Green and rapid strategy for synthesis of novel and known pyrroles by the use of molybdate sulfuric acid

Article abstract of DOI:10.1002/jccs.201300012

Molybdate sulfuric acid as a highly efficient catalyst has been employed for the modified Paal-Knorr synthesis of some novel and known pyrroles under solvent-free conditions. Catalyst loads as low as 1 mol % could be used leading to high yields of pure pyrrole derivatives at an oil bath temperature of 60 oC. This method has advantages such as the use of very low amounts of a recyclable catalyst, avoidance of organic solvents, and high product yields.

Full text of DOI:10.1002/jccs.201300012

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Communication
Green and Rapid Strategy for Synthesis of Novel and Known Pyrroles by the Use of
Molybdate Sulfuric Acid
Bahador Karami,* Saeed Khodabakhshi and Masih Jamshidi
Department of Chemistry, Yasouj University, Yasouj, Zip Code: 75918-74831 P.O. Box 353, Iran
(Received: Jan. 4, 2013; Accepted: Mar. 12, 2013; Published Online: May 28, 2013; DOI: 10.1002/jccs.201300012)
Molybdate sulfuric acid as a highly efficient catalyst has been employed for the modified Paal–Knorr syn-
thesis of some novel and known pyrroles under solvent-free conditions. Catalyst loads as low as 1 mol %
could be used leading to high yields of pure pyrrole derivatives at an oil bath temperature of 60 oC. This
method has advantages such as the use of very low amounts of a recyclable catalyst, avoidance of organic
solvents, and high product yields.
Keywords: Molybdate sulfuric acid; Catalyst; Paal–Knorr; Pyrrole; Solvent-free.
INTRODUCTION
Using eco-friendly catalysts which will improve the
RESULTS AND DISCUSSION
In connection with our studies on new catalyzed or-
ganic reactions,23,24 we found that molybdate sulfuric acid
can be used as a powerful, safe and recyclable catalyst for
the condensation of primary amines 1 and 2,5-hexadione
(2) under solvent-free conditions to afford some novel and
known pyrroles 3 in good to excellent yields (Scheme I).
efficiency or produce a greater yield, has been the subject
of interests specially, in synthesis of organic compounds.1-3
Synthetically, the pyrrole ring, as a class of important het-
erocycles, has attracted considerable attention,4 because
the pyrroles are key core elements of various natural and
biologically active molecules5 including anticancer,6 anti-
mycobacterial,7 and antiviral agents.8 Besides, pyrroles
serve as building blocks for porphyrin synthesis.9-11 The
development of new and convenient synthetic approaches
to these scaffolds is therefore of great interest to the medic-
inal chemistry community. One of the most common meth-
ods for the synthesis of pyrroles is Paal–Knorr cyclization
reaction of primary amines (or ammonia) and 1,4-dike-
tones in the presence of various promoting agents, such as
Scheme I Synthesis of pyrrole derivatives using MSA
zeolite,12,13 Ti(OPri)4,14 Al2O3,15 Bi(NO3)3 5H2O,16
.
Yb(OTf)3,17 Sc(OTf)3,18 p-TSA,19 layered zirconium phos-
phate and zirconium sulfophenyl phosphonate,20 as well as
the microwave technology.21 It should be mentioned that
some of the reported methods suffer from drawbacks, such
as the use of stoichiometric and even excess amounts of un-
recoverable catalyst and hazardous organic solvents, high
cost, long reaction time, and low yield of the products. Fur-
thermore, in conventional systems, an excess of amine usu-
ally has to be used in order to promote the reaction. From
atom-economical point of view, the use of nearly equimolar
amounts of substrates is strongly required. In a recent re-
port, Tamaddon and co-workers used the molybdate sulfu-
ric acid as a reusable solid catalyst in the synthesis of
2,3,4,5-tetrasubstituted pyrroles via a new one-pot [2+2+1]
strategy.22
To determine the simple and suitable conditions for
the Paal–Knorr synthesis of pyrroles in the presence of cat-
alytic amount of MSA, the treatment of 2 with aniline was
chosen as a model reaction. At first, we decided to optimize
the catalyst amount. However, we found that in the absence
of the catalyst, the reaction did not complete in long reac-
tion time. According to the results (Table 1), it can be con-
cluded that the MSA(1 mol%) is better than the other ones.
In another investigation, we have also carried out the
synthesis of 3a at different temperatures (Table 2). At 60
°C, the conversion was found to be the optimum, a further
increase in temperature could not improve the yield further.
Under the optimized reaction conditions (solvent-
free and 60 °C), a number of amines 1 with electron with-
drawing/donating groups were allowed to undergo Paal-
* Corresponding author. Tel: +987412223048; Fax: 987412242167; Email: karami@mail.yu.ac.ir
J. Chin. Chem. Soc. 2013, 60, 1103-1106
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1103

