Radical Trifluoroacetylation of Alkenes Triggered by a Visible-Light-Promoted C–O Bond Fragmentation of Trifluoroacetic Anhydride

Article abstract of DOI:10.1002/anie.202109235

We report a mild and operationally simple trifluoroacylation strategy of olefines, that utilizes trifluoroacetic anhydride as a low-cost and readily available reagent. This light-mediated process is fundamentally different from conventional methodologies and occurs through a trifluoroacyl radical mechanism promoted by a photocatalyst, which triggers a C?O bond fragmentation. Mechanistic studies (kinetic isotope effects, spectroelectrochemistry, optical spectroscopy, theoretical investigations) highlight the evidence of a fleeting CF₃CO radical under photoredox conditions. The trifluoroacyl radical can be stabilized under CO atmosphere, delivering the trifluoroacetylation product with higher chemical efficiency. Furthermore, the method can be turned into a trifluoromethylation protocol by simply changing the reaction parameters. Beyond simple alkenes, this method allows for chemo- and regioselective functionalization of small-molecule drugs and common pharmacophores.

Full text of DOI:10.1002/anie.202109235

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Radical Trifluoroacetylation of Alkenes Triggered by a Visible-
Light-Promoted C−O Bond Fragmentation of Trifluoroacetic
Anhydride
Authors: Kun Zhang, David Rombach, Nicolas Yannick Nötel, Gunnar
Jeschke, and Dmitry Katayev
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202109235
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10.1002/anie.202109235
Angewandte Chemie International Edition
RESEARCH ARTICLE
Radical Trifluoroacetylation of Alkenes Triggered by a Visible-
Light-Promoted C−O Bond Fragmentation of Trifluoroacetic
Anhydride
Kun Zhang,+[a] David Rombach,+[a] Nicolas Yannick Nötel,[a] Gunnar Jeschke[a] and Dmitry Katayev*[a,b]
Dedicated to Professor Peter Kündig on the occasion of his 75th birthday
[a]
[b]
[+]
K. Zhang, Dr. D. Rombach, N. Y. Nötel, Prof. Dr. G. Jeschke. Prof. Dr. D. Katayev
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology ETH Zürich
Vladimir-Prelog-Weg 2, 8093 Zürich (Switzerland)
E-mail: katayev@inorg.chem.ethz.ch
Prof. Dr. D. Katayev
Department of Chemistry
University of Fribourg
Chemin du Musée 9, 1700, Fribourg (Switzerland)
E-mail: dmitry.katayev@unifr.ch
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: Here we report a mild and operationally simple
trifluoroacylation strategy of olefines, that utilizes trifluoroacetic
anhydride as a low-cost and readily available reagent. This light-
mediated process is fundamentally different from conventional
methodologies and occurs through
a trifluoroacyl radical
mechanism promoted by a photocatalyst, which triggers an C−O
bond fragmentation. Detailed mechanistic studies including
kinetic isotope effects, spectroelectrochemistry, optical
spectroscopy, and theoretical calculations highlight the evidence
of a fleeting CF3CO radical under photoredox conditions.
Remarkably, the trifluoroacyl radical can be stabilized under CO
atmosphere, delivering the trifluoroacetylation product with higher
chemical efficiency. Furthermore, method can be turned into a
trifluoromethylation protocol by simple changing the reaction
parameters. Beyond simple alkenes, this method allows for
chemo- and regioselective functionalization of small-molecule
drugs and common pharmacophores.
Direct incorporation of the trifluoromethyl (CF3) group into the core
of the molecules has been extensively studied and is an important
synthetic strategy in the design of new pharmaceutical agents.1-11
Advances in this field have been made possible by the availability
of various radical12-15
,
nucleophilic16-18 and electrophilic
trifluoromethylation reagents that can efficiently be activated
under mild and catalytic conditions.19-21
Trifluoromethyl ketones22,23 are a special subset of fluorinated
compounds that have relevant applications in biological and
medicinal chemistry.24-27 Owing to the high electronegativity of the
CF3 group, an electrophilic carbonyl center of trifluoromethyl
ketones can undergo various transformations as well as promote
the molecule binding affinity with the biological target.28 Recent
studies have shown that these functionalized derivatives act as
potential enzyme inhibitors towards Herpesvirus protease,29
Histone deacetylase,30 SARS-CoV 3CL protease31-32 and serve as
well as a precursor for clinically used glucocorticoid receptor
Scheme 1. Motivation and design of trifluoroacylation reaction. [a]
examples of CF3(CO)-containing biorelevant molecules; [b] multi-step
strategies; [c] electrophilic process; [d] this work.
