Catalyst-Free Oxytrifluoromethylation of Alkenes through Paired Electrolysis in Organic-Aqueous Media

Article abstract of DOI:10.1002/chem.201804708

A mild, catalyst-free electrochemical oxytrifluoromethylation of alkenes has been developed. The procedure is based on the paired electrolysis of sodium triflinate and water in an undivided cell. Anodic oxidation of the triflinate anion generates trifluoromethyl radicals that react with the alkene. Water plays a dual role as oxidant for the cathode and nucleophile. The method has been utilized to prepare a diverse set of 1-hydroxy-2-trifluoromethyl compounds in moderate to excellent yields (27–94 %). Alcohols have also been tested as nucleophiles for this versatile method with moderate yields. Facile recycling of the electrolyte has been demonstrated, and application of electricity avoids the use of stoichiometric amounts of oxidizers in a safe and environmentally benign reaction.

Full text of DOI:10.1002/chem.201804708

A Journal of
Accepted Article
Title: Catalyst Free Oxytrifluoromethylation of Alkenes via Paired
Electrolysis in Organic-Aqueous Media
Authors: Wolfgang Jud, C. Oliver Kappe, and David Cantillo
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201804708
Link to VoR: http://dx.doi.org/10.1002/chem.201804708
Supported by

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Catalyst Free Oxytrifluoromethylation of Alkenes via Paired
Electrolysis in Organic-Aqueous Media
Wolfgang Jud,[a,b] C. Oliver Kappe,*[a,b] and David Cantillo*[a,b]
Abstract:
A
mild,
catalyst
free
electrochemical
hydroxyl group are added to the double bond. The resulting 1-
hydroxy-2-trifluoromethyl compounds provide easy access to
trifluoromethylated 1,3-dioxolanes,[9] lactones,[10] imidazoles[11]
and other 1,2-difunctionalized trifluoromethylated building
blocks.[12] Several methods for the oxytrifluoromethylation of
alkenes have been described in the literature (Scheme 1). Li and
Studer utilized the Togni reagent as CF3 source in combination
with stoichiometric amounts of the sodium salt of TEMPO to
generate a TEMPO-intermediate, that released the desired
product upon treatment with Zn.[13] A one-pot procedure using
the Umemoto reagent and Ir(ppy)3 as photoredox catalyst was
described by Koike and Akita.[14] Jiang and Qing combined
sodium triflinate and 6 equiv tBuOOH (to generate CF3 radicals)
with hydroxamic acid to form another oxyamine intermediate.[15]
The corresponding alcohol was then obtained after reducing the
N-O bond with Mo(CO)6.[15] Notably, these methods utilize
expensive CF3 sources,[13,14] stoichiometric amounts of oxidizing
or reducing agents[13,15] or expensive metal catalysts,[14] which
limits their applicability in large scale synthesis.
oxytrifluoromethylation of alkenes has been developed. The
procedure is based on the paired electrolysis of sodium triflinate and
water in an undivided cell. Anodic oxidation of the triflinate anion
generates trifluoromethyl radicals that react with the alkene. Water
plays a dual role as oxidant for the cathode and nucleophile. The
method has been utilized to prepare a diverse set of 1-hydroxy-2-
trifluoromethyl compounds in moderate to excellent yields (27-94%).
Alcohols have also been tested as nucleophiles for this versatile
method with moderate yields. Facile recycling of the electrolyte has
been demonstrated, and application of electricity avoids the use of
stoichiometric amounts of oxidizers in a safe and environmentally
benign reaction.
Organofluorine compounds have become increasingly important
over the past two decades.[1] Introduction of fluorine atoms into
organic molecules typically provides significant benefits on their
biological properties such as improved lipophilicity, bioavailability
and metabolic stability.[2] Significant research efforts have
therefore been devoted to the development of synthetic tools for
the fluorination and perfluoroalkylation of organic scaffolds. A
particularly interesting moiety is the trifluoromethyl group (CF3).