Communication
Karami et al.
Table 1. Effect of various amounts of MSA for the synthesis of
Table 3. Synthesis of pyrrole derivatives using MSA (1 mol%) at
60 °C under solvent-free conditions
3a at 60 °C under solvent-free conditions
Entry Catalyst amount (mol%) Time (min) Yield (%) [a]
Entry
Product [a]
Time (min) Yield (%) [b]
Mp (°C)
1
2
3
4
5
-
240
40
15 [b]
96
Me
Me
N
1
2
3
5
40
45
96
95
51-52 27
3a
40
95
35
95
45
90
Me
Me
Me
[a] Isolated yields. [b] Not completed.
N
265-266 28
3b
Table 2. Optimization of the temperature for the synthesis of 3a
N
N
Me
Me
using MSA (1 mol %) under solvent-free conditions
Entry
Temperature (°C)
Time (min)
Yield (%) [a]
Me
OH
1
2
3
4
5
25
40
240
240
40
50
65
96
94
77
3c[c]
3d[c]
3e
15
50
15
98
92
95
145-147
108-110
Cl
60
80
40
Me
Me
N
100
40
[a] Isolated yields.
OH
N
Knorr reaction with 2 in a molar ratio of 1:1 with catalyst (1
mol%) affording pyrroles 3a-3k in 15 to 120 minutes
(Table 3).
Me
Me
120-122 27
In another variation, we focused on the synthesis of a
new pyrrole (7) via Paal-Knorr reaction of 7-amino-4-
methylcoumarin (6) with 2 (Scheme II). Firstly, we had to
prepare 6 from the Pechmann condensation of metha-ami-
nophenol (4) with ethylacetoacetate (5) under solvent-free
condition. At the end of the reaction, novel 7 was obtained
in 90% yield.
Me
Me
N
120
40
80
85
147-149 27
3f
NO2
Me
Me
N
48-50 27
3g
Me
Synthesis of 7-(2,5-dimethylpyrrole-1-yl)-
4-methylcoumarin using MSA
Scheme II
Me
Me
N
35
40
85
80
48-50 27
3h
3i
Cl
N
Me
Me
197-200 28
NH2
Me
Me
N
140
125
75
80
Oil 29
3j
Me
Me
Oil 20
N
3k
The design and synthesis of recoverable catalysts is a
[a] Identified by comparison with authentic samples. [b] Refers to
isolated yields. [c] Novel compound.
highly challenging interdisciplinary field combining chem-
1104
www.jccs.wiley-vch.de
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2013, 60, 1103-1106

