Metal-free alkene oxy- and amino-perfluoroalkylations: Via carbocation formation by using perfluoro acid anhydrides: Unique reactivity between styrenes and perfluoro diacyl peroxides

Article abstract of DOI:10.1039/c8sc02547a

We present a strategy for metal-free, alkene difunctionalization-type, oxy- and amino-perfluoroalkylations, using perfluoro acid anhydrides as practical and user-friendly perfluoroalkyl sources. This method provides efficient access to oxy-perfluoroalkylation products via carbocation formation due to the unique reactivity between styrenes and bis(perfluoroacyl) peroxides generated in situ from perfluoro acid anhydrides. This reaction is also applicable to metal-free intramolecular amino-perfluoroalkylation of styrenes bearing a pendant amino group. Synthetic utility of the oxy-trifluoromethylation products was confirmed by demonstrating derivatization via hydrolysis, elimination, and acid-catalyzed substitution with carbon nucleophiles. The mechanism of the carbocation formation was investigated experimentally and theoretically.

Full text of DOI:10.1039/c8sc02547a

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Metal-free alkene oxy- and amino-
perfluoroalkylations via carbocation formation by
using perfluoro acid anhydrides: unique reactivity
between styrenes and perfluoro diacyl peroxides†
Cite this: DOI: 10.1039/c8sc02547a
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have been paid for by the Royal Society
of Chemistry
ab
Elena Valverde,a Shintaro Kawamura, ab Daisuke Sekinea and Mikiko Sodeoka
*
We present a strategy for metal-free, alkene difunctionalization-type, oxy- and amino-perfluoroalkylations,
using perfluoro acid anhydrides as practical and user-friendly perfluoroalkyl sources. This method provides
efficient access to oxy-perfluoroalkylation products via carbocation formation due to the unique reactivity
between styrenes and bis(perfluoroacyl) peroxides generated in situ from perfluoro acid anhydrides. This
reaction is also applicable to metal-free intramolecular amino-perfluoroalkylation of styrenes bearing
a pendant amino group. Synthetic utility of the oxy-trifluoromethylation products was confirmed by
demonstrating derivatization via hydrolysis, elimination, and acid-catalyzed substitution with carbon
nucleophiles. The mechanism of the carbocation formation was investigated experimentally and
theoretically.
Received 10th June 2018
Accepted 20th July 2018
DOI: 10.1039/c8sc02547a
rsc.li/chemical-science
radical intermediate by reaction of the CF3 radical and alkene,
(3) trapping with an O-radical species.5 In 1993, Uneyama re-
Introduction
ported an electrochemical reaction of butyl acrylate with tri-
uoroacetic acid (TFA) and O2 as the trapping agent, affording
CF3-containing alcohol products.5b In 2011, Xiao found that S-
(triuoromethyl)diphenylsulfonium salt could react with
Introduction of peruoroalkyl groups is an important strategy
for modifying the properties of bioactive compounds, agro-
chemicals and functional materials.1 Various methods are
available for C–CF3 bond formation to construct functionalized
CF3-containing compounds, and alkene difunctionalization-
type triuoromethylation has recently attracted particular
interest.2–10 Styrene derivatives are oen used as substrates in
these reactions because of their unique reactivity and the utility
of the products as CF3-containing synthetic building blocks.2–5
For example, transition-metal-catalyzed intermolecular oxy-
triuoromethylation to form C–O bonds has been well studied
styrenes under aerobic conditions to afford ketone products.5c
A
similar transformation was also achieved by using CF3SO2Na in
the presence of O2, obtaining a mixture of ketone and alcohol
products.5e Lei developed the reaction with CF3SO2Na in the
presence of O2 with the aid of K2S2O8 or the combination of
NMP/PPh3, to obtain the ketone or alcohol product selective-
ly.5f,h Fu reported oxazoline forming-triuoromethylation of
allylamide with CF3SO2Na by using oxidant.5g In 2012, Studer
3
3a
(Scheme 1a). As pioneering works, Szabo and we3b indepen-
´
reported
an
efficient
TEMPONa-promoted
oxy-
dently reported Cu-catalyzed intermolecular oxy-
triuoromethylation with Togni reagent,5d,j in which Togni
reagent was decomposed via single electron transfer with
TEMPONa as an electron donor, affording CF3 and TEMPO
radicals and eventually providing the CF3-containing TEMPO
adduct by addition to the alkene. In 2015, Tan and Liu reported
the metal-free oxy-triuoromethylation using hydroxamic acids,
affording products containing an aminoxyl group.5i As regards
metal-free reaction via a carbocation intermediate, Uneyama
developed an electrochemical oxy-triuoromethylation of butyl
methacrylate with TFA and water as the oxygen nucleophile and
solvent by careful tuning the current density to oxidize the
radical intermediate, obtaining the alcohol product in up to
35% yield.5a Further, in 2016, Liu reported an amine-catalyzed
intramolecular oxy-triuoromethylation of alkenes bearing
triuoromethylation of styrenes with Togni reagent in 2012.
