Direct C-H arylations of unactivated arenes catalyzed by amido-functionalized imidazolium salts

Article abstract of DOI:10.1002/adsc.201300877

The synthesis of biaryls from unactivated arenes and a broad range of aryl bromides and chlorides via the direct C-H functionalization can be efficiently performed with the aid of amido-functionalized imidazolium salts as organocatalysts. This method avoids the use of toxic transition metal catalysts and organometallic reagents.

Full text of DOI:10.1002/adsc.201300877

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DOI: 10.1002/adsc.201300877
À
Direct C H Arylations of Unactivated Arenes Catalyzed by
Amido-Functionalized Imidazolium Salts
Debalina Ghosh,a Jhen-Yi Lee,a Chian-Yu Liu,a Yen-Hsin Chiang,a
and Hon Man Leea,*
a
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, R.O.C.
Fax : (+886)-4-721-1190; phone: (+886)-4-723-2105 ext. 3523; e-mail: leehm@cc.ncue.edu.tw
Received: November 29, 2013; Revised: November 17, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300877.
[7]
À
Abstract: The synthesis of biaryls from unactivated
pling reactions[6] and direct C H arylations, we have
arenes and a broad range of aryl bromides and
accumulated a library of effective catalyst systems
based on amido-functionalized carbene ligand precur-
sors, most of which are imidazolium salt derivatives.
Recently, Ong has reported the successful application
À
chlorides via the direct C H functionalization can
be efficiently performed with the aid of amido-func-
tionalized imidazolium salts as organocatalysts. This
method avoids the use of toxic transition metal cat-
alysts and organometallic reagents.
À
of free carbenes in catalyzing the direct C H func-
tionalization of arenes using aryl iodides as coupling
partners.[5c] Thus far, although some effective organo-
À
À
Keywords: C H activation; imidazolium salts; orga-
catalysts for direct C H arylation have been devel-
nocatalysis; transition metal-free conditions; unacti-
vated arenes
oped, coupling partners have been generally limited
to aryl bromides and iodides.[4,5] Thus the develop-
ment of alternative organocatalysts that can effective-
ly utilize aryl bromides as well as chlorides would be
a useful addition to the field. Herein, we report the
use of the above-mentioned inexpensive amido-func-
Biaryls are privileged structural units employed in tionalized imidazolium salts as organocatalysts in the
À
a wide diversity of applications in pharmaceuticals, direct C H arylation of unactivated arenes. To our
drug candidates, and functional materials.[1] Palladi- delight, the catalysts were effective in promoting reac-
um-catalyzed cross-coupling reactions have been tions with a range of aryl bromides and even chlor-
widely used for the construction of these important ides.
building blocks.[2] Recently, transition metal-catalyzed
Initially, a model reaction between 4-bromoanisole
À
direct C H arylation reactions have attracted consid- and benzene was performed employing 20 mol% of
erable attention for the preparation of these scaf- commercially available IMes·HCl (L1) in the pres-
folds.[3] Such methodologies for biaryl construction ence of 3 equiv. of KO-t-Bu at 1008C. The desired
without the need of pre-formed organometallic re- product, 4-methoxybiphenyl (3e), was obtained in
agents are environmentally benign because of the re- 23% yield. The coupling activities did not occur in the
duced waste and fewer reaction steps required. So far, absence of the organocatalyst. Encouraged by this
a wide range of homo- and heteroaromatic biaryls has result, we examined the catalytic performances of
been prepared via these methods.[3] Lately, transition a series of imidazolium salts with amide functionali-
À
metal-free direct C H arylation reactions of unacti- ties (Table 1). When L2 was employed, yield of the
vated arenes without the involvement of organome- desired product increased to 36%, indicating that an
À
tallic reagents as well as transition metal catalysts imidazolium salt with a free N H moiety can effec-
have been successfully demonstrated.[4,5] Various orga- tively catalyze the coupling reaction. Reaction optimi-
nocatalysts such as DMEDA,[4a] 1,10-phenanthro- zation by an increase in catalyst loading to 25 mol%
ACHTUNGTRENNUNG
line,[4b,c] simple alcohols,[5h] and carbenes[5c] in the of L2 resulted in the complete conversion of the start-
presence of tert-butoxide as base are known to effec- ing material with 42% yield of the desired product.
À
tively promote the direct C H arylation of unactivat- Under the optimized conditions (L, 25 mol%; KO-t-
ed arenes with aryl iodides and bromides.
Bu, 1.5 mmol; 4-bromoanisole, 0.5 mmol; benzene,
During the course of our investigations on Pd-car- 2.25 mL; reaction temperature, 1008C; reaction time,
bene complexes and their applications in cross-cou- 20 h), a series of imidazolium salts was screened; the
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Direct C H Arylations of Unactivated Arenes
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Table 1. Organocatalyst screening for direct C H functiona-
lization.[a]
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Figure 1. Comparison of imidazolium salts for direct C H
functionalization of benzene with 4-bromoanisole.
typical reaction time for the aryl bromides. In fact,
longer reaction times (ca. 36 h) were required for the
full conversion of aryl iodides to the coupled products
(see the Supporting Information).
With the L3/KO-t-Bu catalyst system identified, the
substrate scope of the coupling reaction between ben-
zene and a wide range of aryl halides was investigated
[a]
Reaction conditions (unless otherwise specified): 4-bro-
moanisole (0.5 mmol), KO-t-Bu (1.5 mmol), benzene
(2.25 mL), L (25 mol%), 1008C, 20 h, isolated yields.
