An efficient and convenient synthesis of 1,2,3-trisubstituted pyrroles via iodocyclization from ethyl acetoacetate

Article abstract of DOI:10.1016/j.tetlet.2013.03.094

A novel and efficient methodology for the synthesis of 1,2,3-trisubstituted pyrroles by one-pot two-step reaction has been developed. The iodocyclization of a series of β-enamino esters followed by dehydroiodination, led to the formation of corresponding pyrroles. This approach provides an easy access to a wide range of 1,2,3-trisubstituted pyrroles.

Full text of DOI:10.1016/j.tetlet.2013.03.094

Accepted Manuscript
An efficient and convenient synthesis of 1,2,3-trisubstituted pyrroles via iodo‐
cyclization from ethyl acetoacetate
Pengfei Xu, Kunzhu Huang, Zhiguo Liu, Ming Zhou, Wenbin Zeng
PII:
S0040-4039(13)00508-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.094
TETL 42720
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 January 2013
15 March 2013
22 March 2013
Please cite this article as: Xu, P., Huang, K., Liu, Z., Zhou, M., Zeng, W., An efficient and convenient synthesis of
1,2,3-trisubstituted pyrroles via iodocyclization from ethyl acetoacetate, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.03.094
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An efficient and convenient synthesis of 1,2,3-trisubstituted pyrroles
via iodocyclization from ethyl acetoacetate
Pengfei Xu, Kunzhu Huang, Zhiguo Liu, Ming Zhou, Wenbin Zeng*
School of Pharmaceutical Sciences, Central South University
172 Tongzipo Road, Changsha 410013, China.
* Author of correspondence: Prof. Wenbin Zeng, School of Pharmaceutical Sciences, Central South
University, Changsha 410013, China. Tel/Fax: (86)731-8265-0459; Email: wbzeng@hotmail.com.
Abstract
A novel and efficient methodology for the synthesis of 1,2,3-trisubstituted pyrroles by one-pot
two-step reaction has been developed. The iodocyclization of series of ꢀ-enamino esters followed
by dehyroiodination, led to the formation of corresponding pyrroles. This approach provides an
easy access to a wide range of 1,2,3-trisubstituted pyrroles.
Keywords: Pyrroles; One-pot synthesis; Iodocyclization; Tandem reaction
Substituted pyrroles represent an important class of organic compounds which have found in
many bioactive molecules and natural products.1-2 They have also been widely applied in
medicinal and material science.3 In view of their characteristic properties, a variety of methods for
synthesis of substituted pyrroles have been developed. Paula and co-workers reported the efficient
synthesis of 2,3,5-substituted pyrrole derivatives by treatment of 2,3-dihydrofuran derivatives with
trifluoroacetic acid.4 Recently, Lingaiah and co-workers developed a novel method to construct
tetrasubstituted pyrrole ring utilize polyethylene glycol as reaction medium.5 Abu and co-workers
employed a four-component reaction catalyzed by nickel (II) chloride hexahydrate to construct the
tetra-substituted pyrroles.6 However, efficient and convenient methodologies for the synthesis of
1,2,3-trisubstituted pyrroles are not numerous in literature.7-8 In another arena of iodine chemistry,
the nontoxic, inexpensive and readily available iodine has emerged as a very attractive reagent for

various organic transformations.9-11 Particularly, the area of iodine mediated cyclization reaction
has got enormous progress. Several organic compounds such as cis-2,5-disubstituted
furans,12 cis-tetrahydrofurans,13 oxazoles,14 iodobenzenes15 and indolizines16 have been
synthesized via iodocyclization. In this letter, we describe one-pot two-step efficient synthesis of
1,2,3-trisubstituted pyrroles via iodocyclization from ethyl acetoaceate.
Our initial studies focused on the development of the construction of ꢀ-enamino esters which
is a versatile synthetic intermediate via iodine-catalyzed enamination in organic solvent. This
method was successfully applied to enamination of ethyl acetoacetate with various amines in
acetonitrile. To continue our interest in preparing substituted pyrroles, we have designed to
construct 1,2,3-trisubstituted pyrroles from ꢀ-enaminones. To our satisfaction, 1,2,3-trisubstituted
pyrroles were successfully prepared by using ꢀ-enaminones, acetaldehyde, iodine and piperidine
o
at −15 C via one-pot two-step procedure. To the best of our knowledge, this is the first protocol
explored synthesis of 1,2,3-trisubstituted pyrroles using this method.
Table 1. Scope and generality of the synthesis of ꢀ-enaminones
Entry
1
Amine
Product
Yield(%)a
96
2
3
97
97
4
5
96
96
6
7
78
95
H2N
8
87

