Novel and efficient oxidative biaryl coupling reaction of alkylarenes using a hypervalent iodine(III) reagent

Article abstract of DOI:10.1016/S0040-4039(02)02150-0

First facile and efficient oxidative coupling reaction of alkylarenes leading to alkylbiaryls using a combination of hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA), and BF₃·Et₂O has been developed.

Full text of DOI:10.1016/S0040-4039(02)02150-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9241–9244
Novel and efficient oxidative biaryl coupling reaction of
alkylarenes using a hypervalent iodine(III) reagent
Hirofumi Tohma, Minako Iwata, Tomohiro Maegawa and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 13 September 2002; revised 27 September 2002; accepted 30 September 2002
Abstract—First facile and efficient oxidative coupling reaction of alkylarenes leading to alkylbiaryls using a combination of
hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA), and BF3·Et2O has been developed. © 2002 Elsevier
Science Ltd. All rights reserved.
Biaryl compounds serve as key structures of bioactive
natural products and chiral ligands for asymmetric
reactions, and as precursors for electroconductive mate-
rials due to their interesting properties.1 This makes
these compounds attractive synthetic targets. A direct
and efficient route to biaryl compounds is via oxidative
electron transfer of arenes. Several methods for oxida-
tive biaryl coupling of phenol derivatives using toxic
heavy metal oxidants2 such as PbIV, TlIII, VV, RuIV,
MoV and FeIII salts, which often require vigorous reac-
tion conditions, and anodic oxidation reactions3 have
been reported thus far. Over this decade, use of hyper-
valent iodine(III) reagents4 has gained importance as a
safe alternative to heavy metal reagents for performing
a variety of organic transformations. In our continuous
studies on hypervalent iodine chemistry,5,7d we have
recently developed mild and high yielding biphenyl
coupling reactions of phenol ether derivatives via aro-
matic cation radical intermediates6 using a combination
of either phenyliodine(III) bis(trifluoroacetate) (PIFA)
and BF3·Et2O7 or PIFA and heteropolyacid (HPA).8 As
a new stage of our studies on biaryl synthesis, we report
herein the first facile and efficient oxidative coupling
reaction of alkylarenes, which are less electron-rich
than phenol ether derivatives, using PIFA–BF3·Et2O.
tions are limited examples of anodic oxidation
reactions.3 Such results may be due to at least three
major reactions that have been identified in the oxida-
tion of alkylbenzene derivatives by metal oxidants
(MXn): namely (a) aromatic-nuclear substitution; (b)
biaryl coupling, and (c) side-chain substitution (Scheme
1).
These side reactions as well as higher oxidation
potentials10 of alkylarenes compared to phenol deriva-
tives have prevented the practical utility of oxidative
coupling leading to alkylbiaryls.
Therefore, preparative methods for alkylarene dimers
have been limited to metal-catalyzed coupling
reactions1 such as Ullmann, Suzuki, Heck, Stille, and
Negishi reactions via halogenated and/or other func-
tionalized alkylarenes. Despite their utility, these meth-
ods have several drawbacks in their yields of
multi-substituted alkylbiaryls, especially in the prepara-
tion of tetra-ortho-substituted biaryls, except for a few
successful examples.11 In addition, they generally also
require highly reactive organometallic reagents in the
preparation of nucleophilic compounds (i.e. boronic or
tin derivatives).
In contrast to biaryl syntheses from phenols and phenol
ether derivatives, oxidation of alkylarenes often gave
low to moderate yields of biaryls along with some
unsatisfactory byproducts when using the typical oxi-
dants such as heavy metal salts and nitric acid.9 Excep-
Scheme 1. Oxidation of alkylarenes with metal oxidants
* Corresponding author. Tel.: +81-6-6879-8225; fax: +81-6-6879-8229;
e-mail: kita@phs.osaka-u.ac.jp
(MXn).
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02150-0

