Direct intermolecular C-H arylation of unactivated arenes with aryl bromides catalysed by 2-pyridyl carbinol

Article abstract of DOI:10.1039/c4ob01211a

Direct intermolecular C-H arylation employing aryl bromide as the arene source has been developed. This process proceeds via a simple transition-metal-free pathway. With the aid of inexpensive and commercially available 2-pyridyl carbinol and potassium tert-butoxide, various unactivated arene C-H bonds can be directly arylated by aryl bromides through homolytic aromatic substitution. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01211a

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Direct intermolecular C–H arylation of unactivated
arenes with aryl bromides catalysed by 2-pyridyl
carbinol†
Cite this: DOI: 10.1039/c4ob01211a
Received 12th June 2014,
Accepted 23rd July 2014
Yinuo Wu,*a,b,c Pui Ying Choya,b and Fuk Yee Kwong*a,b
DOI: 10.1039/c4ob01211a
www.rsc.org/obc
Direct intermolecular C–H arylation employing aryl bromide as the that this coupling process goes through a homolytic aromatic
arene source has been developed. This process proceeds via a substitution (HAS) pathway.10 After these recent break-
simple transition-metal-free pathway. With the aid of inexpensive throughs, numerous reports have emerged demonstrating
and commercially available 2-pyridyl carbinol and potassium tert- other applicable catalysts for the successful transition metal-
butoxide, various unactivated arene C–H bonds can be directly free C–H arylation.11 In 2013, Liu even showed a simple
arylated by aryl bromides through homolytic aromatic substitution. alcohol which could facilitate the direct C–H arylation of non-
activated arenes with aryl iodides.12 Apart from the added cata-
Biaryl motifs are essential sub-units of a number of syntheti-
lysts, the photoirradiation-stimulated biaryl synthesis was also
cally valuable intermediates. They are often found in many
recently established.13 In early 2014, Wilden showed that the
natural products, biologically active and pharmaceutically
catalyst is not even essential while potassium tert-butoxide
useful compounds.1 In addition, biaryl scaffolds also have
alone could promote the coupling reaction.14 However, a relatively
high relevance in graphene materials science.2 Transition
high reaction temperature (160 °C) is required. In fact, previous
literature reports were mainly focused on aryl iodide coupling.
Thus a catalyst system, which allows general aryl bromides to
metal-catalysed/mediated aromatic carbon–carbon bond con-
struction processes have been successful since 1970s.3
However, organohalide (Ar–X) and organometallic (Ar′–M)
reagents are necessary to be employed in these cross-coupling
reactions. The pre-activation of coupling partners (organo-
metallic reagents), as well as the need for transition metal cata-
serve as the coupling partner, is still in demand. In continuing
our former work on DMEDA-catalyzed C–H arylation of benzene7
and intramolecular C–H arylation by ethylene glycol,15 herein, we
report our efforts of using aryl bromides as the coupling partners
for direct intermolecular C–H arylation of non-activated arenes.
lysts, would lead to problematic metal waste disposal.
A greener and more economical synthetic approach which
We started to embark the C–H bond cross-coupling of
circumvents transition metal catalysts is highly attractive.4
4-bromotoluene with benzene using previously successful pro-
Thus, a transition metal-free biaryl synthesis is highly desir-
prietary organo-promoters (e.g. DMEDA and Phen).16 Yet,
inferior results were obtained. Only less than 5% conversion of
able.5 In 2008, Itami initially reported the C–H arylation of
activated heterocycles under transition metal-free conditions.6
aryl bromides was observed by GC-FID analysis. Inspired from
In 2010, Lei and Kwong,7 Hayashi and Shirakawa,8 and Shi9
our previous work on ethylene glycol-catalysed phenanthridine
independently disclosed further advancements of this process
synthesis,15 we became interested in evaluating simple alco-
for non-activated arenes. The catalyst of N,N′-dimethylethylene-
hols associated with amines, for the C–H arylation of non-acti-
diamine (DMEDA), 1,10-phenanthroline (Phen) and its deriva-
vated arenes with aryl bromides. 2-Pyridyl carbinol was
tives are necessary to be employed under these sodium/
initially chosen as the catalyst for examining the coupling
potassium tert-butoxide-mediated conditions. It is believed
between 4-bromotoluene and benzene (Table 1). To our
delight, the result showed that this coupling was feasible and
excellent product yield was obtained (entry 1). Upon lowering
the reaction temperature, the desired product yields decreased
(entries 1–4). The reaction proceeded well even at room temp-
erature with extended reaction time (entry 5). This example
represents the first direct C–H arylation of a non-activated
arene with non-activated aryl bromide at ambient temperature
under transition metal-free conditions. 10 mol% of the catalyst
aThe Hong Kong Polytechnic University Shenzhen Research Institute (SZRI),
Shenzhen, China
