Oxygen as an oxidant in palladium/copper-cocatalyzed oxidative C-H/C-H cross-coupling between two heteroarenes

Article abstract of DOI:10.1007/s11426-015-5386-x

The palladium/copper-cocatalyzed oxidative C-H/C-H cross-coupling between two heteroarenes by using molecular oxygen as an oxidant instead of metal oxidants has been developed for the first time to construct biheteroaryl motifs. A relatively broad range of thiophenes, furans and indoles can smoothly couple with various N-heteroarenes in satisfactory yields. This catalytic system with O₂ as the terminal oxidant offers clear advantages of economically feasible and eco-friendly processes.

Full text of DOI:10.1007/s11426-015-5386-x

SCIENCE CHINA
Chemistry
• ARTICLES •
doi: 10.1007/s11426-015-5386-x
· SPECIAL ISSUE · CH bond activation
Oxygen as an oxidant in palladium/copper-cocatalyzed oxidative
C–H/C–H cross-coupling between two heteroarenes
Yang Shi, Zhen Wang, Yangyang Cheng, Jingbo Lan, Zhijie She & Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education; College of Chemistry, Sichuan University,
Chengdu 610064, China
Received November 27, 2014; accepted January 7, 2015
The palladium/copper-cocatalyzed oxidative C−H/C−H cross-coupling between two heteroarenes by using molecular oxygen
as an oxidant instead of metal oxidants has been developed for the first time to construct biheteroaryl motifs. A relatively broad
range of thiophenes, furans and indoles can smoothly couple with various N-heteroarenes in satisfactory yields. This catalytic
system with O2 as the terminal oxidant offers clear advantages of economically feasible and eco-friendly processes.
biheteroaryl, molecular oxygen, C−H/C−H cross-coupling, green chemistry
molecular oxygen as an oxidant to deliver biheteroaryl
structures (Scheme 2).
1 Introduction
The biheteroaryl structural motif is ubiquitous in various
natural products, pharmaceuticals and organic functional
materials (Scheme 1) [1]. From the viewpoint of synthetic
simplicity and atom economy, transition metal-catalyzed
oxidative C–H/C–H cross-coupling reactions between two
heteroarenes are undoubtedly one of the most ideal strate-
gies to forge heteroaryl-heteroaryl linkages [2]. However,
these reactions often require stoichiometric amounts of sil-
ver (I), or copper (II) salts as oxidants. Employing atmos-
pheric oxygen or molecular oxygen as an oxidant would
clearly make them more economic, practical and environ-
mentally-friendly. Over the past decade, considerable atten-
tions have been focused on various oxidative coupling reac-
tions by using oxygen as an oxidant [3]. However, oxygen
as an oxidant in transition metal-catalyzed oxidative C–H/
C–H cross-coupling between two different heteroarenes
remains unexplored. Herein, we report an efficient palladium/
copper-cocatalyzed oxidative C–H/C–H cross-coupling of
thiophenes, furans and indoles with N-heteroarenes by using
Scheme 1 Selected medicinal and natural molecules containing bihet-
eroaryl structural motif.
Scheme 2 Palladium/copper-cocatalyzed oxidative C–H/C–H cross-
coupling of thiophenes, furans and indoles with heteroarenes by using O2
as an oxidant.
*Corresponding author (email: jsyou@scu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

