Iron-catalyzed: Ortho trifluoromethylation of anilines via picolinamide assisted photoinduced C-H functionalization

Article abstract of DOI:10.1039/c8ob00511g

A convenient, oxidant-free protocol was developed for the ortho trifluoromethylation of aniline via picolinamide assisted Fe-promoted C-H functionalization under ultraviolet irradiation. In this transformation acetone essentially acted as both a solvent to dissolve reactants and a low-cost radical initiator to efficiently generate a CF₃ radical from Langlois' reagent. A broad substrate scope was tolerated and picolinamide bearing strong electron withdrawing groups also could be transformed into the corresponding products with acceptable yields. Furthermore, the value of this method has been highlighted via the efficient synthesis of the nonsteroidal anti-inflammatory drug floctafenine.

Full text of DOI:10.1039/c8ob00511g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Iron-catalyzed ortho trifluoromethylation of anilines via
picolinamide assisted photoinduced C-H functionalization†
Chengcai Xia,* Kai Wang, Guodong Wang and Guiyun Duan
0Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A convenient, oxidant free protocol was developed for ortho
trifluoromethylation of aniline via picolinamide assisted Fe-
promoted C-H functionalization under ultraviolet irradiation.
Acetone in this transformation essentially acted as both solvent to
dissolve reactants and low-cost radical initiators to generate CF3
radical from Langlois’ reagent efficiently. A broad substrate scope
was tolerated and picolinamide bearing strong electron
withdrawing groups also could be transformed into corresponding
products with acceptable yields. Furthermore, the value of this Scheme 1 Ortho C-H trifluoromethylation of anilines assisted by PA
method has been highlighted via the efficient synthesis of
dangerous reagents, such as chlorine and hydrogen fluoride.3
nonsteroidal anti-inflammatory drug floctafenine.
Subsequently, an increasing number of trifluoromethylation
methods were demonstrated grounded on the use of aryl halides,4
Introduction
aryl boronic acids5 and arylamines6 as substrates, providing safe
In recent years, because of the unique properties, the
approaches to synthesize trifluoromethylated arenes. By contrast,
trifluoromethyl group has been introduced into important
the more effective route to CF3-substituted arenes would be direct
structural units to improve the physicochemical property of a great
trifluoromethylation of C-H bonds of arenes.7 For instance, Greaney
deal of organic compounds, such as drug candidates and
and coworkers reported C-H trifluoromethylation by utilizing
biomolecules (Figure 1).1 Especially trifluoromethylated arenes have
electron-rich arenes as substrate.7c Yu group developed ortho
played an significant part in numerously vital organic compounds.2
trifluoromethylation of benzamides through
a directed C-H
Therefore, the development of practical, safe as well as
environmentally friendly methods for their preparation is a hot
topic in today’s organic synthesis.
cupuration approach.7d And Zhang et al. demonstrated transition-
metal-free direct trifluoromethylation of quinoline amides through
radical cross-coupling.7k Despite these utilities represent very
inspiring progress, excess oxidant, noble metal catalyst as well as
harsh reaction temperature were usually indispensable. There is no
doubt that the synthesis of concentrated peroxides is energy-
intensive and dangerous. In this respect, the advance of an oxidant
The
traditional
approaches
for
the
synthesis
of
trifluoromethylated arenes are based on the utilization of
free
trifluoromethylation
methodology
to
access
trifluoromethylated compounds under environmentally friendly and
safe conditions has become a very important and challenging task
for modern organic synthesis.
So far, photoinduced reaction has attracted more and more
attention in organic synthesis, on account of these transformations
meet the green concept of energy saving and environmental
protection.8 For example, Li et al. described a photoinduced
method for the direct trifluoromethylation of arenes by using
Langlois’ reagent (CF3SO2Na,) as CF3 source in acetone under
ultraviolet irradiation.8a This result brings a new view for the radical
couplings under oxidant free condition. Intrigued by this simple and
efficient strategy, we envisioned that this method could be utilized
to affect the direct ortho trifluoromethylation of anilines.
Figure 1 Representative compounds of (trifluoromethyl)arenes.
Pharmacy College, Taishan Medical University, Taian 271016 (China).
