Photocatalytic/Cu-Promoted C-H Activations: Visible-light-Induced ortho-Selective Perfluoroalkylation of Benzamides

Article abstract of DOI:10.1002/chem.201600229

A visible-light-induced and copper-promoted perfluoroalkylation of benzamides was successfully developed under the assistance of an 8-aminoquinoline directing group. It provides a straightforward method for the synthesis of ortho-perfluoroalkyl-substituted benzoic acid derivatives. The reaction employs a cheap organic dye eosin Y as the photoredox catalyst and is run under the irradiation of a 26 W fluorescent LED light bulb.

Full text of DOI:10.1002/chem.201600229

DOI: 10.1002/chem.201600229
Communication
&
Organic Synthesis
Photocatalytic/Cu-Promoted CÀH Activations: Visible-light-
Induced ortho-Selective Perfluoroalkylation of Benzamides
Xiang Chen,[a] Ze Tan,*[a] Qingwen Gui,[a] Liang Hu,[a] Jidan Liu,[a] Jing Wu,[a, b] and
Guangwei Wang*[b]
many other areas of research due to their unique physical,
Abstract: A visible-light-induced and copper-promoted
perfluoroalkylation of benzamides was successfully
chemical, and biological properties. Among these organofluor-
ine compounds, those bearing trifluoromethyl and perfluor-
developed under the assistance of an 8-aminoquinoline
oalkyl (RF) groups have been receiving significant interest be-
directing group. It provides a straightforward method for
cause of their metabolic stability, lipophilicity and electron-
withdrawing properties.[11] One of the most common ways of
the synthesis of ortho-perfluoroalkyl-substituted benzoic
acid derivatives. The reaction employs a cheap organic
introducing trifluoromethyl or perfluoroalkyl groups involves
dye eosin Y as the photoredox catalyst and is run under
the generation of trifluoromethyl and perfluoroalkyl radicals.[12]
the irradiation of a 26 W fluorescent LED light bulb.
For example, when perfluoroalkyl iodides are treated with
dithionite, perfluoroalkyl radicals are generated and can react
further to form new CÀC bonds.[13] When copper salt was re-
Recently, the development of new methods for the formation
of CÀC and CÀX bonds by transition-metal catalyzed or pro-
moted functionalization of CÀH bonds has been area of inten-
sive research.[1] Since Daugulis’ pioneering work,[2] 8-aminoqui-
noline has emerged as one of the most powerful and versatile
directing groups for transition-metal catalyzed or -promoted
functionalization of CÀH bonds, as exemplified by the huge
number of recent publications in this area.[2–9] Cu-,[2a–d,3c,4] Pd-,[5]
Ni-,[6,3d] Co-,[2e–h,7] and Fe-catalyzed[8] or -mediated chelation-as-
sisted CÀH bond activations to construct CÀC and CÀX bonds
(X=S, O, N, F) [Eq. (1)] with the aid of an 8-aminoquinoline
directing group have been developed by the groups of
Daugulis,[2] Hirano, and Miura,[3c,4a–e] Ge,[4g,h,6j] Kuninobu and
Kanai,[4i,j,5f] Stahl,[4f] Chatani,[3b,d,6a–d] and others.[5a–e,6e–i] Ours and
other groups also independently developed the selective
ortho-sulfonylation and nitration of benzamides bearing the 8-
aminoquinoline group.[9] Besides the 8-aminoquinoline group,
a 2-aminophenyloxazoline group developed by Yu and Dai,
and a (pyridine-2-yl)isopropylamine group developed by Shi
are also powerful bidentate directing groups for transition-
metal-catalyzed or -promoted CÀH activations.[10]
acted with Togni reagent, it is believed that a trifluoromethyl
radical was generated in the process.[14] Interestingly, perfluor-
oalkyl radicals can also be generated from RFÀI in the presence
of a photoredox catalyst under visible light.[15] Though there
are numerous transformations developed by the reaction of
these trifluoromethyl and perfluoroalkyl radicals with various
functionalities, few involve the activation of CÀH bonds.[15h,i,16]
In continuation of our research efforts on the development of
new CÀC and CÀX bond-formation processes by CÀH
cleavage,[9a,b] we have launched a study into the introduction
of trifluoromethyl and perfluoroalkyl groups on arenes by CÀH
activation and herein we report that benzamides bearing an 8-
aminoquinoline group can be selectively ortho-perfluoro-
alkylated in the presence of simple copper salt and a
catalytic amount of photoredox catalyst under visible light
(Scheme 1, [Eq. (2)]).
