Palladium-catalyzed oxidative C-H/C-H cross-coupling of indoles and pyrroles with heteroarenes

Article abstract of DOI:10.1002/anie.201101416

Doubling up: The highly regioselective C3 heteroarylation of either an indole or a pyrrole with an array of electron-rich and electron-poor N-heteroarenes has been carried out using a palladium/copper co-catalytic system. The double C-H activation selecti

Full text of DOI:10.1002/anie.201101416

DOI: 10.1002/anie.201101416
Cross-Coupling
À
À
Palladium-Catalyzed Oxidative C H/C H Cross-Coupling of Indoles
and Pyrroles with Heteroarenes**
Zhen Wang, Kaizhi Li, Dongbing Zhao, Jingbo Lan, and Jingsong You*
The bi-heteroaryl structural motif is prevalent in polymers,
advanced materials, liquid crystals, ligands, molecules of
medicinal interest, and natural products.[1] Transition-metal-
catalyzed cross-coupling reactions of a heteroaryl halide or
surrogate with a heteroaryl metal represents one of the most
powerful and reliable methodologies for the preparation of
bi-heteroaryl compounds.[2] However, from the viewpoint of
synthetic simplicity, atom economy, and sustainable chemis-
try, direct oxidative coupling between heteroarenes through a
(Hetero)arylated indoles and pyrroles represent impor-
tant structural elements for pharmaceuticals, fragrances, dyes,
agrochemicals, materials, and natural products (Scheme 1).
À
À
Transition-metal-catalyzed direct oxidative C H/C H cou-
pling methods to form (hetero)arylated indoles and pyrroles
pose a great synthetic challenge because the indole and
À
double C H activation would be the most ideal strategy for
connecting two heteroarenes, thus avoiding prefunctionaliza-
tion of both of substrates prior to the coupling reaction.[3] In
recent years, a few groups disclosed their pioneering work
À
directed toward transition-metal-catalyzed oxidative C H/
À
C H cross-coupling between a directing-group-containing
arene and an arene,[4] between two simple arenes,[5] and
between a heteroarene and an arene.[6,7] In sharp contrast,
À
metal-catalyzed direct oxidative C C couplings between two
heteroarenes have a limited substrate scope. Arguably the
remaining challenge in this area is to develop a compatible
method for a variety of heteroarenes since such species have
often been documented to undergo homocoupling, and have
inadequate stability for participating in the coupling process.
In addition, the presence of heteroarenes may lead to low
reactivity and selectivity in coupling reactions because of the
binding of the heteroatom in both the substrate and product
to the metal complex. Recently, we reported the first Pd-
À
À
(OAc)2-catalyzed copper-salt-activated oxidative C H/C H
cross-coupling of xanthines, azoles, and pyridine N-oxides
with thiophenes and furans.[8] Quite recently, Ofial and co-
workers described the efficient palladium-catalyzed dehydro-
genative cross-couplings of benzothiazole and benzimidazoles
with N-, O-, and S-containing azoles.[9]
Scheme 1. Selected medicinal and natural molecules containing hetero-
arylated indoles and pyrroles.
[*] Z. Wang, K. Li, D. Zhao, 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
pyrrole substrates and products are susceptible to oxidative
decomposition under the oxidative reaction conditions and
there are elements of C2/C3 regiocontrol.[6a–c,e,f,7b,10] The
palladium-catalyzed regioselective oxidative arylation of
indoles and pyrroles with simple benzenes through dual
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (PR China)
Fax: (+86)28-8541-2203
À
C H functionalization was developed independently by the
groups of Fagnou[6a,b] and DeBoef.[6c,e] Quite recently, Pintori
and Greaney showed that the palladium-catalyzed intramo-
E-mail: jsyou@scu.edu.cn
[**] This work was supported by grants from the National NSF of China
(Nos 21025205, 20972102, 21021001, and 20872101), the Doctoral
Foundation of Education Ministry of China (20090181110045),
PCSIRT (No IRT0846), and the National Basic Research Program of
China (973 Program, 2011CB808600). We thank the Centre of
Testing & Analysis, Sichuan University for NMR, and X-ray
measurements.
À
lecular oxidative C H coupling of an indole ring with an
arene at the indole 2-position was an effective strategy for
synthesizing medium-sized ring compounds.[7b] However,
transition-metal-catalyzed direct oxidative intermolecular
À
À
C H/C H cross-coupling of indoles and pyrroles with
heteroarenes has not been reported to date. Herein we
disclose the solutions to meet these challenges, including the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101416.
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prevention of the oxidative decomposition of sub-
strates and products, the complete inversion in reac-
tivity/selectivity in the two metalation steps of the
catalytic cycle to restrain the formation of intractable
homocoupling, and the control of regioselectivity
[Eq. (1)].