E-mail: xiachc@163.com
†Electronic Supplementary Informaꢀon (ESI) available: Detailed experimental
procedures and analytical data. For ESI or other electronic format see
DOI: 10.1039/x0xx00000x
Very recently, Zhang and coworkers reported an example for
ortho trifluoromethylation of anilines by using nickel as catalyst
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Table 2 Scope investigation for the trifluoromethylation a
Table 1 Initial studies for the trifluoromethylation a
R
R
O
O
Cat.1 (15 mol %)
N
H
N
H
CF3SO2Na
+
N
O
CF3
N
H
UV, acetone, 36 h, rt
1
2
3
R
R
R
O
O
N
H
N
N
H
H
N
CF3
N
CF3
N
CF3
3a: R = H, 72%
3b: R = Me, 67%
3c: R = Br, 57%
3d: R = Cl, 51%
3e: R = CN, 25%
3f: R = NO2, 18%
3g
3i: R = Me, 69%
3j: R = Br, 58%
3k: R = Cl, 50%
3l: R = F, 42%
: R = Me, 60%
3h: R = F, 49%
Entry
1
2
3
4
5
6
7
8
Catalyst
Cu(OTf)2
Ni(OTf)2
Co(OAc)2
FeCl3
Additive
Solvent
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
DCE
MeCN
MeOH
DMSO
H2O
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Yield [%]b
21
trace
trace
66
-
-
-
-
O
O
N
H
N
N
H
N
CF3
N
CF3
3n: 68%
3o: 57%
FeCl2
34
Cat. 1
Cat. 2
Cat. 3
-
-
-
-
-
-
-
-
-
72(71)c
41
O
O
O
N
H
N
N
H
H
N
CF3
N
CF3
N
CF3
30
trace
23
3m: 43%
3p: 70%
3q: 42%
9
10
11
12
13
14
15
16
17
18
19d
20e
21f
22g
23h
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Cat.1 (15 mol %),
acetone (2 mL), irradiation supplied by a photoreactor (λ = 254 nm,
intensity of 4.0 mW cm−2), rt, 36 h, isolated yields.
32
trace
trace
trace
57
43
70
64
58
69
65
-
(λ= 254 nm) at room temperature gave the desired
trifluoromethylated product 3a in a promising 21% yield (Table 1,
entry 1). Examination of other metal catalysts, such as Ni(OTf)2,
Co(OAc)2 and some iron salts was also performed, the yield of 3a
was improved to 72% when ferrocene was employed as a catalyst
(Table 1, entry 6). It was also worth noting that in the absence of
any metal catalyst no reactivity was observed (Table 1, entry 9).
Besides acetone, several solvents were investigated, 1,2-
dichloroethane (DCE) and acetonitrile (MeCN) were not effective to
improve the yield of 3a (Table 1, entry 10 and 11). Other solvents
such as methanol (MeOH), dimethylsulfoxide (DMSO) as well as
water (H2O) did not provide target product 3a (Table 1, entry 12 -
14). Further investigations in additives, catalyst loading and
atmosphere did not increase the yield (Table 1, entries 15–22). The
transformation was retarded when the reaction was carried out in
the dark (Table 1, entry 23).
Na2CO3
KH2PO4
Ac2O
PivOH
-
-
-
-
-
trace
0
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), catalyst (15
mol %), additive (0.4 mmol), solvent (2 mL), irradiation supplied
by a photoreactor (λ = 254 nm, intensity of 4.0 mW cm−2), rt, 36
d
e
b
c
h. Isolated yields. 48 h. Cat. 1 (10 mol %). Cat. 1 (20
mol %). f Under O2. g Under N2. h The reaction was performed in
the dark.
(
Scheme 1a) 10b
. In this transformation, however, stoichiometric
potassium peroxodisulfate (K2S2O8) was employed as oxidant,
making this method did not meet the requirement of green
synthesis. Furthermore, the substrates with electron-withdrawing
groups were inapplicable in their catalytic system.
O
O
TEMPO (4.0 eq.),
Cat.1 (15 mol %)
(a)
N
N
H
CF3SO2Na
+
H
UV, acetone, 36 h, rt
N
CF3
N
Recently, iron-catalyzed C-H functionalization reactions have
found applications to introduce various functional groups to many
substrates. And preeminent advances have been demonstrated by
many groups.9 However, iron-catalyzed trifluoromethylation is
seldom reported.9p,q From the standpoint of energy saving and
being environmentally friendly, we demonstrated an iron-catalyzed
protocol for ortho trifluoromethylation of anilines via picolinamide
assisted10 photoinduced C-H functionalization in the absence of any
1a
3a, trace
2
CF3
Cat.1 (15 mol %)
CF3SO2Na
+
(b)
(c)
Ph
Ph
Ph
Ph
UV, acetone, 36 h, rt
1aa
3aa, 21%
2
O
O
N
N
H
N
X
H
N
N
1aa, X= NH2
1ab, X= OH
1ae
1ac
1ad
oxidants (Scheme 1b)
.
O
N
Cat.1 (15 mol %)
(d)
(e)
+
CF3SO2Na
1ae, 97%
no reaction occurred!
starting material recovered!
Results and discussion
H
UV, acetone, 36 h, rt
N
1af
2
O
N
O
H5/D5
H4/D4
We started our research with the trifluoromethylation of the
amide 1a, which was prepared from the amidation of 2-picolinic
acid and aniline. Treating 1a with 15 mol % Cu(OTf)2, 2 equivalents
of Langlois’ reagent (2), 2 mL acetone under ultraviolet irradiation
Cat.1 (15 mol %)
CF3SO2Na
N
H
+
H
N
UV, acetone, 6 h, rt
N
CF3
1a/1a-D5
2
kH/kD = 0.98
3a/3a-D4
Scheme 2 Mechanistic considerations
2 | J. Name., 2017, 00, 1-3
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oxidation
FeIIILn
1a
FeIILn
3a
revealed that the N atom of pyridine and amide group were
indispensable (Scheme 1c). When the C2- and C6-positions
hydrogen of 1a was substituted by methyl (1af), no product was
acquired and the starting material 1af was recovered (Scheme 1d).
