Synthesis of N-substituted pyrroles under catalyst-and solvent-free conditions

Article abstract of DOI:10.1080/00397911.2011.560744

N-Substituted pyrroles were synthesized under neat conditions by the reaction of aromatic amines with 2, 5-dimethoxytetrahydrofuran in excellent yields.

Full text of DOI:10.1080/00397911.2011.560744

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Synthesis of N-Substituted Pyrroles
Under Catalyst- and Solvent-Free
Conditions
Katla Ramesh a , Sabbavarapu Narayana Murthy a & Yadavalli
Venkata Durga Nageswar a
a Organic Chemistry Division I, Indian Institute of Chemical
Technology , Hyderabad , India
Accepted author version posted online: 27 Dec 2011.Published
online: 14 May 2012.
To cite this article: Katla Ramesh , Sabbavarapu Narayana Murthy & Yadavalli Venkata Durga
Nageswar (2012) Synthesis of N-Substituted Pyrroles Under Catalyst- and Solvent-Free Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:16, 2471-2477, DOI: 10.1080/00397911.2011.560744
To link to this article: http://dx.doi.org/10.1080/00397911.2011.560744
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Synthetic Communications1, 42: 2471–2477, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.560744
SYNTHESIS OF N-SUBSTITUTED PYRROLES UNDER
CATALYST- AND SOLVENT-FREE CONDITIONS
Katla Ramesh, Sabbavarapu Narayana Murthy, and
Yadavalli Venkata Durga Nageswar
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract N-Substituted pyrroles were synthesized under neat conditions by the reaction of
aromatic amines with 2, 5-dimethoxytetrahydrofuran in excellent yields.
Keywords Aromatic amines; catalyst- and solvent-free conditions; 2,5-dimethoxytetra-
hydrofuran
INTRODUCTION
Pyrroles play a pivotal role in the context of heterocyclic chemistry, medicinal
chemistry, and synthetic organic chemistry.[1] The compounds associated with the
pyrrole system as a structural motif exhibit varied biological properties and act as
important intermediates in the synthesis of natural products as well as drug mole-
cules.[2] The methodologies developed for the synthesis of pyrroles include the
Hantzch reaction,[3] which utilizes the reaction of a-chloromethyl ketones, b-ketoe-
sters, and ammonia; the Knorr reaction,[4] which involves the reaction of a-amino-
ketones derived from a-haloketones, ammonia, and b-ketoesters; and the Paal–
Knorr condensation reactions.[5–15] However, the Paal–Knorr reaction,
a
condensation strategy from the corresponding 1,4-ketones and primary amines,
gained prominence for the synthesis of pyrroles. There are many marketed drugs
Received December 17, 2010.
Address correspondence to Yadavalli Venkata Durga Nageswar, Organic Chemistry Division I,
Indian Institute of Chemical Technology, Hyderabad 500607, India. E-mail: dryvdnageswar@gmail.com
2471

2472
K. RAMESH, S. N. MURTHY, AND Y. V. D. NAGESWAR
Figure 1. Atorvastatin.
Scheme 1.
with the pyrrole skeleton, and among them atorvastatin is the most important one
(Fig. 1).
Various methods have been developed for the construction of pyrroles by
employing several strategeis using different catalysts such as AcOH,[5] p-TsOH,[6]
Bi(NO3) ꢀ 5H2O,[7] Sc (OTf)3,[8,9] SnCl2,[11] zirconium catalysts,[12] and heterogeneous
catalysts such as montmorillonite KSF,[13] K10,[14] and Fe(III).[15] Pyrrole synthesis
has also been reported using ionic liquids[16] as well as microwaves.[17] However,
these methodologies have certain limitations such as the use of hazardous catalysts,
organic solvents, and drastic reaction conditions. Performing organic reactions
under neat conditions has gained significance because it minimizes the use of organic
solvents and catalysts, making it economically viable and environmentally benign.
As a part of our ongoing program to develop novel and greener chemical
approaches, we disclose the synthesis of the pyrrole skeleton under neat conditions
using various amines and 2,5-dimethoxy tetrahydrofuran as synthons (Scheme 1).
RESULTS AND DISCUSSION
During our initial study of this methodology,[18–23] a model reaction was con-
ducted with aniline and 2,5-dimethoxytetrahydrofuran in water under catalyst-free
conditions, which did not yield the desired product. No product formation was
observed when the reaction mixture was left at room temperature, under solvent-
and catalyst-free conditions. However, the same reaction, when heated under neat
conditions at 90–95 ꢁC for 12 h, resulted in the desired product in about 56%. The
temperature optimization study on this reaction with different substituted aromatic
amines without using any catalyst or solvent at 100–120 ꢁC resulted in excellent
yields (66–94%) of products.

