Palladium(II)-catalyzed oxidative C-H/C-H cross-coupling of heteroarenes

Article abstract of DOI:10.1021/ja909807f

(Chemical Presented) An efficient methodology for the synthesis of unsymmetrical biheteroaryl molecules has been developed via Pd(II)-catalyzed oxidative C-H/C-H cross-coupling of heteroarenes. An inversion in reactivity and selectivity has been achieved

Full text of DOI:10.1021/ja909807f

Published on Web 01/26/2010
Palladium(II)-Catalyzed Oxidative C-H/C-H Cross-Coupling of Heteroarenes
Peihua Xi, Fan Yang, Song Qin, Dongbing Zhao, Jingbo Lan, Ge Gao, Changwei Hu,* and
Jingsong 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, PR China
Received November 19, 2009; E-mail: jsyou@scu.edu.cn
The structural motif with heteroaryl-heteroaryl bonds is a
predominant substructure of many natural products, pharmaceuti-
cals, and electronic materials. Conventional wisdom states that these
carbon-carbon biheteroaryl linkages are forged via transition metal
catalyzed cross-coupling of a heteroaryl halide or pseudohalide with
a heteroaryl organometallic reagent.1 However, preactivation of
heteroaromatic carbon fragments with metal-containing function-
alities and halides may involve several synthetic steps. In particular,
some important types of heteroaryl organometallic compounds have
Figure 1. Evolution of transition metal catalyzed oxidative (hetero)arylation
of heteroarenes via double C-H activation.
proven challenging to synthesize and may even be inadequately
stable to participate in the cross-coupling process. Thus, catalytic
oxidative C-H/C-H cross-coupling of two heteroarenes would be
the most ideal strategy to solve the problems (Figure 1, C).
with a low catalyst loading of 2.5 mol % of Pd(OAc)2 to afford
93% yield of 2a with complete regioselectivity (Table 1, entry 1).
Transition metal catalyzed direct (hetero)arylation of (hetero)are-
An X-ray analysis of single crystals 2a confirmed that a direct C-H/
nes has emerged and continues to attract worldwide interest, in
C-H cross-coupling took place between C-5 on 2-formylthiophene
which one of two coupling partners, mostly the more troublesome
and C-8 on caffeine (Figure S1a).
(hetero)aryl organometallic species, is substituted with a simple
(hetero)arene itself.2 Quite recently, Fagnou and co-workers made
Subsequently, a variety of thiophenes and furans were tested with
xanthines (e.g., caffeine, n-butyl theophylline, benzylic theophylline,
a significant breakthrough in the Pd(II)-catalyzed oxidative cross-
benzylic theobromine, and 1,3-diethyl xanthine) (Table 1). These
coupling of unpreactivated heteroaryls with simple unactivated
arenes through 2-fold C-H activation (Figure 1, B).3-5 However,
results demonstrated that thiophenes and furans with a relatively
broad range of substituents afforded good to excellent yields.
the metal-catalyzed oxidative cross-coupling of two heteroaryl C-H
Worthy of note was that the reaction of benzothiophene or
benzofuran with caffeine exclusively gave rise to the heteroarylated
products at the 2-position of benzothiophene and benzofuran in 93%
and 66% yields, respectively (Table 1, entries 7 and 10). Interest-
ingly, the reaction of free (NH)-1,3-diethyl xanthine proceeded well
(Table 1, entry 14).
bonds to form unsymmetrical biheteroaryl molecules remains a
daunting hindrance (Figure 1, C).6 Herein, we wish to explore the
Pd(II)-catalyzed C-H/C-H cross-coupling of various N-containing
heteroarenes (e.g., azoles, and pyridine N-oxides) with π-electron-
excessive five-membered heterocycles (e.g., thiophenes, and furans)
(eq 1). We envisioned whether the distinctly differential π-electronic
characteristics between the two types of heteroarenes would
facilitate an inversion in reactivity/selectivity in the two metalation
steps of the catalytic cycle.5a However, we may face a formidable
challenge as such electron-rich five-membered heteroarenes are
susceptible to oxidative homocoupling in the presence of Pd(II)
salts (Figure 1, A).7 In this study, we describe the discovery,
development, and solution of reactions that meet these challenges.