agonists33 (Scheme 1a). In the context of synthetic chemistry, -
unsaturated trifluoromethyl ketones are indispensable building
blocks with an inherent ability to react with bifunctional
1
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10.1002/anie.202109235
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RESEARCH ARTICLE
Table 1. Effects of reaction parameters on trifluoroacetylation of 1.
require prefunctionalized starting materials remains in high
demand at both, an academic and industrial level. During the
preparation of this manuscript a patent by Su et al. has been
published that reports direct acylation of electron rich styrene
derivatives by anhydrides.44 Herein, we report a robust, efficient,
and operationally simple strategy for the trifluoroacylation of
alkenes with trifluoroacetic anhydride, that is enabled by
photoredox catalysis.
The photocatalytic decarboxylative strategy reported by
Stephenson and co-workers for the perfluoroalkylation of
hetero(aromatic) compounds demonstrated a conceptual platform
to generate fluoroalkyl radical species from cheap and readily
available reagents, e. g. perfluoroalkyl anhydrides.45 Since this
pioneering study, the method has successfully been implemented
towards the functionalization of various classes of organic
structures, including complex molecules and materials.46-50 Based
on voltammetric measurements and augmented with in silico work,
we assumed that trifluoroacetic anhydride with an observable
reduction onset at around −1.2 V (vs. SCE) should undergo an
irreversible, exergonic, and reductive single electron transfer
(SET) process to afford the corresponding radical ion species in
the presence of a photocatalyst operating under oxidative
quenching conditions. The ensuing (O)C−O bond fragmentation
could preferentially afford the CF3(CO) radical species (G =
- 20.1 kJ/mol in favor of the trifluoroacyl radical) and
trifluoroacetate anion. The latter reactive radical intermediate
would be trapped in situ with an alkene substrate and eventually
lead to the formation of trifluoroacylated adduct (Fig. 1d).
However, since the liberated CF3(CO) radical has only a limited
entry[a]
cat (mol%)
solvent
Yield (%)[a]
1
2
[Ru] (1%)
[Ir]-1 (1%)
[Ir]-2 (1%)
[Ir]-1 (1%)
[Ir]-1 (1%)
[Ir]-1 (1%)
[Ir]-1 (1%)
[Ir]-1 (1%)
[Ir]-1 (1%)
−
EtOAc
EtOAc
EtOAc
CH3CN
CH2Cl2
DMSO
Acetone
THF
trace
79 (1)
36 (1)
56 (1)
42 (1)
trace
3
4
5
6
7
trace
8
19 (1)
trace
9
DMF
10
11
12[b]
EtOAc
EtOAc
EtOAc
trace
−
trace
[Ir]-1 (1%)
85 (1a)
[a] General conditions: 4-tert-butylstyrene (1.0 equiv), [catalyst] (1 mol%),
and TFAA (2.0 equiv) were irradiated in solvent (2.0 M) with 350 W blue
light at ambient temperature for 12 h. Yields of 1 and 1a were determined
by GC-MS against an internal standard of n-decane. [b] 0.05 M in EtOAc.
•
lifetime and undergoes fragmentation to CF3 and CO,51 the
nucleophiles in synthetic sequences involving trifluoromethyl- and
trifluoroacyl-containing heterocycles, medicinal compounds, and
fluorinated analogues of natural products.34
Despite the development of methods for the construction of CF3-
containing compounds, that has been an area of great interest,
the preparation of -unsaturated trifluoromethyl ketones
overall process has to be operated under well-controlled reaction
conditions. The use of a photoredox catalyst such as tris-(2-
phenylpyridine) iridium (III) [Ir(ppy)3] was seen prevailing due to
its sufficiently low reduction potential of the excited state of
E0(Ir(IV)/Ir(III)*) = −1.73V (vs. SCE). In order to check the
feasibility of this transformation, a systematic screening of
different reaction parameters including photocatalysts, solvents,
and concentrations has been carefully evaluated, and key results
are presented in Table 1. Indeed, operating under
remains
a fundamental challenge for synthetic chemists.
