Facile access to 3-acylindoles through palladium-catalyzed addition of indoles to nitriles: The one-pot synthesis of indenoindolones

Article abstract of DOI:10.1002/chem.201203354

A palladium-catalyzed addition of indoles to nitriles, leading to 3-acylindoles, was reported, and the scope of nitriles was investigated. The strategy described provides a more efficient and atom-economical alternative to indenoindolones. It was found that alkenyl, carbonyl, halogen, methoxy, and nitro groups on aryl nitriles, which could offer opportunities for further synthetic transformations, are all compatible with the conditions. N-unprotected indoles with electron-rich groups show excellent reactivity towards this addition reaction. Under the optimized conditions, an array of indenoindolones are obtained in synthetic useful yields from readily available indoles and nitriles in one pot. The results also show that both the electron-poor and electron-rich substituents could be introduced to indoles and nitriles and that the halogen atoms were compatible under the current conditions.

Full text of DOI:10.1002/chem.201203354

COMMUNICATION
DOI: 10.1002/chem.201203354
Facile Access to 3-Acylindoles through Palladium-Catalyzed Addition of
Indoles to Nitriles: The One-Pot Synthesis of Indenoindolones
Yuanhong Ma, Jingsong You,* and Feijie Song*[a]
Considerable progress has been made over the past
acylation,[12] Vilsmeier–Haack acylation,[13] the reaction of
indole salts with acyl chlorides,[14] and the reaction of indoles
with nitrilium[15] or N-(a-haloacyl)-pyridinium salts.[16]
Among these, Friedel–Crafts acylation is the most effective
method that can give rise to various 3-acylindoles in good
yields under mild conditions. However, the traditional Frie-
del–Crafts reaction, which usually employs AlCl3 as Lewis
acid, suffers from the side reactions involving N1 acylation,
N1/C3 diacylation, and oligomerization of indoles owing to
the multi-atom nucleophilic nature of indoles and the acidic
conditions.[17] To address these issues, NH-protected or elec-
tron-deactivated indoles are used as substrates.[12a,18] Howev-
er, such options either involve troublesome N-protection
and deprotection steps or limit the substrate scope. Recent
work has shown that the sue of SnCl4,[12c] AlEt2Cl,[12b] or
ZrCl4[12g] as Lewis acid not only minimizes the side reactions,
À
decade in transition-metal-catalyzed C H bond functionali-
zation of arenes and heteroarenes.[1] The pioneering work of
Larock showed that palladium could catalyze the addition
reaction of electron-rich arenes with polar nitriles to afford
arylketones.[2] This work was subsequently followed up by a
number of reports including the addition of arylboronic
acids,[3] arylhalides,[4] and benzoic acids[5] to nitriles. Howev-
er, more challenging heteroarenes, which tend to decompose
under transition-metal catalysis, have never been successful-
ly involved in such addition reactions.[6] Following our con-
tinuous interest in the functionalization of heteroarenes,[7]
we herein report a palladium-catalyzed addition of indoles
to nitriles, leading to 3-acylindoles (Scheme 1). It is worth
À
but also extends the substrate scope to free (N H) indoles.
Nevertheless, the requirement of stoichiometric amounts of
Lewis acid makes the procedure environmentally unfriendly
owing to the production of large quantities of salt waste.
Moreover, acyl chlorides as acyl sources can also cause
some handling trouble/hazards. The last two problems were
Scheme 1. Palladium-catalyzed synthesis of 3-acylindoles and indenoindo-
lones.
individually solved by the use of 1,5-diazabicycloACTHNUTRGENUG[N 4.3.0]non-
noting that the transition-metal-catalyzed addition of indoles
5-ene as catalyst[12f] and N-acylbenzotriazoles as the acyl
source.[12d]
[8]
À
with polar C N multiple bonds is under-represented, al-
though the reaction of indoles with non-polar bonds, such as
alkenes and alkynes, has been well-developed.[9] Further-
more, this strategy has been extended to the one-pot synthe-
It was reasoned that nitriles, which are inexpensive,
broadly available, and operationally simple, could serve as
another valuable alternative to acyl chlorides. Although the
reaction of nitriles with indoles has a long history, hydrogen
chloride is needed and indoles seem to be limited to 2-sub-
stituted compounds.[19] Wu and Su recently showed that free
À
sis of indenoindolones through the C3 H acylation of in-
À
À
doles and subsequent intramolecular oxidative C H/C H
coupling of indoles with arenes (Scheme 1).
