Directing-group-assisted copper-catalyzed olefinic trifluoromethylation of electron-deficient alkenes

Article abstract of DOI:10.1002/anie.201307245

Assistance provided: The directing group in the title reaction not only activates the substrates but also allows the stereospecific formation of cis-trifluoromethylated products. The reaction is operationally simple and tolerates a wide variety of functional groups, thus providing an efficient method for the stereoselective synthesis of β-CF₃-functionalized acrylamide derivatives. Copyright

Full text of DOI:10.1002/anie.201307245

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DOI: 10.1002/anie.201307245
Trifluoromethylation Very Important Paper
Directing-Group-Assisted Copper-Catalyzed Olefinic
Trifluoromethylation of Electron-Deficient Alkenes**
Chao Feng and Teck-Peng Loh*
The synthesis of trifluoromethylated organic molecules is
highly sought after because of the potential of these molecules
in the pharmaceutical and agrochemical industry, materials
science etc., owing to the unique effect the CF3 modification
challenge.[10] In continuation of our interest in olefin func-
tionalization[11] and our recently disclosed olefinic trifluoro-
methylation of enamides (Scheme 1a),[12] we herein report
À
the C H trifluoromethylation of electron-deficient alkenes
has on organic molecules.[1] Accordingly, C CF3 bond-form-
by taking advantage of neighboring directing groups (Sche-
me 1b).
À
ing reactions have drawn much attention from the synthetic
community. The development of effective and reliable
methods for the easy introduction of a CF3 group to a vast
variety of synthetically useful molecules is highly desirable.[2]
In this regard, transition-metal-catalyzed methods were
appealing, because a variety of simple molecules, especially
starting materials that are not prefunctionalized, can be
transformed, which is advantageous from the viewpoint of
green chemistry and sustainability.[3] In recent years, tremen-
À
dous efforts have been made toward the formation of C CF3
bonds from hydrocarbon counterparts, and much progress has
already been achieved. Specifically, Yu and co-workers have
reported elegant solutions for the direct trifluoromethylation
À
of aryl C H bonds using a directing-group-assisted activation
[4]
À
Scheme 1. Copper-catalyzed olefinic trifluoromethylation. DMSO=di-
methyl sulfoxide, Ts=4-toluenesulfonyl.
of ortho C H bonds. The final reductive elimination from
the PdIV intermediate was proposed to accomplish the
formation of aryl C CF3 bonds.[5] Recently, the groups of
À
Buchwald, Wang, and Liu have independently explored the
copper-catalyzed allylic trifluoromethylation of simple
alkenes using electrophilic trifluoromethylation reagents,
such as Togniꢀs and Umemotoꢀs reagents.[6] In addition,
Qing and co-workers have demonstrated the copper-cata-
lyzed oxidative trifluoromethylation of heteroarenes and
terminal alkynes.[7] The groups of Sanford[8] and Brase[9]
developed the silver-mediated trifluoromethylation of
arenes through a radical process. While much progress has
The commonly accepted reactivity profile of electrophilic
trifluoromethylation reagents, such as Togniꢀs and Umemo-
toꢀs reagents, is dichotomous, as they can react either as CF3
radicals or cation donors. In the case of electron-deficient
alkenes, the trifluoromethylation through electrophilic addi-
tion and hydrogen elimination is believed to be of little
feasibility. However, we envisioned two other possibilities to
realize this transformation: a sequence of directing-group-
À
assisted C H activation and reductive elimination, and
À
been made in the area of transition-metal-catalyzed aryl C
another following a radical-addition pathway.
À
CF3 and alkyl C CF3 bond formations, the trifluoromethyla-
The ubiquity of acrylates in synthetic organic chemistry
and the ease of their modification led us to select a-phenyl
acrylate derivatives as templates for the direct incorporation
of the CF3 functionality. A systematic screening of the
directing group was conducted with CuCl as catalyst,
MeOH as solvent, and the Togni reagent (1) as electrophilic
trifluoromethylation reagent (Scheme 2). While no desired
product could be detected using acid, ester, benzyl amide, and
phenyl amide as directing groups, the corresponding olefinic
trifluoromethylation product was isolated in encouraging
tion of alkenes, especially of electron-deficient ones, has been
relatively unsuccessful, thus proving to be a formidable
[*] C. Feng, Prof. Dr. T.-P. Loh
Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026 (P. R. China)
Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
637371 (Singapore)
E-mail: teckpeng@ntu.edu.sg
[**] We gratefully acknowledge the USTC Research Fund, the Nanyang
Technological University, and the Singapore Ministry of Education
Academic Research Fund (ETRP 1002 111, MOE2010-T2-2-067, and
MOE 2011-T2-1-013) for the funding of this research. We also thank
Dr. Y. X. Li for support with X-ray analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307245.