In this reaction, the triuoromethyl group is introduced into the
b-position, and then 2-iodobenzoate group derived from the
Togni reagent is introduced at the benzylic position via carbo-
cation intermediate formation with the aid of copper-catalyst.
In contrast to transition-metal-catalyzed reactions, metal-free
oxy-triuoromethylations generally proceed via the following
steps: (1) formation of a CF3 radical, (2) formation of an alkyl
aSynthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1
Hirosawa, Wako, Saitama 351-0198, Japan. E-mail: sodeoka@riken.jp
bRIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-
0198, Japan
† Electronic supplementary information (ESI) available: General experimental
procedures, experimental method, compound characterization, and NMR
spectroscopic data. See DOI: 10.1039/c8sc02547a
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Scheme 1 (a) Proposed mechanisms of previous oxy-trifluoromethylations, (b) our previous work on Cu-catalyzed amino-perfluoroalkylation
with TFAA/urea$H2O2, and (c) metal-free difunctionalization-type perfluoroalkylation of styrenes by using perfluoro acid anhydrides (this work).
a 1,3-diaryl diketone group with Togni reagent, affording dihy- reactivity and selectivity in the formation of the carbocation
drofuran products.5k,6
intermediate without transition-metal-catalyst;9b i.e., styrene
Recently, we have been interested in alkene per- serves as an electron donor to accelerate generation of the
uoroalkylation by using peruoro acid anhydrides, which are peruoroalkyl radical via decomposition of the diacyl peroxide
convenient and practical peruoroalkyl sources because of their by SET. Then, addition of the peruoroalkyl radical to the
low cost, ready availability and reasonable stability compared to resulting radical cation A affords the carbocation B (path a).
conventional peruoroalkylating reagents.9–12 We found that Another possibility is that the peruoroalkyl radical reacts with
peruoro diacyl peroxides prepared in situ from peruoro acid another styrene molecule (having higher electron density
anhydrides and urea$H2O2 showed excellent reactivity and compared to the radical cation A), and the resulting benzyl
selectivity in allylic peruoroalkylation9a and in intramolecular radical intermediate C is oxidized by the radical cation A as an
amino-peruoroalkylation9b of alkenes in the presence of Cu(I) electron acceptor to afford the same benzyl cation intermediate
salt as a catalyst. Our mechanistic studies of the amino- B (path b). In this work, we focused on this carbocation
peruoroalkylation indicated that it proceeds via (1) forma- formation, as a key process in difunctionalization-type per-
tion of a peruoroalkyl radical ($Rf) and Cu(II) species from the uoroalkylation, and aimed to develop metal-free oxy- and
peroxide and Cu(I) catalyst, (2) addition of the Rf radical to the amino-peruoroalkylations of styrene derivatives by using per-
double bond of the alkene, (3) oxidation of the resulting alkyl uoro acid anhydrides. We also carried out various derivatiza-
radical with Cu(II) species to afford a carbocation intermediate tions to conrm the synthetic potential of the products.
