Synthesis of β-CF3 ketones from trifluoromethylated allylic alcohols by ruthenium catalyzed isomerization

Article abstract of DOI:10.1016/j.jfluchem.2013.01.004

This work describes the optimization process for the synthesis of β-trifluoromethylated ketones from trifluoromethylated allylic alcohols. This transformation proceeds through a ruthenium catalyzed isomerization under mild conditions with high atom econom

Full text of DOI:10.1016/j.jfluchem.2013.01.004

Journal of Fluorine Chemistry 152 (2013) 56–61
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of
b
-CF3 ketones from trifluoromethylated allylic alcohols by ruthenium
catalyzed isomerization
a,
Vincent Bizet a, Xavier Pannecoucke a, Jean-Luc Renaud b, , Dominique Cahard
*
*
a UMR 6014 CNRS de l’IRCOF, Universite´ de Rouen et INSA de Rouen, Rue Tesnie`re, F-76821 Mont-Saint-Aignan Cedex, France
b UMR CNRS 6507 LCMT, Universite´ de Caen – ENSICAEN, Avenue du Mare´chal Juin, 14050 Caen, France
A R T I C L E I N F O
A B S T R A C T
Article history:
This work describes the optimization process for the synthesis of
b-trifluoromethylated ketones from
Received 28 November 2012
Received in revised form 2 January 2013
Accepted 3 January 2013
trifluoromethylated allylic alcohols. This transformation proceeds through a ruthenium catalyzed
isomerization under mild conditions with high atom economy. The effect of the CF3 group was analyzed
and it provides fundamental insights into the isomerization reaction.
Available online 31 January 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium
Fluorinated compounds
Catalysis
Isomerization
Atom economy
1. Introduction
a,b-unsaturated acyl-oxazolidinones featuring an internal olefin;
however, the new C(sp3)–CF3 stereogenic centers formed in the
reaction is not at all controlled by the chiral auxiliary (1:1 dr) [5].
The construction of C(sp3)–CF3 stereogenic centers at the
a-
position of a carbonyl function has been the subject of several
successful investigations. Diastereoselective and enantioselective
electrophilic trifluoromethylation have produced high level of
asymmetric induction for mono- and dicarbonyl compounds [1].
Introducing a CF3 group two carbons away from the carbonyl
Thus, the direct introduction of a CF3 group at the remote
with concomitant stereocontrol remains topic to develop.
Alternative synthetic approaches relies on asymmetric reactions
of -CF3- -unsaturated carbonyl compounds by transfer hydro-
genation [6], hydrogenation [7], or conjugate addition [8]. These
methods provide new C(sp3)–CF3 stereogenic centers at the
position by C–H, C–C, or C–heteroatom bond forming reactions with
high enantioselectivities [9]. In addition, highly enantiospecific
sigmatropic rearrangements of mixed ketene acetals [10] or
allyloxyacetates [11] that proceed through well-defined cyclic
transition states have demonstrated high level of chirality transfer.
We have recently developed a new approach to C(sp3)–CF3
b-position
a
b
a,b
function at the remote
enolatechemistryisobviouslynot appropriate in thiscase. The direct
C(sp3)–trifluoromethylation at the
-position of a carbonyl function
is not known. Some rare examples of a C(sp2)–trifluoromethylation
of -unsaturated carbonyl compounds have been reported [2]. A
b-position is a more challenging task because
b-
b
a,b
unique case of nucleophilic conjugate addition of the CF3 group to
cyclohexenone is described by means of the Ruppert-Prakash
reagent in the presence of one equivalent of the bulky Lewis acid
aluminum tris(2,6-diphenylphenoxide) that activates the enone and
masks the carbonyl function to allow the 1,4-addition to take place
exclusively [3]. The radical iodotrifluoromethylation of acryloyl
camphor sultams gave a 4:1 diastereomeric ratio (dr) but the
stereogenic centers at the
b-position of carbonyl functions by
means of the catalytic isomerization of allylic alcohols (Fig. 1) [12].
