Polyethylene glycol (PEG-400) as an efficient and recyclable reaction medium for one-pot synthesis of polysubstituted pyrroles under catalyst-free conditions

Article abstract of DOI:10.1016/j.tetlet.2011.04.095

Polyethylene glycol (PEG) was found to be an inexpensive non-toxic and effective medium for the one-pot synthesis of highly functionalized pyrroles. Utilizing this protocol various pyrrole derivatives were synthesized in excellent yields. Environmental acceptability, low cost, high yields, and recyclability of the PEG are the important features of this protocol.

Full text of DOI:10.1016/j.tetlet.2011.04.095

Tetrahedron Letters 52 (2011) 3401–3404
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Tetrahedron Letters
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Polyethylene glycol (PEG-400) as an efficient and recyclable reaction
medium for one-pot synthesis of polysubstituted pyrroles under
catalyst-free conditions
Lingaiah Nagarapu a, , Raghu Mallepalli b, Lingappa Yeramanchi b, Rajashaker Bantu a
⇑
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Polyethylene glycol (PEG) was found to be an inexpensive non-toxic and effective medium for the one-
pot synthesis of highly functionalized pyrroles. Utilizing this protocol various pyrrole derivatives were
synthesized in excellent yields. Environmental acceptability, low cost, high yields, and recyclability of
the PEG are the important features of this protocol.
Received 22 February 2011
Revised 21 April 2011
Accepted 24 April 2011
Available online 30 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Substituted pyrroles
Catalyst free
Recyclable
PEG-400
Pyrrole moieties are the most important heterocyclic com-
pounds found in various bioactive natural products1 and pharma-
ceutical agents.2 They have also been recognized as versatile
synthetic intermediates in organic synthesis.1a,3 These derivatives
are used as organic conducting materials.4
solvent and catalyst. To the best of our knowledge there are no re-
ports for the synthesis of pyrrole derivatives by using PEG-400 as a
reaction medium under catalyst-free conditions (Scheme 1).
The generality of this reaction was investigated for the synthe-
sis of various pyrrole derivatives by using a variety of phenacyl
bromides and different anilines with dialkylacetylene dicarboxyl-
ates (Table 1). In general, all the reactions were very clean, and
the pyrrole derivatives were obtained in high yields. Phenacyl bro-
mides, bearing electron-withdrawing groups (Br, NO2) at the para-
position gave the desired products in quantitative yields in 10 h,
and also the amines bearing electron-donating groups (Me, OMe),
and electron- withdrawing groups (F) at the para-position gave
the desired products in high yields. Results show that the substitu-
tion groups did not play significant role in governing the reactivity
of the substrate. In the case of chlorides, only trace amount of the
pyrrole derivatives are obtained (Table 1, entry 1). Aliphatic
amines instead of aromatic amines gave the desired product in
moderate yields (Table 1, entries 14–17). However, the reaction
Although several protocols have been developed for the synthe-
sis of pyrrole derivatives,5 many of the methods are associated
with various drawbacks, such as harsh reaction conditions, tedious
experimental procedures, unsatisfactory yields, and long reaction
times and usage of expensive and moisture sensitive catalysts.
Hence, there is a need for a rapid and efficient method for the syn-
thesis of pyrrole derivatives under catalyst-free conditions.
In recent years, polyethylene glycol (PEG) has emerged as a
powerful phase transfer catalyst and is utilized in many useful
organic transformations under mild reaction conditions. Moreover,
PEG is inexpensive, easy to handle, thermally stable, non-toxic, and
recyclable in various organic transformations, such as synthesis of
b-amino sulfides, 2-substituted benzimidazoles, bis-benzimidaz-
oles, 3,4-dihydropyrimidinones, b-keto sulfides, and dibenz[b,f]-
1,4-oxazapine etc.6 This inspired us to focus on the aspect of the
synthesis of biologically active pyrrole derivatives under catalyst-
free conditions by using PEG as an eco-friendly and recyclable
medium. Herein we report the synthesis of pyrrole derivatives by
using PEG-400 as a recyclable medium without adding any organic
O
OR2
OR2
O
OR2
PEG - 400
O
Br R1-NH2
R2O
60 0C,10 h
R
N
R
O
R1
O
⇑
Corresponding author. Tel.: +91 40 27191509; fax: + 91 40 27193382.
E-mail address: lnagarapuiict@yahoo.com (L. Nagarapu).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.095