À
3-Acylindoles and their derivatives are ubiquitous in natu-
ral products, biologically active compounds, and pharma-
ceuticals.[10] They are also versatile precursors for the syn-
thesis of alkaloids and other related heterocycles.[11]
Common methods to 3-acylindoles include Friedel–Crafts
(N H) indoles could be acylated with N-benzyl anilines
À
through iron-catalyzed C3 H activation of indoles, thus
À
demonstrating the power of transition-metal-catalyzed C H
activation in the synthesis of 3-acylindoles.[20] However, their
strategy could only afford 3-aroylindoles. Herein, we report
a palladium-catalyzed addition of N-protected and unpro-
[a] Y. Ma, Prof. Dr. J. You, Dr. F. Song
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
À
tected indole C H bonds with nitriles to give a wide range
of 3-acylindoles, including 3-aroyl, heteroaroyl, and alkoylin-
doles. Key features of this method include good versatility,
high regio- and chemoselectivity, and a simple procedure.
Initially, the reaction of N-methylindole 1a with benzoni-
trile 2a was used to optimize the reaction conditions (Sup-
porting Information, Table S1). After screening a series of
E-mail: jsyou@scu.edu.cn
fsong@scu.edu.cn
conditions, Pd
ladium species, which included PdCl2, [PdAHCTNUGTRENNNUG
ACHTUNGTRENNUNG
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203354.
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and [Pd
(PPh3)2Cl2]. The ligand was crucial for the smooth
(Scheme 2, 3j–3l). Moreover, compound 3a could be isolat-
ed in 62% yield when this palladium-catalyzed reaction was
scaled up to 10 mmol scale, demonstrating the practicability
of the method (Scheme 2).
addition reaction. Among various ligands examined, the bi-
dentate nitrogen ligands showed good activity towards the
reaction, and 1,10-phenanthroline (Phen) gave the best
result in the presence of 10 mol% Pd
(OAc)2 catalyst (76%
The scope of nitriles was then investigated (Scheme 3).
Alkenyl, carbonyl, halogen, methoxy, and nitro groups on
aryl nitriles, which could offer opportunities for further syn-
yield; Supporting Information, Table S1, entry 4). Phosphine
ligand was completely ineffective for the reaction (Support-
ing Information, Table S1, entries 9–11). Further studies in-
dicated that the preformed catalyst [(Phen)Pd
ACHTUNGTRENNUNG
better than when it was prepared in situ from PdACHTUNGTRENNUNG
Phen under otherwise identical conditions (Supporting In-
formation, Table S1, entries 20 and 8). Thus, the best condi-
tions were 10 mol% [(Phen)PdACHTUNTRGNEUNG(OAc)2] as catalyst, H2O/
AcOH as additive, and 1,4-dioxane as solvent at 1408C for
36 h (84% yield; Supporting Information, Table S1,
entry 21).
With the optimized reaction conditions at hand, we next
examined the substrate scope of the addition reaction. As
summarized in Scheme 2, N-methylindoles with electron-
Scheme 3. Palladium-catalyzed addition of N-methylindole 1a to various
nitriles. The reaction was run on a 0.5 mmol scale. Yield of isolated prod-
uct given. [a] The reaction was run at 1208C using nitriles as solvent
owing to the low boiling point of the nitriles. [b] Reaction time was 48 h.
