Synthesis of α-Difluoromethyl Aryl Ketones through a Photoredox Difluoromethylation of Enol Silanes

Article abstract of DOI:10.1021/acs.orglett.1c01177

We report here an efficient and highly straightforward access to α-difluoromethylated ketones through a visible light-mediated difluoromethylation of readily available enol silanes. The method, which takes advantage of the polyvalence of Hu's reagent, N-tosyl-S-difluoromethyl-S-phenylsulfoximine, used here as a CHF2 radical precursor under catalytic photoredox conditions, is practical, scalable, and provides the corresponding α-CHF2 ketones in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.1c01177

pubs.acs.org/OrgLett
Letter
Synthesis of α‑Difluoromethyl Aryl Ketones through a Photoredox
Difluoromethylation of Enol Silanes
Elias Selmi-Higashi, Jinlei Zhang, Xacobe C. Cambeiro, and Stellios Arseniyadis*
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ABSTRACT: We report here an efficient and highly straightforward
access to α-difluoromethylated ketones through a visible light-mediated
difluoromethylation of readily available enol silanes. The method, which
takes advantage of the polyvalence of Hu’s reagent, N-tosyl-S-
difluoromethyl-S-phenylsulfoximine, used here as a CHF2 radical
precursor under catalytic photoredox conditions, is practical, scalable,
and provides the corresponding α-CHF2 ketones in good to excellent
yields.
he incorporation of fluorine atoms in drugs has been
shown to often improve their metabolic stability, enhance
was described with a rather moderate yield of 36%, this was the
first example ever reported in the literature.
T
their lipophilicity, and increase their membrane permeability
and bioavailability.1 This observation has thus triggered a
broad body of work focused on the development of new
synthetic methods allowing a straightforward access to
fluorinated drug analogues mainly through fluorination2 and
trifluoromethylation processes.3 The difluoromethyl group has
recently attracted a revival of interest due to its ability to act as
a weak hydrogen bond donor often compared to carbinols,
thiols, amides, and hydroxamic acids.4 It is therefore not
surprising that the CHF2 motif has become prevalent in many
pharmaceuticals and agrochemicals.5 Nonetheless, unlike the
fluorination and trifluoromethylation reactions, which have
been widely explored over the years, examples of efficient and
reliable difluoromethylations are more sparse,6 particularly for
the synthesis of α-difluoromethylated ketones.
Traditionally, difluoromethylated compounds are prepared
using direct or indirect strategies through electrophilic,7
nucleophilic,8 or radical9 processes. Several effective difluor-
omethylating agents have been reported over the years such as
the tosylsulfoximine I developed by Hu and co-workers,10 the
sulfonium and sulfoxinium salts II and III developed by
Shibata,11,12 the sulfonium salts IV and V developed by Shen13
and Liu,14 respectively, and TMSCHF2 (VI), first reported by
Hu (Figure 1),15 which have been successfully used on a
variety of aromatic and heteroaromatic scaffolds. However, as
mentioned previously, despite the various strategies that have
been unveiled, the synthesis of α-difluoromethyl ketones has
been much less explored and remains an important synthetic
challenge.
A few years later, Paquin and co-workers reported a highly
regioselective gold-catalyzed formal hydration of propargylic
gem-difluorides affording a series of 3,3-difluoroketones in high
yields, including two examples of α-CHF2-substituted ketones
(Figure 1B).17 The method took advantage of the strong
electron-withdrawing character of the fluorine atoms to direct
the selectivity toward the desired carbonyl moiety.
More recently, Akita and co-workers reported a practical and
more general approach to α-CHF2-substituted ketones through
a catalytic photoredox keto-difluoromethylation of aromatic
alkenes (Figure 1C).18 The method was applicable to a variety
of aromatic and heteroaromatic alkenes and could be scaled up
under continuous flow conditions.