Although more detailed investigations of the reaction mechanism
are currently underway, in combination with the DFT calculation
based on the coupling of N-methylimidazole and thiophene, we
proposed a plausible catalytic cycle illustrated in Figure 2 (for the
detailed DFT calculation, see Supporting Information). In the first
metalation step, the DFT calculation suggested that the abstraction
of hydrogen from thiophene should easily take place in the reaction
system. Thus, thiophene would undertake a regioselective electro-
philic C-H substitution (SEAr) of Pd(OAc)2 to generate R-thie-
nylpalladium(II) intermediate IM2 (Figure 3).7a In the second
metalation step, although the calculation showed that dithiophene
might be generated from IM2 via the electophilic transition state
Side-TS (Figure 3b), as compared to the intermediate IM3 related
to the heterocoupling (Figure 3a), the intermediate Side-IM3 related
to the homocoupling might be an unstable complex because its
relative energy is higher than IM2. Therefore, when catalyst,
thiophene, and N-methylimidazole coexist in the reaction system,
IM3 might be the predominant intermediate after the formation of
IM2. It demonstrated that the catalytic system inverted its selectivity
in the crucial metalation step to react with the other heteroarene.
Subsequently, IM3 would go through the concerted metalation-
Xanthines are important biologically active alkaloids. 8-Het-
eroaryl-substituted xanthines are highly potent antagonists at human
A
2B adenosine receptors.8 Following our continuing interest in the
direct C-arylation of xanthines,9 we initially focused on the cross-
coupling of caffeine with 2-formylthiophene with Pd(OAc)2 (Table
S1). After screening several parameters (e.g., solvent, oxidant,
additive, and temperature), a catalytic system comprising Pd(OAc)2
as catalyst, Cu(OAc)2 ·H2O as oxidant, pyridine, and 1,4-dioxane
proved to be efficient. Gratifyingly, the heteroarylation could occur
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1822 J. AM. CHEM. SOC. 2010, 132, 1822–1824
10.1021/ja909807f  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope of Oxidative Cross-Coupling of Xanthines with a
Variety of Thiophenes or Furansa
Figure 3. Energy profiles of (a) the heterocoupling of N-methylimidazole
and thiophene and (b) the homocoupling to dithiophene from IM2 calculated
at the B3LYP/6-311++G(2d,2p), SDD level. Relative energies in kJ/mol
are listed in parentheses. Color code: C (gray), N (blue), O (red), S (yellow),
Pd (cyan), and H (white). Also see Figures S2 and S3.
To further expand the scope of methodology, the cross-coupling
of other N-heteroaromatic substrates with various furans or
thiophenes were investigated (Table 2). It was gratifying to find
that N-methylbenzimidazole was heteroarylated with 2-formylth-
iophene or 2-formylfuran in satisfactory yields (Table 2, entries
1-2). Notably, the reaction of N-methylimidazole with 2-formylth-
iophene gave 2-substituted N-methylimidazole 2q as a major
product (56%) together with a small amount of 2,5-disubstituted
N-methylimidazole 2q′ (10%) (Table 2, entry 3).12 The structure
of 2q was confirmed by an X-ray analysis (Figure S1b). In contrast,
the reaction of benzoxazole with 2-formylthiophene gave a low
yield of heterocoupling product (23%). Fortunately, addition of 20
mol % of CuCl and 20 mol % of 1,10-phenanthroline dramatically
improved the heterocoupling up to 55% yield (Table 2, entry 4).
In addition to the above-mentioned π-electron-rich azoles, 3-un-
substituted indolizine could also couple with 2-acetylthiophene to
furnish 2s in 60% yield (Table 2, entry 5).