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Molybdate Sulfuric Acid as a Highly Efficient Catalyst
istry, materials, science, and engineering from economic
and environmental point of view. It should be noted that the
main disadvantage of many of the reported methods for
Paal–Knorr synthesis of pyrroles is that the catalysts are
destroyed in the work-up procedure and cannot be recov-
ered or reused. In this process, as indicated in Fig. 1, the re-
cycled catalyst was used for five cycles during which a
little loss was observed in the catalytic activities.
13.07, 106.3, 128.82, 138.31 ppm; IR (KBr) n = 3094, 3054,
2977, 2917, 2855, 1639, 1515, 1436, 1396, 1311, 857, 767, 754,
581. 1-(5-Chloro-2-hydroxyphenyl)-pyrrole (3c). 1H NMR
(400 MHz, CDCl3): d = 2.01 (s, 6H), 5.26 (m, 1H), 5.96 (s, 2H),
7.11 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 12.36, 106.68, 107.23, 117.42, 125.07, 126.05,
129.05, 130.13, 151.58 ppm; Anal. Calcd. for C10H8ClNO: C,
62.03; H, 4.16; N, 7.23. Found: C, 62.28; H, 4.10; N, 7.12; IR
(KBr) n = 3365, 2977, 2916, 1584, 1492, 1430, 1381, 1233, 1084,
1
820, 770, 729, 624. 1-(4-Hydroxy-phenyl)-pyrrole (3d). H
EXPERIMENTAL
General. The chemicals were purchased from Merck,
Fluka and Aldrich chemical companies. Molybdate sulfuric
acid25 and 7-amino-4-methylcoumarin26 were prepared according
to our previous reports. The reactions were monitored by TLC
(silica-gel 60 F254, hexane: EtOAc). IR spectra were recorded on a
FT-IR Shimadzu-470 spectrometer and the 1H-NMR spectra was
recorded on a Bruker-Instrument DPX-400 Avance 2 model. All
of the products (except novel compounds) were characterized by
comparison of their spectra and physical data, with those reported
in the literature.27,28
NMR (400 MHz, DMSO-d6): d = 1.93 (s, 6H), 5.74 (s, 2H), 6.81,
6.86 (2d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 9.71 (s, 1H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 13.30, 105.72, 116.09,
128.13, 129.47, 129.97, 151.19 ppm; Anal. Calcd. for C12H13NO:
C, 76.98; H, 7.00; N, 7.48; O, 8.54. Found: C, 77.18; H, 6.90; N,
7.25; IR (KBr) n = 3280, 2920, 1597, 1514, 1407, 1222, 1095,
838, 752. 1-(Naphthyl)-pyrrole (3e). 1H NMR (400 MHz,
CDCl3): d = 1.95 (s, 6H), 6.06 (s, 2H), 77.19 (d, J = 8.4 Hz, 1H),
7.47 (t, J = 7.2 Hz, 2H), 7.57, 7.61 (2d, J = 8, 7.6 Hz, 2H), 7.97 (d,
J = 8 Hz, 2H) ppm; 13C NMR (100 MHz): d = 12.59, 105.44,
123.35, 125.42, 126.28, 126.56, 127.24, 128.08, 128.58, 129.90,
131.93, 134.23, 135.80 ppm; IR (KBr) n = 3060, 2980, 2915,
1594, 1410, 808, 779, 757. 7-(2,5-Dimethylpyrrole-1-yl)-4-
Preparation of pyrrole derivatives using MSA. A mix-
ture of 2,5-hexadione (1 mmol), amine (1 mmol) and MSA (0.01
mmol) was stirred and heated at 60 °C (for 7: 120 °C) in a pre-
heated oil bath for an appropriate time. After completion of the re-
action as indicated by TLC (EtOAc/hexan, 1:3), the reaction mix-
ture was dissolved in hot EtOH and catalyst was separated by fil-
tration. The solvent was evaporated and the product 3 or 7 was pu-
rified by recrystallization in EtOH. The separated catalyst was
washed with diethyl ether, dried at 70 °C for 45 min, and reused in
another reaction.
1
methylcoumarin 7. H NMR (400 MHz, CDCl3): d = 2.10 (s,
6H), 2.53 (s, 3H), 5.96 (s, 2H), 6.37 (s, 1H), 7.19-7.29 (m, 2H),
7.74 (d, J = 8.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): d =
13.15, 18.77, 106.87, 115.29, 116.57, 119.22, 124.17, 125.20,
128.70, 142.05, 151.97, 153.78, 160.45 ppm; Anal. Calcd. for
C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.98; H, 5.77;
N, 5.40; IR (KBr) n = 3066, 2916, 1749, 1616, 1510, 1401, 1166,
1078, 853, 751.
1-(4-(2,5-Dimethyl-pyrrole-1-yl)phenyl)-2,5-dimethyl-
pyrrole (3b). 1H NMR (400 MHz, CDCl3): d = 2.11 (s, 12H), 5.96
(s, 4H), 7.33 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3): d =
CONCLUSIONS
In summary, we have developed a novel and eco-
friendly procedure for the modified Paal–Knorr synthesis
in the presence of catalytic amount of molybdate sulfuric
acid as a green catalyst in solvent-free conditions. The at-
tractive features of this method are the high conversions,
short reaction times, use of environmentally friendly and
recyclable catalyst, and avoidance of organic solvent. All
of these advantages make it a useful strategy for the prepa-
ration of various pyrrole derivatives simply by changing
different substrates.
ACKNOWLEDGEMENTS
Fig. 1. Recyclability of MSA as catalyst for the syn-
thesis of 3a at 60 °C under solvent-free condi-
tions, Reaction time = 45-50 min.
The authors gratefully acknowledge partial support
of this work by the Yasouj University Iran.
J. Chin. Chem. Soc. 2013, 60, 1103-1106
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
1105