9
89
10
11
12
13
14
15
93
92
93
91
92
94
H2N
16
17
88
85
a Yields are given for isolated product
We selected the reaction between ethyl acetoacetate and n-propylamine as a model reaction
for optimizing the reaction conditions, such as solvent and reaction temperature (see
supplementary data Table 1). Various ꢀ-enamino esters 3 were prepared in high yields as shown in
Table 1.
After successfully prepared a series of ꢀ-enamino esters, with the aim to construct 1,2,3-
trisubstituted pyrroles, we selected 3b as a model reaction to examine its behavior under different
conditions. Upon treatment 3b with acetaldehyde, iodine in basic condition, the reaction furnished
the desired product, ethyl 2-methyl-1-propyl-1H-pyrrole-3-carboxylate (Scheme 1).

Scheme 1. Multicomponent one-pot synthesis of 1,2,3-trisubstituted pyrroles
The optimization of the reaction conditions, including reaction temperature, base, and the
equivalent of iodine were then investigated. First, various bases were screened (Table 2, entries 1-
6), and sodium carbonate was proven to be preeminent for this reaction. Then, we observed the
equivalent of iodine also have important influence on the reaction. A less amount of iodine (for
example, 0.5 equiv) resulted in a low yield (55%). In contrast, when the equivalent of iodine
increased to 1.5 equiv, a good yield was achieved (82%). Finally, we examined the influence of
different temperatures and different equivalents of piperidine on this reaction (Table 2, entries 3
and 9-16). To our satisfaction, when the reaction was carried out at −15 oC, it proceeded smoothly
and clean, furnishing 4b in good yield (Table 2; entries 3 and 9-11). A series of experiments were
performed to reveal that the optimal results were obtained: when the reaction of 3b performed
with acetaldehyde (8.0 equiv), iodine (1.5 equiv) sodium carbonate (1.2 equiv) and piperidine
(1.0 equiv) in acetonitrile at −15 oC, whereby the yield of 4b reached up to 82%.
Table 2. Optimization of the synthesis 1,2,3-trisubstituted pyrroles
Entry
1
Iodine
Piperidine
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
0 equiv
Base
Temp.oC
−15
Yield(%)a
53
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
0.5 equiv
1.0 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
KOH
2
LiOH
44
−15
3
Na2CO3
Cs2CO3
NaHCO3
DBU
82
−15
4
69
−15
5
63
−15
6
71
−15
7
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
55
−15
8
67
−15
9
17
−15
10
11
12
13
0.1 equiv
0.5 equiv
2.0 equiv
1.0 equiv
38
−15
54
−15
77
−15
51
−20

14
15
16
1.5 equiv
1.5 equiv
1.5 equiv
1.0 equiv
1.0 equiv
1.0 equiv
Na2CO3
Na2CO3
Na2CO3
0
65
49
48
r.t.
60
a Yields are given for isolated product.
b
Standardization of reaction conditions: 3b (1.0 mmol), piperidine (1.0 mmol), and acetaldehyde
(8.0 mmol).
Having established the optimal conditions for the key cyclization process, we tried to
explore the possibility of the synthesis of 1,2,3-trisubstituted pyrroles by one-pot reaction from
ethyl acetoaceate. To our delight, we successfully established one-pot two-step three-component
reaction in good yields. To a 25 mL round-bottom flask was added 1.0 mmol of ethyl
acetoacetate, 1.2 mmol of various amines, 0.1 mmol of iodine and 6.0 mL of acetonitrile. The
mixture was placed at room temperature for vigorous stirring. After ethyl acetoacetate was
consumed (monitored by TLC), 6.0 mL of acetonitrile, 2.0 mL of water, 8.0 mmol of
acetaldehyde, 1.2 mmol of sodium carbonate, 1.0 mmol of piperidine and 1.5 mmol of iodine were
added . The reaction mixture was allowed to stir at −15 oC for special time. To explore the scope of
this novel transformation, a variety of amines were tested under optimized conditions. In all of the
cases, the transformation from ethyl acetoaceate to 1,2,3-trisubstituted pyrroles derivatives in
moderate to good yields (Table 3). These results indicate that the present protocol is widely
applicable for various amines.
Table 3. Scope and generality of the synthesis of 1,2,3-trisubstituted pyrroles
Entry
1
R1
OEt
Amine
Product
Yield(%)
76
2
3
OEt
OEt
75
71