The isomerization of allylic alcohols is an efficient, selective, atom-
economic, one-step process for isomerization of C55C bond of O-
allylic substrates into saturated carbonyl compounds. The overall
process is equivalent to a sequential two-step oxidation and
reduction reactions or vice versa. From a mechanistic point of view,
a transition metal assists the migration of a hydrogen atom in the
form of a hydride from C1 to C3, the intermediate enol then
tautomerizes to the carbonyl compound [13]. Many transition
metals have been employed in the isomerization of allylic alcohols;
Ru, Rh and Ir catalysts dominate the field, in particular in the
new stereogenic center at
a-position does not contain the
CF3 group [4]. It is only recently that Koksch, Czekelius and
coworkers described a conjugate hydrotrifluoromethylation of
* Corresponding authors. Tel.: +33 2 35 52 24 66.
E-mail address: dominique.cahard@univ-rouen.fr (D. Cahard).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.01.004

V. Bizet et al. / Journal of Fluorine Chemistry 152 (2013) 56–61
57
Access to -CF3 carbonyl compounds
literature procedure from 2-bromo-3,3,3-trifluoropropene [15].
Compound 2 having a trisubstituted olefin was obtained through a
Wittig olefination of the hydrate of 3,3,3-trifluoro-1-phenylpro-
pane-1,2-dione followed by DIBAL-H reduction of the carbonyl
function. This synthetic route was developed in our laboratory and
by
R1 OH
R2
R1
O
redox isomerization
F3C
F3C
R2
this work
is applicable to other substitution patterns of
rated carbonyl compounds [16]. Secondary allylic alcohol 3
featuring a -CF3 group and a disubstituted double bond was
a-CF3-a,b-unsatu-
Fig. 1. Isomerization of CF3 allylic alcohols.
b
development of the asymmetric version [12,14]. Before our work,
the reaction has never been investigated with fluorinated allylic
alcohols; consequently, we undertook an in-depth study with
allylic alcohols that feature a CF3 olefin moiety. Ruthenium
catalysts were selected for this purpose because many ruthenium
complexes, which are stable in many oxidation states, have already
demonstrated high efficiency in the isomerization and because of
their lower cost compared to Rh or Ir catalysts. In addition to the
screening of various reaction parameters (catalyst, solvent, base,
temperature, concentration), the impact of the CF3 group position
prepared from 2-bromo-3,3,3-trifluoropropene via the addition of
the intermediate lithium acetylide to 2-phenylacetaldehyde
followed by a stereoselective Red-Al reduction [17]. A series of
trisubstituted derivatives of
b-CF3 allylic alcohols were synthe-
sized from the corresponding trifluoromethylketones by a Wittig-
Horner olefination that provides stereoselectively E-enones 4a–l
and a further reduction by DIBAL-H to end up with products 5a–l
[18]. One tetrasubstituted derivative 6 was also prepared by a
literature procedure [19] even if this type of fully substituted allylic
alcohol has rarely been successfully transposed because of the high
steric hindrance [20]. It would be a great achievement if the
trifluoromethylated substrate 6 could provide the isomerization
either at the
a- or the b-position of the allylic alcohol was
evaluated. Importantly, all the data collected through this study
provided new insights in the reaction mechanism clearly
highlighting the specific effect of the fluorine atoms in the
isomerization.
product. Finally,
b-CF3 trisubstituted primary allylic alcohols 5m
and 5n were obtained by a straightforward sequence olefination/
reduction [21].
