Gold-catalyzed synthesis of β-trifluoromethylated α,β-unsaturated ketones from CF3-substituted propargylic carboxylates and their reactivity in Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2018.05.054

The synthesis of fluorinated synthetic intermediates has become a field of intense research in organic chemistry. In this article, we report the application of a gold-catalyzed rearrangement to the synthesis of β-trifluoromethylated α,β-unsaturated ketone

Full text of DOI:10.1016/j.tet.2018.05.054

Accepted Manuscript
Gold-catalyzed synthesis of β-trifluoromethylated α,β-unsaturated ketones from CF -
3
substituted propargylic carboxylates and their reactivity in Diels-Alder reactions
Arnaud Boreux, Aubin Lambion, Dominic Campeau, Marina Sanita, Ruben Coronel,
Olivier Riant, Fabien Gagosz
PII:
S0040-4020(18)30602-1
10.1016/j.tet.2018.05.054
TET 29561
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 March 2018
Revised Date: 17 May 2018
Accepted Date: 18 May 2018
Please cite this article as: Boreux A, Lambion A, Campeau D, Sanita M, Coronel R, Riant O, Gagosz
F, Gold-catalyzed synthesis of β-trifluoromethylated α,β-unsaturated ketones from CF -substituted
3
propargylic carboxylates and their reactivity in Diels-Alder reactions, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.05.054.
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Gold-catalyzed synthesis of β-
trifluoromethylated α,β-unsaturated ketones
from CF3-substituted propargylic
carboxylates and their reactivity in Diels-
Alder reactions
Arnaud Boreuxa,b,* , Aubin Lambiona, Dominic Campeauc, Marina Sanitac, Ruben Coronelc, Olivier Rianta,* and
Fabien Gagoszb,c,*
aInstitute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université
catholique de Louvain (UCL), Place Louis Pasteur 1, 1348 Louvain-La-Neuve, Belgium
bLaboratoire de Synthèse Organique, UMR 7652 CNRS/Ecole Polytechnique, Route de Saclay, 91128
Palaiseau, France
cDepartment of Chemistry and Biomolecular Sciences, University of Ottawa, K1N 6N5, Ottawa, Canada

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Gold-catalyzed synthesis of β-trifluoromethylated α,β-unsaturated ketones from CF3-
substituted propargylic carboxylates and their reactivity in Diels-Alder reactions
Arnaud Boreuxa,b, , Aubin Lambiona, Dominic Campeauc, Marina Sanitac, Ruben Coronelc, Olivier Rianta,
and Fabien Gagoszb,c,
aInstitute of Condensed Matter and Nanosciences (IMCN), Molecules, Solids and Reactivity (MOST), Université catholique de Louvain (UCL), Place Louis
Pasteur 1, 1348 Louvain-La-Neuve, Belgium
bLaboratoire de Synthèse Organique, UMR 7652 CNRS/Ecole Polytechnique, Route de Saclay, 91128 Palaiseau, France
cDepartment of Chemistry and Biomolecular Sciences, University of Ottawa, K1N 6N5, Ottawa, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of fluorinated synthetic intermediates has become a field of intense research in
organic chemistry. In this article, we report the application of a gold-catalyzed rearrangement to
the synthesis of β-trifluoromethylated α,β-unsaturated ketones. The scope of the reaction, as
well as the valorization of the products in subsequent transformations has been investigated.
This study allowed for the preparation of various CF3-substituted enones and fluorinated Diels-
Alder adducts from easily accessible starting materials.
Available online
Keywords:
Gold catalysis
2009 Elsevier Ltd. All rights reserved
.
α,β-Unsaturated ketones
Trifluoromethyl group
Propargylic acetates
———
Arnaud Boreux. Current address: Max-Planck Institut Für Kohlenforschung; Tel.: + +49-208-306-2384; e-mail: boreux@kofo.mpg.de
Olivier Riant. Tel.: +32-10-47-87-77; fax: +32-10-47-41-68; olivier.riant@uclouvain.be
Fabien Gagosz. Tel.: +1-613-562-5800; fax: +1-613-562-5170; e-mail: fgagosz@uOttawa.ca

2
Tetrahedron
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1. Introduction
The preparation of fluorinated building blocks is a long-
standing subject of intense research given their utilization in
various domains such as medicinal chemistry or agrochemistry.[1]
In this general field of research, various strategies have emerged
in order to easily and efficiently incorporate the most commonly
employed CF3 group into various structural motifs.[2] Considering
the versatility of the α,β-unsaturated ketone moiety, the
preparation of its β-trifluoromethylated version constitutes a
potential entry towards the facile synthesis of fluorinated patterns
and has therefore been a subject of special attention.[3] Most of
the existing methods for the preparation of CF3-enones such as I
rely on the rearrangement or the modification of small building
blocks already containing the CF3 group (Scheme 1). One of the
main strategies involves a Mannich reaction performed on an in
situ generated CF3-substituted iminium species (Scheme 1-A).[4]
The subsequent elimination of the amine moiety from II delivers
the expected CF3-enone. A similar approach consists in the
dehydration of trifluoromethylated aldol-type adducts III, which
can
be
synthesized
from
commercially
available
trifluoroethylamine[5] or trifluoroacetoacetic acid derivatives[6]
(Scheme 1-B). The use of the unstable trifluoroacetaldehyde to
generate the corresponding aldol product remains elusive.[7]
Besides, several strategies rely on the isomerization of
fluorinated propargylic alcohols such as IV or their derivatives
into the corresponding enones (Scheme 1-C).[8] While β-
disubstituted CF3-enones analogous to I can be efficiently
accessed by a Wittig reaction involving a trifluoromethylated
carbonyl derivative (Scheme 1-D),[9] such a strategy is usually
not applicable to enones I as their preparation also requires
trifluoroacetaldehyde as the CF3-source.[7]
Despite the number of methods reported so far, almost no
synthetic approach to fluorinated enones using easily accessible
CF3-substituted propargylic alcohol derivatives has been
envisioned. To our knowledge, only one paper briefly mentions
the preparation of perfluorinated enones from propargylic
alcohols via a Meyer-Schuster rearrangement.[10] Having in mind
the literature precedents on the gold-catalyzed synthesis of
enones from propargylic carboxylates,[11] and encouraged by our
recent work on fluorinated substrates,[12] we envisioned to extend
this general transformation to the synthesis of β-
trifluoromethylated α,β-unsaturated ketones I (Scheme 1-E). The
low price and the stability of ethyl trifluoroacetate (used as the
CF3 source), as well as its straightforward transformation into the
required CF3-subtituted propargylic carboxylate substrates V,
make this approach a particularly attractive alternative to the
previously reported methods.