with recovery of the Cu(I) species, and (4) nucleophilic cycliza-
tion (Scheme 1b). In the absence of copper catalyst, the reaction
of alkenes gave complex mixtures. Exceptionally, reaction of
Results and discussion
alkenes bearing an aromatic ring at an appropriate position
selectively generated peruoroalkyl group-containing carbo-
cycles, because the aromatic ring acted as a scavenger of the
alkyl radical. We were interested in the unique reactivity of
We chose commercially available 4-chlorostyrene 1a as a model
substrate to explore the reaction. To our delight, aer in situ
generation of bis(triuoroacetyl)peroxide (BTFAP) from tꢀri-
uoroacetic anhydride (TFAA) with urea$H2O2 in DCM at 0 C
styrenes and radical cation species in peruoroalkylation with
for 1 h, reaction with 1a at 40 ꢀC for 1 h afforded the desired oxy-
the peruoro acid anhydride/urea$H2O2 system (Scheme 1c),
triuoromethylation product 2a. Careful tuning of the ratio of
and postulated that the styrene substrate serves to control the
the reagents and the reaction temperature improved the yield.13
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Finally, the reaction with TFAA (10 equiv.) and urea$H2O2 (2.5
equiv.) provided the corresponding oxy-triuoromethylated
product 2a in 80% isolated yield (85% NMR yield) (Scheme
2).14 The scope of the optimized reaction conditions was then
explored using a range of styrene-based substrates (Scheme 3).
Various functional groups at the para position were tolerated
and the corresponding oxy-triuoromethylated products were
formed efficiently (2a–i).15 The usefulness of the reaction was
demonstrated in a gram-scale experiment with 4-uorostyrene
1b, which was transformed into the desired compound 2b in
93% yield (4.7 g). meta- and ortho-substituted styrene substrates
performed well in the oxy-triuoromethylation reaction (2j–n),
although higher temperatures were needed for meta-substituted
substrate because of slow conversion compared to para- and
ortho-substituted styrenes. A disubstituted styrene 1o afforded
the target compound 2o in good yield. The generality of the
reaction was also assessed with several internal alkenes, which
afforded the corresponding difunctionalized products in
moderate to good yields (2p–s). Quaternary carbon centres
could be constructed successfully, and more complex
compounds 2t and 2u were isolated in 59% and 80% yield,
respectively. Finally, this metal-free procedure was applied to
the oxy-peruoroalkylation of styrene-based substrates with
other peruoro acid anhydrides, and the desired products 2b0
and 2d00 were isolated in excellent yields.
To further explore the ability of the styryl functionality to
provide the carbocation intermediate, we next investigated
whether pyrrolidines could be obtained by intramolecular
amino-peruoroalkylation of styrene derivatives bearing
a pendant amino group via nucleophilic cyclization, based on
our previous work.9b,16 In contrast to metal-free oxy-
peruoroalkylation, metal-free amino-peruoroalkylation has
rarely been reported,5a,8 probably because of the lack of appro-
priate N-radical trapping agents. Thus, we examined the reac-
tion of styryl group-containing aminoalkene 3a with in situ-
generated BTFAP under the optimal conditions for the oxy-
triuoromethylation (Scheme 4).17 As we had hoped, the
amino-triuoromethylation proceeded well to afford the corre-
sponding CF3-containing pyrrolidine 4a in 76% yield. This
styrene-driven amino-triuoromethylation was also applicable
to internal alkene 3b, which provided disubstituted pyrrolidine
Scheme 3 Substrate scope of the metal-free oxy-perfluoroalkylation
reaction. aGram-scale synthesis using 2.0 g (16 mmol) of 1b. bRun at
0 ꢀC for 10 min with Cs2CO3 (5 equiv.) as an additive. cRun at 60 ꢀC in
1,2-dichloroethane.
