Mild C?F Activation in Perfluorinated Arenes through Photosensitized Insertion of Isonitriles at 350 nm

Article abstract of DOI:10.1002/adsc.201901126

Fluorinated compounds have become important in the fields of agrochemical industry, pharmaceutical chemistry and materials sciences. Accordingly, various methods for their preparation have been developed in the past. Fluorinated compounds can be accessed via conjugation with fluorinated building blocks, via C?H fluorination or via selective activation of perfluorinated compounds to give the partially fluorinated congeners. Especially the direct activation of C?F bonds, one of the strongest σ-bonds, still remains challenging and new strategies for C?F activation are desirable. Herein a method for the photochemical activation of aromatic C?F bonds is presented. It is shown that isonitriles selectively insert into aromatic C?F bonds while aliphatic C?F bonds remain unaffected. Mechanistic studies reveal the reaction to proceed via the indirect excitation of the isonitrile to its triplet state by photoexcited acetophenone at 350 nm. Due to the relatively mild light used, the process shows high functional group tolerance and various compounds of the class of benzimidoyl fluorides are accessible from aryl isonitriles and commercially available perfluorinated arenes. (Figure presented.).

Full text of DOI:10.1002/adsc.201901126

Title: Mild C–F Activation in Perfluorinated Arenes through
Photosensitized Insertion of Isonitriles at 350 nm
Authors: Frauke Weidlich, Naoto Esumi, Dongyang Cheng, Christian
Mück-Lichtenfeld, Eli Zysman-Colman, and Armido Studer
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901126
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Mild C–F Activation in Perfluorinated Arenes through
Photosensitized Insertion of Isonitriles at 350 nm
Frauke Weidlich,a Naoto Esumi,a Dongyang Chen,b Christian Mück-Lichtenfeld,a Eli
Zysman-Colman, b* and Armido Studer a*
Dedicated to Prof. Eric Jacobsen on the occasion of his 60th birthday.
a
Organisch Chemisches Institut, Westfälische Wilhelms-Universität Münster
Corrensstr. 40, 48149 Münster
E-mail: studer@uni-muenster.de
https://www.uni-muenster.de/Chemie.oc/studer/index.html
Organic Semiconductor Centre, EaStCHEM School of Chemistry, University of St Andrews
b
St Andrews. Fife. UK, Ky16 9ST
E-mail: eli.zysman-colman@st-andrews.ac.uk
http://www.zysman-colman.com/home_en.php
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Fluorinated compounds have become important in It is shown that isonitriles selectively insert into aromatic
the fields of agrochemical industry, pharmaceutical C–F bonds while aliphatic C–F bonds remain unaffected.
chemistry and materials sciences. Accordingly, various Mechanistic studies reveal the reaction to proceed via the
methods for their preparation have been developed in the indirect excitation of the isonitrile to its triplet state by
past. Fluorinated compounds can be accessed via photoexcited acetophenone at 350 nm. Due to the relatively
conjugation with fluorinated building blocks, via C–H mild light used, the process shows high functional group
fluorination or via selective activation of perfluorinated tolerance and various compounds of the class of
compounds to give the partially fluorinated congeners. benzimidoyl fluorides are accessible from aryl isonitriles
Especially the direct activation of C–F bonds, one of the and commercially available perfluorinated arenes.
strongest -bonds, still remains challenging and new
strategies for C–F activation are desirable. Herein a method
for the photochemical activation of aromatic C–F bonds is
presented.
Keywords: C–F activation; fluorine; insertion;
photochemistry; sensitizers; transition-metal free
alternative and less exploited strategy is the selective
defluorination of highly fluorinated and readily
accessible compounds, and various methods have
been developed along those lines.[11–14] However, the
key step C–F activation is not trivial as this -bond is
one of the strongest -C–X bonds (e.g. 154 kcal mol-1
in hexafluorobenzene[13]), and hence the development
of new and broadly applicable methods for C–F
modification is challenging and remains important.
Moreover, a deeper understanding of the mechanisms
of such defluorination reactions is desirable and
necessary for further improving existing methodology.
