Copper/Silver Cocatalyzed Oxidative Coupling of Vinylarenes with ICH2CF3 or ICH2CHF2 Leading to β-CF3/CHF2-Substituted Ketones

Article abstract of DOI:10.1021/acs.orglett.6b00498

A novel copper/silver cocatalyzed oxidative coupling of vinylarenes with ICH₂CF₃ or ICH₂CHF₂ through a radical process has been developed. The transformation provides an attractive approach to β-CF₃/CHF₂-substituted ketones, with the advantages of easily available starting materials and operational simplicity.

Full text of DOI:10.1021/acs.orglett.6b00498

Letter
pubs.acs.org/OrgLett
Copper/Silver Cocatalyzed Oxidative Coupling of Vinylarenes with
ICH2CF3 or ICH2CHF2 Leading to β‑CF3/CHF2‑Substituted Ketones
Niannian Yi,† Hao Zhang,† Chonghui Xu,† Wei Deng,*,† Ruijia Wang,† Dongming Peng,‡ Zebing Zeng,†
and Jiannan Xiang*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha, 410082, P. R. China
‡School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, P. R. China
S
* Supporting Information
ABSTRACT: A novel copper/silver cocatalyzed oxidative
coupling of vinylarenes with ICH2CF3 or ICH2CHF2 through
a radical process has been developed. The transformation
provides an attractive approach to β-CF3/CHF2-substituted
ketones, with the advantages of easily available starting
materials and operational simplicity.
starting materials for the synthesis of β-CF3 ketones, reported
by Cho’s group [Scheme 1, reaction 2].3b The complicated and
expensive ruthenium catalyst should be involved in such a
developed method. Kananovich3c and Dai’s group3d reported
Cu-catalyzed trifluoromethylation of cyclopropanols to give β-
CF3 ketones, respectively [Scheme 1, reaction 3]. However, the
Togni reagent, an expensive trifluoromethylation reagent, is
necessary in those two reactions. Therefore, a simple and
inexpensive way to access β-CF3 ketones still remains elusive.
Based on our continuous research of synthesizing α-
functionalized carbonyl compounds,4 herein we describe a
straightforward synthesis of β-CF3 ketones via copper/silver
cocatalyzed oxidative coupling of vinylarenes with ICH2CF3.
Compared to previous work, this work avoids the use of the
Togni reagent, and β-CF3 ketones are generated from
inexpensive ICH2CF3 and vinylarenes in a one-step reaction.
More importantly, the reaction is also applicable to the
s one of the most important parts of fluorine chemistry,
Alooking for new methods to access fluorine-containing
molecules has been a challenging project. Recently, significant
progress has been made in the synthesis of CF3-containing
molecules.1 A number of methods have been reported for the
synthesis of α-CF3 ketones.2 However, although unique and
useful chemical properties can be expected for β-CF3 ketones,
reports on them are rare, probably due to the lack of efficient
synthetic methods.3
To access β-CF3 ketones, Xiao’s group reported ring-opening
reactions of gem-difluorocyclopropyl ketones promoted by
boron trifluoride [Scheme 1, reaction 1].3a The reaction has
been simply accomplished in relatively good yield, despite the
challenging approach to gem-difluorocyclopropyl ketones.
Then, the propargylic alcohols and ICF3 were used as the
synthesis of β-CHF2 ketones2 5 when the vinylarenes and
u,
Scheme 1. Synthesis of β-CF3 Ketones
ICH2CHF2 are used as the starting materials.
We began our investigation with the use of 4-tert-
butylstyrene and ICH2CF3 as the model reaction (Table 1).
