Manganese (III) acetate mediated synthesis of polysubstituted pyrroles under solvent-free ball milling

Article abstract of DOI:10.1016/j.tetlet.2017.01.016

Under solvent-free ball milling conditions, a simple and mild method was developed for efficient synthesis of 2,5-dimethyl-3,4-dicarboxylate-pyrroles and N-substituted 3,4-diphenylpyrroles via condensation-annulation of amines with acetoacetate and 2-phen

Full text of DOI:10.1016/j.tetlet.2017.01.016

Accepted Manuscript
Manganese (III) acetate mediated synthesis of polysubstituted pyrroles under
solvent-free ball milling
Ji-Chao Zeng, Hui Xu, Fei Yu, Ze Zhang
PII:
S0040-4039(17)30028-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.016
TETL 48519
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 November 2016
2 January 2017
4 January 2017
Please cite this article as: Zeng, J-C., Xu, H., Yu, F., Zhang, Z., Manganese (III) acetate mediated synthesis of
polysubstituted pyrroles under solvent-free ball milling, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.01.016
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Graphical Abstract
Manganese (III) acetate mediated synthesis of
polysubstituted pyrroles under solvent-free ball
millling
Leave this area blank for abstract info.
Ji-Chao Zeng, Hui Xu*, Fei Yu, Ze Zhang*
O
R NH2
CHO
OR'
OR'
R N
O
O
R N
or
Mn(OAc)3
or
OR'
ball milling (30 Hz)
60 min
O
12 examples
12 examples
53-93% yields
44-93% yields

1
Tetrahedron Letters
Manganese (III) acetate mediated synthesis of polysubstituted pyrroles under solvent-
free ball milling
Ji-Chao Zeng, Hui Xu,* Fei Yu, and Ze Zhang*
School of Biological and Chemical Engineering, Anhui Polytechnic University, Wuhu, 241000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Under solvent-free ball milling conditions, a simple and mild method was developed for
efficient synthesis of 2,5-dimethyl-3,4-dicarboxylate-pyrroles and N-substituted 3,4-
diphenylpyrroles via condensation-annulation of amines with acetoacetate and 2-
phenylacetaldehyde, respectively. The use of cheap and safe Mn(OAc)3 as a mediator, no use of
commonly employed acetic acid as solvent, short reaction time and readily available starting
materials make this protocol a good alternative to traditional synthesis of polysubstituted
pyrroles.
Available online
Keywords:
Manganese (III) acetate
Polysubstituted pyrroles
Solvent free
© 2016 Elsevier Ltd. All rights reserved.
Ball milling
Polysubstituted pyrroles represent one of the most important
class of heterocyclic compounds, which are found in a large
number of natural and biologically active compounds and exhibit
a broad range of bioactivities, such as antitumor, anti-
apparatus and were vibrated vigorously at a rate of 1800 rounds
per minute (30 Hz) at room temperature for 60 minutes.
As shown in Table 1, several oxidants were investigated
which are often employed in dehydrogenative annulation
reaction for traditional synthesis of nitrogen-containing
heterocycles in solution. In contrast, Mn(OAc)3 exhibited the
best chemoselectivity and efficiency for generation of the desired
product pyrrole 3b (entry 9), while other oxidants either mainly
promoted the formation of enamine 4b (entries 1–4) or resulted
in significant side reactions (entries 5–8). In absence of any
oxidant, the starting materials remained a lot, poorly affording
enamine 4b (entry 10). When the Mn(OAc)3 mediated reaction
was carried out by heating in several organic solvents, it also
suffered from serious side reactions and thus gave the desired
product 3b in very poor yield (entries 11–13). Using this solvent-
free ball milling technique to perform such Mn(OAc)3 mediated
reaction, the desired product 3b was easily obtained in good-to-
excellent yield. This efficiency may be somewhat related to the
high mechanical energy and considerable heat caused by local
high pressure, friction and shear strain during the high speed ball
milling process. In traditional solution methods for Mn(OAc)3
involved reactions, acetic acid is almost invariably used as
solvent due to its poor solubility in other organic solvents. In
those cases, the separation procedure is rather tedious since large
quantities of aqueous sodium hydrogen carbonate have to be
used to remove the acetic acid, and so considerable amounts of
aqueous waste would be generated.
inammatory,
and
antibiotic
activities.1 Furthermore,
polysubstituted pyrroles are widely used as synthetic building
blocks, pharmacophores, and various kinds of functional
materials.2 Therefore, it is a hot research topic in the area of
organic synthetic chemistry to develop simple and efficient
methods for synthesis of these molecules, especially for
convenient one-step synthesis of polysubstituted pyrroles.
Indeed, since the initial synthesis of pyrrole by Paal-Knorr
reaction,3 a large number of methods have been developed for
synthesis of polysubstituted pyrroles.4,5 Most of these approaches
are sufficiently powerful, but they often involve special or
expensive starting materials, preliminary preparation of some
kind of intermediates or precursors, employment of noble- or
heavy-metal catalysts, relatively high reaction temperature or
long reaction time. To overcome these problems for more
environmental and economical construction of such N-
heterocycles, herein we wish to develop a straightforward
protocol via Mn (III) acetate promoted radical cyclization6,7
under solvent-free ball milling.8,9
Firstly, we selected a model reaction of ethyl acetoacetate (1a)
with 4-methylaniline (2b) under solvent-free ball milling to
optimize the reaction condition for synthesis of pyrrole 3b
(Table 1). In a typical procedure, all the reactants, together with
a stainless ball (7.0 mm in diameter) were introduced into a
stainless jar (25 mL). The same mixture was also introduced into
a second parallel jar. The two reaction vessels were sealed with
screw caps, fixed on the vibration arms of a ball-milling
Employing the optimized Mn(OAc)3 as the oxidant and
solvent-free ball milling as the reaction condition, we therefore
developed a general method10 for efficient synthesis of a series
of polysubstituted pyrroles as shown in Table 2.
____________
 Corresponding author. Tel./fax: +86 553 2871254; e-mail: michaelxxu@hotmail.com; zhangze@ustc.edu.cn

