Catalytic C-H arylation of unactivated heteroaromatics with aryl halides by cobalt porphyrin

Article abstract of DOI:10.1016/j.tetlet.2012.01.051

Direct C-H arylation of unactivated heteroaromatics with aryl halides catalyzed by cobalt porphyrin is reported. The reaction is proposed to go through a homolytic aromatic substitution reaction. The aryl radical is electrophilic and a SOMO-HOMO interaction is predominant in the aryl radical addition process.

Full text of DOI:10.1016/j.tetlet.2012.01.051

Tetrahedron Letters 53 (2012) 1571–1575
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic C–H arylation of unactivated heteroaromatics with aryl halides
by cobalt porphyrin
⇑
Ying Ying Qian, Ka Lai Wong, Meng Wen Zhang, Tsz Yiu Kwok, Ching Tat To, Kin Shing Chan
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:
Direct C–H arylation of unactivated heteroaromatics with aryl halides catalyzed by cobalt porphyrin is
reported. The reaction is proposed to go through a homolytic aromatic substitution reaction. The aryl rad-
ical is electrophilic and a SOMO–HOMO interaction is predominant in the aryl radical addition process.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 18 November 2011
Revised 30 December 2011
Accepted 13 January 2012
Available online 21 January 2012
Keywords:
C–H arylation
Cobalt porphyrin
Heteroaromatics
Heterobiaryl
Heterobiaryls are very important structural motifs as they are
commonly found in drugs, natural products, and optoelectronic
user-friendly and cost-effective. However, cobalt remains less-ex-
plored as a catalyst for the direct C–H arylation of heteroaromatics.
Recently, we have reported the cobalt(II) porphyrin-catalyzed di-
1
materials. 2-Acylhydrazino-5-arylpyrrole derivatives are used as
2
12
antifungal reagents against Candidae (Fig. 1a). The potential HIV-
rect C–H arylation of unactivated arenes with aryl halides. The
3
integrase inhibitor is constituted of an arylfuran moiety (Fig. 1b).
reaction mechanism was proposed to proceed through a homolytic
aromatic substitution followed by hydrogen atom abstraction to
give the corresponding biaryls. However, the electronic influence
on the homolytic aromatic substitution process remains unclear.
This led us to turn our attention to both electron rich and poor
heteroaromatics, for investigation of the electronic effect of aryl
radical addition onto the heteroaromatics and the synthesis utility.
Herein, we report the successful direct C–H arylation of heteroaro-
matics with aryl halides to give the heterobiaryls. Electron rich
heteroaromatics reacted faster suggesting the importance of the
electrophilic aryl radical in homolytic aromatic substitution.
2
-Arylpyrrole is the precursor of a potential anti-inflammatory
4
and analgesic agent 5-aryl-1,2-dihydro-1-pyrrolizinones. There-
fore, facile and convenient syntheses of heterobiaryls are attractive.
Transition metal catalysts have been widely used in cross-
coupling reactions to construct heterobiaryls.5
–10
Heterobiaryls
were first synthesized from heteroarylsilanes and aryl halides with
a stoichiometric use of copper(I) salt.5 2- and 3-arylfurans have
been prepared by the nickel-catalyzed cross-coupling of 2- and
6
3
-halofurans with aryl Grignard reagents. Later, heterobiaryls syn-
7
8
thesized by the palladium-catalyzed Kumada, Suzuki–Miyaura,
Stille9 and Hiyama cross-couplings have also been reported.
However, palladium catalysts and preactivation of heteroaromatics
are required in most of the works.
,1d
10
Both p-excessive pyrrole and furan underwent successful direct
C–H arylation with aryl halides (Table 1). In the presence of a cata-
II
lytic amount of Co (tap) (tap = tetrakis-4-anisylporphyrinato dian-
t
Utilization of cheap and more abundant transition metal com-
plex as a catalyst for the direct C–H arylation is attractive. Recently,
ion) (5 mol %), together with KOH (10 equiv) and BuOH (10 equiv),
4-iodotoluene (1 equiv) was successfully coupled with pyrrole
1
st row transition metal catalysts have gained much attention in
cross-coupling reactions. They are much cheaper and less toxic,
1
a,c,5
such as Fe and Ni.
On the other hand, the direct C–H arylation
R
OH
of heteroaromatics with aryl halides have been achieved in some
heterocycles, such as oxazoles, 1,2,3-triazoles, and indoles. Direct
C–H arylation avoids preactivation of heteroaromatics, which is
HO2C
HO
O
1
1
H
N
R
Ar
N
H
N
H
O
F
a
b
⇑
Corresponding author. Tel.: +852 39436376; fax: +852 26035057.
E-mail address: ksc@cuhk.edu.hk (K.S. Chan).
Figure 1. (a) Structure of 2-acylhydrazino-5-arylpyrrole derivatives; (b) structure
of HIV-integrase inhibitor candidate.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.051

