Triphyrin catalyzed direct C-H arylation of benzene with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2014.09.043

Transition-metal free direct C-H arylation of benzene with aryl halides was achieved by meso-aryl-substituted [14]triphyrins(2.1.1) catalysts in an air atmosphere. Various aryl halides underwent successful direct C-H arylation of benzene to give moderate to high yields of biaryls. A radical mechanism is proposed for this triphyrin catalyzed C-H arylation reaction.

Full text of DOI:10.1016/j.tetlet.2014.09.043

Tetrahedron Letters 55 (2014) 6180–6183
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Tetrahedron Letters
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Triphyrin catalyzed direct C–H arylation of benzene with aryl halides
Zhao-Li Xue a, Ying Ying Qian b, Kin Shing Chan b,
⇑
a School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, People’s Republic of China
b Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2014
Revised 22 August 2014
Accepted 9 September 2014
Available online 16 September 2014
Transition-metal free direct C–H arylation of benzene with aryl halides was achieved by meso-aryl-
substituted [14]triphyrins(2.1.1) catalysts in an air atmosphere. Various aryl halides underwent
successful direct C–H arylation of benzene to give moderate to high yields of biaryls. A radical mechanism
is proposed for this triphyrin catalyzed C–H arylation reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C–H arylation
Triphyrin
Biaryl synthesis
Organocatalyst
Benzene derivatives
H
N
Me
Me
N
Biaryl subunit is a key skeleton in many biologically active phar-
maceuticals, such as valsartan and losartan (Fig. 1).1 Cross-coupling
reaction is one of the most important methods in biaryl formation.2
In the past century, various metal containing catalysts were used for
the biaryl synthesis.2 First, the homo-coupling of aryl halides uses
copper(I) salt as a stoichiometric reagent.3 After the first discovery
of homo-coupling reactions, palladium catalysts were widely used
in Kumada,4 Negishi,5 Suzuki,6 Stille,7 and Hiyama8 type coupling
reactions. In order to avoid the use of expensive palladium, first
row transition metal catalysts, such as iron,9 cobalt,10 nickel,11
and copper,12 have been used in cross-coupling reactions.
However, the removal of metal or organometallic complexes
from pharmaceuticals is essential and usually takes a lot of efforts
and expenses.13 To avoid the transition metal contamination prob-
lem of pharmaceuticals from the origin, organocatalysts have
attracted much attention. The first metal-free cross-coupling reac-
tion was reported by Itami on potassium tert-butoxide mediated
C–H arylation.14 However, aryl halides can only couple with elec-
tron-deficient nitrogen containing heterocycles. After the initial
report, various organocatalysts were discovered to expand the sub-
strate scope and increase the catalytic efficiency, such as DMEDA,15
phenanthroline,16 quinoline-1-amino-2-carboxylic acid,17 porphy-
rin,18 amino acid,19 or ethylene glycol.20 However, most of them
require stoichiometric amount of tBuOK and high loadings of cata-
lysts (more than 10 mol %).
N
N
N
Cl
OH
N
HN
N
HO2C
N
N
N
O
nBu
(a) Valsartan
nBu
(b) Losartan
Figure 1. Structure of (a) valsartan and (b) losartan.
[14]Triphyrins(2.1.1)21 (trip) is a new kind of contracted porphy-
rins which has a tripyrrolic framework with four meso-carbon
atoms. Trip is closely related to tribenzotriphyrin but carries a
(2.1.1) bridge pattern. It is an aromatic compound having an
[14]annulenic circuit and exhibits a characteristic optical property,
in which the absorption maxima at the longest wavelength appears
in the region close to 600 nm. It is the first example of boron-free
ring contracted porphyrins.22
Herein, we report the successful direct C–H arylation of benzene
with aryl halides catalyzed by a low loading of meso-aryl-substi-
tuted [14]triphyrins(2.1.1)21 (Fig. 2) (down to 1 mol %) and KOH.
