Ceric (IV) ammonium nitrate (CAN) mediated synthesis of pyrrole-2,3,4,5-tetracarboxylates by reaction of dimethyl acetylenedicarboxylate with an amine

Article abstract of DOI:10.1016/j.tetlet.2013.09.128

A simple one-step method for efficient synthesis of pyrrole-2,3,4,5- tetracarboxylates by reaction of dimethyl acetylenedicarboxylate with an amine using ceric (IV) ammonium nitrate as one electron oxidant is described.

Full text of DOI:10.1016/j.tetlet.2013.09.128

Accepted Manuscript
Ceric (IV) ammonium nitrate (CAN) mediated synthesis of pyrrole-2,3,4,5-tet-
racarboxylates by reaction of dimethyl acetylenedicarboxylate with an amine
Sridhar Madabhushi, Venkata Sairam Vangipuram, Kishore Kumar Reddy
Mallu, Raveendra Jillella, Srinivas Kurva, Shanthan Rao Pamulaparthi
PII:
S0040-4039(13)01703-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.128
TETL 43628
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 July 2013
25 September 2013
28 September 2013
Please cite this article as: Madabhushi, S., Vangipuram, V.S., Mallu, K.K.R., Jillella, R., Kurva, S., Pamulaparthi,
S.R., Ceric (IV) ammonium nitrate (CAN) mediated synthesis of pyrrole-2,3,4,5-tetracarboxylates by reaction of
dimethyl acetylenedicarboxylate with an amine, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.09.128
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Graphical Abstract
Ceric (IV) ammonium nitrate (CAN) mediated synthesis of pyrrole-2,3,4,5-
tetracarboxylates by reaction of dimethyl acetylenedicarboxylate with an amine
Sridhar Madabhushi, Venkata Sairam Vangipuram, Kishore Kumar Reddy Mallu, Raveendra
Jillella, Srinivas Kurva and Shanthan Rao Pamulaparthi
1

Ceric (IV) ammonium nitrate (CAN) mediated synthesis of pyrrole-2,3,4,5-
tetracarboxylates by reaction of dimethyl acetylenedicarboxylate with an
amine
Sridhar Madabhushi,* Venkata Sairam Vangipuram, Kishore Kumar Reddy Mallu,
Raveendra Jillella, Srinivas Kurva and Shanthan Rao Pamulaparthi
Fluoroorganics Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500607,
India
Abstract: A simple one-step method for efficient synthesis of pyrrole-2,3,4,5-
tetracarboxylates by reaction of dimethyl acetylenedicarboxylate with an amine using ceric
(IV) ammonium nitrate as one electron oxidant is described.
Keywords:ceric (IV) ammonium nitrate, dimethyl acetylenedicarboxylate, aliphatic amine,
cyclocondensation reaction, one electron oxidation.
Pyrroles are an important class of heterocycles and appear as the structural motifs in many
natural products,1 conducting polymers,2 pharmaceuticals,3 agrochemicals4 and fluorescent
dyes5. As a result, studies on synthesis of pyrroles have received high importance in organic
synthesis and the classical approaches for the preparation of pyrroles include Knorr reaction,6
Paal-Knorr condensation reaction7 and Hantzsch reaction.8 In recent years, several new
strategies were reported in literature for the synthesis of pyrroles, which include
multicomponent and multi-step methods,9 transition metal catalyzed cyclization of N-
containing acyclic substrates,10 aza-Wittig reaction11and reductive couplingof N-acyl 2-
aminoketone derivatives using a low valent titanium reagent12 etc. Since some of these
methods suffer from one or more of the disadvantages such as harsh reaction conditions, long
reaction times, low yields, and use of expensive reagents, continuous studies on development
of new and efficient methods for the synthesis of pyrroles with operational simplicity,
*Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail address: smiict@gmail.com (S. Madabhushi).
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economic viability and high selectivity are still of great significance.
Ceric(IV) ammonium nitrate(CAN) is an important and versatile reagent for a variety of
organic transformations,13 which include carbon-carbon bond formation reactions, carbon-
heteroatom bond formation reactions and intramolecular cyclization.CAN acts as a one
electron oxidant and it was extensively studied as a driving tool particularly for construction
of a variety of heterocycles such as indoles,14 pyrozoles,15 benzothiozoles,16 piperidines,17
tetrahydroquinolines,18 quinolines,19 quinoxalines,20 tetrahydropyrans21 and coumarines.22
However, studies on the synthesis of pyrroles using CAN are so far not known in literature
and herein, we report for the first time, CAN mediated synthesis of pyrrole-2,3,4,5-
tetracarboxylates by cyclocondensation of dimethyl acetylenedicarboxylate(DMAD) with an
aliphatic amine. Here, two molecules of DMAD and one molecule of an aliphatic amine
were found to react in the presence of CAN to give a poylfunctionalized pyrrole. In this
method, pyrroles were obtained in 55-75% yields under reflux in 1,4-dioxane as shown in
Scheme 1.
Scheme 1: CAN mediated three component synthesis of pyrrole-2,3,4,5-tetracarboxylates.
In our preliminary experiments, we studied CAN mediated cyclocondensation reaction of
DMAD with benzylamine1a using a variety of solvents such as 1,4-dioxane, 1,2-
dichloroethane, N,N-dimethylformamide, tetrahydrofuran and toluene (eq. 1). In these
solvents, tetramethyl-1-benzyl-1H-pyrrole-2,3,4,5-tetracarboxylate 2a was formed in
3

