An efficient and convenient synthesis of pentasubstituted pyrroles from alkyl acetoacetates, dialkyl acetylenedicarboxylates, and amines

Article abstract of DOI:10.1016/j.tetlet.2014.06.025

A simple and efficient synthesis of pentasubstituted pyrroles has been developed using a one-pot, two-step reaction. The synthesis of a series of 4-hydroxypenta-1,3-diene-tricarboxylates from alkyl acetoacetates and dialkyl acetylenedicarboxylates in the presence of K₂CO₃, followed by cyclization with amines, gave the corresponding pyrroles in excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.06.025

Accepted Manuscript
An efficient and convenient synthesis of pentasubstituted pyrroles from alkyl
acetoacetates, dialkyl acetylenedicarboxylates and amines
Hossein Mehrabi, Mohammad Anary-Abbasinejad, Fatemeh Mirhashemi
PII:
S0040-4039(14)01004-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.025
TETL 44749
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2014
17 May 2014
5 June 2014
Please cite this article as: Mehrabi, H., Anary-Abbasinejad, M., Mirhashemi, F., An efficient and convenient
synthesis of pentasubstituted pyrroles from alkyl acetoacetates, dialkyl acetylenedicarboxylates and amines,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.025
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An efficient and convenient synthesis of pentasubstituted pyrroles from
alkyl acetoacetates, dialkyl acetylenedicarboxylates and amines
Hossein Mehrabi*, Mohammad Anary-Abbasinejad, Fatemeh Mirhashemi
Department of Chemistry, Vali-e-Asr University of Rafsanjan, 77176 Rafsanjan, Iran.
* Corresponding author. E-mail: mehraby_h@yahoo.com (H. Mehrabi)
Abstract- A simple and efficient synthesis of pentasubstituted pyrroles has been developed using
a one-pot, two-step reaction. The synthesis of a series of 4-hydroxypenta-1,3-diene-
tricarboxylates from alkyl acetoacetates and dialkyl acetylenedicarboxylates in the presence of
K2CO3, followed by cyclization with amines, gave the corresponding pyrroles in excellent yields.
Keywords: pentasubstituted pyrroles; alkyl acetoacetates; dialkyl acetylenedicarboxylates;
amines.
Polysubstituted pyrroles are molecular frameworks which have significant importance in
materials science.1 They have also been employed as anti-oxidants,2a antibacterial,2b,c
ionotropic,2d,e antitumor,2f anti-inflammatory,2g,h and antifungal agents.2i Moreover, they are a
highly versatile class of intermediates in the synthesis of natural products as well as in
heterocyclic chemistry.3
The growing importance and wide utility of polysubstituted pyrroles has led to the search for
new methods for the efficient synthesis of these heterocycles.
Pyrroles have been prepared via several classical methods,4a such as the Barton-Zard,4b
Hantzsch,4c,d Knorr,5a,b Trofimov,5c Paal-Knorr,6a,b and Clauson-Kaas6c-e reactions and their
modifications. In addition, these heterocycles have also been synthesized from Huisgen 1,3-
1