Scheme 1. Previously reported strategies for the preparation of β-
CF3-substituted enones and our approach by gold catalysis
2. Results and discussion
Propargylic carboxylate 1a was chosen as a model substrate
and we attempted to find some suitable experimental conditions
to produce the corresponding enone 2a. The main results of our
study are compiled in Table 1. On the basis of previous
finding,[11] we started our investigation by using the
(XPhos)AuNTf2 complex 3 as the catalyst and evaluated several
80:1 co-solvent / water mixtures. As seen in Table 1, the best
result was obtained using acetone as the co-solvent and heating
the reaction mixture at 40°C for 2 hours in the presence of 4
mol% of 3 (entry 1). Under these conditions, the CF3-enone 2a
was obtained in 89% NMR yield. The use of dioxane as an
alternative co-solvent proved to be far less efficient (entry 2).
Lowering the catalyst loading to 2 mol% while using either
acetone or butanone as the co-solvent led to a significant drop in
the yield of 2a (entries 3 and 4). A small library of gold(I)
complexes (used at a 2 mol% loading) were then screened using
acetone as the co-solvent. The use of complex 4, bearing a
tBuXPhos ligand and SbF6- as the counteranion, resulted in a
lower yield in 2a (entry 5), and (PPh3)AuNTf2, which was
previously reported to be highly efficient for such a type of
reaction,[11a] was found to be completely inactive with our
fluorinated substrate (entry 6). In sharp contrast, the NHC-
coordinated gold complex 6 displayed an excellent catalytic
activity (entry 7). Substrate 1a was indeed completely consumed
after 2 hours of reaction and the yield of 2a was assessed by 1H
NMR to be greater than 95%. Gold complexes 7, 8 and 9, which
possess strong π-accepting ligands, were almost inactive in the
present transformation (entries 8-10). A similar observation was
made with gold(III) complex 11 while the use of the AuCl3 salt

3
led a very moderate yield in 2a (entries 11-12). Notably, neither a
silver salt (entries 13 and 14) or a Brønsted acid (entry 15) could
be used as a viable catalyst for the reaction. In these cases, and
under the same reaction conditions, the starting material was
fully recovered.
yields (69-88%). Not surprisingly, the presence of a free
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alcohol (1f) led to a complex reaction and the formation of
multiple products. Such a result can probably be attributed to a
competitive interaction between the nucleophilic OH group and
the gold-activated alkyne moiety. The reaction was also
attempted with substrates possessing different fluorinated groups
at the propargylic positions. As attested by the reactions of
propargylic acetates 2g-i possessing either a CF3, a CF2H or a
CF2CF3 group, increasing or decreasing the degree of fluorination
did not change the reactivity. Finally, while a series of substrates
possessing an aromatic group on to the alkyne terminus could be
efficiently converted into the corresponding enones (see 2j-o).
Both electron-rich (2l-m) and electron-poor aromatic groups (2n)
were tolerated. A limit in reactivity was however attained with
substrates 1n and 1o under the optimized conditions. The
reaction of 1n, which possesses a polysubstituted aromatic
moiety, required an increased 5 mol% loading of the catalyst to
reach completion. Enone 2n was obtained in a good 72%
following this slight modification. Similarly, enone 2o derived
from the difluoromethylated substrate 1o could be isolated in
89% yield after 18 hours of reaction in the presence of 4 mol% of
6.
Table 1. Optimization of the reaction conditions
Entry
Catalyst
x
Co-solvent
NMR Yielda
1
2
(XPhos)AuNTf2 3
(XPhos)AuNTf2 3
(XPhos)AuNTf2 3
(XPhos)AuNTf2 3
[(L1)Au(NCCH3)]SbF6 4
(PPh3)AuNTf2 5
(IPr)AuNTf2 6
4
4
2
2
2
2
2
2
2
2
2
2
Acetone
Dioxane
Acetone
Butanone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
89%
29%
55%
26%
30%
< 5%
> 95%
< 5%
9%
3
4
5
6
7
8
(L2)AuNTf2 7
9
[(L2)Au(NCCH3)]SbF6 8
(L3)AuNTf2 9
10
11
12
< 5%
20%
< 5%
AuCl3 10
(Pyridinecarboxylato)
AuCl2 11
13
14
15
AgOTf
AgNTf2
4
4
/
Acetone
Acetone
Acetone
No reaction
No reaction
No reaction
HCl (2 equiv)
aThe yield was assessed by 1H NMR using 1,3,5-trimethoxybenzene as an
internal standard.
In light of these results, the use of gold complex 6 in a 80:1
acetone/water solvent mixture at 40°C was initially retained as an
optimal set of reaction conditions and we started to study the
scope of the transformation. Unfortunately, preliminary tests
showed that several substrates could not be completely converted
under these conditions. However, it appeared that simply
increasing the concentration of the starting material from 0.1 to
0.4 mol.L-1 allowed for a better reaction rate and consequently a
complete consumption of the substrates. These slightly modified
conditions were thus applied to a series of fluorinated propargylic
carboxylate substrates 1 which were converted into the
corresponding enones 2 (Scheme 2). Enone 2a, derived from
model substrate 1a was isolated in 88% yield while substrate 1b
possessing a simple alkyl chain at the alkyne terminus could be
converted into the corresponding enone 2b in 76% yield. The
reactivity of several substrates 1c-f bearing a functional group on
this side chain was also studied. It was shown that the method
was compatible with the presence of a phthalimide moiety (1c), a
silicon-protected alcohol (1d) or a bromine atom (1e). The
corresponding enones 2c-e were obtained in good to excellent
Scheme 2. Scope of the reaction with substrates mono-
substituted at the propargylic position
We next evaluated the reactivity of substrates possessing a
quaternary propargylic center in an attempt to access β-
disubstituted α,β-unsaturated ketones (Scheme 3). While non
fluorinated substrates had been reported in the literature to react
similarly whatever the degree of substitution at the propargylic
position,[11] a surprising contrasting reactivity was observed in the
present case. When a simple methyl group was installed at the
propargylic position, such as in 1p, a clean conversion into the
corresponding enone 2p was observed. However, the use of more
sterically demanding groups led to disappointing results. The
reactions of alkyl- or aryl-substituted substrates 1q-t led either to

4
Tetrahedron
ACCEPTED MANUSCRIPT
a recovery of the starting material (1q-r) or to the formation of
multiple products which were difficult to analyze (1s-t).[13]
Scheme 4. One-pot cascade reaction for the synthesis of
trifluomethylated cyclohexene derivatives.
Scheme 3. Scope of the reaction with substrates mono-
We decided to introduce the diene in the reaction mixture in a 4-
fold excess in order to favor the subsequent intermolecular
cycloaddition and compensate for the potential consumption in
side reactions induced by the electrophilic gold complex.