Scheme 2. Directing group screening.
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52% yield simply by employing a Ts-protected imide as the
directing group, thus highlighting the importance of the
no desired product was obtained, thus highlighting the
importance of the solvent for the success of this olefinic
trifluoromethylation (Table 1, entries 8–13). Much to our
surprise, the reaction efficiency dramatically improved when
polar aprotic solvents were employed. Among all the solvents
examined, DMSO proved to be the best choice, affording
product 3a in 83% yield (Table 1, entry 14). Interestingly, the
yield of the reaction marginally improved to 85% with the use
of CuCl as the catalyst (Table 1, entry 16). We reasoned that
the excellent results with DMSO as solvent may, to a large
extent, be due to the fact that it acts as an effective ligand,
stabilizing the reaction intermediate in the catalytic cycle.
Expectedly, no desired product was obtained in the absence of
a copper catalyst (Table 1, entry 17).
À
acidity of the amide moiety in this olefinic C CF3 bond
formation. In sharp contrast to the olefinic trifluoromethyla-
tion of enamides, this reaction occurs selectively in the cis
position with respect to the Ts-protected imide group, thus
indicating the possible involvement of this directing group in
À
the formation of the C CF3 bond. The structure of 3a was
unambiguously confirmed by single-crystal X-ray diffraction
analysis.[13]
The optimization of the reaction conditions was carried
out with 2-phenyl-N-tosylacrylamide (2a) as the model
substrate. Initially, various copper salts were tested with
methanol as solvent in the hope to increase the efficiency of
the reaction. CuI catalysts such as CuBr, CuI, and CuOAc
catalyzed the reaction, but produced the desired product in
relatively low yield compared with the use of CuCl (Table 1,
With the optimized reaction conditions in hand, the scope
of the reaction was investigated (Scheme 3). In general, the
reaction tolerated a wide variety of substrates with both
electron-donating and electron-withdrawing substituents to
produce the desired trifluoromethylation products in moder-
Table 1: Optimization of reaction conditions.[a]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
CuOAc
[Cu(MeCN)4PF6]
Cu2O
Cu(OAc)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuCl
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
tBuOH
HFIP
MeCN
THF
toluene
DCE
52
40
48
46
12
65
38
trace
trace
–
9
10
11
12
13
14
15
16
17
–
trace
–
83
78
85
–
DMSO
DMF
DMSO
DMSO
–
[a] Reaction conditions: 2a (0.1 mmol), 1 (0.12 mmol), catalyst
(0.01 mmol), solvent (0.5 mL), 808C, 20 h. [b] Yields of isolated products
are given. DCE=dichloroethane, DMF=N,N-dimethylformamide, HFI-
P=hexafluoroisopropanol.
entries 2–4). The cationic CuI analogue [Cu(MeCN)4PF6] was
not suitable as reaction catalyst, which is in sharp contrast to
the olefinic trifluoromethylation of enamides (Table 1,
entry 5). Pleasingly, the yield of the reaction could be
improved to 65% when Cu2O was employed as catalyst
(Table 1, entry 6). In contrast, the use of Cu(OAc)2 as catalyst
did not improve the yield (Table 1, entry 7). We noted that in
reactions with methanol as the solvent, TsNH2 could be
detected in the crude mixture. In order to obviate unproduc-
tive reaction pathways and to further improve the yield, we
therefore examined a series of solvents. Disappointingly,
when solvents such as tBuOH, HFIP, MeCN, THF, toluene,
and DCE were used instead of MeOH, trace amounts or even
Scheme 3. Reaction scope of acrylate derivatives. Reaction conditions:
2 (0.1 mmol), 1 (0.12 mmol), CuCl (0.01 mmol), DMSO (0.5 mL),
808C, 20 h. Yields of isolated products are given. [a] O:A=8.3:1.
[b] O:A=5.6:1. [c] O:A=5.3:1. O:A=olefinic versus allylic trifluoro-
methylation.
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ate to excellent yields. a-Aryl acrylate derivatives with
electron-donating groups were good substrates and afforded
the desired products (3b–3h) in high yields, especially in the
case of p-OMe-substituted substrate 2e, which was trans-
formed to the corresponding product 3e in 90% yield. It is
noteworthy that sulfur-containing compounds (e.g. 2g) are
compatible with this reaction and do not have a deleterious
effect originating from catalyst deactivation. The reaction of
biphenyl substrate 2i was also highly effective, delivering
product 3i in 86% yield. When 2j, derived from 2-naphthyl
acrylate, was employed as substrate, the product was isolated
in 66% yield. Halogen substituents are also tolerated in this
olefinic trifluoromethylation, thus enabling further elabora-
tion of the products (3k, 3l) into more complex molecules. In
addition, substrates that contain electron-withdrawing sub-
stituents were also amenable to the reaction conditions, but
afforded the corresponding products (3m, 3n) in moderate
yields. Much to our surprise, this reaction also allows the use
of a-alkyl acrylate derivatives as viable substrates. It is
generally accepted that alkenes that possess a hydrogen atom
in a position are more inclined to undergo allylic trifluoro-
3
[6]
À
methylation to form a C(sp ) CF3 bond, whereas they are
more apt to participate in the olefinic trifluoromethylation in
the present reaction. In all a-alkyl acrylate derivatives
examined, the olefinic trifluoromethylation was the dominant
reaction, accompanied by the minor formation of an allylic
Scheme 4. Control experiments.