In previous work, we introduced a method for the
photochemical insertion of isonitriles into aromatic
C–F bonds.[12] Upon irradiation with a high pressure
mercury lamp (exc = 254 nm) and using a large
excess of a perfluorinated arene (mostly acting as a
co-solvent) various benzimidoyl fluorides were
successfully prepared, as exemplified in Scheme 1 for
Introduction
Over the past decades, fluorinated compounds have
gained great importance in agrochemical industry and
medicinal chemistry.[1–7] Around one quarter of drugs
in use in 2014 contain fluorine atoms as their
incorporation improves both the pharmacokinetics
and membrane permeability compared to their non-
fluorinated congeners.[2] The fluorine atom is about
the size of the hydrogen atom[8] giving fluorinated and
non-fluorinated
molecules
similar
structural
characteristics while they differ strongly in most other
physical and electronic properties. Along with the
conjugation of organic compounds with fluorinated
building blocks, an obvious synthetic route to defined
fluorinated compounds is the fluorination of their
non-fluorinated derivatives, an approach that has been
investigated extensively in the past.[2,6,9,10] An
1
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
the
insertion
of
isocyanobiphenyl
into functionality. Initial reactions of xanthone 1a,
perfluorobenzene. Mechanistic studies revealed that prepared in four steps from xanthone (see Supporting
the reaction proceeds from an isonitrile in its excited Information),[25–27] and hexafluorobenzene (2) (50-
triplet state.[12,15] Unfortunately, high energy light was 300 equiv.) were conducted under an argon
required for the excitation of the substrate isonitriles,
resulting in a limited functional group tolerance.
atmosphere and irradiation (exc = 350 nm) for up to
40 hours to give imidoyl fluoride 3a (see Supporting
Information). The reaction temperature in the
experimental setup was around 40 °C. A large excess
of the perfluoroarene 2 was required in order to obtain
a high conversion. The solvent was varied and
acetone was found to be the best solvent to run this
reaction in. Progress of the isonitrile insertion was
followed by GC-MS analysis and it was observed that
the reaction rate decreases over time. All reactions
were very clean and along with unreacted substrate 1a
only product 3a was identified by GC-MS in the
crude mixture.
Based on the hypothesis that the reaction likely
involves a triplet state of the isonitrile,[12,15] the use of
an external photosensitizer was considered next. To
this end, four photosensitizers were tested (see Table
1). While the use of benzophenone, phenylacetone
and 4’-(trifluoromethyl)acetophenone led to low
yields between 7 and 29%, a much higher yield of
77% was achieved upon using acetophenone.
Through further optimization of the reaction
conditions and by conducting the reaction under air, a
yield of 97% could be achieved. (Scheme 2).
Scheme
1.
UV-light
mediated
insertion
of
isocyanobiphenyl into perfluorobenzene.[12]
We therefore decided to generate the active excited
triplet state of an aryl isonitrile via photosensitization
with an external photosensitizer. This alternative
strategy should permit the isonitrile insertion into C–F
bonds to be conducted upon irradiation with light of
longer wavelengths. Photosensitization describes the
indirect excitation of a substrate via an excited
photosensitizer. This photosensitizer can either
interact with the substrate via singlet electron transfer,
in what is typically known as photoredox catalysis, or
via energy transfer. There are three primary energy
tranfer mechanisms: radiative, Förster and Dexter. In
the former two, overlap between the emission of the
photosensitizer and the absorption of the substrate is
required while in Dexter energy transfer, orbital
overlap is necessary to permit the double electron
transfer to occur.[16–18] This orbital overlap can occur
Table 1. Variation of the photosensitizer in the reaction of
1a with 2.
transiently through
collisions
between the
photosensitizer and the substrate in solution. Through
this triplet-triplet energy transfer[18] the substrate can
be indirectly excited (sensitized) to its triplet state at a
wavelength that would not be suitable to directly
excite it. Herein we disclose our first results on the
Entry Acetone
[mL]
Sensitizer
Time Yield
[h]
[%]a)
1
2
3
1.9
1.5
1.9
Benzophenone
Phenylacetone
4‘(Trifluoro
methyl)aceto
phenone
23
23
23
16
7
29
photosensitization of isonitriles at 350 nm,
wavelength where direct excitation
a
of
isocyanobiphenyl is not possible, and the use of these
photoexcited intermediates in C–F insertion reactions.