Acetone was also replaced by dioxane in order to be able to heat
the reaction mixture to a higher temperature and a 5 mol%
loading of gold complex 6 was employed. Gratifyingly, reacting
1j and 13 under these conditions at 80°C for 15h led to the
efficient formation of cycloadduct 14j which could be isolated in
70% yield. This yield is similar to that obtained for the formation
of enone 2j from 1j (75%, see Scheme 2) what tends to prove
that 2j was mainly converted into 14j and therefore attests of the
chemoselectivity of the overall sequence. While part of the diene
was observed to oligomerize under the reaction conditions
employed, this side reaction appeared to be slow enough to
prevent competition with the cascade process. The sequence was
also applied to aryl-substituted substrates 1k and 1l which were
converted with a similar efficiency into cycloadducts 14k and
14l, respectively (Scheme 4). The reaction of substrates 1d and
1g, which possess an alkyl chain on the alkyne terminus,
delivered products 14d and 14g in a somewhat lower yield (58%
and 44%, respectively). In these cases, part of the enones 2d and
2g intermediately formed, remained unreacted at the end of the
process. This decrease in efficiency can be attributed to the
reduced reactivity of the enone dienophile partner in the
cycloaddition step combined with the slow degradation of the
diene under the reaction conditions. This one-pot cascade
reaction is particularly useful in the case of CF3-enones that
would be difficult to isolate due to their high volatility. An
example is given with the conversion of 1v into 14v via
intermediate 2v. A limit in reactivity was found with substrates
disubstituted at the propargylic position. For instance, no trace of
cycloadduct 14p could be observed when 1p was used as the
substrate. The only product observed was enone 2p.
substituted at the propargylic position
Interestingly, when the methyl-substituted benzoate derivative 1u
was employed as the substrate and reacted with 5 mol% of 3, its
rapid conversion (15 min) into a mixture of enone 2u and
allenoate 12u was observed.[14] Running the reaction for a longer
time (19h) led to the gradual disappearance of 12u and the
accumulation of enone 2u. This result tends to support the
involvement of a CF3-allenoate intermediate of type VI (see
Scheme 1) in the formation of β-trifluoromethylated α,β-
unsaturated ketones I from propargylic carboxylates V. The
reasons why the hydration step in the conversion of 1u into 2u is
comparatively slow and why the overall process is sensitive to
the steric nature of the additional substituent at the propargylic
position remain unclear. While the present procedure seems to be
limited to the formation of CF3-substituted enones that do not
possess an extra substituent at the β position, it appears to be de
facto complementary to the methods previously reported to
access such compounds.
Having in hand a relatively general and high yielding method
to produce β-CF3 α,β-unsaturated ketones, we then investigated
their reactivity. We initially considered the possibility to perform
a one pot cascade of reactions and focused on a Diels Alder
cycloaddition between the in situ formed enone and a diene as a
potential subsequent transformation.[15] The selectivity of the
gold-catalyzed reaction, which mainly produces the desired
enone and a carboxylic acid as a by-product, and to the mildness
of the experimental conditions should allow to perform the
targeted gold-catalyzed enone formation / Diels Alder reaction
sequence in a one-pot manner. We attempted to validate this
approach by reacting the propargylic carboxylate 1j with 2,3-
dimethylbutadiene 13 in the presence of gold complex 6 (Scheme
4).

5
In order to improve the yields in cycloaddition products, more
especially when alkyl-substituted alkynes are used as substrates,
we envisioned to introduce diene 13 in the reaction mixture once
the formation of the intermediate enone would have been
complete (Scheme 5). This one-pot sequential process turned out
to be effective as the yield in cycloadduct 14j could be
significantly improved (87% versus 70%). The effect was even
more pronounced in the case of compound 14g derived from the
alkyl-substituted alkyne substrate 1g (77% versus 44%). The
perfluoroethyl cyclohexene derivative 14h could also be obtained
following the same procedure.
be much faster than the cycloaddition.[16] Isoprene could also be
ACCEPTED MANUSCRIPT
employed as the diene partner in this process: its reaction with
enone 2j derived from propargylic carboxylate 1j led to the
formation of compound 16j which was isolated in 65% yield as a
4:3 mixture of regioisomers.
Reactions with isolated CF3-enones were also attempted
(Scheme 7). The Diels-Alder reaction between butadiene and
enone 2a in dioxane at 120°C delivered cycloadduct 15a with the
very same efficiency as when the one-pot procedure was
employed. This result highlights the synthetic interest of the
cascade process developed as no purification of the intermediate
enone is required to obtain the subsequent Diels-Alder product in
good yield. Finally, a Doebner–Miller reaction was also
attempted between enone 2a and p-methoxy-aniline (Scheme 8).
After many attempts, it was found that the desired quinoline 18
could be produced in a very moderate 33% yield following a
two-step sequence of Michael addition / oxidative cyclization in
the presence of 5 mol% of triflic acid in refluxing toluene under
air.[17]
Scheme 5. One-pot sequential synthesis of trifluoromethylated
cyclohexene derivatives.
The gold-catalyzed enone formation / Diels Alder cascade
process was also attempted with other dienes than 2,3-
dimethylbutadiene (Scheme 6).
Scheme 7. Reactions with isolated enone 2
3. Conclusions
In conclusion, an application of the gold-catalyzed [3,3]-
sigmatropic rearrangement of propargylic carboxylates to the
synthesis of β-trifluoromethylated α,β-unsaturated ketones has
been developed. The reaction was found to be efficient for the
synthesis of various CF3-enones monosubstituted at the β
position and could also be applied to polyfluoroalkylated
substrates. A limit in reactivity was however found with
substrates being disubstituted at the propargylic position. The
involvement of this transformation in a one-pot cascade process
involving a subsequent Diels-Alder reaction was studied and led
to the preparation of various trifluoromethylated cycloadducts.
4. Experimental section
Scheme 6. Gold-catalyzed enone formation / Diels Alder cascade
process: variation on the diene
4.1 General information
The use of simple butadiene, generated by cycloreversion of
sulfolene under thermal conditions, led to the formation of
cycloadducts 15a and 15j in respectively 72% and 76% yield. It
must be noted that compound 15a was obtained as a 7:1 mixture
of anti and syn isomers. This should not be the result of a non-
concerted cycloaddition reaction and could most probably be
attributed to an in situ E/Z isomerization of the enone that would
Unless otherwise noted, all reactions for the synthesis of
substrates were performed under dry oxygen-free argon or
nitrogen atmosphere. The scope of the gold-catalyzed reaction
was carried out using technical dioxane. Gold-catalyzed reactions
were performed in closed vials using 1,3,5-trimethoxybenzene as
an internal standard for the optimization. Thin Layer
Chromatography were performed on aluminium plates bearing a

6
Tetrahedron
0.25 mm of Merck Silica Gel 60F254, visualized by
63.4, 41.6, 31.8, 27.0, 20.1, 19.4; MS (HRMS EI): Calcd for [M-
ACCEPTED MANUSCRIPT
fluorescence quenching at 254 nm and chemical revelation using
acidic solution of para-anisaldehyde or basic solution of
potassium permanganate. Flash chromatography was performed
using silica gel 60 (40-63 µm). Commercial reagents were
purchased from Acros, Fluorochem, TCI, Sigma-Aldrich, Alfa-
Aesar and used as received. NMR analysis were performed at
room temperature on Bruker AMX or DPX Fourier Transform
tBu] C20H20F3O2Si: 377.1185; Found: 377.1188.