Traditional methods for the synthesis of CF3-enone adducts
employed classical approaches based on Mannich type
reactions,35 aldol-type condensations,36,37,38 and additionally
several methods rely on rearrangements39-41 (Scheme 1b). It has
also been shown previously that methyl cinnamates can undergo
reactions with TMSCF3 to form the corresponding CF3-enones.42
However, these strategies are limited to electron rich alkenes and
make use of prefunctionalized building blocks containing a CF3
group, that are often difficult to access. Direct functionalization of
the sp2 C−H bond of alkenes with a trifluoroacyl group would be
advantageous for the step-economic synthesis of -unsaturated
trifluoromethyl ketones. Trifluoroacetic anhydride (TFAA) is a
precious acylation reagent in synthesis, however due to its
[Ru(bpy)3(PF6)2]
catalysis,
only
trace
amounts
of
trifluoroacetylation product of 4-tert-butylstyrene could be
detected.
While carrying out the process in the presence of catalytic
amounts of Ir(ppy)3 (1 mol%) in ethyl acetate (EtOAc) under blue-
light irradiation in high-intensity visible-light photoreactors for 12
hours led to the formation of 1 in 79% yield (entries 1-3, Table 1)
in both a chemoselective and regioselective fashion. Further
screening of the solvents and concentrations revealed no
beneficial effects of optimizing these both parameters (entries 4-
9). Using optimal reaction conditions, no significant reactivity was
observed in the dark or without a catalyst (entries 10-11). We
were also pleased to find that reducing the concentration to 0.05
M led to the formation of only difunctionalized adduct 1a in 85%
(entry 12). Notably, no redox mediator such as pyridine N-oxide
is required to forge an alkene fluoroalkylation pathway.
electronic
properties,
this
reagent
is
inactive
for
trifluoroacetylation of non-activated alkenes. In the early 90’s,
Balenkova and co-workers reported the method for the activation
of TFAA by freshly in situ generated BF3(gas)/Me2S complex at -
60 ºC, allowing direct olefinic trifluoroacetylation ostensibly via an
electrophilic pathway (Scheme 1c).43 Although these methods
provide routes for the synthesis of CF3-enone derivatives, the
requirement of complex and harsh reaction conditions, multi-step
chemical pathways and lack of chemo- and regioselectivity,
restrict synthetic chemists to access this privileged class of
unsaturated ketones.34 Hence, a mild, direct and practical
approach towards the trifluoroacetylation of alkenes that does not
The newly developed trifluoroacetylation protocol is characterized
by a fairly simple reaction setup involving the irradiation of 2.0
equivalents of TFAA and 1 mol% of commercially available
photocatalyst Ir(ppy)3 in EtOAc for 12 h. With these optimized
reaction conditions in hand, the applicability of the protocol was
examined with respect to a wide array of readily available olefins
2
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10.1002/anie.202109235
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RESEARCH ARTICLE
Table 2. Representative scope of the alkene C(sp2)−H trifluoroacetylation.[a]
[a] Alkene (1.0 equiv), [Ir]=Ir(ppy)3 (1 mol%), and TFAA (2.0 equiv) were irradiated in EtOAc (2.0 M) in a 350 W blue LED reactor at ambient temperature
for 12 h. Isolated yields are reported. Isolated products composing of both (E) and (Z) are reported in parenthesis (ratio). [b] Volatile compound. Yield of
58% determined by 19F NMR analysis with an internal standard. Crystal structure of 31 as ORTEP drawing with 50% probability thermal ellipsoids.[76]
and resulted in up to 94% isolated yield of the corresponding -
unsaturated trifluoromethyl ketones as the (E)-isomer (unless
otherwise indicated in Table 2). Aryl substituted olefines
containing both electron donating and electron withdrawing
common functional groups at ortho-, meta- and para-positions
were successfully trifluoroacylated in 40-85% isolated yields. It is
noteworthy that halogen substituents (3, 5, 6, 9, 12) and ester (7)
groups remained untouched under the reaction conditions,
3
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10.1002/anie.202109235
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RESEARCH ARTICLE
Table 3. Direct trifluoroacetylation of complex molecules and biorelevant compounds. [a]
[a] Standard reaction conditions. Isolated yields are reported. Crystal structure of 45 as ORTEP drawing with 50% probability thermal ellipsoids.[76]
Figure 1. Scale-up and applications in the synthesis of various trifluoromethylated heterocycles. [a] SC(NH2)2 (1.5 equiv), EtOH, 80 ºC, 23 h, HCl; [b];
1,2-phenylenediamine (2.0 equiv), EtOH, 80 ºC, 20 h; [c]; pyrrolidine (0.12 equiv), CH2(CN)2 (1.0 equiv), benzene, 80 ºC, 20 h; [d]; SC(NH2)2 (1.5 equiv),
Na (4.0 equiv), EtOH, 80 ºC, 48 h; [e] S(NH4)2 (0.74 equiv), EtOH, rt, 1 h.