Finally, Wang, Wu, and co-workers just reported a visible-
light-promoted radical difluoromethylation of enol acetates
using [Ph3PCHF2]+Br− as a CHF2 radical precursor (Figure
1D), affording the corresponding α-CHF2-substituted aryl
ketones in moderate to good yields after 36 h.19
Our group has also been involved in the development of new
strategies toward the synthesis of difluoromethylated com-
pounds. In this context, we recently reported a general method
for the synthesis of CHF2-containing lactones, lactams,
glutaramides, succinimides, quinolinones, and Weinreb amides
via a sequential C-selective electrophilic difluoromethylation/
palladium-catalyzed decarboxylative protonation.20 The meth-
Received: April 8, 2021
Published: May 24, 2021
In 2012, Mikami and co-workers developed a direct α-
difluoromethylation of lithium enolates using fluoroform as an
electrophilic difluoromethylating agent (Figure 1A).16
Although only one example of α-CHF2-substituted ketone
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a
Table 1. Systematic Study
a
Reaction conditions: 1 (0.1 mmol, 1 equiv), I (0.2 mmol, 2 equiv),
photocatalyst (1 mL), rt, 24 h, under an argon atmosphere, 8 W blue
b
LED (460 nm). NMR determined using benzotrifluoride as an
c
internal standerd. Reaction run in the absence of light. [2,6-DTP =
2,6-di-tert-butylpyridine, DABCO = 1,4-diazabicyclo[2.2.2]octane].
decreased considerably the overall yield. The best results were
obtained with 2,6-di-tert-butylpyridine (2,6-DTP) (entry 7),
which afforded the desired α-difluoromethylated product 2a in
an improved 85% yield. Several solvents, such as MeCN,
DMSO, DMF, and toluene, were also evaluated under
otherwise identical conditions (entries 8−11), but the best
solvent remained acetone. Ultimately, increasing the amount of
the CHF2 radical precursor to 2 equiv led to the best outcome
with up to 93% yield (entry 12) and, most importantly,
complete recovery of the additional equivalent of I, thus
pointing out its role in the catalytic cycle. It is worth
mentioning that in the absence of fac-Ir(ppy)3 or when
running the reactions in the dark, all of the starting material
was recovered intact (entries 13−14), while varying the
amount of H2O did not improve the yield (results not shown,
see SI for more details).
Figure 1. Strategies for the synthesis of α-difluoromethyl
ketones.10−19
od, which proved particularly effective, relied on the use of N-
tosyl-S-difluoromethyl-S-phenylsulfoximine I as a difluorocar-
bene precursor. Interestingly, this reagent can also be used as a
radical CHF2 source when subjected to catalytic photoredox
conditions as showcased by Akita and co-workers.18,21 This
prompted us to explore a new route toward α-CHF2-
substituted ketones through a key photochemical radical
difluoromethylation of readily available enol silanes, which is
very complementary to Wang and Wu’s method (Figure 1E).
We report here the results of our endeavor. To evaluate the
feasibility of this photocatalytic difluoromethylation, we chose
enol silane 1a as a model substrate.22 The latter was prepared
in one step and 92% yield starting from commercially available
acetophenone (see Supporting Information (SI) for more
details). In our initial screening, we evaluated two common
metal-based photocatalysts, namely Ru(bpy)3·6H2O (entry 1)
and fac-Ir(ppy)3 (entry 2), as well as an organic photocatalyst,
eosin Y (entry 3). The reactions were run in acetone at rt for
24 h under visible light irradiation (8 W blue LED, 460 nm),
using a 2 mol % catalyst loading, 1.5 equiv of Hu’s reagent I,
and 2 equiv of H2O. Interestingly, only fac-Ir(ppy)3 provided
the desired α-difluoromethylated product 2a (77%), which was
not surprising considering the higher reduction power (E*ox)
of fac-Ir(ppy)3 in its photoexcited state (−2.19 V vs SCE)23
over all the other photocatalysts, allowing it to reduce the
difluoromethylated sulfoximine I (−2.26 V vs Cp2Fe in
DMSO)18 to the corresponding CHF2 radical. With this result
in hand, we also screened various bases, as we believed they
could potentially help promote the desilylation step, however,
the use of DABCO (entry 4) completely inhibited the reaction,
while the use of Na2CO3 (entry 5) and quinoline (entry 6)
After having identified the best set of reaction conditions, we
next examined the substrate scope by evaluating a series of silyl
enol ethers (Figure 2A).