4.2.4. (E)-8-bromo-1,1,1-trifluorooct-2-en-4-one 2e
Yellow oil; 38.5 mg (Product/starting material in a 1:0.07
mixture, 69% yield); purified by flash chromatography (PE/Et2O
90:10); H NMR (400 MHz, CDCl3): 6.72 (dq, J = 15.9, 1.6 Hz,
1
1H), 6.61 (q, J = 15.9, 6.2 Hz, 1H), 3.42 (t, J = 6.4 Hz, 2H), 2.68
1
(t, J = 7.0 Hz, 2H), 1.93 – 1.86 (m, 2H), 1.85 – 1.77 (m, 2H); 19
F
Spectrometer operating at 300 /400/500 MHz for H, 75/100/125
MHz for 13C, 282 MHz for 19F. Residual solvent peaks of CDCl3
NMR (282 MHz, CDCl3): -66.3; 13C NMR (101 MHz, CDCl3):
197.4, 134.0 (q, J = 5.6 Hz), 128.8 (q, J = 35.3 Hz), 122.5 (q, J =
270.4 Hz), 40.9, 33.1, 31.9, 22.0; MS (HRMS EI): Calcd for
C8H10BrF3O: 257.9867; Found: 257.9878.
1
were used as internal references: 7.26 ppm for H spectra and
77.16 ppm for 13C spectra. The following abbreviations were
used in order to describe de peaks multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, quint = quintuplet, hex =
hexuplet, hept = heptuplet, m = multiplet, br = broad. High
resolution mass spectra were recorded on a JMS-GCmateII mass
spectrometer, on a Thermo Scientific QExactive or on a Kratos
Analytical Concept instrument (University of Ottawa Mass
Spectrum Centre). Infrared absorption spectra were recorded as a
liquid deposition on a ZnSe crystal on a Shimadzu FTIR 8400
Spectrophotometer or in solutions in CCl4 using NaCl cells on a
Perkin-Elmer FT 2000, on a Perkin-Elmer Spectrum Two or on a
Bomem Michaelson 100 FTIR spectrometer.
4.2.5. (E)-1,1,1-trifluoro-7-phenylhept-2-en-4-one 2g
Yellow oil; 38.0 mg (78%); purified by flash chromatography
(PE/Et2O 95:5); H NMR (400 MHz, CDCl3): 7.32 – 7.28 (m,
1
2H), 7.23 – 7.16 (m, 3H), 6.68 (dq, J = 15.9, 1.7 Hz, 1H), 6.55
(dq, J = 15.9, 6.3 Hz, 1H), 2.69 – 2.61 (m, 4H), 2.03 – 1.96 (m,
2H); 19F NMR (282 MHz, CDCl3): -66.2; 13C NMR (101 MHz,
CDCl3): 197.9, 141.2, 134.3 (q, J = 5.6 Hz), 128.6, 128.6, 128.5
(q, J = 35.3 Hz), 126.3, 122.6 (q, J = 270.4 Hz), 41.1, 35.0, 25.0;
MS (HRMS EI): Calcd for C13H13F3O: 242.0918; Found:
242.0927.
4.2. General procedure for the gold-catalyzed rearrangement
of α-trifluoromethyl propargylic acetate
4.2.6. (E)-7,7,8,8,8-pentafluoro-1-phenyloct-5-en-4-one 2h
IPrAuNTf2 (0.02 eq) was weighted in a vial. A solution of
propargyl acetate (1 eq) in acetone/water 80 : 1 (0.4-0.5 M) was
added and the mixture was stirred at 40 °C during the specified
time. The mixture was filtered over silica (Et2O). Purification by
Colorless oil; 48.0 mg (82%); purified by flash
chromatography (PE/Et2O 96:4); H NMR (400 MHz, CDCl3):
1
7.32 – 7.28 (m, 2H), 7.23 – 7.17 (m, 3H), 6.74 (dt, J = 16.0, 1.9
Hz, 1H), 6.59 (dt, J = 16.0, 11.5 Hz, 1H), 2.69 – 2.62 (m, 4H),
2.04 – 1.96 (m, 2H); 19F NMR (282 MHz, CDCl3): -85.6, -118.0
(d, J = 11.9 Hz); 13C NMR (101 MHz, CDCl3): 197.5, 141.2,
136.21 (t, J = 6.9 Hz), 128.6, 128.6, 127.6 (t, J = 23.7 Hz), 126.3,
118.6 (qt, J = 285.9, 36.8 Hz), 112.0 (tq, J = 251.6, 39.3 Hz),
41.3, 34.9, 25.0; MS (HRMS EI): Calcd for C14H13F5O:
292.0886; Found: 292.0882.
flash
column
chromatography
afforded
the
pure
trifluoromethylated enone.
4.2.1. (E)-7-(benzyloxy)-1,1,1-trifluorohept-2-en-4-one 2a
Colorless oil; 47.8 mg (88%); purified by flash
1
chromatography (PE/EtOAc 95:5); H NMR (400 MHz, CDCl3):
7.37 – 7.27 (m, 5H), 6.71 (dq, J = 16.0, 1.7 Hz, 1H), 6.58 (dq, J =
16.0, 6.3 Hz, 1H), 4.48 (s, 2H), 3.51 (t, J = 5.9 Hz, 2H), 2.76 (t, J
= 7.1 Hz, 2H), 2.00 – 1.93 (m, 2H); 19F NMR (282 MHz, CDCl3):
-66.2; 13C NMR (101 MHz, CDCl3): 198.0, 138.3, 134.4 (q, J =
5.5 Hz), 128.7, 128.5 (q, J = 35.2 Hz, 127.8, 127.8, 122.6 (q, J =
270.54 Hz, 73.1, 69.0, 38.7, 23.8; MS (HRMS EI): Calcd for
C14H15F3O2: 272.1024; Found: 272.1024.
4.2.7. (E)-1,1-difluoro-7-phenylhept-2-en-4-one 2i
Slightly yellow oil; 39.3 mg (88%); purified by flash
chromatography (pentane/Et2O 80:20); 1H NMR (400 MHz,
CDCl3): 7.32 – 7.26 (m, 2H), 7.23 – 7.16 (m, 3H), 6.59 (dtd, J =
16.1, 9.6, 4.1 Hz, 1H), 6.47 (dtd, J = 16.1, 2.6, 0.7 Hz, 1H), 6.21
(tdd, J = 54.9, 4.2, 0.8 Hz, 1H), 2.68 – 2.60 (m, 4H), 2.02 – 1.95
(m, 2H); 19F NMR (282 MHz, CDCl3): -116.4 (dd, J = 55.4, 9.5
Hz); 13C NMR (101 MHz, CDCl3): 198.8, 141.4, 133.7 (t, J =
23.9 Hz), 133.6 (t, J = 9.6 Hz), 128.6 (x2), 126.2, 113.1 (t, J =
237.4 Hz), 40.4, 35.1, 25.2; MS (HRMS EI): Calcd for
C13H14F2O: 224.1013; Found: 224.1013.