With eighteen allylic alcohols at hand, our initial investigation
started with
ruthenium complexes in the isomerization of the
a
survey of the catalytic activity of different
-CF3 secondary
2. Results and discussion
b
allylic alcohol 5a (Table 1). The reactions were performed at
temperatures comprised between 30 and 60 8C using 10 mol % of
catalyst in toluene (0.5 M) in the presence of one equivalent of
Cs2CO3 to give the ketone 7a as the expected product accompanied
All the allylic alcohols required for the study were readily
synthesized from commercially available sources of trifluoro-
methylated reactants (Scheme 1). Allylic alcohol 1 featuring an a-
CF3 group and a disubstituted olefin moiety was prepared via a
-CF3 disubstituted secondary allylic alcohols
OH
Ph
Zn, CuClcat
Br
PhCHO
+
Pyr/THF (1:2)
51%
1
CF3
CF3
-CF3 trisubstituted secondary allylic alcohols
O
NaNH2, THF
HMDScat
DIBAL-H, CH2Cl2
–78°C, 5 min
Ph OH
Ph
Ph
O
CF3
Ph3P+ Ph
Cl–
Ph
+
Ph
76%
68%
HO OH
CF3
CF3
OH
Bn
2
-CF3 disubstituted secondary allylic alcohols
OH
Br
CF3
BnCHO
Red-Al
LDA
F3C
Li
F3C
Bn
THF
48%
toluene, –78°C
27%
F3C
3
-CF3 trisubstituted secondary allylic alcohols
(See Table 3 for the nature of R1 and R2 groups)
R1
O
R1 OH
DIBAL-H
O
O
R1 CF3
NEt3, DMF, THF
Ph3P+
CH2Cl2, 0°C
R2
+
F3C
R2
F3C
R2
Cl–
50-97%
58-98%
4a-l
5a-l
-CF3 tetrasubstituted secondary allylic alcohols
NaNH2, THF
F3C
t-Bu
OH
Ph
t-BuLi / TMEDA
F3C
EtO
H
Ph3P+ Ph
Cl–
6
PhCHO
37%
CF3CO2Et
Ph
Ph
-CF3 trisubstituted primary allylic alcohols
DIBAL-H
CH2Cl2, 0°C
R1
O
R1
O
O
O
NaH, THF
70-99%
(EtO)2P
+
R1 CF3
F3C
OEt
F3C
OH
OEt
92-99%
4m-n
5m-n
Scheme 1. Preparation of a library of allylic alcohols.

58
V. Bizet et al. / Journal of Fluorine Chemistry 152 (2013) 56–61
Table 1
Catalyst screening.
10 mol% catalyst
Ph OH
Ph
O
Ph
O
+
F3C
Ph
toluene (0.5 M)
Cs2CO3 (1 equiv.)
F3C
ketone 7a
Ph
F3C
enone 4a
Ph
5a
Entry
Catalyst
Time (h)
T (8C)
7a (yield %)a
4a (yield %)a
1
2
RuCl2(PPh3)3
1
2
30
30
50
50
50
50
48
60
50
50
90
90
56
94
72
30
4
9
<1
<1
2
RuCl2(PPh3)3 (1 mol%)
[Ru(Cp*)(MeCN)3]PF6
(RuCl2(C6H6))2
3
3
4
3
5
(RuCl2(p-Cym))2
6
6
6
RuCl2(p-Cym)(PMe3)
[RuCl(p-Cym) (PMe3)2]PF6
RuCl3ꢀxH2O
6
4
7
5
8
5
2
4
4
3
9
(RuCl2(Indenyl))2
[RuCl2(R-BINAP)]x
15
8
61
77
10
a
Yields were determined by 19F NMR using trifluorotoluene as internal standard.
by 1–9% of enone 4a. Application of a threshold temperature
appeared necessary to allow the reaction to happen within a
the catalyst loading to 1 mol%; furthermore, the reaction became
very clean and quantitative without detection of side product
(Table 1, entry 2).
reasonable time. Unlike the isomerization of
b-disubstituted
substrates with Ru or Rh complexes that typically required
temperatures in the range 70–100 8C, it is noteworthy that we
conduct the reactions between 30 and 60 8C for sterically more
hindered trisubstituted substrates. Concerning the nature of the
ruthenium complexes, ruthenium(II) are suitable while rutheniu-
m(III) is not active in this isomerization reaction. From Table 1, we
can also conclude that electron rich ancillary ligands, such as
Toluene is the most appropriate solvent for this isomerization
whereas other solvents, e.g. CH3CN, CH2Cl2, THF, i-PrOH, PhCF3,
failed to produce the target
b-CF3 ketone in good yields (Table 2,
entries 1–6) as it is also the case for a deviation of the concentration
of the reaction mixture (Table 2, entries 7–9). Indeed, an optimized
0.5 M toluene solution of the substrate permits full conversion. It is
worth noting that the use of wet toluene does not impede the
reaction course [22]. The amount and the nature of the base are
important parameters since in the absence of base there is no
conversion and inorganic bases, in particular Cs2CO3, are preferred
to organic ones (Table 2, entries 10–15). A catalytic amount of
Cs2CO3 should theoretically allows the reaction to go to comple-
tion, but in practice, one equivalent of base is really needed
probably due to the heterogeneity of the system [23].
pentamethylcyclopentadienyl or trimethylphosphine, have
a
detrimental effect in this process (entries 3, 6, 7 or 5 versus 4).
