Elements of regiocontrol in the direct heteroarylation of indoles/pyrroles: Synthesis of Bi- and fused polycyclic heteroarenes by twofold or tandem fourfold C-H activation

Article abstract of DOI:10.1002/chem.201203004

Cross-coupling: The chelation-directed control and catalytic-system-based control strategies effectively switch the C2/C3-site selectivity in the heteroarylation of indoles and pyrroles with N-heteroarenes by a palladium-catalyzed twofold C-H activation to form biheteroarenes and are further extended to the synthesis of complex fused tri- and tetracyclic heteroarenes by a tandem fourfold C-H activation (see scheme). Copyright

Full text of DOI:10.1002/chem.201203004

DOI: 10.1002/chem.201203004
Elements of Regiocontrol in the Direct Heteroarylation of Indoles/Pyrroles:
Synthesis of Bi- and Fused Polycyclic Heteroarenes by Twofold or Tandem
À
Fourfold C H Activation
Zhen Wang, Feijie Song, Yinsong Zhao, Yumin Huang, Lei Yang, Dongbing Zhao,
Jingbo Lan, and Jingsong You*[a]
The transition-metal-catalyzed dehydrogenative cross-cou-
pling between two heteroarenes by oxidizing two carbon–
hydrogen bonds has emerged as a promising strategy for bi-
heteroaryl formation.[1] This process can avoid the tedious
and costly prefunctionalization of substrates that is usually
ACHTUNGTRENiNGNU mide, and pamicogrel, are among the most important bi-
heteroaryl structural motifs.[5] Although the C2 H arylation
of indoles and pyrroles has been well-established in the liter-
À
ature,[6] the C2 H heteroarylation of such molecules still re-
À
mains challenging, probably owing to the general reluctance
of heteroaryl halides to undergo coupling reactions.[7] There-
fore, it should be an ideal strategy to solve the problem by
dehydrogenative coupling of two heteroarenes. Recently, we
À
À
À
À
required in C X/C M or C H/C X coupling reactions.
Considering that some significant heterocyclic halides and
metallics are difficult to prepare and may be inadequately
stable to participate in the coupling reactions, this strategy is
even more attractive for the synthesis of biheteroaryl mole-
cules that cannot be achieved by traditional coupling meth-
ods. One fundamental challenge in this field is the control of
regioselectivity when heteroarene substrates contain multi-
À
and others reported the palladium-catalyzed oxidative C H/
À
C H cross-coupling of indoles and pyrroles with various
types of heteroarenes (e.g., azoles, indolizines, and pyridine
N-oxides) at the C3 site.[4b–e] Following our continuing ef-
forts to functionalize indoles/pyrroles, we herein gain switch-
ing of the C2/C3 selectivity by the use of two different strat-
egies (Scheme 1). Strategy 1 introduces a coordinating func-
À
ple reactive C H bonds. Compared with the cross-coupling
of arenes/arenes[2] and arenes/heteroarenes,[3] the dehydro-
genative cross-coupling between two heteroarenes is surpris-
ingly under-represented, probably owing to the tendency for
homocoupling of heteroarenes and the extra binding of mul-
tiple nitrogen atoms to the metal complex. The regiocontrol
of the coupling is still in its infancy despite a vital structural
feature of biheteroaryl molecules in pharmaceuticals, mate-
rials, and natural products.[4] In these limited examples, the
reactions generally occur preferentially at the more reactive
À
C H bonds that are attributed to inherent electronic bias,
[4b–e]
such as the C3 H of indoles, pyrroles,
and indolizine,[4a]
À
À
À
Scheme 1. Strategies for the regiocontrol in the oxidative C H/C H cou-
plings of indoles/pyrroles.
and the C2 H of thiophenes, furans, azoles,[4f,g] and N-het-
eroarene N-oxides.[4a–e] Undoubtedly, it is highly desirable to
develop powerful strategies to overcome the natural selec-
tivity of heteroarenes and achieve regioselectivity switching.