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L. Nagarapu et al. / Tetrahedron Letters 52 (2011) 3401–3404
Table 1
Entry
Halides
Amines
NH2
Acetylene dicarboxylates
Producta
Yieldb (%)
O
MeO
O
O
O
O
1
2
Br
Br
Br
OMe
OMe
89
N
N
N
O
OMe
O
O
O
NH2
EtO
O
OEt
OEt
3
4
89
85
O
OEt
O
O
NH2
MeO
OMe
OMe
O
O
OMe
O
NH2
EtO
O
O
Br
O
O
OEt
OEt
N
5
84
O
O
OEt
O
NH2
MeO
O
O
Br
Br
OMe
OMe
6
7
8
9
81
80
83
81
O2N
O2N
Br
N
N
O
O2N
O
OMe
NH2
NH2
NH2
EtO
O
OEt
OEt
O
O2N
O
OEt
O
O
MeO
O
Br
OMe
OMe
N
O
OMe
O
O
EtO
O
O
OEt
OEt
Br
Br
N
O
OEt
O
O
Br
O
NH2
MeO
O
Br
OMe
OMe
F
N
F
10
11
80
88
O
O
OMe
O
NH2
EtO
O
O
O
Br
OEt
OEt
MeO
N
OEt
O
OMe

L. Nagarapu et al. / Tetrahedron Letters 52 (2011) 3401–3404
3403
Table 1 (continued)
Entry
Halides
Amines
Acetylene dicarboxylates
Producta
Yieldb (%)
O
NH2
MeO
O
O
Br
OMe
OMe
F
O2N
N
F
12
13
82
84
O
OMe
O
O2N
O
NH2
MeO
O
O
O
Br
OMe
MeO
OMe
O2N
N
OMe
O
O2N
OMe
OMe
O
MeO
O
O
O
Br
Br
14
15
NH4OAC
41
75
OMe
N
H
O
O
MeO
OMe
O
O
NH2
OMe
OMe
N
O
O
OMe
O
O
O
MeO
O
Br
Br
OMe
OMe
16
17
H3C–NH2
61
59
N
CH3
O
O
O
OMe
O
NH2
MeO
OMe
OMe
N
O
O
OMe
O
O
NH2
MeO
O
Br
OMe
OMe
18
0
N
O
OMe
O
a
Reaction conditions: phenacyl bromide (1.0 mmol), amine (1.0 mmol), diethyl or dimethyl acetylenedicarboxylate (1.0 mmol), PEG (5 mL), 60 °C.
Isolated yields.
b
Prod. Rep. 2000, 17, 435; (c) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones,
A. R. Nat. Prod. Rep. 2006, 23, 517.
2. (a) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705; (b) Kidwai, M.;
Venkataramanan, R.; Mohan, R.; Sapra, P. Curr. Med. Chem. 2002, 9, 1209; (c)
La Regina, G.; Silvestri, R.; Artico, M.; Lavecchia, A.; Novellino, E.; Befani, O.;
Turini, P.; Agostinelli, E. J. Med. Chem. 2007, 50, 922.
3. (a) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 54; (b) Abid, M.; Landge, S. M.; Török, B. Org. Prep. Proced. Int. 2006,
38, 495.
4. (a) Facchetti, A.; Abboto, A.; Beverina, L.; van der Boom, M. E.; Dutta, P.;
Evmenenko, G.; Pagani, G. A.; Marks, T. J. Chem. Mater. 2003, 15, 1064; (b) Pu, S.;
Liu, G.; Shen, L.; Xu, J. Org. Lett. 2007, 9, 2139.
5. Some recent examples: (a) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed.
2005, 44, 5664; (b) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org.
Chem. 2005, 5277; (c) Shiner, C. M.; Lash, T. D. Tetrahedron 2005, 61, 11628; (d)
Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 16158; (e) Abid, M.;
Teixeira, L.; Török, B. Org. Lett. 2008, 10, 933; (f) Lu, Y. D.; Arndtsen, B. A. Angew.
Chem., Int. Ed. 2008, 47, 5430; (g) Das, B.; Reddy, G. C.; Balasubramanyam, P.;
Veeranjaneyulu, B. Synthesis 2010, 1625.
6. (a) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev. 2002, 102, 3325; (b)
Kamal, A.; Reddy, D. R.; Rajender Tetrahedron Lett. 2005, 46, 7951; (c) Suryakiran,
N.; Srikanth Reddy, T.; Ashalatha, K.; Lakshman, M.; Venkateswarlu, Y.
Tetrahedron Lett. 2006, 47, 3853.
with aliphatic
a-bromo ketone was not successful (Table 1, entry
18). The structures of all the products were determined from their
analytical and spectral (IR, 1H NMR and 13C NMR) data7 and by
direct comparison with the authentic samples.
In conclusion, we have developed an efficient and facile method
for the synthesis of polysubstituted pyrrole derivatives by treat-
ment of phenacyl bromides, amine, and dialkyl acetylenedicarbox-
ylate using PEG as a recyclable medium without the addition of
any additive or organic co-solvent. The mild reaction conditions,
less expensive of reaction medium, operational simplicity, and
high yields are the advantages of the protocol.
Acknowledgment
The authors are thankful to J. S. Yadav, Director, IICT, for his
kind help and support and UGC-BSR New Delhi for financial
assistance.
7. General procedure for the synthesis of substituted pyrroles by using PEG as a
reaction medium: A mixture of the dialkylacetylene dicarboxylate (1.0 mmol),
phenacyl bromide (1.0 mmol), and aniline (1.0 mmol) was taken in 5 ml of
polyethylene glycol, and stirred at 60 °C for the appropriate time. After
completion of the reaction, as monitored by TLC, the reaction mass was
References and notes
1. (a) Finar, I. L. Organic Chemistry Stereochemistry and Chemistry of Natural
Products; Longman: London, 1975. fifth Ed., Vol. 2, 885–913; (b) O’Hagan, D. Nat.