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Shi et al. Sci China Chem June (2015) Vol.58 No.6
2 Experimental
3 Results and discussion
Xanthine (3,7-dihydro-purine-2,6-dione) is a kind of purine
bases found in most human body tissues and fluids and in
other organisms [4]. 8-Heteroaryl-substituted xanthines are
potent antagonists at human A2B adenosine receptors [5].
Therefore, the oxidative C–H/C–H cross-coupling of thio-
phenes and furans with xanthines (e.g., caffeine, theophyl-
line, and theobromine) to prepare 8-heteroaryl-substituted
xanthines was first investigated. Based on our recent re-
search progresses in oxidative C–H/C–H cross-coupling [6],
caffeine (1a) and 2-formylthiophene (2a) were chosen as
model substrates to optimize the reaction condition (Table
1). Gratifyingly, the biheteroaryl 3a was obtained in 33%
yield by using O2 as the oxidant (Entry 1). It is known that
copper salts have been used as catalyst or activator in direct
C–H arylation of N-heteroarenes. The addition of 20 mol%
of Cu(OAc)2·H2O as an additive significantly improved the
yield from 33% to 71% (Entry 2). The reduction of the
amount of Cu(OAc)2·H2O resulted in a decreased yield of
58% (Entry 3). We rationalized that a relatively acidic
C2–H bond of azole might undergo C–H cupration with
Cu(OAc)2 and subsequent transmetalation with the hetero-
aryl-PdLn species to form the key heterocoupling interme-
diate heteroaryl-Pd-azole complex [6a–6c]. After screening
several palladium catalysts, Pd(dppf)Cl2 proved to be supe-
rior to Pd(OAc)2, Pd(MeCN)2Cl2, Pd(PPh3)2Cl2, Pd(acac)2,
and Pd(PPh3)4, which improved the coupling yield to 95%
(Entries 4–9). It should be noted that the reaction even
smoothly underwent in 83% yield under air (Entry 10). Fi-
nally, the catalytic system composed of Pd(dppf)Cl2 (2.5
mol%) and pyridine (1.0 equiv.) gave the best result (95%
yield) in the presence of 1 atm of O2 as the terminal oxidant
and 20 mol% of Cu(OAc)2·H2O as a cocatalyst in 1,4-di-
oxane at 140 °C for 30 h.
2.1 General methods
NMR spectra were obtained on a Bruker AMX-400 (Swit-
zerland) or a Varian Inova 400 spectrometer. The H NMR
1
(400 MHz) chemical shifts were measured based on CDCl3
or DMSO-d6 or TMS as the internal reference (CDCl3,
=7.26 ppm; DMSO-d6, =2.50 ppm; TMS, =0.00 ppm).
The 13C NMR (100 MHz) chemical shifts were given using
CDCl3 or DMSO-d6 as the internal standard. High-resolution
mass spectra (HR-MS) were obtained with a Waters-Q-
TOF-Premier (ESI, U.K.). Unless otherwise noted, all rea-
gents were commercially available and used without further
purification.
2.2 Optimization of the oxidative C–H/C–H cross-
coupling between two heteroarenes by using O2 as the
terminal oxidant
A flame-dried Schlenk test tube with a magnetic stirring bar
was charged with Pd catalyst (0.0125 mmol, 2.5 mol%),
additive, caffeine (1a, 97 mg, 0.5 mmol), pyridine (0.5
mmol, 1.0 equiv.) and 1,4-dioxane (1.0 mL). After the reac-
tion mixture was stirred for 10 min at room temperature,
2-formylthiophene (2a, 168.2 mg, 1.5 mmol, 3.0 equiv.)
was added. The resulting mixture was heated at 140 °C for
30 h under 1 atm of oxygen or air, and then cooled to am-
bient temperature. The mixture was diluted with 30 mL of
CH2Cl2, filtered through a celite pad, and then washed with
10–20 mL of CH2Cl2. The combined organic extracts were
concentrated and the resulting residue was purified by col-
umn chromatography on silica gel (CH2Cl2/acetone=14:1,
v/v) to provide 1,3,7-trimethyl-8-(5-formylthiophen-2-yl)-
xanthine (3a) as a yellow solid.
With the optimized conditions in hand, we next explored
the scope of the methodology with respect to the -electron-
rich heteroarenes. As summarized in Table 2, a wide array
of -electron-rich heteroarenes (e.g., thiophenes, furans,
indoles, benzothiophenes and benzofurans) smoothly cou-
pled with caffeine to give the desired biheteroaryl products
in moderate to excellent yields (3a–3k). No matter het-
eroarenes contain an electron-donating or electron-with-
drawing group, all of them could be well converted to the
desired products. A variety of functional groups such as
aldehyde, methoxyl, acetyl and cyan could be highly toler-
ated under the reaction conditions. To our delight, 2-metho-
xylthiophene, which exhibited a low reactivity by using
stoichiometric amounts of Cu(OAc)2·H2O in our previously
reported catalytic system [6a], could proceed well under our
catalytic system with O2 as the terminal oxidant (3c). Wor-
thy of note was that the coupling reaction occurred at the
sterically less hindered C5-position when 3-methylthio-
phene was used as a coupling partner (3d).
2.3 General procedure for the oxidative C–H/C–H
cross-coupling of thiophenes and furans with N-
heteroarenes using O2 as the terminal oxidant
A flame-dried Schlenk test tube with a magnetic stirring bar
was charged with Pd(dppf)Cl2 (0.0125 mmol, 2.5 mol%),
Cu(OAc)2·H2O (0.1 mmol, 0.2 equiv.), N-heteroarene (1,
0.5 mmol), pyridine (0.5 mmol, 1.0 equiv.) and 1,4-dioxane
(1.0 mL). After the reaction mixture was stirred for 10 min
at room temperature, thiophene, furan or indole (2, 1.5
mmol, 3.0 equiv.) was added. The resulting mixture was
heated at 140 °C for 30 h under 1 atm of oxygen, and then
cooled to ambient temperature. The mixture was diluted
with 30 mL of CH2Cl2, filtered through a celite pad, and
then washed with 10–20 mL of CH2Cl2. The combined or-
ganic extracts were concentrated and the resulting residue
was purified by column chromatography on silica gel to
provide the desired product.

