Free porphyrin catalyzed direct C-H arylation of benzene with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2012.05.073

A general procedure for free porphyrin catalyzed direct C-H arylation of benzene was demonstrated. This air tolerant, transition-metal-free process provides a promising system for cheap and efficient synthesis of biaryls in a user-friendly approach.

Full text of DOI:10.1016/j.tetlet.2012.05.073

Tetrahedron Letters 53 (2012) 3911–3914
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Tetrahedron Letters
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Free porphyrin catalyzed direct C–H arylation of benzene with aryl halides
⇑
Yeuk Sze Ng, Chung Sum Chan, Kin Shing Chan
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general procedure for free porphyrin catalyzed direct C–H arylation of benzene was demonstrated. This
air tolerant, transition-metal-free process provides a promising system for cheap and efficient synthesis
of biaryls in a user-friendly approach.
Received 23 March 2012
Revised 10 May 2012
Accepted 15 May 2012
Available online 19 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
C–H arylation
Free porphyrin
Biaryls
Organocatalyst
Biaryl motifs are widely present in a variety of natural products
O
and drugs, such as Diovan and MicardisÒ as hypertension medi-
1
Ò
N
tBu
N
COOH
N
2
,3
cine (Fig. 1). Their sales are up to billion and possess large values.
N
N
A cheap and efficient way to prepare such fine chemicals with
biaryl motif is of great interest.
nPr
N
COOH
The aryl–aryl bond formation was first reported by Ullmann in
1
901 using aryl halides and a stoichiometric amount of elemental
N
4
NH
N
copper. Since then, various transition metal catalyzed systems
were developed for the synthesis of both symmetrical and unsym-
metrical biaryls from aryl halides and activated arenes. Though
Diovan
Micardis
5
Figure 1. Structures of DiovanÒ and MicardisÒ.
with mild conditions, these reactions often require expensive late
5c,6
7
transition metal catalysts such as palladium,
ruthenium, or
8
gold for maximal efficiency. Moreover, the need of preactivation
also made the reaction less convenient.
X
X
The direct C–H arylation of arenes with aryl halides using
cheaper first row transition metal catalysts was developed rapidly
H (por)
9
N
H
2
in recent years. Yet, metal contamination in products requires an
H (ttp): X = Me
additional purification step especially in drug industry.10
2
N
N
H (tpp): X = H
2
The transition metal free, organocatalytic C–H arylation of arenes
with aryl halides has been reported recently. Itami first reported the
potassium tert-butoxide mediated cross coupling of nitrogen-based
H
N
H (tap): X = OMe
2
H (t4-Clpp): X = Cl
2
11
12
13
heterocycles with haloarenes. Shortly after, Lei–Kwong, Shi,
X
X
and Shirakawa–Hayashi14 have reported the direct C–H arylation
of unactivated arenes with aryl halides using DMEDA, 1,10-phenan-
throline, and 1,10-bathophenanthroline catalysts, respectively. La-
tely, further improvements in organocatalysts such as the use of
Figure 2. Structures of free base porphyrins.
1
5
0
were also reported. These findings provide a very promising ap-
proach for clean, efficient, and cheap synthesis of biaryl motif. Here-
in, we describe the free base porphyrin H (por) catalyzed direct C–H
2
quinoline-1-amino-2-carboxylic acid, 2,3 -biimidazo[1,2-a]pyri-
0
16
17
din-2 -one radical, and Al(OH)(bpydc) metal-organic framework
arylation of benzene with aryl halides in air.
Previously, our group has reported the cobalt(II) porphyrin
catalyzed C–H arylation, we adopt the same reaction conditions
⇑
Corresponding author. Tel.: +852 39436376; fax: +852 26035057.
E-mail address: ksc@cuhk.edu.hk (K.S. Chan).
1
8
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.073

