Efficient N-arylation of azole compounds utilizing selective aryl-transfer TMP-iodonium(III) reagents

Article abstract of DOI:10.1016/j.tetlet.2019.04.012

It was determined that diaryliodonium(III) triflates bearing a trimethoxybenzene (TMP) auxiliary are more reactive than the reported selective aryl-transfer iodonium salts in the N-arylation of benzimidazoles and other types of azole compounds under catalytic conditions. The TMP-iodonium(III) salts can thus effectively facilitate the reaction at 50 °C or below, producing the corresponding N-arylated biaryls without the formation of TMP-derived coupling byproducts. Utilization of this TMP reagent under mild conditions would prevent the underlying problem of participation of the auxiliary group in the coupling reactions, which is observed while using the iodonium(III) salts that require elevated temperatures.

Full text of DOI:10.1016/j.tetlet.2019.04.012

Accepted Manuscript
Efficient N-arylation of azole compounds utilizing selective aryl-transfer TMP-
iodonium(III) reagents
Daichi Koseki, Erika Aoto, Toshitaka Shoji, Kazuma Watanabe, Yasuko In,
Yasuyuki Kita, Toshifumi Dohi
PII:
S0040-4039(19)30332-6
https://doi.org/10.1016/j.tetlet.2019.04.012
TETL 50727
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 January 2019
20 March 2019
3 April 2019
Please cite this article as: Koseki, D., Aoto, E., Shoji, T., Watanabe, K., In, Y., Kita, Y., Dohi, T., Efficient N-
arylation of azole compounds utilizing selective aryl-transfer TMP-iodonium(III) reagents, Tetrahedron Letters
(2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.012
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Graphical Abstract
Efficient N-arylation of azole compounds utilizing
selective aryl-transfer TMP-iodonium(III)
reagents
Daichi Koseki, Erika Aoto, Toshitaka Shoji, Kazuma Watanabe, Yasuko In,
Yasuyuki Kita and Toshifumi Dohi*

Tetrahedron Letters
TETRAHEDRON
LETTERS
Pergamon
Efficient N-arylation of azole compounds utilizing selective
aryl-transfer TMP-iodonium(III) reagents
Daichi Koseki,a Erika Aoto,a Toshitaka Shoji,a Kazuma Watanabe,a Yasuko In,b
Yasuyuki Kitac and Toshifumi Dohia*
aCollege of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan
bOsaka University of Pharmaceutical Sciences 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
cResearch Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan
Tel +81(77)5614908; E-Mail: td1203@ph.ritsumei.ac.jp
Abstract—It was determined that diaryliodonium(III) triflates bearing a trimethoxybenzene (TMP) auxiliary are more reactive
than the reported selective aryl-transfer iodonium salts in the N-arylation of benzimidazoles and other types of azole
compounds under catalytic conditions. The TMP-iodonium(III) salts can thus effectively facilitate the reaction at 50 °C or
below, producing the corresponding N-arylated biaryls without the formation of TMP-derived coupling byproducts.
Utilization of this TMP reagent under mild conditions would prevent the underlying problem of participation of the auxiliary
group in the coupling reactions, which is observed while using the iodonium(III) salts that require elevated temperatures.
Keywords; arylation; hypervalent compounds; iodine, nitrogen heterocycles
© 2019 Elsevier Science. All rights reserved.
Diaryliodonium (III) salts, ArI+Ar’X-, (where Ar, Ar’ = aryl,
X− = counterion), represent one of the unique classes of
hypervalent iodine compounds having two carbon ligands,
which show practical applicability in scientific fields.1 With
the liberation of more stable monovalent iodine acting as a
driving force, these salts are often utilized as arylating
agents and benzyne precursors in organic synthesis.2 By
virtue of the excellent nucleofugality of the aryl iodide
moiety,3 diaryliodonium(III) salts are much more reactive
than aryl halides toward nucleophiles, bases, and
organometallic reagents in these reactions. Recently, their
high reactivity drew a considerable attention from synthetic
chemists working on challenges in the practical
applicability of the aryl-coupling processes (Scheme 1).4
Thus, relying on the high reactivity of the
diaryliodonium(III) salts, practical arylations not requiring
precious palladium catalyst have become possible in the
coupling strategies of many nucleophilic molecules.5 Due
to the compatibility of a broad range of functional groups,6
development of such improved coupling methods has been
actively investigated, especially for the C-N bond
formation during the synthesis of N-containing bioactive
molecules.7 To this end, optimizing the structure and
reactivity of the iodonium(III) salts should obviously be
important for further advancement of the aryl amination
strategy.8 Herein, we report an efficient N-arylation of
azole compounds utilizing the specific diaryliodonium(III)
salts containing the 2,4,6-trimethoxyphenyl (TMP)
Scheme 1. Diaryliodonium(III) salts in coupling reactions.
(Nu = nucleophilic group, FG = functional group, such as an
organometallic element)
Scheme 2. Efficient N-arylation of azole compounds utilizing reactive
and selective TMP-iodonium(III) salts.
(Aux = auxiliary to enhance the reactivity for arylation)

