Palladium-catalyzed oxidative cyclization of tertiary enamines for synthesis of 1,3,4-trisubstituted pyrroles and 1,3-disubstituted indoles

Article abstract of DOI:10.1021/ol501394k

A novel and efficient palladium-catalyzed intramolecular oxidative cyclization of tertiary enamines for the synthesis of 1,3,4-trisubstituted pyrroles and 1,3-disubstituted indoles has been developed. Trifluoroacetic acid plays an important role in the reaction. A series of pyrroles and indoles with substitution patterns that are not easily accessible by traditional routes were synthesized in good yields under mild conditions.

Full text of DOI:10.1021/ol501394k

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Oxidative Cyclization of Tertiary Enamines for
Synthesis of 1,3,4-Trisubstituted Pyrroles and 1,3-Disubstituted
Indoles
Xiao-Li Lian, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient palladium-catalyzed intramolecular
oxidative cyclization of tertiary enamines for the synthesis of 1,3,4-
trisubstituted pyrroles and 1,3-disubstituted indoles has been developed.
Trifluoroacetic acid plays an important role in the reaction. A series of
pyrroles and indoles with substitution patterns that are not easily
accessible by traditional routes were synthesized in good yields under
mild conditions.
Scheme 1. Palladium-Catalyzed Oxidative Cyclization of
Tertiary Enamines
itrogen-containing aromatic heterocycles, such as pyr-
Nroles and indoles, are ubiquitous scaffolds in numerous
bioactive natural and synthetic compounds, pharmaceuticals,
and functional materials.1 Therefore, novel and efficient
methods for the synthesis of these heterocycles have been
and continue to be a very active area of research.2 Over the past
decades, a number of protocols have been developed for the
synthesis of various pyrroles.3 However, 1,3,4-trisubstituted
pyrroles, especially those containing three different substitu-
ents, are still one of the most challenging compounds in organic
synthesis4 because (1) conventional methods are mainly
suitable for the synthesis of 2,5-disubstituted or polysubstituted
pyrroles5 and (2) the functionalization of simple pyrroles
usually suffers from a lack of selectivity and polymerization.6
Recently, a novel palladium-catalyzed oxidative cyclization of
N-aryl enamines to synthesize substituted indoles has been
developed by Glorius and co-workers.7 Palladium-catalyzed
aerobic oxidative cyclization of N-aryl imines or N-allyl imines
for the synthesis of 2-arylindoles or 2-arylpyrroles has
emerged.8,9 The secondary enamines or N-substituted imines
was employed as the readily available starting materials, thus
making these reactions promising for NH indoles or NH
pyrroles synthesis.7−10
The cross-coupling reactions of tertiary enamines are very
rare,11 and it has been noted that tertiary enamines, unlike their
secondary enamine homologues, are generally inactive in
palladium-catalyzed C−H activation reactions.12 We hypothe-
sized that oxidative cyclization of the 2-fold C−H bond of
tertiary enamines for the synthesis of pyrroles or indoles may
be achieved by improving the electrophilicity of palladium
catalysts under acidic conditions (Scheme 1).13 In this paper,
we describe the development of a palladium-catalyzed intra-
molecular oxidative cyclization of tertiary enamines for the
synthesis of 1,3,4-trisubstituted pyrroles and 1,3-disubstituted
indoles under mild conditions.
We commenced our study by investigating the palladium-
catalyzed oxidative cyclization of (E)-ethyl 3-(allyl(phenyl)-
amino)acrylate 1a (Table 1). Only a trace of pyrrole 2a was
observed in the presence of the Pd(OAc)2 catalyst and
stoichiometric Cu(OAc)2 in CH3CN at 60 °C (Table 1,
entry 1). Then, various acids were screened as additives to
improve the reaction efficiency. Expectedly, a 22% yield of
pyrrole product 2a was obtained when 1.0 equiv of p-TsOH
was used, while acetate acid shows no reactivity (Table 1,
entries 2−3). Indeed, the yield of 2a was dramatically improved
to 61% when PivOH was used as an additive (Table 1, entry 5).
Further improvement was made by using TFA, in which case a
70% yield of pyrrole 2a was obtained (Table 1, entry 6).
Optimization of different palladium catalyst precursors and
solvents revealed that Pd(OAc)2 and CH3CN was the most
suitable catalyst and solvent respectively for this reaction (Table
1, entries 7−12). Finally, the reaction temperature was also
varied, and 60 °C gave the best result (Table 1, entries 13−14).
With the optimized conditions established, the scope of the
reaction was investigated (Scheme 2). This new palladium-
catalyzed oxidative cyclization reaction displayed good func-
