Palladium-Catalyzed Synthesis of 3-Trifluoromethyl-Substituted 1,3-Butadienes by Means of Directed C-H Bond Functionalization

Article abstract of DOI:10.1021/acs.orglett.7b00704

A palladium-catalyzed C-H bond functionalization of acrylamides was developed to build up stereoselectively trifluoromethylated 1,3-butadienes. Using a tertiary amide as a directing group, olefins were selectively functionalized with 2-bromo-3,3,3-trifluoropropene to access these important fluorinated compounds. The methodology was extended to the construction of pentafluoroethyl-substituted 1,3-dienes. Mechanistic studies supported by density functional theory calculations suggested a redox neutral mechanism for this transformation.

Full text of DOI:10.1021/acs.orglett.7b00704

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of 3‑Trifluoromethyl-Substituted 1,3-
Butadienes by Means of Directed C−H Bond Functionalization
Qun Zhao, Vincent Tognetti, Laurent Joubert, Tatiana Besset, Xavier Pannecoucke,
Jean-Philippe Bouillon,* and Thomas Poisson*
́
Normandie Universite, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
S
* Supporting Information
ABSTRACT: A palladium-catalyzed C−H bond functionalization of acrylamides was developed to build up stereoselectively
trifluoromethylated 1,3-butadienes. Using a tertiary amide as a directing group, olefins were selectively functionalized with 2-
bromo-3,3,3-trifluoropropene to access these important fluorinated compounds. The methodology was extended to the
construction of pentafluoroethyl-substituted 1,3-dienes. Mechanistic studies supported by density functional theory calculations
suggested a redox neutral mechanism for this transformation.
Scheme 1. State of the Art and Present Work
luorinated molecules play an important role in the drug
Fdiscovery process. Indeed, the unique properties of the
fluorine atom,1 like its electronegativity and small size, along with
the unique features of the C−F bond, give it a pivotal role in
medicinal chemistry. As a consequence, a phalanx of marketed
drugs bear at least one fluorine atom.2 Hence, the implementa-
tion of new transformations, the discovery of original reagents to
introduce the fluorine atom or fluorinated groups, and the design
of new fluorinated building blocks became an active field of
research.3 As part of this blossoming research area, the
introduction of the CF3 group received a lot of attention toward
accessing important trifluoromethylated molecules.4
1,3-Butadienes are versatile building blocks in organic
chemistry.5 This key synthetic unit is widely used to access
more complex molecules through cycloaddition reactions,6
Ziegler−Natta polymerization,7 or conjugated addition,8 for
instance. Moreover, this motif is widely found in natural
products, particularly in retinoids.9 Quite surprisingly, the
synthesis of fluorinated 1,3-butadienes and particularly the
trifluoromethylated ones is scarcely depicted in the literature. In
spite of the obvious advantage that this motif represents in the
toolbox of fluorinated building blocks, their access remains
underexplored (Scheme 1). Indeed, their synthesis relies on (1) a
poorly stereoselective olefination reaction of trifluoromethyl
ketones using phosphonium ylides or phosphonate-stabilized
carbanions,10 (2) the dehydration of the 2-(trifluoromethyl)-2,3-
butanediol to synthesize the corresponding β-(trifluoromethyl)-
butadiene,11 (3) the Negishi cross-coupling reaction with vinyl
halides,12 and (4) a unique example of decarboxylative
trifluoromethylation of an α,β,γ,δ-unsaturated carboxylic acid.13
Therefore, the need to develop a stereoselective and efficient
access to these building blocks appears as a matter of importance.
As part of our ongoing research program devoted to the direct
introduction of fluorinated building blocks14 and stimulated by
recent progress dealing with the transition-metal-catalyzed C−H
bond functionalization of olefins to access 1,3-dienes,15 we report
herein a stereoselective access to 3-trifluoromethylated-1,3-
butadienes. By using a palladium-catalyzed directed C−H bond
functionalization of α-substituted acrylamides with 2-bromo-
3,3,3-trifluoropropene (BTP), an inexpensive and nonozone
depleting fluorinated reagent,16 the first catalytic process to
selectively synthesize the Z-trifluoromethylated 1,3-dienes was
designed.
At the outset of the study, we chose the α-phenyl-N,N-
diisopropylacrylamide 1a as a model substrate to find suitable
reaction conditions (Table 1).