2
Tetrahedron Letters
Table 1. Optimization of the reaction condition for synthesis of fully substituted pyrrole 3ba
O
NH2
O
O
O
O
Reaction conditions
+
N
+
NH
O
O
O
O
1a
2b
3b
4b
Yieldb
Entry
Oxidant
Reaction condition
Time
3b
4b
1
Cu(OAc)2·H2O
Co(OAc)2·4H2O
Mn(OAc)2·4H2O
AgOAc
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
CH3COOH / 80 oC
PhCH3 / 80 oC
THF/ 60 oC
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
2h
2h
2h
not detected
not detected
not detected
17%
94%
82%
54%
75%
5%
2
3
4
5c
6 c
7c
8 c
(NH4)2Ce(NO3)6
AlCl3
trace
not detected
trace
15%
27%
15%
trace
30%
36%
25%
28%
I2
PhI(OAc)2
trace
9
Mn(OAc)3·2H2O
none
95%
10 d
11c
12 c
13 c
not detected
trace
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
trace
trace
a Reactions were carried out with 1a (2.0 mmol), 2b (1.0 mmol), and oxidant (2.0 mmol) at room temperature with a vibration
frequency of 30 Hz for entries 1–10; heating in 10 mL solvent for entries 11–13.
b Yield was determined by HPLC analysis.
c The starting materials were completely consumed, accompanying with several side products.
d Most of starting materials remained.
Table 2. Mn(OAc)3-mediated synthesis of 2,5-dimethyl-3,4-dicarboxylate-pyrroles under solvent-free ball millinga, b
O
O
O
Mn(OAc)3
OR'
OR'
+
R N
R NH2
ball milling (30 Hz)
60 min
OR'
2
1
O
3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
3b, 93%
3a, 90%
3c, 84%
3d, 70%
O
O
O
O
O
O
O
O
O
O
O
O
Cl
N
Cl
N
N
Br
N
O
Cl
O
O
O
3g, 59%
3h, 65%
3f, 73%
3e, 71%
O
O
O
O
O
O
O
O
O
O
HN
N
N
HN
O
O
O
O
O
O
3i, 65%
3lc, 81%
3j, 55%
3k, 44%
a Reactions were carried out with 1 (2.0 mmol), 2 (1.0 mmol), and Mn(OAc)3·2H2O (2.0 mmol) at room temperature with a vibration frequency of 30
Hz for 60 minutes.
b Isolated yield combined from two parallel runs.
c Obtained from the reaction of preliminarily prepared enamine 4b with isobutyl acetoacetate under standard condition.
From Table 2 we can see that anilines bearing electron-
unsubstituted pyrrole (3j, 3k) can also be obtained in moderate
yield when NH4OAc was employed instead of anilines by
following this protocol. Some other 1,3-dicarbonyl compounds
including acetylacetone and 1,3-cyclohexanedione were also
attempted. Unfortunately, the corresponding fully substituted
withdrawing groups or substituents at ortho position afforded
relatively lower yield. Accordingly, ethyl acetoacetate exhibited
higher efficiency than isobutyl acetoacetate due to obvious steric
effect. It is worth pointing out that the corresponding N-

