Copper-catalyzed α-selective C–H trifluoromethylation of acrylamides with TMSCF3

Article abstract of DOI:10.1016/j.cclet.2019.02.011

A copper-catalyzed α-selective C–H trifluoromethylation of acrylamides with TMSCF₃ is described. A wide range of arenes and heteroarenes at the β-position of acrylamides are compatible with the reaction, affording the corresponding (E)-trifluor

Full text of DOI:10.1016/j.cclet.2019.02.011

Accepted Manuscript
Title: Copper-Catalyzed α-selective C–H trifluoromethylation
of acrylamides with TMSCF3
Authors: Shang-Zheng Sun, Hui Xu, Hui-Xiong Dai
PII:
DOI:
Reference:
S1001-8417(19)30072-5
https://doi.org/10.1016/j.cclet.2019.02.011
CCLET 4813
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Chinese Chemical Letters
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Revised date:
Accepted date:
22 December 2018
22 January 2019
19 February 2019
Please cite this article as: Sun S-Zheng, Xu H, Dai H-Xiong, Copper-Catalyzed α-
selective C–H trifluoromethylation of acrylamides with TMSCF3, Chinese Chemical
Letters (2019), https://doi.org/10.1016/j.cclet.2019.02.011
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Communication
Copper-catalyzed α-selective C–H trifluoromethylation of acrylamides with TMSCF3
Shang-Zheng Sun b, Hui Xu a, Hui-Xiong Dai,a
a Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 201203, China
b Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
Graphical Abstract
A copper-catalyzed α-selective C–H trifluoromethylation of acrylamides with TMSCF3 is described. A wide range of arenes
and heteroarenes at the β-position of acrylamides are compatible with the reaction, affording the corresponding (E)-
trifluoromethylated products in moderate to good yields. The reaction proceeded fast and can be completed within 30 min.
ARTICLE INFO
ABSTRACT
Article history:
A copper-catalyzed α-selective C–H trifluoromethylation of acrylamides with TMSCF3 is described. A
wide range of arenes and heteroarenes at the β-position of acrylamides are compatible with the reaction,
affording the corresponding (E)-trifluoromethylated products in moderate to good yields. The reaction
proceeded fast and can be completed within 30 minutes.
Received 22 December 2018
Received in revised form 25 January 2019
Accepted 28 January 2019
Available online
Keywords:
α-Selectivity
C–H trifluoromethylation
Copper
Acrylamides
Heterocycle
Organofluorine compounds are widely employed in pharmaceuticals, agrochemicals and materials due to their extraordinary physical
and chemical properties [1]. Specifically, introducing the trifluoromethyl (CF3) moiety into biologically active molecules has shown to
dramatically improve metabolic stability, lipophilicity and membrane permeability [1,2]. As an effective strategy in drug modification,
the development of an economical and efficient protocol to install the trifluoromethyl group into organic molecules is highly desirable.
In the past decade, a number of transition-metal-catalyzed trifluoromethyl- ation reactions have been reported [3]. Notably, transition-
———
 Corresponding author.
E-mail address: hxdai@simm.ac.cn