bState Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong, China. E-mail: wuyinuo0217@163.com, fuk-yee.kwong@polyu.edu.hk
cSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01211a
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Table 1 Initial optimization of reaction conditionsa
Table 2 Transition metal-free direct C–H arylation of benzene with
ArBra
Entry
Catalyst loading
Base
Temp./°C
% yieldb
Entry
ArBr
Product
% yieldb
1
2
3
40 mol%
40 mol%
40 mol%
40 mol%
40 mol%
30 mol%
20 mol%
10 mol%
5 mol%
40 mol%
—
40 mol%
40 mol%
40 mol%
40 mol%
40 mol%
40 mol%
40 mol%
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
—
KOt-Bu
K2CO3
NaOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
80
60
40
r.t.
r.t.
80
80
80
80
80
80
80
100
120
80
80
80
80
96
75
58
35
68
95
95
95
1
88
60
2c
4
5c
6
3
69
7
8
9
65
10
11
12
13
14d
15e
16f
17g
18h
n.r.
n.r.
n.r.
Trace
8
n.r.
n.r.
n.r.
n.r.
4
5
81
80
6
7
8
9
76
60
46
50
a Reaction conditions: 4-bromotoluene (1.0 mmol), benzene (8.0 mL),
catalyst (as indicated in table), and KOt-Bu (2.0 mmol) were stirred
under nitrogen at indicated temperatures for 24 hours. b Calibrated GC
yields were reported, using dodecane as the internal standard.
c 72 hours was applied. d 4-Chlorotoluene was used instead of
4-bromotoluene. e 4-Pyridyl carbinol was used instead of 2-pyridyl
carbinol. f 3-Amino-1-propanol was used as the catalyst.
g 2-Aminobenzyl alcohol was used as the catalyst. h 2-Amino-4-hydroxy-
6-methylpyrimidine was used as the catalyst.
were sufficient to promote this reaction (entries 6–9). In the
absence of either 2-pyridyl carbinol or potassium tert-butoxide,
no reaction occurred (entries 10 and 11). A survey of other
bases indicated that KOt-Bu was crucial to this biaryl synthesis
(entries 1, 12 and 13). Nevertheless, aryl chlorides were found
inapplicable (entry 14). To our surprise, when 4-pyridyl carbinol
(the regioisomer of 2-pyridyl carbinol), 3-amino-1-propanol,
2-aminobenzyl alcohol and 2-amino-4-hydroxy-6-methylpyrimi-
dine were evaluated as the promoter, no observable substrate
conversion was detected (entries 15–18). Thus, 10 mol% of
2-pyridyl carbinol was the best catalyst loading for catalyzing the
reaction with potassium tert-butoxide at 80 °C for 24 hours.
With the preliminary optimized reaction conditions in
hand, we next examined the generality of the catalyst system
for direct arylation of benzene with various aryl bromides
(Table 2). In general, 10 mol% of 2-pyridyl carbinol was
sufficient to catalyse the reaction. Notably, the direct arylation
could be performed at room temperature with extended reaction
time with specific substrates (entries 2 and 14). Electron-donat-
ing aryl bromides afforded the corresponding desired product
10
11
43
70
12
13
72
55
14c,d
20
a Reaction conditions: aryl bromides (1.0 mmol), benzene (8.0 mL),
in good-to-excellent yields. Cyano and fluoro groups were com- 2-pyridyl carbinol (10 mol%), KOt-Bu (2.0 mmol) were stirred at 80 °C
under nitrogen for 24 hours (reaction times for each substrate were not
patible under these reaction conditions (entries 4–8). Sterically
hindered ortho-substituted aryl bromides furnished the desired
optimized). b Isolated yields. c The reaction was performed with 40 mol
% 2-pyridyl carbinol under room temperature for 72 hours. d GC yield
product in moderate yields (entries 9 and 10). Heteroaryl bro- was obtained.
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Table 3 Transition metal-free direct arylation of unactivated arenes
with ArBra
Conclusions
In summary, we have reported a general C–H arylation of un-
activated arenes with a wide range of aryl/heteroaryl bromides
in the presence of 2-pyridyl carbinol and potassium tert-butox-
ide. Various aryl bromides were coupled well with unactivated
arenes under mild reaction conditions. Particularly noteworthy
is that only 10 mol% of the catalyst is enough to promote the
arylation. The use of 2-pyridyl carbinol provides a simple and
inexpensive protocol to tackle the challenging C–H arylation
under transition-metal-free conditions. Further investigations
are currently underway.
Entry ArBr Ar′H
Product
% yieldb
1
2
78
78
We thank the Research Grants Council of Hong Kong
(CERG: PolyU5010/13P) and Shenzhen Strategic New Industry
Development Fund (JCYJ20130401152508653) for financial
support. F. Y. K. thanks the Croucher Foundation for the
Croucher Senior Research Fellowship 2013. We are grateful to
Prof. Albert S. C. Chan’s research group (PolyU Hong Kong) for
sharing of GC-FID and GC-MS instruments.
3
4
62
48
5
72 (o/m/p
4 : 2 : 1)
a Reaction conditions: aryl bromides (1.0 mmol), unactivated arenes
(8.0 mL), 2-pyridyl carbinol (10 mol%), KOt-Bu (2.0 mmol) were stirred
at 80 °C under nitrogen for 24 hours (reaction times for each substrate
were not optimized). b Isolated yields.
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Scheme 1 Kinetic isotope effect studies (reaction conditions are the
same as in Table 2, entry 1 except that 80 equiv. of either benzene or
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transformation.
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