Aerobic Ru-catalyzed direct C2-olefination of N-heteroarenes with alkenes directed by a removable N-dimethylcarbamoyl group

Article abstract of DOI:10.1039/c3cc44787a

A highly efficient and selective Ru-catalyzed direct C2-olefination of indoles, pyrroles, and carbazoles assisted by a removable N-dimethylcarbamoyl group has been developed by using O₂ as the terminal oxidant. Both electron-deficient and unactivated alkenes are applicable to the protocol. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc44787a

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Aerobic Ru-catalyzed direct C2-olefination of
N-heteroarenes with alkenes directed by a removable
N-dimethylcarbamoyl group†
Cite this: Chem. Commun., 2013,
49, 8830
Received 26th June 2013,
Accepted 30th July 2013
Luo-Qiang Zhang, Shiping Yang, Xiaolei Huang, Jingsong You and Feijie Song*
DOI: 10.1039/c3cc44787a
www.rsc.org/chemcomm
A highly efficient and selective Ru-catalyzed direct C2-olefination in the C2-olefination of indoles using an inexpensive, robust and
of indoles, pyrroles, and carbazoles assisted by a removable highly selective ruthenium complex as the catalyst.
N-dimethylcarbamoyl group has been developed by using O2 as
The Ru(II)-catalyzed Csp2–H activation/C–C coupling reactions
the terminal oxidant. Both electron-deficient and unactivated have made remarkable progress within the last few years.10 In sharp
alkenes are applicable to the protocol.
contrast to the oxidative Heck coupling reaction of arenes,11 the
reactions of heteroarenes with alkenes catalyzed by ruthenium are
The indole unit is a ubiquitous skeleton found in a great number of very rare. In 2011, Miura and coworkers reported the carboxylic acid-
pharmaceuticals and bioactive compounds.1 Consequently, the assisted direct olefination of heteroarenes with alkenes to obtain the
modification of the indole ring has attracted significant attention ortho-vinyl substituted heteroarene carboxylic acids in the presence
from chemists for a long time.2 The oxidative Heck coupling of of a ruthenium catalyst.12 During the preparation of this manu-
indoles with alkenes through twofold C–H bond cleavage, as script, Lanke and Prabhu reported a Ru-catalyzed highly efficient
pioneered by Fujiwara and Moritani,3 is one of the most sustainable C2-olefination of indoles with the aid of the N-benzoyl group.13
and straightforward protocols for the functionalization of indoles. However, stoichiometric amounts of Cu(OAc)2ÁH2O are used as the
However, the reaction preferentially occurs at the more electron-rich oxidant and alkenes are limited to electron-deficient acrylates.
C3 position of the indole ring due to the electrophilic nature of Arguably, the development of new protocols that could employ
the coupling reaction. Therefore, the highly efficient and selective environmentally benign oxidants and exhibit wide substrate scope
C2-olefination of 2,3-unsubstituted indoles, which can override the for both coupling partners is still highly desirable and useful in
inherent selectivity of indoles, has been a challenging project. this area. Herein, we would like to report a Ru-catalyzed direct
Palladium complexes have been demonstrated to be efficient C2-olefination of indoles/pyrroles with alkenes assisted by a
catalysts for the oxidative coupling of indole C2–H bonds with removable N-dimethylcarbamoyl group using O2 as the terminal
alkenes. Palladium-catalyzed C2-olefination of indoles by using oxidant (Scheme 1). Various alkenes including acrylates, acrylo-
N-(2-pyridyl)methyl4 and N-(2-pyridyl)sulfonyl5 as the directing nitriles, sulfones, phosphonates and especially, styrene derivatives
group has been reported by Ricci and Carretero, respectively. The successfully participate in the olefination reaction. In addition, a
reaction of indole-3-carboxylic acids with alkenes under Pd catalysis highly selective metal-catalyzed mono-ortho-olefination of carbazoles
offers another method to obtain 2-alkenylated indoles through a is also disclosed in the paper.
tandem carboxylic acid-directed coupling–decarboxylation process.6
Considering that the carbamoyl group has been well recognized
Gaunt et al. have reported a practical, non-directed C2-olefination of as a good removable directing group,14 our study commenced with
indoles by the judicious choice of solvent using palladium as the coupling of N,N-dimethyl-1H-indole-1-carboxamide 1a and butyl
the catalyst.7 One isolated example of Rh-catalyzed coupling of acrylate 2a to optimize the reaction conditions (eqn (1), see ESI† for
N-acetylindole with styrene has been reported in 2010, affording details). Initial attempt showed that 3a could be obtained in 87%
the 2-alkenylated product in 37% yield.8 Following our recent work
on the regioselective functionalization of indoles,9 we are interested
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.
E-mail: fsong@scu.edu.cn; Fax: +86-28-85412285
† Electronic supplementary information (ESI) available: Detailed experimental
Scheme 1 Ru-catalyzed C2-olefination of N-heteroarenes with alkenes.
procedures and analytical data. See DOI: 10.1039/c3cc44787a
c
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Table 2 Scope of substituted alkenesa
yield in the presence of 2.5 mol% [RuCl2(p-cymene)]2 and 10 mol%
AgSbF6 by using 1.5 equiv. of Cu(OAc)2 as the oxidant and toluene as
the solvent at 130 1C for 24 h (ESI,† Table S1, entry 1). Further
optimization showed that O2 (1 atm) could be successfully employed
as the oxidant in combination with 20 mol% of Cu(OAc)2 (ESI,†