The C2-heteroarylated indole and pyrrole derivatives,
such as (S)-nicotine, sempervirine, phorbazole C, granulat-
[4a]
À
tional group to the nitrogen atom of indoles and pyrroles to
lead to C H activation of the proximal site (C2 site), thus
suppressing the naturally preferential C3 selectivity. Strategy
2 is dependent on Pd catalytic systems to regulate the C2/C3
À
À
selectivity in C H functionalizations.
These strategies that involve chelation-directed and cata-
lytic-system-based control effectively promote the C2/C3
heteroarylation of indoles and pyrroles with N-heteroarene
N-oxides, xanthines, and indazoles to form biheteroarenes
and are further extended to the synthesis of complex fused
[a] Dr. Z. Wang, Dr. F. Song, Y. Zhao, Y. Huang, L. Yang, Dr. D. Zhao,
Prof. Dr. J. Lan, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of the
Ministry of Education, College of Chemistry
and State Key Laboratory of Biotherapy, West China Hospital
West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P.R. China)
Fax : (+86)28-85412203
À
tri- and tetracyclic heteroarenes by a tandem fourfold C H
activation that involves C3 heteroarylation of indoles/pyr-
roles and subsequent C3-heteroaryl-directed intramolecular
C2 arylation of indoles/pyrroles. During preparation of this
manuscript, Miura et al. reported the copper-catalyzed or
E-mail: jsyou@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203004.
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Chem. Eur. J. 2012, 18, 16616 – 16620

COMMUNICATION
-mediated oxidative C2 heteroarylation of indoles/pyrroles
with 5-aryloxazoles and benzoxazoles. Meanwhile, the au-
thors demonstrated that this method was not amenable to
other electron-deficient heteroarenes, such as pyridine N-
oxide.[8] Thus, these two methodologies are complementary
to each other.
Pyridines and related azine derivatives, such as quinolines
and quinoxalines, are important types of heteroarenes, and
their corresponding N-oxides are also vital intermediates to
obtain functionality at neighbouring positions to the nitro-
gen atom, and they can be deoxygenated to afford free
azines.[9] Thus, our investigation started with the dehydro-
genative cross-coupling of indoles with quinoline N-oxide
Scheme 2. The effect of different directing groups on the dehydrogena-
tive cross-coupling of N-protected indole 2 with quinoline N-oxide (1a).
Standard conditions: indole
2
(0.5 mmol), 1a (2.0 mmol), Pd
ACHTUNGTRENNUNG(OAc)2
(20 mol%), DPPB (20 mol%), CuAHCTUGNTR(EUNNNG OAc)2·H2O (1.5 mmol), and pyridine
(1.0 mmol) in 1,4-dioxane at 1408C for 30 h under a N2 atmosphere.
À
(1a). Chelation-assisted C H bond activation by using the
electrophilic nature of the palladium(II) center constitutes
À
one of the most common strategies towards the ortho-C H
functionalization of arenes. However, this strategy is rela-
À
tively rarely used in the C H functionalization of heteroar-
enes. We envisioned that the C2-selective heteroarylation of
indoles and pyrroles could be achieved by tethering a suita-
ble directing group at the nitrogen atom (Scheme 1). Con-
sidering that the pyridyl group is a widely used directing
group for molecular design,[10] 1-(pyridin-2-yl)-1H-indole
(2a) was first employed to optimize the reaction conditions
(Table S1 in the Supporting Information). It was anticipated
that solvents, ligands, oxidants, and additives would signifi-
cantly influence the reactivity and selectivity. After screen-
ing various conditions, the heterocoupling product 3a was
obtained in 53% yield when Pd
bis(diphenylphosphino)butane (DPPB) (20 mol%) were
used in combination with Cu(OAc)2·H2O (3.0 equiv) as the
ACHTUNGRTEN(NUGN OAc)2 (20 mol%) and 1,4-
AHCTUNGTRENNUNG
oxidant and pyridine (2.0 equiv) as an additive in 1,4-diox-
ane at 1408C for 30 h. It was suspected that DPPB, which
was oxidized to the phosphine oxide under the above condi-
tions,[11] served as a ligand to maintain the high reactivity of
the PdACHTUNGTRENNUNG(OAc)2 catalyst. Pyridine might work to stabilize the
Scheme 3. Highly selective oxidative cross-coupling of indoles/pyrroles
with N-heteroarene N-oxides. Reaction conditions: indole/pyrrole
(0.5 mmol), N-heteroarene N-oxide (2.0 mmol), Pd(OAc)2 (10–
20 mol%), DPPB (10–20 mol%), Cu(OAc)2·H2O (1.5 mmol), and pyri-
2
palladium intermediate and prevent the formation of Pd
black.[3a] Notably, the cross-coupling occurred almost exclu-
sively at the indole C2 position. On the other hand, the ho-
mocoupling of 2a and 1a could also be effectively overcome
and gave only 3 and 8% homocoupling yields, respectively.