A plethora of methods for the trifluoromethylation of many
functional groups have been described during this decade.[3]
Trifluoromethyl sources can be classified according to the
electrophilic or nucleophilic character of the CF3 group, and
include relatively complex reagents such as the Umemoto´s or
Togni´s reagents, or simple and inexpensive chemicals like
trifluoroiodimethane, triflyl chloride, trifluoroacetic acid salts or
sodium triflinate.[3]
Trifluoromethylations of unactivated alkenes are especially
challenging transformations.[4] Electrophilic CF3 reagents
typically fail unless the olefin bond is activated by electron-donor
groups in the vicinity or metal catalysts (e.g. copper catalysts)
are used as additive.[5] In the latter case, radical mechanisms
are usually invoked.[5,6] Thus, methods based on the generation
of CF3 radicals via photoredox catalysis are suitable and often
preferred alternatives.[7] Oxytrifluoromethylation of alkenes is an
attractive 1,2-difunctionalization[8] in which the CF3 and a
[a]
[b]
W. Jud, Prof. Dr. C. O. Kappe, Dr. D. Cantillo
Center for Continuous Flow Synthesis and Processing (CC FLOW)
Research Center Pharmaceutical Engineering GmbH (RCPE)
Inffeldgasse 13, 8010 Graz, Austria
W. Jud, Prof. Dr. C. O. Kappe, Dr. D. Cantillo
Institute of Chemistry
University of Graz
Heinrichstrasse 28, 8010, Graz, Austria
E-mail: oliver.kappe@uni-graz.at; david.cantillo@uni-graz.at
Scheme 1. a) Background of methods for the oxytrifluoromethylation of
styrenes and (b) catalyst-free electrochemical procedure developed in this
work.
Supporting information for this article is given via a link at the end of
the document
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In the past few years, electrochemistry is seeing
a
acetone/water (ε = 35.7 and 20.5 for MeCN and acetone,
respectively), electrolyses in THF and MeTHF (ε = 7.5 and 7.0)
were carried out at 20 mA. For dioxane (ε = 2.2) only 10 mA
could be applied. The electrolyte used as additive had a minor
influence on the reaction outcome (entries 8-10), and its
concentration negligible influence (see Figure S2 in the
Supporting Information). Conversion increased with the
substantial resurgence as
a greener alternative to many
synthetic routes involving redox processes.[16,17]. As electrons
are essentially the reagent utilized for the redox process, the use
of large amounts of often hazardous oxidizing or reducing
reagents can be avoided. Thus, electrochemical reactions are
considered safe and “inherently green”.[18] In this context,
electrochemical difunctionalization of alkenes is a powerful and
versatile synthetic tool very recently established.[19] The group of
Li has developed an elegant methodology for the radical
diazidation,[20] dichlorination[21] and chlorotrifluoromethylation[22]
of alkenes based on electrocatalysis mediated by Mn(II) salts,
using TFA as sacrificial oxidant. More recently Mei, Du and Han
have reported the oxysulfuration of alkenes using an undivided
cell and Pt electrodes,[23] while Lei has described oxy- and
aminosulfuration of alkenes under similar conditions.[24]
substrate
concentration
(Figure
S2c).
However,
at
concentrations higher than 0.2 M the triflinate was not fully
soluble in the solvent mixture.
