Catalytic trifluoromethylation of iodoarenes by use of 2-trifluoromethylated benzimidazoline as trifluoromethylating reagent

Article abstract of DOI:10.3762/BJOC.16.198

The trifluoromethylation of iodoarenes was accomplished by use of a 2-trifluoromethylbenzimidazoline derivative as the trifluoromethylating reagent and a catalytic amount of Cu(I) in the presence of 2,2'-bipyridyl as the ligand. Through a mechanistic study, we found that the oxidative addition of the iodoarene to the Cu(I)–CF₃ species is the rate-determining step.

Full text of DOI:10.3762/BJOC.16.198

Catalytic trifluoromethylation of iodoarenes by use of
-trifluoromethylated benzimidazoline as
2
trifluoromethylating reagent
Tatsuhiro Uchikura, Nanami Kamiyama, Taisuke Ishikawa and Takahiko Akiyama*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 2442–2447.
Department of Chemistry, Faculty of Science, Gakushuin University,
Mejiro, Toshima-ku, Tokyo, 171-8588, Japan
https://doi.org/10.3762/bjoc.16.198
Received: 31 July 2020
Email:
Accepted: 15 September 2020
Published: 30 September 2020
Takahiko Akiyama* - takahiko.akiyama@gakushuin.ac.jp
*
Corresponding author
This article is part of the thematic issue "Organo-fluorine chemistry V".
Guest Editor: D. O'Hagan
Keywords:
benzimidazoline; catalysis; copper; fluorine chemistry;
trifluoromethylation
© 2020 Uchikura et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The trifluoromethylation of iodoarenes was accomplished by use of a 2-trifluoromethylbenzimidazoline derivative as the
trifluoromethylating reagent and a catalytic amount of Cu(I) in the presence of 2,2'-bipyridyl as the ligand. Through a mechanistic
study, we found that the oxidative addition of the iodoarene to the Cu(I)–CF3 species is the rate-determining step.
Introduction
The introduction of a trifluoromethyl group is one of the most trifluoromethylating reagent in the presence of 3 equiv of a
attractive reactions in drug discovery [1,2]. In the past decade, copper salt [22]. The benzimidazoline derivatives could be
trifluoromethylation reactions of aryl halides in the presence of readily prepared from relatively cheap materials, namely, tri-
transition-metal complexes were reported [3-21]. CuCF3 is a fluoromethylacetophenone and phenylenediamine derivatives
useful species for the trifluoromethylation of aryl halides and (Figure 1b). Herein we report a catalytic trifluoromethylation of
there are a number of precursors of CuCF3 for trifluoromethyla- iodoarenes by use of benzimidazoline derivatives in the pres-
tion reactions. In contrast, the catalytic generation of CuCF3 ence of a catalytic amount of copper salts and a bipyridyl ligand
was less investigated [15-21]. For example, R3SiCF3, a (Figure 1c).
fluoral derivative, and trifluoroacetates were employed
as precursors of CuCF3 species for the catalytic trifluoromethyl- Results and Discussion
ation of iodoarenes (Figure 1a) and the development of novel We first investigated the reaction conditions by use of
types of trifluoromethylating reagents is still desired. We have p-iodonitrobenzene (1a) and 2-phenyl-2-trifluoromethyl-1-
recently reported the trifluoromethylation of iodoarenes methylbenzimidazoline (2) (Table 1). Using 3 equiv of CuI
by use of 2-aryl-2-trifluoromethylbenzimidazoline as the gave 4-trifluoromethyl-1-nitrobenzene (3a) quantitatively, as
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Beilstein J. Org. Chem. 2020, 16, 2442–2447.
we had reported previously (Table 1, entry 1) [22]. Decreasing
the CuI catalyst loading to 20 mol % lowered the yield of 3a
even at a high temperature (Table 1, entries 2 and 3). In order to
stabilize the copper(I) catalyst, a bipyridyl ligand was em-
ployed in the reaction [23]. By this, the trifluoromethylation
proceeded with a catalytic amount of CuI in the presence of
0
.8 equiv of 2,2’-bipyridyl to furnish product 3a in 80% yield
(
(
Table 1, entry 4). However, smaller amounts of CuI
10 mol %) and 2,2’-bipyridyl (20 mol %) gave compound 3a in
lower yields (Table 1, entries 5 and 6). Benzonitrile was the sol-
vent of choice (Table 1, entries 7 and 8). Replacing CuI by
CuBr or CuCl gave similar results (Table 1, entries 9 and 10).
