A macrocyclic aromatic pyridone pentamer as a highly efficient organocatalyst for the direct arylations of unactivated arenes

Article abstract of DOI:10.1039/c3cc00019b

A macrocyclic aromatic pyridone pentamer was shown to catalyze highly efficient transition-metal-free arylations of unactivated aromatic C-H bonds with aryl iodides and bromides in the presence of potassium tert-butoxide. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc00019b

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A macrocyclic aromatic pyridone pentamer as a highly
efficient organocatalyst for the direct arylations of
unactivated arenes†
Cite this: Chem. Commun., 2013,
49, 2323
Received 2nd January 2013,
Accepted 1st February 2013
Huaiqing Zhao, Jie Shen, Juanjuan Guo, Ruijuan Ye and Huaqiang Zeng*
DOI: 10.1039/c3cc00019b
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A macrocyclic aromatic pyridone pentamer was shown to catalyze macrocyclic ion-binding pentamers P5 could also serve as efficient
highly efficient transition-metal-free arylations of unactivated aro- catalystsforthedirectarylationsoftheinertaromaticC–Hbondswith
matic C–H bonds with aryl iodides and bromides in the presence of aryl halides in the absence of transition metals. To the best of our
potassium tert-butoxide.
knowledge, there has been no related report using the backbone-
rigidified folding molecules such as P57 as the organocatalysts in the
Biaryl is a pivotal scaffold in the synthesis of pharmaceuticals, transition-metal-free cross-coupling reactions.
natural products, agrochemicals and functional materials.1 Over
the past decades, various strategies have been developed, the pre-
vailing methods of which are the transition-metal-catalyzed cross-
coupling reactions of organometallic reagents with haloarenes.2
However, these methods not only suffer from sensitive organo-
metallic reagents and expensive metal catalysts, but also often
produce undesired, toxic and stoichiometric side products. As an
efficient and green alternative to transition-metal-catalyzed reactions,
organocatalysts attract more and more attention from the synthetic
The cross-coupling reaction of 4-iodoanisole (1a)withbenzene(2a)
chemists, providing a strategic solution to assemble diverse
molecules. A very recent development involves generating biaryl
molecules with the use of organocatalysts interacting with tert-
butoxide (t-BuOÀ) to initiate the aryl radicals via the single-electron
transfer (SET) that subsequently promote the direct arylations of
unactivated arenes.3
was chosen as the model reaction for optimizing the reaction condi-
tions. A control experiment was firstly performed with the use of 3.0
equivalents of KOt-Bu at 120 1C but without the use of any catalyst, and
Table 1 Optimization of arylation reaction conditionsa
Aromatic foldamers with backbones rigidified by H-bonds have
been the subject of intense attention over recent years, due to their
versatile properties and potential applications including molecular
recognition,4 ion channels,5 and differential binding of alkaline metal
ions.6 Aromatic foldamers, however, have been rarely applied as
organocatalysts for chemical transformations. Recently, we reported
a novel class of H-bonded macrocyclic aromatic pentamers (P5) made
up of five pyridone motifs that enclose an appropriately sized interior
decorated with five carbonyl O-atoms to display tight binding of 108
Entry Catalyst (equiv.) Base (equiv.)
T (1C) t (h) Yieldb (%)
1
2
3
4
5
6
7
8
P5a (0.00)
P5a (0.05)
P5a (0.05)
P5a (0.05)
P5a (0.05)
P5a (0.05)
P5a (0.03)
P5a (0.02)
P5a (0.01)
P5a (0.02)
P5a (0.02)
P5a (0.02)
P5b (0.02)
P5c (0.02)
P5d (0.02)
KOt-Bu (3.0)
KOt-Bu (3.0)
NaOt-Bu (3.0) 120
LiOt-Bu (3.0)
KOH (3.0)
K3PO4 (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (2.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
120
120
24
24
24
24
24
24
24
24
24
24
24
20
24
24
24
8
95
3
120
120
120
120
120
120
120
110
120
120
120
120
0
2
0
M
À1 in the water–CHCl3 system toward alkali metal ions.6b,c Inspired
99 (96)
99 (96)
56
by the recent elegant works on the use of organocatalysts to promote
transition-metal-free arylation reactions,3 we speculated that
9
10
11
12
13
14
15
53
74
85
14
49
42
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543. E-mail: chmzh@nus.edu.sg; Fax: +65-6779-1691;
Tel: +65-6516-2683
† Electronic supplementary information (ESI) available: The details of experi-
ments and a full set of characterization data including 1H, 13C NMR and HRMS.