3
pyrroles cannot be obtained. These results demonstrate that only
-carbonyl esters work well in this reaction, which may be
ascribed to the fact that the reactivity of β-enaminone is
somewhat lower than that of β-enaminoester.
even in absence of Mn(OAc)3, though the conversion is very
low. Therefore, we inferred that the formation of pyrrole 3b
should go through addition-cyclization of 1a with in situ
generated enamine 4b. To confirm this point, we treated
preliminarily prepared enamine 4b with one equivalent 1a in
presence of Mn(OAc)3 under ball milling. As expected, pyrrole
3b formed smoothly. But it should be emphasized that two molar
equivalents of Mn(OAc)3 are required for the completion of the
reaction (93% yield), since one molar equivalent of Mn(OAc)3
afforded only 46% yield. When enamine 4b was directly treated
with equivalent Mn(OAc)3 in absence of 1a under the standard
condition, the reaction gave trace of 3b. In this case, 3b may be
formed via addition-cyclization of enamine 4b with trace of 1a
that was in situ generated from slight decomposition of 4b. It is
also possible that 3b comes from the homodimerization of two
enamines as reported.13
As to the mechanism of this reaction, we initially speculated
that it may undergo through oxidative free radical coupling of
acetoacetate in presence of Mn(OAc)3 to generate intermediate
1,4-diketone,11 which then could proceed via classical Paal–
12
Knorr reaction with amine to afford the final pyrrole.3, To
verify the reaction mechanism, we performed some controlled
experiments as outlined in Scheme 1. We first carried out the
reaction of ethyl acetoacetate 1a with equivalent Mn(OAc)3 in
absence ofany amine under the standard condition, but it did not
afford the proposed 1,4-diketone (<2% yield). This result denied
our original hypothesis. On the other hand, direct ball milling of
1a and equivalent aniline 2b can easily generate enamine 4b
Mn(OAc)3
Ball Milling
30 Hz, 60 min
O
O
O
Mn(III)
OH
O
O
O
O
O
O
O
Mn(OAc)3
O
O
O
O
no reaction
1a
OR'
OR'
OR'
OR'
OR'
(I)
O
H
H
N
Tol-NH2 (2b)
Ball Milling
30 Hz, 60 min
1a, Mn(OAc)3 (1 equiv)
Ball Milling
N
OR'
R
O
RNH2
-H2O
2
Tol-NH2(2b)
Ball Milling
30 Hz, 60 min
21%
R
30 Hz, 60 min
O
O
(II)
4
46%
1
Mn(OAc)3
O
O
1a, Mn(OAc)3 (2 equiv)
Ball Milling
Tol
NH
O
O
O
O
Mn(OAc)2
+ HOAc
30 Hz, 60 min
O
3b
Tol
N
93%
O
OR'
OR'
O
-H2O
OR'
OR'
H
R
N
Mn(OAc)3 (1 equiv)
Ball Milling
30 Hz, 60 min
4b
N
O
R
O
trace
3
(III)
Scheme 1 Controlled experiments
Scheme 2 Proposed reaction mechanism
Table 3. Mn(OAc)3-mediated synthesis of N-substituted 3,4-diphenylpyrroles under solvent-free ball millinga, b
OHC
Mn(OAc)3
+
R N
R NH2
ball milling (30 Hz)
60 min
2
5
H3C
CH3
N
N
H3C
N
N
5c, 87%
5d, 65%
5b, 90%
5a, 93%
Cl
H3CO
N
Br
N
Cl
N
Cl
N
5g, 61%
5h, 53%
5e, 63%
5f, 56%
Cl
N
N
N
N
5j, 55%
5l, 86%
5i, 70%
5k, 85%
a Reactions were carried out with 2-phenylacetaldehyde (2.0 mmol), 2 (1.0 mmol), and Mn(OAc)3·2H2O (2.0 mmol) at room
temperature with a vibration frequency of 30 Hz for 60 minutes.
b Isolated yield, average of two parallel runs.