1
572
Y. Y. Qian et al. / Tetrahedron Letters 53 (2012) 1571–1575
Table 1
Cobalt-catalyzed arylation of pyrrole and furan with 4-halotoluenes
II
5
mol% Co (tap)
1
0 equiv KOH
10 equiv BuOH
t
Y
Y
X
+
N , dark, 200 oC, time
2
100 equiv
1a, 2a
X = I, Br
Y = NH, O
Entry
Aryl halide
Solvent
Time (min)
Product
Yield (%)
74
H
N
H
N
I
1
2
15
30
1
2
a
a
Br
I
52
O
O
3
4
60
60
62
42
Br
Table 2
Cobalt-catalyzed arylation of pyrrole and furan with aryl iodides
II
5
mol% Co (tap)
1
0 equiv KOH
10 equiv BuOH
t
Y
Y
FG
I
+
FG
N2, dark, 200 oC, time
1
00 equiv
1
b-d
2
b-d
Y = NH, O
Entry
1
Aryl halide
Solvent
Time (min)
30
Product
Yield (%)
54
H
N
H
Cl
I
N
Cl
1
b
1
H
N
I
2
3
30
30
69
66
1
c
H
MeO
I
N
MeO
Cl
d
O
O
Cl
I
4
5
6
60
60
60
49
52
62
2
b
O
I
2
c
O
MeO
I
MeO
2
d
(
100 equiv) at 200 °C under N
2
to give a 74% yield of 2-(4-methyl-
higher reactivity. The Ar–halogen bond cleavage is likely the
rate-limiting step.
phenyl)pyrrole 1a in only 15 min (Table 1, entry 1). When furan
was used instead of pyrrole, a longer reaction time of 1 h was
required for completion (Table 1, entry 3).
Arylbromides reacted slower than aryliodides (Table 1). 4-Bro-
motoluene reacted with pyrrole and furan to give the correspond-
ing coupling products 1a and 2a in 52% and 42% yields,
respectively. However, the reaction took longer time and gave low-
er yields of the products. The weaker carbon–iodine bond
The direct C–H arylation is general for both electron rich and
electron deficient aryl iodides. Pyrrole and furan reacted with
electronically different 4-chloroiodobenzene, iodobenzene, and
4-iodoanisole to give the corresponding coupling products in good
yields in similar time (Table 2, entries 1–6). Therefore, the elec-
tronic effect of aryl radicals is not significant in this reaction
2
system. This agrees well with the orthogonal nature of the sp rad-
1
3
(
65.0 kcal/mol) of 4-iodotoluene compared with the carbon–bro-
ical orbital to the delocalized
p
system in an aryl radical rendering
13
mine bond (80.4 kcal/mol) in 4-bromotoluene accounts for the
the inductive effect through
r-bond insignificant.