We next examined a set of potential directing groups
under the standard conditions (Scheme 2). Besides 2-pyridyl,
the 2-pyrimidyl group was also proven to be a good direct-
ing group to afford the desired coupling product in 54%
yield, and only trace amounts of the C3 product were de-
tected, along with very small amounts of the homocoupling
products. The unsatisfactory directing ability of a one-atom
longer group (2-pyridylmethyl and 2-pyridylsulfonyl) on the
reaction indicated that a five-membered palladacycle might
be involved as an intermediate in the catalytic cycle.
1
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
dine (1.0 mmol) in 1,4-dioxane at 1408C for 30 h under a N2 atmosphere.
[a] Reaction temperature was 1508C. [b] Reaction temperature was
1308C. [c] 1,4-Dioxane/DMSO (14:1) was used as the solvent. DMSO=
dimethyl sulfoxide, Py=2-pyridyl, Pym=2-pyrimidyl.
cient N-heteroarene N-oxides, such as pyridine N-oxide, qui-
noline N-oxide, and quinoxaline N-oxide, all smoothly un-
derwent the dehydrogenative coupling with the 2-pyridyl or
2-pyrimidyl-protected indoles to afford the desired 2-hetero-
arylated products in acceptable yields. The pyrimidyl group
showed a similar reactivity to the pyridyl group in directing
this type of coupling reaction. Compared with indoles, the
pyrrole derivatives are generally more sensitive to homocou-
pling and decomposition under oxidative conditions. Howev-
er, it was interesting to observe that pyrroles could also be
The scope of this methodology with respect to indoles/
pyrroles and N-heteroarene N-oxides was next investigated,
and the results are summarized in Scheme 3. To our delight,
a variety of substituents on the indole scaffold, such as
alkyl, chloride, methoxy, and benzyloxy groups, were well
tolerated under the standard conditions. The electron-defi-
À
À
involved in the C H/C H cross-couplings with N-heteroar-
ene N-oxides and afforded the desired products in satisfying
yields. It should be noted that in all cases indoles/pyrroles
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J. You et al.
almost exclusively underwent
À
the direct C H heteroaryla-
tion at the C2 position. The
structure of 3 f was confirmed
by an X-ray analysis of single
crystals (Figure S2 in the Sup-
porting Information).[12]
Xanthines, such as caffeine,
theophylline and theobro-
mine, are an important type
of biologically active alka-
loids. However, extending the
above-mentioned
oxidative
reaction to xanthines has
proven to be a challenging
proposition. In fact, the dehy-
drogenative coupling of ben-
zylic theobromine 4a with 1-
(pyridin-2-yl)-1H-indole (2a)
only afforded the desired
Scheme 4. Selective oxidative cross-coupling of indoles or pyrroles with xanthines. Reaction conditions: xan-
thine 4 (0.5 mmol), indole or pyrrole 5 (1.5 mmol), PdACTHNUGTRENUNG(OAc)2 (10 mol%), Phen (20 mol%), AgF (2.0 mmol),
and pyridine (0.5 mmol) in 1,4-dioxane (1.5 mL) at 1508C for 30 h under a N2 atmosphere. Isolated yields of
C2-heteroarylated products of indoles or pyrroles. [a] CuF2 (1.5 mmol) was used as an oxidant.