3
912
Y. S. Ng et al. / Tetrahedron Letters 53 (2012) 3911–3914
II
Table 1
while switching Co (por) to H
(por) only. 4-Iodotoluene 1a in the
(ttp) (Fig. 2), 10 equiv
2
Free porphyrin catalyzed direct C–H arylation of benzene with 4-iodotoluene
presence of 5 mol % tetratolylporphyrin H
of KOH, and 10 equiv of BuOH successfully coupled with benzene
at 200 °C to produce 4-methylbiphenyl 2a in 73% yield in 10 h un-
2
t
5
1
1
mol% H (por)
2
0 equiv tBuOH
der N
difference when the reaction was carried out in air (Table 1, entry
). Thus the reaction can be carried out conveniently without purg-
ing off oxygen with nitrogen. However, the product yield dropped
significantly in an O atmosphere (Table 1, entry 2).
The catalytic activity of various electronically different porphy-
rins was examined by employing H (tpp), H (tap), and H (t4-Clpp)
Fig. 2). Among all porphyrins tested (Table 1, entries 3–6),
2
(Table 1, entry 1). To our delight, there was no significant
0 equiv KOH
I
H
2
00 °C, atmosphere
3
dark, time
1a
100 equiv
Atmosphere
2
a
2
Entry
Por
Time (h)
Yielda (%)
1
2
3
4
5
6
ttp
ttp
ttp
tpp
tap
N
O
Air
Air
Air
Air
2
10
10
10
14
15
14
73
2
2
2
b
2
55
(
75
78
75
76
H
2
(ttp) was found to be the most effective with the shortest reac-
(tpp), H (tap), and H (t4-Clpp) gave similar
yields but in longer times.
tion time, while H
2
2
2
t
4-Clpp
a
We screened both group I and II metal hydroxides and alkoxide
for study of base effect (Table 2). Only group I metal hydroxides
promoted the formation of 2a (Table 2, entries 1–3), with the per-
GC yield.
b
2
6% 1a recovered.
t
formance increased down the group, CsOH/ BuOH was the most
effective base system to give 76% of 2a in 2 h (Table 2, entry 3).
2 2
Group II metal hydroxides, Ba(OH) and Ca(OH) , were all ineffec-
tive (Table 2, entries 4 and 5). The strongest base BuOK was not
effective as well (Table 2, entry 6).
Table 2
Base effect on direct C–H arylation of benzene with 4-iodotoluene
t
Trace amounts of meta- and para-tert-butoxytoluene 3a and 3b
(<5%) were detected in 1:1 ratio by GC/MS (Table 2, entries 2 and
5
mol% H (ttp)
2
1
0 equiv tBuOH
t
ꢀ
3
), suggesting the elimination–addition of 1a with BuO via aryne
n equiv Base
I
H
intermediate is operating. This side reaction became dominant
200 °C, air
t
dark, time
when BuOK was used with 3a and 3b formed in 33% and 31%
1
a
100 equiv
2a
Yielda (%)
yields, respectively (Table 2, entry 6).
The coupling protocol is general to aryl iodides (Table 3). Both
electron rich and moderate electron poor aryl iodides reacted
smoothly to give the corresponding biaryl products in good yields
Entry
Base
n equiv
Time
2
1 (recovered)
1
2
3
4
5
6
NaOH
KOH
CsOH
10
10
10
5
5
10
2 d
10 h
2 h
4 d
4 d
1 h
16
75
76
0
81
(Table 3, entries 1–6). The decreased reactivity with 2-iodotoluene
b
0
0
b
suggests that the steric effect of an ortho-methyl group is impor-
tant (Table 3, entry 3).
Ca(OH)
Ba(OH)
2
89
69
2
0
The coupling of 1-chloro-4-iodobenzene with benzene yielded
terphenyl 2f as the major product together with 2g (Table 3, entry
6). The couplings of aryl bromide and chloride with benzene are
less efficient. The coupling with 4-bromotoluene afforded a moder-
ate yield of 2a in 48% (Table 3, entry 7). 4-Chlorotoluene was unre-
t
c
BuOK
17
0
a
b
c
GC yield.
Trace amounts 3a and 3b.
3% 3a and 31% 3b.
3
Table 3
Free porphyrin catalyzed direct C–H arylation of benzene with various aryl halides
5
mol% H (ttp)
2
t
1
0 equiv BuOH
0 equiv CsOH
00 °C, air
dark, time
1
X
H
2
FG
FG
1
100 equiv
2
Entry
1
Aryl halide
Time (h)
2
Product
Yielda (%)
65
I
1
a
2a
I
2
3
2
4
65
54
1
b
2b
2c
2d
I
1
c
I
1
4
5
2
4
68
58
d
MeO
I
1
MeO
2
e
e