Table S1, entry 6), which made the protocol greener and more
attractive. Finally, the yield of 3a reached 93% by using 30 mol% of
NaOAc as the additive and changing the solvent to dichloroethane
(DCE) at 100 1C (ESI,† Table S1, entry 14). Indoles with other
potential directing groups such as N-acetyl, benzoyl, 2-pyrimidyl,
and 4-toluenesulfonyl only afforded trace amounts of the alkenylated
products, indicating that the N-dimethylcarbamoyl group served as
both the directing and activating group with the use of oxygen as the
oxidant.
(1)
Next, we decided to explore the scope of indoles with butyl
acrylate 2a as the model olefin (Table 1). Various indoles with
substituents at the C5, C6, or C7 position of the indole ring
smoothly coupled with 2a to afford the desired 2-alkenylated
indoles. It seems that the weak electron-withdrawing and electron-
donating groups in indoles had negligible effects on the olefination
reaction. However, the strong electron-withdrawing groups such as
nitro and cyano groups decreased the reactivity of indoles to some
extent (Table 1, 3g and 3h). Chloro and bromo atoms were well
tolerated under the standard conditions, demonstrating the high
functional group tolerance of the Ru catalysis. The 3-methyl sub-
stituent on the indole ring did not hinder the olefination reaction,
a
Conditions: 1a (1.0 equiv.), 2 (1.5 equiv.), [RuCl2(p-cymene)]2 (2.5 mol%),
AgSbF6 (10 mol%), Cu(OAc)2 (20 mol%), O2 (1 atm), and NaOAc (30 mol%)
in DCE (1.0 mL) at 100 1C for 15 h. Isolated yields. 3 equiv. of alkenes
were used.
b
affording the desired 3k in 66% yield. However, the 2-methyl-
substituted 1a failed to couple with 2a, indicating that the C3
position of indoles was unreactive under the current catalytic
conditions.
Subsequently, the scope of alkenes was examined and the results
are summarized in Table 2. A wide range of electrophilic alkenes
including ester, cyano, phosphonate, and sulfonyl substituted
alkenes coupled efficiently with indole 1a to give 2-alkenylated
indoles in satisfactory yields (Table 2, 3l–3r). Importantly, the
challenging non-activated styrene derivatives successfully
participated in the olefination reaction and their reactivities were
comparable to the electron-deficient alkenes (Table 2, 3s–3w). In a
few cases, increased amounts of alkenes were required in order to
obtain synthetically useful yields (Table 2, 3r and 3w).
Table 1 Scope of substituted indolesa
Application of this protocol to other related N-heteroarenes
has gained encouraging success. The coupling of pyrrole 1l with
butyl acrylate 2a resulted in a highly selective formation of
2-alkenylated pyrrole 4a in 87% yield (Scheme 2). Interestingly,
the double alkenylated product 4b could also be obtained in
51% yield by the use of Ag2CO3 as the oxidant.
Despite the importance of carbazole derivatives in various
biologically active compounds and materials science,15 the C–H
functionalization of carbazoles is much less developed than other
heteroarenes. Very recently, Carretero et al. reported the first
Pd-catalyzed olefination of carbazoles directed by the N-(2-pyridyl)-
sulfonyl group, which mainly afforded di-o-alkenylated products.16
However, the metal-catalyzed highly selective mono-o-olefination of
carbazoles is scarce. Gratifyingly, this reaction was realized by the
utilization of the method described herein (Scheme 3). Not only
butyl acrylate, but also non-activated styrene coupled with carbazole
a
Conditions: 1 (1.0 equiv.), 2a (1.5 equiv.), [RuCl2(p-cymene)]2 (2.5 mol%),
AgSbF6 (10 mol%), Cu(OAc)2 (20 mol%), O2 (1 atm), and NaOAc (30 mol%)
in DCE (1.0 mL) at 100 1C for 15 h. Isolated yields.
c
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Scheme 2 Ru-catalyzed direct olefination of N-dimethylcarbamoyl pyrrole.
Condition A: 1l (1.0 equiv.), AgSbF6 (10 mol%), Cu(OAc)2 (20 mol%), O2
(1 atm), and NaOAc (30 mol%) in DCE (1.0 mL) at 100 1C for 15 h. Condition
B: 1l (1.0 equiv.), AgSbF6 (20 mol%), Ag2CO3 (2.5 equiv.), and NaOAc (60 mol%)
in DCE (1.0 mL) under N2 at 100 1C for 15 h.
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Scheme 3 Ru-catalyzed direct olefination of N-dimethylcarbamoyl carbazole.
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Scheme 4 The deprotection of the directing group.
1m to form the corresponding mono-o-alkenylated products selec-
tively, although styrene exhibited lower reactivity than acrylate.
To further demonstrate the synthetic utility of this metho-
dology, the deprotection of the N-dimethylcarbamoyl group was
then attempted. As expected, it can be easily removed after the
coupling reaction under basic conditions, affording the corre-
sponding free (N–H) indoles in good yields (Scheme 4).14
In conclusion, we have developed a highly efficient and
selective Ru-catalyzed C2-olefination of indoles and other
related N-heteroarenes by using the N-dimethylcarbamoyl as
the unique and removable directing group. Key features of this
protocol include the employment of an atmosphere of O2 as the
terminal oxidant and the wide substrate scope with respect to
both heteroarenes and alkenes. Further studies to explore the
reaction mechanism are currently underway in the lab.
We thank the financial support from the National Basic
Research Program of China (973 Program, 2011CB808600) and
the National NSF of China (J1103315/J0104, 21202105,
21025205, and 21021001).
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Notes and references
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c
8832 Chem. Commun., 2013, 49, 8830--8832
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