19F-NMR monitoring of the reaction mixture revealed
consumption of more than
1 equiv CF3SO2Na even at
conversions below 90%. We hypothesized that part of the CF3
radicals are trapped by e.g. H2O, forming side-products that
could not be detected (e.g. gaseous CF3OH). This effect was
more pronounced at higher conversions. Applying 2.2 F/mol of
electricity (10% excess) 85% conversion was achieved with the
optimal solvent combination. 3.2 F/mol were required to increase
the conversion to 97% (see Figure S4 in the Supporting
Information). Ultimately, excellent conversion and selectivity for
the desired product 2a was achieved by increasing the amount
of charge applied to 3.2 F/mol and 1.6 equiv of CF3SO2Na, both
in acetone and THF as solvent (Table 1, entries 11 and 12) (a
GC-FID chromatogram of the crude reaction mixture is shown in
Figure S5). Unsurprisingly, minor amounts (<10%) of the
acetone aldol condensation product were observed when
acetone was used as co-solvent. This compound is likely formed
as a result of the basic conditions due to OH- formation during
the reaction.[27] Gratifyingly, this volatile impurity could be
removed from the product by simple evaporation.
Given the important drawbacks of the oxytrifluoromethylation
of alkenes using traditional synthetic methods or even
photoredox catalysis, we envisaged
a novel strategy to
accomplish this transformation based on the paired electrolysis
of cheap and readily available sodium triflinate as CF3 source
and water. Thus, anodic oxidation of the CF3SO2 anion releases
the CF3 radical.[25] Upon addition to the double bond, a second
anodic oxidation would generate the corresponding benzyl
cation (Scheme 1b). Water is concurrently reduced in the
cathode, generating hydrogen gas and the hydroxide anion that
acts as nucleophile.
To evaluate this hypothesis, we began our investigation with
a series of reactions using 4-tert-butyl styrene as model
substrate and several electrolytes, electrodes, and solvent
combinations (Table 1). In a typical experiment the substrate
(0.2 M), the electrolyte (0.1 M) and CF3SO2Na were dissolved in
a 10:1 organic solvent/water mixture and electrolyzed under
argon atmosphere at constant current. Optimization reactions
were carried out on 0.5 mmol scale. Apart from serving as
oxidant and nucleophile, water helped to solubilize the sodium
triflinate salt. Initial attempts (Table 1, entries 1-3) demonstrated
the viability of this synthetic approach. Good conversions and
moderate selectivities were obtained in MeCN/water using
graphite, platinum and stainless steel (SS) cathodes after
applying 2.2 F/mol (10% excess over the theoretical required
current) and 60 mA. Variable amounts of the products derived
from the trifluoromethylation and trifluoromethanesulfonylation of
the styrene aromatic ring were obtained as the main side-
products of the reaction. These side reactions support a radical
mechanism with both CF3 and CF3SO2 radicals as intermediates
(vide infra). Graphite was utilized as anode in all cases.
Stainless steel showed a slightly better performance as a
cathode and was therefore chosen for subsequent experiments
as an inexpensive and practical material.
Table 1. Optimization of the electrochemical oxytrifluoromethylation of
alkenes using t-butyl styrene 1a as model sobstrate.[a]
Q
CF3
Conv.
Selec.
[%][d]
Entry Solventb Cathode Electrolyte
[F/mol] [equiv][c] [%][d]
1
MeCN
MeCN
MeCN
Graphite Bu4NBF4
2.2
2.2
2.2
2.2
2.2
2.2
2.2
3.0
3.0
3.0
3.2
3.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.6
1.6
85
85
89
73
93
86
80
95
95
92
98
93
67
67
73
77
87
82
88
86
87
82
87
89
2
Pt
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
Bu4NBF4
LiClO4
3
SS
4
MeTHF SS
Dioxane SS
5
6
THF
SS
7
Acetone SS
8
THF
THF
THF
THF
SS
SS
SS
SS
9
The organic solvent utilized had a significant influence on the
reaction performance (Table 1, entries 3-7). Best results were
achieved in dioxane, THF and acetone (entries 5-7). Despite the
presence of the electrolyte, the maximum current that could be
applied to the cell (keeping the potential within the desired ca. 3-
4 V range) depended on the solvent utilized. As expected, the
values correlated well with the dielectric constant of the solvent,
which ultimately determines the conductivity.[26] While 60 mA
could be applied to the reaction mixtures in MeCN/water and
10
11
12
Et4NBF4
Et4NBF4
Et4NBF4
Acetone SS
[a] Conditions: 0.5 mmol scale, constant current electrolysis under Ar
atmosphere and 400 rpm stirring in a IKA Electrasyn 2.0 reactor. [b] A 10:1
mixture of the solvent and water was used. [c] Equiv of CF3SO2Na. [d]
Determined by GC-FID.
