Phosphine-free, palladium-catalyzed arylation of heterocycles through C-H bond activation with pivalic acid as a cocatalyst

Article abstract of DOI:10.1002/chem.200802001

A new palladium-catalyzed methodology was developed for the direct C-arylation of azoles with a broad spectrum of aryl bromides without the presence of phosphines, the aid of CuI, or other metal additives by using pivalic acid as a cocatalyst. The method also allowed the direct C-arylation of the N-heterocycle N-oxides, and to a lesser degree, the perfluoroaromatics. It was also found that the method can not only be applied to the synthesis of 8-aryl-substituted caffeines, but also 8-arylated theophyllines and theobromines. The result showed thatthe method can tolerate an array of functional groups including ester, nitrile, nitro, aldehyde, methoxy, trifluoromethyl, fluoro, and chloro substituents, and can found its applications in a number of fields such as synthetic and medicinal chemistry both in industry and in academia.

Full text of DOI:10.1002/chem.200802001

COMMUNICATION
DOI: 10.1002/chem.200802001
Phosphine-Free, Palladium-Catalyzed Arylation of Heterocycles
À
through C H Bond Activation with Pivalic Acid as a Cocatalyst
Dongbing Zhao, Weida Wang, Shuang Lian, Fei Yang, Jingbo Lan, and Jingsong You*[a]
Direct C-arylation of heteroaromatics has recently re-
ceived a great deal of attention as an effective approach for
creating aryl–heteroaryl linkages and has been used exten-
sively throughout natural product synthesis, as well as in the
pharmaceutical, and materials industries,[1] because the use
of organometallic reagents can be avoided in traditional
ichiometric amounts of copper salts (1–3 equiv) or silver ad-
ditives are generally required to improve these phosphine-
free, Pd-catalyzed coupling reactions. Recently, Do and
Daugulis made a significant breakthrough and discovered
that the ligand-free Cu catalytic system was susceptible to
the C-arylation of a variety of azoles.[6] However, the cou-
À
cross-coupling processes. Direct C H arylation of heterocy-
pling process required a large excess of aryl iodide
cles has been achieved by using Rh,[1a,2] Cu,[3] and more ex-
tensively, Pd-based catalysis.[4] Despite impressive progress
in this area, these methodologies still suffer from several no-
table deficiencies. First, the majority of these reactions re-
quire more reactive, but generally less available and signifi-
cantly more expensive aryl iodides, and only scattered exam-
ples of the use of aryl bromides have emerged. Second, ex-
tended reaction times and/or elevated temperatures (140–
1608C) are often necessary to achieve good yields. Third,
unavailability, high expense, air or moisture sensitivity, and/
or specificity of the ligands (mainly electron-rich, bulky
phosphines), are often encountered in the reactions.[1,2,4]
More importantly, most methods are applied to only a few
types of heterocycles, thus limiting the scope of the method-
ologies.[1,3,4]
(3 equiv). Furthermore, the use of strongly basic tBuOLi
and relatively high temperatures would significantly limit its
scope and functional-group tolerance.
Xanthines (e.g., caffeine, theophylline, and theobromine)
are a type of important biologically active alkaloids. 8-Aryl
or heteroaryl-substituted xanthines are highly potent and se-
lective antagonists for human A2B adenosine receptors.[7]
Traditional strategies for the preparation of such molecules
involve the construction of the xanthine rings by nontrivial
multistep reaction sequences.[8] In contrast, direct arylation
of xanthines at the C8 position should be the shortest and
most efficient route to 8-arylated xanthines for the purpose
of medicinal chemistry screening programmes. However,
there are few full investigations, with only two examples
using limited aryl halides.[6,9] In particular, although inexpen-
sive aryl chlorides were employed, the Daugulis methodolo-
gy required the expensive, air-sensitive butyldi-1-adamantyl-
phosphine as a ligand. In contrast, herein we report a novel
phosphine-free catalytic route to the preparation of 8-arylat-
ed xanthines with a relatively high level of functional-group
compatibility.
From an industrial and economic standpoint, a ligand-free
process would provide much-needed impetus for the devel-
opment of improved catalyst systems. In recent years, phos-
À
phine-free, palladium-catalyzed C H bond arylation of
azoles and related heteroarenes have been reported.[5] How-
ever, these methods are typically restricted to only one type
of heterocycle, even under harsh conditions, such as elevat-
ed temperature and/or microwave assistance. Moreover, sto-
Our first exploration for the phosphine-free, palladium-
catalyzed C-arylation of xanthines focused on the coupling
of caffeine 1 with p-bromotoluene 2a (Scheme 1). However,
initial reaction screens led to disappointing results in the ab-
[a] D. Zhao, W. Wang, S. Lian, F. Yang, Prof. Dr. J. Lan, Prof. Dr. J. You
Key Laboratory of Green Chemistry
and Technology of Ministry of Education
College of Chemistry and State Key Laboratory of Biotherapy
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P.R. China)
Fax : (+86)28-85412203
E-mail: jsyou@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802001.
Scheme 1. Arylation of caffeine with p-bromotoluene.
Chem. Eur. J. 2009, 15, 1337 – 1340
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1337

