Ligand-free trifluoromethylation of iodoarenes by use of 2-Aryl-2-trifluoromethylbenzimidazoline as new trifluoromethylating reagent

Article abstract of DOI:10.1016/j.jfluchem.2018.12.006

N-Methyl 2-aryl-2-trifluoromethylbenzimidazolines were synthesized and utilized in the trifluoromethylation reaction of iodoarenes in the presence of copper(I) salt and base. Iodoarenes bearing electron-donating and electron-withdrawing groups were tolerant to this reaction in the absence of a ligand and gave trifluorotoluene derivatives in good to high yields.

Full text of DOI:10.1016/j.jfluchem.2018.12.006

Accepted Manuscript
Title: Ligand-Free Trifluoromethylation of Iodoarenes by Use
of 2-Aryl-2-trifluoromethylbenzimidazoline as New
Trifluoromethylating Reagent
Authors: Masamichi Miyagawa, Taisuke Ishikawa, Kota
Shinkai, Takahiko Akiyama
PII:
S0022-1139(18)30436-6
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.12.006
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Received date:
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28 October 2018
10 December 2018
11 December 2018
Please cite this article as: Miyagawa M, Ishikawa T, Shinkai K, Akiyama T, Ligand-Free
Trifluoromethylation of Iodoarenes by Use of 2-Aryl-2-trifluoromethylbenzimidazoline
as New Trifluoromethylating Reagent, Journal of Fluorine Chemistry (2018),
https://doi.org/10.1016/j.jfluchem.2018.12.006
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Ligand-Free Trifluoromethylation of Iodoarenes by Use of
2-Aryl-2-trifluoromethylbenzimidazoline as New Trifluoromethylating Reagent
Masamichi Miyagawa, Taisuke Ishikawa, Kota Shinkai, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku,
Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
ORCID
Takahiko Akiyama: 0000-0003-4709-4107
Masamichi Miyagawa: 0000-0002-0874-6726
Graphical abstract
Highlights
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

・New trifluoromethylating reagent
・Relatively wide functional group tolerance
・Cu(I)-catalyzed trifluomethylation in the absence of ligand
Abstract
N-Methyl 2-aryl-2-trifluoromethylbenzimidazolines were synthesized and utilized in the

trifluoromethylation reaction of iodoarenes in the presence of copper(I) salt and base.
Iodoarenes bearing electron-donating and electron-withdrawing groups were tolerant to this
reaction in the absence of a ligand and gave trifluorotoluene derivatives in good to high
yields.
The development of novel methods for the construction of fluorine-containing compounds is
an important topic of research interest in organic chemistry because more than 20% of
pharmaceuticals and agrochemicals contain fluorine atoms [1]. The trifluoromethyl group, in
particular, possesses beneficial characteristics, such as high lipophilicity, permeability, and
metabolic stability [2]. Much effort has been exerted in the development of novel
trifluoromethylation reactions and trifluoromethylating reagents, [3] the latter of which are
divided into nucleophilic [4], electrophilic [5], and radical trifluoromethylating reagents [6]. As
interest in trifluoromethylated compounds has surged, the development of new types of
trifluoromethylating reagents is desired for the syntheses of useful trifluoromethylated
compounds.
Iodoarene is the representative substrate in trifluoromethylation reactions [7–10]. In
metal-mediated trifluoromethylation reactions, copper salt is most commonly used because
of the ease of generation of trifluoromethylcopper species. Chen’s group firstly reported the
trifluoromethylation of iodoarenes with copper(I) catalyst in which trifluoromethylcopper was
the reactive species [11]. Thereafter, a variety of trifluoromethylating reagents, including the
Ruppert-Prakash reagent [7], trifluoroacetate salt [8], fluoroform [9], and others [10], were
synthesized and used in the trifluoromethylation reaction with copper(I) salt.
We reported an enantioselective transfer hydrogenation reaction of ketimines where
benzothiazoline is used as the hydrogen donor in combination with a chiral phosphoric acid
[12]. The aromatization of benzothiazoline to yield benzothiazole is the driving force of the
reaction. We hypothesized that a trifluoromethyl group would be transferred from
benzothiazoline derivatives to other molecules (Figure 1). Based on this hypothesis, we
synthesized 2-aryl-2-trifluoromethylbenzimidazolines and evaluated them as a new type of
trifluoromethylating reagent. The advantage of this new reagent includes easy synthesis
and handling, low cost, no volatility, and moisture and air stability. In addition, trifluoromethyl
source of the reagent is 2,2,2-trifluoroacetophenone which is stable and commercially
available and one of the most economical and efficient trifluoromethyl source but rarely used
as versatile trifluoromethylating reagent [10c]. We describe herein the ligand-free