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performed best (2c-g). As expected, the amount of side-
products derived from the CF3 or CF3SO2 radical addition to the
aromatic ring was higher for electron-rich substrates (2j, 2k, 2n).
In such cases purification by column chromatography was
required, thus decreasing the isolated yield. Previously reported
oxytrifluoromethylation procedures[13-15] were also based on the
generation of CF3 radicals, mediated by light or oxidizing agents.
Selectivity issues related to the radical reactivity would therefore
be analogous to the present electrochemical method. Oxidation
of the alkene was not observed in any case (as expected from
CV analysis of both electron rich and poor styrenes – see Figure
Recovery and reuse of the electrolyte was possible and was
tested for Et4NBF4, further increasing the value of this synthetic
protocol. Thus, a reaction mixture performed under optimal
conditions in either THF or acetone (Table 1, entries 11 and 12)
was evaporated under reduced pressure. Sequential addition of
MeCN and diethyl ether enabled the separation of NaOH and
then the electrolyte (soluble in MeCN but insoluble in Et2O). This
simple procedure resulted in an electrolyte recovery of ca. 93%,
which could be used for subsequent reactions without any loss
of efficiency.
With the optimal conditions in hand, a diverse set of alkenes
was subjected to the electrochemical oxytrifluoromethylation
procedure (Scheme 2). Substrates were typically subjected to
electrolysis both in THF/H2O and acetone/H2O for comparison
(see Table S3). Electrolyses for preparative purposes were then
performed in the best solvent on a 2 mmol scale. In the cases
where the conversion and selectivity were very high (> 95%),
isolation of the pure products could be accomplished by simply
filtering the reaction mixture through a plug of silica and
evaporating the solvent (excess of triflinate, hydroxide, and
electrolyte remained in the silica). Products obtained with lower
purity were isolated by column chromatography. Substrates
bearing halogens as electron withdrawing groups typically
S7).
Non-terminal
alkenes
(2m-o).
were
Notably,
also
successfully
during the
oxytrifluoromethylated
electrochemical functionalization of α-methyl styrene (product 2l)
acetophenone was observed as side product. This side reaction
most likely occurred via a olefin cleavage pathway similar to that
described by Fry and coworkers.[28]
Reactions in alcohols as nucleophilic solvents were also
tested to evaluate the extent of alkoxytrifluoromethylation
produced in a 10:1 mixture with water (Scheme 3). As expected,
the proportion of alkoxy vs hydroxyl derivative augmented with
the nucleophilic character of the solvent (MeOH > EtOH >
iPrOH). Isolation of the alkoxytrifluoromethylated compounds 3a-
c was problematic due to their low boiling point. As they partially
evaporated with the solvent relatively low yields were obtained.
The reaction in MeOH did not require the use of water as
additive. Using pure MeOH as solvent and following the general
reaction conditions excellent yield and selectivity for the
corresponding methoxytrifluoromethylated compound was
obtained (see Figure S6).
Scheme
3.
Reactions
in
alcohols
as
nucleophilic
solvents.
Alkoxytrifluoromethylation products are typically favored. Electrolysis in MeOH
could also be performed without water as additive.
