A solvent-free synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates via triethylphosphite mediated reductive cyclization of ethyl 2-nitro-5-oxo-3,5- diarylpentanoates under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2013.08.007

Ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates have been synthesized in good yields from ethyl 2-nitro-5-oxo-3,5-diarylpentanoates by treatment with triethylphosphite under microwave irradiation. The integrity of the mechanism proposed has been augmented by <

Full text of DOI:10.1016/j.tetlet.2013.08.007

Accepted Manuscript
A solvent-free synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates via trie‐
thylphosphite mediated reductive cyclization of ethyl 2-nitro-5-oxo-3,5-diary‐
lpentanoates under microwave irradiation
Rajni Khajuria, Yeshwinder Saini, Kamal K. Kapoor
PII:
S0040-4039(13)01344-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.007
TETL 43364
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Khajuria, R., Saini, Y., Kapoor, K.K., A solvent-free synthesis of ethyl 3,5-diaryl-1H-
pyrrole-2-carboxylates via triethylphosphite mediated reductive cyclization of ethyl 2-nitro-5-oxo-3,5-
diarylpentanoates under microwave irradiation, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.08.007
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A solvent-free synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates via triethylphosphite mediated
reductive cyclization of ethyl 2-nitro-5-oxo-3,5-diarylpentanoates under microwave irradiation
Rajni Khajuria, Yeshwinder Saini, Kamal K. Kapoor a*
aDepartment of Chemistry, University of Jammu, Jammu-180 006, INDIA
*E-mail: k2kapoor@yahoo.com
Abstract
Ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates have been synthesized in good yields from ethyl 2-nitro-5-oxo-3,5-
diarylpentanoates by treatment with triethylphosphite under microwave irradiation. The integrity of the
mechanism proposed has been augmented by 31P NMR and EIMS experiments.
Keywords:reductive cyclization, ethyl 2-nitro-5-oxo-3,5-diarylpentanoates, triethylphosphite, ethyl 3,5-diaryl-
1H-pyrrole-2-carboxylates, microwave irradiation.
Pyrroles are an important class of nitrogen-containing heterocycles1 found widely in natural and bio-active
molecules,2
possessing
antibacterial,3
antifungal,4
antiinflammatory,5antioxidative,6
antitumor,7
antitubercular,8hypolipidemic9 and immune suppressant activities.10 In addition, they act as inhibitors of
retroviral reverse transcriptases [i.e., human immunodeficiency virus type 1 (HIV 1)], cellular DNA
polymerasesand protein kinases.11 There are several pyrrole moiety containing drugs available in the market and
some of them are: atrovastatin (Lipitor)(hyperlipidemic),12 BM 212 (antifungal and antimycobacterial),13
tallimustine (anticancer), pyrrolomycin B, pyoluteorin and pyrrolnitrin (antibiotics).14 The most celebrated
biological context of pyrroles is the tetrapyrrole scaffold of heme and related porphinoid co-factors e.g. heme b,
vitamin B12, chlorophyll α and factor 430. Furthermore, pyrroles are important structural motifs of natural
alkaloids, co-enzymes15 and unnatural heterocyclic derivatives. They are also widely used in materials science16
as semi conductors, chemosensors, fluorescent sensors and for image diagnosis.
There are many methods for the synthesis of pyrrole derivatives, including the classical Hantzch procedure,17
cyclocondensation of α-aminoketones with β-ketoesters or β-diketones (Knorr synthesis),18 cyclocondensation
of primary amines with 1,4-dicarbonyl compounds (Paal Knorr synthesis),19 1,3-dipolar cycloaddition of
azomethine ylides to alkynes followed by aromatization of the intermediate pyrrolines,20 Cu-assisted
cycloisomerization of alkynyl imines,21 rhodium-catalysed hydroformylation of β-alkynylamines with CO/H2,22
condensation of nitroolefins or esters of vicinal nitro alcohols with stabilized α-isocyano anions,23 rhodium(II)
acetate-catalysed intramolecular N-H insertion reaction of δ-amino-γ,γ-difluoro-α-diazo-β-ketoesters,24 reductive
cyclization of 2-aryl succinonitriles25 and various other cycloaddition and transition metal-catalysed cyclization
strategies.26 Ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates have been prepared from ethyl 2-nitro-5-oxo-3,5-
diarylpentanoates by heating with reducing systems such as a combination of tributylphosphine and
diphenyldisulphide,27 formamidinesulfinic acid (thiourea-S,S-dioxide).28 However, most of these methods suffer
from one or more disadvantages such as the involvement of multistep laborious protocols, use of harsh reaction
conditions, use of expensive reagents, tedious work-up procedures and generation of toxic by-products. Triethyl
phosphite has been used in the syntheses of carbazoles, indoles, indazoles and related compounds.29 In our
continuing efforts30 to develop newer methodologies in organic synthesis, we contemplated the use of
1