4
1.9
Acetophenone
24
77
a)
Yields were determined from 19F-NMR spectra with
Ph–CF3 as the internal standard.
Results and Discussion
With optimized conditions in hand, the reaction scope
was tested using isonitrile 1a in combination with
Xanthones are a class of heterocyclic natural products
that show diverse biological activities and also useful
various
perfluorinated
arenes
(Scheme 2).
photochemical
characteristics.
Antibacterial,
200 equivalents of each perfluoroarene were used and
the benzimidoyl fluorides 3a-f were obtained in 46-
97% isolated yields. In contrast to the parent
perfluorobenzene, for all other fluoroarenes tested a
regiochemistry problem arises. The reaction of
isonitrile 1a and perfluorotoluene provided the ortho-
and meta-derivatives 3b as major products with an
antifungal and antiviral characteristics as well as
cytotoxic activities towards cancer cells could be
demonstrated.[19,20] Further, their photochemical
characteristics, especially their triplet states and their
use as photocatalysts, were studied intensively.[21–24]
We
therefore
decided
to
choose
the
2-isocyanoxanthone (1a) bearing an isonitrile
2
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
overall yield of 77% and the CF3-group in 3b meta- and para-products (see 3d-f), ortho-products
remained unreacted. With methyl were obtained as major regioisomers for compounds
pentafluorobenzoate, the ortho-product 3c was bearing an electron withdrawing group (EWG) along
regioselectively formed in 74% yield while with the fluorine atoms (see 3b-c).[12] The reasons
pentafluorobenzene delivered the meta- and para- behind the observed regioselectivity are currently not
products 3d with the meta-derivative as the major fully understood. As expected, due to the large excess
compound in 54% overall yield. Light-mediated of the perfluoroarene substrate used in these
reaction
of
isonitrile
1a
with
trimethyl experiments, double C–F insertion leading to
(perfluorophenyl)silane afforded the meta- and para- bisimidoyl fluorides was never observed.
products 3e (46%) with moderate regioselectivity. To further underline the applicability of the reaction
Pentafluorotoluene led to an overall yield of 60% with and to check whether the xanthone moiety is required
the para-product 3f being formed as the major isomer for the C–F activation, the readily accessible
along with its meta-congener.
isonitrile 1b, prepared according to a literature
protocol over two steps,[27] was tested in combination
with various perfluoroarenes (Scheme 3). Pleasingly,
reaction of isonitrile 1b with hexafluorobenzene
provided the benzimidoyl fluoride 3g quantitatively
and it was possible to lower the equivalents of
substrate 2 to 100 without diminishing the yield.
Notably, all reactions with 1b had to be carried out
under argon using dried acetone and acetophenone,
since the product imidoyl fluorides readily hydrolyse.
With pentafluorobenzene (100 equiv.) the meta-
product 3h was the major isomer formed and the
regioselectivity was the same as that observed for the
reaction with isonitrile 1a. As compared to the
analogous reaction with 1a, the yield was
significantly higher (83% versus 54%). Reaction of
1b with 1,2,4,5-tetrafluorobenzene afforded 20%
of 3i using 200 equivalents of the perfluorinated
arene. With pentafluorobenzenes bearing a methyl or
a trimethylsilyl group (100 equiv.) the general
reactivity trend was followed and isonitrile 1b
provided higher yields as compared with the yields
obtained for the analogous reactions with isonitrile 1a.
Using 1,2,3,4,5-pentafluoro-6-methylbenzene, the
para-product 3j was obtained as the major product
Scheme 2. Scope of C–F activation with 2-
isocyanoxanthone (0.1 mmol) varying the perfluorinated
[a]
[b]
[c]
arene
(
reaction time is 48 h.