SYNTHESIS OF N-SUBSTITUTED PYRROLES
2473
Scheme 2. Proposed mechanism for formation of pyrroles.
In general, the reaction was carried out with different substituted aromatic
amines, followed by the addition of 2,5-dimethoxytetrahydrofuran and stirring at
100–120 ꢁC to give the corresponding N-substituted pyrroles in excellent yields.
These reactions proceeded efficiently without using any catalyst or solvent. This
methodology is compatible with various substituted anilines and is equally effective
with anilines bearing electron-donating as well as electron-withdrawing substituents
in the aromatic ring. However, under the present conditions, aliphatic amines and
sterically hindered o-substituted anilines failed to react under optimized reaction
conditions. The probable mechanism for the formation of pyrrole is shown in
Scheme 2.
EXPERIMENTAL
Thin-layer chromatography (TLC) was carried out using silica-gel 60 F254
precoated plates. Visualization was accomplished with an ultraviolet lamp or I2 stain.
1
All products were characterized by their NMR and mass (MS) spectra. H and 13C
NMR were recorded at 200 MHz in CDCl3 using tetramethylsilane (TMS) as an inter-
nal standard. Chemical shifts are reported in parts per million (ppm, d).
General Procedure
2,5-Dimethoxytetrahydrofuran (1.2 mmol) was added to aniline (1.0 mmol) and
stirred for 4 h at 110–120 ꢁC until completion of the reaction as indicated by TLC.
The reaction mixture was extracted with ethyl acetate (3 ꢂ 10ml). The organic layers
were extracted with a water and brine solution and dried over anhydrous Na2SO4.
The combined organic layers were evaporated under reduced pressure, and the resulting
product was further purified by column chromatography using ethyl acetate and hexane
(0.2:9.8) as eluent (up to 90% yields). All the compounds were characterized by IR, 1H
NMR,13C NMR, and mass spectroscopy and compared to authentic samples.[8]