Scheme 2. Palladium-catalyzed addition of N-protected indole 1 to ben-
zonitrile 2a. The reaction was run on a 0.5 mmol scale. Yield of isolated
product given.
thetic transformations, were all compatible with the condi-
tions (Scheme 3, 3n–3t). It is worth stressing that both the
non-polar alkenyl group and polar carbonyl group were un-
reactive to the addition reaction (Scheme 3, 3s and 3t), ex-
hibiting the high chemoselectivity of the reaction towards
the CꢀN triple bond. The chloro and methyl substituents
on the ortho position of the nitrile group did not hinder the
addition reaction (Scheme 3, 3r and 3u). Apart from aryl ni-
triles, aliphatic nitriles also proceeded well to give the de-
sired products (Scheme 3, 3v–3x). More importantly, vari-
ous heteroaryl (pyridyl, furyl, thiophenyl, pyrrolyl, and in-
rich (Me, OMe, OBn), electron-poor (Cl, Br), and sterically
hindered (2-methyl) groups all smoothly coupled with ben-
zonitrile 2a, giving rise to the corresponding C3 acylated
products in good to excellent yields. The halogen groups on
the indole ring were compatible with the addition reaction
(Scheme 2, 3 f and 3g). N-Aryl-protected indoles could also
be involved in the acylation reaction, albeit with lower reac-
tivity than the corresponding N-methyl-protected compound
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Synthesis of Indenoindolones
COMMUNICATION
dolyl)-substituted nitriles successfully reacted with indoles
to afford the corresponding 3-heteroaroylindoles in modest
to good yields (Scheme 3, 3ya–3ye).
We were pleased to find that this method was applicable
À
to free (N H) indoles (Scheme 4). Notably, N-unprotected
indoles with electron-rich groups showed excellent reactivity
towards this addition reaction (Scheme 4, 4d and 4e).
Scheme 6. Palladium-catalyzed one-pot synthesis of indenoindolones. The
reaction was run on a 0.5 mmol scale. Yield of isolated product given.
See the supporting information for details.
PivOH, and base (pyridine or K2CO3) were found to be cru-
cial for the smooth happening of the reaction. Finally, a
one-pot strategy to indenoindolones was achieved by the
Scheme 4. Palladium-catalyzed synthesis of free (N-H) 3-acylindoles. The
reaction was run on a 0.5 mmol scale. Yield of isolated product given.
extra addition of 20 mol% of Pd
ACHTUNGRTEN(NUGN OAc)2, 3.0 equiv of Cu-
N1 Acylation and N1, C3 diacylation or indole oligomeriza-
tion byproducts were not observed with the current catalytic
system.
ACHTUGNERTN(NUNG OAc)2, 2.0 equiv of PivOH, 0.5 equiv of K2CO3, and 3 ꢁ
molecular sieves to the reaction solution at the first step
(Supporting Information, Table S3).
Moreover, other electron-rich N-heterocycles, such as pyr-
roles, indolizines, and pyrroloACTHNUTRGNEUGN[2,1-a]isoquinolines reacted
smoothly with nitriles to afford the desired products in satis-
factory yields (Scheme 5). When pyrrole was employed as
the substrate, both the C2- and C3-acylated pyrroles were
obtained (2-acylpyrrole was the major product).
Under the optimized conditions, an array of indenoindo-
lones were obtained in synthetic useful yields from readily
available indoles and nitriles in one pot (Scheme 6). Both
the electron-poor and electron-rich substituents could be in-
troduced to indoles and nitriles. Once again, the halogen
atoms were compatible under the current conditions. The
structure of product 6a was confirmed by single-crystal X-
ray analysis (Supporting Information, Figure S1).[24] It is
worth noting that although many methods describing the
synthesis of indenoindolones are available in the litera-
ture,[25] a two-step route involving Friedel–Crafts reaction of
indoles with 2-halobenzoyl chlorides and subsequent palladi-
um-catalyzed intramolecular arylation of 3-(2-halobenzyl)-
indoles is the most common and general method.[26] Un-
doubtedly, the strategy described herein provides a more ef-
ficient and atom-economical alternative to indenoindolones.
In conclusion, we have developed a general, highly selec-
tive, and operationally simple approach to 3-acylindoles
through palladium-catalyzed addition of indoles to nitriles.