However, we selected the most stable and readily available
CuI as the catalyst for further investigations. Thus, the
trifluoromethylation of p-iodonitrobenzene proceeded by use of
2
-phenyl-2-trifluoromethyl-1-methylbenzimidazoline in the
presence of catalytic amounts of CuI and 2,2’-bipyridyl as
ligand.
We next screened for 2,2’-bipyridyl ligands to be used with CuI
(
Table 2). 4,4’-Dimethyl-2,2’-bipyridyl (4b) gave product 3a in
a higher yield than 2,2’-bipyridyl (4a), whereas 5,5’- and 6,6’-
dimethylbipyridyl (4c and 4d) were not effective. From these
results, the substituents at 4,4’-positions were expected to be
beneficial for the reaction, and other 4,4’-substituted bipyridyl
ligands were investigated. We found that 4,4’-di-tert-butyl-2,2’-
bipyridyl (4e) afforded the best result (91% yield). On the other
hand, 2,2'-bipyridyl ligands bearing electron-donating (–OMe,
Figure 1: Trifluoromethylation of aryl halides.
Table 1: Screening for reaction conditionsa.
4
f) and -withdrawing (–CF3, 4g) groups furnished 3a in low
entry
X
Y
solvent
temp.
yieldb
1
2
3
4
5
6
7
8
3
0
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
MeCN
DMF
60 °C
60 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
90 °C
quant
36%
40%
80%
59%
63%
32%
30%
72%
79%
0.2
0.2
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0
0
0.8
0.8
0.2
0.8
0.8
0.8
0.8
9c
PhCN
PhCN
10d
aPerformed with 2a (0.050 mmol) and 1a (0.10 mmol) in solvent (1.0 mL). bDetermined by 19F NMR spectroscopy (benzotrifluoride was used as the
internal standard). cCuBr was used instead of CuI. dCuCl was used instead of CuI.
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Beilstein J. Org. Chem. 2020, 16, 2442–2447.
Table 2: Screening for diamine ligandsa.
ligand
yieldb
ligand
yieldb
56%
80%
4a
4g
82%
72%
19%
64%
57%
trace
4
b
c
4h
4
4i
4
d
e
4j
9
1%
3%
26%
40%
4k
4
7
–
4f
aPerformed with 2a (0.050 mmol) and 1a (0.10 mmol) in solvent (1.0 mL). bDetermined by 19F NMR spectroscopy (benzotrifluoride was used as the
internal standard).
yields. Moreover, other electron-withdrawing ligands, i.e., m-iodonitrobenzene afforded the trifluoromethylated product in
phenanthroline derivatives (4h and 4i), and electron-donating a decreased yield of 35% due to the higher electron density of
ligands such as 2,2’-biimidazole (4j) and tetramethylethylenedi- the meta-position compared to the ortho- and para-positions.
amine (4k) gave inferior results.
Iodoarenes bearing other electron-withdrawing substituents,
such as p-cyano, p-acetyl, and p-methoxycarbonyl, were also
We next screened for the generality of the reaction towards suitable and gave products 3d–f in moderate to high yields.
various substrates under the optimized conditions (Figure 2). Furthermore, the presence of a formyl group was also tolerated
Electron-deficient aryl iodides were well tolerated furnishing in the reaction, and p-formyltrifluoromethylbenzene (3g) was
the corresponding trifluoromethylation products in high yields. obtained in 40% yield. However, the electron-rich substrate
Among the tested nitrophenyl derivatives, p- and o-nitro- 2-methoxyiodobenzene (1h) gave product 3h in only a modest
phenyliodide gave the products in highest yields. In contrast, yield (30%).
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Beilstein J. Org. Chem. 2020, 16, 2442–2447.
Figure 2: Scope of aryl iodides. Yields determined by 19F NMR spectroscopy and used ligand is given in parenthesis.
Heteroaryl iodides were also suitable substrates (Figure 3). in Supporting Information File 1). Therefore, CuI and 2 gener-
-Iodopyridine (5a) gave the expected trifluoromethylation ated CuCF3 species as the active species for the trifluoromethyl-
2
product 6a in 80% yield. 2-Iodoquinoline (5b) and 1-iodoiso- ation [24].
quinoline (5c) were also suitable substrates to furnish desired
products 6b and 6c in high yields. Furthermore, iodopyrazine Then, the dependence of the conversion on the reaction time
was applicable to furnish 6d in 63% yield.
was estimated (Figure 4) and no induction period was observed.