224 equiv. of
231 equiv. of
and
the
overall
yield
was
99%.
perfluorinated substrate were used.
perfluorinated substrate were used). Xan = xanthon-2-yl.
Trimethyl(perfluorophenyl)silane provided the meta-
product 3k as the major product (73%). The reaction
with perfluorotoluene (100 equiv.) proceeded in high
The overall yields in this series depend on the yield (84%) delivering the ortho-product 3l as the
major isomer in analogy to the reaction with
perfluorinated arenes with electron-poor systems isonitrile 1a. In general higher yields were achieved
using 1b instead of 1a which might also be due to a
significantly decreases upon replacement of a fluorine better solubility of the resulting benzimidoyl fluorides.
electronic nature of the substituents on the
generally showing higher yields. The yield
The
reaction
of
isonitrile 1b
and
atom by a hydrogen atom, as documented by
perfluoropyridine (100 equiv.) afforded exclusively
comparing yields obtained for 3a and 3d. Of note,
upon replacing two fluorine atoms in the parent the meta-product 3m with complete regioselectivity
and moderate yield (57%).
tetrafluorobenzene as the substrate, only traces of the Especially challenging is the selective C–F activation
perfluorobenzene with hydrogen atoms using 1,2,4,5-
in the presence of other C–halogen bonds, since
corresponding C–F insertion product were detected by
254 nm irradiation used in our previous study caused
GC-MS (not shown). The electronic character of the
substituent is obviously controlling the efficiency and C–halogen bond homolysis. Along these lines, we
reacted isonitrile 1b with chloropentafluorobenzene
also the regioselectivity of the reaction. While
electron-donating groups (EDG) lead to mixtures of (100 equiv.) and obtained the targeted product 3n
exclusively as the meta-isomer in 81% yield.
3
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
Unfortunately, bromopentafluorobezene was not were isolated in high yields (99% and 93%,
stable under the applied conditions. Isonitrile 1b was respectively). Importantly, we found that a ketone
also
tested
in
the
reaction
with moiety in the isonitrile component is not required as
methyl(perfluorophenyl)sulfane and the para- can be seen by the quantitative transformation of
isomer 3o was selectively formed in excellent yield 4-isocyano-1,1’-biphenyl (1e) to the imidoyl
(92%). Notably, using our previously reported fluoride 3r. This fact significantly expands the
conditions (exc = 254 nm),[12] the corresponding
isonitrile scope. Of note, irradiation of 1e in the
absence of acetophenone with C6F6 did not lead to the
formation of the targeted 3r. The isonitrile 1e was
also tested in the reaction with 2,3,4,5,6-pentafluoro
benzonitrile. While this particular C–F insertion did
not proceed under our previously disclosed
conditions,[12] product 3aa was obtained in excellent
91% yield with the para-isomer being formed as
major compound.
benzimidoyl fluoride could not be prepared, further
underlining the advantage of using milder longer
wavelength light in combination with
a
photosensitizer to conduct these C–F insertion
reactions.
Scheme 3. Scope of C–F activation in perfluorinated
Scheme 4. Scope of the C–F activation in
hexafluorobenzene (200 equiv.) varying the isonitrile
component ([a] reaction time was 48 h).
arenes with 1b (0.1 mmol) and 100 equiv. of perfluorinated
[b]
substrate ([a] reaction time was 48 h.
perfluorinated substrate were used.
perfluorinated substrate were used).
200 equiv. of
89 equiv. of
[c]
1-Isocyanobiphenyl (1f) worked well leading to 3s in
61% yield while 1-isocyanonaphthalene (1g) afforded
3t with slightly lower efficiency (44%) and
(4-isocyanophenyl)(phenyl)ketone (1h) gave 3u in a
The scope of the C–F activation was further tested
with respect to the isonitrile component keeping
hexafluorobenzene as the reaction partner (Scheme 4).