Tetrahedron Letters
auxiliary group9 to enhance the reactivity in aryl aminations.
Mes-iodonium(III) salts (Mes = Mesityl),19 especially for
the transition metal-catalyzed couplings.20 More recent
investigations on TMP-iodonium(III) salts have further
expanded the scope and utility of the nucleophiles and
coupling partners employed in this reaction.8f–g,9,10
While retaining the selective aryl-transfer ability of the
TMP-iodonium(III) salts,10 valuable N-aryl azole
compounds, not only known as the privileged structures in
pharmaceutical sciences showing a variety of biological
activities, but also employed as building blocks and ligands
in synthetic chemistry,11 are smoothly obtained in good
yields under mild reaction conditions (Scheme 2).
Very recently, Pan et al. reported an efficient arylation of
1H-indazoles by utilizing the auxiliary diaryliodonium(III)
salts, MesI+ArX−, as N2-selective aryl-transfer agents.21,22
However, the formation of more sterically congested N1-
aryl indazoles and benzimidazoles was rather slow under
the catalytic conditions.23 In fact, N-arylation of
benzimidazole 1a using Mes-iodonium(III) salt 2a’ did not
proceed efficiently at 50 °C, even in the presence of a
stoichiometric amount of the copper catalyst (see Scheme
3).24
In the N-arylation strategy of azoles, continuous efforts are
being made for realizing mild reaction conditions by
modulating the organic ligands in the transition metal-
catalyzed coupling of aryl halides and related aryl
electrophiles.12
Alternatively,
Chan-Lam-Evans-type
reactions, using arylboronic acids, were reported for the N-
arylation of azoles at ambient temperature, despite the
necessity of long reaction time and nearly stoichiometric
amount of copper catalyst.13 Aryllead,14a triarylbismuth,14b–d
arylsiloxanes,14e and arenediazonium salts14f were also
employed as aryl sources to develop efficient coupling
reactions under mild conditions. Regarding the
diaryliodonium(III) salt, the N-arylation of azole compound
accelerated by a combined palladium/copper catalytic
system for the synthesis of benztriazole was reported in
1998 by Beletskaya and co-workers.15 Since then, several
reports
on
the
N-arylation
of
azoles
with
diaryliodonium(III) salts have appeared in the literature, but
typically, the reaction scope was limited to the salts bearing
same aryl groups (Ar2I+X−).16
Scheme 3. N-arylation of benzimidazole 1a employing Mes-
iodonium(III) salt.
[conditions: cat. copper(I) acetate, triethylamine (2 equiv) in
toluene (0.1 M of benzimidazole 1a) at 50 °C for 12 h under
nitrogen atmosphere]
The
chemical
and
physical
properties
of
diaryliodonium(III) salts are highly dependent on the nature
of the aryl groups, and for tuning their reactivities in the
coupling reactions, several useful auxiliaries have been
developed so far.17 For the diaryliodonium(III) salts having
a reactive electron-deficient aryl moiety, to exclude the
possibility of transfer of the dummy aryl group, an
electron-donating functionality was supportively introduced
(see Figure 1).18 Utilization of the auxiliary and the dummy
ligand in diaryliodonium(III) salts for a selective aryl-
transfer has become much popular after the discovery of
a cat. 10 mol%. b cat. 100 mol% (stoichiometric).
Thus, for the N-arylation of benzimidazoles, we next turned
our attention to the reaction of the TMP-iodonium(III) salt.
Although the utility of the TMP auxiliary in the
iodonium(III) salts for a selective aryl-transfer in other
reactions has been reported by Olofsson,10a,b Stuart,8f–g,10c
and our group,9 to the best of our knowledge, the reactivity
of TMP-iodonium(III) salt in copper catalysis has not been
investigated in detail in terms of the synthetic scope. In the
present study, to our delight, TMP-iodonium(III) salts
showed higher reactivities compared to that of Mes salt 2a’
in the desired coupling reactions. p-Tolyl benzimidazole
3aa was thus quantitatively obtained, once the reaction was
conducted employing TMP-iodonium(III) salt 2a under the
same conditions as in Scheme 3 (see Eq. 1 in Table 1).
Benzimidazole 1a could smoothly react with p-tolyl (2,4,6-
trimethoxyphenyl)iodonium(III) triflate 2a at 50 °C in
toluene in the presence of triethylamine as a base (2 equiv.)
and copper(I) catalyst (10 mol%), giving arylated product
3aa in 99% yield after the reaction time of 6 h (Table 1,
entry 1). The reaction conditions with benzimidazole 1a
were further investigated using TMP salt 2a as the standard
substrate. The economical inorganic bases, such as sodium
carbonate, sodium hydrogen carbonate, and sodium acetate,
were less effective than triethylamine, probably due to their
low solubility in toluene (entries 2–4, also see entry 5). As
Figure 1. Diaryliodonium(III) salts having auxiliary group for selective
aryl-transfer in coupling reactions
(EWG = electron-withdrawing group, EDG = electron-donating
group)