triethylphosphite for the synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates via reductive cyclization of
ethyl 2-nitro-5-oxo-3,5-diarylpentanoates.
Firstly the requisite starting materials viz. ethyl 2-nitro-5-oxo-3,5-diarylpentanoates (γ-nitroketones) 2a-g were
synthesized by the reaction of 1,3-diarylpropenones (chalcones) 1a-g with ethylnitroacetate following the Davey
and Tivey procedure31 using diethylamine as a base in ethanol (Scheme1). 1,3-Diarylpropenones were, in turn,
prepared by an aldol/dehydration reaction of the corresponding aldehyde and acetophenone.32
O
O2N
O
O
O
Et2NH, EtOH
Reflux
O
O N
+
2
R2
R1
R1
O
R2
1a-g
2a-g
Scheme 1. Synthesis of ethyl 2-nitro-5-oxo-3,5-diarylpentanoates 2a-g.
The above prepared ethyl 2-nitro-5-oxo-3,5-diphenylpentanoate 2a(1.0 mmol) was taken in triethylphosphite
o
(3.0 mmol) without any solvent and was exposed to microwave irradiation [power 80 W, 90 C] for 30 min
(TLC). To our delight, the formation of the expected product ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 3a, as
characterized by comparison of its physical and spectral data33 with the authentic sample,34 was noticed (Scheme
o
2).The above mentioned reaction upon conventional heating at 120 C for 3 h also resulted in the formation of
desired product 3a but the yield of the product (18%) was very low and starting material was recovered intact.
Moreover, microwave heating has been extensively used for carrying out chemical reactions and has become a
useful non-conventional energy source for speeding-up organic syntheses.35 Replacing triethylphosphite with
trimethylphosphite without changing the reaction conditions [P(OMe)3: 3 equivalents, MWI, 90 oC, 30 min] was
found to be equally successful and the desired product 3a was obtained in 89% yield. It was observed that
trimethylphosphite was a strong irritant with severe pungent smell and was found extremely difficult to handle.
In view of these facts, we decided to pursue future experiments with triethylphosphite under microwave
irradiation. To explore the scope of this methodology, a variety of ethyl 2-nitro-5-oxo-3,5-diarylpentanoates 2a-
g were subjected to aforementioned reductive cyclization reaction and the formation of the desired products 3a-
g was observed in good to excellent yields (82-94%, Table 1).
O
O2N
O
O
µW, 80 W, 90 oC, 30 min
OEt
OEt
O
EtO
P
+
O
NH
3a
2a
Scheme 2. Synthesis of ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 3a.
Table 1: Triethylphosphite mediated synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates 3a-g
2

R2
O
O2N
O
O
OEt
OEt
µW, 80 W
O
+
EtO
P
R1
R2
O
N
H
R1
2a-g
3a-g
Entry
1
R1
R2
Producta
Mpb [lit. mp oC]
Time (min)
Yieldc (%)
90
H
H
136-138
[139-140]34
30
O
OEt
NH
3a
OMe
2
3
4
5
H
4-OMe
4-OH
4-F
131-133
[135]36
50
87
82
93
94
O
OEt
NH
3b
OH
H
207-209
[205-206]37
40
50
50
O
OEt
NH
3c
F
4-F
147-149
[149-150]37
O
OEt
NH
F
3d
4-Cl
H
182-183
[185]36
O
OEt
NH
Cl
3e
3