The selected isonitriles were readily prepared from
their aniline derivatives over two steps.[27,28] These
reactions were carried out without careful exclusion
of air and moisture, as hydrolysis of the product
imidoyl fluorides turned out to be unproblematic in
these cases. Isomers of 3-isocyanoacetophenone (1b)
and 2-isocyanoxanthone (1a) were tested first and we
found that both isonitriles 1c and 1d are eligible
substrates in the reaction with C6F6, and 3p and 3q
good
yield
(76%).
2-Isocyano-1,3-dimethyl
benzene (1i) and 1-isocyano-4-methoxybenzene (1j)
were converted to their corresponding benzimidoyl
fluorides 3v and 3w in 57% and 34% yield,
respectively.
Further,
isonitrile
and
nitro
functionalities in the isonitrile component are
tolerated, as documented by the successful
preparation of the benzimidoyl fluorides 3x (89%)
and 3y (72%). 5-Isocyanobenzo[d][1,3]dioxole (1m)
4
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
was also successfully used in the reaction with C6F6 to solution. There is a small overlap of these emission
give the targeted product 3z in high yield (84%). spectra and the absorption spectra of 1a and 1b. In
These studies show that the scope with respect to the
isonitrile component is broad and different functional
groups are tolerated.
aceto
ne as
the
In order to examine the reaction pathway and to
account for the reactivity difference of the tested
photosensitizers in the reaction (Table 1), we
calculated the structures and energies of the singlet
and triplet excited states of 1a along with
acetophenone and benzophenone (Figure 1). The
computations show that acetophenone has an
energetical higher S1 state (3.84 eV) compared to 1a
(3.71 eV), but that the S1 state of benzophenone is
slightly lower at 3.67 eV. The T1 states of 1a and
acetophenone are similar at 3.33 and 3.28 eV,
solve
nt, the
emiss
ion
spectr
a
of
aceto
pheno
ne
and
benzo
respectively, while that of benzophenone is stabilized phenone are red-shifted, showing a shoulder peak at
at 3.06 eV. The small energy difference between the 368 nm and a broad peak at 402 nm. In this solvent,
excited triplet states of acetophenone and 1a[29] seems the spectral overlap is negligible. Thus, Förster
to enable Dexter energy transfer between the two.
energy transfer can be excluded as the sensitization
mechanism due to poor spectral overlap between the
donor acetophenone/ benzophenone and the acceptor
isonitrile.
Figure 2. UV-vis absorption spectra of 1a and 1b in
acetonitrile.
1
1a in MeCN
1b in MeCN
1
Acetophenone in MeCN
Benzophenone in MeCN
Acetophenone in Acetone
Benzophenone in Acetone
Figure 1. DFT and TDA modelling of the energies of the
HOMO/LUMO orbitals and the S1 and T1 states of 1a,
acetophenone, and benzophenone and the electron density
distribution of the frontier molecular orbitals at the
PBE0/6-31G(d,p) level.[30,31]
In order to corroborate a Dexter mechanism
experimentally, we first measured the absorption
spectra of 1a and 1b in acetonitrile. Near the 350 nm
excitation wavelength used for the photoreaction, 1a
possesses a much more absorptive band at 320 nm
compared to the weak absorption detected for 1b
(Figure 2). We next investigated the spectral overlap
between the emission spectra of acetophenone or
benzophenone and the absorption spectra of 1a or 1b
(Figure 3). Both acetophenone and benzophenone
exhibited sharp emission at 366 nm in acetonitrile
0
200
0
300
400
500
600
/ nm
Figure 3. Normalized UV-vis absorption spectra of 1a and
1b and emission spectra of acetophenone and
benzophenone in MeCN and acetone (휆exc = 330 nm).
5
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
Figure 4. DFT enthalpies of intermediates for the reaction of triplet phenyl isonitrile with C6F6 (2a). Geometries, enthalpic
corrections and excitation energies: ωB97X/6-31G(d,p), electronic energies: PWPB95-D3/def2-TZVP (see Supporting
Information).
Finally, the CF insertion reaction between a
photoexcited aryl isonitrile and a fluoroarene was
investigated computationally.[12] As a test reaction,
Conclusion
the insertion of triplet phenyl isonitrile into C6F6 (2a)
was addressed by using density functional theory
(DFT) methods (Figure 4). We started the model
In conclusion, we have introduced a mild method for
the photosensitized insertion of various isonitriles into
the C–F bond of perfluorinated arenes to afford
benzimidoyl fluorides in moderate to good yields.