Although the dimeric (RuCl2(C6H6))2 gave a high conversion at
50 8C for 3 h (Table 1, entry 4), a good comprise was found with the
ruthenium(II) complex RuCl2(PPh3)3, which is much cheaper, and
provides a complete conversion after one hour at 30 8C (Table 1,
entry 1). The desired
b-CF3 saturated ketone 7a is always
accompanied by the corresponding enone 4a resulting of an
incomplete redox process. In this case, the abstraction of the
Encouraged by the discovery of this new route to
carbonyl compounds, we next examined the scope of the reaction
with different -CF3 substituted secondary allylic alcohols and we
undertook a comparison of our trifluoromethylated allylic alcohols
b-CF3
hydrogen
a
to the OH group by the metal is not followed by a
b
subsequent 1,4-hydride addition. Fortunately, we were able to
minimize the proportion of enone 4a to less than 1% by lowering
with non-fluorinated substrates. From all the
b
-CF3 substituted
Table 2
Screening of solvent, concentration and base.
Ph OH
Ph
Ph
O
10 mol% RuCl2(PPh3)3
solvent, base, 30°C, 2h
Ph
O
+
F3C
F3C
Ph
F3C
Ph
5a
7a
4a
Entry
Solvent
Concentration (M)
Base
7a (yield %)a
4a (yield %)a
1
2
toluene
CH3CN
CH2Cl2
THF
0.5
0.5
0.5
0.5
0.5
0.5
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
90
4
9
2
3
<1
<1
<1
37
18
15
0
<1
<1
<1
4
4
5
i-PrOH
PhCF3
6
7
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
10
4
8
0.25
0.1
0.5
0.5
0.5
0.5
0.5
0.5
9
<1
<1
<1
<1
0
10
11
12
13
14
15
Et3
N
<1
<1
28
0
DBU
t-BuOK
K2CO3
K3PO4
without
16
0
1
0
a
Yields were determined by 19F NMR using trifluorotoluene as internal standard.

V. Bizet et al. / Journal of Fluorine Chemistry 152 (2013) 56–61
59
Table 3
Isomerization of various
b-CF3 substituted allylic alcohols.
R1 OH
R1
O
1 mol% RuCl2(PPh3)3
R2
F3C
R2
toluene (0.5 M)
Cs2CO3 (1 equiv.)
F3C
Entry
Allylic alcohol
R1
Time (h)
T (8C)
Ketone (yield %)a
R2
1
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
Ph
2
4
30
30
30
30
30
60
30
60
60
30
70
50
40
7a, 95
7b, 76
7c, 65
7d, 73
7e, 66
7f, 93
7g, 63
7h, 71
7i, 76
7j, 77
7k, 75
7l, 93
8, 40
Me
Ph
3
Bn
Ph
5
4
p-MeOC6H4
p-CF3C6H4
Ph
Ph
3
5
Ph
2
6
Me
Me
Me
Me
Ph
2
7
Bn
3
8
o-MeOC6H4
p-MeOC6H4
p-BrC6H4
Ph
2
9
3
10
11
12
13
5j
2
5k
5l
t-Bu
Ph
12
24
3
(H3C)2C5CH(CH2)2
3
H
Bn
a
Yields for analytically pur products (all conversions determined by 19F NMR using trifluorotoluene as internal standard were >99% with less than 5% side-products).
