A palladium/copper bimetallic catalytic system: Dramatic improvement for Suzuki-Miyaura-type direct C-H arylation of azoles with arylboronic acids

Article abstract of DOI:10.1002/chem.201001338

Bimetallic catalytic system: Palladium/copper bimetallic-catalyzed Suzuki-Miyaura-type coupling has been disclosed for direct C-H arylation of azoles, instead of azole halides or pseudohalides, with arylboronic acids (see scheme).

Full text of DOI:10.1002/chem.201001338

DOI: 10.1002/chem.201001338
A Palladium/Copper Bimetallic Catalytic System: Dramatic Improvement for
À
Suzuki–Miyaura-Type Direct C H Arylation of Azoles with
N
rylboronic Acids
Bo Liu, Xurong Qin, Kaizhi Li, Xiyu Li, Qiang Guo, Jingbo Lan, and Jingsong You*[a]
The Suzuki–Miyaura coupling ranks as one of the most
powerful and reliable biaryl forming reactions.[1] Traditional-
ly, these transition-metal catalyzed cross-couplings require
aryl halides or pseudohalides to react with boronic acids.[2]
As a variety of metal-mediated biaryl formations through
arylation of azoles with arylboronic acid hitherto. In this
context, we wish to develop an efficient general methodolo-
gy to achieve the direct Suzuki–Miyaura-type coupling of a
wide range of azoles with arylboronic acids.
Our initial exploration focused on the monometallic palla-
À
À
aromatic C H activation have been popularized, the
dium(II)-catalyzed C H arylation of various azoles with ar-
ylboronic acids in the presence of inorganic oxidants (e.g.,
Suzuki–Miyaura-type reactions, in which aryl halides or
pseudohalides are replaced by (hetero)arenes, have recently
attracted attention. This type of cross-coupling is not only
an efficient and complementary process to form biaryls, but
also is in connection with sustainable chemistry. Whereas
CuACTHUNTGRNEUNG(OAc)2, Ag2CO3, and Ag2O), organic oxidants (e.g.,
DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), and BQ
(benzoquinone)), and/or dioxygen (O2). Whereas p-electron
excessive five-membered heterocycles (i.e., thiophenes,
furans, and pyrroles) smoothly coupled with arylboronic
acids through an electrophilic mechanism, the azoles investi-
gated herein gave only trace amount to low yields of the de-
sired products.[4,5] Although both types of heteroarenes are
electron-rich, the C2 sites of azoles are relatively electron-
deficient. We believe that the distinctly differential p-elec-
tronic characteristics may induce the clear distinctness of re-
activity. Owing to the relatively acidic C2 sites, azoles are
À
the Suzuki–Miyaura-type direct C H arylation of arenes
(which generally require a directing group) has been devel-
oped greatly,[3] the coupling of heteroarenes with arylboron-
ic acids still remains elusive. In comparison with arenes, het-
eroarenes themselves are susceptible to oxidative homocou-
pling and decomposition as well as self-coupling of arylbor-
onic acids in the presence of a PdII species. As far as we
know, only a few successful examples relative to heteroar-
enes have been described so far. Shi et al. described a PdII-
catalyzed cross-coupling of electron-rich heteroarenes (i.e.,
pyrrole, furan, and thiophene derivatives) with arylboronic
acids under mild conditions.[4] Studer et al. reported the first
À
unsusceptible to electrophilic C H substitution (SEAr) of
PdII under mild conditions. Considering that CuI salts have
À
been used as catalysts or activators in direct C H arylations
of azoles,[7] we envisioned whether the additional introduc-
I
À
À
direct C H arylation of indoles with arylboronic acids and
tion of a catalyic amount of Cu salt could assist the C2 H
the 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO)
as an external mild oxidant at room temperature.[5] Al-
though the aryl–azole structural motifs are ubiquitous in
biologically important natural products, synthetic pharma-
bond activation to generate an azole–copper species, which
could undertake a transmetalation to arylpalladium(II) in-
termediate to enable a catalytic cycle. Herein, we disclose
an efficient palladium/copper co-catalytic system for the
direct C H arylation of a variety of azoles with arylboronic
acids to extend current synthetic methodologies.
ceuticals, and materials,[6] it is unknown that the direct C H
À
À
Xanthines (e.g., caffeine, theophylline, and theobromine)
are important biologically active alkaloids with imidazole
skeletons. 8-(Hetero)aryl-substituted xanthines are highly
potent and selective antagonists at human A2B adenosine re-
ceptors.[8] Following our continuing interest in the direct C
arylation of xanthines, we initially focused on the heterocou-
pling of caffeine 1 with phenylboronic acid 2a (Scheme 1).
In this model reaction we screened several parameters (e.g.,
oxidant, base, solvent, and additive) shown in Table 1.
[a] B. Liu, X. Qin, K. Li, X. Li, Q. Guo, 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.201001338.
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Chem. Eur. J. 2010, 16, 11836 – 11839

