Synthesis of Polycarbonyl Pyrroles via K2S2O8-Mediated Oxidative Cyclization of Enamines

Article abstract of DOI:10.1021/acs.orglett.6b03060

A novel K₂S₂O₈-promoted oxidative cyclization of enamines is described. A variety of enamines having diverse functional groups and substitution patterns react well using K₂S₂O₈ as the oxidant in the absence of catalyst. This protocol provides a very simple route for the synthesis of polycarbonyl pyrroles and has the advantages of readily available starting materials, mild reaction conditions, and a wide scope of substrates.

Full text of DOI:10.1021/acs.orglett.6b03060

Letter
pubs.acs.org/OrgLett
Synthesis of Polycarbonyl Pyrroles via K2S2O8‑Mediated Oxidative
Cyclization of Enamines
Peng Gao,*,†,‡ Juan Wang,† Zi-Jing Bai,† Li Shen,† Yun-Yun Yan,† De-Suo Yang,† Ming-Jin Fan,†
and Zheng-Hui Guan*,‡
†Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences,
Baoji, Shaanxi 721013, P. R. China
‡Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710127, P. R. China
S
* Supporting Information
ABSTRACT: A novel K2S2O8-promoted oxidative cyclization of enamines
is described. A variety of enamines having diverse functional groups and
substitution patterns react well using K2S2O8 as the oxidant in the absence
of catalyst. This protocol provides a very simple route for the synthesis of
polycarbonyl pyrroles and has the advantages of readily available starting
materials, mild reaction conditions, and a wide scope of substrates.
olysubstituted pyrroles are an important class of five-
In recent years, radical reactions have attracted broad interest
in organic synthesis and have been widely applied in medicinal
and materials chemistry.7−9 In this context, a variety of
transition-metal-free radical cyclization processes have been
successfully established for the synthesis of functional
heterocyclic compounds via intra- or intermolecular carbon−
carbon or carbon−heteroatom bond formations.10 Despite
considerable progress in this field, exploration of simpler and
efficient methods are still highly appealing. Very recently,
K2S2O8 was found to be a useful oxidant in oxidative reactions
because of its characteristics of easy availability, good stability,
and low toxicity.11 Thus, studies focusing on the development
of K2S2O8-mediated oxidative reactions meet the requirement
of sustainable chemistry. In continuation of our efforts on the
synthesis of pyrroles,12 herein we report an efficient K2S2O8-
mediated oxidative cyclization of enamines for the synthesis of
dicarbonyl or tetracarbonyl pyrroles.
In preliminary experiments, (Z)-methyl 3-amino-3-phenyl-
acrylate (1a) was chosen as a model substrate to optimize the
reaction conditions (Table 1). Treatment of 1a with 1.0 equiv
of tert-butyl hydroperoxide (TBHP) in DCE at 100 °C under
air for 5 h afforded the desired pyrrole 2a in 19% yield (Table
1, entry 1). Then various reaction parameters were screened,
including the oxidant, solvent, and temperature. A range of
oxidants such as PhI(OAc)2, IBX, NaBO3·4H2O, (NH4)2S2O8,
Na2S2O8, and K2S2O8 were tested, and K2S2O8 showed the
highest efficiency (Table 1, entries 2−7). Increasing the loading
of K2S2O8 to 1.2 equiv improved the yield of 2a to 87% (Table
1, entry 8), while the yield of 2a was decreased when the
loading of K2S2O8 was further increased (Table 1, entry 9). The
solvent also plays a key role in this transformation. The product
yield decreased when DCE, CH3CN, or toluene was used as the
P
membered heterocycles and exist in numerous natural
products and bioactive molecules.1 Carbonyl groups in these
molecules are key moieties that are closely related to their
biological activities (Figure 1). For example, ningalins A is
Figure 1. Selected examples of functional polycarbonyl pyrroles.
isolated from Western Australian ascidian,1a methoxatin acts as
a bacterial coenzyme,1b and atorvastatin is used for the
treatment of dyslipidemia.1c Thus, extensive attention has
been paid to developing methods for the construction of
pyrroles containing carbonyl groups. The classic Paal−Knorr2
and Hantzsch3 reactions have been frequently used to assemble
pyrroles with a single carbonyl group on the ring. In the past
several decades, novel methods such as transition-metal-
catalyzed coupling4 and multicomponent reactions5 have been
established for the synthesis of functional multicarbonyl
pyrroles. Following these strategies, one or two carbonyl
groups can be introduced into the pyrrole compound. In
addition, oxidative cyclization of enamines using various
oxidants,6 including Pb(OAc)4,6a PhI(OAc)2,6b and CAN,6c
has provided alternative approaches for the synthesis of
dicarbonyl pyrroles. However, the development of novel and
practical methods for the synthesis of multicarbonyl pyrroles,
especially symmetrical multicarbonyl pyrroles, is still highly
desirable.
Received: October 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03060
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of the Synthesis of Dicarbonyl Pyrroles
a
b
Conditions: 1a (0.5 mmol), oxidant, solvent (5 mL), 5 h. Isolated
yields.
solvent (Table 1, entries 10−12). The reaction temperature has
