Communications
DOI: 10.1002/anie.200907281
Aromatic Substitution
Unusual ipso Substitution of Diaryliodonium Bromides Initiated by a
Single-Electron-Transfer Oxidizing Process**
Toshifumi Dohi, Motoki Ito, Nobutaka Yamaoka, Koji Morimoto, Hiromichi Fujioka, and
Yasuyuki Kita*
The diaryliodonium salts Ar1I+Ar2Xꢀ, which have two aryl
groups bound to an iodine atom as a ligand, represent one of
the most popular classes of hypervalent iodine compounds[1]
and they have application as important arylating agents in
organic synthesis.[2] In general, the aryla-
Herein, we report a unique single-electron-transfer (SET)
oxidizing strategy using diaryliodonium salts as selective
heteroaryl transfer agents during ipso substitution. Recently,
ꢀ
our research group has reported a metal-free C H coupling
method of thiophenes and aromatic compounds using iodo-
nium salts.[8] The method, using TMSBr in hexafluoroisopro-
panol (HFIP), is useful for the coupling reaction of the
thiophene iodonium salts and introduces aromatic nucleo-
philes to the g positions of the iodine(III)–carbon bonds
[Eq. (1)]. However, this reaction is not suitable for coupling
through the ipso substitution of the thiophene iodonium salts
1a-X [X = OTs, Br; Eq. (2)].
tion of nucleophiles with these iodonium
salts is assumed to involve the tricoordi-
nated intermediate A before the final
ligand-coupling (LC) steps.[3] Owing to
the competition of the two LC pathways
of Ar1 and Nu (LCAr1) or Ar2 and Nu
(LCAr2) at the iodine atoms in the inter-
mediates, a mixture of two types of
1
2
ꢀ
ꢀ
arylated products, Ar Nu and Nu Ar , are potentially
obtained in the unsymmetrical salts (Ar1 ¼ Ar2) during the
aromatic substitution. Previous studies have revealed that the
product produced from these pathways should be effected by
both electronic and steric factors exerted by the two differ-
ential aryl rings of the initial salts—where the nucleophiles
would preferentially react with a relatively electron-deficient
aryl ring and/or sterically congested ipso carbon atom (i.e. the
so-called “ortho effect”).[4] Therefore, the introduction of
nucleophiles to an electron-rich heteroaromatic ring is known
to be particularly difficult through typical thermal LC
processes, which involve the collapse of the intermediate
A.[5–7] Despite their rich chemistry, the utility of diaryliodo-
nium salts as a heteroaryl transfer agent in LC processes has
been somewhat limited.
To overcome this drawback, screening was undertaken to
find a suitable acid additive that accelerated the reaction by
activating the thiophene iodonium salt 1a using the modified
reaction conditions shown in Table 1. Among the general
acids and typical silicon- and boron-based Lewis acids we
examined (Table 1, entries 2–5),[9] the yield of 3aa was
significantly enhanced when TMSOTf was added (Table 1,
entry 3). Similarly, a Brønsted acid (TfOH) performed as a
good catalyst for the present ipso-substitution process
(Table 1, entry 6). Other additives, such as trifluoroacetic
acid and other analogous superacids (i.e. HNTf2), did not
improve the yield of 3aa. The aromatic nucleophile 2a did not
react with 1a under the reported conditions. Moreover, other
general methods for activating iodonium salts with transition
metals were unsuccessful.[10] Pleasingly, our method permitted
the formation of the ipso-substitution product of the hetero-
aryl ring. Further optimization using TMSOTf as the acid
additive[11] led to a dramatic improvement in the yield of 3aa
(74%; Table 1, entries 7 and 8). The major by-product was
2,3-dimethylthiophene after formal protonolysis.
[*] Dr. T. Dohi, N. Yamaoka, Dr. K. Morimoto, Prof. Dr. Y. Kita
College of Pharmaceutical Sciences
Ritsumeikan University, 1-1-1 Nojihigashi
Kusatsu, Shiga 525-8577 (Japan)
Fax: (+81)77-561-5829
E-mail: kita@ph.ritsumei.ac.jp
Dr. T. Dohi, M. Ito, Prof. Dr. H. Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1–6
Yamada-oka, Suita, Osaka 565-0871 (Japan)
[**] This work was supported by Grants-in-Aid for Scientific Research (A)
from the Japan Society for the Promotion of Science (JSPS), Grants-
in-Aid for Young Scientists (B) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), and the Ritsu-
meikan Global Innovation Research Organization (R-GIRO) project.
T.D. acknowledges support from the Industrial Technology Research
Grant Program from the New Energy and Industrial Technology
Development Organization (NEDO) of Japan. M.I. acknowledges a
Research Fellowship for Young Scientists from JSPS.
The unique and selective ipso substitution at the hetero-
aryl ring is a general phenomenon of thienyliodonium
Supporting information for this article is available on the WWW
3334
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 3334 –3337