sence of an additive, and the highest yield was 55%
(Table 1, entry 4). Very recently, direct arylations of ben-
zenes with aryl halides have been carried out by cooperative
Table 1. Optimization of the coupling of caffeine with p-bromotoluene.[a]
Entry
Base
Additive
Solvent
Yield [%][b]
Scheme 2. Cooperative metalation deprotonation (CMD) for the aryla-
tion of xanthine; T.M. target molecule.
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Ag2O
tBuOK
Cs2CO3
K3PO4
K3PO4
K3PO4
none
none
none
none
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
tBuCO2H
o-NO2-Ph-CO2H
toluene
dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
<10
30
50
55
85
trace
<10
75
K3PO4), K3PO4 was found to be the most effective (Table 1
entries 4–9). Remarkably, by using a carboxylic acid as the
À
additive enabled efficient C H bond functionalization of
caffeine. Thus, the best results were obtained by using
9
10
11
96
50[c]
60
K3PO4 as a base in the presence of PdACTHUNGRTNEUNG(OAc)2 (5 mol%) in
combination with pivalic acid (10 mol%) in DMF at 1208C
for 7 h.
With optimized conditions now in hand, we explored the
scope of this process with respect to aryl halide structure as
summarized in Scheme 3. It was gratifying to find that our
catalyst system accelerated the arylation of caffeine with a
DMF
[a] Reactions were carried out by using Pd
(2 equiv), additive (10 mol%), caffeine (1 mmol), and p-bromotoluene
(1.5 mmol) in
[c] 908C; 12 h.
ACHTUNGRTEN(NNUG OAc)2 (5 mol%), base
a 1.0m solution for 7 h at 1208C. [b] Isolated yield.
action of palladium or rutheni-
um catalysts and carboxylic
acids through a proton abstrac-
tion mechanism, which was first
proposed by Echavarren and
Maseras.[10] We rationalized
that this concept might be em-
ployed to facilitate this type of
C-arylation of N-heterocy-
cles.[11] As expected, incorpora-
tion of a catalytic amount of
carboxylic acid dramatically im-
proved the coupling of caffeine
with p-bromotoluene. As illus-
trated in the transition-state
model in Scheme 2, the carbox-
ylate anion can lower the
À
energy of C H bond cleavage
and serve as a catalytic proton
shuttle from caffeine to the sto-
ichiometric amount of inorganic
base.[10–11] Obviously, the prefer-
ential regiochemistry for the re-
acting sites that are arylated de-
À
pends on C H acidity, not on
heterocyclic nucleophilicity.
In this model reaction, we
screened several parameters
(e.g., solvent, base, additive,
and temperature) shown in
Table 1. Among the solvents in-
vestigated, DMF was clearly
the best choice (Table 1 en-
tries 1–4). After screening a va-
riety of bases (i.e., K2CO3,
Scheme 3. Catalytic C-arylation of caffeine with a variety of aryl bromides. Reactions were carried out by
using Pd
(1.5 mmol) in a 1.0m DMF solution for 7 h at 1208C. Isolated yield given in parenthesis. Compound 3l was
heated for 24 h. Under standard conditions, compound 3q was formed in 99% yield; when using Pd(OAc)2
(2 mol%) and pivalic acid (10 mol%) for 24 h 98% yield was achieved; when Ag2CO3 (0.5 equiv) was added,
ACHTUGNTREN(NUNG OAc)2 (5 mol%), K3PO4 (2 equiv), pivalic acid (10 mol%), caffeine (1 mmol), and aryl halide
ACHTUNGTRENNUNG
Ag2O, tBuOK, Cs2CO3, and 92% yield was achieved from the aryl iodide.
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Chem. Eur. J. 2009, 15, 1337 – 1340

