-
nable to further transformation (enaminone 3i). The vinylogous
pyridinone compound 3j was isolated albeit in moderate yield.
Racemic acetate 3k and chiral diethylester 3l also proved to
be applicable in this reaction. In the case of acyclic enamides
3m–p a clean regio- and diastereoselectivity was observed.
Their E configuration was confirmed by NOE experiments.
Meanwhile, it was found that in the ysatine series, the oxotri-
fluoromethylated adduct 4q was isolated. In this case, we
assume that no elimination step occurred as the electron-
donor property of the nitrogen atom lowers the acidity of 4q.
A similar result was obtained in the benzoxazine series, leading
to the oxotrifluoromethylated adduct 4r isolated as a 3:7 ratio
(cis/trans). As expected, when benzopyridoxazine derivative
was used as a substrate, no coupling product was obtained
(4s), demonstrating the probable complexation of iron with
the pyridyl nitrogen atom. The reaction was also performed
with NH-indole leading to a mixture of CF3-indole derivatives
3t at the C2, C3 or C7 positions. No reaction occurred with the
deactivated N-SO2Ph indole, and unfortunately no chemoselec-
tivity was observed for compound 3v. It is worth noting that
the nature of the solvent can be advantageously modified by
using methanol, as reported in Scheme 1. Compound 5a, iso-
lated with 59% yield as a cis/trans isomer mixture, demon-
strates the ability of a potential iminium ion intermediate to
react with different nucleophiles. No elimination step was ob-
served. Mixed acetals represent an important class of inter-
mediate that can be further functionalized and give access to
diversity.
While the mechanistic details of this iron-catalyzed trifluoro-
methylation of enamide remains still unclear, we propose that
FeCl2 acts first as a single-electron oxidant, triggering this
transformation via a CF3-alkyl radical (A, Scheme 2) and releas-
ing ortho-iodobenzoate.[14] To probe this hypothesis, we initiat-
ed an investigation in the presence of a catalytic amount
(20 mol%) of radical inhibitors or scavengers: TEMPO, benzo-
quinone or TBHT. In all cases, inhibition of the coupling reac-
tion was observed. A complete inhibition occurred in the pres-
ence of TEMPO, and the corresponding TEMPO adduct derived
C
from CF3 or the proposed CF3 alkyl radical A was observed
The scope of the reaction was then extended to a range of
enamides which serve as suitable reaction partners, furnishing
the desired trifluoromethylated compound in moderate to
good yield with a complete b-regioselectivity (Scheme 1). In
view of the better results obtained with dichloromethane as
solvent it was used here, but with the promising results ob-
tained in our preliminary studies (Table 1), different green sol-
vents could also have been employed. The nature of the elec-
tron-withdrawing group onto the nitrogen atom was first in-
vestigated leading to the desired trifluoromethylated enamides
3a–f with high yields. The oxotrifluoromethylated derivative
4a was isolated in 55% yield as a mixture of diastereoisomers
(cis/trans 45:55), when the reaction was conducted for only
which is suggestive of an atom transfer-type radical addition
pathway.[15] Then the iron assists single-electron oxidation of
intermediate A leading to the corresponding cation B and its
resonance cation C. This process allows the regeneration of
the catalyst as initiator. Finally, the nucleophilic attack of the
ortho-iodobenzoate anion proceeds with cation C to generate
the intermediate 4 as a mixture of cis and trans isomers.
The structure of 4a-trans was unambiguously determined
by X-ray analysis (Figure 2).[16] This hypothesis was confirmed
by HRMS analysis and 19F NMR spectroscopy studies which
confirm the formation of the disubstituted compound 4 first,
prior to the enamide formation.[15] We assume that the oxotri-
fluoromethylated product 4 is then deprotonated by ortho-io-
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À
dobenzoate (ArCO2 ) to afford the desired b-CF3-en-
amide 3. It is likely that FeCl2 occurs for the second
time in the reaction as a Lewis acid to promote the
elimination step. In order to gain insight into ener-
getic and structural properties, ab initio calculations
were performed on compound 4a. The optimization
at the DFT level of theory[17] of the four isomer geo-
metries of 4a (mol1 R/R, mol2 S/S, mol3 S/R and
mol4 or 4a-trans R/S) provides some information on
the relative energies compared to the 4a-trans crys-
tal structure (Figure 2). All four isomers have lower
total energy relative to crystal structure, and as at-
tempted, the 4a-cis isomer, formed from cationic in-
termediate (B or C) via a favored chair transition
state, has the lowest energy conformation. Interest-
ingly, during geometry optimization the 4a-cis mole-
cule adopts a conformational change from an initial
axial and equatorial position to an equatorial and
axial for CF3 and ArCO2 substituents, respectively. Im-
portantly, the 4a-cis (mol1) and 4a-trans (mol4) iso-
mers have the lowest total energy compared to
other corresponding isomers such as mol2 (S/S cis)
and mol3 (S/R trans) respectively. This result suggests
a more stable conformation of the 4a-cis (R/R) and
4a-trans (R/S) isomers, which corroborates the pro-
posed reaction mechanism.
For acyclic enamide, the stereochemical outcome
of this reaction may be explained by the steric inter-
action between CF3 and the amido group, thereby
giving the more stable E compound.
In summary, this method is the first example of
iron(II)-catalyzed trifluoromethylation of enamide
using mild and simple reaction conditions. The
method is cost-effective and uses the easy to handle
Togni’s reagent as the electrophilic CF3 source. Of im-
portance, greener reaction conditions can also be
used to achieve this process. This methodology
allows rapid access to a variety of b-trifluoromethylat-
ed useful nitrogen-containing building blocks. We are
Scheme 1. Scope of the Fe-catalyzed trifluoromethylation of enamides 1. [a] Oxotrifluoro-
methylated compound 4 was not isolated unless otherwise specified. [b] Reaction con-
ducted for 2 h only. [c] Reaction conducted in the presence of methanol as solvent.
Scheme 2. Proposed reaction mechanism.
Figure 2. X-ray structure of 4a-trans.
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Acknowledgements
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COSMI. R.R.-R. thanks the MESR for a doctoral fellowship.
Keywords: CÀH functionalization · iron-catalyzed reactions ·
synthetic methods · Togni’s reagent · trifluoromethylation
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[16] CCDC 1026952 (4a-trans) and 1030369 (6) contain the supplementary
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[17] See the Supporting Information for computational details.
Received: December 3, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Synthetic Methods
R. Rey-Rodriguez, P. Retailleau, P. Bonnet,
I. Gillaizeau*
&& – &&
The iron age: The first example of the
FeII-catalyzed trifluoromethylation of en-
amide using mild and simple reaction
conditions is reported (see scheme). The
method is cost-effective and uses the
easy-to-handle Togni’s reagent as the
electrophilic CF3 source.
Iron-Catalyzed Trifluoromethylation of
Enamide
Chem. Eur. J. 2015, 21, 1 – 5
www.chemeurj.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