A
B
O
O
N
N
C
N
This phenomenon showed that this strategy has
a high
FeIIILn
SET
N
H
FeIILn
regioselectivity. Further exploration about kinetic isotope effects
(KIE) was carried out, giving a low ratio (k = 0.98), revealing that the
C-H cleavage process was not the rate determining step (Scheme
2e).11
-H+
O
O
N
N
H
N
FeIILn
N
CF3
D
According to experimental results, we made sure that the crucial
role of both heterocyclic nitrogen and amide, most likely as
bidentate binding site for a metal atom.10d But the role of carbonyl
of amide could not be confirmed. Therefore, two possible
mechanisms were proposed. First of all, based on the previous
work,10b a possible mechanism which involve the coordination of
FeIIICF3Ln and oxygen atom of carbonyl was presented in the
supporting information. In the second place, carbonyl of amide just
enhanced the acidity of NH to make it good for deprotonation in
FeIILn
O
E
G
CF3
N
FeIII CF3
UV
acetone
N
F
CF3SO2Na
Ln
2
Scheme 3 Proposed mechanism
With the optimized reaction condition in hand, we next sought to
study the substrate scope of this trifluoromethylation (Table 2).
Numerous picolinamide derivatives could be efficiently transformed
into desired products in moderate to good yields. Functional groups
such as methyl, bromo and chloro groups at para-position of
anilines were well tolerated (3b-d). It was worth mentioning that
picolinamide with strong electron withdrawing groups also could be
converted into corresponding products (3e, 3f). Substrates with
methyl and fluoro groups at ortho-position underwent the
transformation smoothly in 60% and 49% yields respectively (3g,
3h). For the meta-substituted anilines, the reactions tend to occur
on the less hindered site due to the steric bias (3i-l). Pleasingly,
naphthyl derived picolinamide also could take place in this reaction
as well, affording the target product 3m in 43% yield. The amides,
which were synthesized from the amidation of the analogues of 2-
picolinic acid and aniline could also turn into corresponding
products in acceptable yields (3n-q).
some case. Therefore,
a different mechanism was suggested
(Scheme 3). Firstly, FeIILn A converted into FeIIILn B through the
oxidation of air. Then, FeIIILn combined with substrate 1a to
generate aryl-FeIIILn complex C. Subsequently, aryl-FeIILn complex D
was formed through the process of single electron transfer (SET).
Meanwhile, aryl-FeIILn complex D transformed into aryl-FeIIICF3Ln
complex F in the presence of trifluoromethyl radical, which was
generated from Langlois’ reagent 2 under ultraviolet irradiation.
Next, aryl-FeIIICF3Ln complex
F
underwent intramolecular
trifluoromethylation via pentacyclic transition state to give cationic
intermediate G. After the formation of aryl-FeIILn complex H via
deprotonation, target product 3a was obtained through a metal
dissociation process.
Finally, we proved the synthetic utility of our method by the
removal of the PA group in
a facile way, affording the 2-
Based on the previous work,8a we knew that the electronic
excitation of acetone involves the transition of a lone pair electron
from oxygen atom to the carbonyl carbon under ultraviolet
irradiation (λ = 254 nm), the resulting electron-deficient oxygen
atom of the carbonyl n, π* state may abstract one electron from
CF3SO2Na to generate a CF3 radical. In order to obtain more
understanding of the mechanism, several control experiments were
performed. Firstly, the transformation was completely inhibited
when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was used as a
free radical inhibitor (Scheme 1a). Meanwhile, the trifluoromethyl
radical was captured by 1,1-diphenylethylene (1aa), and the
corresponding adduct 3aa was isolated in 21% yield (Scheme 1b). It
was showed that a radical pathway might be involved in this
trifluoromethylation. Subsequently, aniline 1aa, phenol 1ab,
substrates 1ac, 1ad and 1ae were tested under standard conditions
respectively, but no target product was detected. These results
(trifluoromethyl) aniline 4a in 90% yield, which was further
transformed, yielding the nonsteroidal anti-inflammatory drug
floctafenine (5a) in 45% yield (Scheme 3).12
Conclusions
In summary, we have developed a simple and practical protocol
for photoinduced ortho trifluoromethylation of anilines under
oxidant free condition. This clean photochemical protocol
demonstrated a broad substrate scope and variously desired
products were efficiently obtained in moderate to good yields.
Furthermore, the nonsteroidal anti-inflammatory drug floctafenine
was efficiently synthesized through this strategy. Preliminary
researches verified that a radical mechanism is involved.
Conflicts of interest
There are no conflicts to declare
Acknowledgements
This work was supported by the Projects of Medical and Health
Technology Development Program in Shandong Province (No.
2015WS0102), the Shandong Provincial Natural Science Foundation
(ZR2017LB006) and Science Foundation of Educational Commission
of Shandong Province of China (J17KA248).
Scheme 4 Removal of PA group and synthesis of floctafenine
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB00511G
An oxidant free protocol was developed for ortho trifluoromethylation of aniline via picolinamide
assisted Fe-promoted C-H functionalization under ultraviolet irradiation.