Fluoroalkylated molecules are widely exploited in applica-
tions, such as materials, agrochemicals, pharmaceuticals, and
[a] X. Chen, Prof. Dr. Z. Tan, Q. Gui, L. Hu, J. Liu, J. Wu
State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering, Hunan University
Changsha 410082 (P. R. China).
Scheme 1. 8-Aminoquinoline-assisted CÀC and CÀX bond-formation
E-mail: ztanze@gmail.com
reactions with benzamide derivatives.
[b] J. Wu, Prof. G. Wang
Department of Chemistry
Collaborative Innovation Center of Chemical Science and Engineering
Tianjin University, Tianjin 300072 (P. R. China)
E-mail: wanggw@tju.edu.cn
We commenced our study by choosing the reaction of N-
(quinolin-8-yl)benzamide (1a) with n-C4F9I (2a) as the model
reaction. When 1a was treated with five equivalents of n-C4F9I
in the presence of 5% mmol of [Ru(bpy)3Cl2]·6H2O (bpy=2,2’-
bipyridine),[15a,b,g,h,17] 1.5 equiv of Cu(OAc)2, and 1 equiv of
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under http://dx.doi.org/10.1002/
chem.201600229.
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ble light, indicating the reaction is truly a photocatalytic
reaction (Table 1, entries 9 and 10). Based on these results, we
decided to set reacting the N-(quinolin-8-yl) benzamide with
five equivalents of n-C4F9I and one equivalent of Cs2CO3 in the
presence of 3 mol% eosin-Y and 1.6 eqiuvalents of
Cu(OAc)2·H2O in DMAc under the irradiation of a 26 W
fluorescent bulb at 608C for 12 h as our optimized standard
conditions.
Table 1. Optimization of the reaction conditions[a]
Entry
Cu salts
Photocatal.
Base
Solvent
Yield [%][b]
1
2
3
4
5[d]
6
7[e]
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2 H2O
Cu(OAc)2 H2O
Cu(OAc)2 H2O
Cu(OAc)2 H2O
Cu(OAc)2 H2O
–
[Ru][c]
eosin-Y
eosin-Y
eosin-Y
eosin-Y
eosin-Y
eosin-Y
eosin-Y
–
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
21
55
63
71
<5
trace
trace
trace
<5
<5
With the optimized conditions in hand, the scope and limita-
tion of the reaction were examined and the results were sum-
marized in Table 2. From the table we can see that benzamides
with a wide variety of different substituents can be efficiently
.
.
.
.
.
.
9
10[d]
Cu(OAc)2 H2O
Cu(OAc)2 H2O
.
Table 2. Photocatalytic and copper-promoted perfluoroalkylation of
benzamides[a,b]
–
[a] Reaction conditions: N-(quinolin-8-yl)benzamide (0.5 mmol), n-C4F9I
(2.5 mmol), Cu(OAc)2·H2O (0.8 mmol), eosin-Y (3 mol%), Cs2CO3 (0.5 mmol),
DMAc (0.2m), N2, 608C, under visible light,12 h. [b] Isolated yield. [c] [Ru]=
[Ru(bpy)Cl2]·6H2O. [d] Without fluorescent light. [e] T at RT.