Tetrahedron Letters
Table 1. N-arylation of benzimidazole employing TMP-iodonium(III) salt:
Reaction conditions (Eq. 1)a
deactivation of the catalyst was relatively slow even under
an oxygen atmosphere (entry 13). Nonetheless, in the
absence of the copper catalyst, the reaction did not proceed
at 50 °C. It should be emphasized that p-tolyl
benzimidazole 3aa was selectively produced along with the
theoretical formation of TMP iodide, while the formation
of byproduct 3aa’, resulting from the transfer of TMP from
iodonium salt 2a to benzimidazole 1a, was negligible in the
reaction system of entry 1.
Table 2. N-phenylation of various azoles 1a–i using TMP-iodonium(III)
salt 1b and phenyl(2,4,6-trimethoxyphenyl)iodonium(III) triflatea
Entry
Base
Solvent
Yield of 3aab
Entry
1
Azole
Arylation product
Yieldb
1
2
3
triethylamine
toluene
toluene
toluene
99% (99%)c
trace
sodium carbonate
99%
sodium hydrogen
carbonate
50%
1a
1b
3ab
3bb
2c
4
5
6
7
sodium acetate
none
toluene
toluene
32%
15%
96%
63%
81%
triethylamine
triethylamine
dichloromethane
3c
N,N-dimethyl
formamide
quant
(1.16:1)d
1c
3cb
8
triethylamine
triethylamine
triethylamine
triethylamine
triethylamine
triethylamine
acetonitrile
toluene
toluene
toluene
toluene
toluene
trace
3%
9d
4c
5c
6c
quant
10e
11f
12g
13h
49%
57%c
49%
76%
(1.06:1)d
1d
1e
3db
3eb
84%
(1.05:1)d,e
a The reactions were performed using TMP-iodonium(III) salt 2a (0.24
mmol) in the presence of copper(I) acetate (10 mol%) and base (2 equiv)
in solvent (0.1 M) at 50 oC under nitrogen atmosphere for benzimidazole
1a (0.20 mmol), unless otherwise noted.
b Yields were determined by 1H NMR based on benzimidazole 1a used.
c Isolated yield based on benzimidazole 1a used.
d Copper(II) acetate (10 mol%) was instead used.
e Copper(I) chloride (10 mol%).
quant
(1.08:1)d,e
1f
3fb
7
98%
97%
1g
3gb
8f
f Copper(I) bromide (10 mol%).
g Copper(I) iodide (10 mol%).
h Under oxygen atmosphere.
1h
1i
3ha
3ib
9
97%
a solvent, the use of non-polar toluene and dichloromethane
effectively transferred the aryl group onto benzimidazole
1a (entries 1 and 6), while the use of polar solvents resulted
in low conversions of the substrate25 (for example, see
entries 7 and 8). For this N-arylation, only copper(I) salts
could work as catalysts (see entry 9), and copper(I) acetate
gave the better result than CuX (X = I, Br, Cl) that produce
unstable TMP-iodonium(III) halides (entries 1, 10–12).
Furthermore, no strict care had to be taken to exclude
molecular oxygen from the reaction mixture; the
a The reactions were examined under the conditions of Table 1, entry 1
using TMP-iodonium(III) salt 2b (0.24 mmol).
b Isolated yield based on benzimidazole 1a used.
c Dichloromethane was used as a solvent.
d The ratio of regioisomers (N1 versus N3-arylated product).
e The average of two runs.
f TMP-iodonium(III) salt 2a was used instead of 2b.

