Efficient synthesis of substituted pyrroles through iron-mediated oxidation reaction of 3-methylenehexane-2,5-dione with primary amines

Article abstract of DOI:10.1080/00397911.2018.1533972

An efficient route has been developed for the synthesis of multiple substituted pyrrole derivatives from the readily available agents through iron-mediated oxidative aromatization process in good to excellent yields. This method is well tolerated with a diverse broad range of substrates and a complementary approach to currently available synthetic methods.

Full text of DOI:10.1080/00397911.2018.1533972

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient synthesis of substituted pyrroles
through iron-mediated oxidation reaction of 3-
methylenehexane-2,5-dione with primary amines
Xi Chen, JiaCheng Yuan & Min Zhou
To cite this article: Xi Chen, JiaCheng Yuan & Min Zhou (2018): Efficient synthesis of substituted
pyrroles through iron-mediated oxidation reaction of 3-methylenehexane-2,5-dione with primary
amines, Synthetic Communications, DOI: 10.1080/00397911.2018.1533972
To link to this article: https://doi.org/10.1080/00397911.2018.1533972
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https://doi.org/10.1080/00397911.2018.1533972
Efficient synthesis of substituted pyrroles through
iron-mediated oxidation reaction of 3-methylenehexane-
2,5-dione with primary amines
Xi Chen, JiaCheng Yuan, and Min Zhou
School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huaian,
Jiangsu, China
ABSTRACT
ARTICLE HISTORY
Received 3 July 2018
An efficient route has been developed for the synthesis of multiple
substituted pyrrole derivatives from the readily available agents
through iron-mediated oxidative aromatization process in good to
excellent yields. This method is well tolerated with a diverse broad
range of substrates and a complementary approach to currently
available synthetic methods.
KEYWORDS
dehydrogenation;
iron; pyrroles
GRAPHICAL ABSTRACT
Introduction
Pyrroles are the privileged nitrogen-containing heterocycles and are widely encountered
in the scaffolds of bioactive natural products[1] and pharmaceutical agents,[2] exhibiting
pronounced bioactivities such as antitumor,[3] anti-inflammatory,[4] antibacterial[5] and
antifungal effects.[6] Moreover, they are also employed as building blocks in organic
synthesis to construct the more structurally complicated scaffolds.[7] In light of their
numerous applications, considerable research efforts have been contributed to the devel-
opment of novel synthetic methods for the efficient construction of pyrroles.
Traditional synthetic methods include the Knorr,[8] Pall-Knorr,[9] and Hantzsch reac-
tions,[10] which have been used for more than a century. While the development of effi-
cient and facile methods for the preparation of pyrrole derivatives from readily available
starting materials is still desired as the highly important class of compounds has more
and more applications. Recently, many novel synthetic approaches through oxidative
aromatization of 2,3-dihydropyrrole intermediates have been reported, which represent
CONTACT Xi Chen
chenxi.wozai@163.com
School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical
Science College, Huaian, Jiangsu 223005, China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

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X. CHEN ET AL.
Scheme 1. One-pot cyclization-oxidation sequence to synthesize pyrroles.
an attractive strategy.[11–20] For example, Zhang’s group has reported the synthesis of
multiple substituted pyrroles from activated cyclopropanes and anilines through iron-
mediated oxidative aromatization of the 2,3-dihyropyrrole intermediate in moderate to
good yields (Scheme 1).[12] Additionally, Liu’s group has disclosed the formation of
highly substituted pyrroles from 2-acetyl-3-methylene-1,4-dicarbonyl compounds and
primary amines through TBHP and activated carbon oxidative aromatization of
2,3dihyropyrrole.[16] In continuation of our studies on the heterocycle synthesis,[21] we
wish to report herein a synthetic approach to multiple substituted pyrroles from 3-
methylenehexane-2,5-dione and primary amines using iron through a tandem
Aza–Michael addition, and oxidative aromatization. The protocol provides a potential
route for the synthesis of multiple pyrroles in moderate to excellent yields and a com-
plementary approach to currently available synthetic access to pyrroles.
Results and discussion
Initially, 3-methylenehexane-2,5-dione 1a and aniline 2a were selected as model sub-
strates to explore the optimal reaction conditions for the cyclization/oxidation sequence
to generate the highly substituted pyrrole 3a. As shown in Table 1, firstly we screened
different iron catalysts to explore the effect on the reaction yield. It was found that a
promising reaction yield was obtained when a mixture of 1a and 2a in DCE was heated
.
at reflux in the presence of FeCl3 6H20 or anhydrous FeCl3 for 24 h (80% and 78%,
.
Table 1, entries 1–2), whereas the other iron salts including Fe2O3, Fe2(S04)3 xH20,
.
Fe(acac)3, Fe(NO3)3 9H20, FeCl2, Fe(OTf)2 all displayed poor activities, offering the
desired product 3a in 5–49% yields (Table 1, entries 4–9). While, a moderate reaction
yield was observed when the FeBr3 was involved (Table 1, entry 3). These results dem-
.
onstrated that the FeCl3 6H20 and FeCl3 were the optimal catalysts for this transform-
ation. Furthermore, in consideration of hygroscopic properties and higher price of
.
FeCl3, FeCl3 6H20 was selected to further optimize the reaction conditions to improve
the reaction yields. Next, we turned our attention to probe the effects of different sol-
vents on the reaction outcomes. Screening of the solvents revealed that most of them
afforded reaction yields lower than those reactions performed in DCE (trace to 38%,
Table 1, entries 10–13). It is worth mentioning that if the reaction was conducted in
water, the desired product was obtained in 10% yield (Table 1, entry 14). It was found