The desired β-CF3 ketone (3a) was obtained in 12% yield
under the conditions of NiSO4 (10 mol %), TBHP (3 equiv),
Et3N (1 equiv), and CH3CN (1 mL) in a sealed tube at 80 °C
for 24 h (entry 1). A variety of transition-metal salts were
examined, and the results were shown in entries 2−11. Among
the salts tested, Cu(acac)2 performed better than other
catalysts, with an up to 42% yield. The reactions with other
oxidants, such as DTBP, K2S2O8, and H2O2, gave products in
low yields (entries 12−14). Then, different solvents were
examined, and the results indicated that none of the other
solvents was superior to CH3CN (entries 15−18). Moreover, a
base played an important role in the reaction. Organic bases
Received: February 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00498
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening the Optimal Reaction Conditions
Scheme 2. Substrate Scope for the Reaction of Vinylarenes
with ICH2CF3
ab
,
b
entry
catalyst
NiSO4
cocatalyst
oxidant
solvent
yield (%)
1
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
K2S2O8
H2O2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
12
20
23
17
30
22
25
27
34
32
42
5
2
CoSO4
3
Ag2SO4
4
Fe2(SO4)3
CuSO4
5
6
CuBr
7
CuBr2
8
Cu(OAc)2
Cu(NO3)2
Cu(OTf)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
9
10
11
12
13
14
15
16
17
18
17
23
11
24
21
28
19
11
7
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DMF
DMSO
THF
c
19
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
d
20
e
21
22
23
24
25
NiSO4
45
48
57
40
68 (62)
49
CoSO4
a
Reaction conditions: 1 (0.75 mmol), 2a (0.5 mmol), Cu(acac)2 (20
mol %), Ag2SO4 (20 mol %), Et3N (0.5 mmol), TBHP (1.5 mmol,
70% in water), and CH3CN (1 mL) in sealed tube at 80 °C for 24 h.
Ag2SO4
Fe2(SO4)3
Ag2SO4
f
26
g
b
Isolated yield.
27
a
Reaction conditions: 1a (0.75 mmol), 2a (0.5 mmol), catalyst (10
mol %), cocatalyst (10 mol %), Et3N (0.5 mmol), oxidant (1.5 mmol),
examined and gave the desired products (3f and 3g). Terminal
vinylarenes bearing electron-donating substituents such as
methyl (3h and 3o), methoxy (3i and 3n), and acetoxy (3j)
were also tolerated under the reaction conditions. However, the
yields of 3g, 3n, and 3o were about 30%, likely due to the steric
effect of substituents on aromatic rings. 2-Vinylnaphthalene was
also a suitable substrate for the reaction (3k). Interestingly,
when heterocyclic alkenes were used as the substrates, the
corresponding products were successfully achieved (3l and
3m). Unfortunately, the desired β-CF3 ketones would not be
obtained when aliphatic alkenes were applied.
Moreover, we explored the reactivity of various terminal
vinylarenes with ICH2CHF2 under the optimized conditions,
and the corresponding β-CHF2 ketones were smoothly
achieved in moderate yields (Scheme 3). Similarly, the bulky
aromatic rings impacted the yields of the reaction due to the
steric effect of substituents. However, the reaction could hardly
occur when CH3CH2I was used as the starting material.
We also explored the reactivity of the Cu(acac)2/Ag2SO4
cocatalyzed oxidative coupling reaction for large-scale synthesis
of 3a (Scheme 4). The reaction of 4-tert-butylstyrene (1a, 15
mmol) with ICH2CF3 (2a, 10 mmol) gave the desired β-CF3
ketone (3a) in 60% yield under the standard conditions.
Control experiments were carried out in order to explore the
reaction mechanism (Scheme 5). The reaction using ICH2CF3
and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was tested
under the standard conditions, and the desired product
TEMPO−CH2CF3 was detected by GC-MS, and the yield
b
solvent (1 mL) in sealed tube at 80 °C for 24 h. The yield was
determined by 19F NMR with trifluoromethylbenzene as an internal
c
d
standard. Et3N was replaced by DBU (0.5 mmol). Et3N was replaced
e
by pyridine (0.5 mmol). Et3N was replaced by K2CO3 (0.5 mmol).
Cu(acac)2 (20 mol %) and Ag2SO4 (20 mol %) were used, and the
number in parentheses was isolated yield. Cu(acac)2 (20 mol %) was
f
g
used.
were relatively better than the inorganic, and Et3N was the best
choice (entries 19−21). Interestingly, further exploration
showed that the yield increased significantly from 42% to
57% when Ag2SO4 was used as a cocatalyst (entry 24), but
other additives had little impact on the reaction (entries 22, 23,
and 25). Increasing the loading of Cu(acac)2 and Ag2SO4 to 20
mol % led to a considerable increase in the yield up to 68%
(entry 26). When 20 mol % Cu(acac)2 was used separately, the
product 3a was obtained in 49% yield (entry 27).