The reaction appeared to be tolerant to substrates bearing
electron-donating groups on the aromatic ring independently
of their position. Hence, the ortho- (2b, 52%), meta- (2c, 48%),
and para-methyl-substituted (2d, 54%) derivatives as well as
the para-tert-butyl- (2e, 62%) and the para-methoxy
derivatives (2f, 64%) were all obtained in decent yields. The
reaction appeared to be equally tolerant to substrates bearing
electron-withdrawing groups on the aromatic ring such as the
ortho- (2g, 49%), meta- (2h, 54%), and para-bromo-
substituted (2i, 63%) derivatives, as well as the para-chloro-
(2j, 72%), the para-fluoro- (2k, 75%), the para-trifluorometh-
yl- (2l, 76%) and the para-cyano derivatives (2m, 51%), which
were also obtained in good yields. The method was also used
to prepare the 2-naphthyl derivative 2n (44%) as well as the
tertiary α-difluoromethyl ketones 2o (52%) and 2p (68%).
Quaternary α-difluoromethyl ketones proved much more
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Figure 2. Full survey. aConditions: 1 (0.2 mmol, 1 equiv), I (0.4 mmol, 2 equiv), fac-Ir(ppy)3 (4 μmol, 2 mol %), base (0.2 mmol, 1 equiv), H2O
b
(0.4 mmol, 2 equiv), solvent (2 mL), rt, 24 h, under an argon atmosphere, 8 W blue LED (460 nm), isolated yields. Reaction run over 3 days
instead of 24 h [θ: dihedral angle between the planes of the phenyl and enol fragments].
difficult to obtain, as showcased by the low yields obtained for
2q (15%) and 2r (13%) after running the reaction over 72 h
instead of 24 h.24 Nonetheless, the reaction was successfully
applied to heteroaromatic precursors such as the N-methyl
imidazole- (2s, 62%), the N-benzyl pyrazole- (2t, 50%), the
benzothiophene- (2u, 60%) and the 2-furan-derivatives (2v,
44% yield), as well as vinyl ketones such as 2u (46% yield),
with the latter process being completely chemoselective.
Unfortunately, the method could not be applied to alkyl
ketones (2x).
On the basis of the available literature precedents,18,21 we
initially hypothesized that the difluoromethylation reaction was
mediated by the in situ generation of a CHF2 radical from I
upon a one-electron reduction by the excited catalyst. To
confirm this, we ran fluorescence quenching experiments using
either I or 1a as the quencher, which showed compound I to
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be a far more efficient quencher (see SI for more details). In
addition, a reaction between 1a and I in the presence of
TEMPO under otherwise identical conditions resulted after 24
h in the formation of only 5% of the α-difluoromethylated
ketone 2a along with 53% of the TEMPO−CHF2 adduct
(Figure 2B). These data strongly support an oxidative
quenching pathway, resulting in a one-electron reduction of I
and subsequent decomposition releasing the CHF2 radical.
We also studied the radical addition onto the silyl enol ether
by DFT using the PBE0 functional with Grimme D3
dispersion corrections, SMD solvent model for acetone as
implemented in Gaussian 16,25 and the trimethylsilyl analogue
of 1a, 1o, and 1q as a conformationally simplified model
substrate. Our model (Figure 2D) reflects a highly exergonic
addition (ΔG = −34.0 kcal/mol) mediated by an early, readily
accessible transition state (ΔG⧧ = 7.4 kcal/mol, 2.58 Å C−
CHF2 distance). These data are consistent with a rapid and
irreversible radical addition. Furthermore, our model correctly
anticipates the decrease in reactivity caused by the presence of
α-substituents (e.g., propiophenone- and isubutyrophenone-
derived silyl enol ethers 3o and 3q) due to less accessible
transition states. The effect of the substituents at the α position
seems to relate to an intramolecular steric repulsion that causes
a loss of planarity of the aromatic ring and consequent loss of
conjugation. This is consistent with the good yield obtained
experimentally with 1p, in which the α-substituent forms a
bicyclic system with the aromatic ring, thus maintaining a
coplanar arrangement with the enol. Finally, our calculations
predicted that the ketyl radical B resulting from the addition
was a reasonably good reductant, with a reduction potential for
its corresponding silyloxonium (C) of EC = −0.23 V (all
potentials reported vs SCE).26 This enables its easy oxidation
by the oxidized form of the catalyst Ir(ppy)3+ (EIr+ = +0.77 V),
closing the photoredox catalytic cycle. In sharp contrast, C is
not strong enough of a reductant to propagate a chain reaction
through single electron transfer with compound I (EI = −2.26
V). This was further supported by an intermittent irradiation
experiment, which showed the reaction only to occur during
irradiation and abruptly stop in the absence of light (see SI for
more details).