Yields are not optimized except for entry 1.
secondary allylic alcohols, the reaction lead to saturated ketones
quantitatively (Table 3). Substrates featuring a rather sterically
hindered trisubstituted alkene moiety (Table 3, entries 1–12)
behave equally well to one with a disubstituted alkene (Table 3,
entry 13), clearly demonstrating that the steric bulk of the CF3
group, whose molar volume is similar to that of an isopropyl group,
is not detrimental to the reactivity. Attempts to isolate the
clearly indicate that the bulkiness of the CF3 substituent does not
impede the reaction and that the electron-withdrawing effect of the
CF3 very significantly enhances the rate of the reaction.
Although there are several methods in the literature for the
direct trifluoromethylation of carbonyl compounds, the access to
a
-CF3 carbonyls by isomerization is not known. An extension of the
work done with -CF3 allylic alcohols would be the study of -CF3
allyl alcohols 1 and 2 (see Scheme 1 for their preparation).
However, and appeared inert under the isomerization
b
a
isomerization product of b-CF3 substituted primary allylic alcohols
5m (R1 = Ph) or 5n (R1 = Bn) led to the corresponding saturated
alcohol as the main product along with aldol condensation
products. In these two cases, the isomerization took place giving
the expected aldehydes, which are prone to reduction under the
1
2
conditions. For this type of substrate, the strongly electron-
withdrawing CF3 group weakens the hydride character of the
hydrogen atom at the alcohol function and prevents hydride
abstraction by the ruthenium complex.
The mechanism of the isomerization has been investigated in
details [13f,24]; however, the case of trifluoromethylated allylic
alcohols deserves a specific interest. Indeed, we have demonstrat-
ed by kinetic studies, deuterium-labeling experiments, crossover
reaction conditions leading to the saturated alcohols and to
deprotonation leading to aldol products. The highly sterically
hindered -CF3 tetrasubstituted secondary allylic alcohol 6 was
a-CH
b
also submitted to the isomerization conditions but no desired
rearranged product was observed even after 15 h at 110 8C. The
isomerization of allylic alcohols is fostered thanks to the CF3 group;
however, this capability of the CF3 group is annihilated in the
special case of a tetrasubstituted alkene.
experiments, and X-ray analyses that the isomerization of
b-CF3
allylic alcohols into the corresponding saturated ketones is a
ruthenium-mediated syn-specific 1,3-hydrogen shift [12]. The
The effect of the CF3 substituent was analyzed in a comparison of
our trifluoromethylated allylic alcohols with non-fluorinated
substrates. Replacement of the CF3 group in 5a by a methyl group
(either the E or Z isomer) required both a much higher reaction
temperatureand a longerreactiontime but theyields remained poor
and some by-products were observed (Scheme 2, 9 ! 10). Even, a
less hindered disubstituted substrate failed to provide the isomer-
ized product in good yield (Scheme 2, 11 ! 12). These observations
main differences in reactivity between b-CF3 allylic alcohols and
non-fluorinated counterparts are: (i) the electron-withdrawing CF3
group accelerates the overall reaction rate, (ii) the bulkiness of the
CF3 group does not impede the reaction even for trisubstituted
substrates, (iii) the rate-determining step in the isomerization of
b
-CF3 substituted substrates is the b-elimination while it is the
insertion for non-fluorinated substrates. The successive steps of
the mechanism are proposed in Fig. 2, which also illustrates the
enantiospecificity of the process from optically pure (R)-5a.
The fact that the intermediate enone stays coordinated to the
metal combined with a rapid insertion step make the enantios-
pecific isomerization highly efficient with complete retention of
the chiral information. Since chiral optically enriched allylic
alcohols are readily available, the enantiospecific approach is a
Ph OH
Ph
Ph
O
1 mol% RuCl2(PPh3)3
10
Me
Me
Ph
toluene, Cs2CO3
100°C, 15h
E- orZ-9
10% from Z–9
21% from E–9
convenient method to access chiral non-racemic
b-CF3 carbonyl
OH
Ph
O
1 mol% RuCl2(PPh3)3
compounds. However, the mechanism of the reaction does not
argue in favor of a direct enantioselective version starting from
racemic allylic alcohols by means of a chiral ruthenium catalyst.
