Regioselective 1,4-trifluoromethylation of α,β-unsaturated ketones via a S-(trifluoromethyl)diphenylsulfonium salts/copper system

Article abstract of DOI:10.3762/bjoc.9.257

Regioselective conjugate 1,4-trifluoromethylation of α,β- unsaturated ketones by the use of shelf-stable electrophilic trifluoromethylating reagents, S-(trifluoromethyl)diphenylsulfonium salts and copper under mild conditions is described. A wide range of acyclic aryl-aryl-enones and aryl-alkyl-enones were converted into β- trifluoromethylated ketones in low to moderate yields.

Full text of DOI:10.3762/bjoc.9.257

Regioselective 1,4-trifluoromethylation of
α,β-unsaturated ketones via a S-(trifluoromethyl)di-
phenylsulfonium salts/copper system
Satoshi Okusu, Yutaka Sugita, Etsuko Tokunaga and Norio Shibata*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2189–2193.
Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya
466-8555, Japan
doi:10.3762/bjoc.9.257
Received: 27 August 2013
Accepted: 10 October 2013
Published: 23 October 2013
Email:
Norio Shibata* - nozshiba@nitech.ac.jp
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
* Corresponding author
Keywords:
1,4-addition; copper; fluorine; Michael addition; organo-fluorine;
trifluoromethylation
© 2013 Okusu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Regioselective conjugate 1,4-trifluoromethylation of α,β-unsaturated ketones by the use of shelf-stable electrophilic trifluoro-
methylating reagents, S-(trifluoromethyl)diphenylsulfonium salts and copper under mild conditions is described. A wide range of
acyclic aryl–aryl–enones and aryl–alkyl–enones were converted into β-trifluoromethylated ketones in low to moderate yields.
Introduction
One of the challenges in synthetic organic chemistry is the [1-11], not a 1,4-addition (Scheme 1), with the exception of
nucleophilic 1,4-addition of the trifluoromethyl (CF3) group non-general examples of 1,4-additive trifluoromethylation of
into electron-deficient internal alkenes as represented by the (trifluoromethyl)trimethylsilane (Me3SiCF3, Ruppert–Prakash
Michael addition reaction, even in a racemic, non-stereoselec- reagent) to very specific substrates such as trans-1-benzoyl-2-
tive fashion [1-5]. The nucleophilic trifluoromethylation to (dimethylamino)ethylene [12], 2-polyfluoroalkylchromones
conjugated alkenes essentially occurs solely via a 1,2-addition [13,14], isoxazoles with a nitro group at the 4-position [15], and
Scheme 1: Trifluoromethylation of α,β-unsaturated ketones.
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Beilstein J. Org. Chem. 2013, 9, 2189–2193.
Morita–Baylis–Hillman adducts (via SN2’ [16] or successive by a copper via SET process, although the reaction mechanism
SN2’/SN2’ mode [17]).
is not clear. We envisaged that the system could be applicable
to the conjugated 1,4-trifluoromethylation to simple chalcones.
Sevenard and co-workers reported the nucleophilic 1,4-tri- During the preparation of this article, the Nicewicz group
fluoromethylation to chromones, coumarins and cyclohex-2- showed a single example of conjugate trifluoromethylation of
enone using the Ruppert–Prakash reagent, which was achieved chalcone with sodium trifluoromethanesulfinate salt in the pres-
by blocking the carbonyl moiety of the substrates with a bulky ence of N-methyl-9-mesitylacridinium as a photoredox catalyst
aluminium-centered Lewis acid with low to moderate yields resulting in a low product yield of 31% as a mixture of regioiso-
[18]. Dilman and co-workers partially overcame this problem mers (C2/C3 1.1:1) [22]. We disclose herein the regioselective
by using highly electrophilic alkenes bearing either Meldrum’ 1,4-addition of the CF3 group into simple conjugated acyclic
acids [19], or two geminal nitrile groups [20]. However, direct enones including chalcones using S-(trifluoromethyl)diphenyl-
1,4-trifluoromethylation to conventional α,β-unsaturated sulfonium salt 3 and a copper system in 11–37% yields
ketones such as chalcone is very tough, presumably due to the (12 examples).
hardness of the CF3 anion. Recently, we reported the copper-
mediated trifluoromethylation at the benzylic position by using Results and Discussion
shelf-stable electrophilic trifluoromethylating reagents, S-(tri- We initiated our investigation with the reaction of chalcone (1a)
fluoromethyl)diphenylsulfonium salts, in good to high yields using a series of electrophilic trifluoromethylating reagents 3
under mild conditions [21]. In this reaction, a bromide at the [23-26] in the presence of copper in DMF at 60 °C (Table 1),
benzylic position would be replaced by a CF3 anion mediated based on previously reported conditions [21]. First, the tri-
Table 1: Optimization of CF3 reagents, metal, and solvent for copper-mediated conjugate trifluoromethylation of chalcone (1a).a
Entry
CF3 reagent
metal
solvent
Yield (%)b
1
3a
Cu
Cu
Cu
Cu
Ni
DMF
4
2
3a
NMP
6
3
3a
DMSO
11
4
3a
DMF/H2O (1:1)
DMF/H2O (1:1)
DMF/H2O (1:1)
NMP/H2O (1:1)