chemistry. A first experiment run with 1i (0.1 mmol scale)
under our previously optimized conditions [2 equiv of I, 2 mol
% of fac-Ir(ppy)3, 2 equiv of H2O, acetone, rt, 8 W blue LED
(460 nm), 10 mL PFA coil (Ø = 1 mm), 0.1 mL.min−1 flow
rate (residence time = 1.7 h)], afforded the corresponding α-
difluoromethyl ketones 2i in 34% NMR yield, which compared
favorably with the result obtained under the standard batch
conditions over 24 h. After fine-tuning the catalyst loading (5
mol % instead of 2 mol %) and the reaction concentration
(0.05 M instead of 0.1 M), we were able to maintain a low
reaction time and reach up to 91% yield. These conditions
were eventually applied to convert 1 mmol of 1i in only 5 h
and 90% isolated yield (Figure 2C).
In summary, we have developed a straightforward method
for the direct difluoromethylation of enol silanes through a
visible-light-driven photoredox catalytic process. The method
affords the corresponding α-CHF2 substituted ketones in good
to excellent yields under mild conditions. Moreover, the
method is practical and readily scalable under continuous flow
conditions. Most importantly, these α-difluoromethylated
ketones are useful building blocks, which have already been
shown to undergo various postfunctionalizations such as α-
brominations, asymmetric reductions, hydrations, acetal
dehydrofluorinations, halohydrin formations, and amida-
tions,18−20 thus offering great perspectives for medicinal
chemistry applications.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01177.
1
Details of experimental procedures, H, 13C, and 19F
NMR spectra, HPLC chromatograms, and detailed
computational data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Stellios Arseniyadis − Department of Chemistry, Queen Mary
University of London, London E1 4NS, U.K.; orcid.org/
0000-0001-6831-2631; Email: s.arseniyadis@qmul.ac.uk
We therefore propose the following mechanism (Figure 2E),
where the excited *Ir(ppy)3 catalyst transfers an electron to I,
promoting its decomposition to the CHF2 radical in
conjunction with N-tosylsulfimate, which may be subsequently
protonated. Then, addition of the electrophilic CHF2 radical
onto the silyl enol ether affords the corresponding ketyl radical
Authors
Elias Selmi-Higashi − Department of Chemistry, Queen Mary
University of London, London E1 4NS, U.K.
Jinlei Zhang − Department of Chemistry, Queen Mary
University of London, London E1 4NS, U.K.
+
A, which is in turn oxidized by Ir(ppy)3 to generate the
silyloxonium species B. The latter ultimately undergoes
desilylation to afford the desired ketone product 2a, with the
base acting as a proton acceptor. Alternatively, α-deprotona-
tion can also occur to afford the difluoromethylated silyl enol
ether 2′a, which was observed in several cases and could be
isolated (see SI for more details). Nonetheless, 2′a can be
quantitatively hydrolyzed to the desired ketone upon workup
with TFA (4 equiv).
With the aim of scaling up the reaction, we immediately
became interested in developing a continuous flow process.27
Indeed, the narrow width of the flow reactor coil would ensure
a more uniform distribution of the light within the entire
reaction mixture, which would in turn increase the effective
concentration of active catalyst and therefore result in shorter
reaction times and improved scalability, not to mention the
reduced safety concerns that are usually associated with flow
Xacobe C. Cambeiro − School of Science, University of
Greenwich, Chatham Maritime ME4 4TB, U.K.;
orcid.org/0000-0002-7365-7201
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01177
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the China Scholarship Council
(CSC) and Queen Mary University of London for financial
support. This work is dedicated to Professor Christian Bruneau
(Rennes Institute of Chemical Sciences, Université de Rennes
1) for his outstanding contribution to catalysis.
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