Mediator and Additive Free Trifluoromethyl-Fluorination of Terminal Alkenes by Persistent Perfluoroalkyl Radical

Article abstract of DOI:10.1002/ejoc.201900651

It was found that the persistent perfluoro-3-ethyl-2,4-dimethyl-3-pentyl radical (PPFR) can serve as a source of both trifluoromethyl-radical and fluorine atom in the reactions with terminal olefins. This dual reactivity allows for the direct and operationally convenient di-functionalization of C=C bond to 1-CF₃-2-F-alkanes. Preliminary data strongly suggest potentially high synthetic value of this methodologically new transformation.

Full text of DOI:10.1002/ejoc.201900651

A Journal of
Accepted Article
Title: Mediator and Additive Free Trifluoromethyl-Fluorination of
Terminal Alkenes by Persistent Perfluoroalkyl Radical
Authors: Azusa Sato, Maxim V. Ponomarenko, Taizo Ono, Gerd-Volker
Röschenthaler, and Vadim A. Soloshonok
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900651
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900651
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10.1002/ejoc.201900651
European Journal of Organic Chemistry
COMMUNICATION
Mediator and Additive Free Trifluoromethyl-Fluorination of
Terminal Alkenes by Persistent Perfluoroalkyl Radical
Azusa Sato,[a] Maksym V. Ponomarenko,*[b] Taizo Ono,[c] Gerd-Volker Röschenthaler,[b] and Vadim A.
Soloshonok*[d]
Abstract: It was found that the persistent perfluoro-3-ethyl-2,4-
dimethyl-3-pentyl radical (PPFR) can serve as a source of both
trifluoromethyl-radical and fluorine atom in the reactions with terminal
olefins. This dual reactivity allows for the direct and operationally
convenient di-functionalization of C=C bond to 1-CF3-2-F-alkanes.
Preliminary data strongly suggest potentially high synthetic value of
this methodologically new transformation.
compounds.[4] PPFR belongs to a type of persistent radicals
perfectly stable at ambient conditions in the open air. It can be
detected and monitored by routine GC technique, and it is
synthetically available on kg scale via fluorination of industrially
available hexafluoropropene trimer with F2 in high yield.[5]
Properties of this reagent were studied since its discovery in 1985,
but until recently, its synthetic application remained unexplored.[5-
6]
A unique feature of PPFR is the ability to release a
trifluoromethyl radical by simple heating of the vigorously stirred
reaction mixture in a sealed flask.[4] This thermolytic initiation
leads to β-elimination of one trifluoromethyl radical from PPFR
(Scheme 1).
Introduction
Organofluorine chemistry has been one of the most successful
and established fields of chemistry, and various organofluorine
compounds are now used in fine chemical industries, ranging
from medicinal to material sciences.[1] Over 25% of the modern
pharmaceuticals and ~50% of agrochemicals contain such
fluorinated functionalities in their structures.[1a,2] Among various
fluorine containing substituents trifluoromethyl function is one of
F
F
F3C
F3C
F3C
F
F
90 °C
CF3
F
CF
3
+
F
CF3
F
F
the most important group. Therefore, incorporation of
a
CF3
CF3
CF3 CF3
trifluoromethyl group is now quite a generalized paradigm in the
design of new functional materials with improved properties.[3]
The demands for new operationally convenient and practical
synthetic methodologies towards trifluoromethylated organic
compounds are continuously increasing.
A
PPFR
Scheme 1. Thermolysis of PPFR.
Recently we demonstrated that perfluoro-3-ethyl-2,4-
dimethyl-3-pentyl radical (PPFR) is
trifluoromethyl radical in trifluoromethylation reactions of aromatic
a useful source of a
The fact that there are no other degradation pathways,
makes PPFR uniquely chemically clean source of
a
trifluoromethyl radical. Accordingly, the use of PPFR in
trifluoromethylation reactions allows to avoid any other
oxidizing/reducing agents, additives, as well as any type of
irradiation, typically required in the initiation step of the radical
trifluoromethylation reactions.[3a-j,3l]
However, despite of these obviously useful advantages,
PPFR has not been explored as a reagent for synthetic organic
chemistry, except for the aromatic trifluomethylation,[4] and radical
polymerizations reported by Ameduri et al.[7]
Motivated by the successful use of PPFR for aromatic
trifluorination, we continued the exploration of new synthetic
applications of PPFR as a trifluoromethylating reagent in the
reactions with unsaturated substrates. Herein we present a
discovery of the trifluoromethyl-fluorination of unactivated
terminal olefins using PPFR as a source of both trifluoromethyl
group and fluorine atom.