Yields were determined by GC.
Isolated yield using 20 mol% L.
[b]
[c]
results indicated that the structures of the imidazoli- (Table 2). Reaction progress was monitored by TLC,
um salts play a crucial role in the reaction outcome. and the reactions were stopped after complete con-
Compound L3 featuring a more flexible benzyl in- sumption of the starting materials. Bromoarenes with
stead of a rigid mesityl group afforded the desired electron-donating substituents were found to be excel-
product in 72% yield. A drastic decline in efficiency lent substrates, affording the corresponding biaryl
was observed with L4 bearing an electron-withdraw- scaffolds in good yields (70–78% yields, entries 1, 2, 4,
ing 4-fluorobenzyl group. In this case, the homocou- 7). Pleasingly, the coupling reactions provided accept-
pling product from 4-bromoanisole was observed. The able yields (58–71%, entries 3, 5, 6) even with sterical-
transformation was also attenuated using L5 with ly hindered ortho-substituted aryl bromides after pro-
a smaller methyl group. A comparison of activities be- longed reaction times (36 h). Although electron-defi-
tween L3 and L6 (72 vs. 46%) indicated that the steri- cient aryl bromides led to the rapid consumption of
cally encumbered group attached to the NH moiety starting bromides (10–18 h), moderate yields of prod-
was also detrimental to the coupling activities. The ucts were obtained (61–63%, entries 10–13). It is
NH proton on the catalyst was proven to be crucial, worth noting that the reported reaction conditions are
as its replacement with a methyl group led to a drastic compatible with bromoarenes substrates with poten-
decrease in product yield (42% for L2 vs. 18% for tially sensitive nitrile, ketone, and esters groups. Het-
L7). Cross-coupling failed to proceed when L9, an ab- erocyclic haloarenes such as 2-bromothiophene and 2-
normal carbene precursor was employed. Intriguingly, bromopyridine were also found to be suitable sub-
[6a]
the Pd(II) complex comprising L3 and PCy3
strates, providing yields of 82 and 63%, respectively
(2.5 mol%) was less efficient in mediating the forma- (entries 8 and 9). In general, aryl chlorides followed
tion of 3e (48% yield), firmly establishing the essence the same reactivity pattern as that of bromides, af-
of the transition metal-free conditions.
fording slightly lower yields (50–56%, entries 14–18).
To better understand the reaction profile, the prog- Electron-rich 4- and 3-chloroanisoles could be utilized
ress of the coupling reactions catalyzed by L3, L4, as coupling partners, giving the desired coupled prod-
and L6 was monitored by GC chromatography ucts in reasonable yields (54 and 56%, entries 14 and
(Figure 1). The superiority of L3 over the other cata- 15). To the best of our knowledge, this is the first
lysts was confirmed and its reaction rate slowed down report on the use of chloroanisoles for the prepara-
drastically after 10 h. Bases other than KO-t-Bu were tion of biaryls via transition metal-free intermolecular
[8]
À
found to be ineffective. It is also noteworthy that, direct C H arylation of unactivated arenes. Sterical-
contrasting to most reports in the literature,[4,5] aryl io- ly congested aryl chlorides such as 2-chloroanisole
dides appeared to be less compatible under the pres- and 2-chloro-1,3-dimethylbenzene, however, were un-
ent reaction conditions and can be recovered after the reactive under the identical conditions.
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Debalina Ghosh et al.
Table 2. Imidazolium salt-catalyzed direct arylation of ben-
zene with aryl halides.[a]
Table 2. (Continued)
[a]
Reaction conditions (unless otherwise specified): ArBr
(0.5 mmol), KO-t-Bu (1.5 mmol), benzene (2.25 mL), L3
(25 mol%), 1008C, 10–24 h.
ArCl (1.0 mmol), KO-t-Bu (3.0 mmol), benzene
(4.5 mL).
Time was prolonged to 36 h.
ArBr (0.5 mmol), KO-t-Bu (3.0 mmol), benzene
(4.5 mL), 36 h.
[b]
[c]
[d]
[e]
[f]
ArBr (0.5 mmol), KO-t-Bu (4.5 mmol), benzene
(7.0 mL), 36 h.
35% of 10-bromo-9-phenylanthracene was isolated.
When 1,4-dibromobenzene was employed, double
coupling took place, providing para-terphenyl in 65%
yield (entry 19). The more challenging substrate 1-
bromo-4-chlorobenzene underwent double arylation
as well to furnish the desired product in comparable
56% yield (entry 20). More interestingly, three-fold
arylation of 1,3,5-tribromobenzene occurred smoothly,
affording a respectable yield of 1,3,5-triphenylben-
zene as a single product (58%, entry 21). The reac-
tions of 2,6-dibromopyridine and 9,10-dibromoanthra-
cene were also investigated (entries 22 and 23), with
the corresponding heteroaromatic arylated products
being obtained in 53 and 32% yields, respectively.
Next we investigated the coupling reactions of dif-
ferent unactivated arenes under our new catalytic
conditions. Monosubstituted arenes such as anisole
and benzonitrile afforded mixtures of regioisomers fa-
voring ortho-substitution over the meta- and para-po-
sitions with moderate yields in all cases (Table 3, en-
tries 1–3). When naphthalene was employed as the
coupling partner, a-arylated 5d predominated (74%
regioselectivity, entry 4). para-Xylene and mesitylene
afforded the desired biaryls in relatively longer times
with moderate yields of 58 and 42%, respectively (en-
tries 5 and 6).
Most notable throughout the entire study was the
absence of side products due to dehalogenation from
the corresponding aryl halides. Also, in all of the
above reactions, regioisomers with respect to the aryl
halides were not detected, ruling out the possibility of
a benzyne mechanism.[9] In fact, the aforementioned
ortho-selectivity with respect to the monosubstituted
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Adv. Synth. Catal. 2014, 356, 406 – 410