tional-group tolerance and proved to be a general method for
Received: May 14, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501394k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Palladium-Catalyzed Oxidative Cyclization of N-
Allyl Aryl Tertiary Enamines for Synthesis of 1,3,4-
a
Trisubstituted Pyrroles
entry
catalyst
additive
solvent
t (°C)
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
−
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
60
60
60
60
60
60
60
60
60
60
60
60
100
40
3
5
2
HOAc
p-TsOH
TCA
PivOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
3
22
20
61
70
40
36
52
12
7
4
5
6
7
8
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
14
DMA
toluene
CH3CN
CH3CN
14
58
24
a
Reaction conditions: 1a (0.2 mmol), [Pd] (5 mol %), Cu(OAc)2 (2.2
equiv), acid (1.0 equiv) in CH3CN (2 mL) at 60 °C, 12 h, in air;
isolated yield.
facile construction of 1,3,4-trisubstituted pyrroles that have not
been easily accessible. N-Allyl aryl tertiary enamines with
electron-donating groups, such as methyl and methoxyl, or
electron-withdrawing groups, such as fluoro, chloro, and
bromo, on the aryl rings reacted smoothly and resulted in the
corresponding 1,3,4-trisubstituted pyrroles 2b−2j in good
yields, thus indicating that the electronic nature of the
substrates has little influence on the cyclization reaction.
Ethyl 4-methyl-1-(o-tolyl)-1H-pyrrole-3-carboxylate 2e was
obtained in a slightly lower yield which may be due to the
steric effect of the ortho-methyl group on the aryl ring. β-
Naphthyl substituted tertiary enamine 1k was also tolerated and
afforded the corresponding 2k in 45% yield.
In addition, phenyl tertiary enamines with a difference in
vinyl or allyl groups, such as dimethyl 2-(allyl(phenyl)amino)-
maleate 1l, (E)-ethyl 3-(but-2-en-1-yl(phenyl)amino)acrylate
1m, and (E)-ethyl 3-((3-methylbut-2-en-1-yl)(phenyl)amino)-
acrylate 1n, show good reactivity, producing the corresponding
pyrroles 2l−2n in 55−65% yields. However, no reaction
occurred when (E)-ethyl 3-(cyclohex-2-en-1-yl(phenyl)amino)-
acrylate 1o was employed as the substrate.
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), Cu(OAc)2
(2.2 equiv), TFA (1.0 equiv) in CH3CN (2 mL) at 60 °C, 8−12 h, in
air; isolated yields.
Encouraged by the aforementioned results, we envision that
the palladium-catalyzed intramolecular oxidative coupling
reaction may occur at a vinyl C−H bond and an aryl C−H
bond to afford 1,3-disubstituted indoles when N-alkyl aryl
tertiary enamines were used as the substrates. After a brief
survey of reaction conditions,14 a 68% yield of butyl 1-methyl-
1H-indole-3-carboxylate 4a was obtained in the presence of
PdCl2, Cu(OAc)2, and TFA in CH3CN at 100 °C (Table 2,
entry 1). Therefore, a series of N-alkyl indole-3-carboxylate
4a−4h were synthesized (Table 2). It should be noted that 1,7-
annulated indole-3-carboxylate 4i which was an important
synthetic precursor for a high-affinity 5-HT3 receptor
antagonist was easily synthesized in 51% yield,15 thus implying
that our method is of synthetic utility (Table 2, entry 9).
However, when (E)-ethyl 3-(diphenylamino)acrylate 3j was
employed as the substrate, the corresponding ethyl 1-phenyl-
1H-indole-3-carboxylate 4j was obtained only in 15% yield,
along with 41% of diphenylamine as the byproduct.
On the basis of the above results and previous reports, a
tentative mechanism for the reaction is proposed in Scheme 3.
The reaction begins with an electrophilic palladation of the
vinyl C−H bond of tertiary enamine 1 under acidic conditions
to give a vinylpalladium intermediate A.11,13 Intramolecular 5-
exo-trig cyclization of A affords the intermediate B, which
undergoes β-hydride elimination and tautomerization to form
the 1,3,4-trisubstituted pyrrole 2 (Cycle I).9 Alternatively,
intramolecular aryl C−H activation of the vinylpalladium
intermediate A′ gives the intermediate D.8,11,16 Then, reductive
elimination of intermediate D produces the 1,3-disubstituted
indole 4 (Cycle II). In these catalytic cycles, the Pd(0) was
B
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Table 2. Palladium-Catalyzed Oxidative Cyclization of N-
Scheme 3. A Tentative Mechanism for Palladium-Catalyzed
Oxidative Cyclization of Tertiary Enamines
Alkyl Aryl Tertiary Enamines for Synthesis of 1,3-
a
Disubstituted Indoles
studies on the substrate scope and mechanism of the reaction
are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectral data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: guanzhh@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (Grant No. 21272183)
and the Fund of the Rising Stars of Shanxi Province
(2012KJXX-26).
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