K2CO3 in DMF at 608C under the irradiation of a 26 W fluores-
cent LED light bulb for 12 h, the desired product perfluoro-n-
butylated benzamide 3a was isolated in 21% yield (Table 1,
entry 1). Since we found a large amount of 1a remained
intact, optimization of the reaction conditions is conducted
to obtain a better yield. When the photoredox catalyst
[Ru(bpy)3Cl2]·6H2O was switched to an organic dye eosin-
Y,[15c,i,18] much to our delight, we found that higher conversion
was reached in a much shorter time and the desired product
3a was obtained in 55% yield (Table 1, entry 2). The catalyst
loading can be as low as 3 mol%. After a series of tests on the
source of copper salts, we found that Cu(OAc)2·H2O performed
the best as compared to other catalysts including CuCl2, CuCl,
CuI, CuO, CuBr2, and Cu2(OH)2CO3 (please see the Supporting
Information). Optimization studies also showed that a further
increase in yield could be obtained when K2CO3 was replaced
with Cs2CO3 (Table 1, entry 3). However, other bases such as
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), NaOAc, KHCO3 etc.
all proved to be less efficient (please see the Supporting Infor-
mation). Finally the yield could be elevated to 71% when we
ran the experiment in N,N-dimethylacetamide (DMAc), whereas
the use of DMSO, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-
dinone (DMPU), and N-methylpyrrolidone (NMP) gave either
comparable or slightly lower yields (Table 1, entry 4 and the
Supporting Information). If the light was turned off, very little
reaction took place, which suggests that light was essential for
the reaction to proceed (Table 1, entry 5). It also should be
noted that no product was formed in the absence of base
(Table 1, entry 6). Running the reaction at 60–708C led to
much fewer side products while lower temperature resulted in
a much slower reaction. No desired product was isolated when
either the reaction was run at room temperature or in the ab-
sence of Cu(OAc)2·H2O (Table 1, entries 7 and 8). On the other
hand, the desired product was formed in less than 5% yield
when eosin-Y was omitted in the presence (or absence) of visi-
[a] Reaction run under standard conditions. [b] Isolated yields.
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perfluoro-n-butylated in yields between 53–71% (Table 2, 3b–
3p). Not only electron-withdrawing groups but also -donating
groups are well tolerated on the phenyl ring of the benza-
mides. Substrates bearing groups such as methyl, ethyl, tert-
butyl, phenyl, fluoro, chloro, ethoxy, trifluoromethyl, and nitro
as well as ester groups all underwent the desired perfluoroal-
kylation in good yields. We do see that substrates bearing an
ortho-substituent did give the desired products in slightly
lower yields, indicating the reaction was slightly sensitive to
steric hindrance (Table 2, 3p, 3x, and 3ab). As for the perfluor-
oalkylation reagent, we were able to successfully carry out the
corresponding perfluoro-n-hexylation, perfluoro-n-octylation,
as well as perfluoro-n-propylation and all the desired
volved in the rate-determining step (Scheme 2). Additionally,
we have carried out reactions to see whether the reaction is
a chain process or not. We have turned off the lamp after run-
ning the reaction of 1a with 2a under the standard conditions
for 4 h and an hour later, the lamp was switched on again.[21]
What we have found is that the yield of 3a did not increase
after the light was turned off and it started to go up again
when the lamp was switched back on. This means that the
reaction is
a photoinduced process in which no chain
propagation is involved.
Next the removal of the 8-aminoquinoline auxiliary was
demonstrated (Scheme 3). Though direct hydrolysis of the
perfluoralkylated products were isolated in yields
ranging between 41–68% (Table 2, 3q–3ac).