Xanthines (e.g., caffeine, theophylline, theobro-
mine, etc.) are important biologically active alkaloids.
8-(Hetero)aryl-substituted xanthines are highly potent
antagonists at human A2B adenosine receptors.[11] As
part of our ongoing effort to synthesize (hetero)aryl-
substituted xanthines,[8,12] we initially focused on the
cross-coupling of caffeine with 1-benzylindole to
optimize the conditions (see Table S1 in the Supporting
Information). After screening several parameters (e.g.,
palladium source, solvent, oxidant, ligand, additive,
temperature, etc.), we found that the addition of extra
X-Phos could greatly prevent the decomposition of N-
alkylindoles, and dramatically improved the yield of
the desired product 3a to up to 70% (Table S1,
entry 9). DMSO played a critical role in the reaction
efficiency, and the absence of DMSO diminished the
yield of 3a (Table S1, entries 5 and 8). We supposed
that DMSO might act as a ligand to prevent the
formation of palladium black.[6f,13] Excitingly, a cata-
lytic amount of CuCl further advanced the catalytic
Scheme 2. Selective cross-coupling of indole derivatives with caffeine. For all
reactions 0.5 mmol caffeine (2a) and 3.0 equiv indole 1 were used under an N2
atmosphere. Yields of the isolated product are based on 2a. [a] Carried out at
1208C. [b] Carried out at 1408C without X-Phos. DMSO=dimethyl sulfoxide,
X-Phos=2-(dicyclohexylphosphino)-2’,4’,6’-tri-iso-propyl-1,1’-biphenyl, Pd-
(dppf)Cl2 =[1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
efficiency and C3/C2 regioselectivity. Finally, the cross-
coupling reactions proceeded well when 5 mol% of [Pd-
electron-withdrawing or 2-substituted groups required rela-
tively higher reaction temperatures (up to 120–1408C; 3i–k).
Notably, the reaction of 1-benzyl-7-aza-1H-indole proceeded
well and result in an 88% yield (3e).
(dppf)Cl2]
was
employed
in
combination
with
X-Phos (5 mol%), CuCl (0.2 equiv), Cu(OAc)2·H2O
(3.0 equiv), and pyridine (1.0 equiv) in 1,4-dioxane/DMSO
(9:1; Table S1, entry 10). This transformation was highly
regioselective by reacting at C3 of the indole, and other
regioisomeric products were not observed. An X-ray analysis
We subsequently applied this protocol to other xanthines
(e.g., benzylic theobromine, benzylic theophylline, n-butyl
theophylline, etc.) to synthesize xanthine-substituted indoles
3l–n in good to excellent yields (Scheme 3). Simple purine
heterocycles are attractive as “functional” p components in
organic materials with biological relevance.[15] Recently, the
C arylation of purines with aryl boronic acids and aryl halides
has started to attract interest.[12c,16] Our methodology was
suitable for the synthesis of the purine-substituted indoles
3o–p. In addition to these important alkaloids with imidazole
skeletons, the catalytic system could also effectively promote
the cross-coupling of N-alkylindoles with other azoles (e.g.,
benzothiazoles, benzoxazoles, oxazoles, etc.) at the C2 site of
azoles in synthetically useful yields (3q–r, t). Interestingly, the
2-substituted thiazole was amenable to the oxidative coupling
reaction at the C5-position of the thiazole in 70% yield (3s).
However, indolizines were limited under the standard reac-
tion conditions, and gave only a trace amount of product.
N-Heteroarene N-oxides are a key intermediate in many
transformations that assemble functionality adjacent to the
nitrogen atom. The N-oxides may also be converted into the
deoxygenated products by hydrogenolysis with Pd/C/H2. The
À
À
of single crystals of 3a confirmed that a direct C H/C H
cross-coupling took place between C3 on the 1-benzylindole
and C8 on caffeine (see Figure S1 in the Supporting Informa-
tion).[14]
With optimized conditions now in hand, we examined the
scope of this methodology with respect to indoles as
summarized in Scheme 2. Gratifyingly, we found that a
relatively broad range of indole derivatives could couple
with caffeine with complete C3 selectivity and good yields.