To gain some insights into the reaction mechanism a series
of cyclic voltammetry and radical trapping experiments were
carried out (Figure 1). Cyclic voltammetry only revealed that
anodic oxidation of the triflinate, followed by an irreversible
reaction, occurs at a potential of ca. 1.3 V (vs Ag/AgCl), well
below the potential required for the oxidation of the styrene
substrate 1a (2.2 V) (Figure 1a) and even electron rich
compounds such as 4-methoxystyrene (2.1 V) (Figure S7),
explaining the good selectivity observed in most cases. The
voltammogram of a mixture of triflinate, substrate and water did
not reveal any other features, apart from the two expected
consecutive oxidation peaks. Although formation of
trifluoromethylated and trifluomethanesulfonylated aromatics as
side products during many reactions suggested the formation of
Scheme 2. Reaction scope for the electrochemical oxytrifluoromethylation of
a
alkenes. See Supporting Information for experimental details.
Essay
corrected; the isolated product (70%) contained acetophenone as impurity.
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the corresponding radicals (vide supra), we performed a radical
trapping control experiment using butylated hydroxytoluene (2,6-
di-tert-butyl-4-methylphenol) (BHT) as additive. BHT was
selected as radical trapping agent because its oxidation occurs
Figure 1. (a) Cyclic voltammograms of CF3SO2Na, t-butyl styrene (1a) and a typical reaction mixture (see Supporting Information for details), (b) compounds
observed by GC-MS chromatography that point to the presence of the radical species highlighted red, and (c) proposed pathway for the electrochemical
oxytrifluoromethylation. Radicals for which experimental evidence has been provided are highlighted.
at higher potential than for the triflinate, as determined by CV
(see Figure S7). Thus, electrochemical oxytrifluoromethylation of
1a was carried out in THF adding 1 equiv BHT. GC analysis of
the resulting solution revealed a complex mixture of products,
including a large amount of unreacted alkene (a detailed
description of this experiment is included in the Supporting
Information). Gratifyingly, evidence of the intermediacy of the
elusive benzyl radical species 4 (Figure 1c) could be provided by
the GC-MS detection of compound 6 (Figure 1b).
Thus, in the proposed mechanism (Figure 1c) anodic
oxidation of the triflinate anion produces the corresponding
radical that decomposes to a CF3 radical releasing SO2. Addition
of the CF3 radical to the alkene, in the vicinity of the anode,
results in intermediate 4, which is further oxidized to the benzyl
cation 5. Two molecules of water are concurrently reduced on
the cathode, releasing hydrogen and two hydroxide anions.
Reaction of 5 with OH- (or with water present in the solution)
produces the desired oxytrifluoromethylated product 2.
In summary, we have developed a mild, electrochemical
procedure for the oxytrifluoromethylation of alkenes. This
catalyst-free protocol is based in the paired electrolysis of
sodium trifluoromethanesulfinate and water in an undivided cell.
Anodic oxidation of the CF3SO2 anion is the source of CF3
radicals, while water plays a dual role as oxidant at the cathode
and nucleophile to provide the hydroxyl groups for the reaction.
Evidence of the proposed mechanism, in which a benzyl radical
(4) is oxidized at the anode in a second reaction step has been
provided by radical trapping experiments with BHT. The
electrochemical method has been tested for a diverse set of
substituted terminal and non-terminal alkenes, providing
moderate to excellent yields for the desired 1-hydroxy-2-
trifluoromethyl compounds.
Acknowledgements
The CC FLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport,
Innovation and Technology (BMVIT), the Austrian Federal
Ministry of Science, Research and Economy (BMWFW), and by
the State of Styria (Styrian Funding Agency SFG).
Keywords: trifluoromethylation • alkenes • electrochemistry •
radical reactions • sustainable chemistry
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10.1002/chem.201804708
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
Wolfgang Jud, C. Oliver Kappe* and
David Cantillo*
Page No. – Page No.
Catalyst Free Oxytrifluoromethylation
of Alkenes via Paired Electrolysis in
Organic-Aqueous Media
Electricity and water are key ingredients in this alkene difunctionalization method.
Paired electrolysis of sodium trifluoromethanesulfinate and water in an undivided
cell enables a mild, catalyst-free oxytrifluoromethylation of styrenes. Trapping
experiments provide evidence of a mechanism involving three radical
intermediates.
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