Bis(triarylmethylium)-mediated diaryl ether synthesis: Oxidative arylation of phenols with N,N-dialkyl-4-phenylthioanilines

Article abstract of DOI:10.1021/ja051839n

Various aryl 4-dialkylaminophenyl ethers were readily synthesized without heating in good yield from phenols and N,N-dialkyl-4-phenylthioanilines. This oxidative arylation of phenols was successfully promoted by a bis(diphenylmethylium)naphthalenediyl dication via ipso-substitution of the phenylthio group in the anilines through a radical process. Copyright

Full text of DOI:10.1021/ja051839n

Published on Web 06/16/2005
Bis(triarylmethylium)-Mediated Diaryl Ether Synthesis: Oxidative Arylation of
Phenols with N,N-Dialkyl-4-phenylthioanilines
Terunobu Saitoh and Junji Ichikawa*
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 22, 2005; E-mail: junji@chem.s.u-tokyo.ac.jp
Table 1. Effect of the 4-Substituents of Anilines 3a
Diaryl ethers constitute an important class of compounds in
medicinal and agricultural chemistry, exemplified by the vanco-
mycin family.1 The classical Ullmann ether synthesis, copper(I)-
mediated coupling between phenols and aryl halides, has been
extensively used for the preparation of diaryl ethers;2 however, harsh
reaction conditions at high temperatures for long hours have
severely limited its utility. Recently, several improved methods have
been reported for the Ullmann synthesis that use ionic liquids3 or
catalysts, such as copper-phenanthroline complexes,4 a 1,3-
diketone,5 or an amino acid.6 Moreover, palladium-catalyzed
coupling reactions using electron-rich bulky phosphine ligands7 and
SNAr-based reactions of aryl fluorides2,8 or metal-arene complexes2
have been employed for diaryl ether formation. Despite the
usefulness of these methods, assembling diaryl ethers under mild
reaction conditions still remains a challenge.
entry
Y
3
5a (%)
1
2
3
4
5
6
7b
Br
Cl
F
3a
3b
3c
3d
3e
3f
23
33
no reaction
SnnBu3
SMe
SPh
40
7
68
SPh
3f
93c
a All reactions were performed in the molar ratio of 4a:3a-f:1a )
2:1:1.2. b Molar ratio: 4a:3f:1a ) 1:2:1.1 (see text). c Yield based on 4a.
1,8-Bis(diphenylmethylium)naphthalenediyl 1 was first intro-
-
duced by the group of Gabba¨ı as the BF4 salt,9 and our group
developed an independent synthesis affording the perchlorate salt.10
These dications undergo reduction with an especially high oxidation
potential, compared with those of other dications11 and monotri-
arylmethyliums.12 In this process, a neutral compound, 1,1,2,2-
tetraphenylacenaphthene (2), is formed via C-C bond formation
between the two carbocation centers (Scheme 1).13
ether 5a was produced in 93% yield. For comparison, the arylation
of phenol 4a with 3f was examined by employing DDQ,16 a triaryl-
aminium radical cation,17 or cerium ammonium nitrate (CAN),18
which are widely used as oxidants. While DDQ gave ether 5a in
48% yield, (4-BrC6H4)3N+•SbCl6- and CAN resulted in undesirable
side reactions without forming 5a. Thus, dication 1a is a superior
oxidizing agent in the arylation.
Scheme 1. Reduction of Dications 1
To explore the scope of the oxidative diaryl ether formation,
the reactions of several other phenols with 3f were examined. As
shown in Table 2, 4-substituted phenols (4-methoxy- and 2,4-
dimethylphenols) and sterically hindered phenols (2,6-dimethyl- and
2,4,6-trimethylphenols) underwent the arylation to afford the
corresponding diaryl ethers 5a-d in good yield when treated with
1a and then 3f in MeCN at -40 °C (conditions A) (entries 1 and
4-6). The reaction of halogen-substituted phenols with 3f gave
better yields of 5e-h in CH2Cl2 at -78 °C (conditions B, entries
7-10), compared with conditions A. Even a highly hindered 2,6-
dichlorophenol was transformed to the corresponding ether 5h in
82% yield (entry 10). However, 1- and 2-naphthols gave no
arylation products, probably due to the ease of oxidative self-
coupling.19
Recently, we found that the dications 1 act as an organic two-
electron oxidant in the synthesis of benzidines via self-coupling of
N,N-dialkylanilines.10 Our interest in the oxidizing ability of
dications 1 prompted us to apply the oxidative coupling of N,N-
dialkylanilines to the arylation of phenol oxygens. In this com-
munication, we report an oxidative method using dication 1a for
the synthesis of diaryl ethers from phenols and N,N-dialkyl-4-
phenylthioanilines.14
As an arylation reagent of phenol oxygens, 4-substituted N,N-
diethylanilines 3 were adopted to suppress the self-coupling reaction
at the para position. 4-Methoxyphenol (4a) was chosen as a model
substrate and was treated with 3a-f in the presence of dication 1a
at -40 °C in CH3CN. The results are summarized in Table 1. Aryl
bromide 3a, chloride 3b, and arylstannane 3d gave the desired diaryl
ether 5a along with N,N,N′,N′-tetraethylbenzidine (entries 1, 2, and
4). Although diaryl ether 5a was obtained only in 7% yield in the
reaction with 4-methylthioaniline 3e (entry 5), the yield of 5a was
dramatically improved by using 4-phenylthioaniline 3f up to 68%
yield (entry 6).15 Moreover, when 2.0 molar amounts of 3f were
used and the addition order was changed (conditions A, vide infra),
N,N-Dibenzyl- and N,N-diallylanilines 3g,h could also be
employed as arylation reagents. The corresponding diaryl ethers
5i,j with 4-dibenzylamino and 4-diallylamino groups were obtained
in 69 and 86% yield under conditions B and A, respectively.
Deprotection of the groups on the nitrogen provides an amino group,
which acts as a surrogate for a wide range of functional groups.20
A plausible reaction mechanism for the above-mentioned diaryl
ether synthesis is shown in Scheme 2. Treatment of phenols 4 with
dication 1a generates aryloxyl radicals 6.21 Subsequently added
4-phenylthioaniline 3f is also oxidized by the remaining dication
1a, leading to a stable radical cation 7,22 which traps 6 on the sulfur
atom to afford sulfonium salts 8.23 Successive 1,2-migration of the
9
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J. AM. CHEM. SOC. 2005, 127, 9696-9697
10.1021/ja051839n CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. 4-Dialkylaminophenylations of Various Phenolsa
of radical cation 7. Bis(phenylthio)aniline 10 (32% yield) and 11
(62% yield) were isolated as coproducts in the arylation of 4a (Table
2, entry 1), which supports the two pathways from 9 to 5.
In conclusion, various aryl 4-dialkylaminophenyl ethers were
readily synthesized without heating in good yield from phenols and
N,N-dialkyl-4-phenylthioanilines. This oxidative arylation of phe-
nols was successfully promoted by dication 1a via ipso-substitution
of the phenylthio group in the anilines through a radical process.
Acknowledgment. We thank Prof. K. Narasaka for valuable
discussion, and Prof. H. Nishihara, Dr. M. Murata, and Mr. Y.
Hasegawa for the ESR measurement (The University of Tokyo).
We are grateful to Central Glass Co., Ltd. for financial support.
This work was also supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
Supporting Information Available: Spectroscopic data and ex-
perimental details. This material is available free of charge via the
Internet at http://pubs.acs.org.
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a All reactions were carried out in the molar ratio of 4:1a:3f-h )
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(22) The color of the reaction mixture changed from red to blue upon addition
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