Synthesis of Pyrrole via a Silver-Catalyzed 1,3-Dipolar Cycloaddition/Oxidative Dehydrogenative Aromatization Tandem Reaction

Article abstract of DOI:10.1021/acs.joc.7b00180

Pyrroles are an important group of heterocyclic compounds with a wide range of interesting properties, which have resulted in numerous applications in a variety of fields. Despite the importance of these compounds, there have been few reports in the literature pertaining to the synthesis of pyrroles from simple alkenes using a one-pot sequential 1,3-dipolar cycloaddition/aromatization reaction sequence. Herein, we report the development of a benzoyl peroxide-mediated oxidative dehydrogenative aromatization reaction for the construction of pyrroles. We subsequently developed a one-pot tandem reaction that combined this new method with a well-defined silver-catalyzed 1,3-dipolar cycloaddition reaction, thereby providing a practical method for the synthesis of multisubstituted pyrroles from easy available alkenes. The mechanism of this oxidative dehydrogenative aromatization reaction was also examined in detail.

Full text of DOI:10.1021/acs.joc.7b00180

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Article
Synthesis of Pyrrole via a Silver-catalyzed 1,3-Dipolar Cycloaddition /
Oxidative Dehydrogenative Aromatization Tandem Reaction
Yan Liu, Huayou Hu, Xiang Wang, Sanjun Zhi, Yuhe Kan, and Chao Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00180 • Publication Date (Web): 22 Mar 2017
Downloaded from http://pubs.acs.org on March 24, 2017
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The Journal of Organic Chemistry
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Synthesis of Pyrrole via a Silver-catalyzed 1,3-Dipolar
Cycloaddition / Oxidative Dehydrogenative
Aromatization Tandem Reaction
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Yan Liu, †, ‡ Huayou Hu, †, ‡, * Xiang Wang, † Sanjun Zhi, † Yuhe Kan † and Chao Wang ‡, *
† Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and
Chemical Engineering, Huaiyin Normal University, Huaian 223300, P. R. China
‡ School of Material Science and Engineering, Southwest University of Science and Technology,
Mianyang 621010, P. R. China
njuhhy@hotmail.com ; wangchao@swust.edu.cn
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RECEIVED DATE
ABSTRACT: Pyrroles are an important group of heterocyclic compounds with a wide range of
interesting properties, which have resulted in numerous applications in a variety of fields. Despite the
importance of these compounds, there have been few reports in the literature pertaining to the synthesis
of pyrroles from simple alkenes using a one-pot sequential 1,3-dipolar cycloaddition/aromatization
reaction sequence. Herein, we report the development of a benzoyl peroxide-mediated oxidative
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The Journal of Organic Chemistry
Page 2 of 18
dehydrogenative aromatization reaction for the construction of pyrrolidines. We subsequently developed
a one-pot tandem reaction that combined this new method with a well-defined silver-catalyzed
1,3-dipolar cycloaddition reaction, thereby providing a practical method for the synthesis of
multi-substituted pyrroles. The mechanism of this oxidative dehydrogenative aromatization reaction was
also examined in detail.
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INTRODUCTION
Pyrroles are an important class of aromatic heterocyclic compounds that can be found in a large
number of natural products.1 Pyrrole derivatives play critical roles in numerous biologically important
compounds, such in as chlorophyll, hemoglobin, and vitamin B12. Furthermore, the pyrrole skeleton can
be found in several marketed drugs, such as atorvastatin, aloracetam, elopiprazole, isamoltane, and
ketorolac (Fig. 1).2 A large number of synthetic pyrrole derivatives has also been prepared with a wide
variety of interesting properties, and many of these systems have found important applications in
biology, medicine, materials science, and the dye industry.3 In light of their importance, pyrrole
derivatives have attracted considerable attention from the organic chemistry community, culminating in
the development of several new strategies for the synthesis of compounds belonging to this class. 4
Figure 1. Pyrrole in some marketed drugs.
OH
CO2H
H
CO2H
N
O
N
N
HO2C
N
O
NH2
H
Porphobilinogen
Ketorolac
Isamoltane
F
Ph
CHO
O
N
H
NH
i-Pr
N
Ph
N
OH
CO2H
HO
N
N
O
NHAc
F
Atorvastatin
Elopiprazole
Aloracetam
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The Journal of Organic Chemistry
During the past three decades, 1,3-dipolar cycloaddition reactions have been used extensively to
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provide powerful synthetic methods for the construction of nitrogen-containing five-membered
heterocycles, such as isoxazolidine, pyrazole, indolizine, and triazole.5 This strategy has also been used
prepare pyrrolidines.6 However, despite considerable progress toward the synthesis of indolizines,7 there
have been very few reports pertaining to the synthesis of pyrroles using a one-pot 1,3-cycloaddition
reaction. The few methods that have been reported in this area are generally limited by their requirement
for electron-deficient alkyne substrates8 and their analogs, such as (E)-1,2-bis(phenylsulfonyl)ethane,9
((1-bromovinyl)sulfonyl)benzene,10 and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one,11 which are
expensive and difficult to access, as well as lacking in sufficient structural diversity. These limitations
could be attributed in part to a lack of suitable methods for the oxidative dehydrogenative aromatization
of pyrrolidines. Although 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ),12
o-iodoxybenzoic acid,13 and manganese dioxide14 have been used previously to promote the oxidative
dehydrogenative aromatization reactions of isolated pyrrolidines, the overall synthetic efficiency of
these reactions can be reduced considerably by their requirement to conducted as step-wise processes.
Furthermore, DDQ is expensive and toxic, and its consumption during the course of these reactions
results in the formation of toxic by-products. We recently reported a series of synthetic methods for the
construction of indolizines using a tandem one-pot 1,3-dipolar cycloaddition/oxidative dehydrogenative
aromatization reaction sequence.15 As part of our ongoing research towards the oxidative
dehydrogenative aromatization reactions of nitrogen-containing heterocycles, we report herein the
development of a practical synthetic method for the construction of pyrroles via a tandem reaction
sequence starting from simple alkenes (Scheme 1).
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Scheme 1. Different oneꢀpot synthetic pathways for the construction of pyrroles from alkenes
using a 1,3ꢀdipolar cycloaddition reaction.
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