Received: March 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00704
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope
b
entry
x
additive
solvent
yield (%)
1
2
3
4
15
15
15
15
15
15
15
15
15
10
10
10
10
10
AgOTf
AgBF4
AgSbF6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
DMI
DMI
DMI
DMI
DMI
45
30
30
NR
47
c
5
AgOTf
d
6
e
AgOTf
41
7
AgOTf
NR
66
8
9
AgOTf
AgOTf
60
f
g
10
AgOTf
76 (62)
11
12
13
14
In(OTf)3
Bi(OTf)3
Sc(OTf)3
Yb(OTf)3
40
17
NR
NR
a
Conditions: 1a (0.2 mmol), BTP (1 mmol), additive (0.3 mmol),
b
solvent (2 mL), 120 °C, 16 h. Yields were determined by 19F NMR
using α,α,α-trifluoroacetophenone as an internal standard. 2 equiv of
PivOH was added. 2 equiv of TFA was added. 2 equiv of CsOPiv
was added. 2 equiv of AgOTf was used. Isolated yield. NR: no
c
d
e
f
g
reaction.
Using Pd(acac)2 as a catalyst17 in the presence of AgOTf as an
additive in DMF at 120 °C, we were delighted to observe the
desired product 2a in 45% NMR yield as a single Z stereoisomer
without traces of homocoupling product (Table 1, entry 1).18
This result demonstrated the effectiveness of the N,N-
diisopropyl group as a directing group.19 Then a survey of Ag
salts revealed that AgOTf was the best additive for this reaction,
and its presence was crucial to convert 1a into 2a since in its
absence no reaction occurred (entries 2−4). Interestingly, the
addition of acids, such as PivOH or TFA, did not affect the
reaction outcome (entries 5 and 6), while the addition of a base
(CsOPiv) suppressed the reaction (entry 7). The solvent of the
reaction was found to be an important parameter, and among the
polar aprotic solvents tested (entries 1, 8−10), DMI (1,3-
dimethyl-2-imidazolidinone) was the best one. The desired
product 2a was isolated in 62% yield using a decreased amount of
Pd(acac)2 in the presence of 2 equiv of AgOTf. (entry 10).
Finally, to gain more insight into the role displayed by AgOTf,
several other additives and particularly Lewis acids were tested
(entries 11−14). Interestingly, In(OTf)3 and Bi(OTf)3 were
prompted to promote the reaction (entries 11 and 12), albeit in
lower yields than AgOTf. These results precluded the use of
AgOTf as an oxidant in the course of the reaction.
Having set up the optimized reaction conditions, we turned
our attention to the extension of the substrate scope of the
reaction (Scheme 2). First, acrylamides bearing halogenated
arenes at the α-position were tested. Pleasingly, fluorine,
chlorine, and even bromine substituents were well tolerated,
giving the corresponding 1,3-dienes (2b−f) in good yields as a
single diastereoisomer. α-Methoxy-substituted aryl acrylamides
1g and 1h were also used as substrates, and the targeted dienes 2g
and 2h were isolated in moderate to good yields. We found that
α-naphthyl- and even α-thienyl-substituted acrylamides were
suitable substrates to access the trifluoromethylated butadienes
2i and 2j.
a
Conditions: 1 (0.2 mmol), BTP (1 mmol), AgOTf (0.4 mmol), DMI
b
(2 mL), 120 °C, 2 h, isolated yields provided. Yields determined by
19F NMR using α,α,α-trifluoroacetophenone as an internal standard.
c
d
Reaction was performed on a 4 mmol scale. Reaction was carried out
under an air atmosphere.
Note that simple acrylamide 1k, as well as β-substituted ones
(1l and 1m), furnished the corresponding trifluoromethylated
1,3-dienes, albeit in lower yields. Interestingly, these substrates
furnished the opposite stereoisomer with regard to the α-aryl-
substituted acrylamides. We assume that this reverse stereo-
selectivity could arise from an in situ palladium-catalyzed
isomerization of the products.20 Finally, in order to demonstrate
the synthetic utility of our process, the reaction was carried out
on a 4 mmol scale using 1a as a starting material. The 1,3-
butadiene 2a was isolated in a 55% yield. Pleasingly, this
transformation was not sensitive to an air atmosphere since a
similar yield was obtained.
We then extended the methodology toward the introduction
of the pentafluoroethyl analogue of the BTP (Scheme 3).
By using similar reaction conditions, the reaction of 2-bromo-
3,3,4,4,4-pentafluorobutene 3 with α-aryl-acrylamides was
performed. Acrylamides 1a,c,f,h,i were tested to give the
corresponding pentafluoroethylated dienes 4a−e in somewhat
lower yields compared with the reaction carried out with BTP.