Acetophenone was identified as a suitable sensitizer
and C–F activation reactions could be achieved upon
irradiation at 350 nm. The rather mild light used to
mediate these reactions warrant high functional group
tolerance. The transition-metal free reaction provides
ready access to benzimidoyl fluorides with, in
selected cases, high regioselectivity. Previous
mechanistic studies showed that these C–F activation
reactions proceed via the triplet state of the aryl
isonitriles. While in previous work the triplet state
was generated upon 250 nm excitation, the
acetophenone-sensitized process proceeds likely via a
Dexter energy transfer at 350 nm, as analyzed by
excited state calculations and spectroscopic studies.
3
calculation from the triplet adduct A which has a
lower energy than the T1 energy of 1a (76.8 kcal/mol).
A transition structure TSA-C for 1,2-migration of F to
3
the imidoyl carbon has been located, but the energetic
barrier is rather high (ΔH≠ = 24.2 kcal/mol) and this
path leads to an excited triplet state 3C* of the product.
The activation energy required for F-migration to the
ortho-position of the fluorinated arene is lower (3TSA-
3
B, ΔH≠ = 16 kcal/mol) and intermediate B is formed
exothermically. Thus, 3B is likely an intermediate. We
could not locate a transition structure for the direct
3
conversion of B to one of the triplet states of the
product, but it is reasonable to assume that a pathway
involving the mixing of π,π and n,π states exists. The
3
lowest triplet intermediate we could locate is C, a
π,π*-excited triplet state of the product imidoyl
fluoride. It will revert to the singlet state (1C) by
intersystem crossing involving the rotation of the C-N
bond.
6
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
Experimental Section
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anilines:
[5]
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Aromatic isonitriles 1a-m were synthesized from their
aniline derivatives according to a literature known
procedure.[27] The aniline derivative (1.0 equiv.) was
dissolved in dry THF (0.6 M) under argon. Acetic
anhydride (2.3 equiv.) and formic acid (2.7 equiv.) were
stirred under argon for 2 h at 55 °C and subsequently added
dropwise to the aniline solution at 0 °C. The reaction
mixture was stirred at rt for 2 h. The reaction was quenched
by adding saturated aqueous NaHCO3 solution. The
aqueous layer was extracted with EtOAc (3x). The
combined organic layers were dried over MgSO4 and the
solvent was removed in vacuo. The product, used further
without any purification, was dissolved in dry THF (0.6 M)
under argon, Et3N (6.7 equiv.) was added and the solution
was cooled to 0 °C. POCl3 (1.7 equiv.) was added dropwise
and the mixture was stirred for 1 h at 0 °C. The reaction
was quenched with saturated aqueous Na2CO3 solution and
the resulting mixture was stirred for 1 h at rt. The mixture
was extracted with EtOAc (3x) and the combined organic
layers were dried over MgSO4. The solvent was removed in
vacuo and the product was isolated via flash column
chromatography with pentane and diethyl ether. The
solvent was removed in vacuo until about 50 mL remained
and the product 1 was finally freeze dried to prevent it from
polymerization.[32]
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Isonitrile 1 (0.1 mmol, 1.0 equiv.) was added to a Schlenk [20] L. M. M. Vieira, A. Kijjoa, Curr. Med. Chem. 2005,
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Acknowledgements
We thank the Westfälische Wilhelms-University of Münster for
continuous financial support.
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7
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10.1002/adsc.201901126
Advanced Synthesis & Catalysis
FULL PAPER
Mild C–F Activation in Perfluorinated Arenes
through Photosensitized Insertion of Isonitriles at
350 nm
Adv. Synth. Catal. Year, Volume, Page – Page
Frauke Weidlich, Naoto Esumi, Dongyang Chen,
Christian Mück-Lichtenfeld, Eli Zysman-Colman,*
Armido Studer*
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