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Table 1. Optimization of reaction conditionsa.
Entry
Catalyst
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Time/h
Yieldb(%)
1
2
3
4
5
6
7
8
FeCl3.
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
24
24
78
80
65
20
49
5
FeCl3 6H2O
FeBr3
Fe2O3
Fe2(S04)3 xH20
.
Fe(acac)3
.
Fe(NO3)3 9H20
39
19
25
38c
23
15
5
FeCl2
9
Fe(OTf)2
DCE
.
10
11
12
13
14
15
16e
17f
FeCl3.6H2O
toluene
EtOH
1,4-dioxane
CH3CN
H2O
DCE
DCE
FeCl3.6H2O
FeCl3.6H2O
FeCl3.6H2O
FeCl3.6H2O
FeCl3.6H2O
FeCl3.6H2O
FeCl3 6H2O
10d
75
55
34
DCE
aA solution of 1a (0.5 mmol) and 2a (0.6 mmol, 1.2 equiv) with Iron salts (0.25 mmol, 0.5 equiv) in solvent (2 mL) was
b
c
heated at reflux in air; Isolated yield; The reaction temperature is 100 ꢀC; d35% of 1a was recovered; e,fThe tempera-
ture is 60 ꢀC and 40 ꢀC, respectively.
that prolonging the reaction time was not beneficial to this transformation (Table 1,
entry 15). When the reaction temperature was lowered to 60 or 40 ꢀC, the yield of 3a
was reduced to 55 or 34%, respectively (Table 1, entries 16, 17).
With the optimal reaction conditions in hand, we proceeded to investigate the gener-
ality of this cascade process to the synthesis of structurally diverse pyrroles 3. As shown
in Table 2, this method was compatible with significant structural variations both in the
amines and 3-methylenehexane-2,5-dione substrates. The substitution patterns on the
phenyl rings displayed limited effects on the reaction yields (3a–g). An increase in reac-
tion yields was observed when the anilines with electron-donating groups on the phenyl
ring such as methoxyl were involved in this process (3c–d). While, the electron-with-
drawing groups on the phenyl ring such as the nitro, fluorine resulted in a significant
drop on the yield (3i–j). It is well worth mentioning that a broad range of functional
groups on the phenyl ring such as nitro, bromine, chlorine was well tolerated in this
transformation to generate the corresponding products in 40–77% yields (3i–l). These
products could be used as building blocks to synthesize structurally more complicated
molecules. In addition to the aromatic amines, the aliphatic amines could also be
involved smoothly in this reaction to afford the corresponding pyrroles 3m and n in 85
and 88% excellent yields. Probing the 3-methylenehexane-2, 5-dione substrates implied
that the more hindered R2 ¼ ethyl, R3 ¼ methyl or R2 ¼ methyl, R3 ¼ ethyl appeared to
be good candidates for this process, giving the products in 72% and 70% yields respect-
ively (3o, 3q). Additionally, the substrate with a phenyl group in R1 position could also
generate the product in good yield (3p). While the reactions did not proceed well and

4
X. CHEN ET AL.
Table 2. Scope of iron-mediated synthesis of pyrroles 3.
none of the desired products were obtained when a phenyl group was placed at R2 or
R3 position.
To gain insights into the mechanism, the intermediate II was synthesized beforehand,
.
which was subsequently added to a mixture of FeCl3 6H2O in DCE under the same con-
ditions and the desired pyrrole 3a was obtained in 75% yield (Scheme 2). On the basis
of the reaction outcomes and previously reported literature, a plausible mechanism for

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Scheme 2. Oxidative aromatization of 2,3-dihydropyrrole intermediate ii to pyrrole 3a.
Scheme 3. A Proposed mechanism for the reaction.
the reaction of 3-methylenehexane-2,5-dione 1a and primary amine 2 is proposed in
Scheme 3. Treatment of 1a and 2 in DCE generated the enamine intermediate I, which
was followed by intramolecular Aza–Michael addition resulting in the formation of
intermediate II. The subsequent single electron-transfer oxidation of intermediate II by
Fe3þ and O2 would generate the radical species III, which was subjected to sequential
radical dehydrogenation and deprotonation reactions to afford the pyrroles 3.
Experimental
To a solution of substrate 3-methylenehexane-2,5-dione 1 (0.5 mmol) and amines 2
(0.6 mmol) in DCE (2.0 mL) was added to FeCl3.6H2O (0.25 mmol). The mixture with
air was stirred at reflux for 24 h. The mixture was cooled to room temperature, filtered
through celite, washed with ethyl acetate and concentrated under vacuum. The resulting
residue was purified by column chromatography using hexane/ethyl acetate (v/v, 20/1 to
10/1) as the eluent to give the desired product.
Conclusions
In summary, we have developed an efficient Fe(III)-mediated domino reaction for the
synthesis of the biologically meaningful multisubstituted pyrroles derivatives 3 in mod-
erate to excellent yields from readily available 3-methylenehexane-2,5-dione derivatives
1 and primary amines 2 in the presence of air. The method was well tolerated with a
diverse range of substrates and had great potential as a complementary approach to the
currently available synthetic methods.

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X. CHEN ET AL.
Funding
We gratefully thank the financial support from National Natural Science Foundation of China
(21702073), HuaiAn Science and Technology Bureau (HAG2015020), and Research Foundation
of Jiangsu Food & Pharmaceutical Science College (JSSPMS2017201).
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