À
C CF3 bond. For example, in the case of 2o the ratio of
olefinic versus allylic trifluoromethylation products was as
high as 8.3:1. It is worth mentioning that when Baylis–
Hillman adduct 2r was employed, the reaction proceeded
selectively and afforded the olefinic trifluoromethylation
product 3r in 60% yield. We believe that the reversal of the
reaction pattern is a result of the effect of the directing group
and the discrimination of proton elimination because of the
introduced CF3 functionality.
In order to gain more insights into the reaction mecha-
nism, several control experiments were conducted
(Scheme 4). Under the optimized reaction conditions but
with the addition of a radical scavenger, such as TEMPO,
BHT, and 1,1-diphenylethylene, the yield of the reaction
between 2a and 1 decreased significantly, with none reaching
full conversion.[14] When the substrate 2q was subjected to the
optimized reaction conditions as a radical clock, the reaction
turned out to be rather messy, with no trace of the desired
olefinic trifluoromethylation product being detected. Fur-
Scheme 5. Proposed reaction mechanism.
C, which is characterized by its cationic radical nature. The
association of the pendant cationic alkene radical with the
metal center in an intramolecular fashion produces the CuIII
intermediate D, which bears a positive charge in a position to
the carbonyl group. Once D is formed, the ensuing hydrogen
elimination delivers the CuIII intermediate E, which under-
goes reductive elimination and further ligand exchange with
another molecule of 2 to afford the desired cis olefinic
trifluoromethylation product 3 and regenerate intermediate
A for the next catalytic cycle.
À
thermore, in the hope to find out whether the C CF3 bond
À
formation in this reaction follows a C H activation pathway,
an intermolecular KIE experiment was carried out using 2a
and [D2]-2a, affording a KIE value of 1:1. This result clearly
À
showed that the cleavage of the olefinic C H bond is not
involved in the rate-determining step. Collectively, these
experiments indicate the involvement of radical species in this
catalytic process.
Based on all experimental results, a reaction mechanism
was tentatively proposed (Scheme 5). The reaction starts with
a ligand exchange between the CuI catalyst and substrate 2 to
give intermediate A, which further undergoes oxidation by
1 to produce CuIII intermediate B. At this stage, intra-
molecular single-electron transfer (SET) affords intermediate
In conclusion, we have reported the copper-catalyzed
olefinic trifluoromethylation of electron-deficient alkenes.
The directing group was found to have a tremendous effect on
À
the success of this C CF3 bond formation. This reaction
tolerates a-aryl- as well as a-alkyl-substituted acrylate
derivatives and a broad range of synthetically useful func-
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Rassias, V. Gouverneur, Chem. Eur. J. 2012, 18, 8583; for
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cycle.
3
À
selected examples of transition-metal-catalyzed C(sp ) CF3
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Experimental Section
An oven-dried Schlenk tube (5 mL) was charged with 1 (0.12 mmol),
2 (0.1 mmol), and CuCl (0.01 mmol) in this sequence. The Schlenk
tube was evacuated and backfilled with nitrogen for three times,
followed by the addition of anhydrous DMSO (0.5 mL) through
a syringe, and then closed tightly. After stirring at 808C for 20 h, water
(20 mL) was added and the resulting mixture was extracted with
dichloromethane (2 ꢁ 20 mL). Removal of the solvent in vacuo and
purification of the residue by column chromatography on silica gel
afforded the desired product 3.
Received: August 18, 2013
Published online: && &&, &&&&
À
Keywords: alkenes · C H activation · copper · cross-coupling ·
trifluoromethylation
.
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1
[14] Yields were determined through H NMR analysis using mesi-
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4
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Trifluoromethylation
C. Feng, T.-P. Loh*
&&&& — &&&&
Directing-Group-Assisted Copper-
Catalyzed Olefinic Trifluoromethylation of
Electron-Deficient Alkenes
Assistance provided: The directing group
in the title reaction not only activates the
substrates but also allows the stereospe-
cific formation of cis-trifluoromethylated
products. The reaction is operationally
simple and tolerates a wide variety of
functional groups, thus providing an
efficient method for the stereoselective
synthesis of b-CF3-functionalized acryl-
amide derivatives.
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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