4b as
a
syn-diastereomer.18 In this reaction, the oxy-
reaction. This observation suggested that this amino-
triuoromethylation does not proceed via nucleophilic substi-
tution of the oxy-triuoromethylation product under the
conditions. Alkenyl amine 3c featuring a 6-membered ring as
a tethering group in the carbon chain was tolerated, and the
spirocyclic product 4c was formed in high yield. The use of acid
anhydrides bearing longer peruoroalkyl chains furnished
C2F5- and C3F7-substituted pyrrolidines 4a0 and 4a00 in good
yields.
triuoromethylation product was obtained as a by-product in
40% yield, and it was not converted to the amino-
triuoromethylation product 4b even upon prolonged
To further expand the chemical space of the per-
uoroalkylated compounds, we focused on the reactivity of the
peruoroacetoxy group, as a labile functional group, in the oxy-
triuoromethylation products (Scheme 5). First, we examined
the reaction of 2b, as a representative substrate, with bases.
When DBU was reacted with 2b in DME, the alcohol 5b was
Scheme 2 Metal-free oxy-trifluoromethylation of styrene 1a with
TFAA/urea$H2O2 under optimized conditions.
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Scheme 4 Metal-free amino-perfluoroalkylation reaction of alkenes.
obtained in quantitative yield. On the other hand, KHMDS as
the base was found to give the vinyl product 6b via elimination
reaction. Next, we attempted to construct attractive carbon
skeletons and examined SN1-type nucleophilic substitution
reactions with various carbon nucleophiles in the presence of
acid catalysts. The triuoroacetoxy group was readily dissoci-
ated with triic acid, and trapping of the resulting carbocation
with arenes resulted in C–C bond formation to give 7b and 8b.19
In the presence of a catalytic amount of B(C6F5)3 to promote
formation of the carbocation, allylation with allylsilane pro-
ceeded to afford 9b in good yield.20 This approach was also
applicable to the reaction with a ketene silyl acetal as a nucleo-
philic partner, providing 10b. The presented procedures for the
substitution reactions of the benzylic triuoroacetoxy group
provide rapid access to various peruoroalkyl-group-containing
molecules, which should be useful building blocks in organic
synthesis.
Finally, we focused on the reaction mechanism of the per-
uoroalkylation (Scheme 1c). The reaction starts with the
generation of an electrophilic CF3 radical via decomposition of
the diacyl peroxide, i.e. BTFAP which is formed in situ from
TFAA and urea$H2O2. Decomposition of BTFAP would be trig-
gered by SET with styrene as the electron donor and/or by
heating (Scheme 6). To trace the decomposition, TEMPO
instead of styrene was reacted with in situ-generated BTFAP
(Scheme 7a). TEMPO-CF3 adduct 11 was obtained in only 2%
yield, which suggested that thermal decomposition would be
very slow under these reaction conditions.21 Furthermore, the
decomposition could not be observed by 19F NMR monitoring of
Scheme 5 Examples of derivatization of benzyl trifluoroacetate 2b: (a)
hydrolysis and elimination reaction (b) intermolecular C–C bond
formation reactions.
the peroxide in CD2Cl2 at 40 ꢀC without any substrate.13 Yoshida
similarly found that aromatic compounds such as benzene
accelerate the decomposition of BTFAP by SET.11b The HOMO
level of 4-chlorostyrene 1a (ꢁ6.41 eV), used as the model
substrate in this work, is higher than that of benzene (ꢁ7.09
eV).13 Accordingly, decomposition of BTFAP was concluded to
be induced by SET with styrene under the present conditions at
ꢀ
40 C, affording CF3 radical and radical cation A. Radical trap-
ping with TEMPO under the optimized conditions afforded the
CF3-containing TEMPO-benzyl adduct 12, generated via the
benzyl radical intermediate C, in 7% yield (Scheme 7b). In
addition to 12, TEMPO-CF3 11 was formed, together with
a mixture of oxy-triuoromethylation products 2a and its
Scheme 6 Possible pathway of decomposition of BTFAP.