Note that the stereochemistry of the diene 4e was
unambiguously assigned through X-ray crystallographic anal-
ysis.21 Even though the reaction yields remained moderate, this
process represents the unique access to this class of
perfluorinated 1,3-dienes to date.
B
DOI: 10.1021/acs.orglett.7b00704
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Extension to the Introduction of the 3,3,4,4,4-
Pentafluorobuten-2-yl Motif
Scheme 5. Proposed Mechanism and DFT Calculations
a
a
Conditions: 1 (0.2 mmol), 3 (1 mmol), AgOTf (0.4 mmol), DMI (2
b
mL), 140 °C, 2 h, isolated yields provided. Yields determined by 19
NMR using α,α,α-trifluoroacetophenone as an internal standard.
F
To gain insight into this transformation, we conducted
mechanistic studies (Scheme 4). We first studied the kinetic
Scheme 4. Mechanistic Studies
a
Standard Gibbs energy profile (kcal·mol−1).
Lewis acids in the course of the optimization study (Table 1).
Note that according to these calculations and the observed KIE,
the carbopalladation step can be considered as the rate-
determining step of this transformation.
Another plausible reaction pathway relied on the oxidative
addition of the organopalladium species A onto the C−Br bond
of the BTP. However, DFT calculations revealed that the
formation of the Pd(IV) intermediate D is unlikely.21 Indeed, the
intermediate D, resulting from an endothermic oxidative
addition, is much higher in energy than the species C resulting
from the carbopalladation reaction (ca. 25.5 kcal·mol−1 with
respect to C). Therefore, according to DFT calculations, a
Pd(II)/Pd(IV) mechanism can be ruled out in favor of a redox-
neutral Pd(II)/Pd(II) pathway.
In summary, we developed a straightforward and stereo-
selective access to trifluoromethylated 1,3-dienes by using a
palladium-catalyzed C−H bond functionalization of acrylamides
using BTP as an inexpensive coupling partner. The reaction
proceeded well and was applied to a broad range of substrates. In
addition, the reaction was extended to the introduction of the
3,3,4,4,4-pentafluorobuten-2-yl motif. A plausible mechanism
involving a redox neutral process was suggested as supported by
mechanistic experiments and DFT calculations.
isotopic effect (KIE). An initial set of experiments showed that
no H/D scrambling occurred when 1a was reacted in DMF-d7
under the standard reaction conditions without BTP.21 A similar
result was obtained with [D]-1a when it was reacted in DMF.21
Then parallel reactions revealed a KIE = 1.1. This result
suggested that the C−H bond activation is not the rate-
determining step of the transformation. Finally, we attempted to
extend the reaction to 2-bromopropene as a coupling partner.
Interestingly, under the standard reaction conditions, no trace of
product was detected in the reaction media. This result clearly
points out the strong influence of the fluorinated group on the
olefin, the so-called “fluorine effect”.22
Thus, we proposed the following mechanism for this
transformation, supported by DFT calculations at the M06-L/
6-311+G(d)-SDD level of theory (Scheme 5).21 First, we
assumed the formation of the palladacycle intermediate A, where
the metal is coordinated to the oxygen atom of the carbonyl
group, as supported by calculations. Then, A coordinated to BTP
to form intermediate B. Subsequently, B underwent a
carbopalladation reaction leading to the organopalladium
intermediate C according to an exothermic process and an
activation energy (ca. 25 kcal·mol−1) consistent with the
experimental data. Finally, the final product 2 was released
according to a bromide elimination step favored by the Ag salt.23
The role of the Ag salt was supported by the efficiency of other
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00704.
C
DOI: 10.1021/acs.orglett.7b00704
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Procedures; characterization data; 1H, 13C, and 19F NMR
Letter
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spectra; characterization data for the X-ray crystal
structure of 4e; computational details, views, and
Cartesian coordinates of optimized complexes; discussion
about DFT results (PDF)
X-ray data for compound 4e (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jean-philippe.bouillon@univ-rouen.fr.
*E-mail: thomas.poisson@insa-rouen.fr.
ORCID
Thomas Poisson: 0000-0002-0503-9620
Notes
The authors declare no competing financial interest.
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Supporting Information.
ACKNOWLEDGMENTS
This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-
0029), and the Region Normandie (Crunch Network). Q.Z.
́
thanks the China Scholarship Council (CSC) for a doctoral
fellowship.
■
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