75,70,60,20 and 40% yields respectively.
This reaction, however, did not proceed in
solvents such as methanol, acetonitrile and dimethyl sulfoxide.
Next, DMAD was reacted with a variety of aliphatic primary amines 1a-k in the presence of
CAN under reflux in 1,4-dioxane and obtained corresponding N-alkyl pyrrole derivatives 2a-
k in 55-75% yield as shown in Table 1. In our study, however, the reaction of an aryl amine
with DMAD in the presence of CAN gave only monoaddition product and formation of
pyrrole-2,3,4,5-tetracarboxylate was not observed.
Table 1: CAN mediated synthesis of pyrrole-2,3,4, 5-tetracarboxylates.
Entry
a
Amine 1
Pyrrole 2
Reaction
time (h)
3
%yielda
75
b
4
70
4

c
3.5
68
55
d
e
5
4
63
Continued.
Table 1: Continued.
Entry
f
Amine 1
Pyrrole 2
Reaction
time (h)
3.5
%yielda
72
g
3
70
MeO2C
CO2Me
CO2Me
MeO2C
N
h
MeO2C
MeO2C
CO2Me
CO2Me
4
69
65
N
N
i
MeO2C
MeO2C
CO2Me
CO2Me
4.5
5

j
MeO2C
MeO2C
CO2Me
CO2Me
5
4
60
73
N
k
aIsolated yields. All products gave satisfactory1H&13C NMR, IR and Mass spectral data.
The plausible mechanism for CAN mediated synthesis of pyrrole 2,3,4,5-tetracarboxylates by
reaction of DMAD with an amine is shown in Scheme 2. In this mechanism, initially one
molecule of amine adds to two molecules of DMAD forming an adduct, which, in the next
step, undergoes intramolecular cyclization by CAN induced one electron oxidation and
converts into a pyrrole 2,3,4,5-tetracarboxylate. In the absence of CAN, we observed the
formation of only 1:1 addition product of DMAD and amine. This reaction was found to
require one equivalent of CAN and use of excess CAN did not improve the yield of pyrrole.
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Scheme 2: Plausible mechanism for the formation of pyrrole-2,3,4,5-tetracarboxylates.
In summary, this work shows a new and efficient method for synthesis of pyrrole 2,3,4,5-
tetracarboxylates by ceric (IV) ammonium nitrate (CAN) mediated one electron transfer
oxidation reaction of dimethyl acetylenedicarboxylate with an amine.
Acknowledgments: Authors are thankful to CSIR, New Delhi for the financial support under
the project CSC-0123(Indus Magic). VSV is thankful to the Director, IICT for the financial
support; KKRM and RJ are thankful to CSIR, New Delhi and SK is thankful to UGC, New
Delhi for the award of research fellowship.
Supplementary data: Supplementary data associated (experimental procedures,
characterization data and 1H & 13C NMR spectra of the compounds) is submitted.
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23. Typical procedure for synthesis of pyrroles-2,3,4,5-tetracaboxylates catalyzed by ceric
(IV) ammonium nitrate (CAN) : Dimethyl acetylenedicarboxylate (1.33g, 9.34 mmol),
benzylamine1a (0.5g, 4.67 mmol), 1,4-dioxane (5 ml) and ceric ammonium nitrate(CAN)
(2.55g, 4.67 mmol) were taken into a 25 ml round-bottomed flask fitted with a condenser
and nitrogen balloon. The mixture was refluxed for 3h and after completion of the reaction
(TLC), the reaction mixture was filtered, concentrated under reduced pressure and the
mixture was purified by column chromatography (100-200 mesh silica gel, EtOAc- hexane
= 1:10) to afford tetra methyl 1-benzyl-1H-pyrrole-2,3,4,5-tetracarboxylate 2a (1.8g, 75%)
as a yellow liquid, which was characterized by the following spectral data:
1H NMR (CDCl3, 300 MHz) δ: 7.27 (t, J = 7.9Hz, 3H), 7.06 (d, J = 7.9 Hz, 2H), 5.73 (s,
2H), 3.86 (s, 6H), 3.79 (s, 6H); 13C NMR (75 MHz, CDCl3): δ = 163.5, 163.3, 135.9,
129.9, 128.4, 127.6, 126.5, 119.9, 52.5, 52.3, 50.0; IR (neat): υ 2955, 2924, 2853, 1726,
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1546, 1505, 1446, 1356, 1251, 1116, 1080, 883 cm-1; ESIMS: 390 (M+1), 412 (M+Na);
HRMS: Exact mass obtained for C19H20O8N: 390.1184 (calculated: 390.1183).
11