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L. Nagarapu et al. / Tetrahedron Letters 52 (2011) 3401–3404
extracted with ethyl acetate (3 Â 5 mL) and separated PEG. The combined
(ESI): m/z 381 [M+1]; Anal Calcd for (C20H16N2O6): C, 63.16; H, 4.24; N, 7.37.
Found: C, 63.09; H, 4.18; N, 7.29.
organic layers were evaporated under reduced pressure, and the crude product
was purified by column chromatography using silica gel (60–120 mesh) and
hexane/EtOAc, 9:1). The recovered PEG was vacuum dried and reused for three
cycles without significant loss of activity.
Diethyl 5-(4-nitrophenyl)-1-phenyl-1H-pyrrole-2,3-dicarboxylate (Table 1, entry
7): 1H NMR (200 MHz, CDCl3, TMS): d 8.44 (d, 2H, J = 8.87 Hz), 7.83 (d, 2H,
J = 8.87 Hz), 7.71–7.64 (m, 2H), 7.59–7.54 (m, 2H), 7.46 (s, 1H), 7.27 (s, 1H), 4.53
(dd, 2H, J = 7.98, 7.17 Hz) 4.36 (dd, 2H, J = 7.17 Hz), 1.50 (t, 3H, J = 6.98 Hz), 1.35
(t, 3H, J = 6.98 Hz); 13C NMR (50 MHz, CDCl3, TMS): d 165.4, 159.8, 146.7, 140.2,
139.0, 129.0, 128.8, 128.3, 126.0, 125.1, 123.8, 122.7, 122.4, 121.0, 61.5, 61.2,
14.0, 13.8; Mass (ESI): m/z 409 [M+1]; Anal Calcd for (C22H20N2O6): C, 64.70; H,
4.94; N, 6.86. Found: C, 64.62; H, 4.88; N, 6.79.
Dimethyl 1,5-diphenyl-1H-pyrrole-2,3-dicarboxylate (Table 1, entry 2): 1H NMR
(300 MHz, CDCl3, TMS): d 7.67–7.22 (m, 10H), 6.95 (s, 1H), 3.80 (s, 3H), 3.70 (s,
3H); 13C NMR (75 MHz, CDCl3, TMS): d 166.6, 160.1, 139.3, 133.1, 128.8, 128.4,
127.6, 127.0, 126.0, 125.8, 124.8, 123.1, 52.3, 51.8; mass (ESI): m/z 336 [M+1];
Anal Calcd for (C20H17NO4): C, 71.63; H, 5.11; N, 4.18. Found: C, 71.57; H, 5.01;
N, 4.11.
Diethy 5-(4-bromophenyl)-1-phenyl-1H-pyrrole-2,3-dicarboxylate (Table 1, entry
9): 1H NMR (300 MHz, CDCl3, TMS): d 7.52–7.39 (m, 5H), 7.36–7.25 (m, 4H), 6.91