4.2.2. (E)-2-(8,8,8-trifluoro-5-oxooct-6-en-1-yl)isoindoline-
1,3-dione 2c
White solid; 57.0 mg (88%); purified by flash chromatography
(PE/EtOAc 80:20); 1H NMR (400 MHz, CDCl3): 7.85 – 7.80 (m,
2H), 7.73 – 7.69 (m, 2H), 6.70 (dq, J = 16.0, 1.6 Hz, 1H), 6.59
(dq, J = 16.0, 6.1 Hz, 1H), 3.70 (t, J = 6.7 Hz, 2H), 2.70 (t, J =
7.0 Hz, 2H), 1.74 – 1.65 (m, 2H); 19F NMR (282 MHz, CDCl3): -
66.3; 13C NMR (101 MHz, CDCl3): 197.6, 168.5, 134.1 (q, J =
5.6 Hz), 134.1, 132.1, 128.6 (q, J = 35.2 Hz), 123.4, 122.5 (q, J =
270.5 Hz), 41.1, 37.4, 27.9, 20.5; MS (HRMS EI): Calcd for
C16H14F3NO3: 325.0926; Found: 325.0921.
4.2.8. (E)-1-([1,1'-biphenyl]-4-yl)-4,4,4-trifluorobut-2-en-1-
one 2k
White solid; 48.6 mg (88%); purified by flash chromatography
1
(PE/EtOAc 95:5); H NMR (400 MHz, CDCl3): 8.08 – 8.05 (m,
2H), 7.77 – 7.74 (m, 2H), 7.66 – 763 (m, 2H), 7.59 (dq, J = 15.5,
2.0 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.45 – 7.41 (m, 1H), 6.86 (dq, J
= 15.5, 6.6 Hz, 1H); 19F NMR (282 MHz, CDCl3): -66.1; 13C
NMR (101 MHz, CDCl3): 187.6, 147.0, 139.6, 135.0, 131.1 (q, J
= 5.6 Hz), 130.4 (q, J = 35.1 Hz), 129.6, 129.2, 128.7, 127.8,
127.5, 122.7 (q, J = 270.2 Hz); MS (HRMS EI): Calcd for
C16H11F3O: 276.0762; Found: 276.0762.
4.2.3. (E)-8-((tert-butyldiphenylsilyl)oxy)-1,1,1-trifluorooct-2-
en-4-one 2d
Colorless oil; 70.0 mg (81%); purified by flash
1
chromatography (PE/EtOAc 95:5); H NMR (400 MHz, CDCl3):
7.67 – 7.65 (m, 4H), 7.45 – 7.36 (m, 6H), 6.68 (dq, J = 15.9, 1.7
Hz, 1H), 6.57 (dq, J = 15.9, 6.2 Hz, 1H), 3.68 (t, J = 6.1 Hz, 2H),
2.59 (t, J = 7.2 Hz, 2H), 1.78 – 1.71 (m, 2H), 1.60 – 1.55 (m,
2H), 1.05 (s, 9H); 19F NMR (282 MHz, CDCl3): -66.2; 13C NMR
(101 MHz, CDCl3): 198.0, 135.7, 134.3 (q, J = 5.4 Hz), 134.0,
129.8, 128.5 (q, J = 35.4 Hz), 127.8, 122.6 (q, J = 270.3 Hz),
4.2.9.
(E)-1-(4-chloro-2-fluoro-5-methylphenyl)-4,4,4-
trifluorobut-2-en-1-one 2n
White solid; 20.1 mg (72%); reaction performed on a 0.105
mmol scale; purified by flash chromatography (PE/EtOAc 95:5);

7
1H NMR (400 MHz, CDCl3): 7.74 (dd, J = 7.8, 0.4 Hz, 1H), 7.43
– 7.37 (m, 1H), 7.23 (d, J = 10.5 Hz), 6.79 (dqd, J = 14.8, 6.6, 1.5
Hz, 1H), 2.39 (s, 3H); 19F NMR (282 MHz, CDCl3): -65.6 (d, J =
4.8 Hz), -112.4 (d, J = 7.7 Hz); 13C NMR (101 MHz, CDCl3):
185.4 (d, J = 3.4 Hz), 160.0 (d, J = 255.9 Hz), 141.5 (d, J = 10.6
Hz), 134.0 (dq, J = 11.6, 5.8 Hz), 133.5 (d, J = 3.5 Hz), 132.7 (d,
J = 2.6 Hz), 130.2 (qd, J = 35.2, 1.0 Hz), 123.3 (d, J = 12.1 Hz),
122.6 (q, J = 270.2 Hz), 117.8 (d, J = 26.7 Hz), 19.4; MS (HRMS
EI): Calcd for C11H7ClF4O: 266.0122; Found: 266.0121.
– 7.69 (m, 2H), 7.65 – 7.62 (m, 2H), 7.50 – 7.46 (m, 2H), 7.43
ACCEPTED MANUSCRIPT
– 7.39 (m, 1H), 3.81 (td, J = 10.3, 5.8 Hz, 1H), 3.07 – 2.95 (m,
1H), 2.36 – 2.17 (m, 4H), 1.70 (s, 3H), 1.65 (s, 3H); 19F NMR
(282 MHz, CDCl3): -70.9; 13C NMR (101 MHz, CDCl3): 201.8,
146.2, 139.9, 135.3, 129.1, 129.1, 128.4, 127.6, 127.4, 124.3,
122.8, 40.7 (q, J = 25.7 Hz), 40.2 (q, J = 2.1 Hz), 35.6, 30.0 (q, J
= 3.0 Hz), 18.8, 18.7 (the CF3 carbon was not observed due to the
overlapping of the small quadruplet with other peaks); MS
(HRMS EI): Calcd for C22H21F3O: 358.1544; Found: : 358.1540.
4.2.10. (E)-4,4-difluoro-1-phenylbut-2-en-1-one 2o
4.3.2 (trans-3,4-dimethyl-6-(trifluoromethyl)cyclohex-3-en-1-
yl)(4-methoxyphenyl)methanone 14l
White solid; 32.6 mg (89%); purified by flash chromatography
1
(PE/EtOAc 95:5); H NMR (400 MHz, CDCl3): 7.99 – 7.96 (m,
White solid;
47.5 mg (76%); purified by flash
2H), 7.65 – 7.61 (m, 1H), 7.54 – 7.50 (m, 2H), 7.34 (dtd, J =
15.7, 3.1, 1.1 Hz, 1H), 6.86 (dtd, J = 15.7, 10.6, 3.9 Hz, 1H), 6.35
(tdd, J = 55.0, 3.9, 1.0 Hz, 1H); 19F NMR (282 MHz, CDCl3): -
116.8 (dd, J = 55.5, 10.3 Hz); 13C NMR (101 MHz, CDCl3):
189.1, 136.8, 135.7 (t, J = 23.5 Hz), 133.9, 130.1 (t, J = 9.5 Hz),
129.0, 128.9, 113.0 (q, J = 237.5 Hz); MS (HRMS EI): Calcd for
C10H8F2O: 182.0543; Found: 182.0563.
chromatography (PE/EtOAc 97.5:2.5); 1H NMR (400 MHz,
CDCl3): 7.98 – 7.94 (m, 2H), 6.96 – 6.94 (m, 2H), 3.87 (s, 3H),
3.72 (td, J = 10.4, 5.6 Hz, 1H), 3.01 – 2.91 (m, 1H), 2.33 – 2.04
(m, 4H), 1.68 (s, 3H), 1.62 (s, 3H); 19F NMR (282 MHz, CDCl3):
-71.0; 13C NMR (101 MHz, CDCl3): 200.6, 163.9, 130.8, 129.6,
127.7 (q, J = 280.4 Hz), 124.4, 122.7, 114.0, 55.6, 40.7 (q, J =
25.5 Hz), 39.8 (q, J = 1.5 Hz), 35.6, 23.0 (q, J = 2.9 Hz), 18.7,
18.7; MS (HRMS EI): Calcd for C17H19F3O2: 312.1337; Found:
312.1340.