Indoles having an N-protecting group such as methyl, benzyl,
or MOM group all gave the corresponding N-protected
xanthine-substituted indoles 3a–c, whereas the protection of
the indole with the TIPS (triisopropylsilyl) group afforded the
N-unprotected indole derivative 3d. Interestingly, the N-
unprotected indole could also be oxidatively cross-coupled
with caffeine, albeit in a diminished yield of 39%. Avariety of
substituents on the indole substrates (e.g., alkyl, chloride,
nitro, benzyloxy groups, etc.) were tolerated. Indoles with the
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pyridinyl–indolyl linkage and its analogue are
important structural motifs for pharmacophores,
natural products, and synthetic building blocks
(Scheme 1). Clearly, the most direct method for
synthesizing these heteroaryl–heteroaryl linkages
should be oxidative coupling of an indole with a
six-membered N-heteroarene or the correspond-
ing N-oxide.[17,18] To our delight, p-electron-poor
N-heteroarene N-oxides (e.g., pyridine N-oxide,
quinoline N-oxide, quinoxaline N-oxide, pyrazine
N-oxide, etc.) smoothly underwent the dehydro-
genative couplings with the N-alkylated indoles in
good yields, thus affording a general and reliable
method for forging the pyridinyl–indolyl bonds
(Scheme 4; 3u–y). Notably, the coupling of 1-
benzylindole with quinoxaline N-oxide gave 2-(1-
benzyl-indol-3-yl)-quinoxaline N-oxide (3x) as a
major product (84% yield) with a concomitant of
a small amount of the deoxygenated product 3x’
(8% yield). Inspired by the deoxygenation,[18] we
investigated the reaction in the absence of added
oxidants, but only 14% yield of 3x’ was obtained.
Fortunately, our method was suitable for more
Scheme 4. Selective oxidative cross-coupling of indoles with a variety of N-hetero-
arene N-oxides. For all reactions 0.5 mmol indole 1 and 3.0 equiv N-heteroarene N-
oxide 2 were used under an N2 atmosphere. Yields of isolated product is based on
indole 1. [a] Carried out at 1108C, 2 (0.5 mmol), and indole 1. [b] Pyridine (2 equiv),
carried out at 1408C.
sensitive pyrroles. This palladium/copper bimetallic catalytic
system could effectively avoid the decomposition of pyrrole
substrates. Pyrroles coupled with a number of N-heteroarenes
(e.g., xanthines, purines, benzothiazoles, benzoxazoles, N-
heteroarene N-oxides, etc.) to afford the heteroarylated
pyrroles in synthetically useful yields (Scheme 5; 4a–h).
Notably, the previously reported oxidative coupling reactions
of pyrroles, except the sterically bulky N-TIPS pyrrole,
occurred predominantly at the C2 position of pyrro-
les.[6b,10b–d,19] More interestingly, our catalytic system gave
Scheme 5. Selective oxidative cross-coupling of pyrroles with a
variety of N-heteroarenes. For all reactions 0.5 mmol N-heteroarene
2 and 3.0 equiv of pyrrole 1 were used under an N2 atmosphere.
Yields of isolated product based on N-heteroarene 2. [a] Carried out
at 1308C. [b] [Pd(dppf)Cl2] (5.0 mol%). [c] CuBr (20 mol%), pyridine
(2.0 equiv), and 1,4-dioxane (1.5 mL).
only the C3 product, which provided an efficient and
complementary route to form 3-heteroarylated pyrroles.
The structure of 4a was confirmed by an X-ray analysis
(Figure S2).[14]
À
À
In the previous examples, the oxidative C H/C H
cross-couplings of (hetero)arenes with arenes usually
employed a large amount of one of the coupling compo-
nents in up to 100 equivalents.[4–6] In this study, these
examples indeed used only up to 3.0 equivalents, and the
reactions were reasonably selective for the cross-coupled
products as opposed to the statistical distribution of
Scheme 3. Selective oxidative cross-coupling of indoles with a variety of
azoles. For all reactions 0.5 mmol N-heteroarene 2 and 3.0 equiv indole
were used under an N2 atmosphere. Yields of isolated product are based
on 2. [a] Carried out at 1208C. [b] Carried out at 1308C. [c] Carried out at
1408C.
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products. For example, the reactions of indoles (3.0 equiv)
with azoles afforded the homocoupled of indoles in yields in a
range of 5–10%, whereas the reactions arising from N-
heteroarene N-oxides (3.0 equiv) gave a negligible amount of
unwanted bis(N-oxide). In addition, this palladium/copper
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dimerization of pyrrole substrates.
In conclusion, we have developed a palladium/copper co-
À
catalytic double C H activation that allows, for the first time,
the highly regioselective C3 heteroarylation of indoles and
pyrroles with an array of N heteroarenes. The homocoupling
and decomposition of the starting material and product are
suppressed successfully under the optimized oxidative reac-
tion conditions. Additionally studies aimed at elucidating the
mechanism of the reactions, and at extending this catalytic
methods to other cross-coupling reactions are underway. We
anticipate that this approach may represent a practical route
to unsymmetrical bi-heteroaryl molecules in medical, mate-
rial, and natural product chemistry.
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Received: February 25, 2011
Published online: May 5, 2011
À
Keywords: C H activation · bimetallic catalysis ·
cross-coupling · heterocycles · palladium
.
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