Direct C–H arylation of benzene with 4-iodotoluene was first
achieved with 5 mol % of H(trip), 5 equiv of KOH, and 10 equiv of
tBuOH at 200 °C in 2 h in air to give 83% yield of 4-methylbiphenyl
(2a) (Table 1, entry 1). Lowering the catalyst loading to 1 mol %
gave similar product yield in 3 h (Table 1, entry 2). Reducing the
KOH loading to 5 equiv gave 95% yield of 2a in 8 h (Table 1, entry
3). Incomplete conversion was observed with 2 equiv of KOH after
3 days (Table 1, entry 4). With 1 mol % of H(trip) and 5 equiv of
⇑
Corresponding author. Tel.: +852 39436376; fax: +852 26035057.
E-mail address: ksc@cuhk.edu.hk (K.S. Chan).
http://dx.doi.org/10.1016/j.tetlet.2014.09.043
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Z.-L. Xue et al. / Tetrahedron Letters 55 (2014) 6180–6183
6181
Table 2
Catalyst electronic effect
X
X
NH
catalyst (1 mol%)
KOH (5 equiv)
N
N
tBuOH (10 equiv)
air, dark, 180 oC, time
I
+
1a
2a
100 equv
X
X
H(Me-trip): X = CH3
H(trip): X = H
Entry
Catalyst
Time (h)
Yield 1a (%)a
Yield 2a (%)ab
H(F-trip): X = F
1
2
3
H(Me-trip)
H(trip)
H(F-trip)
16
24
24
/
/
1
83
89
76
Figure 2. General structure of meso-aryl-substituted [14]triphyrins(2.1.1).
a
GC yield.
b
Trace amount of biphenyl was observed by GC–MS.
KOH at 180 °C, the reaction also gave high yield of 2a in 1 day
(Table 1, entry 5). The reaction did not complete after 3 days when
the temperature was lowered to 150 °C (Table 1, entry 7). Both the
reaction rate and yield are similar when the reaction was carried
out in N2 atmosphere (Table 1, entries 5 and 6). Without catalyst,
the reaction is very slow and gave only 22% yield of 2a after 2 days
(Table 1, entry 8). For better functional group compatibility,
1 mol % of H(trip), 5 equiv of KOH, 10 equiv of BuOH, and 180 °C,
in an air atmosphere were used as the optimized and most conve-
nient conditions for further studies.
We then examined the electronic effects of the catalysts. Both
the electron-rich and -deficient triphyrins catalyzed the reaction
successfully with similar rates and yields (Table 2). The electron
rich triphyrin reacted slightly faster with similar yield of 2a.
Various aryl iodides reacted successfully to give biaryls
(Table 3). Electron rich aryl iodides reacted smoothly with benzene
to give moderate to high yields of biaryls (Table 3, entries 1–4). The
sterically hindered 2-iodotoluene also reacted smoothly to give
58% yield of 2-iodobiphenyl (Table 3, entry 4) together with reduc-
tion product of toluene. On the other hand, electron-deficient halo-
substituted aryl iodides underwent cross-coupling twice to give
terphenyl besides biaryl (Table 3, entries 6–10). For the 4-chloro-
iodobenzene, p-terphenyl was isolated as the major product
(Table 3, entry 6). However, due to the stronger Ar–F bond
(125 kcal/mol), 4-fluorobiphenyl was isolated as the major product
for 4-fluoroiodobenzene without C–F cleavage (Table 3, entry 7).23
For 2-fluoroiodobenzene, 2-fluorobiphenyl was obtained as the
major product (Table 3, entry 8). When 2-chloroiodobenzene and
2-bromoiodobenzene were used, both the cleavage of Ar–Cl and
Ar–Br bond occurred together with the Ar–I bond cleavage to give
2-halobiphenyl 2e. O-terphenyl 4 was obtained as the major prod-
uct for both 2-chloroiodobenzene and 2-bromoiodobenzene cases
(Table 3, entries 9 and 10).
To gain more insight of the reaction mechanism, a radical scav-
enger, TEMPO was added to the reaction mixture to test if any rad-
ical intermediate was formed (Eq. 1). Both the reaction rate and
yield decreased significantly, which suggests that radical interme-
diates were involved in the reaction.