Indeed, all our attempts to use chiral Ru(II) complexes as catalyst
in the isomerization failed to deliver a reasonable level of
stereoinduction.
12
Ph
Ph
Ph
toluene, Cs2CO3
30°C, 9h
E–11
33%
Scheme 2. Comparison with non-fluorinated substrates.

60
V. Bizet et al. / Journal of Fluorine Chemistry 152 (2013) 56–61
H
PPh3
Ph
Ph
H OH
Ph
[RuCl2(PPh3)3]
O
Cl
PPh3
Ru
CF3
PPh3
Ph
(R)-5a
Cs2CO3
CsHCO3
CsCl
F3C
+ PPh3 - PPh3
O
H
Ph
CF3
H
Ph
Ph
PPh3
Cl
-elimination
Ph
O
(R)-7a
Ru
PPh3
Ph
(R)-5a
F3C
O
O
H
H
Ph
PPh3
Cl
PPh3
Cl
Ph3P
PPh3
O
Ru
Ru
Ph
Ph3P
PPh3
PPh3
Ph
Ru Cl
PPh3
or
Ph
H
F3C
F3C
Ph
F3C
Insertion
Fig. 2. Reaction mechanism
3. Conclusion
mixture was heated for 2 h at 30 8C. Then, the reaction mixture was
filtered through a pad of celite, concentrated under reduced
pressure and purified by column chromatography on silica gel
(petroleum ether/ethyl acetate: 99/1) to give the desired 4,4,4-
trifluoro-1,3-diphenylbutan-1-one 7a. Yield: 95%; white solid
We have developed straightforward conditions for the isomeri-
zation of -trifluoromethylated secondary allylic alcohols. The
b
ruthenium(II) complex RuCl2(PPh3)3 is suitable to conduct the
intramolecular 1,3-hydrogen shift at temperatures comprised
between 30 and 70 8C in toluene in the presence of Cs2CO3. The
rather low reaction temperature for this transformation as well as
the easy reaction with trisubstituted allylic alcohols are ascribed to
the electron-withdrawing effect of the CF3 group, which strongly
accelerate the insertion step compared to non-fluorinated sub-
strates. A mechanistic study revealed that the rate-determining
(mp = 66 8C). 1H NMR (CDCl3)
J = 4.3 Hz), 3.64 (dd, 1H, J = 17.8 Hz, J = 8.8 Hz), 4.11–4.25 (m,
1H), 7.18–7.87 (m, 10H); 13C NMR (CDCl3)
38.4 (q, J = 2.0 Hz), 44.9
d
3.52 (dd, 1H, J = 17.8 Hz,
d
(q, J = 27.4 Hz), 127.1 (q, J = 279.5 Hz), 128.2, 128.4, 128.8, 128.9,
129.2, 133.7, 134.7 (q, J = 1.9 Hz), 136.4, 195.4; 19F NMR (CDCl3)
d
ꢁ70.2 (d, J = 9.7 Hz); HRMS Calcd for C16H13F3O (M+), 278.0918,
Found 278.0920; IR (neat) 3068, 1680, 1300, 1250, 1187, 1153,
1103 cmꢁ1
n
step is the
b
-elimination and that the isomerization proceeds
.
through a metal-mediated syn-specific 1,3-hydrogen shift allowing
an enantiospecific version from optically enriched allylic alcohols
with a total transfer of chirality. However, appropriate conditions
for an enantioselective version remain to be found.
Acknowledgments
This work is promoted by the interregional CRUNCh network.
V.B. thanks the Re´gion Haute-Normandie for a fellowship. Johnson-
Matthey is acknowledged for a generous loan of catalysts.
4. Experimental
Appendix A. Supplementary data
4.1. General remarks
1H (300 MHz), 13C (75.5 MHz) and 19F (282 MHz) NMR spectra
were recorded on Bruker AVANCE 300. Chemical shifts in NMR
spectra are reported in parts per million from TMS or CFCl3
resonance as the internal standard. IR spectra were recorded on a
Perkin-Elmer IRFT 1650 spectrometer. The conversion and ratio of
the corresponding products were determined by 19F NMR analysis
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.
01.004.
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