[a]
[b]
Dr. A. Sato Author(s)
Department of Chemistry
Tokyo Women’s Medical University
8-1 Kawada-cho, Shinjuku-ku, 162-8666 Tokyo (Japan)
Dr. M. V. Ponomarenko, Prof. Dr. G.-V. Röschenthaler
Department of Life Sciences and Chemistry
Jacobs University Bremen gGmbH
Campus Ring 1, 28759 Bremen (Germany)
E-mail: m.ponomarenko@jacobs-university.de
http://groeschent.user.jacobs-university.de/
Dr. T. Ono
Fluorine Division, Central Research Center
Mitsubishi Material Electronic Chemicals Co., Ltd.
3-1-6 Barajima, Akita city, Akita 010-8585 (Japan)
Prof. Dr. Vadim A. Soloshonok
Department of Organic Chemistry I, Faculty of Chemistry
University of the Basque Country UPV/EHU
Paseo Manuel Lardizabal 3, 20018 San Sebastian, Spain
IKERBSQUE, Basque Foundation for Science
Maria Diaz de Haro 3, 48013 Bilbao (Spain)
E-mail: vadym.soloshonok@ehu.eus
[c]
[d]
Results and Discussion
http://www.ikerbasque.net/vadym.soloshonok
We selected allylcyclohexane (1a) as the model terminal alkene
for our study. First reactions were carried out under the conditions
Supporting information for this article is given via a link at the end of
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10.1002/ejoc.201900651
European Journal of Organic Chemistry
COMMUNICATION
similar to those previously described in our report on the aromatic
trifluoromethylation.[4] The vigorously stirred reaction mixture of
1a with 3 equivalents of PPFR in 1,2-dichloroethane (1,2-EDC),
forming two phases, was heated at 90 °C for 24 h. To our surprise
the product of trifluoromethyl-fluorination 2a was observed as a
major compound in the reaction mixture. The yield of 2a was
estimated to be at least 82% by 19F NMR and GC experiments
conducted on the crude reaction mixture (Table 1, entry 1). When
the same reaction was carried out using one equivalent of PPRF
only a half amount of olefin 1a was consumed giving 45% NMR
yield of the 1-CF3-2-F product 2a (Table 1, entry 2). We found that
the use of two equivalents of PPFR in this trifluoromethyl-
fluorination reaction gives the highest possible yield of the product
2a isolated in 84% (Table 1, entry 3). Yields of product 2a were
significantly lower for the reactions conducted in other organic
solvents selected as the reaction medium (Table 1, entries 4–7).
It is interesting to note that, despite full solubility of PPFR in CCl4
at the reaction temperature and complete consumption of 1a, not
even traces of expected product 2a were observed in the reaction
mixture (Table 1, entry 5). The reactions carried out in a 1,2-
EDC/THF mixture or in EtOAc were accompanied by significant
decomposition (Table 1, entry 6, 7).[8] Additionally, we observed
decomposition of EtOAc under the reaction condition (Table 1,
entry 7).
The use of three-fold excess of PPFR was found to be
crucial in the trifluoromethyl-fluorination reactions of olefins
containing aromatic substituents. When olefins 1b,c were reacted
with three equivalents of PPRF in 1,2-EDC the corresponding 1-
CF3-2-F products 2b,c were obtained in low yields (Table 1,
entries 8, 9). These reactions were accompanied with a side
trifluoromethylation of the aromatic functions[4] that hampered
isolation of the products 2b,c from the reaction mixtures. The side
products containing the CF3-group in the aromatic ring were also
observed by 19F NMR when 1b,c were reacted with two
equivalents of PPFR. However, due to the greater reactivity of the
terminal double bonds of 1b,c, these reactions proceeded more
selectively simplifying the isolation step and giving the products
2b,c in substantially higher yields (Table 1, entries 11, 13). The
reaction of 1b with PPFR did not benefit from shortening the
reaction time (Table 1, entry 12). We could not completely avoid
the competitive side aromatic trifluoromethylation, but only the
olefin conversion, as well as the product yield, were reduced.