allowing further structural elaboration besides the trifluoroacetyl
group. Alkene building blocks including di- and tri-substituted aryl
substrates (9-13) furnished the corresponding unsaturated
ketones in 76-94% chemical yields. Substrates adorned with a
substituent flanking the -position of styrene (14-26) as well as
alkenes bearing polycyclic aromatic hydrocarbons (27, 28) and
heterocyclic systems 29-31 (31 including SC-XRD), all gave the
desired trifluoroacylated adducts. Similarly, the key precursors
(32, 33 and 34) of most recognized anti-inflammatory drugs
bearing trifluoromethylated pyrazole moieties such as Mavacoxib,
Celecoxib and SC-56052-55 were all synthesized using this
photoredox protocol in satisfactory yields. In most cases, we were
unable to observe trifluoromethylated or difunctionalized alkene
adducts. Having enabled for the trifluoroacetylation of alkenes
4
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10.1002/anie.202109235
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RESEARCH ARTICLE
with
a
simple reagent, we subsequently investigated the
applications, we successfully prepared trifluoromethylated
heterocyclic systems with different heteroatoms (S-, O-, and N-)
and of different ring-size. The synthesis of these products via a
direct trifluoromethylcarbonation pathway using conventional
methodologies remains a great challenge (Fig. 1).
application of our protocol in late-stage functionalization.
Trifluoroacetyl-containing compounds have in recent decades
proven to be an important class of molecules for the preparation
of biorelevant substances, and as such we foresaw that our
approach could be of particular value in the context of medicinal
chemistry. (Table 3). Each of these architecturally complex
molecules underwent alkene trifluoroacetylation to deliver the
corresponding CF3-enone adducts in moderate to good yields.
For example, derivatives of L-camphanic acid (35), naproxen (36),
and (-)-10-camphorsulfonylamide (37) selectively underwent
trifluoromethylacetylation reaction demonstrating the protocol’s
tolerance to amides and sulfonamides. Our protocol was also
successfully applied in the trifluoroacetylation of a series of known
drugs and naturally occurring derivatives including clofibrate (38),
AHTN (39), vitamin E (40), menthol (41), estrone (42), vanillin (43)
and fenofibrate (46) with good chemical efficiency. The reaction
conditions were also suitable for more structurally complex
bioactive precursors. Derivatives from cholesterol (44) and
nitogenin (45) bearing several unsaturated fragments with long
alkyl side chains underwent trifluoroacetylation exclusively at the
less-hindered olefin. However, the substrate scope was limited to
aryl substituted alkenes and could not be expanded to aliphatic
compounds. To demonstrate the utility of this protocol, at first, a
photocatalytic functionalization of 4-tert-butylstyrene with a
CF3CO group has been performed on 15.6 mmol scale without
significant decrease in isolated yield (67%) (Fig. 1). For further
Next, we turned to investigation of the mechanism of the reaction
using a combined experimental, spectroscopic and computational
approach on the level of DFT and DLPNO-CCSD(T) (see ESI,
computational chemistry for details). Due to the very high
reduction potential of the excited state of the catalyst
(E0(Ir(IV)/Ir(III)*) = -1.73V vs. SCE)56 we considered the initiation
of the catalytic cycle by single electron photoreduction of TFAA
(A) by the excited state of the catalyst (B*) which previously has
not been described. Yet, the initiation pathway of forming acyl
radicals has recently been reviewed.57 The viability of this
mechanistic pathway has been confirmed by in silico experiments,
showing an exergonic extrusion of trifluoroacetate (−20.1 kJ/mol
at 298K) from C which is only turned exergonic by its strongly
positive TdS term of 60 kJ/mol in solution. Experimentally, this
hypothesis is fully consistent with cyclic voltammetry data,
indicating an onset potential of −1.2 V (vs. SCE) of the irreversible
reduction of TFAA (see ESI, Fig. S3 & S5), as well as with Stern-
Volmer quenching studies that indicated a highly efficient
quenching of the excited T1-state of B by A (KSV =2∙109 mol-1s-1)
(Fig. 2, C).