COMMUNICATION
With optimized conditions now in hand, we explored the
scope of this methodology with respect to arylboronic acid
structure as summarized in Table 2. It was gratifying to find
Table 2. Catalytic C arylation of caffeine with various arylboronic acids.[a]
À
Scheme 1. Direct C H arylation of caffeine with phenylboronic acid.
Table 1. Optimization of the coupling of caffeine with phenylboronic
acid.[a]
Entry Oxidant
Base
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
BQ
DDQ
O2
Ag2O
Ag2CO3
KF
KF
KF
KF
KF
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
dioxane
trace
trace
trace
trace
trace
46
42
38
30
trace
trace
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
9
10
11
12
13
14
15
16
17
o-xylene trace
DMF
NMP
NMP
NMP
56
62
76
[a] Conditions: Reactions were carried out by using Pd
ACHTUNGRTEN(NGNU OAc)2 (5 mol%), Cu-
AHCTUNGTRENNUNG
CuCl
CuBr
CuCl+BQ NMP
(0.5 mmol), and arylboronic acid (1.0 mmol) in a 0.5m NMP solution for 30 h at
808C (isolated yields in parentheses).
66
82[c]
[a] Reactions were carried out by using PdACTHNUGRTENNUG(OAc)2 (5 mol%), CuACHUTNGTREN(NUGN OAc)2
(1 equiv), base (1 equiv), copper(I) salt (10 mol%), caffeine (0.5 mmol),
and phenylboronic acid (1 mmol) in a 0.5m solution for 30 h at 808C.
[b] Isolated yields. [c] 0.5 equiv of BQ. DMSO=dimethyl sulfoxide,
TBAF=tetra-n-butylammonium fluoride, DMF=N,N-dimethylforma-
mide, NMP=N-methyl-2-pyrrolidone.
that our catalyst system accelerated the arylation of caffeine
with a wide array of arylboronic acids. Whether the arylbor-
onic acids were electron-rich or electron-poor, all of them
afforded good to excellent yields (Table 2, 3a–k). Owing to
the importance of fluorobiaryl products in medicinal and
materials chemistry, fluoroarylboronic acids were investigat-
ed accordingly. The reaction conditions were also suitable
for a variety of fluoroarylboronic acids (Table 2, 3i–k).
Among the oxidants investigated, CuACTHNUTRGENUG(N OAc)2 was the best
choice (Table 1, entries 1–6). After screening a variety of
bases (e.g., KF, K3PO4, Cs2CO3, Na2CO3, and TBAF·3H2O),
KF was found to be the most effective (Table 1, entries 6–
10). Subsequently, a 62% yield of heterocoupling product
was obtained in NMP by using one equivalent of KF as the
We next applied this protocol to other xanthines to pre-
pare 8-aryl theophylline and theobromine derivatives in
good to excellent yields (Table 3, entries 4a–c). Simple
purine heterocycles are attractive as “functional” p compo-
nents in organic materials with biological relevance.[9] Re-
cently, C arylation of purines has started to attract inter-
est.[10] Our methodology could be applicable to the synthesis
of various 8-arylated purines (Table 3, entries 4d–f). In addi-
tion to these important alkaloids, this bimetallic catalytic
system was proven to effectively promote the cross-coupling
of a relatively wide range of azoles (e.g., benzoimidazole,
benzoxazole, thiazoles, and oxadiazoles) with arylboronic
acids to give moderate to good yields with excellent regiose-
base and CuACHTUNGTRENNUNG(OAc)2 as the oxidant (Table 1, entries 6 and
11–14). Excitingly, as a catalytic amount of CuI was em-
ployed as the co-catalyst, catalytic efficiency could be im-
proved significantly. Copper(I) chloride was proven to be
superior to other sources of the copper salt (Table 1,
entry 15).
It is well known that the transmetalation between arylbor-
onic acids and PdII species readily leads to undesired homo-
coupling of arylboronic acids, which suppresses the genera-
tion of the cross-coupling product. BQ has been widely used
as the oxidant or additive in some oxidative cross-coupling
reactions. To our delight, addition of BQ restrained the ho-
mocoupling to improve the yield of target compound upon
to 82% (Table 1, entry 17). Thus, the best result was ob-
lectivity (at a relatively acidic CACTHNUTRGNEUNG
(sp2) position; Table 3, en-
tries 4g–m).
It is important to stress that the cross-coupling reactions
of azoles investigated in Table 3 proceeded more sluggishly
in the absence of CuCl, and the yields of aryl azoles general-
ly decreased to around 15–30%. Based on this observation,
this type of Suzuki–Miyaura coupling is assumed to mainly
involve two plausible catalytic routes: 1) The CuCl-mediated