C-Arylation of N-Heterocycles
COMMUNICATION
wide array of aryl bromides. Whether the aryl bromides
were electron rich, electron poor, or sterically hindered, all
of them afforded good to excellent yields (3a–q). In addi-
tion, we found that heteroaryl bromide was also reactive
(3r). High-yielding arylation was possible with aryl iodide,
but Ag2CO3 (0.5 equiv) had be used as an additive to im-
prove the yield of the desired product (3q).[4c] It is impor-
tant to stress that these reaction conditions were compatible
with the presence of important functional groups such as
ester, cyano, aldehyde, and nitro groups on the aryl bromide,
which may be subject to further synthetic transformations
(3l–p).
the catalytic efficiency. For example, the azoles with a rela-
2
À
tively acidic sp C H bond (i.e., benzothiazole, benzoxazole,
and 4,5-dimethylthiazole) were arylated with p-bromoto-
luene in good yields under the optimized reaction conditions
(4d–f). Interestingly, although recent examples have re-
quired the use of phosphine ligands in these reactions,[13]
both the quinoline N-oxide and 2-p-tolylpyridine N-oxide
underwent arylation to afford the desired products in 82 and
62% yields (4g–h), respectively. In addition to N-heterocy-
cles, our method was also suitable for the pentafluoroben-
zene (4i, 80% yield).[14]
In conclusion, we have developed a new palladium-cata-
lyzed methodology that allows, for the first time, the direct
C-arylation of azoles with a broad spectrum of aryl bro-
mides without the presence of phosphines, the aid of CuI, or
other metal additives by using pivalic acid as a cocatalyst.
This process also allows the direct C-arylation of the N-het-
erocycle N-oxides, and to a lesser extent, the perfluoroaro-
matics. Particularly noteworthy is that our protocol can tol-
erate an array of functional groups such as ester, nitrile,
nitro, aldehyde, methoxy, trifluoromethyl, fluoro, and chloro
substituents. This work should find wide applications in syn-
thetic and medicinal chemistry both in industry and in aca-
demia.
Although not yet investigated in detail, the arylation of
caffeine could occur with substantially low catalyst loading.
As shown for 3q in Scheme 3, the coupling of caffeine with
p-methoxybromobenzene was performed in 98% yield with
2 mol% of Pd
(24 h).
ACHTUNGTRENNUNG(OAc)2 despite the extended reaction time
We subsequently determined that our method was not
only applicable to the synthesis of 8-aryl-substituted caf-
feines, but also 8-arylated theophyllines and theobromines.
In this context, theophylline and theobromine were first
converted into the corresponding xanthine derivatives by
modification at the N1 or N7 position, followed by coupling
with the aryl bromide (Scheme 4, 4a–c). For example, ben-
zylic theophylline and theobromine were arylated with p-
bromotoluene in 85 and 95% yields, respectively (Scheme 4,
4a,b). The benzylic group may also be removed by hydroge-
Acknowledgements
nation to afford important biologically active 8-arylated free
This work was supported by grants from the National Natural Science
Foundation of China (nos. 20572074, 20602027 and 20772086). We also
thank the Centre of Testing and Analysis, Sichuan University for NMR
spectroscopy measurements.
[7,12]
À
(NH) xanthines.
Keywords: arylation · ligand-free synthesis · heterocycles ·
palladium · pivalic acid
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Received: September 29, 2008
Published online: December 29, 2008
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