6
4-Me
H
167-169
45
89
[168-170]38
O
OEt
NH
Me
3f
Me
Me
7
H
4-N(Me)2
137-138
40
83
N
[135-137]34
O
OEt
NH
3g
aAll the products were identified by comparison of their physical and spectral data with those of authentic
samples.
bLiterature reference of melting point.
cIsolated yield.
It is pertinent to mention that this methodology is not limited only to diaryl substituents since a reaction of ethyl
o
2-nitro-5-oxo-3-methyl-5-phenylpentanoate under similar conditions [P(OEt)3: 3 equivalents, MWI, 90 C, 30
min] yielded ethyl 3-methyl-5-phenyl-1H-pyrrole-2-carboxylate39 in 82% yield.
In light of the mechanism proposed by Cadogen et al.,29 and Hollimanet al.,40 following mechanism is proposed
for the current reaction.
OEt
OEt
EtO
EtO
EtO
EtO
P
EtO
EtO
O
P
OEt
O
O
O
EtO
EtO
O
O
N
O
P
O
O
P
P
OEt
N
O
N
OEt
OEt
O
O
N
_
O
O
EtO
O
O
O
O
O
H
R2
R1
R1
R2
R2
R2
R1
R1
O
O
H
O
O
O
H
N
N
N
OEt
OEt
O
_
NH
HO
EtO
P
O
R1
O
H
O
R1
_
O
H2O
H migration
O
H
H
H
R2
R2
R2
R1
R1
R2
Scheme 3.Mechanism for the P(OEt)3 promoted reductive cyclization of ethyl 2-nitro-5-oxo-3,5-
diarylpentanoates 2a-g.
To establish the integrity of the above proposed mechanism leading to the formation of triethylphosphate in the
reaction, 31P NMR (CDCl3, 162 MHz) and EIMS experiments were conducted. It was found that the singlet at
δ:138.7 ppm, corresponding to phosphorus in triethylphosphite disappeared from the spectrum of the aliquot
taken from the reaction mixture [2a, P(OEt)3, MWI] after 30 min, revealing the disappearance of triethyl
phosphite with the appearance of a singlet at δ: -0.87 ppm corresponding to triethylphosphate. Also the presence
of two singlets at δ 9.47 and 5.20 ppmin the 31P NMR suggests the formation of diethyl phosphite in the reaction
by the hydrolysis of triethylphosphite. EIMS of this aliquot displayed diagnostic molecular ion peaks at m/z 183
4

(M+H)+ and 205 (M+Na)+ corresponding to triethylphosphate and at m/z 139 (M+H)+ and 161 (M+Na)+
corresponding to diethylphosphite.
In summary, an efficient method for the preparation of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates has been
developed via reductive cyclization of various ethyl 2-nitro-5-oxo-3,5-diphenylpentanoates with
triethylphosphite under microwave irradiation without any solvent.
Acknowledgements
The authors are grateful to the Department of Science and Technology, GOI, New Delhi for funding (Project
No. SR/S1/OC-38/2010) and the NMR facility under PURSE.
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33. Procedure for the synthesis of ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 3a: A mixture of ethyl 2-
nitro-5- oxo-3,5-diphenylpentanoate (0.341 g, 1.0 mmol) and triethylphosphite (0.498 g, 3.0 mmol) in a
closed vessel was irradiated in a microwave synthesizer (CEM Discover) at 90 oC(80 W) for 30 min.
After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and the
volatiles were removed under vacuum at 70 oC to give a brown colored residue, which was taken in ethyl
acetate (30 mL). The ethyl acetate solution was washed with water (3 × 15 mL), brine (1 × 15 mL), dried
(anhydrous Na2SO4) and concentrated on rotary evaporator. The resultant after column chromatography
over silica (60-120mesh) using a gradient of a mixture of petroleum ether-ethyl acetate yielded crystalline
ethyl 3,5-diphenyl-1H-pyrrole-2-carboxylate 3a (0.262 g, 90%). Mp. 136-138oC (lit. m.p. 139-140oC).34
1H NMR (CDCl3, 400MHz): δ (ppm) 9.45 (br s, 1H, exchangeable with D2O), 7.64-7.61(m, 4H), 7.50-
7.30 (m, 6H), 6.66 (d,J = 3.2 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz,3H); 13CNMR (CDCl3,
100 MHz): δ (ppm) 161.27, 135.38, 135.08, 133.46, 131.06, 129.56, 129.09, 128.36, 127.95, 127.69,
127.14, 124.78, 118.60, 109.95, 60.45, 14.25; IR (KBr) (υmax, cm-1): 3313, 1662; Anal. Calcd for
C19H17NO2: C, 78.33; H, 5.88; N, 4.81%. Found: C, 78.38; H, 5.82; N, 4.73%.
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6

Graphical abstract
A solvent-free synthesis of ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates via triethylphosphite mediated reductive
cyclization of ethyl 2-nitro-5-oxo-3,5-diarylpentanoates under microwave irradiation
Rajni Khajuria, Yeshwinder Saini, Kamal K. Kapoor a*
aDepartment of Chemistry, University of Jammu, Jammu-180 006, INDIA
*E-mail: k2kapoor@yahoo.com
O
R2
O
O2N
O
OEt
O
R2
EtO
P
R1
OEt
1a-g
+
O
O
Et2NH, EtOH
Reflux
µW, 80 W
R1
R2
N
H
O
O2N
R1
2a-g
O
3a-g
7