metal-catalyzed C–H activation to introduce the CF3 moiety would be the most efficient method [4]. Sanford, Yu, Shi et al. have reported
the palladium-catalyzed direct C–H trifluoromethylation of arenes by Pd(II)/Pd(IV) redox catalysis [5]. In addition to this, copper-
catalyzed/mediated [6] and silver-mediated [7] C–H trifluoromethylation of arenes have also been reported.
Scheme 1. Metal-catalyzed directed C–H activation of alkene.
Recently, trifluoromethylation of alkenes has drawn more and more attentions. Many synthetic methods have been developed including
cross-coupling reactions of trifluoromethylation reagent with vinyl halides [8], vinyl sulfonates [9] and vinyl borons [10] or
decarboxylative trifluoromethylation [11]. However, direct C–H trifluoromethylations of alkenes are rarely reported. Generally, during
metal-catalyzed directed C–H activation of alkenes, five membered cyclometalation intermediates are formed, resulting in C–H
functionalization selectively at the β-position (Scheme 1) [12]. Loh [13] and Besset [14] have reported the Cu-catalyzed or mediated β-
C–H trifluoromethylation of alkenes, independently. Recently, our group developed a Pd-
α-selective olefinic C−H
activation to construct 4-imino-lactam derivatives (Scheme 2, a) [15]. In addition, Bi reported a copper-catalyzed α-selective
trifluoromethylation of α, β-unsaturated carbonyl compounds with Togni´s reagent (Scheme 2, b) [16]. To the best of our knowledge,
the transition-metal catalyzed or mediated C–H trifluoromethylation of alkenes involved the electrophilic trifluoromethylation reagents,
such as Togni [17] or Umemoto reagents [18]. Promoted by our interest in copper-mediated ortho C–H trifluoromethylation [19] and
other transformations [20], we questioned whether a catalytic C–H trifluoromethylation of alkenes with readily available nucleophilic
trifluoromethylation reagents such as Ruppert-Prakash regent (TMSCF3, TMS = trimethylsilyl) could be designed. If successful, such a
platform might offer a new approach for the preparation of trifluoromethyl-substituted olefin. Herein, we reported a Cu (II)-catalyzed
direct α-selective C–H trifluoromethylation of β-substituted acrylamides with TMSCF3 (Scheme 2, c).
Scheme 2. Catalytic-olefinic C–H functionalization.
We began our investigation with N-phenyl or alkyl substituted cinnamamide, and found N-isopropyl substituted cinnamamide gave
the best result (Table S1 in Supporting information). Treatment cinnamamide 1a with 5 equiv. of TMSCF3 in the presence of 1 equiv. of
Cu(OAc)2, 1.5 equiv. of Ag2CO3 and 4 equiv. of KF in DMSO at 80 ºC afforded the α-selective C–H trifluoromethylation compounds in
29% yield. Ag2CO3 played an important role in the reaction system, and the yield reduced significantly without Ag2CO3 (Table S5 in
Supporting information). Exceptionally, the cinnamic acid did not show any reactivity. Increasing the temperature to 120 ºC for 6 h, the
yield was improved to 41%.
Table 1
Reaction optimization.a
Cu(OAc)2
(equiv.)
Entry
Base
Additive
Yield (%)b
1
2
3
4
5
1.0
1.0
1.0
1.0
-
-
-
-
-
-
n.r.
56
52
41
50
LiF
NaF
KF
1.0
K2HPO4