noticeable amounts of acetyl-fluoride as
a
product of
Table 1. Optimization of the reaction condition of 1a-c with PPFR
Olefin
conversion, %
Entry
R
PPFR, equiv
Solvent
Time, h
Yield, %[a]
1
2
3
4
5
6
7
8
Cyclohexyl (a)
Cyclohexyl (a)
Cyclohexyl (a)
Cyclohexyl (a)
Cyclohexyl (a)
Cyclohexyl (a)
Cyclohexyl (a)
Ph (b)
3
1
2
2.1
2
2
2
3
3
1,2-EDC
1,2-EDC
1,2-EDC
CHCl3
CCl4
1,2-EDC/THF[c]
AcOEt
1,2-EDC
1,2-EDC
1,2-EDC
1,2-EDC
1,2-EDC
24
24
24
24
24
24
24
24
24
24
17
24
100
50[b]
100
79[b]
100
83[b]
67 (82)
(45)
84
(52)
(0)
(9)
Complex mixture[d]
100
100
100
93[b]
100
(~40)[e]
33[e]
61 (82)
52 (76)
59
9
m-Cl-C6H4 (c)
Ph (b)
Ph (b)
11
12
13
2
2
2
m-Cl-C6H4 (c)
[a] Isolated yields; yields shown in parentheses were observed by 1H, 19F NMR using p-fluoroanisole as an internal
standard. [b] The olefin was observed by 1H NMR of the reaction mixture. [c] 1,2-EDC/THF = 1.5/1 mixture was used. [d]
CH3C(O)F was observed by 19F NMR. [e] The complex mixture containing CF3-Ar products.
1 giving the corresponding 1-CF3-2-F functionalized products 2.
Due to the fact that the use of two equivalents of this reagent is
essential to complete the reactions, we assumed that one
equivalent of PPFR provides the CF3-radical[4] and the second
equivalent serves as a source of the fluorine introduced in the
products 2. This dual reactivity of PPFR is observed for the first
time.
To the best of our knowledge, there are only a few literature
approaches providing access to 1-CF3-2-F functionalized alkanes.
The first reported method for preparation of 1-CF3-2-F-alkanes
was based on deoxyfluorination of 1-CF3-substituted secondary
The structures of the products 2 were unambiguously
confirmed by NMR spectroscopy. The typical appearance of
1-CF3CH2-2-CHF-group in NMR spectra corresponds to the
literature data described for the similar products[9] (e.g. for 2a: 1H
NMR δ 4.90 dm, 2JHF = 49.4 Hz, CFH; 13C NMR δ 85.9 dq, 1JCF
=
171.7, 3JCF = 3.5 Hz, CHF; 19F NMR δ –64.0 td, J = 10.4, 7.6 Hz,
3F, CF3, –181.4 m, 1F, CHF).
Thus, we found that PPFR acts as a trifluoromethyl-
fluorinating reagent in reactions with terminal unactivated olefins
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10.1002/ejoc.201900651
European Journal of Organic Chemistry
COMMUNICATION
alcohols using SF4/HF system[10] or DAST reagent.[11] Another
literature approach is based on radical addition of methanol to
CF3CH=CFH under UV-irradiation in the presence of peroxides,
affording 2,4,4,4-tetrafluorobutanol in moderate yield.[12] Several
substituted 1,1-difluoroarylcyclopropanes were transformed to the
corresponding 1,3,3,3-tetrafluoropropyl-arenes using up to 11
equivalents of Olah’s reagent (HF-Pyridine) in the presence of
m-chloroperbenzoic acid (1.1 equiv) and PhI (>20%).[13] 2-(4-
Fluoro-6,6,6-trifluoro-2-hydroxyhexyl)isoindoline-1,3-dione
containing terminal 1-CF3CH2-2-CHF-group was prepared in 55%
yield starting from the corresponding 2-fluoro-homoallylic alcohol
benzyl ether by means of CuI-catalyzed trifluoromethylation
reaction with the Togni reagent.[14] All these methods requires the
use of either already trifluoromethylated or mono/di-fluorinated
starting materials, and cannot be qualified as general approaches
towards 1-CF3-2-F-alkanes due to the restrictions on functional
group tolerance, the substrate choice, its availability, as well as
necessity of special equipment.