Tetrahedron Letters
Using phenyliodonium(III) triflate 2b, we then confirmed
These results conclude that TMP-iodonium(III) salts 2 are
generally more reactive than the Mes-iodonium(III) salt in
the N-arylation of benzimidazoles and related compounds.
Note that using this TMP auxiliary is indispensable not
only for the reactivity, but also for the aryl-transfer
selectivity.9,10 During the coupling of iodonium(III) salts
2a–f, the TMP group was not introduced onto substrate 1.
To clarify the specificity of the TMP auxiliary, we thus
conducted the following control experiments using related
iodonium(III) salts 2’’a and 2’’’a (Scheme 5). First,
anisyl(p-tolyl)iodonium(III) triflate 2’’a was reacted with
benzimidazole 1a by the standard N-arylation procedure,
which furnished two arylation products, 3aa (for tolyl
transfer) and 4 (for anisyl transfer), without any selectivity
(Eq. 1). Also, 2,4-dimethoxyphenyl(p-tolyl)iodonium(III)
triflate 2’’’a induced a competitive aryl-transfer to some
extent (Eq. 2). Therefore, in terms of selectivity, simple
anisyl and 2,4-dimethoxyphenyl groups were found to be
poor auxiliaries, although the distribution of the products
slightly improved in the latter case. Regarding the
structural features of TMP-iodonium(III) salt, X-ray
crystallographic analysis of a representative compound
suggested that in this hypervalent molecule, there exist
unique secondary bonding interactions between the
iodine(III) center and the two ortho-methoxy groups in
TMP.28 Although further investigation is required to make
some conclusion, the reason behind high reactivities of
TMP-iodonium(III) salts 2a–f compared to that of Mes salt
2a’ (see Scheme 3) in our N-arylation might thus lie in the
facile reductive elimination step of the TMP salts, which
alleviates the conformational rigidity in their hypervalent
iodine state.
the general utility of TMP-iodonium salts for the N-
arylation of benzimidazoles and related compounds (Table
2).26 Even in this case, benzimidazole 1a was efficiently
converted into target product 3ab by the selective phenyl
transfer (entry 1). For 2-methylbenzimidazole 1b, the steric
requirement somehow decreased the yield of arylation
product 3bb, and dichloromethane was found to be a better
solvent in this case (entry 2). All 5-substituted
benzimidazoles 1c–f could readily react with TMP-
iodonium(III) salt 2b regardless of the electron-rich and
deficient groups, but two regioisomers, N1 and N3-arylated
products 3cb–fb, were unselectively produced (entries 3–6).
Imidazoles 1g and 1h could also be used in this reaction,
which resulted in N-arylated imidazoles 3gb and 3ha (for
p-tolyl salt 2a) in nearly quantitative yields (entries 7 and
8). Similarly, the reaction with pyrazole 1i afforded
corresponding product 3gb in excellent yield (entry 9).
Subsequently, the scope of TMP-iodonium(III) salts 2a–f27
in the N-arylation of benzimidazole 1a was investigated
(Scheme 4). As the transferring aryl group, the electron-
rich p-anisyl ring of TMP salt 2c could be selectively
introduced, despite a slight decrease in the yield (84%). In
addition, thienyl salt 2d could quantitatively convert
substrate 1a into corresponding N-linked heteroaromatic
biaryl 3ad. On the other hand, ortho-substituted aryl groups
were less reactive in this N-arylation process, which is
consistent with the observations in the reported copper-
catalyzed
reactions.5,6
In
fact,
mesityl(2,4,6-
trimethoxyphenyl)iodonium(III) triflate 2f did not transfer
the Mes group onto benzimidazole 1a under the reaction
conditions due to steric influence of the bulky Mes ring.
Scheme 4. Transferring aryl groups.
a Dichloromethane was used as a solvent.
ND = not determined
Scheme 5. Selectivity of aryl-transfer for iodonium(III) salts, 2’’a and
2’’’b, related to the TMP in N-arylation of benzimidazole 1a.