little influence on the reaction efficiency, and 100 °C is still the
best choice (Table 1, entries 13 and 14). Thus, the optimized
procedure was chosen as follows: 1a (0.5 mmol) and K2S2O8
(0.6 mmol) in DMSO at 100 °C.
Scheme 2. Scope of the Synthesis of Tetracarbonyl Pyrroles
With optimized reaction conditions available, the scope of
this oxidative cyclization reaction was then investigated. The
reaction showed good functional group tolerance and proved to
be a practical procedure for the synthesis of dicarbonyl pyrroles
(Scheme 1). Enamines containing an electron-donating
substituent such as a methyl or methoxyl group on the aryl
ring furnished the corresponding products in 58−85% yield
(2b−g). It should be noted that the lower yield of product 2c
might be due to the steric effect of the o-methyl group.
Substituents such as F, Cl, and Br on the aryl ring of the
enamine were smoothly tolerated in the reaction, and the
desired products were obtained in good yields (2h−j) and
could be derivatized to give various functionalized pyrrole
compounds. Trifluoromethyl and phenyl groups also were
compatible with the reaction and gave the corresponding
products in 83% and 73% yield, respectively (2k and 2l). It was
remarkable that heterocyclic and N-butyl-substituted enamines
were tolerated as well, providing the desired pyrroles in
moderate yields (2m−o). However, alkyl-substituted enamine
1p failed to yield the desired product 2p.
To further demonstrate the synthetic practicality of this
method, we next focused on the synthesis of tetracarbonyl
pyrroles (Scheme 2). When enaminone 3a was employed in the
reaction, the desired tetracarbonyl pyrrole 4a was obtained in
81% yield, and this was further proved by X-ray analysis (Figure
2). Encouraged by this result, we evaluated the scope and
generality of this transformation. Aryl enaminones 3 with
electron-donating substituents (−Me, −OMe) were well-
tolerated, delivering the desired products in 57−80% yield
(4b−f). Enaminones with electron-withdrawing substituents
such as F, Cl, and Br all reacted well and were transformed into
the corresponding tetracarbonyl pyrroles in moderate yields
(4g−i). In addition, the biaryl and fused-ring substrates gave
the products in 81% and 53% yield, respectively (4j and 4k).
The heteroaromatic substrate 3l was also smoothly converted
B
DOI: 10.1021/acs.orglett.6b03060
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Initially, oxidation of enamine 1 by K2S2O8 generates amino
radical cation A, which reacts with a second molecule of
enamine 1 to form intermediate B. Then intramolecular C−N
bond formation leads to intermediate C. Oxidation of C
generates intermediate D. Finally, sequential elimination of H+
and NH3 from D produces the product 2.
In summary, we have developed an efficient and practical
oxidative cyclization of enamines for the synthesis of
polycarbonyl pyrroles under transition-metal-free conditions.
A range of functionalized dicarbonyl or tetracarbonyl pyrroles
were obtained in high yields using inexpensive, stable, and
commercially available K2S2O8 as the sole oxidant. Moreover,
the gram-scale reaction demonstrates the potential usefulness of
this transformation in organic synthesis. Further studies of
oxidative cyclization of enamines are ongoing in our group.
Figure 2. X-ray of structure of 4a.
to the corresponding tetracarbonyl pyrrole 4l in very good
yield.
For practical purposes, we attempted the scaled-up synthesis
of pyrrole 2a (Scheme 3a). The reaction using 10 mmol of 1a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03060.
Scheme 3. Gram-Scale Synthesis of 2a and Derivatization
Reactions
Experimental procedures, analytical data, and NMR
spectra of the products (PDF)
X-ray data for 2a (CIF)
X-ray data for 4a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gaopeng_hx@bjwlxy.edu.cn.
*E-mail: guanzhh@nwu.edu.cn.
ORCID
Peng Gao: 0000-0003-1292-0691
Zheng-Hui Guan: 0000-0003-4901-5951
furnished 2a in 82% yield without any significant decrease in its
efficiency. Furthermore, to probe the utility of the reaction,
several derivatization reactions were carried out. Reduction of
2a with LiAlH4 gave pyrrole derivative 5a in 78% yield (Scheme
3b). On the other hand, Suzuki coupling of 2j with p-
tolylboronic acid afforded 6a in 95% yield (Scheme 3c). These
successful conversions of 2a and 2j illustrated that polycarbonly
pyrroles are potential intermediates in organic synthesis.
We next focused on the mechanism of this reaction. A
control experiment in which 2 equiv of 2,2,6,6-tetramethylpi-
peridin-1-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol
(BHT) was added to the model reaction failed to afford the
pyrrole product 2a, suggesting that the reaction may involve a
radical process. On the basis of our experimental results and the
literature,6,13 a possible mechanism is proposed (Scheme 4).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21272183, 21472147, and 21622203), Shaanxi
Provincial Key Laboratory Project (15JS004), Baoji University
of Arts and Sciences (ZK15046), and Northwest University
(334100038) for financial support.
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