trifluoromethylation of iodoarenes by use of 2-aryl-2-trifluoromethylbenzimidazoline in the
presence of copper(I) salt.
Figure 1. Transfer of trifluoromethyl group by aromatization.
We commenced with the development of a new trifluoromethylating reagent (Table 1).
We synthesized benzothiazoline 3 and benzimidazoline 4 by mixing
2,2,2-trifluoroacetophenone and 2-aminobenzenethiol or 1,2-phenylenediamine in
autoclave conditions, respectively, and attempted to carry out the trifluoromethylation
reaction of 3-nitro-1-iodobenzene (1a) in the presence of copper(I) chloride and potassium
carbonate. However, the yields of 3-trifluoromethyl-1-nitrobenzene (2a) were very low. The
attempted reaction with 4 furnished 2H-benzimidazole 6 in 35% yield, and 1a and 4 were
recovered in 100% and 28% yield, respectively (Scheme 1). This indicates that the
conversion of 4 hardly proceeded and the hydrogen transfer reaction competed with the
trifluoromethyl group transfer reaction. Thus, a methyl group was introduced to the nitrogen
atom in 4 to suppress the hydrogen transfer from the benzimidazoline skeleton [13]. When
N-methyl 2-phenyl-2-trifluoromethylbenzimidazoline (5a) was applied to the
trifluoromethylation reaction, desired product 2a was generated in 49% yield. Gratifyingly, a
new trifluoromethylating reagent was developed by employing a benzimidazoline skeleton.
Table 1. Examination of trifluoromethylating reagents.

Yield of 2a (%)b)
Entry
Trifluoromethylating reagent
1
2
3
0
3
5
4
49
5a
a) Reaction conditions: 1a (0.10 mmol), trifluoromethylating reagent (0.20 mmol), copper
chloride (0.30 mmol), potassium carbonate (0.40 mmol), and propionitrile (1.0 mL). b) NMR
yields based on 19F NMR measurement.
Scheme 1. Formation of 2H-benzimidazole from benzimidazoline.
Then, we optimized the reaction conditions and continued our investigation of the
2-substituents of 5. 4-Fluorophenyl and 4-methoxyphenyl groups were introduced to
N-methylbenzimidazoline because we speculated that the electron-withdrawing and
electron-donating properties would have an influence on the transfer reaction of the
trifluoromethyl group. In particular, we expected that the introduction of a 4-methoxyphenyl
group at 2-position would accelerate the transfer of the trifluoromethyl group. We examined

5a–c in the reactions with 1-iodonaphthalene (1b) and 4-cyano- (1c), 4-formyl- (1d), and
4-nitro-1-iodobenzenes (1e). Remarkable changes in yields were not observed, indicating
that the substituents on benzimidazoline did not have an impact on the trifluoromethyl group
transfer.
Table 2. Screening for 2-substituents of N-methylbenzimidazoline.
With the optimized reaction conditions in hand, we studied the substrate scope of
iodoarenes (Scheme 2). The trifluoromethylation reaction using benzimidazoline had wide
functional group tolerance. Iodoarenes having electron-withdrawing groups, such as nitro,
cyano, ester, formyl, and carbonyl groups, gave trifluoromethylated products 2c–h in good

to excellent yields. On the other hand, the reaction of iodoarenes bearing electron-donating
groups provided corresponding trifluorotoluenes 2i–k in moderate to good yields.
2-Iodopyridine also furnished 2-trifluoromethylpyridine 2l in 57% yield. When 2-, 3-, and
4-iodotoluenes, iodobenzene, and 1-chloro-4-iodobenzene were subjected to the
trifluoromethylation reaction, corresponding trifluorotoluenes 2m–q were obtained in
approximately 40% yields. This might be due to the high volatility of the trifluoromethylated
products in the reaction conditions.
Scheme 2. Substrate scope of iodoarenes. NMR yields based on 19F NMR measurement.
a) 5b was used in place of 5a. b) 5c was used in place of 5a.

The proposed reaction mechanism is shown in Scheme 3. The reaction of
benzimidazoline, copper (I) chloride, and base afforded I, and the subsequent elimination of
benzimidazole 7 generated trifluoromethyl copper species II. NMR analysis of the mixture of
5a, potassium carbonate, and copper (I) chloride showed the signal of trifluoromethyl copper
species II at -27.6 ppm, which is consistent with the NMR data of the previous report.[7g]
This result supports the proposed mechanism. Following oxidative addition to the iodoarene
and reductive elimination provided the trifluoromethylated arene. The reason for the high
yields of iodoarenes bearing electron-withdrawing groups compared to the yields of
iodoarenes bearing electron-donating groups is ascribed to the promotion of the former
oxidative addition step.
Scheme 3. Proposed reaction mechanism.
In conclusion, we have achieved the trifluoromethylation of iodoarenes by developing a
new type of trifluoromethylating reagent. Inspired by the hydrogen transfer reaction of
benzothiazoline, we synthesized 2-trifluoromethylbenzimidazoline, which functioned as a
trifluoromethylating reagent in the presence of copper(I) salt. The aromatization of
benzimidazoline to furnish benzimidazole is the driving force of the reaction. The salient
features of the present reaction are as follows: (1) the addition of ligand is not required and
(2) the reaction has wide functional group tolerance to give trifluorotoluenes in good to high

yields.

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