Communication
Karami et al.
14. Yu, S. X.; Quesne, P. W. L. Tetrahedron Lett. 1995, 36, 6205.
15. Ballini, R.; Barboni, L.; Bosica, G.; Petrini, M. Synlett 2000,
391.
REFERENCES
1. Rostamizadeh, S.; Shadjou, N.; Hasanzadeh, M. J. Chin.
Chem. Soc. 2012, 59, 866.
16. Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K. Tetra-
hedron Lett. 2005, 46, 2643.
2. Rashedian, F.; Saberi, D.; Niknam, K. J. Chin. Chem. Soc.
2010, 57, 998.
17. Zuo, B.; Chen, J. X.; Liu, M. C.; Wu. H. Y.; Su, W. K. Chin.
Chem. Lett. 2009, 20, 423.
3. Karami, B.; Khodabakhshi, S.; Nikrooz, M. J. Chin. Chem.
Soc. 2012, 59, 187.
18. Chen, J.; Wu, H.; Zheng, Z.; Jin, C.; Zhang, X.; Su, W. Tetra-
hedron Lett. 2006, 47, 5383.
4. (a) Harn, P.-J.; Lin, C.-Ch.; Wu, H.-J. J. Chin. Chem. Soc.
2010, 57, 1321. (b) Wilson, K.; Clark, J. H. Pure Appl. Chem.
2000, 72, 1313.
19. Raghavan, S.; Anuradha, K. Synlett 2003, 711.
20. Curini, M.; Montanari, F.; Rosati, O.; Lioy, E.; Margarita, R.
Tetrahedron Lett. 2003, 44, 3923.
5. Bandyopadhyay, D.; Rivera, G.; Salinas, I.; Aguilar, H.;
Banik, B. K. Molecules 2010, 15, 1082.
6. Shinohara, K.; Bando, T.; Sugiyama, H. Anti-cancer Drugs
2010, 21, 228.
21. Danks, T. N. Tetrahedron Lett 1999, 40, 3957.
22. Tamaddon, F.; Farahi, M.; Karami, B. J. Mol. Catal. A:
Chem. 2012, 356, 85.
7. Ragno, R.; Marshall, G. R.; Di-Santo, R.; Costi, R.; Massa,
S.; Rompei, R.; Artico, M. Bioorg. Med. Chem. 2000, 8,
1423.
23. (a) Karami, B.; Khodabakhshi, S.; Nikrooz, M. Polycyclic
Aromat. Compd. 2011, 31, 97. (b) Karami, B.; Ghashghaee,
V.; Khodabakhshi, S. Catal. Commun. 2012, 20, 71.
24. Karami, B.; Eskandari, K.; Farahi, M.; Barmas, A. J. Chin.
Chem. Soc. 2012, 59, 473.
8. Dabur, R.; Ali, M.; Singh, H.; Gupta, J.; Sharma, G. L.
Pharmazie 2004, 59, 568.
9. Nonn, A. Angew. Chem. Int. Ed. 1995, 34, 1795.
10. Weidner, M. F.; Sigurdsson, S. T. Biochemistry 1990, 29,
9225.
25. Karami, B.; Zare, Z.; Eskandari, K. Chem. Pap. 2012, 67,
154.
26. Karami, B.; Kiani, M. Catal. Commun. 2011, 14, 62.
27. Zhang, Z-H.; Li, J-J.; Li, T-S. Ultrason. Sonochem. 2008, 15,
673.
11. Woo, J.; Sigurdsson, S. T. J. Am. Chem. Soc. 1993, 115,
3407.
12. Sreekumar, R.; Padmakumar, R. Synth. Commun.1998, 28,
1661.
28. Veisi, H. Tetrahedron Lett. 2010, 51, 2109.
29. De, S. K. Catal Lett. 2008, 124, 174.
13. Texier-Boullet, F.; Klein, B.; Hamelin, J. Synthesis 1986,
409.
1106
www.jccs.wiley-vch.de
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2013, 60, 1103-1106