4.2.11. (E)-1-(benzyloxy)-6,6,6-trifluoro-5-methylhex-4-en-3-
one 2p
4.3.3 5-((tert-butyldiphenylsilyl)oxy)-1-((1R,6R)-3,4-dimethyl-
6-(trifluoromethyl)cyclohex-3-en-1-yl)pentan-1-one 14d
Slightly yellow oil; reaction performed on a 0.048 mmol
scale; 11.2 mg (86%); purified by flash chromatography
(PE/EtOAc 95:5); H NMR (400 MHz, CDCl3): 7.36 – 7.29 (m,
5H), 6.64 (dt, J = 2.9, 1.4 Hz, 1H), 4.52 (s, 2H), 3.78 (t, J = 6.1
Hz, 2H), 2.83 (t, J = 6.1 Hz, 2H), 2.17 (d, J = 1.5 Hz, 3H); 19F
NMR (282 MHz, CDCl3): -72.2; 13C NMR (101 MHz, CDCl3):
198.9, 139.6 (q, J = 30.1 Hz), 138.0, 128.6, 127.9, 127.8, 126.7
(q, J = 5.3 Hz), 123.4 (q, J = 274.3 Hz), 73.5, 65.1, 44.9, 12.7 (q,
J = 1.3 Hz); MS (HRMS EI): Calcd for C14H15F3O2: 272.1024;
Found: 272.1035.
1
Colourless oil; reaction performed on a 0.133 mmol scale;
65.4 mg (Product/enone in a 9:1 mixture, 58% yield); purified by
flash chromatography (PE/EtOAc 97.5:2.5); 1H NMR (400 MHz,
CDCl3): 7.69 – 7.65 (m, 4H), 7.47 – 7.35 (m, 6H), 3.67 (t, J = 6.1
Hz, 2H), 2.82 – 2.72 (m, 2H), 2.52 (t, J = 7.2 Hz), 2.26 – 2.03
(m, 4H), 1.72 – 1.54 (m, 10H), 1.06 (s, 9H); 19F NMR (282 MHz,
CDCl3): -73.2; 13C NMR (101 MHz, CDCl3): 212.1, 135.7, 134.1,
129.7, 127.8, 124.0, 122.8, 63.7, 45.5, 42.9, 40.5 (q, J = 25.7 Hz),
34.3, 32.0, 29.9, 27.0, 20.0, 19.4, 18.7 (the CF3 carbon was not
observed due to the overlapping of the small quadruplet with
other peaks); MS (HRMS EI): Calcd for C30H40F3O2Si: 517.2744;
Found: 517.2745.
4.2.12. (E)-7-(benzyloxy)-1,1,1-trifluoro-2-methylhept-2-en-4-
one 2u
Colorless oil; reaction performed on a 0.048 mmol scale; 21.3
mg (66%); purified by flash chromatography (PE/Acetone 98:2);
1H NMR (400 MHz, CDCl3): 7.38 – 7.27 (m, 5H, H), 6.59 (hept,
J = 1.5 Hz, 1H), 4.48 (s, 2H), 3.50 (t, J = 6.0 Hz, 2H), 2.67 (t, J =
7.1 Hz, 2H), 2.14 (d, J = 1.5 Hz, 3H), 1.94 (tt, J = 7.1, 6.0 Hz,
2H); 19F NMR (282 MHz, CDCl3): -71.2 (d, J = 1.5 Hz); 13C
NMR (101 MHz, CDCl3): 200.4, 139.3, 139.0, 138.4, 128.5,
127.8 (x2), 126.8 (q, J = 5.4 Hz), 123.4 (q, 274.4 Hz), 73.1, 69.1,
41.7, 23.9, 12.6 (q, J = 1.4 Hz); MS (HRMS EI): Calcd for
C15H17F3O2: 286.1181; Found: : 286.1217.
4.3.4 1-(trans-3,4-dimethyl-6-(trifluoromethyl)cyclohex-3-en-
1-yl)-4-phenylbutan-1-one 14g
White solid; 50.1 mg (55%); purified by flash chromatography
1
(PE/EtOAc 97.5:2.5); H NMR (400 MHz, CDCl3): 7.31 – 7.26
(m, 2H), 7.21 – 7.17 (m, 3H), 2.83 – 2.74 (m, 2H), 2.68 – 2.58
(m, 2H), 2.53 (td, J = 7.1, 3.4 Hz, 2H), 2.23 – 2.01 (m, 4H), 1.91
(p, J = 7.4 Hz, 2H), 1.63 (s, 3H), 1.61 (s, 3H); 19F NMR (282
MHz, CDCl3): -71.0 (d, J = 6.6 Hz); 13C NMR (101 MHz,
CDCl3): 211.9, 141.8, 128.6, 128.5, 127.7 (q, J = 280.2 Hz),
126.1, 124.0, 122.8, 45.6 (q, J = 1.4 Hz), 42.4, 40.4 (q, J = 25.8
Hz), 35.1, 34.3, 29.8 (q, J = 2.8 Hz), 24.9, 18.7, 18.7; MS
(HRMS EI): Calcd for C19H23F3O: 324.1701; Found: 324.1715.
4.3. General procedure for the one-pot gold-catalyzed
rearrangement/Diels-Alder reaction
4.3.5 1-(trans-3,4-dimethyl-6-(trifluoromethyl)cyclohex-3-en-
1-yl)ethanone 14v
IPrAuNTf2 (0.05 eq) was weighted in a vial. A solution of
propargyl acetate (1 eq) in dioxane/water 80 : 1 (0.4-0.5 M) was
added. The diene (4 eq) was added immediately (one-pot with all
reagents) or after the specified time of stirring at 80 °C
(sequential one-pot). The mixture was then stirred at 80 °C in the
sealed vial and the solvents were removed under reduced
pressure. Purification by flash column chromatography afforded
the pure Diels-Alder adduct. A more detailed procedure for each
example can be found in the supporting information.