2474
K. RAMESH, S. N. MURTHY, AND Y. V. D. NAGESWAR
Spectral Data of Principal Compounds
1-Phenyl-1H-pyrrole (Table 1, Entry 1)[10]. Yield 90%, Rf 1.5% EtOAc=
1
n-hexane); IR (KBr): 3443, 2922, 2852, 1717, 1462, 1375, 1274, 759 cmꢃ1; H NMR
(200 MHz, CDCl3) d ¼ 6.3 (s, 2H, arom), 7.05 (s, 2H, arom), 7.12 (m, 2H, arom)
7.36–7.42 (m, 3H, arom); 13C NMR (75 MHz, CDCl3) d ¼ 96.1, 110.4, 119.2,
120.4, 125.5, 129.5, 135.6; MS m=z (EI): 143(M)þ. Anal. calcd. for C10H9N: C,
83.88; H, 6.34; N, 9.78. Found: C, 83.84; H, 6.30; N, 9.72.
1-(4-Fluorophenyl)-1H-pyrrole (Table 1, Entry 2). Yield 91%, Rf 1.5%
EtOAc=n-hexane; IR (KBr): 3423, 3067, 2921, 2852, 1877, 1515, 1460, 1329, 1228,
1
1100, 1072, 830 cmꢃ1; H NMR (200 MHz, CDCl3) d ¼ 6.3 (m, 2H, arom), 6.97
(m, 2H, arom), 7.0–7.1 (m, 2H, arom), 7.2–7.3 (m, 2H, arom); 13C NMR
(75 MHz, CDCl3) d ¼ 96.1, 110.5, 116.1, 116.4, 119.5, 122.3, 125.6, 135.6; MS m=z
(EI): 161 (M)þ. Anal. calcd. for C10H8 FN: C, 74.52; H, 5.00; N, 8.69. Found: C,
74.48; H, 4.95; N, 8.64.
1-(4-Chlrophenyl)-1H-pyrrole (Table 1, Entry 3)[8]. Yield 89%, Rf 1.5%
1
EtOAc=n-hexane; H NMR (200 MHz, CDCl3) d ¼ 5.48 (t, 2H), 6.18 (t, 2H, arom),
6.4–6.5 (m, 4H, arom); 13C NMR (75 MHz, CDCl3) d ¼ 108.4, 118.3, 123.5, 130.1,
135.4, 142.2; MS m=z (EI): 177 (M)þ. Anal. calcd. for C10H8ClN): C, 67.62; H,
4.54; N, 7.89. Found: C, 67.58; H, 4.50; N, 7.84.
1-(4-Bromophenyl)-1H-pyrrole (Table 1, Entry 4). Yield 90%, Rf 1.5%
1
EtOAc=n-hexane; H NMR (200 MHz, CDCl3, TMS) d ¼ 6.1 (t, 2H, arom), 6.28
(t, 2H, arom), 6.46–6.89 (m, 4H, arom); 13C NMR (75 MHz, CDCl3) d ¼ 108.5,
119.5, 120.3, 125.3, 126.9, 131.1, 135.6; m=z 223 (M þ H)þ. Anal. calcd. for
C10H8BrN): C, 54.08; H, 3.63; N, 6.31. Found: C, 54.02; H, 3.59; N, 6.28.
1-(4-Nitrophenyl)-1H-pyrrole (Table 1, Entry 5)[8]. Yield 80%, Rf 2.0%
1
EtOAc=n-hexane; H NMR (200 MHz, CDCl3) d ¼ 6.37 (t, 2H, arom), 7.11 (t, 2H,
arom), 7.4–7.5 (d, 2H, arom, J ¼ 9.0 Hz), 8.2–8.3 (d, 2H, arom, J ¼ 9.4 Hz); 13C
NMR (75 MHz, CDCl3) d ¼ 96.18, 112.6, 119.0, 119.3, 125.57, 136.7; MS m=z
(EI): 188 (M)þ. Anal. calcd. for C10H8N2O2): C, 63.82; H, 4.28; N, 14.89. Found:
C, 63.78; H, 4.25; N, 14.84.
1-(4-Methoxyphenyl)-1H-pyrrole (Table 1, Entry 7)[10]. Yield 94%, Rf
1.5% EtOAc=n-hexane; IR (KBr): 3432, 3094, 2921, 2851, 1707, 1642, 1527, 1478,
1
1316, 1270, 1196, 1091, 1027, 771 cmꢃ1; H NMR (200 MHz) d ¼ 3.83 (s, 3H), 6.23
(s, 1H, arom), 6.91–6.97 (t, 4H, arom), 7.25–7.31 (t, 3H, arom); 13C NMR
(75 MHz) d ¼ 55.4, 96.1, 109.8, 114.5, 119.6, 125.3, 138.6; MS m=z (EI): 173 (M)þ.
Anal. calcd. for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.24; H, 6.35;
N, 8.02.
1-(3,4-Dimethoxyphenyl)-1H-pyrrole (Table 1, Entry 8). Yield 90%, Rf
1
2.0% EtOAc=n-hexane; H NMR (200 MHz) d ¼ 3.62 (s, 3H), 3.89 (s, 3H), 6.75–
6.24 (m, 7H, arom); 13C NMR (75 MHz) d ¼ 56.6, 102.1, 111.0, 115.4, 125.0,
134.9, 148.2, 152.1; MS m=z (EI): 203 (M)þ. Anal. calcd. for C12H13NO2: C,
70.92; H, 6.45; N, 6.89. Found: C, 70.89; H, 6.40; N, 6.85.