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Direct C H Arylations of Unactivated Arenes
Table 3. Imidazolium salts-catalyzed direct arylation of
arene with aryl bromides.[a]
Scheme 1. A plausible mechanism.
Scheme 2. Kinetic isotopic effects experiment.
[a]
Reaction conditions (unless otherwise specified): ArBr
(0.5 mmol), KO-t-Bu (1.5 mmol), arene (2.25 mL), L3
(25 mol%), 1008C, 24 h.
volved a radical pathway. A further support for the
radical pathway came from the use of AIBN to ini-
tiate the coupling reaction producing the desired
product, albeit in a lower yield (see the Supporting
Information).
Isotopic labeling experiments were also conducted
by subjecting 4-bromoanisole to the coupling reaction
[b]
A mixture of isomers, the yield and their ratios deter-
1
mined by H NMR spectroscopy.
[c]
ArBr (1.0 mmol), KO-t-Bu (3.0 mmol), arene (4.5 mL).
Time was prolonged to 30 h.
36 h, 1208C.
[d]
[e]
arenes is consistent with a homolytic aromatic substi- with equimolar amounts of benzene and benzene-d6
tution (HAS) mechanism.[4c,10] Previous studies have (Scheme 2) and the corresponding products were ob-
also established the importance of bidentate chelation tained in a ratio of 6:5 (kH/kD =1.24). This low kinetic
with K+ as an essential structural property for organo- isotope effect indicated that the rate-determining step
catalystic activity.[4] The salts selected for study in- is not the cleavage of the aromatic C H bond, but
À
cluding L3 fulfill this condition; upon deprotonation a single electron-transfer process. A possible mecha-
of the imidazolium C-2 position and the amido NH nism for the transformation under the new catalytic
group, a chelate carbene complex is formed. Based on system is provided in Scheme 1. The major difference
the above information, we propose the involvement from that reported by Ong on the use of amino/NHC
of an aryl radical anion intermediate in the coupling ligand in similar coupling reactions is the facile depro-
reaction, which is initiated by the chelate complex tonation of the CONH proton leading to a stable po-
comprising an amido-functionalized carbene ligand tassium chelate intermediate.[5c]
(Scheme 1). To verify our proposal, a radical trapping
In conclusion, we have developed an effective orga-
experiment was carried out using TEMPO (1 equiv., nocatalyst system based on amido-functionalized imi-
see the Supporting Information), a typical radical dazolium salts for the synthesis of biaryls via C-H
scavenger, for the reaction between 4-bromoanisole functionalization of unreactive arenes with aryl bro-
and benzene. The reaction was completely sup- mides and even chlorides. The metal-free conditions
pressed, suggesting that the transformation indeed in- described allowed for the preparation of biaryls in
Adv. Synth. Catal. 2014, 356, 406 – 410
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Debalina Ghosh et al.
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Experimental Section
General Procedure for the Cross-Coupling of Aryl
Halides with Arenes
An oven-dried Schlenk tube equipped with a magnetic stir
bar was charged with aryl halides (0.5 mmol, if solid), L3
(41 mg, 0.12 mmol) and KO-t-Bu (168 mg, 1.5 mmol) under
a nitrogen atmosphere at room temperature. Anhydrous
benzene/arene (2.25 mL) and aryl halides (0.5 mmol, if
liquid) were then added using a syringe. The tube was then
sealed and the resulting mixture was stirred at the specified
temperature until complete consumption of starting material
as monitored by TLC. After cooling to room temperature,
the reaction mixture was quenched and extracted with ethyl
acetate (10 mLꢁ3). The organic layers were combined,
dried over Mg2SO4 and concentrated under reduced pres-
sure. The crude products were purified through flash
column chromatography on 230–400 mesh silica gel using
hexane or hexane/ethyl acetate as eluent with a suitable
ratio according to the TLC experiments. The regioisomeric
distributions of isomers were determined by GC and con-
firmed by 1H NMR spectroscopy.
Acknowledgements
We thank the National Science Council of Taiwan for sup-
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