82% NMR yield; purified by flash chromatography (PE to
PE/Et2O 95:5); 1H NMR (400 MHz, CDCl3): 2.84 (td, J = 9.3, 5.9
Hz, 1H), 2.78 – 2.69 (m, 1H), 2.27 – 2.06 (m, 4H), 2.23 (s, 3H),
1.63 (s, 6H); 19F NMR (282 MHz, CDCl3): -71.2 (d, J = 7.4 Hz);
13C NMR (101 MHz, CDCl3): 210.1, 127.6 (q, J = 279.9 Hz),
123.8, 122.9, 46.4 (q, J = 1.6 Hz), 40.4 (q, J = 25.9 Hz), 33.7,
29.8 (q, J = 0.9 Hz), 29.7 (q, J = 2.8 Hz), 18.7, 18.7; MS (HRMS
EI): Calcd for C11H15F3O: 220.1075; Found: 220.1070.
4.3.1
[1,1'-biphenyl]-4-yl(trans-3,4-dimethyl-6-
(trifluoromethyl)cyclohex-3-en-1-yl)methanone 14k
4.3.6 1-trans-3,4-dimethyl-6-(perfluoroethyl)cyclohex-3-en-1-
yl)-4-phenylbutan-1-one 14h
White solid; reaction performed on a 0.133 mmol scale; 32.2
mg (68%); purified by flash chromatography (PE/EtOAc
97.5:2.5); 1H NMR (400 MHz, CDCl3): 8.06 – 8.04 (m, 2H), 7.72

8
Tetrahedron
Colorless oil; 62.6 mg (Product/enone in a 94:6 mixture,
127.7, 127.6, 123.0, 121.9 (q, J = 276 Hz), 116.7 (q, J = 2 Hz),
ACCEPTED MANUSCRIPT
79% yield); purified by flash chromatography (PE/Et2O 95:5); 1H
NMR (400 MHz, CDCl3): 7.31 – 7.27 (m, 2H), 7.21 – 7.18 (m,
3H), 2.89 – 2.87 (m, 2H), 2.70 – 2.48 (m, 4H), 2.18 – 2.10 (m,
4H), 1.93 (p, J = 7.3 Hz, 2H), 1.62 (s, 6H); 19F NMR (282 MHz,
CDCl3): -83.0, -111.1 (d, J = 267.8 Hz), -125.6 (dd, J = 268.2,
24.5 Hz); 13C NMR (101 MHz, CDCl3): 211.7, 141.8, 128.6,
128.5, 126.1, 123.8, 122.8, 119.3 (qt, J = 286.9, 36.8 Hz), 116.8
(ddq, J = 257.4, 255.1, 36.8 Hz), 44.6, 41.8 (d, J = 2.4 Hz), 37.9
(dd, J = 20.3, 18.6 Hz), 35.1, 34.2, 29.4 – 29.3 (m), 24.9, 18.7,
18.7; MS (HRMS EI): Calcd for C20H23F5O: 374.1669; Found:
374.1665.
101.5, 73.2, 69.1, 55.6, 29.7, 29.1; MS (HRMS EI): Calcd for
C21H20F3NO2: 375.1446; Found: 375.1414.
Acknowledgments
We are deeply appreciative of financial support from the Ecole
Polytechnique, Université catholique de Louvain (UCL), FNRS
(FRIA grant for A. Boreux) and thank Rhodia Chimie Fine (Dr.
F. Metz) for a generous gift of HNTf2. Stéphanie Jazzard is
acknowledged for the preparation of several fluorinated
substrates.
4.3.7
Phenyl(trans)-6-(trifluoromethyl)cyclohex-3-en-1-
yl)methanone 15j
References and notes
White solid; 38.4 mg (76%); purified by flash chromatography
(PE/EtOAc 97.5:2.5); H NMR (400 MHz, CDCl3): 7.98 – 7.96
1
1. (a) Thayer, A. M. Chem. Eng. News 2006, 84, 15. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320. (c) Wang, J.; Sanchez-Rosello, M.; Acena, J. N.; del
Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu,
H. Chem. Rev. 2014, 114, 2432; (d) Gillis, E. P.; Eastman, K. J.;
Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem.
2015, 58, 8315; (d) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu,
W.; Acena , J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem.
Rev. 2016, 116, 422;(e) Meanwell, N. A. J. Med. Chem. 2018,
ASAP.
(m, 2H), 7.61 – 7.57 (m, 1H), 7.51 – 7.47 (m, 2H), 5.80 – 5.72
(m, 2H), 3.80 (ddd, J = 9.9, 8.5, 6.8 Hz, 1H), 3.04 – 2.98 (m,
1H), 2.52 – 2.25 (m, 4H); 19F NMR (282 MHz, CDCl3): -70.9;
13C NMR (101 MHz, CDCl3): 202.0, 136.5, 133.6, 128.9, 128.5,
127.7 (q, J = 280.3 Hz), 125.0, 123.8, 39.8 (q, J = 25.8 Hz), 39.2
(q, J = 1.9 Hz), 28.8, 23.6 (q, J = 3.1 Hz); MS (HRMS EI): Calcd
for C14H13F3O: 254.0918; Found: 254.0912.
4.3.8 trans-4-(benzyloxy)-1-(6-(trifluoromethyl)cyclohex-3-en-
1-yl)butan-1-one 15a
2. For a selected review, see: Alonso, C.; Martinez de Marigorta, E.;
Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
3. For a review on β-fluoroalkylated α,β-unsaturated carbonyl
compounds, see : Billard, T. Chem. Eur. J. 2006, 12, 974. Selected
examples for the use of CF3-enones: (a) Zhu, Y.; Dong, Z.; Cheng,
X.; Zhong, X.; Liu, X.; Lin, L.; Shen, Z.; Yang, P.; Li, Y.; Wang,
H.; Yang, W.; Wang, K.; Wang, R. Org. Lett. 2016, 18, 3546; (b)
Kawai, H.; Okusu, S.; Yuan, Z.; Tokunaga, E.; Yamano, A.;
Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2013, 52,
2221−2225; (c) Matoba, K.; Kawai, H.; Furukawa, T.; Kusuda,
A.; Tokunaga, E.; Nakamura, S.; Shiro, M.; Shibata, N. Angew.
Chem., Int. Ed. 2010, 49, 5762; (d) Sanz-Marco, A. Synlett 2015,
26, 271.
4. (a) Ates, C.; Janousek, Z.; Viehe, H. G. Tetrahedron Lett. 1993,
34, 5711; (b) Xu, Y.; Dolbier, W. R. Tetrahedron Lett. 1998, 39,
9151; (c) Blond, G.; Billard, T.; Langlois, B. R. J. Org. Chem.
2001, 66, 4826; (d) Large, S.; Roques, N.; Langlois, B. R. J. Org.
Chem. 2000, 65, 8848.
White solid; 45.5 mg (72%); purified by flash chromatography
(hexane/acetone 93:7); H NMR (400 MHz, CDCl3): 7.38 – 7.26
1
(m, 5H), 5.74 – 5.63 (m, 2H), 4.48 (s, 2H), 3.54 – 3.43 (m, 2H),
2.89 – 2.81 (m, 1H), 2.80 – 2.72 (m, 1H), 2.66 (t, J = 7.1 Hz,
2H), 2.42 – 2.33 (m, 1H), 2.23 – 2.17 (m, 2H), 2.23 – 2.10 (m,
1H), 1.94 – 1.85 (m, 2H); 19F NMR (282 MHz, CDCl3): -70.1 (d,
J = 8.1 Hz); 13C NMR (101 MHz, CDCl3): 211.5, 138.4, 128.4,
127.7, 127.6, 127.5 (q, J = 280 Hz), 124.7, 123.7, 72.9, 69.1, 44.5
(q, J = 1.7 Hz), 39.5, 39.4 (q, J = 25.9 Hz), 27.4, 23.5, 23.4 (q, J
= 3.1 Hz); MS (HRMS EI): Calcd for C18H21F3O2: 326.1493;
Found: 326.1447.