SYNTHESIS OF N-SUBSTITUTED PYRROLES
2475
Table 1. Synthesis of N-substituted pyrroles under catalyst- and solvent-free conditionsa
Entry
1
Aniline
2,5-Dimethoxy teterahydrofuran
Product
Time (h) Yield (%)b
4
90
91
89
90
85
88
94
90
88
2
3
4
5
6
7
8
9
4.5
6
4.5
3.5
4
5
6.5
5
10
11
7
5
66
90
12
5
90
(Continued )

2476
K. RAMESH, S. N. MURTHY, AND Y. V. D. NAGESWAR
Table 1. Continued
Entry
13
Aniline
2,5-Dimethoxy teterahydrofuran
Product
Time (h) Yield (%)b
No reaction
18
14
No reaction
20
aReaction conditions: aniline (1.0 mmol), 2,5-dimethoxytetrahydrofuran (1.2 mmol), 100–120 ꢁC, 4–7 h.
bIsolated yield.
1-(4-Methylphenyl)-1H-pyrrole (Table 1, Entry 9)[8]. Yield 88%, Rf (2.0%
EtOAc=n-hexane; 1H NMR (200 MHz) d ¼ 3.63 (s, 3H), 6.21 (t, 2H, arom),
7.21–7.96 (m, 6H, arom); 13C NMR (75 MHz) d ¼ 55.3, 110.8, 114.9, 120.4, 126.5,
132.7; MS m=z (EI): 157 (M)þ. Anal. calcd. for C11H11N): C, 84.04; H, 7.05; N,
8.91. Found: C, 84.01; H, 7.01; N, 8.88.
1-(2,6-Dimethylphenyl)-1H-pyrrole (Table 1, Entry 10)[8]. Yield 66%, Rf
2.0%EtOAc=n-hexane; 1H NMR (200 MHz) d ¼ 2.43 (s, 6H), 6.14–6.53 (m, 4H,
arom), 7.12–7.59 (m, 3H, arom); 13C NMR (75 MHz) d ¼ 20.9, 112.3, 125.9, 126.9,
127.5, 142.5; MS m=z (EI): 171 (M)þ. Anal. calcd. for C12H13N: C, 84.17; H, 7.65;
N, 8.18. Found: C, 84.14; H, 7.60; N, 8.14.
1-(2-Pyridyl)-1H-pyrrole (Table 1, Entry 11)[10]. Yield 90%, Rf 2% EtOAc=
n-hexane; IR: 3045, 2912, 1597, 1530, 1483, 1458, 1367; 1H NMR (400 MHz, CDCl3)
d ¼ 5.91–5.61 (s, 4H, pyrrole), 7.27–7.20 (m, 1H, pyridine), 7.29 (t, 1H, J ¼ 6.4 Hz,
pyridine), 7.85 (t, 1H, J ¼ 7.8 Hz, pyridine), 8.72 (d, 1H, J ¼ 4.4 Hz, pyridine); 13C
NMR (100 MHz, CDCl3) d ¼ 110.9, 120.0, 125.3, 126.6, 138.0, 148.2, 152.1; MS
m=z (EI): 144 (M)þ. Anal. calcd. for C9H8N2: C, 74.98; H, 5.59; N, 19.43. Found:
C, 74.92; H, 5.53; N, 19.39.
1-(Naphthalene-1-yl)-1H-pyrrole (Table 1, Entry 12)[10]. Yield 90%, Rf
;
2.0% EtOAc=n-hexane; mp: 120 ꢁC; IR: 3052, 1600, 1575, 1532, 1500 cmꢃ1 1H
NMR (200 MHz): d ¼ 6.00 (s, 2H, arom), 7.15 (d, 1H, J ¼ 8.3 Hz), 7.40–7.60 (4H,
m), 7.98 (2H, d, J ¼ 8.2 Hz), 8.01–8.09 (2H, arom); 13C NMR (75 MHz) d ¼ 108.4,
120.7, 123.1, 125.1, 126.3, 128.3,134.3; MS m=z (EI): 193 (M)þ. Anal. calcd. for
C14H11N: C, 87.01; H, 5.74; N, 7.25. Found: C, 87.00; H, 5.71; N, 7.20.
CONCLUSION
In conclusion, we have developed an efficient, simple, economically viable, and
environmentally friendly methodology for the synthesis of N-substituted pyrroles
in excellent yields from different substituted aromatic amines and 2,5-dimethoxy
tetrahydrofuran without using any catalyst or solvent under neat conditions. This
straightforward, simple methodology may find widespread application in synthetic
organic and medicinal chemistry.

