Oxidative trifluoromethylation of unactivated olefins: An efficient and practical synthesis of α-trifluoromethyl-substituted ketones

Article abstract of DOI:10.1002/anie.201303576

An economical approach to α-CF₃-substituted ketones, which are important intermediates in synthetic and medicinal chemistry, employs olefins and the readily available Langlois reagent (CF₃SO ₂Na). The reaction is operationally simple, proceeds at room temperature, and exhibits an excellent tolerance toward a wide variety of functional groups. Copyright

Full text of DOI:10.1002/anie.201303576

Angewandte
Chemie
DOI: 10.1002/anie.201303576
Trifluoromethylation
Oxidative Trifluoromethylation of Unactivated Olefins: An Efficient
and Practical Synthesis of a-Trifluoromethyl-Substituted Ketones**
Arghya Deb, Srimanta Manna, Atanu Modak, Tuhin Patra, Soham Maity, and Debabrata Maiti*
The incorporation of a CF3 group in a compound of
pharmacological relevance usually results in significant en-
hancement of its lipophilicity, binding selectivity, and meta-
bolic stability.[1–5] A number of highly effective methods for
the incorporation of a CF3 moiety into commonly used
synthetic scaffolds have been reported.[2–9] In this context, the
synthesis of a-CF3-substituted carbonyl compounds[10–14] has
recently drawn significant attention, owing to their impor-
tance for both pharmaceutical and synthetic research.
Generally, a-CF3-substituted carbonyl compounds are
prepared from silyl enol ethers and enolates by using various
radical and electrophilic trifluoromethylating agents
(Scheme 1).[6–8] Strong bases, such as lithium diisopropyla-
mide (LDA), are often employed in the synthesis of these
precursors, thus limiting the available methods by extra
and thus circumvented the problem of 1,2 addition of the CF3
[11]
=
group across the C O bond (Scheme 1).
Despite this
significant progress to construct a-CF3-substituted carbonyl
scaffolds,[5–9] utilization of widely available olefin feedstock in
conjunction with an economic trifluoromethylation source
remains elusive. In this context, note that “although styrenes
can be used directly in the recently reported[12] radical
trifluoromethylation with costly [Ph2SCF3]+OTfÀ, the yields
of the a-CF3-substituted acetophenone products are only 20–
40%.”[11a]
We have recently reported the stereoselective nitration of
olefins through the formation of nitro radicals.[13] During this
study, we envisaged a radical trifluoromethylation of olefins
by employing the Langlois reagent (CF3SO2Na), because it
has been utilized effectively as the source of the CF3
radical.[2d,14] Herein, we disclose the oxidative trifluorome-
thylation of unactivated olefins with inexpensive CF3SO2Na
as the CF3 source for the synthesis of a-CF3-substituted
ketones in excellent yields (Scheme 2). Employing an olefin
as the synthetic precursor rather than a preformed substrate
and carrying out the reactions in an open flask at room
temperature make this method advantageous.
Scheme 2. Oxidative trifluoromethylation of olefins. FG=functional
group.
Scheme 1. Synthesis of a-CF3-substituted ketones.
We began our study with the reaction of 2-vinyl naphtha-
lene and benchtop-stable CF3SO2Na in presence of a catalytic
amount of AgNO3/K2S2O8.[15] Optimized reaction conditions,
which include the use of two equivalents of triflinate and
20 mol% of AgNO3/K2S2O8 in DMF at room temperature,
gave the a-CF3-substituted ketone in excellent yield. With
these operationally simple and optimized reaction conditions
established, we evaluated the scope and limitations of the
method. We first explored the substrate scope with styrene
derivatives (Scheme 3). The reaction with styrene afforded 2-
trifluoromethylacetophenone (3a) in an excellent yield of
92%. A wide variety of substituents/functional groups,
ranging from NO2 (3h and 3l), CN (3g), CHO (3k), to
CO2Me (3i), remained intact during the reaction, owing to the
exceptionally mild reaction conditions. Consistent with our
expectations, halogenated styrenes could also be successfully
transformed (3d–f). 2-Substituted styrene derivatives reacted
efficiently to generate a-CF3-substituted ketones (3n–p).
Also, naphthalenes with vinyl groups at positions 1 and 2
synthetic steps and precautionary measures. MacMillan and
co-workers successfully generated a-CF3-substituted carbonyl
compounds from aldehydes, ketones, esters, and amides.[9]
Enantiopure a-CF3-substituted carbonyl scaffolds were also
reported in recent years.[9b,c,10] In 2012, a nucleophilic trifluor-
omethylation of a-halogenated ketones was developed by
Grushin and co-workers, who used fluoroform-derived CuCF3
[*] A. Deb, S. Manna, A. Modak, T. Patra, S. Maity, Dr. D. Maiti
Department of Chemistry
Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
E-mail: dmaiti@chem.iitb.ac.in
[**] This work is supported by DST. Fellowships to A.D., A.M., and S.M.
(CSIR-India), and to T.P. (UGC-India) are gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303576.
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Scheme 4. Synthesis of a-CF3-substituted ketones from b-substituted
styrenes. Olefin (0.25 mmol), CF3SO2Na (0.05 mmol), AgNO3
(20 mol%), K2S2O8 (20 mol%), 24 h.
substituted carbonyl compound 4d under the optimized
reaction conditions (around 65% yield). Also, a styrene
with a methyl group at the b position (4a) reacted as
efficiently as the unsubstituted styrene itself (3a). The scope
of this oxidative trifluoromethylation method was tested on
heteroaromatic olefins (Scheme 5). The 3-vinyl benzothio-
phene gave the expected a-CF3-substituted ketone in 86%