Tetrahedron Letters
Lu, N.; Huang, L.; Xie, L.; Cheng, J. Eur. J. Org. Chem. 2018,
In summary, we have revealed in this study that TMP
auxiliary diaryliodonium(III) salts 2 are the promising
entries among the selective aryl-transfer agents in the N-
arylation of benzimidazoles and related compounds.
Exploiting the reactivity of the TMP auxiliary is critical for
achieving an efficient N-arylation process using
diaryliodonium(III) salts 2. Thus, the reactions can be
performed at around 50 °C or lower, which definitively
expels the problem of participation of the auxiliary groups
in the coupling reactions observed at elevated temperatures.
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Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research (C) from JSPS. T.D. acknowledges the research
fund of the Asahi Glass Foundation and support from the
Ritsumeikan Global Innovation Research Organization (R-
GIRO) project. D.K. thanks The Pharmaceutical Society of
Japan (PSJ) for support of the Nagai Memorial Research
Encouragement.
Highlights:
Efficient aryl amination of azole compounds
Coupling reaction employing reactive pseudo-halide
TMP-iodonium(III) for reactive/selective aryl-transfer
Pannecoucke, X.; Poisson, T. Chem.-Eur. J. 2017, 23, 17318.
7. See ref. 5d and following reviews: (a) Torborg, C.; Beller, M.
Adv. Synth. Catal., 2009, 351, 3027; (b) Cooper, T.; Campbell,
I.; Macdonald, S. Angew. Chem., Int. Ed., 2010, 49, 8082; (c)
Brown, D. G.; Bostrom, J. J. Med. Chem., 2016, 59, 4443; (d)
Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachalb, P.;
Krska, S. W. Chem. Soc. Rev., 2016, 45, 546.
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Tetrahedron Letters
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26. Typical experimental procedure for the reactions in Table 2:
To a stirred solution of copper(I) acetate (2.4 mg, 0.020 mmol,
0.10 equiv.), benzimidazole 1a (23.6 mg, 0.20 mmol), and
TMP iodonium(III) salt 2a (124.8 mg, 0.24 mmol, 1.2 equiv)
in toluene (2 mL), triethylamine (56 L, 0.4 mmol, 2 equiv)
was added under a nitrogen atmosphere. The mixture was
stirred for 5 min at room temperature, and the resulting
solution was then heated to 50 °C for 6 h (the reaction
progress was monitored by TLC). After cooling to room
temperature, the reaction was quenched by adding 5%
aqueous ammonia solution (4 mL). The aqueous layer was
extracted thrice with 20 mL of dichloromethane and the

Tetrahedron Letters
combined organic extracts were dried with anhydrous sodium
sulfate. The organic solvents were then evaporated under
reduced pressure, and the residue was purified by flash
column chromatography on silica gel (eluent: n-hexane/ethyl
acetate = 1/1) to obtain pure N-phenyl benzimidazole 3aa
(38.5 mg, 0.198 mmol) in 99% yield.
27. The reactive diaryliodonium(III) salts having electron-
deficient aryl moiety are known to smoothly react with many
types of nucleophiles under the catalyst-free conditions
without any problem in the aryl-transfer selectivity (see Fig. 1
and ref. 18). Thus, this study would focus on the TMP-
iodonium(III) salts 2a–f that do not bear an electron-
withdrawing aryl group.
28. A pure sample compatible for the X-ray crystallographic
analysis was obtained by recrystallization from a
dichloromethane-hexane solution of phenyl(2,4,6-
trimethoxyphenyl)iodonium(III) acetate. For the
crystallographic data in CIF, please see CCDC: 1555121.

Tetrahedron Letters
Highlights:
Efficient aryl amination of azole compounds
Coupling reaction employing reactive pseudo-halide
TMP-iodonium(III) for reactive/selective aryl-
transfer