To our delight, our synthetic strategy was also suitable for
π-electron-poor N-heteroarene N-oxides while CuBr (10 mol %)
was used as additive.5d For example, quinoline and pyridine
N-oxides were monoheteroarylated with 2-methylthiophene, 2,3-
dimethylfuran, 2-formylthiophene, or benzothiophene to afford the
corresponding heterocoupling products in moderate to good yields
(Table 2, entries 6-12). In addition, it is noteworthy that the
synthesis of 2-(5-methylthiophen-2-yl)-quinoline N-oxide (2t) was
performed without problems on an ∼2 g scale, which should
represent a potential bench-scale preparation.
a Reaction conditions: 1 (0.5 mmol), thiophenes or furans (3 equiv),
Pd(OAc)2 (2.5 mol %), Cu(OAc)2 ·H2O (1.5 equiv), pyridine (1.0 equiv),
and 1,4-dioxane (0.6 mL) at 120 °C for 20 h. b Isolated yield based on
1. c CuCl (10 mol %) as additive.
Figure 2. Plausible catalytic cycle of oxidative C-H/C-H cross-coupling
Although these examples used up to 3-4 equiv of one of the
coupling components, the reactions were indeed reasonably selective
for the cross-coupled products as opposed to the statistical distribu-
tion of products. For example, the reactions of 2-formylthiophene
with various azoles gave the homocoupling yields of 2-formylth-
iophene in a range of ∼10% as the reactions arising from
benzothiophene afforded a negligible amount of unwanted biben-
zothiophene.
In summary, we haVe deVeloped for the first time the low catalyst
loading, highly efficient and regioselectiVe Pd(II)-catalyzed oxida-
tiVe cross-coupling of heteroaromatic compounds Via 2-fold C-H
actiVation. The use of substoichiometric Cu(I) as an activator has
been found to induce enhanced reactivity in reactions with azoles
of heteroarenes.
deprotonation (CMD) process to form the key heterocoupling
intermediate IM4, which might be rate-determining in the entire
reaction.10
Considering that Cu(I) salts have been extensively used as
catalyst or activator in direct C-arylation of N-heteroarenes,9a,11
we speculated whether an additional introduction of substoichio-
metric Cu(I) salt into this catalytic system could assist the C-H
bond activation of N-heteroarenes. As expected, a catalytic amount
of CuCl significantly improved catalytic efficiency and regioselec-
tivity (Table 1, entries 3-4, 9-11).
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C O M M U N I C A T I O N S
Supporting Information Available: Data and copies of 1H and 13
C
Table 2. Scope of Oxidative Cross-Coupling of N-Heteroarenes
with a Variety of Thiophenes or Furans
NMR and HRMS spectra for all new compounds, two CIF files, ORTEP
diagrams of 2a and 2b, experimental procedures, and computational
details. This material is available free of charge via the Internet at http://
pubs.acs.org.
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and pyridine N-oxides. This catalytic system allows the C-H/C-H
heterocoupling of not only electron-rich N-containing heteroarenes
(e.g., xanthines, azoles, and indolizines) but also electron-poor
pyridine N-oxides with diverse thiophenes or furans. We anticipate
that this finding may have a broader impact on the synthesis of
unsymmetrical biheteroaryl molecules in medical, material, and
natural product chemistry and have more potential industrial use.
(12) Fagnou and co-workers have described the arylation undergoes C-5 on
N-methylimidazole rather than C-2 as a CMD mechanism is suggested to
occur. On the contrary, Cu(I) salts are known to mediate C-2 arylation on
the same substrate. Therefore, it may be possible that an (even catalytic)
amount of copper(I) formed from copper(II) salts promotes the C-2 arylation
of imidazoles. See: Lie´gault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826 Also see ref 11.
Acknowledgment. This work was supported by grants from
the National NSF of China (Nos 20972102, 20732003, and
20772085) and PCSIRT (No IRT0846). We thank the Centre of
Testing & Analysis, Sichuan University for NMR measurements.
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