See DOI: 10.1039/c3cc00019b
a
1a (0.2 mmol), base, catalyst and benzene (3 mL) in a sealed Schlenk tube.
b Yields were determined by 1H NMR (isolated yield in parentheses).
c
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the desired product was obtained with 8% yield (Table 1, entry 1). In
With the optimal conditions in hand, we investigated the aryla-
sharp contrast, 95% yield can be obtained with the use of 5 mol% of tions of benzene with a range of aryl halides. Simple iodobenzene 1d
P5a (Table 1, entry 2). Various bases such as NaOt-Bu, LiOt-Bu, KOH and other aryl iodides bearing electron-donating or withdrawing
and K3PO4 were then tested, giving rise to either no product or very low groups can be efficiently coupled withbenzenetoproduce the desired
yields (Table 1, entries 3–6). Surprisingly, a reduction in catalyst products in high yields of 83–98% (Table 2, entries 1–9). Notably,
loading from 5 to 3 and further to 2 mol% led to very clean reactions sterically hindered aryl iodides 1c and 1j gave isolated yields of 94%
with 96% isolated yield in both cases (Table 1, entries 7 and 8).8a
A
and 75%, respectively (Table 2, entries 3 and 10). Interestingly,
catalyst loading as low as 2 mol% is quite significant since all the arylation using dihalide 1h additionally produced p-terphenyl 3i as
hitherto reported organocatalysts for catalyzing the same arylation the by-product in 15% yield (Table 2, entry 8), and 1i largely underwent
reactions require from 10 to 40 mol% catalyst loadings.3,8b After double phenylation to afford 3i as the major product in 94% yield with
screening various factors (e.g., amount of base, temperature and the use of 5 rather than 3 equivalents of t-BuOK (Table 2, entry 9).
reaction time; Table 1, entries 9–12), the best conditions for promoting While this newly discovered catalyst can be used to promote the
the arylations involve the use of 2 mol% of P5a and 3 equivalents of arylation of aryl bromides under either optimized conditions or a
KOt-Bu at 120 1C for 24 h. An additional testing of other analogous longer reaction time, producing the desired biaryl products in 25–90%
macrocycles P5c and P5d, which differ from P5a by their exterior side (Table 2, entries 12 and 13), aryl chlorides such as chlorobenzene 1p
chains, reveals P5a to be the best catalyst (Table 1, entries 13–15).
were unreactive under the identical conditions (Table 2, entry 16).
The substrate scope and regioselectivities in arylations were
further explored on the different arenes. Reactions of 1a with
substituted benzenes invariably afforded regioisomeric mixtures
with a high ortho ratio (Table 3, entries 1, 2, 5 and 6). The arenes
with electron-withdrawing groups (Table 3, entries 4–6) coupled with
1a more efficiently than those carrying electron-donating groups
(Table 3, entries 1–3), highlighting the importance of the relative
acidity of aromatic C–H bonds in the arylation reactions and
suggesting the P5a-mediated direct arylation of aromatic C–H bonds
to proceed by homolytic aromatic substitution with aryl radicals3c
that differs from the typical transition-metal-catalyzed reactions.
Consistent with the involvement of aryl radicals in the arylation
reactions promoted by macrocycle P5a, addition of one equivalent of
free radical scavengers of either TEMPO or 1,1-diphenylethelene put
the reaction to a complete stop and no desired product could be
obtained (Table 4). These results contrast well with 99% yield
obtained without the use of radical scavengers (Table 1, entry 8).