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Scheme 9 Activation energies of (a) addition of CF3 radical to 1a and
(b) SET between benzyl radical C and radical cation A.
mechanistic studies supported our original hypothesis shown
in Scheme 1c, in which substrate styrene itself acts as SET donor
to trigger the peruoroalkyl radical formation from the diacyl
peroxide. The resulting peruoroalkyl radical could react with
styrene affording benzyl radical intermediate C, which is rapidly
oxidized to the benzyl cation B by the radical cation A. The
generated benzyl cation intermediate B is trapped by the per-
uoro carboxylate anion or amine yielding the desired oxy- and
amino-peruoroalkylation products, 2 and 4.
Scheme 7 TEMPO trapping test: (a) reaction of TEMPO with BTFAP
and (b) oxy-trifluoromethylation in the presence of TEMPO.
hydrolysis product 5a. Furthermore, a known radical probe
alkene 13, 1-phenyl-1-(trans-2-phenylcyclopropyl)ethane,8b was
subjected to the reaction (Scheme 8). The corresponding ring-
opening product 14 was formed via the radical intermediate
as the major product, along with a complex mixture of other
products.13 These results proved that the CF3 radical reacts with
styrene 1a (path b, Scheme 1c), although both path a and path
b may be operated. Indeed, DFT calculation indicated that the
activation energy of the reaction of the CF3 radical with 1a is low
(DG‡ ¼ +10.3 kcal molꢁ1, Scheme 9a). Next, we considered the
oxidation step of the benzyl radical to the carbocation B.
Comparison of the calculated LUMO levels of potential
oxidants, BTFAP and radical cation A, indicated that radical
cation A (ꢁ6.26 eV) has a lower LUMO level than that of BTFAP
(ꢁ2.35 eV). In addition, the LUMO level of A was closer to that of
Cu(II)(O2CCF3)2 (ꢁ5.09 eV) which was reported to oxidize the
radical intermediate in the amino-peruoroalkylation reaction
(Scheme 1b).9b Thus, radical cation A was considered to act as
the oxidant, affording carbocation B, which leads to the desired
products. The DFT calculated activation energy of oxidation of
benzyl radical C with A was DG‡ET ¼ +6.2 kcal molꢁ1 (Scheme
9b), which is much lower than that of the addition of CF3 radical
to 1a suggesting rapid conversion of the highly reactive benzyl
radical C to the metastable benzyl cation intermediate B. These
Conclusions
We have developed a mild and efficient method for the metal-
free oxy- and amino-peruoroalkylation of styrenes via carbo-
cation intermediates, using peruoro acid anhydrides as inex-
pensive and practical peruoroalkyl sources. The oxy-
triuoromethylation products were derivatized to a variety of
CF3-containing unique molecules. We believe this method will
prove useful in medicinal and agro-chemistry discovery
programs. In addition, the unique reactivity between styrene
and peruoro diacyl peroxide may provide clues to design new
reactions and catalysts in the future.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by JSPS KAKENHI (No. 15K17860) and
Project Funding from RIKEN. E. V. is grateful for a JSPS Post-
doctoral Fellowship (15F15340). The computational study was
conducted on the HOKUSAI-GW (RIKEN).
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Y. Zhang, Org. Lett., 2017, 19, 5260; (x) Y. F. Cheng,
S-triuoromethyl xanthates prepared from TFAA:
Chem. Sci.
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only
9%
yield
of
tetrahydroisoquinoline was formed and 81% yield of an
oxy-triuoromethylation product (alcohol) was obtained.
See ESI† for details.
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´
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13 See ESI† for details.
14 Isolated yields were slightly lower than NMR yields because
of hydrolysis of 2 during isolation by means of silica-gel
column chromatography.
similar reaction conditions was very slow giving a small
amount of complex mixture of products. A trace amount of
CF3 radical generated via thermal decomposition could
cause undesired reactions in the absence of an appropriate
electron acceptor.
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Chem. Sci.