4
5
6
OEt
OEt
OEt
64
48
64
OEt
OEt
7
8
OEt
OEt
63
64
O
O
N
N
4g
4h
9
OEt
OEt
OEt
62
62
61
10
11
OEt
12
13
14
15
16
17
18
19
20
OEt
OEt
OEt
OEt
Me
Me
Me
Me
Me
63
65
51
46
79
71
68
70
53
O
N
4l
a Yields are given for isolated product
A plausible mechanism for the synthesis of 1,2,3-trisubstituted pyrroles is illustrated in
Scheme 2. Initially, 3e was obtained from the condensation of ethyl acetoacetate 1 with n-
propylamine, which is expected to proceed through an addition-elimination mechanism.17 The
intermediate 5, generated by acetaldehyde and piperidine, reacts with 3e to form 6 by

Knoevenagel condensation. Subsequently, the key intermediate 7 undergoes concomitant
iodocyclization with elimination of HI and spontaneous aromatization to afford the final product
4b. Similar reactions involving iodocyclization were already described in related literatures. 18-21
Scheme 2. Proposed mechanistic pathway for one-pot synthesis of 1,2,3-trisubstituted
pyrroles
In conclusion, we have developed an efficient and facile method to prepare 1,2,3-
trisubstituted pyrrole derivatives by the treatments of acetaldehyde, ethyl acetoaceate, sodium
carbonate, piperidine and iodine. The mild reaction conditions, low cost of reaction substrates,
operational simplicity and good yields render this protocol very attractive.
Acknowledgment
We are grateful to National Natural Science Foundation of China (30900377, 81271634),
New Century Excellent Talents Project (NCET-10-0800), the Fundamental Research Funds for
the Central Universities, and Hunan Provincial Natural Science Foundation of China (12JJ1012)
References
1. Andersen, R. J.; Faulkner, D. J.; Cun, H. H.; van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc.
1985, 107, 5492.
2. Lainton, J. A. H.; Hoffman, J. W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995, 36,

1401.
3. Niziurski, M. R. E.; Cava, M. P. Heterocycles 1992, 34, 2003.
4. Paula, M. T. F.; Hernani, L. S. M.; Luis, S. M. Tetrahedron Lett. 2002, 43, 4491.
5. Lingaiah, N.; Raghu, M.; Lingappa, Y.; Rajashaker, B. Tetrahedron Lett. 2011, 52, 3401.
6. Abu, T. K.; Mohan, L.; Prasanta, R. B.; Sidick, B.; Parameswaran, S.; Sanjukta, P.
Tetrahedron Lett. 2012, 53, 4145.
7. Wing, H. C.; Albert, W. M . L.; Ka, M. L.; Tin, Y. L. J. Chem. Soc. Perk. T. 1994, 1, 2355.
8. Yuri, N. R.; Michael, T. H. L.; Roland, B. Chem. Commun. 1999, 5, 447.
9. Phukan, P. J. Org. Chem. 2004, 69, 4005.
10. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Tetrahedron Lett. 2002, 43, 879.
11. Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem. 2001, 66, 7527
12. Rychnovsky, S. D.; Bartlet, P. A. J. Am. Chem. Soc. 1981, 103, 3963.
13. Bartlett, P. A.; Holmes, C. P. A. Tetrahedron Lett. 1983, 24, 1365.
14. Martin, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521.
15. Matsumoto, S.; Takase, K.; Ogura, K. J. Org. Chem. 2008, 73, 1726.
16. Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett. 2007, 48, 6863.
17. Datta, B.; Madhusudana Reddy, M. B.; Pasha, M. A. Synthetic Commun. 2011, 41, 2331.
18. Suckling, C. J. Angew. Chem. 1988, 100, 555.
19. Helena, M. C. F.; Femando, L. C. P.; Fatima, S. L.; Marta, R. S. N. Tetrahedron 1999, 55,
10915.
20. Laurie, D.; Lucas, E.; Nonhebel, D. C.; Suckling, C. J.; Walton, J. C. Tetrahedron 1986, 42,
1035.
21. Ajoy, K. B.; Manuel S. L.; Elvia, V. C. Curr. Org. Chem. 2011, 15, 1058.

An efficient and convenient synthesis of 1,2,3-trisubstituted pyrroles
via iodocyclization from ethyl acetoacetate
Pengfei Xu, Kunzhu Huang, Zhiguo Liu, Ming Zhou, Wenbin Zeng*