Figure 3 shows the proposed mechanism for the H(trip) cata-
lyzed cross-coupling of aryl iodide with benzene. Aryl iodide first
undergoes electron transfer from OHꢀ mediated by H(trip) to give
aryl iodide radical anion. The aryl iodide radical anion then
t
H(trip) (1 mol%)
KOH (5 equiv)
I
tBuOH (10 equiv)
TEMPO (1 equiv)
ð1Þ
(1)
+
air, dark, 180 oC, 3 d
15% (GC)
100 equv
undergoes halogen anion dissociation to give aryl radical. Aryl rad-
ical reacts with benzene through radical addition to give cyclohexa-
dienyl radical intermediate, which gives biaryl radical anion
through deprotonation by base. The biaryl anion radical then trans-
fers an electron to aryl iodide to regenerate aryl iodide anion radical
and biaryl product. When the functional group is halogen, the hal-
ogen-substituted biaryl radical anion can further eliminate a halo-
gen anion to give biaryl radical, which couples with another
benzene to give terphenyl. When the functional group is an ortho-
halogen, the aryl radical can further eliminate the other halogen
to give benzyne, which combines with benzene to give biphenyl.
In conclusion, the direct C–H arylation of benzene with aryl
iodides is successfully catalyzed by 1 mol % of triphyrin to give
the biaryl conveniently in an air atmosphere. A radical mechanism
Table 1
Optimization of direct C–H arylation of benzene with iodotoluene catalyzed by H(trip)
H(trip) (m mol%)
KOH (n equiv)
tBuOH (10 equiv)
air, dark, temp, time
I
+
1a
n (KOH)
2a
100 equiv
Entry
m (H(trip))
Temp °C
Time (h)
Yield 1a (%)a
Yield 2a (%)ab
1
2
3
5
1
1
1
1
1
1
/
10
10
5
2
5
5
5
5
200
200
200
200
180
180
150
180
2
3
8
72
24
24
72
48
2
3
5
20
/
/
43
50
83
80
95
63
89
82
35
22
4
5
6c
7
8
a
b
c
GC yield.
Trace amount of biphenyl was observed by GC–MS.
In N2.

6182
Z.-L. Xue et al. / Tetrahedron Letters 55 (2014) 6180–6183
Table 3
Substrate effect
H(trip) (1 mol%)
I
KOH (5 equiv)
FG
tBuOH (10 equiv)
air, dark, 180 oC, 1 d
FG
+
+
+
+
100 equiv
2
2e
4
1
3
Entry
FG
Yield 2 (%)d
Yield 2e (%)e
Yield 3 (%)d
Yield 4 (%)d
1
2
p-OMe
p-Me
m-Me
o-Me
H
p-Cl
p-F
o-F
2b (64)
2a (82)
2c (68)
2d (58)
2e (87)
2f (<5)
2g (60)
2h (45)
2i (12)
2j (8)
<1
<1
<1
10
/
/
/
/
/
/
/
/
/
/
/
20
60
60
3
4a
5
/
6
7
8
14
/
8
21
19
70
16
/
/
/
9b
10c
o-Cl
o-Br
a
Toluene was observed by GC–MS in 28% yield.
2-Iodobiphenyl (2k) was isolated in 9% yield. Trace amount of iodobenzene and chlorobenzene was observed by GC–MS.
2-Iodobiphenyl (2k) was isolated in 11% yield. Trace amount of iodobenzene and bromobenzene was observed by GC–MS.
Isolated yield.
GC yield.
b
c
d
e
FG
I
-
OH
TriP
FG
FG
I
-
I
FG
I
FG
FG = o-X
FG
FG = X
-X
-
- X
or
Ph
Ph
-
H2O
FG
OH-
H
Figure 3. Proposed mechanism for TriP catalyzed cross-coupling reactions.
is proposed for this triphyrin catalyzed reaction. For dihalobenz-
enes, they can undergo coupling reaction twice to give terphenyl
even for the Ar–F bond. Studies of their organocatalysts and their
mechanistic roles are ongoing.
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
043.
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