4
Tetrahedron Letters
Based on the results from these controlled experiments,
Supplementary data (experimental procedure, characterization
data and NMR spectra of the products) associated with this
article can be found, in the online version, at XXX.
accompanying with related literatures on Mn(OAc)3-promoted
generation of carbon-centered radicals from carbonyl compounds
and their oxidative addition-cyclization to alkenes,6 we speculate
that the reactions mainly go through a mechanism as shown in
Scheme 2, which may involve the following steps: (a) formation
of enamine 4 from acetoacetate 1 and amine 2; (b) generation of
Mn(III)-enolate I from 1 promoted by equivalent Mn(OAc)3; (c)
generation of carbon-centered radical II via free radical addition
of I to enamine 4; (d) formation of enamine III via oxidative
elimination with another equivalent Mn(OAc)3; (e)
intramolecular Aldol-like condensation and dehydration to
achieve the formation of final product 3. This mechanism is
further supported by a fact that the reaction of preliminarily
prepared enamine 4b with equivalent isobutyl acetoacetate under
the standard condition smoothly afforded the corresponding
pyrrole 3l in 81% yield (Table 2). This result demonstrates a
potential alternative of this protocol to synthesis of 3,4-
asymmetric-disubsitutied-pyrroles. But anyway, we cannot
definitely exclude that maybe minor products are formed through
reported mechanism of homodimerization from enamines.13-16
Then we extended this method to synthesize N-substituted 3,4-
diphenylpyrroles by using 2-phenylacetaldehyde instead of
acetoacetates.10 As expected, a series of N-substituted 3,4-
diphenylpyrroles were obtained by following this mild and
efficient protocol (Table 3). This reaction was firstly reported by
Jia et al, in which they employed AgOAc as mediator by
refluxing in THF for 8 hours (25-80% yields).13 Huang, Deng
and co-workers has developed a Cu(OTf)2-promoted method, but
the substrates were limited within alkylamines.14 Recently, Wan,
Wen and co-workers employed TBHP to achieve this reaction,
which can only be applied to anilines.15 Herein, we achieved this
transformation using cheap and safe Mn(OAc)3 as mediator
under solvent-free ball milling at room temperature for only one
hour, and the desired products were obtained in good to excellent
yields (53-93%). As shown in Table 3, this method exhibited
wide scope for amine 2, in which both anilines bearing either
electro-donating or electro-withdrawing groups and aliphatic
amines worked well. Other alkyl aldehydes such as n-
butylaldehyde and phenylpropylaldehyde were also tried, but the
reaction didn’t work as desired to afford the corresponding
products. Maybe the employed aldehydes require theβ-phenyl
group to form the enolate to facilitate the reaction. As to this
reaction mechanism, it should go through homodimerization of
two enamines as other papers demonstrate.13-16
References and notes
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J. C. Chem. Soc. Rev. 2014, 43, 4633; (b) Gulevich, A. V.; Dudnik, A.
S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084; (c) Joshi,
S. D.; More, U. A.; Kulkarni, V. H.; Aminabhavi, T. M. Curr. Org.
Chem. 2013, 17, 2279.
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S.; Luo, X.-Y.; Deng, W.-P. J. Org. Chem. 2016, 81, 8653; (b)
Ambethkar, S.; Padmini, V.; Bhuvanesh, N. New J. Chem. 2016, 40,
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Liu, J.-H.; Liu, P.; Zhang, Q.-C. RSC Adv. 2016, 6, 68454; (d) Xu, H.;
Wang, F.-J.; Xin, M.; Zhang, Z. Eur. J. Org. Chem. 2016, 925; (e) Mou,
X.-Q.; Xu, Z.-L.; Xu, L.; Wang, S.-H.; Zhang, B.-H.; Zhang, D.; Wang,
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R. J.; Tonks, I. A. Nat. Chem. 2016, 8, 63.
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7999; (c) Pan, X.-Q.; Zou, J.-P.; Zhang, W. Mol. Divers. 2009, 13, 421;