An additional kinetic isotope experiment yielded a kH/kD value of
1.09 (Scheme 1), demonstrating that the cleavage of the aromatic
C–H bond is not the rate-limiting step in the arylation reaction.
Table 2 Direct arylations of benzene with aryl halidesa
Entry
Ar group
Product
Yield (%)
1
2
96
83
3
94
4
5
98
89
6
7
92
84
Table 3 Direct arylations of aryl iodide with arenesa
8b
9c
80
94
Entry Arenes
Product
Yield (%) Ratio of o/m/pb
10
75
1
2
60
50
1.0/0.23/0.21
1.0/0.44/0.38
11
86
80
60
12d
13d
3
4
44
65
14e
25
15
16
90
0
5
6
79
85
1.0/0.48/0.37
1.0/0.76/0.32
a
Ar–X 1 (0.2 mmol), KOt-Bu (3 equiv.), P5a (2 mol%) and benzene
b
a
(3 mL) in a sealed Schlenk tube, 120 1C, 24 h, isolated yields. 15%
p-terphenyl 3i was isolated. 5 equiv. of KOt-Bu was used. Reaction
time: 48 h. 17% p-terphenyl 3i was isolated.
1a (0.2 mmol), KOt-Bu (3 equiv.), P5a (2 mol%) and arenes 2 (2 mL) in
c
d
b
a sealed Schlenk tube, 120 1C, 48 h, isolated yields. Ratio of products
e
determined by 1H NMR analysis.
c
2324 Chem. Commun., 2013, 49, 2323--2325
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Table 4 Arylation reactions with radical scavengers
excellent yields were obtained for broad substrates. P5a thus repre-
sents one of the most efficient additions into the toolbox, currently
with a limited collection of organocatalysts for radical-mediated
coupling reactions. P5a may, further, hold promise in producing
other types of molecular skeletons via reactions where radicals play an
important role.9a
Entry
Additive (equiv.)
Yield of 3aa (%)
1
2
TEMPO (1.0)
Diyldibenzene (1.0)
0
0
a
Yields were determined by 1H NMR.
Notes and references
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8 (a) Lowering down the concentration of P5a likely discourages the self-
aggregation and increases the effective concentration of monomeric
macrocycles for them to efficiently interact with KOt-Bu to promote
better arylation reactions; (b) Such a low catalyst loading may arise
from the likelihood that the planar and electron-rich nature of the
macrocyclic backbone in P5a greatly facilitates the initial stage invol-
ving the endothermic formation of high energy intermediate species I
and subsequent reduction of the aryl halide by t-butoxide as proposed
in Scheme 2. Of further interest to note is that 18-crown-6 gave 25%
yield under the optimized conditions used for P5a.
Scheme 2 The proposed catalytic cycle of arylation reactions.
On the basis of the above data and related results reported by
others,3,9 a radical-mediated catalytic mechanism is very likely as
illustrated in Scheme 2. In the proposed catalytic cycle, the cation-
binding macrocycle P5a encapsulates the K+ inside its cavity and
forms the complex I, which subsequently transfers a single electron to
iodobenzene 1, yielding the intermediate radical anion II and cation
III. From II, aromatic radical IV is formed that adds to benzene 2a to
generate biaryl radical V. Oxidation of V by III produces cations VI and
VII of which VI is deprotonated by a t-butoxide anion generated in situ
to afford cross-coupled product 3, and VII reacts with KOt-Bu to
re-generate complex I that allows the catalytic cycle to continue.
In summary, we disclose here a novel foldamer-based H-bond-
rigidified organocatalyst P5a,7 enabling the efficient construction of
biaryls via direct arylations of unactivated arenes with iodoarenes and
bromoarenes in the presence of KOt-Bu by using as low as 2 mol%
catalyst loading in a transition-metal-free fashion. Very good to
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c
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