product in 21% yield under the standard conditions. We ra-
tionalized that the low reactivity might be attributed to
extra binding of multiple nitrogen atoms and oxygen atoms
in xanthines to the metal complex, which led to metal se-
questration and deactivation. After extensive efforts, we
found that the C2/C3 selectivity of heteroarylation of in-
doles/pyrroles with xanthines could be regulated through
the use of different directing groups, oxidants, and ligands
(Table S2 in the Supporting Information). The N,N-dime-
thylcarbamoyl group was proven to be the best among the
directing groups investigated (e.g., N,N-dimethylcarbamoyl,
acetyl, 2-pyridyl, and 2-pyrimidyl). Interestingly, the oxidant
containing the FÀ counterion was crucial for achieving the
regioselectivity switch in this type of cross-coupling reac-
tions. For example, changing the oxidant from Ag2CO3 to
AgF resulted in a dramatic reversal in the regioselectivity
from a 1:7 C2/C3 ratio of 1:7 (in 40% total yield) to a C2/
C3 ratio of 1.5:1 (in 85% total yield) under otherwise iden-
tical conditions (Table S2, entries 4 and 5). We assumed that
the presence of the FÀ anion might facilitate the formation
of monomeric Pd species rather than trinuclear Pd carboxy-
late clusters, which favored the C2 site selectivity.[3b,e,4f] Fur-
ther addition of 1,10-phenanthroline (Phen) to the catalytic
system greatly improved the C2/C3 ratio to 4.1:1, and the
C2-heteroarylated product was obtained in 70% yield
(Table S2, entry 9; Scheme 4, 6a). Finally, we found that
xanthines, such as benzylic theobromine, caffeine, and n-
butyl theophylline, could all couple with indoles/pyrroles to
give the desired products with relatively high C2 selectivities
and good yields (Scheme 4; also see the Supporting Infor-
mation). The structures of 6a and 6e were determined by a
single-crystal X-ray analysis (Figures S3 and S4 in the Sup-
porting Information).[12] Given their widespread occurrence
in biologically important compounds, it was gratifying to see
that the current catalytic system was also applicable to an
indazole to form the C2-heteroarylated product in 50%
yield (Scheme 4, 6 f).
It is worth noting that the catalyst-based control strategy
with a judicious choice of oxidant provided a powerful path-
way for achieving a reversal of the C2/C3-site selectivity of
À
À
the oxidative C H/C H heteroarylation of indoles or pyr-
roles with heteroarenes. For example, benzylic theobromine
4a could react with the N,N-dimethylcarbamoyl indole 5b
to afford the C2-heteroarylated product in 59% yield by
using the optimized catalytic system composed of Pd
and Phen in combination with AgF as oxidant (Scheme 5,
Condition A), whereas [Pd(dppf)Cl2], CuCl, and X-Phos
with Cu(OAc)2·H2O as oxidant mainly gave the C3-hetero-
ACHTUNGTRENNUNG(OAc)2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
arylated product in 65% yield (Scheme 5, Condition B).[13]
Complex fused polycyclic heteroarenes that are widely
found in natural products and biologically active pharma-
ceuticals are often difficult to access by classical synthetic
routes.[14] In this work, by taking advantage of Strategy 2,
which was mentioned above, N1-benzyl-substituted pyrroles/
À
indoles were designed to undergo a tandem fourfold C H
Scheme 5. Catalytic system-based switching of the regioselectivity of
À
C H heteroarylation of indole 5b with benzylic theobromine (4a).
Yields of the isolated products are shown. dppf=1,1’-Bis(diphenylphos-
phino)ferrocene, X-Phos=2-dicyclohexylphosphino-2’,4’,6’-triisopropylbi-
phenyl.