0 eq.
20 eq.
20 eq.
40 eq.
100 eq.
200 eq.
300 eq.
400 eq.
500 eq.
Ir(ppy)3
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
4.0x106
2.0x106
0.0
hv448nm, 70s
photochemistry
hv448nm, 250s
0.4V, 5 min
0.4V, 10 min
electrochemistry
0.02
0.01
0.00
500
550
600
650
700
450 500 550 600 650 700 750 800 850
300
400
500
/ nm
600
700
/ nm
Figure 2. Mechanistic studies. A, Proposed catalytic cycles. B, Comparison of the UV-VIS spectra of irradiation of (Ir(ppy)3 in the presence of TFAA with
the electrochemical formation of Ir(IV) by spectroelectro chemistry. Spectra were scaled for a better comparability. C, Stern-Volmer quenching of Ir(ppy)3*
by TFAA. D, Control experiments. E, Photocyclovoltammetric experiments. F, Hammett equation.
5
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RESEARCH ARTICLE
In contrast, only weak quenching of B* was observed in the
presence of styrene or TFA (see ESI, Fig. S22 & S23). This is
aligned with very low reduction potentials of -2.6 V58 and T1
energies of ~60-65 kcal/mol, that are typical for -unsubstituted
The results of the substrate scope were at this stage extensively
analyzed. It turned out that the use of 4-fluorostyrene led to the
formation of the two reaction products (1’ and 1a’) that could be
isolated in 48% (32) and 31% (54) yield, respectively.
Furthermore, exclusive formation of CF3 adducts 52 and 53 using
other electron-deficient olefins followed this trend and fully
outcompeted any addition of radical D to the substrate. These
results hinted on comparable rates of a bimolecular reaction of D
with the substrate (see ESI, Fig. S43) and the unimolecular
decarbonylation of the COCF3 radical (D & TS-1), offering a
potential handle for switchability. While the fragmentation forming
CO and the •CF3 radical (E) was found to be exergonic
(K ~ 1.7∙103 M) we continued to investigate the kinetics of this
process. In good agreement with the previous experimental data
in the gas phase (G‡ = 41.9-51.9 kJ/mol)63-69 our theoretical
investigations confirmed a low decarbonylation barrier in solution
styrenes59 and excludes both, electron and energy transfer by
*
Ir(ppy)3 (T1 = 55.2
kcal/mol).60 Significant
singlet
state
contributions to the reaction mechanism by 1B* were excluded due
to ultrafast sub-ps depopulation of the S1 state 1B* by intersystem
crossing (kISC,calc = 6.9 × 1012 s−1).61 However, the weak quenching
effect of trifluoroacetic acid could potentially be attributed to some
formation of COCF3 radicals by single electron reduction of the
CF3COOH2+ formed by autoprotolysis in minor amounts, followed
by dehydration. Further, under irradiation of a solution of the
catalyst in the presence of TFAA a new characteristic weak broad
absorption feature between 500 to 700 nm was observed, which
also has been found by electrochemical oxidation of Ir(ppy)3 in
MeCN (see Fig. 2, B). This feature was assigned to the Ir(IV)
cation.62 Simultaneously a novel emission between 470 nm to
(G‡ = 39.6 kJ/mol) resulting in a half-lifetime of radical D of t1/2
~
0.98 µs in solution applying Eyring’s theory ( = 1). Due to the
competitive formation of the CF3 radical, we expected a high
sensitivity of the product outcome dependent on the collision
probability with the substrate. Indeed, we found that low substrate
concentrations (0.01 M) resulted in almost exclusive formation of
the CF3 product 1a’, while increasing substrate concentration up
to 2.0 M shifted the product distribution towards the
trifluorocarbonylated compound 1’. This finding corroborates the
mechanistic proposal of the initial addition of D to the substrate K.
+
520 nm was detected. The initial build-up of Ir(ppy)3 is in
agreement with proposed irreversible and fast fragmentation of
•
the radical anion C under formation of the metastable COCF3
radical and trifluoroacetate. To shine even more light into the
reaction mechanism, we combined the photochemical depletion
of the excited state B by TFAA with cyclovoltammetric analysis.