SYNTHESIS OF N-SUBSTITUTED PYRROLES
2477
ACKNOWLEDGMENTS
S. N. M. thanks the Council of Scientific and Industrial Research and K. R.
thanks the University Grants Commission, New Delhi, for the award of fellowships.
REFERENCES
1. Hayakawa, Y.; Kawasaki, K.; Seto, H. Tetrahedron Lett. 1992, 33, 2701.
2. Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,
E. F. V. Scriven (Eds.); Pergamon: Oxford, UK, 1996; vol. 2, p. 119.
3. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
4. Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635.
5. Knorr, L. Ber. 1884, 17, 2863.
6. Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465.
7. Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K. Tetrahedron Lett. 2005, 46, 2643.
8. Chen, J.; Wu, H.; Zheng, Z.; Jin, C.; Zhang, X.; Su, W. Tetrahedron Lett. 2006, 47, 5383.
9. Chen, J.-X.; Liu, M.-C.; Yang, X.-L.; Ding, J.-C.; Wu, H.-Y. J. Braz. Chem. Soc. 2008,
19(5), 877–883.
10. Rivera, S.; Bandyopadhyay, D.; Banik, B. K. Tetrahedron Lett. 2009, 50, 5445.
11. Arumugam, P.; Perumal, P. T. Chem. Lett. 2006, 35, 632.
12. Curini, M.; Montanari, F.; Rosati, O.; Lioy, E.; Margarita, R. Tetrahedron Lett. 2003,
44, 3923.
13. Banik, B. K.; Samajdar, S.; Banik, I. J. Org. Chem. 2004, 69, 213.
14. Texier-Boullet, F.; Klein, B.; Hamelin, J. Synthesis. 1986, 409.
15. Wang, B.; Kang, Y. R.; Yang, T.; Yang, L. M. Synth. Commun. 2005, 35, 1051.
16. Yadav, J. S.; Reddy, B. V. S.; Eeshwaraiah, B.; Gupta, M. K. Tetrahedron Lett. 2004,
45, 5873.
17. Werner, S.; Iyer, P. S. Synlett. 2005, 1405.
18. Narender, M.; Reddy, M. S.; Kumar, V. P.; Reddy, V. P.; Nageswar, Y. V. D.; Rao, K. R.
J. Org. Chem. 2007, 72, 1849.
19. Madhav, B.; Murthy, S. N.; Reddy, V. P.; Nageswar, Y. V. D.; Rao, K. R. Tetrahedron
Lett. 2009, 50, 6025.
20. Murthy, S. N.; Madhav, B.; Kumar, A. V.; Nageswar, Y. V. D.; Rao, K. R. Tetrahedron.
2009, 65, 5251.
21. Murthy, S. N.; Madhav, B.; Kumar, A. V.; Nageswar, Y. V. D.; Rao, K. R. Helv. Chim.
Acta. 2009, 92, 2118.
22. Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett. 2010,
51, 3649.
23. Shankar, J.; Karnakar, K.; Srinivas, B.; Nageswar, Y. V. D. Tetrahedron Lett. 2010,
51, 3938.