yield (5a). Olefins with heterocycles that contain nitrogen
atoms, such as pyrazole and indazole, were also successfully
employed (5b and 5d, respectively).
Scheme 3. Synthesis of a-CF3-substituted ketones from styrenes. Reac-
tion conditions: olefin (0.25 mmol), CF3SO2Na (0.5 mmol), AgNO3
(20 mol%), K2S2O8 (20 mol%), 24 h. [a] K2S2O8 (10 mol%). [b] 508C.
[c] AgNO3 (10 mol%). [d] 73% yield on a 3 mmol scale. [e] ArCHO
isolated, 18%.[15] brsm=based on recovered starting material.
gave the desired products in 89% (3r) and 95% (3q) yields,
respectively. The formation of the a-CF3-substituted ketone
occurred exclusively at the styrene olefin in presence of
a terminal aliphatic olefin (3s). In case of alkyne-bearing
product 3t, the formation of the a-CF3-substituted ketone
occurred only at the styrene moiety (3t) and the terminal
alkyne remained intact during the oxidative trifluoromethy-
lation. Such examples underscore the power of the present
strategy to affect the highly selective formation of a-CF3-
substituted ketones. Styrenes with covalently attached cis-
verbenol formed ArCOCH2CF3 selectively in 75% yield (3u).
Because of the very mild conditions employed in the
present method, a chloromethyl group (3m), which can be
easily oxidized to the corresponding aldehyde, was also
tolerated.[13] These examples outline the factors that deter-
mine the selectivity, and they can be successfully implemented
to generate a-CF3-substituted ketones in complex molecules.
Products derived from a,b-substituted olefins are ubiq-
uitous in synthetic chemistry and we thought to react these
olefins under standard conditions (Scheme 4). Interestingly
1,2-dihydro-naphthalene and 1,2-dihydro-indene were trans-
formed successfully to cyclic ketones containing CF3 groups
(4b and 4c, respectively). As anticipated, both cis and trans
stilbenes reacted successfully to form the same a-CF3-
Scheme 5. Synthesis of a-CF3-substituted ketones from heteroaromatic
olefins. For reaction conditions, see Scheme 3.
Vinyl cycloalkanes were reacted successfully to produce
a-CF3-substituted carbonyl compounds in useful yields
(Scheme 6, products 6a and 6b). Unfortunately, aliphatic
olefins with long chains (e.g., dodecene, tetradecene, and 10-
bromo-1-decene etc.) gave an inseparable mixture of two
uncharacterized products that contain the CF3 moiety.
Further studies are ongoing in our laboratory to synthesize
these products in pure form.
To further confirm the generation of a-CF3-substituted
ketones from the oxidative trifluoromethylation method,
Scheme 6. Oxidative trifluoromethylation of vinyl cycloalkanes.
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characterization (in addition to analytical studies) of 3g and
5d were carried out by single-crystal X-ray diffraction
studies.[16]
Compounds that contain an a-CF3-substituted carbonyl
moiety are useful synthetic precursors (Scheme 7).[5–9,15] The
addition of CF3 and OH groups across an olefin is yet to be
realized in a single step.[11a,17] But such much desired OH/CF3-
substituted compounds (7a) can be prepared easily by
reduction of a-CF3-substituted ketones. Furthermore, the
a position of CF3-substituted ketones can be brominated (7c).
air and K2S2O8 can be the source of the oxygen atom of the
ketone (Scheme 8c).
Formation of Ag0 in the reaction mixture was confirmed
by X-ray photoelectron spectroscopy (XPS).[15] Based on
these studies, a catalytic cycle that involves AgI/Ag0 has been
proposed (Scheme 9). A detailed mechanistic investigation is
currently under way in our laboratory.
Scheme 9. Plausible mechanistic pathway.
In conclusion, we have discovered a direct, efficient, and
general method to access a-CF3-substituted ketones.[17,18]
Simple unactivated olefins have been employed as the
starting materials. Wide functional-group tolerance, mild
reaction conditions, and the use of an inexpensive trifluor-
omethylating agent are key features of this reaction. Because
of its operational simplicity and predictable reactivity pattern
in complex settings, we expect this method to find broad
application in synthetic, medicinal, and agrochemical
research.
Scheme 7. Synthetic utility of a-CF3-substituted ketones.
Received: April 26, 2013
Revised: June 20, 2013
Published online: && &&, &&&&
A preliminary investigation of the reaction mechanism
suggested that the reaction is likely to involve a CF3 radical.
Under the optimized reaction conditions, 2-vinyl naphthalene
Keywords: ketones · Langlois reagent · olefins ·
did not produce an a-CF -substituted ketone in the presence
.
3
synthetic methods · trifluoromethylation
of TEMPO (Scheme 8a). Consistent with this observation,
TEMPO-CF3 was detected in the reaction mixture by
19F NMR spectroscopy. In the absence of air, the formation
of the a-CF3-substituted ketone was retarded (Scheme 8b).
Furthermore, an 18O-labeling experiment confirmed that both
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Angewandte
Chemie
Communications
Trifluoromethylation
A. Deb, S. Manna, A. Modak, T. Patra,
S. Maity, D. Maiti*
&&&& — &&&&
An economical approach to a-CF3-sub-
stituted ketones, which are important
intermediates in synthetic and medicinal
chemistry, employs olefins and the readily
available Langlois reagent (CF3SO2Na).
The reaction is operationally simple,
proceeds at room temperature, and
exhibits an excellent tolerance toward
a wide variety of functional groups.
Oxidative Trifluoromethylation of
Unactivated Olefins: An Efficient and
Practical Synthesis of a-Trifluoromethyl-
Substituted Ketones
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!