Irradiation of the mixture B and TFAA in MeCN over 6 min at
448 nm caused full depletion of the Ir(III)/Ir(IV) feature of B in
cyclic voltammetry and a new species oxidized at 0.6 V vs. Fc+/Fc
appeared, indicating an irreversible oxidation of Ir(ppy)3. This was
also observed in UV-VIS spectrocopic analysis (see Fig. 2, B and
C). The same experiment in the presence of tBu-styrene resulted
The formation of an electron deficient intermediate (F) during the
first irreversible step was also indicated by a Hammett study (see
Fig. 2, F) showing a significant negative reaction parameter ( = -
1.61). It is in good correlation with our experimental findings that
styrene derivatives bearing electron-withdrawing substituents
undergo trifluoroacetylation slower than electron-rich derivatives
(see Fig. 2, A, bottom line).
in
a
preservative effect on the Ir(III)/Ir(IV) couple B/B+,
corroborating the mechanistic hypothesis of a back electron
transfer by radical H (see Fig. 2, E and S4-S11).
100
80
60
40
20
0
0
1
2
5
10
CO pressure / bar
Figure 3. Mechanistic studies. A, Potential energy surface scan of the --bond of the carbonyl shows favored antiperiplanar configuration of the
trifluorocarbonyl moiety. Irradiation (blue LEDs, 450 nm) of 1’’ (Z-2) has been performed in the presence of Ir(ppy)3 (1 mol%) in EtOAc. B, CO pressure
experiments. C, KIE experiment. D, H/D scrambling experiment.
6
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Although this generally imposes some limitations on the method,
we considered the equilibrium between radicals D and E, as
another adjusting screw potentially capable of overcoming these
limitations. The equilibrium is expected to be shifted towards
radical D if the partial pressure of CO is increased. We were
thrilled by the observed continuous shift of the product distribution
under variation of the partial pressure of CO from 1 to 10 bar,
finally almost completely suppressing of the formation of the
trifluoromethylation product 1a’ (Fig. 3, B). The calculation of the
reduction potential of benzylic radical F (E0 = 0.76 V (vs. SCE)
indicated an almost vanishing driving force for back electron
transfer to Ir(IV) (E0(Ir(IV)/Ir(III)) = 0.77V vs. SCE)54 in order to
form the benzylic cation species 60. This value is in good
agreement with reported data for benzylic radicals and
comparable to the parent benzyl radical (E0 = 0.73 V) rather than
the phenylethyl radical (E0 = 0.37 V), showing levelling out of
hyperconjugative and inductive effects.70
Last but not least, the reasons for the complete stereoselectivity
of the process was investigated in due course. In this mechanistic
model, the conformation of G is controlling the configuration of the
preferentially formed enol. A potential energy surface scan
around the Cbenzyl-C-CH2 bond, which is expected to be the
stereodetermining conformer, revealed the origin of this finding.
The minimum energy conformation (C -CH2154.6°of G
bz
-C
turned out to be lower by more than 19 kJ/mol comparing with the
alternative Z-conformation G’ (C -CH20°)indicating the
bz
-C
preference for the formation of E-product see Fig. 3, A and ESI.
However, to elucidate the possibility of a Z→E isomerization of
primarily formed Z--unsaturated trifluoromethyl ketones under
our reaction conditions, we investigated the photoisomerization of
(Z)-2 under blue LED irradiation. Indeed, after irradiation of the
reaction solution for 12 hours, a 2:1 mixture of isomers with the
excess of thermodynamically favorable E-configuration was
detected (see ESI, p.83).
Our attempts to get further insight into the process of formation
and the fate of the key radicals by light-dependent EPR-
spectroscopy were not successful (for details, see ESI) due to the
high reactivity of TFAA and the presumably short lifetime of the
two radicals under the reaction conditions. Neither a quantum
yield determination turned out to be successful due to the
heterogenicity of the reaction mixture.