Shi et al. Sci China Chem June (2015) Vol.58 No.6
3
Table 1 Optimization of the oxidative C−H/C−H cross-coupling of 1a
with 2a by using O2 as the terminal oxidant a)
To further expand the scope of methodology, we applied
this protocol to other N-heteroarenes for the synthesis of
biheteroarenes (Table 3). Purines as “functional” -compo-
nents are prevalent in organic functional molecules with
biological relevance [7]. Recently, direct arylation of pu-
rines has attracted a growing number of attentions [8]. To
our delight, various purine derivatives could couple with a
series of thiophenes in satisfactory yields under O2 atmos-
phere (4a–4k). Dimethylamino, widely used as a functional
group in organic functional materials, was also well toler-
ated under the current catalytic system. The (hetero)aryl
indolizine units are a type of important components of nat-
ural products, fluorescent materials and bioactive molecules
[9]. Our protocol was also suitable for the synthesis of thi-
ophenyl-substituted indolizines (4l–4o).
Biheteroaryls containing pyridines and related azines are
frequently found in natural products, pharmaceuticals, and
functional synthetic materials [10]. One of the most effec-
tive methods for the construction of these biheteroaryl link-
ages would be the direct C–H (hetero)arylation of electron-
poor N-heteroarene N-oxides due to the high reactivity
of C–H bond adjacent to the nitrogen atom [11]. It was
Entry
Pd source
Pd(OAc)2
Addtive (equiv.)
Yield (%) b)
1
33
71
58
53
54
63
86
95
82
83
82
84
72
–

2
Pd(OAc)2
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.2)
3
Pd(OAc)2
4
Pd(MeCN)2Cl2
Pd(PhCN)2Cl2
Pd(PPh3)2Cl2
Pd(acac)2
5
6
7
8
Pd(dppf)Cl2
Pd(PPh3)4
9
10 c)
11 d)
12
13 e)
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(OAc)2
a) Reaction conditions: caffeine (1a, 0.5 mmol), 2-formylthiophene (2a,
3.0 equiv.), Pd source (2.5 mol%), additive, and pyridine (1.0 equiv.) in
1,4-dioxane (1.0 mL) at 140 °C for 30 h under 1 atm of O2 or air; b) iso-
lated yield based on caffeine; c) under air; d) the reaction was carried out at
130 °C; e) dppf (2.5 mol%) was added.
Table 3 Scope of oxidative C–H/C–H cross-coupling of N-heteroarenes
with a variety of thiophenes a, b)
Table 2 Scope of oxidative C–H/C–H cross-coupling of caffeine with a
variety of thiophenes or furans or indolea, b)
a) Reaction conditions: caffeine (1a, 0.5 mmol), thiophene, furan or
indole (2, 3.0 equiv.), Pd(dppf)Cl2 (2.5 mol%), Cu(OAc)2·H2O (0.2 equiv.),
and pyridine (1.0 equiv.) in 1,4-dioxane (1.0 mL) at 140 °C for 30 h under
1 atm of O2; b) isolated yield based on caffeine after column chromatog-
raphy.
a) Reaction conditions: N-heteroarene (1, 0.5 mmol), thiophene or furan
(2, 3.0 equiv.), Pd(dppf)Cl2 (2.5 mol%), Cu(OAc)2·H2O (0.2 equiv.), and
pyridine (1.0 equiv.) in 1,4-dioxane (1.0 mL) at 140 °C for 30 h under 1
atm of O2; b) isolated yield based on N-heteroarene after column chroma-
tography.

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Shi et al. Sci China Chem June (2015) Vol.58 No.6
Table 4 Scope of oxidative C–H/C–H cross-coupling of N-heteroarene
N-oxides with a variety of thiophenes or furans a, b)
This work was supported by the National Basic Research Program of Chi-
na (2011CB808601), the National Natural Science Foundation of China
(21432005, 21372164, 21172155, 21272160, 21321061, J1103315) and
Sichuan Provincial Foundation (2012JQ0002). We thank the Comprehen-
sive Training Platform of Specialized Laboratory, College of Chemistry,
Sichuan University for NMR measurements.
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column chromatography.
delightful that our catalytic system with O2 as the terminal
oxidant could also effectively promote the cross-coupling of
various N-heteroarene N-oxides (e.g., pyridine N-oxide,
quinoline N-oxide, and quinoxaline N-oxide) with thio-
phenes or furans at the C2 position of N-heteroarene
N-oxides (Table 4). It was noteworthy that the synthesis of
2-(5-methylthiophen-2-yl)-quinoline N-oxide (5a) could be
performed without problems on gram scale (~2 g), which
avoided the use of stoichiometric amounts of metal oxidant
and should represent a potential bench-scale preparation.
4 Conclusions
In summary, we have developed a Pd(II)/copper-cocatal-
yzed oxidative C–H/C–H cross-coupling of -electron-rich
five-membered heterocycles (e.g., thiophenes, furans, in-
doles, benzothiophenes and benzofurans) with various
N-containing heteroarenes (e.g., purines, indolizines and
N-heteroarenes N-oxides) by using molecular oxygen as the
terminal oxidant. A variety of functional groups are well
tolerated under the catalytic system. We anticipate that this
facile and efficient process may be emerged as a powerful
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