Y. S. Ng et al. / Tetrahedron Letters 53 (2012) 3911–3914
3913
Table 3 (continued)
Entry
Aryl halide
Time (h)
2
Product
Yielda (%)
I
Cl
6
66
1
f
2f
Cl
7
2
g
Br
7
8
7
48
1
h
2a
2a
Cl
Traceb
72
1
i
a
isolated yield.
b
8
7% 1i recovered.
5
mol% H (ttp)
2
I
1
0 equiv CsOH
t
10 equiv BuOH
d6
(1)
2
00°C, dark, air, 2 h
d5
50 equiv
50 equiv
total 72%a
k /k = 1.0 ± 0.1
H
D
aGC yield
5
1
1
mol% H (ttp)
2
0 equiv tBuOH
0 equiv CsOH
n equiv TEMPO
00°C, air
dark, time
I
H
(2)
2
1a
100 equiv
2a
n = 0
t = 2 h
t = 3 d
76%a
27%
a,b
aGC yield, b10% of 1a recovered n = 1
Based on the above data, a radical chain mechanism was pro-
posed for the coupling of aryl iodides with benzene (Fig. 3).19
The reaction is initiated by a one electron reduction of aryl iodide
with base, mediated by a free porphyrin. The aryl iodide radical an-
ion then undergoes C–I bond dissociation to give an aryl radical
and an iodide. The aryl radical then adds to a benzene molecule
to give an aryl-substituted cyclohexadienyl radical intermediate.
It is then deprotonated by base to give a biaryl radical anion. Final-
ly, this radical anion undergoes a single electron transfer to an-
other aryl iodide to complete the catalytic cycle and give the
biaryl product. Termination in the middle of the radical chain oc-
curs when the aryl-substituted cyclohexadienyl radical intermedi-
ate reacts with an oxygen molecule to give the biaryl product and a
I
OH/ BuO-
t
H (por)
2
t
OH/ BuO
I
I
radical anion
I
2
0
hydroperoxy radical.
In summary, the air tolerant free base porphyrin catalyzed C–H
arylation of benzene with aryl halides to yield biaryls is demon-
strated. A radical chain mechanism was proposed according to pre-
liminary mechanistic study. Further studies are ongoing.
t
H O/ BuOH
2
OH/ BuO-
t
H
Acknowledgment
Figure 3. Proposed reaction mechanism.
We thank the Research Grants Council (No. 2160338) of the
HKSAR, the People’s Republic of China for the financial support.
active, with only a trace amount of product formed (Table 3,
entry 8).
Supplementary data
To gain more insight into the reaction mechanism, a competi-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
tion experiment was performed to study the kinetic isotopic effect
1
(
Eq. 1). A small KIE value of 1.0 ± 0.1 (by H NMR) was measured.
0
73.
Therefore, the C–H bond cleavage is not the rate determining step.
To test the radical nature of any intermediate formed, a radical
scavenger, TEMPO was added to the reaction (Eq. 2). Both the yield
and rate of the reaction decreased significantly. Therefore, the aryl
radical generated from an aryl halide is an intermediate.
References and notes
1.
Shioe, K.; Takeuchi, Y.; Harayama, T.; Abe, H. Chem. Pharm. Bull. 2010, 58, 435–
37.
4

3
914
Y. S. Ng et al. / Tetrahedron Letters 53 (2012) 3911–3914
2
.
Sunjic, V.; Parnham, M. J. Signposts to Chiral Drugs: Organic Synthesis in Action;
Springer Basel AG, 2011. 55–68.
Gooßen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664.
Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174–2185.
(a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374–4376;
11. Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673–4676.
12. Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F.
Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737–16740.
13. Sun, C.-L.; Li, H.; Yu, D.-G.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.;
Shi, Z.-J. Nat. Chem. 2010, 2, 1044–1049.
3.
4.
5.
(
(
b) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. Soc. 1977, 42, 1821–1823;
c) Li, S.; Lin, Y.; Cao, J.; Zhang, S. J. Org. Chem. 2007, 72, 4067–4072; (d)
14. Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
15537–15539.
Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918–920.
Murata, M.; Shimazaki, R.; Watanabe, S. Synthesis 2001, 2231–2233.
Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936–
15. Qiu, Y.; Liu, Y.; Yang, K.; Hong, W.; Li, Z.; Wang, Z.; Yao, Z.; Jiang, S. Org. Lett.
2011, 13, 3556–3559.
16. Yong, G.-P.; She, E.-L.; Zhang, Y.-M.; Li, Y.-Z. Chem. Commun. 2011, 47, 11766–
11768.
6
7
.
.
5
945.
8
9
.
.
Han, J.; Liu, R.; Guo, R. J. Am. Chem. Soc. 2009, 131, 2060–2061.
(a) Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org. Lett. 2009, 11, 2679–2682;
17. Liu, H.; Yin, B.; Gao, Z.; Li, Y.; Jiang, H. Chem. Commun. 2012, 48, 2033–2035.
18. 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.
19. Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018–5022.
20. Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706–13707.
(
1
b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185–
5192.
1
0. Berkessel, A.; Grõger, H. Asymmetric Organocatalysis: From Biomimetic Concepts
to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005.