With the optimized conditions in hand, the substrate scope
of the transformation was then investigated. A variety of
terminal vinylarenes could efficiently undergo the desired β-
CF3 ketones in moderate to good yields (Scheme 2). Terminal
vinylarenes bearing electron-withdrawing substituents such as
fluoro- (3c), chloro- (3d), and bromo- (3e) at the para-
position afforded the corresponding products in good yields.
However, when 1-nitro-4-vinylbenzene was used as a substrate,
the reaction could hardly occur. Other halostyrenes at the m-
and o-position, 3-bromostyrene and 2-chlorostyrene, were
B
DOI: 10.1021/acs.orglett.6b00498
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope for the Reaction of Vinylarenes
with ICH2CHF2
Scheme 6. Possible Mechanism
a b
,
•
CF3CH2 radical is captured by styrene to produce an
t
intermediate A, which can be combined with the BuOO•
radical to afford an intermediate B. Finally, the intermediate B
is converted into the β-CF3 ketone (C) by removing one
tBuOH under the reaction conditions.
The theory of Hard-Soft-Acid-Base (HSAB) likely explains
the reason why Ag2SO4 plays an important role in this
reaction.7 According to the HSAB theory, Ag+ belongs to the
soft acid and I− belongs to the soft base. The soft acid is
combined with the soft base to form a stable compound. In
a
Reaction conditions: 1 (0.75 mmol), 2b (0.5 mmol), Cu(acac)2 (20
mol %), Ag2SO4 (20 mol %), Et3N (0.5 mmol), TBHP (1.5 mmol,
70% in water), and CH3CN (1 mL) in sealed tube at 80 °C for 24 h.
b
Isolated yield.
•
other words, ICH2CF3 is easier to split into the CF3CH2
radical when Ag2SO4 presents in the reaction system.
Scheme 4. Large-Scale Synthesis of 3a
In summary, a simple and effective approach to the synthesis
of β-CF3/CHF2 ketones via the direct copper/silver cocatalyzed
oxidative coupling of vinylarenes with ICH2CF3 or ICH2CHF2
has been developed. Meanwhile we also demonstrate that the
reaction is accomplished through a radical process, though the
catalyst silver salt is intriguing and not clear yet. Further study
for insights into reaction mechanism and for synthetic
applications to other bioactive molecules by using the oxidative
coupling reaction is currently underway.
Scheme 5. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00498.
Experimental procedure, mechanistic study, character-
ization data, and copies of 1H, 13C, and 19F NMR spectra
(PDF)
was estimated as 71% by 19F NMR (Scheme 5A). Notably,
when TEMPO was added to the reaction of 4-tert-butylstyrene
and ICH2CF3 under the standard conditions, the desired β-CF3
ketone (3a) was not detected and TEMPO−CH2CF3 was
formed in 60% yield by 19F NMR (Scheme 5B). The control
experiments showed that the reaction proceeded through a
radical process.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jnxiang@hnu.edu.cn.
*E-mail: weideng@hnu.edu.cn.
Notes
The authors declare no competing financial interest.
Based on our experimental results and previous reports,1n,6
a
ACKNOWLEDGMENTS
possible radical mechanism for oxidative coupling of vinyl-
■
arenes is proposed in Scheme 6. Initially, tBuOOH is excited to
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21502049 and 51573040),
Hunan Provincial Natural Science Foundation of China (Nos.
13JJ5018 and 14JJ7028), the Planned Science and Technology
form the BuO• radical and the BuOO• radical by a copper
t
t
•
catalyst, and ICH2CF3 generates the CF3CH2 radical in the
presence of copper/silver catalysts and a base. Then, the
C
DOI: 10.1021/acs.orglett.6b00498
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Project of Hunan Province, China (No. 2015WK3003), and
Hunan Provincial Innovation Foundation for Postgraduate
(No. CX2015B076).
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DOI: 10.1021/acs.orglett.6b00498
Org. Lett. XXXX, XXX, XXX−XXX