Unfortunately, attempts to carry out the perfluor-
oalkylation with perfluoro-2-iodopropane failed
(Table 2, 3ad). It should be mentioned that in a relat-
ed study reported by Chatani,[19] when 1a was treat-
ed with perfluoro-2-iodopropane in toluene in the
presence of nickel salt, what was actually formed was
Scheme 3. Removal of the 8-aminoquinoline auxiliary.
the benzylated product instead of the perfluoro-isopropylated
product, even though a perfluoroisopropyl radical was pro-
posed as the intermediate. Even more disappointingly, trifluor-
omethylation with CF3I, the most important transformation in
terms of synthetic value, only provided the desired product
3ae in 17% yield (Table 2, 3ae). Since it has been reported
that the generation of trifluoromethyl radicals from CF3I was
not efficient with eosin-Y, we next examined the reaction using
[Ru(bpy)3Cl2]·6H2O as the catalyst.[15h,i] However, much to our
disappointment, the reaction did not improve either. We sur-
mise that the problem of trifluoromethylation may have some-
thing to do with the low boiling point of CF3I. This problem, in
theory, can be resolved by running the reaction in a continuous
flow reactor.[15h,i,20] In addition, we also found pyridine-derived
amide was not applicable for the perfluoro-n-butylation either
(Table 2, 3af).
isolated product 3a was not successful, the hydrolysis was
smoothly effected after N-methylation with methyl iodide
followed by regular alcohol hydrolysis; and 2-(perfluoro-n-
butyl)benzoic acid was isolated in 62% overall yield.
Based on the reported literature[22] and the evidence above,
a plausible mechanism for the photocatalysis-assisted and
copper-promoted perfluoroalkylation of the CÀH bond of
N-(quinolin-8-yl)benzamides is shown in Scheme 4. Firstly, A
cyclometalated complex A is generated from CÀH activation of
1a with copper salt. Meanwhile, perfluoroalkyl radicals are
formed by the reaction of perfluoroalkyl iodides with excited
To prove the mechanism of this transformation, a control
experiment was conducted under the optimized conditions.
When a stoichiometric amount of radical scavenger 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO) was added to the per-
fluoro-n-butylation reaction, no desired product was detected.
This result suggested that our reaction is likely to involve a radi-
cal process. Additionally, the kinetic isotopic effect (KIE) was
examined by studying the intermolecular competition reaction
between 1a and its deuterated analogue [D5]1a, and KH/KD
was determined to be around 3.0. This large KIE observed
suggested that the cleavage of the ortho CÀH bond may be in-
Scheme 4. Proposed reaction mechanism.
Scheme 2. Deuterium-labeling experiment.
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radicals react with CuII-complex A to form a CuIII-complex B.
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In summary, we have developed a novel and highly selective
method for the synthesis of ortho-perfluoroalkylated benza-
mides starting from N-8-quinolinyl benzamides and perfluor-
oalkyl iodides by copper-promoted CÀH activation of aryl sp2
CÀH bonds. Notably the reaction employs an organic dye as
the photoredox catalyst and visible light as the reaction initia-
tor. The catalyst is cheap and the reaction is very simple to
run. Our protocol represents one of the few examples of merg-
ing photoredox chemistry with transition-metal-catalyzed or
-promoted CÀH activation together.[16a,23] Further studies on
the clarification of the reaction mechanism and application to
other substrates are underway and the results will be reported
in due course.
Experimental Section
General reaction
Benzamide 1a (0.5 mmol), Cu(OAc)2·H2O (150 mg, 0.75 mmol),
eosin-Y (11 mg, 3 mmol%), Cs2CO3 (163 mg, 0.5 mmol), perfluoro-
butyl iodide 2a (2.5 mmol), and anhydrous DMAc (1 mL) were
added to a 35 mL Schlenk flask equipped with a high-vacuum
PTFE valve-to-glass seal. Then the flask was sealed under N2 and
stirred at 608C under the irradiation of CFL for 12 h. After the
completion of the reaction, the mixture was extracted with ethyl
acetate and the combined organic layer was dried over sodium
sulfate. Concentration in vacuo followed by silica gel column purifi-
cation with petroleum ether/ethyl acetate eluent (8:1 to 10:1) gave
the desired product 3a in 71% yield.
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Keywords: CÀH activation · chelation-assisted · Cu-promoted ·
perfluoroalkylation · photocatalysis
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Received: January 18, 2016
Published online on March 16, 2016
Chem. Eur. J. 2016, 22, 6218 – 6222
www.chemeurj.org
6222
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