The electronic structure of F suggested a potential enolizability
forming the conjugate enole H-cis or H-trans. The localized
radical F was found to be thermodynamically slightly more stable
by about 10.4 kJ/mol indicating a keto-enol equilibrium. However,
the reduction potential of the enol tautomers H-cis/J-cis (H-trans/
J-trans) showed a lowering of the reduction potential to 0.43
(0.47 V) (vs. SCE) renting the back electron transfer to Ir(IV)
exergonic by 32.8 kJ/mol. To further support this hypothesis, the
trifluoroacetylation reaction of tert-butylstyrene in the presence of
1.0 equivalent of TFA was carried out. We were pleased to find a
1:4 mixture of -H (N) and -D (M) labelled reaction products,
confirming the existence of a significantly long lived keto-enole
equilibrium (see Fig. 3, D). Furthermore, the absence of any H/D
scrambling during incubation of the reaction product 1 with TFA
excludes potential reprotonation of the product causing this effect
and rules out a simple deprotonation of G to 1` (Fig 2, A).
In conclusion, we have developed an efficient and practical
protocol where the simple reagent TFAA undergoes chemo- and
regioselective trifluoroacylation reaction with a broad range of
alkenes including complex natural products to access -
unsaturated trifluoromethyl ketone derivatives. Detailed
mechanistic studies have provided evidence that C-CF3 and C-
COCF3 bond formation can be controlled by the chosen reaction
conditions. With this remarkable disclosure, we anticipate that this
trifluoroacetylation approach will be a valuable tool for the
synthetic chemist in drug discovery and development in the future.
Next, kinetic isotope effect measurements using -d2 labelled
styrene as substrate, allowed to determine the -contributions to
the overall kinetic isotope effects which were expected to be
characteristic for radical attack on styrenes. Addition of the
COCF3 radical to the styrene molecule was found to be strongly
exergonic (RG0= 96.4 kJ/mol) and irreversible and is the only
step expected to be reflected in an observable kinetic isotope
effect under competition conditions. Our mechanistic proposal is
aligned with an observed -secondary kinetic isotope effect of
about 0.96 ± 0.02 per -H/D-CO using -d2 styrene as substrate
(see ESI for details). For similar radical attack reactions on
styrene derivatives -KIEs of 0.88-0.95 was previously observed
due to rehydridisation of the-C from sp2 to sp3.72
Acknowledgements
Dr. Nils Trapp is acknowledged for obtaining all X-ray
crystallographic data. Funding: D.K acknowledges the Swiss
National Science Foundation (SNSF, PCEFP2_186964) for the
financial support of this research. D.R acknowledges the Swiss
National Science Foundation (SNSF, CRSK-2_195863) for
financial support of this research. D.K. and D.R. thank Prof.
Antonio Togni for his support. D.R. further thanks Prof. Erick
Moran Carreira for his support. Generous continued support by
the ETH Zurich and the University of Fribourg is acknowledged.
Further we thank Prof. Christophe Copéret for support with the
SEC infrastructure and Darryl Nater for spectroelectrochemical
measurements. Prof. Hans-Achim Wagenknecht and Prof. Frank
Breher are acknowledged for their continuous support, their
generosity and for allowance to use their infrastructure for
spectroscopic measurements. Further we thank Dr. Benson Jelier
for the design and construction of the photoreactors and Armin
Limacher for his kind support with GC-FID and GC/MS
measurements.
Furthermore, a series of experiments using d8-styrene was
carried out to gain more insight into the complementary
contributions to the overall kinetic isotope effect. Due to a
potentially underlying unknown side products in both, optimized
GCMS and GC-FID data, the determined kinetic isotope effects
was flawed by a significantly large errors and could not be
interpreted to support or discard our mechanistic proposal.
However, a significant involvement of the highly reducing enolate
anion L (E0(1/L) = -1.59 V vs. SCE) (see ESI, Fig. S59) to the
dominant reaction pathway is unlikely due to the formation of TFA
as a side product but cannot be ruled out. Alternatively, this step
might also directly employ a proton coupled electron transfer as
previously described for the corresponding anions.73-75
Conflict of interest
The authors declare no conflict of interest.
7
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10.1002/anie.202109235
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RESEARCH ARTICLE
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Keywords: late-stage functionalization
•
organofluorine
compounds • photoredox • radical mechanisms • radical
trifluoroacetylation
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9
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The elusive trifluoroacyl radical can be generated via C−O bond fragmentation of trifluoroacetic anhydride under photoredox conditions
and undergoes olefinic C−H bond trifluoroacetylation in a mechanistically unique fashion. The protocol is operationally simple, scalable,
and enables the late-stage diversification of complex biorelevant molecules delivering the corresponding -unsaturated trifluoromethyl
ketones in a single chemical step.
@KatayevLab
10
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