unprecedent intermolecular fluorine atom transfer resulted from
the C(sp3)–F bond cleavage is not yet fully understood, and it will
be a subject of our further study. We cannot completely exclude
possible formation of HF traces under the reaction conditions,
which can potentially assist the fluorine transfer step.[18] However,
the observation of only compound C as a product of the fluorine
elimination from PPFR is a clear evidence that fluorine anion is
unlikely to be involved. Presence of the catalytic amount of
fluorine anion should lead to isomerization of C and its
thermodynamic equilibrium with D in ca. a C/D = ½ ratio,[8] which
is not supported by our GC-experimental data.
F
F3C
F3C
CF3
CF3
F
CF3
90 °C
CF3
PPFR
F3C
F
C2F5
F
CF3
F
CF3
C
A
Z-, E-
There are only two recent literature reports which can be
considered as one step trifluoromethyl-fluorination reactions of
olefins. Both these methods are based on complex reactions of
terminal alkenes, which involve radical and oxidative steps, with
either TMSCF3 / CsF / PhI(OAc)2 / AgOTf / Selectfluor system[9]
PPFR
R
R
CF3
CF3
R
F
2
1
B
Figure 1. Plausible mechanism of the trifluoromethyl-fluorination of 1 with PPFR.
or
S-(trifluoromethyl)dibenzothiophenium
tetrafluoroborate
(the Umemoto reagent) / CsF / Cu(OTf)2 / bathocuproine / 4,4′-
di(methoxycarbonyl)-2,2′-bipyridine system under visible light
irradiation.[15]
In sharp contrast to the mentioned above literature methods
the discovered in this work one-step trifluoromethyl-fluorination of
terminal olefins 1 with PPFR does not require any additional
reagents, mediators, or irradiation.
The high regioselectivity of the trifluoromethyl-fluorination
reaction of 1 (Table 1) obviously suggests that the addition of the
•
electrophilic CF3 -radical to the terminal carbon of the double bond,
which is typical for radical trifluoromethylations of olefins,[3a,9,16] is
an initial step (Figure 1). This leads to the formation of the
intermediate alkyl radical B, along with the chemically neutral
perfluorinated Z- and E-olefins A. The subsequent recombination
of radical B with the second equivalent of PPFR gives the final
product 2 (Figure 1). This last step should be accompanied by the
formation of the olefin C as a result of the fluorine radical
abstraction from PPFR. The formation of the corresponding C=C
bond of the more thermodynamically stable olefins A and C is a
Scheme 2. GC-analysis of the PPFR layer. Fluorine atoms are omitted for clarity.
With the optimized reaction conditions in hand we studied
the substrate generality of the discovered trifluoromethyl-
fluorination reaction using various terminal olefins 1d–u (Scheme
3). Most of the selected olefins react with PPFR leading to the
formation of the corresponding 1-CF3-2-F-products 2 in moderate
to good yields. The substrates 1 containing electron withdrawing
functions typically provide better yields of 2. This observation can
be possibly attributed to the electron-donating properties of
electron rich substituents (1f,s,t olefins).[8] The reactions of all
substrate olefins, bearing aromatic groups, with PPFR were
accompanied with the side aromatic-trifluoromethylation that in
some cases complicated the product isolation step. Furthermore,
styrene 1u polymerizes under the reaction conditions, not even
traces of the trifluoromethyl-fluorinated product were observed in
the reaction mixture.
•
good driving force of both the CF3 -radical formation and fluorine
radical abstraction steps.
In order to support the proposed mechanism of the
trifluoromethyl-fluorination of olefins
1
(Figure 1) with
experimental data, we conducted a detailed study of the reaction
mixtures composition using the GC-technique.[5,8,17] We found that
the products of PPFR transformation consist mainly of two
compounds, namely E-A (45%) and C (46%) (Scheme 2).