9242
H. Tohma et al. / Tetrahedron Letters 43 (2002) 9241–9244
Table 1. Oxidative biaryl coupling of mesitylene (1a) with
In order to develop a facile and efficient synthesis of
biaryls directly from alkylarenes (type (b) reaction), we
examined PIFA-induced oxidative coupling reaction of
mesitylene (1a) under various reaction conditions.12
Consequently, 2,2%,4,4%,6,6%-hexamethylbiphenyl (2a)
was the major product when using PIFA–BF3·Et2O
(Table 1), a reagent which we have previously devel-
oped for biaryl synthesis from phenol ethers. On the
other hand, no reaction occurred either in the absence
of additives or in the presence of heteropolyacid,
H3[PW12O40], and complex mixtures involving 3 and 4
but not 2a were obtained when the reactions were
carried out in (CF3)2CHOH or CF3CO2H.
PIFA
Entry
Temp. (°C)
Conc. PIFA (M)
Yielda (%)
1
2
3
4
5
6
7
rt
0.05
0.05
0.05
0.05
0.02
0.4
6b
0
8b
−40
−78
−78
−78
−78
52
70
45
94
0.4
No reactionc
a Yields are based on GC analyses with n-tetradecane as the internal
standard. Yields are based on consumed PIFA.
b ca. 1 equiv. of 1a was recovered. 3 and 4 were also obtained.
c In the presence of galvinoxyl.
Table 2. Oxidative biaryl coupling of alkylarene (1) with PIFA–BF3·Et2O
Entry
Substrate
R1
R2
R3
R4
R5
Reaction time (h)
Product
Yield (%)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
Et
H
H
H
H
Me
Me
Me
Me
Et
Me
Me
Me
H
H
H
H
H
H
Me
Me
Me
Et
H
I
H
6
6
3
6
6
6
6
2a
2b
2c
2d
2e
5a
2f+5b
90
74
Me
Me
Me
Me
Me
75b
84
64c
Me
Me
46
20 (2f)
43 (5b)
1g
Me
R6
R7
R8
8
9
10
11
12
1h
1i
1j
1k
1l
Me
Et
H
H
H
Me
H
H
H
H
H
6
4
4
3
3
2g
2h
2i
2j
2k
82
89
80
94
96
nBu
Me
Me
Me
a Isolated yields.
b 10 equiv. of 1c was used at −40°C.
c 10 equiv. of 1e was used at 0°C.

H. Tohma et al. / Tetrahedron Letters 43 (2002) 9241–9244
9243
A plausible reaction mechanism is shown in Scheme 2.
Cation radical A is initially formed from 1, then a
second molecule of 1 attacks A under the reaction
conditions in a manner analogous to those of our
previously developed PIFA-induced reactions6–8 or typ-
ical heavy metal oxidations9 yielding aromatic cation
radicals. Formation of A was supported by effective
inhibition of the reaction of 1a to form A in the
presence of galvinoxyl, which is an efficient radical
scavenger (entry 7, Table 1).
Furthermore, a cation radical of 1g,9g which was
formed by mixing PIFA and 1g in CH2Cl2 at −20°Cꢀ
0°C in the presence of BF3·Et2O after degassing, was
detected by electron spin resonance (ESR) spectroscopy
(Chart 1).
Scheme 2. Plausible reaction mechanism.
On the other hand, in the reactions of durene (1f) or
pentamethylbenzene (1g) with PIFA, nucleophilic
attack of a second molecule of 1f or 1g yielded diaryl-
methane 5 as the major product. Product 5 will be
formed via benzylic cation B rather than via the more
unstable cation radical A.
In conclusion, we have developed a novel and efficient
non-metallic oxidative biaryl coupling reaction of alkyl-
arenes using PIFA–BF3·Et2O under mild reaction con-
ditions. This methodology provides a facile and direct
route to alkylbiaryl compounds without introducing
any directing groups into alkylarenes before the cou-
pling reaction. Further optimization and application of
this reaction to the syntheses of various biaryls and
oligoaryls that may have utility as artificial bioactive
molecules and electroconductive materials are now
underway.
Chart 1. ESR spectra of cation radical of 1g generated by
PIFA–BF3·Et2O.
After improving the reaction conditions (temperature
and the concentration of PIFA), we finally obtained 2a
in 94% yield (GC) with perfect control of the possible
side reactions (entry 6, Table 1).
Typical experimental procedure is as follows: BF3·Et2O
(2.0 mmol) and PIFA (1.0 mmol) were added sequen-
tially to a stirred solution of alkylbenzene or alkylnaph-
thalene (1) (2.0 mmol) in CH2Cl2 (2.5 mL) at −78°C
under a nitrogen atmosphere. The mixture was stirred
for 6h under the same reaction conditions. Aqueous
work-up with saturated NaHCO3 at 0°C followed by
column chromatography (SiO2/n-hexane) gave the cor-
responding biphenyl or binaphthyl compound 2.
Acknowledgements
This work was financially supported by the Grant-in-
Aid for Scientific Research (S) (No. 13853010) and for
encouragement of Young Scientists (No. 13771331)
from the Ministry of Education, Science, Sports and
Culture, Japan. H.T. also thanks the Hoh-ansha Foun-
dation for a research fellowship.
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This reaction was applicable to various alkylbiphenyl
and binaphthyl syntheses. The results are summarized
in Table 2. Although oxidation of inactive monoalkyl-
benzenes such as toluene and t-butylbenzene did not
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mesitylene (1a), triethylbenzene (1b), xylene (1c), and
alkylnaphthalenes (1h–l) with PIFA–BF3·Et2O pro-
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