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Direct Heteroarylation of Indoles/Pyrroles
COMMUNICATION
activation to concisely synthesize fused tri- and tetracyclic
heteroarenes 7a–7d from the corresponding pyrroles and in-
doles in moderate to good yields (Scheme 6). The structures
of 7a and 7d were confirmed by X-ray analysis of single
Scheme 7. Deprotection of the pyrimidyl group tethered to the nitrogen
atom of indole.
and pyrroles with an array of N-heteroarenes by a palladi-
À
um-catalyzed twofold C H activation. Interestingly, the re-
sulting C3-heteroaryl indoles/pyrroles can direct the second
intramolecular arylation in one pot, leading to a concise ap-
proach to complex fused polycyclic heteroarenes through a
À
tandem fourfold C H activation. Further studies aimed at
À
gaining insight into the mechanism of the oxidative C H/
À
C H coupling reactions and extending these strategies to
other coupling reactions are currently underway.
Scheme 6. Palladium-catalyzed tandem coupling reactions of indole or
pyrrole derivatives with N-heteroarenes. Reaction conditions: N-hetero-
arene (0.5 mmol), indole or pyrrole (1.5 mmol), [Pd
ACHTUNGTRNE(NNUG dppf)Cl2] (5 mol%),
Experimental Section
X-Phos (5 mol%), CuCl (20 mol%), Cu(OAc)2·H2O (3.0 equiv), and pyr-
AHCTUNGTRENNUNG
idine (1.0 equiv) in 1,4-dioxane (1.5 mL) at 1508C for 30 h under a N2 at-
mosphere. [a] In 1,4-dioxane/DMSO (9:1, v/v) at 1108C.
À
General procedure for the cross-coupling of indole or pyrrole C2 H with
N-heteroarene N-oxides: A flame-dried pressure tube was charged with
Pd
(OAc)2
(22.4 mg,
0.1 mmol),
DPPB
(42.6 mg,
0.1 mmol),
Cu(OAc)2·H2O (300 mg, 1.5 mmol), N-heteroarene N-oxide (2.0 mmol),
and the indole or pyrrole derivative (0.5 mmol). The tube was then
capped with a rubber septum, evacuated, and backfilled three times with
nitrogen. Pyridine and solvent were added by syringe under a N2 atmos-
phere. The septum was then replaced by a teflon-coated screw cap, and
the mixture was stirred at the indicated temperature for 30 h and then
cooled to ambient temperature. The mixture was diluted with CH2Cl2
(30 mL), filtered through a Celite pad, and then washed with CH2Cl2
(10–20 mL). The combined organic phases were concentrated under re-
duced pressure, and the resulting residue was purified by column chroma-
tography on silica gel to provide the desired product.
crystals (Figures S5 and S6 in the Supporting Informa-
tion).[12] The C3-heteroarylated product of N-benzylindole
with caffeine was observed at the early stage of the reaction
and was gradually transformed to the desired product 7a.
Two control experiments illustrated that the intramolecular
cross-coupling step did not occur when the N-heteroaryl
group at the C3 site of indole/pyrroles was changed to the
phenyl group, clearly indicating that the N-heteroarene
moiety played a crucial role in promoting the second cou-
pling process (see the Supporting Information). Thus, this
one-pot process might involve the following two sequential
À
General procedure for the cross-coupling of indole or pyrrole C2 H with
xanthines and azoles: A flame-dried pressure tube was charged with
Pd(OAc)2 (11.2 mg, 0.05 mmol), Phen (18.0 mg, 0.1 mmol), the indole or
pyrrole derivative (1.5 mmol), xanthine or azole (0.5 mmol), and an oxi-
dant (1.5 or 2.0 mmol). The tube was then capped with a rubber septum,
evacuated, and backfilled three times with nitrogen. Pyridine (39.6 mg,
0.5 mmol) and 1,4-dioxane (1.5 mL) were added by syringe under a N2 at-
mosphere. The septum was then replaced by a teflon-coated screw cap,
and the mixture was stirred at the indicated temperature for 30 h. The
mixture was then cooled to ambient temperature, diluted with CH2Cl2
(30 mL), filtered through a Celite pad, and then washed with CH2Cl2
(10 mL). The combined organic phases were concentrated under reduced
pressure and the residue was purified by column chromatography on
silica gel or aluminium oxide (neutral) to provide the desired product.