Additionally, small amount of Z-A olefin (9%) was detected. In our
control experiment we stirred neat PPFR at the reaction
temperature for the same time. This gave us a mixture of Z- and
E-A olefins as major products slightly contaminated by C and D
olefins that corresponds to the literature data.[5] Thus, the result
observed is in perfect agreement with our assumption that PPFR
delivers both the CF3-radical and the fluorine atom in the
trifluoromethyl-fluorination reactions. The mechanism of this
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10.1002/ejoc.201900651
European Journal of Organic Chemistry
COMMUNICATION
PPFR (2 equiv)
olefins to the corresponding 1-CF3-2-F-products. Preliminary data
demonstrate that the operational ease of this transformation
coupled with its predictable reactivity and substrate generality
bodes well for its widespread synthetic application.
F
CF3
R
R
O
1,2-EDC
90 °C, 24h
inert atmosphere
1d-v
2d-u
O
O
CF3
EtO
O
CF3
CF3
Experimental Section
4
4
F
F
F
2d, 52%
2e, 34%
General procedure for the trifluoromethyl-fluorination reactions of terminal
olefins with PPFR radical: PPFR (2 equiv) was added to a solution of the
corresponding olefin substrate 1 (1 equiv) in 1,2-dichloroethane (0.6 M) in
a 10–25 mL glass vial (or ampule) under nitrogen atmosphere. The vial
was supplied with a magnetic stir bar ensuring vigorous stirring, and then
it was tightly closed with a Teflon cap. After being stirred for 24 h at 90 ºC,
the reaction mixture was cooled down to ambient temperature, the upper
1,2-dichloroethane layer was removed by a syringe, the bottom layer was
washed twice with either 1,2-dichloroethane or methylene chloride. The
1,2-dichloroethane/CH2Cl2 layers were combined, and then the organic
solvents were evaporated. The pure products 2 were isolated by column
chromatography on SiO2.
O
O
O
O
CF3
4
4
F
F
OMe
2f, 45%
O
2g, 44%
O
S
O
O
CF3
O
CF3
4
4
F
F
Br
2i
, 32%
O
2h
, 27%
O
O
CF3
O
CF3
4
3
Acknowledgements
F
F
F3C
F3C
2k, 53%
2j
, 62%
O
The authors gratefully acknowledge financial support (AS, GVR)
from the German Research Foundation (Grant DFG RO 362/65-
1) and IKERBASQUE, the Basque Foundation for Science, Spain
(VAS).
O
O
CF3
O
CF3
2
4
F
F
F3C
[b]
2m
, 31% (79%
)
2l
, 15%
Keywords: fluorination • radical reactions • synthetic methods •
O
O
trifluoromethylation
CF3
CF3
, 50%
N
N
3
2
F
F
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2p, 52%
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Cl
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F
O
CF3
CF3
CF3
7
OMe
2s, 0%
2r, 66% (77%[b]
)
MeO
F
CF3
Cl
O
O
F
2t
2u
, 0%
, 0%
Scheme 3. Scope of the trifluoromethyl-fluorination of olefins. [a]The d.r.
observed by NMR of the reaction mixture is 66/34. [b]Observed by 1H, 19F NMR
using p-fluoroanisole as an internal standard.
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10.1002/ejoc.201900651
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COMMUNICATION
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10.1002/ejoc.201900651
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
The dual reactivity of the persistent
perfluoro-3-ethyl-2,4-dimethyl-3-pentyl
radical (PPFR) allows for both
trifluoromethylation and fluorination of
terminal olefins. This new approach
towards di-functionalized 1-CF3-2-F-
alkanes demonstrates the widespread
synthetic potential.
Key Topic Synthetic Method
Azusa Sato, Maksym V. Ponomarenko,
Taizo Ono, Gerd-Volker Röschenthaler,
Vadim A. Soloshonok
Page No. – Page No.
Mediator and Additive Free
Trifluoromethyl-Fluorination of
Terminal Alkenes by Persistent
Perfluoroalkyl Radical
This article is protected by copyright. All rights reserved.