Both N-protected and unprotected indoles are feasible for
the addition reaction. Other electron-rich N-heterocycles
Scheme 5. Pd-catalyzed acylation of other N-heteroarenes. The reaction
was run on 0.5 mmol scale. Yield of isolated product given.
Indenoindolones, which are polycyclic derivatives of in-
doles, are found frequently in a variety of biologically and
pharmaceutically relevant molecules.[21] Given the success of
the general and efficient approach to 3-acylindoles, we next
attempted its combination with the intramolecular cycliza-
tion of 3-indolylarylketones to synthesize indenoindolones
in one pot (Scheme 6). Although the intramolecular oxida-
(for example, pyrroles, indolizines, and pyrroloACHTUNTRGNEU[GN 2,1-a]isoqui-
nolines) can also react with nitriles to yield the acylated
products. Compared with conventional Friedel–Crafts acyla-
tion, the major disadvantage of this procedure may be the
high temperature of 1408C. Furthermore, this transforma-
tion is combined with the palladium-catalyzed intramolecu-
À
À
tive C H/C H coupling of 3-indolylarylketones has been
known for a long time, only one example was reported, and
50 mol% Pd
action of 3-indolylarylketones was first optimized (Support-
ing Information, Table S2) and Pd(OAc)2, Cu(OAc)2,
ACHTUNGTRENNUNG
(OAc)2 was required.[22,23] Thus, the coupling re-
À
À
lar oxidative C H/C H coupling of 3-indolylarylketone to
give an access to indenoindolones in one pot. We expect the
A
ACHTUNGTRENNUNG
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J. You, F. Song and Y. Ma
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Experimental Section
General procedure for the palladium-catalyzed addition of indoles to ni-
triles:
[(Phen)Pd
A
sealable tube with
a magnetic stir bar was charged with
ACHTUNGTRENNUNG(OAc)2] (20.2 mg, 0.05 mmol), indole derivative (0.5 mmol), ni-
trile (1.5 mmol), H2O (200 mL), CH3COOH (300 mL), and 1,4-dioxane
(1.0 mL) under air. The resulting solution was heated at 1408C for 36 h
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 mL of CH2Cl2. The combined organic phases were concentrated and
the resulting residue was purified by column chromatography on silica
gel to provide the desired product.
General procedure for the palladium-catalyzed one-pot synthesis of in-
denoindolones: A sealable tube with a magnetic stir bar was charged
with [(Phen)PdACHTUNGTRENNUNG(OAc)2] (20.2mg, 10mol%), indole (0.5mmol), nitrile
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ACHTUNGRTEN(NUNG OAc)2 (22.4mg,
20mol%), Cu(OAc)2 (270.0mg, 1.5mmol), PivOH (102.0mg, 1.0mmol),
ACHTUNGTRENNUNG
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Acknowledgements
This work was supported by grants from the National Basic Research
Program of China (973 Program, 2011CB808600), and the National NSF
of China (Nos 21025205, 21202105, and 21021001). We thank the Centre
of Testing & Analysis, Sichuan University, for NMR measurements.
À
Keywords: acylindoles · C H activation · heteroarenes ·
indenoindolones · palladium
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Synthesis of Indenoindolones
COMMUNICATION
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619–627. Also see reference [21e].
[24] CCDC 898274 (6a) contains the supplementary 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.
Received: September 19, 2012
Revised: November 14, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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J. You, F. Song and Y. Ma
À
C H Functionalization
Y. Ma, J. You,* F. Song* . . . . &&&& — &&&&
Facile Access to 3-Acylindoles through
Palladium-Catalyzed Addition of
Indoles to Nitriles: The One-Pot
Synthesis of Indenoindolones
Well-connected: The palladium-cata-
lyzed addition of indoles to nitriles
affords 3-acylindoles. The reaction pro-
ceeds with high selectivity, wide sub-
strate scope, broadly available starting
materials, and an operationally simple
procedure. Combination with the pal-
ladium-catalyzed intramolecular oxida-
tive coupling of 3-indolylarylketone
gives access to indenoindolones in a
one-pot synthesis.
&
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!