Although benzimidazoline 2 was completely consumed after
Finally, a mechanistic study of the reaction was carried out. 24 h, the yield of the trifluoromethylation product continued to
First, the active species of the reaction was investigated by increase up to 48 h. This suggests that product generation
NMR analysis. The generation of Cu(I)–CF3 was observed by proceeded slower than the cleavage of the C–CF3 bond of benz-
mixing benzimidazoline 2 and CuI in EtCN at 90 °C (Figure S1, imidazoline.
Figure 3: Scope of heteroaryl iodides. Yields determined by 19F NMR spectroscopy and used ligand is given in parenthesis.
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Beilstein J. Org. Chem. 2020, 16, 2442–2447.
Figure 4: Time course of the trifluoromethylation reaction.
We propose a mechanism for the reaction, as shown in Figure 5. (Table 2), and the reaction with benzimidazoline proceeded
The Cu(I)–CF3 species, generated through the reaction of benz- rapidly (Figure 4), the oxidative addition was suggested to be
imidazoline 2 with CuI under basic conditions, underwent an the rate-determining step.
oxidative addition reaction with the aryl iodide to generate a
Cu(III) complex. A subsequent reductive elimination furnished Conclusion
the trifluoromethylarene and Cu(I). Because an electron-donat- In conclusion, we have developed a catalytic trifluoromethyla-
ing ligand was more effective than an electron-deficient one tion of aryl iodides by using trifluoromethylated benzimidazo-
line derivatives. The mechanistic study revealed that the oxida-
tive addition was the rate-determining step of this reaction.
2
-Phenyl-2-trifluoromethyl-1-methylbenzimidazoline is a novel
type of trifluoromethylating reagents that might be useful for
organic synthesis.
Experimental
General procedure of trifluoromethylation: Aryl iodide 1
(
0.1 mmol), 2 (56 mg, 0.2 mmol), CuI (3.8 mg, 0.02 mmol),
,2’-bipyridyl (12.5 mg, 0.08 mmol), and potassium carbonate
55.6 mg, 0.4 mmol) were mixed in benzonitrile (1.0 mL), and
2
(
the mixture heated to 90 °C. After 48 h, hexafluorobenzene was
added as an internal standard and the mixture analyzed by
1
9F NMR spectroscopy for the calculation of the NMR yield.
Then, the crude products were purified by preparative TLC to
Figure 5: Proposed mechanism of the catalytic cycle.
give pure products 3.
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Beilstein J. Org. Chem. 2020, 16, 2442–2447.
1
1
1
7.Knauber, T.; Arikan, F.; Röschenthaler, G.-V.; Gooßen, L. J.
Chem. – Eur. J. 2011, 17, 2689–2697. doi:10.1002/chem.201002749
8.Li, Y.; Chen, T.; Wang, H.; Zhang, R.; Jin, K.; Wang, X.; Duan, C.
Synlett 2011, 1713–1716. doi:10.1055/s-0030-1260930
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Supporting Information
Supporting Information File 1
Details of screening experiments, synthetic procedures and
characterization data of new compounds, and copies of
spectra.
20.Aikawa, K.; Nakamura, Y.; Yokota, Y.; Toya, W.; Mikami, K.
[https://www.beilstein-journals.org/bjoc/content/
Chem. – Eur. J. 2015, 21, 96–100. doi:10.1002/chem.201405677
2
2
2
2
1.Shimizu, N.; Kondo, H.; Oishi, M.; Fujikawa, K.; Komada, K.; Amii, H.
supplementary/1860-5397-16-198-S1.pdf]
Org. Synth. 2016, 93, 147–162. doi:10.15227/orgsyn.093.0147
2.Miyagawa, M.; Ishikawa, T.; Shinkai, K.; Akiyama, T. J. Fluorine Chem.
2019, 219, 29–31. doi:10.1016/j.jfluchem.2018.12.006
3.The bipyridyl ligands stabilize the copper(I) catalyst for catalytic
reaction (see ref. [6]).
Funding
JSPS KAKENHI Grant Numbers JP17H03060, JP20H00380,
4.From the examination of an aryl group at the 2-position of
benzimidazolines, electron-rich moieties were more reactive than
electron-deficient ones (Table S5, see Supporting Information File 1).
These results suggest that an oxidative addition step proceeds by
nucleophilic process.
and JP20H04826 (Hybrid Catalysis)
ORCID® iDs
Tatsuhiro Uchikura - https://orcid.org/0000-0002-0327-3675
Takahiko Akiyama - https://orcid.org/0000-0003-4709-4107
License and Terms
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