DMSO/H2O (1:1)
DMF/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
DMSO/H2O (1:1)
23
5
3a
9
6
3a
Zn
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
trace
trace
5
7
3a
8
3a
9c
10c
11
12c
13
14
15
16
17c,d
3a
25
3a
37
3b
24
3b
27
3c
trace
0
3d
3e
trace
0
Me3SiCF3
3a
tracee
aThe reaction of 1a with 3 (2.0 equiv) was carried out in the presence of metal (3.0 equiv) at 60 °C. bIsolated yield. c3 (4.0 equiv) and metal (6.0 equiv)
were used. dThe reaction was performed in the presence of TEMPO (4.0 equiv). eO-Trifluoromethylated TEMPO was detected in 2% by 19F NMR.
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fluoromethylation of 1a with S-(trifluoromethyl)diphenylsul- product formation was inhibited by TEMPO and O-trifluoro-
fonium salt 3a was attempted, and a desired product 2a was methylated TEMPO was detected in 2% by 19F NMR analysis
obtained in only 4% yield (Table 1, entry 1). Next the solvent (Table 1, entry 17).
was screened for yield improvement. We attempted the same
reaction using NMP and DMSO, and the desired product 2a With suitable conditions in hand, the scope of copper-mediated
was obtained in 6% and 11% yields (Table 1, entries 2 and 3, conjugate trifluoromethylation of α,β-unsaturated ketones 1
respectively). Interestingly, adding water (DMF/H2O 1:1) effec- with 3a was explored with a variety of substrates selected in
tively improved the yield to 23% (Table 1, entry 4). Reactions order to establish the generality of the process (Table 2). With
mediated by other metals, such as Ni and Zn, either gave poor respect to the aryl ketone group, aromatic rings substituted with
yields (Table 1, entries 5 and 6). The use of larger excesses of either electron-donating or -withdrawing substituents, such as
S-(trifluoromethyl)diphenylsulfonium salt 3a (4.0 equiv) and methyl, methoxy, fluoro and chloro were tolerated (Table 2,
Cu (6.0 equiv) in DMF/H2O (1:1) led to an increase in the yield entries 2–4). A heteroaromatic, furanyl-substituted enone was
of 2a (Table 1, entry 9). The best result was obtained by treating compatible with the same reaction conditions (Table 2, entry 6).
1a at 60 °C in DMSO/H2O (1:1) in the presence of S-(trifluoro- We next examined substrates differing in the nature of the
methyl)diphenylsulfonium salt 3a (4.0 equiv) and Cu β-aryl substituents under the same reaction conditions. A series
(6.0 equiv), leading to the isolation of 2a in 37% yield (Table 1, of compounds with aromatic rings substituted with either elec-
entry 10). Using 4.0 equiv of Umemoto’s reagent 3b instead of tron-donating or -withdrawing substituents, such as methyl,
3a gave the product 2a in 27% yield (Table 1, entry 12). S-(Tri- methoxy, fluoro and chloro were also acceptable. Furthermore,
fluoromethyl)benzothiophenium salt 3c [24], trifluoromethyl- the β-alkyl-substituted enone also produced the desired product
sulfoxinium salt 3d [25], and hypervalent iodine(III) CF3 2l (Table 2, entry 12).
reagent 3e [26] did not proceed or provided only a trace amount
of the desired product 2a under the same reaction conditions Based on these results, we hypothesized the reaction mecha-
(Table 1, entries 13–15). No reaction was observed using nism as shown in Scheme 2. First, the conjugate trifluoro-
Ruppert–Prakash reagent in the presence of Cu under the same methylation of α,β-unsaturated ketones would be initiated by a
conditions (Table 1, entry 16). In all the cases, the reaction was single-electron transfer between S-(trifluoromethyl)diphenylsul-
regioselective and a trace amount of regioisomers and/or fonium salt 3a and copper. The intermediate 4 decomposes to
byproducts was detected in a crude mixture analyzed by give the CF3 radical whose generation is supported by the
19F NMR. Under the best conditions shown in entry 10, we TEMPO inhibition experiment. Ph2S was formed and checked
re-examined the reaction, but in the presence of TEMPO. The by the 1H NMR spectroscopy. The resulting CF3 radical reacted
Table 2: Copper-mediated conjugate trifluoromethylation of α,β-unsaturated ketones 1 with 3a.a
Entry
1
Ar
R
2
Yield (%)b
1
1a
1b
1c
1d
1e
1f
Ph
Ph
2a
2b
2c
2d
2e
2f
37
20
11
13
22
13
12
12
17
18
13
36
2
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
2-furanyl
Ph
Ph
3
Ph
4
Ph
5
Ph
6
Ph
7
1g
1h
1i
4-MeC6H4
4-MeOC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
Me
2g
2h
2i
8
Ph
9
Ph
10
11
12
1j
Ph
2j
1k
1l
Ph
2k
2l
Ph
aThe reaction of 1a with 3a (4.0 equiv) was carried out in the presence of Cu (6.0 equiv) at 60 °C. bIsolated yield.
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nology, Japan, by Grants-in-Aid for Scientific Research from
MEXT (Ministry of Education, Culture, Sports, Science and
Technology) (24105513, Project No. 2304: Advanced Molec-
ular Transformation by Organocatalysts) and JST (ACT-C:
Creation of Advanced Catalytic Transformation for the Sustain-
able Manufacturing at Low Energy, Low Environmental Load).
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