(s, 1H), 4.25 (dd, 2H, J = 7.55, 6.79 Hz) 4.14 (dd, 2H, J = 7.55, 6.79 Hz), 1.29 (t, 3H,
J = 6.79 Hz), 1.15 (t, 3H, J = 6.79 Hz); 13C NMR (75 MHz, CDCl3, TMS): d 165.8,
159.9, 139.5, 132.3, 131.5, 130.8, 129.4, 128.9, 128.5, 126.1, 125.4, 124.2, 121.0,
61.3, 60.9, 14.0, 13.8; mass (ESI): m/z 442 [M+1]; Anal Calcd for (C22H20BrNO4):
C, 59.74; H, 4.56; N, 3.17. Found: C, 59.66; H, 4.59; N, 3.11.
Diethyl 1,5-diphenyl-1H-pyrrole-2,3-dicarboxylate (Table 1, entry 3): 1H NMR
(300 MHz, CDCl3, TMS): d 7.47–7.22 (m, 10H), 6.94 (s, 1H), 4.27 (dd, 2H, J = 6.79,
7.55 Hz) 4.13 (dd, 2H, J = 6.79, 7.55 Hz), 1.27 (t, 3H, J = 6.79 Hz), 1.16 (t, 3H,
J = 6.79 Hz); 13C NMR (75 MHz, CDCl3, TMS): d 166.1, 159.8, 139.5, 133.1, 128.7,
128.4, 127.6, 127.0, 126.1, 125.6, 124.6, 123.3, 121.9, 61.2, 60.7, 13.9, 13.8; mass
(ESI): m/z 364 [M+1]; Anal Calcd for (C22H21NO4): C, 72.71; H, 5.82; N, 3.85.
Found: C, 72.63; H, 5.76; N, 3.78.
Diethyl 1-ethyl-5-phenyl-1H-pyrrole-2,3-dicarboxylate (Table 1, entry 17): 1H
NMR (200 MHz, CDCl3, TMS): d 7.59–7.05 (m, 5H), 6.85 (s, 1H), 4.49–3.98 (m,
6H), 1.67–0.99 (m, 9H): 13C NMR (50 MHz, CDCl3, TMS): d 167.0, 160.1, 133.7,
128.4, 127.3, 126.7, 124.7, 123.4, 122.3, 120.3, 61.2, 60.5, 44.4, 16.9, 14.1, 14.0;
mass (ESI): m/z 316 [M+1]; Anal Calcd for (C18H21NO4): C, 68.55; H, 6.71; N,
4.44. Found: C, 68.47; H, 6.65; N, 4.39.
Dimeth 5-(4-nitrophenyl)-1-phenyl-1H-pyrrole-2,3-dicarboxylate (Table 1, entry
6): 1H NMR (200 MHz, CDCl3, TMS): d 8.24 (d, 2H, J = 8.87 Hz), 7.59 (d, 2H,
J = 8.87 Hz), 7.50–7.45 (m, 3H), 7.38–7.33 (m, 2H), 7.03 (s, 1H), 3.82 (s, 3H), 3.72
(s, 3H); 13C NMR (50 MHz, CDCl3, TMS): d 166.2, 160.2, 146.9, 140.4, 139.1,
129.0, 128.8, 128.2, 126.0, 125.8, 124.9, 123.8, 122.8, 120.7, 52.4, 52.1; mass