6
7
8
1.0
0.1
0.2
0.2
0.2
0.2
KH2PO4
LiF
LiF
LiF
LiF
-
-
-
-
55
43
49
61
61
73
9c
10d
11e
Pyridine
Pyridine
KH2PO4
a Reaction conditions: 1a (0.1 mmol), 2 (0.5 mmol), Cu(OAc)2 (0.1 mmol), base (0.4 mmol), Ag2CO3 (0.15 mmol), DMSO (1.0 mL), 120 oC, 6
h.
b Yields were determined by 1H NMR analysis using CH2Br2 as internal standard.
c Ag2CO3 (0.2 mmol), 0.5 h.
d Ag2CO3 (0.2 mmol), pyridine (20 mol%), 0.5 h.
e Ag2CO3 (0.2 mmol), pyridine (20 mol%), KH2PO4 (0.4 mmol), 0.5 h.
We also examined the influence of base, and found LiF and KH2PO4 shown the best result (Table 1, entries 1-6). Pleasingly, lowering
the amount of Cu(OAc)2 to 20 mol% has little effect on the yield (Table 1, entries 7-8), indicating that the reaction could proceed
catalytically.Increasing the loading of Ag2CO3 to 2 equiv. could improve the yields to 61% within 30 min (Table 1, entry 9). Ligands
have been proved to promote the copper-catalyzed C–H functionalization [21], thus various ligands were added to improve the yield
(Table S7 in Supporting information). To our delight, further addition of 20 mol% pyridine ligand could improve the yield to 73% (Table
1, entries 10 and 11).
With the optimized conditions in hand, we turned our attention to explore the generality of the Cu-catalyzed α-selective C–H
trifluoromethylation of acrylamides with TMSCF3. As shown in Scheme 3, a wide range of cinnamamide substrates with both electron-
rich (1a-1f) and electron-deficient substituents (1i, 1j, 1p, 1q) were tolerated, affording the trifluoromethylation products in moderate to
good yields. The trifluoromethoxy (1g, 1h) and trifluoromethyled substrates (1i, 1j) gave the desired products in good yields under the
standard conditions, thus giving access to multiple fluorine containing compounds. Notably, the halogen containing substrates (1k-1o)
were well tolerant, leaving an additional functional group for further transformation. Additionally, the cyano and nitro substituted
cinnamamide (1p, 1q) could be employed in the reaction, affording the products in 57% and 60% yields respectively. Encouraged by
previous results, we wondered whether our protocol could be extended to heterocycle-containing compounds. By far now, the copper-
catalyzed olefinic trifluoromethylation of heterocycle-based substrates remains a challenge [22]. We were pleased to find that the pyridyl
(1r-1t), thienyl (1u) and thiazolyl (1v) substituted acrylamides were all compatible in the reaction, thus allowing for the construction of
the corresponding trifluoromethylated products in moderate yields.
To further demonstrate the utility of our methodology, we conducted the reaction on a gram scale and provided 3a in 56% yield
(Scheme 4).
Scheme 4. Scale up reaction.

Scheme 3. Scope of substrates. Reaction conditions: 1a-1v (0.2 mmol), 2 (1.0 mmol), Cu(OAc)2 (20 mol%), pyridine (20 mol%), Ag2CO3 (0.4
mmol), KH2PO4 (0.8 mmol), DMSO (2 mL), 120 oC, 0.5 h. Yield means isolated yield.
Control experiments were carried out to explore the reaction mechanism. As shown in Scheme 5, reaction a, copper is essential in the
reaction and no reaction occurred without copper catalyst. The yields dropped significantly to 10% in the absence of Ag2CO3.
Additionally, we conducted radical trapping experiments under the standard conditions as shown in Scheme 5, reaction b. The commonly
used radical quencher 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) inhibited the reaction
completely, which indicated a radical pathway or a single electron transfer (SET) mechanism may be involved in the reaction. However,
the radical-trapped adduct (TEMPO-CF3) was not detected by GC-MS and NMR analysis of the crude reaction mixture [23]. Based on
the control experiments and literature precedents, we proposed a plausible radical mechanism [16,24]. As shown in Scheme 5, reaction
c, CF3 radical is generated from TMSCF3 through an AgCF3 species [7a,7b,20]. The CF3 radical then attacks the α-position of 1 that has
a slightly higher electron density, thus forming the radical intermediate A. Subsequently, the carbocation intermediate B is formed by
Cu(II) through the SET process. Finally, the more stable (E)-configuration product 3 is obtained after deprotonation.

Scheme 5. (a) Control experiments, (b) radical trapping experiments, (c) proposed mechanism.
In conclusion, we have developed Cu(OAc)2 catalyzed α-selective C–H trifluoromethylation of acrylamide with TMSCF3 as
nucleophilic CF3 source. This protocol is characterized by its exceedingly fast reaction rate with excellent regioselectivity and good
functional group compatibility. Further investigations into related processes and understanding of the mechanistic intricacies are currently
ongoing in our laboratories.
Acknowledgment
We gratefully acknowledge the National Natural Science Foundation of China (Nos. 21472211, 21502212, 21772211), Youth
Innovation Promotion Association CAS (Nos. 2014229 and 2018293), Institutes for Drug Discovery and Development, Chinese
Academy of Sciences (No. CASIMM 0120163006), Science and Technology Commission of Shanghai Municipality (No. 17JC1405000)
for financial support.
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