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Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 321; (f) Snider, B. B.
Chem. Rev. 1996, 96, 339.
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Balci, M. Tetrahedron 2016, 72, 6815; (b) Lofstrand, V. A.; Matsuura,
B. S.; Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Tetrahedron
2016, 72, 3775; (c) Li, L.; Wang, J.-J.; Wang, G.-W. J. Org. Chem.
2016, 81, 5433; (d) Zhang, G.-Y.; Li, C.-K.; Li, D.-P.; Zeng, R.-S.;
Shoberu, A.; Zou, J.-P. Tetrahedron 2016, 72, 2972; (e) Chuang, C.-P.;
Chen, Y.-J. Tetrahedron 2016, 72, 1911.
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Elguero, J. Adv. Heterocycl. Chem., 2014, 112, 117; (b) Boldyreva, E.
Chem. Soc. Rev., 2013, 42, 7719; (c) Wang, G.-W. Chem. Soc. Rev.,
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Chem. Soc. Rev., 2011, 40, 2317; (f) Rodríguez, B.; Bruckmann, A.;
Rantanen, T.; Bolm, C. Adv. Synth. Catal. 2007, 349, 2213.
In conclusion, a simple and mild method has been developed
by using solvent-free ball milling technique for efficient
synthesis of polysubstituted pyrroles via Mn(OAc)3-mediated
oxidative radical annulation. Following this method, a series of
2,5-dimethyl-3,4-dicarboxylate-pyrroles and N-substituted 3,4-
diphenylpyrroles were successfully synthesized in moderate to
excellent yields from various amines, acetoacetate and 2-
phenylacetaldehyde, respectively. The advantages including use
of cheap and safe Mn(OAc)3 as mediator, no use of commonly
employed acetic acid as solvent, short reaction time and readily
available starting materials make this protocol a good alternative
to traditional synthesis of polysubstituted pyrroles.
9. For some recent examples: (a) Nagamani, C.; Liu, H.; Moore, J. S. J.
Am. Chem. Soc. 2016, 138, 2540; (b) Hermann, G. N.; Becker, P.; Bolm,
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Wang, F.-J.; Xu, H.; Xin, M.; Zhang, Z. Mol. Divers. 2016, 20, 659.
10. General procedure for solvent-free ball milling synthesis of pyrrole 3
and 5: Acetoacetate 1 or 2-phenylacetaldehyde (2.0 mmol), amine 2 (1.0
mmol) and Mn(OAc)3·2H2O (2.0 mmol), together with a stainless ball
of 7.0 mm in diameter, were introduced into a stainless jar (25 mL). The
same mixture was also introduced into a second parallel jar. The two
reaction vessels were sealed with screw caps, fixed on the vibration
arms of a ball-milling apparatus (mixer mill MM400, Retsch GmbH,
Haan, Germany) and were vibrated vigorously at a rate of 1800 rounds
per minute (30 Hz) at room temperature for 60 minutes. The mixture
was diluted with EtOAc and water. The aqueous layer was separated
and extracted with EtOAc. The combined organic layer was dried
over magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel with
Acknowledgments
We are grateful to financial support from Natural Science
Foundation of China (21242013) and Key Projects for
Outstanding Young Talents in Colleges and Universities of
Anhui Province (No. gxyqZD2016121).
Supplementary data

5
EtOAc/petroleum ether as the eluent, affording the desired product 3 or
5 as yellow solid. For characterization data of all products, see:
Supplementary data.
13. Li, Q.-J.; Fan, A.-L.; Lu, Z.-Y.; Cui, Y.-X.; Lin, W.-H.; Jia, Y.-X. Org.
Lett. 2010, 12, 4066.
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Wetterau, L. A.; Graham, D. G. J. Org. Chem., 1991, 56, 6924.
15. Gao, Y.; Hu, C.-F.; Wan, J.-P.; Wen, C.-P. Tetrahedron Lett. 2016, 57,
4854.
16. (a) Tsai, A.-I.; Chuang, C.-P. Tetrahedron 2006, 62, 2235; (b) Chuang,
C.-P.; Wu, Y.-L. Tetrahedron 2004, 60, 1841.

6
Tetrahedron
Highlights:
1. Polysubstituted pyrroles are synthesized under mechanochemical ball milling.
2. Solvent-free radical cyclization is efficiently accomplished mediated by Mn(OAc)3.
3. The mechanism involves radical addition, oxidative elimination and condensation.
4. The method exhibits mild condition, short time, simple work up and broad scope.