process might occur through the formation of the azole–
tained by using 1 equiv of Cu
of KF as the base, and 0.5 equiv of BQ as the additive in the
presence of bimetallic catalytic system of Pd(OAc)2 (5
mol%) and CuCl (10 mol%) in NMP at 808C for 30 h.
ACHTUNGRTEN(NUNG OAc)2 as the oxidant, 1 equiv
AHCTUNGTRENNUNG
Chem. Eur. J. 2010, 16, 11836 – 11839
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J. You et al.
Table 3. Catalytic C arylation of (hetero)arenes with boronic acids.[a]
ylboronic acids (Scheme 3).[14] Interestingly, this bimetallic
catalytic method was capable of allowing the direct synthesis
À
of 3-arylated indolizines from indolizine through the C H
arylation with arylboronic acids in one step.
Scheme 3. Synthesis of 3-arylated indolizines.
In conclusion, we have developed for the first time a class
À
of Suzuki–Miyaura-type direct C H arylation of azoles in-
stead of azole halides or pseudohalides with arylboronic
acids. The bimetallic catalytic system not only allows the C
arylation of a broader spectrum of azoles with various aryl-
boronic acids under relatively mild conditions, but is also ap-
plied to the direct synthesis of 3-arylated indolizines from
indolizines. We believe that this methodology would provide
a powerful complement for the traditional Suzuki–Miyaura
coupling reactions.
[a] Conditions: Reactions were carried out by using Pd
(OAc)2 (1 equiv), KF (1 equiv), CuCl (10 mmol%), BQ (0.5 equiv), hetero-
arene (0.5 mmol), and arylboronic acid (1.0 mmol) in a 0.5m NMP solution
for 30 h at 1008C (isolated yields in parentheses). [b] 808C. [c] 1208C. [d] Cu-
(PPh3)2NO3 (10 mmol%) was added instead of CuCl.
ACHTUNGRTEN(NGNU OAc)2 (5 mol%), Cu-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
copper species IM2, and subsequent transmetalation with ar-
ylpalladium species IM1 to form the key heterocoupling in-
termediate IM3, followed by reductive elimination to pro-
duce the desired product. Pd0 could be reoxidized by Cu-
Experimental Section
A flame-dried Schlenk test tube with a magnetic stirrer bar was charged
with Pd
ACHTUNGTRENNUNG
onic acid (1.0 mmol), CuAHCTUNTGRENNUNG
ACHTUNGTRENNUNG(OAc)2 to complete the catalytic cycle; 2) Given that other
(0.25 mmol), KF (0.5 mmol), and NMP (1.0 mL) under N2. A rubber
septum was replaced with a glass stopper, and the system was then evacu-
ated twice and back-filled with N2. The reaction mixture was stirred for
5 min at room temperature, and then heated at the indicated temperature
for 30 h. The reaction mixture was then cooled to ambient temperature,
diluted with CH2Cl2 (20 mL), filtered through a celite pad, and washed
with CH2Cl2 (10–20 mL). The combined organic extracts were concen-
trated and the resulting residue was purified by column chromatography
on silica gel to provide the desired product.
oxidants including inorganic oxidants, organic oxidants, and/
or dioxygen mentioned above were completely incapable of
fulfilling the catalytic cycle, we rationalized that an (even
catalytic) amount of copper(I) formed from CuACTHNUGTRENUNG(OAc)2 could
promote the formation of the azole–copper species to carry
out the transmetalation in the absence of CuCl
(Scheme 2).[7,11,12]
Acknowledgements
This work was supported by grants from the National NSF of China (Nos
20972102, 20872101 and 20772086) and PCSIRT (No IRT0846). We
thank the Centre of Testing & Analysis, Sichuan University for NMR
measurements.
Scheme 2. Plausible catalytic cycle of Suzuki–Miyaura-type direct C-aryl-
ACHTUNGTRENNUNGation of azoles with arylboronic acids.
À
Keywords: bimetallic catalysis · C H activation · copper ·
heteroarenes · palladium · Suzuki–Miyaura coupling
Indolizine derivatives are a type of N-fused heterocycles
broadly found in biologically important natural products
and synthetic pharmaceuticals.[13] The synthesis of 3-arylated
indolizines described previously required two steps, in which
indolizine was first pre-activated to 3-chloroindolizine, and
then underwent a typical Suzuki–Miyaura coupling with ar-
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Pd/Cu Bimetallic Catalytic System
COMMUNICATION
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Received: May 17, 2010
Published online: September 6, 2010
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