5. Marrec, O.; Borrini, J.; Billard, T.; Langlois, B. Synlett, 2009, 8,
1241.
4.4. Synthesis of the CF3-quinoline 18
6. Xiong, H.-Y.; Yang, Z.-Y.; Chen, Z.; Zeng, J.-L.; Nie, J.; Ma, J.-
A. Chem. – Eur. J. 2014, 20, 8325.
A solution of enone (1.0 eq, 0.08 mmol) and p-anisidine (1.1
eq) in toluene (0.2 M) was charged to an NMR tube. Triflic acid
(0.05 eq) was added, the tube was quickly sealed, shaken
vigorously, and heated to 110 °C for 2 h 30. The solution was
cooled to room temperature, diluted with DCM and washed with
H2O. The aqueous layer was extracted with DCM (x3). The
organic phases were combined and filtered through silica gel.
The volatiles were removed under reduced pressure to give a pale
yellow oil. The oil was then dissolved in toluene (0.2 M) and
charged to an NMR tube. Triflic acid (0.05 eq) was added, the
tube was quickly sealed, shook vigorously, and heated to 110 °C
for 15h. The solution was cooled to room temperature, diluted
with DCM and washed with H2O. The aqueous layer was
extracted with DCM (x3). The organic phases were combined,
dried over MgSO4, and evaporated under reduced pressure. The
crude product was the purified by flash chromatography eluting
with hexane/acetone 8 : 2 to afford the quinoline (white solid, 8.6
mg, 30% yield).
7. Molines, H.; Wakselman, C. J. Fluorine Chem. 1980, 16, 97.
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Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073;
(c) Jeon, S. L.; Kim, J. K.; Son, J. B.; Kim, B. T.; Jeong, I. H.
Tetrahedron Lett. 2006, 47, 9107; (d) Yamazaki, T.; Kawasaki-
Takasuka, T.; Furuta, A.; Sakamoto, S. Tetrahedron, 2009, 65,
5945; (e) Watanabe, Y.; Yamazaki, T. J. Org. Chem. 2011, 76,
1957; (f) Hariss, L.; Hadir, K. B.; El-Masri, M.; Roisnel, T.; Grée,
R.; Hachem, A. Beilstein J. Org. Chem. 2017, 13, 2115; (g) Jeong,
I. H.; Jeon, S. L.; Kim, M. S.; Kim, B. T. J. Fluorine Chem. 2004,
125, 1629.
9. Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org. Chem.
2006, 71, 3545.
10. Filyakova, V. I.; Latypov, R. R.; Kotel’nikova, A. L.; Pashkevich,
K. I. Bull. Acad. Sci. URRS, Div. Chem. Sci. 1987, 36, 190.
11. (a) Yu, M.; Li, G.; Wang, S.; Zhang, L. Adv. Synth. Catal. 2007,
349, 871; (b) Yu, M. Zhang, G. Zhang, L. Org. Lett. 2007, 9,
2147; (c) de Haro, T.; Nevado, C. Chem. Commun. 2011, 47, 248;
(d) Zhang, G. Peng, Y. Cui, L. Zhang, L. Angew. Chem. Int. Ed.
2009, 48, 3112; (e) Wang, S.; Zhang, L.; J. Am. Chem. Soc. 2006,
128, 8414; (f) Yu, M.; Zhang, G.; Zhang, L. Tetrahedron, 2009,
65, 1846; (g) Wang, D.; Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088;
1H NMR (400 MHz, CDCl3): 8.11 (d, J = 9.2 Hz, 1H), 7.54
(s, 1H), 7.43 (dd, J = 2.7, 9.2 Hz, 1H), 7.38 – 7.28 (m, 5H), 7.32
(d, J = 2.7 Hz, 1H), 4.55 (s, 2H), 3.86 (s, 3H), 3.59 (t, 2H, J = 5.8
Hz), 3.22 (t, 2H, J = 7.8 Hz), 2.12 – 2.03 (m, 2H); 19F NMR (282
MHz, CDCl3): -67.2; 13C NMR (101 MHz, CDCl3): 159.2, 148.8,
145.2 (q, J = 34 Hz), 143.4, 138.3, 132.3, 129.4, 128.4, 127.7,
for
a gold-catalyzed synthesis of enones from propargylic
alcohols, see: (h) Ye, L.; Zhang, L. Org. Lett. 2009, 11, 3646.
12. Boreux, A.; Lonca, G. H.; Riant, O.; Gagosz, F. Org. Lett. 2016,
18, 5162.

9
13. Any attempt to improve the reactivity of these substrates by
ACCEPTED MANUSCRIPT
changing the nature of the solvent, increasing the reaction
temperature or the loading of the catalyst failed.
14. The presence of allenoates was observed in several cases by
monitoring the reaction by 1H and 19F fluorine NMR.
15. For the use of CF3-enones in Diels-Alder reactions, see: (a)
Leuger, J.; Blond, G.; Fröhlich, R.; Billard, T.; Haufe, G.;
Langlois, B. R. J. Org. Chem. 2006, 71, 2735.; for selected
examples where gold catalysis allows for the generation of one of
the Diels-Alder reaction partners, see: (b) Wang, X.; Yao, Z.;
Dong, S.; Weo, F.; Wang, H.; Xu, Z.; Org. Lett. 2013, 15, 2234;
(c) Borreiro, N. V.; DeRatt, L. G.; Barbosa, L. F.; Abboud, K. A.;
Aponick, A. Org. Lett. 2015, 17, 1754; (d) Yan, J.; Tay, G. L.;
Neo, C.; Lee, B. R.; Chan, P. W. H. Org. Lett. 2015, 17, 4176; (e)
Sun, N.; Xie, X.; Chen, H.; Liu, Y. Chem. Eur. J. 2016, 22, 14175;
(f) Hosseyni, S.; Wojtas, L.; Li, M.; Shi, X. J. Am. Chem. Soc.
2016, 138, 3994.
16. The isomerization of the final product by keto-enol tautomerism
under the reaction conditions is unlikely since no isomerization
was observed for the analogous formation of compound 15j, a
cycloadduct that would be more prone to such a process.
Moreover, the syn/anti ratio was found to not evolve during the
course of the reaction.
17. Any attempt to perform the reaction in a one-pot sequential
manner from propargylic acetate 1a failed. The use of additional
oxidant in the second step of the process did not improve the yield
in quinoline 18.
Supplementary material (procedures, physical and spectral
data of the prepared compounds, NMR spectra) is available free
of charge on xxx.