dipoles, derived from the addition of alkyl(aryl) isocyanides to dimethyl acetylenedicarboxylate,
which are trapped by succinimide,7 cyclobutene-1,2-diones,8 and benzoyl chloride.9
Triarylphosphine-induced domino reactions of acetylenedicarboxylates with unsaturated
compounds,10 oxidative free radical reactions of enamino esters,11 primary aliphatic amines,
alkynoates and 1,2-diaza-1,3-dienes,12 and tertiary amines as well as other catalyst-assisted
domino reactions,13 have also been described for their preparation. Various catalysts and/or
reagents such as FeCl3,14 palladium,15 NiCl2·6H2O,16 CeCl3·7H2O (under microwave),17 silica-
supported tungstic acid,18 and TiO2,19 have been employed for this purpose. All these methods
have their merits, but many involve the use of a metal catalyst, the removal of which often
requires cumbersome work-up and purifications. Herein we report a metal-free, one-pot, two-
step synthesis of pentasubstituted pyrroles from alkyl acetoacetates, dialkyl
acetylenedicarboxylates and amines as starting materials.
We began our investigation with the construction of 4-hydroxypenta-1,3-diene-
tricarboxylates, which are versatile synthetic intermediates, from alkyl acetoacetates and dialkyl
acetylenedicarboxylates (Table 1). The initial reaction was attempted using ethyl acetoacetate
(1a) and dimethyl acetylenedicarboxylate (2a) (Table 1, entry 1). When 1a and 2a were treated
in the presence of K2CO3 as a base in ethanol at room temperature, methyl 4-ethoxycarbonyl-5-
hydroxy-3-methoxycarbonylhexa-2,4-dienoate (3a) was obtained in 98% yield. Various 4-
hydroxypenta-1,3-diene-1,2,3-tricarboxylates 3 were prepared in excellent yields as shown in
Table 1.
Table 1.
After the successful preparation of 4-hydroxypenta-1,3-diene-1,2,3-tricarboxylates 3a-d, and
with the aim to construct pentasubstituted pyrroles, we selected 3a as a model compound to
2

examine its reactions with an amine under different conditions. Upon treatment of 3a with
benzylamine (4a) in acetic acid, the reaction furnished the desired product, 4-ethyl 2,3-dimethyl
1-benzyl-5-methyl-1H-pyrrole-2,3,4-tricarboxylate (5a) (Scheme 1).
Scheme 1.
The optimization of the reaction conditions, including the reaction solvent, equivalents of
acid, time, and the temperature, was then investigated. First, solvent-free conditions and various
solvents were screened (Table 2, entries 1–9), with ethanol proving to be the best for this
reaction. Next, we observed that the amount of acetic acid also had an important influence on the
reaction. A lower amount of acetic acid (for example, 5 mol%) in ethanol at room temperature
resulted in a lower yield of 75%. A good yield of 83% was achieved using 10 mol% of acetic
acid. Increasing the amounts of acid (for example, 15 and 20 mol%) did not improve the yield.
When the reaction was carried out at room temperature for 12 hours, the product was obtained in
83% yield (Table 2, entry 8), but under reflux conditions, the desired product was formed in 90%
yield after 12 hours (Table 2, entry 9).
Table 2.
With the optimized conditions in hand (Table 2, entry 9), we next investigated the possibility
of the synthesis of pentasubstituted pyrroles via a one-pot reaction from alkyl acetoacetates,
dialkyl acetylenedicarboxylates and amines. To a 25 mL round-bottom flask was added ethyl
acetoacetate (1a) (1.0 mmol), dimethyl acetylenedicarboxylate (2a) (1.0 mmol), K2CO3 (1.0
mmol), ethanol (10.0 mL) and the mixture was stirred vigorously at room temperature. After the
ethyl acetoacetate had been consumed (monitored by TLC), ethanol (5.0 mL), benzylamine (4a)
(1.0 mmol), and acetic acid (10 mol%) were added. The mixture was allowed to stir under reflux
conditions for 12 hours to give the expected product in 90% yield. To explore the scope of this
3

novel transformation, various alkyl acetoacetates, dialkyl acetylenedicarboxylates and amines
were utilized under the optimized one-pot conditions. The results in Table 3 show that all the
reactions proceeded smoothly to afford the corresponding pentasubstituted pyrroles in good
1
yields. All the products are novel, to the best of our knowledge, and were characterized by H,
13C NMR and IR spectroscopy and CHN analysis.
Table 3.
A possible mechanism for the synthesis of 4-ethyl 2,3-dimethyl 1-benzyl-5-methyl-1H-
pyrrole-2,3,4-tricarboxylate (5a) is illustrated in Scheme 2. This conversion involves the initial
reaction of ethyl acetoacetate (1a) with dimethyl acetylenedicarboxylate (2a) in the presence of
K2CO3 to form 3-ethyl 1,2-dimethyl 4-hydroxypenta-1,3-diene-1,2,3-tricarboxylate (3a). Next,
the carbonyl group in compound 3a could be activated by acetic acid and undergo nucleophilic
addition with benzylamine (4a) followed by elimination of a molecule of H2O. The subsequent
cyclization of this intermediate is favoured kinetically resulting in formation of the five-
membered ring. The final stage in the sequence must involve an oxidation in which two
hydrogens are removed to afford the final product 5a.
Scheme 2.
In summary, we have developed an efficient and facile method for the synthesis of
pentasubstituted pyrrole derivatives by treatment of alkyl acetoacetates, dialkyl
acetylenedicarboxylates and amines using acetic acid. The mild reaction conditions, low cost of
the starting materials, operational simplicity, and excellent yields are advantages of the protocol.
Supporting Information: full experimental details, IR, 1H and 13C NMR spectra and CHN data of
products 5a-p can be found online.
4