Y. Y. Qian et al. / Tetrahedron Letters 53 (2012) 1571–1575
1573
The direct C–H arylation of pyrrole and furan was highly regio-
selective to give 2-arylheteroaromatics and highly chemoselective
orbital interaction between phenyl radical and heteroaromatics is
considered. For approximation, the ionization energy (I.E.) corre-
sponds to the negative energy of the highest occupied molecular
1
4
as no N–H atom abstraction or N-arylation was observed.
However, when -excessive thiophene and -deficient pyridine
1
6
p
p
orbital (HOMO), and the electron affinity (E.A.) corresponds to
the negative energy of the lowest unoccupied molecular orbital
were examined, it is surprising that the arylation of thiophene and
pyridine are not regioselective. For thiophene, both 2- and 3-ary-
lated thiophene were obtained in a 3:1 ratio (Eq. (1)). While for
pyridine, the ortho, meta, para selectivities follow closely with
the statistical ratio (Eq. 2).15
The regioselectivity of the arylation can be rationalized using
the stability of the 2- and 3-arylheterocyclic radical intermediates.
There are more resonance structures associated with 2-arylhetero-
cyclic radical intermediate than 3-arylheterocyclic one (Fig. 2).
However, in the case of thiophene, the S atom expands the valance
to d orbital. Thus both 2- and 3-arylthiophenium radical interme-
diates are stabilized by resonance without a large difference.
Therefore, 3-arylthiophene is formed as well.
1
7
(LUMO). The energy of the singly occupied molecular orbital
(SOMO) correlates with the I.E. of the phenyl radical. Table 4 shows
the SOMO–HOMO energy level differences are much smaller than
the SOMO–LUMO energy level differences. Thus the SOMO–HOMO
interaction dominates the reactivity. The product ratio per C–H
bond against the SOMO–HOMO energy level difference is shown
in Figure 3. The linear correlation of increasing reactivity with
the smaller SOMO–HOMO energy level difference further supports
the SOMO–HOMO interaction in the aryl radical addition process,
2
0
and the aryl radicals are therefore electrophilic.
Based on the above data, the mechanism proposed for the direct
C–H arylation of heteroaromatics is shown in Figure 4. First, the
II
5
mol% Co (tap)
1
0 equiv KOH
t
S
S
S
10 equiv BuOH
:
I
+
o
N , dark, 200 C, 10 h
2
ð1Þ
3
:
1
100 equiv
3
a
3a'
total yield : 59%
N
II
5
1
1
mol% Co (tap)
0 equiv KOH
0 equiv BuOH
N
t
I
+
o
N , dark, 200 C, 6 h
2
ð2Þ
100 equiv
o m p
: : = 2.4 : 2 : 1
4a
total yield : 46%
In order to investigate the nature of the homolytic aromatic
substitution, competition arylation reactions with an equimolar
mixture of heteroaromatic and benzene were carried out (Table
aryl radical is generated by a carbon halogen bond cleavage with
Co (tap). The aryl radical then adds to the heteroaromatics to give
II
the heteroaryl radical intermediate. The radical intermediate is
2
1
3). The aryl radicals reacted faster with substrates electron richer
then deprotonated with a tert-butoxide or a hydroxide anion to
give the heteroaryl radical anion. Then, intermolecular dissociative
electron transfer from the heteroaryl radical anion to the starting
aryl halide furnishes aromatization and completes the chain.22
Curran and co-workers recently proposed that an oxygen molecule
than benzene. This suggests that the aryl radicals are electrophilic.
To gain a more quantitative understanding on the reactivities of
heteroaromatics on heterobiaryl formation, the frontier molecular
2
3
is a radical chain carrier for aromatization of the intermediate A.
Y
Y
Y
II
Ar
Ar
Ar
However, this Co (tap)-catalyzed direct C–H arylation of hetero-
aromatics was much slower under air than under N and required
2
a longer reaction time of 1 h. Thus, oxygen did not facilitate the
aromatization in this reaction system. Moreover, a base is essential
for the reaction supporting the deprotonation step in the mecha-
Y = S only
2
-arylheterocyclic radical intermediate
2
4
III
nism. For the cobalt complex part, Co (tap)X undergoes ligand
III
Y
Y
substitution with KOH to give Co (tap)OH, which rapidly regener-
II
25
ates Co (tap) and H
2
O
2
.
2 2
H O then quickly decomposes to give
2
6
water and oxygen by base.
Ar
Ar
Y = S only
In summary, a convenient method of preparing heterobiaryls by
direct C–H arylation of heteroaromatics with aryl halides catalyzed
by cobalt(II) porphyrin was successfully demonstrated. The SOMO–
HOMO interaction is dominant in the aryl radical addition process,
which suggests that the aryl radicals are electrophilic.
3
-arylheterocyclic radical intermediate
Figure 2. Resonance structures of 2- and 3-arylheterocyclic radical intermediates
Y = NH, O, S).
(