À
À
oxidative C H/C H couplings: 1) the heteroarylation of in-
doles/pyrroles with various N-heteroarenes, such as xan-
thines and 4,5-dimethylthiazole, first occurred at the C3 po-
sition; 2) the N3 atom of azoles was well positioned to fur-
À
ther direct C2 H bond activation of indoles/pyrroles to ful-
À
À
fill the intramolecular oxidative C H/C H cross-coupling
between the indole/pyrrole C2 position and the benzene
ring of the benzyl group that is tethered at the indole/pyr-
role N1 site.[15] To the best of our knowledge, this is the first
palladium-catalyzed cascade reaction involving the cleavage
À
General procedure for the cross-coupling of indole C3
tandem reaction of indoles or pyrroles with N-heteroarenes: A flame-
H
and the
[14]
À
À
of four C H bonds and the formation of two C C bonds.
To further increase the synthetic utility of our methodolo-
gy, a deprotection was performed to remove the directing
group that was tethered to the nitrogen atom of indole. The
2-pyrimidyl group of 3j could be removed conveniently in
the presence of NaOEt in DMSO to afford the correspond-
dried pressure tube equipped with a magnetic stir bar was charged with
[Pd
ACHTUNGTRENNUNG
CuCl (10.0 mg, 0.1 mmol), CuAHCTNUGTRENNNUG
erocycle (0.5 mmol), and the indole/pyrrole derivative (1.5 mmol). The
tube was then capped with a rubber septum, evacuated, and backfilled
three times with nitrogen. Pyridine (39.6 mg, 0.5 mmol) and 1,4-dioxane
(1.5 mL) were added by syringe under an N2 atmosphere. The septum
was then replaced by a teflon-coated screw cap, and the mixture was
heated at 1508C for 30 h and then cooled to ambient temperature. The
mixture was diluted with CH2Cl2 (30 mL), filtered through a Celite pad,
and then washed with CH2Cl2 (10 mL). The combined organic phases
À
ing free (N H) biheteroarene 3j’ in 68% yield (Scheme 7).
In conclusion, the “chelation-directed control” and “cata-
lytic system-based control” strategies can effectively switch
the C2/C3 site selectivity in the heteroarylation of indoles
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J. You et al.
were concentrated under reduced pressure, and the resulting residue was
purified by column chromatography on silica gel or aluminium oxide
(neutral) to provide the desired product.
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This work was supported by grants from the National Basic Research
Program of China (973 Program, 2011CB808600), and the National Sci-
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and J1103315 J0104).
À
À
8174; for C H/C H cross-couplings between arenes and indoles/pyr-
roles, see references 3a–c and 3e.
À
Keywords: C H activation · cross-coupling · heterocycles ·
regiocontrol · tandem reactions
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À
À
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[11] The coupling reaction of quinoline N-oxide with 1-(pyrimidin-2-yl)-
1H-indole was analyzed by in situ 31P NMR spectroscopy. A broad
peak at d=34.1 ppm (in CDCl3) was observed, which was consistent
with the 13P NMR specrum of DPPBO2. These results indicated that
DPPB was oxidized to DPPBO2 under the current coupling condi-
tions. For details, see Figure S1 in the Supporting Information.
[12] CCDC-885272 (3 f), CCDC-885273 (6a), CCDC-885274 (6e),
CCDC-885275 (7a), and CCDC-885276 (7d) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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Received: August 23, 2012
Revised: October 9, 2012
Published online: November 29, 2012
16620
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