Acknowledgments
We are thankful to the Office of Graduate Studies of Vali-e-Asr University of Rafsanjan for
partial support of this work.
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O
O
O O
MeO
MeO
OEt
MeO
O
OEt
NH
2AcOH (10 mol%)
N
+
O
EtOH, reflux
MeO
HO
4a
5a
3a
Scheme 1.
Scheme 2.
8

Table 1. Synthesis of 4-hydroxypenta-1,3-diene-tricarboxylates
O O
R2O
O
OR1
R2O
O
O
O
EtOH, K2CO3
r.t., 3 h.
+
R1O
O
OR2
R2O
HO
1
2
3
Entry R1
R2
Product
Yield (%)a
O O
MeO
OEt
O
1
2
Et
Et
Me
Et
98
3a
MeO
HHO
O O
EtO
OEt
O
95
3b
EtO
HHO
O O
MeO
O
OMe
3
4
Me
Me
Me
Et
97
95
3c
MeO
HHO
O O
EtO
O
OMe
3d
EtO
HHO
a Yields are given for isolated products.
9

Table 2. Optimization of the conditions for the synthesis
of pentasubstituted pyrrolesa
Entry Solvent
Temp/Time (oC/h) Yield (%)b
1
2
3
4
5
6
7
8
9
solvent-free
r.t. / 24
0
H2O
r.t. / 24
45
H2O
reflux / 24
r.t. / 24
58
MeCN
MeCN
MeOH
MeOH
EtOH
EtOH
trace
trace
65
reflux / 24
r.t. / 24
reflux / 24
r.t. / 12
77
83
reflux / 12
90
a Reaction conditions: 3a (1.0 mmol), benzylamine (4a)
(1.0 mmol), AcOH (10 mol%).
b Yields are given for isolated products.
10

Table 3. One-pot synthesis of pentasubstituted pyrroles
11

Entry
R1
R2
R3
Product
Yield (%)a
CH2
1
Et
Me
90
CH2
2
3
Et
Et
Et
87
93
CH2
Me
H3C
CH2
4
Et
Et
85
H3C
CH2
5
6
Et
Et
Me
95
90
H3CO
CH2
Et
H3CO
12

O O
N
MeO
MeO
OEt
CH2
7
8
Et
Et
Me
78
80
H3C
O
5g
CH2
Et
H3C
CH2
9
Me
Me
Me
Me
Me
83
90
86
84
CH2
10
11
12
Et
CH2
Me
H3C
O O
EtO
EtO
OMe
CH2
Et
N
H3C
O
CH3
5l
CH2
13
Me
Me
93
H3CO
13

CH2
14
Me
Et
88
H3CO
O O
N
MeO
MeO
OMe
CH2
15
16
Me
Me
Me
75
77
H3C
O
5o
O O
EtO
EtO
OMe
CH2
Et
H3C
N
O
5p
a Yields are given for isolated products.
14

Graphical Abstract
An efficient and convenient synthesis of
Leave this area blank for abstract info.
pentasubstituted pyrroles from alkyl acetoacetates,
dialkyl acetylenedicarboxylates and amines
Hossein Mehrabi*, Mohammad Anary-Abbasinejad, Fatemeh Mirhashemi
15