1
574
Y. Y. Qian et al. / Tetrahedron Letters 53 (2012) 1571–1575
Table 3
Competition reaction between heteroaromatics and benzene
II
5
mol% Co (tap)
1
0 equiv KOH
10 equiv BuOH
Y
t
Y
I +
+
+
n
N , dark, 200 oC, 10 h
n
2
50 equiv
50 equiv
1a - 4a
5
n = 1, 2
Y = NH, O, S, N
Entry
1
Heteroaromatics
Product ratio (1a–4a:5)
Product ratio per C–H bond
6.00
Total yield (%)
40
H
N
4.00:1.00
O
S
N
2
3
2.30:1.00
1.65:1.00
3.45
2.48
63
69
4
0.55:1.00
0.66
33
Table 4
SOMO–HOMO and SOMO–LUMO energy level differences between phenyl radical and heteroaromatics
Entry
Heteroaromatics
I.E. (eV)18
E.A. (eV)19
SOMO–HOMO energy level difference (eV)
SOMO–LUMO energy level difference (eV)
/
1
8.32
1.10
/
H
N
2
8.27
ꢀ2.38
0.05
10.61
O
S
N
3
4
8.81
8.86
ꢀ1.76
ꢀ1.17
0.49
0.54
10.08
9.49
5
9.26
ꢀ0.62
0.94
8.94
Figure 3. Product ratio per C–H bond against SOMO–HOMO energy level difference.

Y. Y. Qian et al. / Tetrahedron Letters 53 (2012) 1571–1575
1575
Y
Ar
X-
KOH
+
H O
H O + 1/2 O
2 2
2
2
n
ArX
-
II
Co (tap)
Ar
Y
III
Co (tap)OH
ArX
n
KX
t
H O / BuOH
III
2
Co (tap)X
-
t
-
Ar
KOH
OH / BuO
Ar
H
Y
X = I, Br
n
Y
n
n = 1, 2
A
Y = NH, O, S, N
Figure 4. Proposed reaction mechanism.
Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787–1789; (c) Raheem, M. A.;
Nagireddy, J. R.; Durham, R.; Tam, W. Synth. Commun. 2010, 40, 2138–2146.
. Lee, D. H.; Taher, A.; Ahn, W. S.; Jin, M. J. Chem. Commun. 2010, 46, 478–480.
10. Lee, D. H.; Jung, J. Y.; Jin, M. J. Chem. Commun. 2010, 46, 9046–9048.
11. (a) Besselièvre, F.; Lebrequier, S.; Mahuteau-Betzer, F.; Piguel, S. Synthesis 2009,
Acknowledgment
9
We thank the Research Grants Council (No. 400308) of the
HKSAR, the People’s Republic of China for the financial support.
3
7
511–3512; (b) Verrier, C.; Martin, T.; Hoarau, C.; Marsais, F. J. Org. Chem. 2008,
3, 7383–7386; (c) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V.
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4
5
922–4925; (e) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529–
535; (f) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428–7431.
Supplementary data (including experimental procedures, 1
NMR spectra, characterization of products) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2012.01.051.
H
12. To, C. T.; Chan, T. L.; Li, B. Z.; Hui, Y. Y.; Kwok, T. Y.; Lam, S. Y.; Chan, K. S.
Tetrahedron Lett. 2011, 52, 1023–1026.
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toluene was observed by GC–MS.
1
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