Synthesis of substituted pyrroles via Amberlyst-15 mediated MCR under ultrasound

Article abstract of DOI:10.1016/j.tetlet.2013.11.073

A faster and efficient synthesis of polysubstituted pyrroles has been achieved via a four-component reaction from β-ketoesters, benzylamines, aromatic aldehydes, and nitromethane in the presence of Amberlyst-15 under ultrasound. A variety of pyrrole derivatives were synthesized by this simple and straightforward methodology in good yields.

Full text of DOI:10.1016/j.tetlet.2013.11.073

Accepted Manuscript
Synthesis of substituted pyrroles via Amberlyst-15 mediated MCR under ultra-
sound
P. Radha Krishna Murthi, D. Rambabu, M.V. Basaveswara Rao, Manojit Pal
PII:
S0040-4039(13)02020-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.073
TETL 43868
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 September 2013
14 November 2013
17 November 2013
Please cite this article as: Radha Krishna Murthi, P., Rambabu, D., Basaveswara Rao, M.V., Pal, M., Synthesis of
substituted pyrroles via Amberlyst-15 mediated MCR under ultrasound, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.11.073
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis of substituted pyrroles via Amberlyst-15
mediated MCR under ultrasound
Leave this area blank for abstract info.
P. Radha Krishna Murthi, D. Rambabu,
M. V. Basaveswara Rao,* Manojit Pal*
O
R1NH2
RO
H3C
Ar
O
O
+
Amberlyst-15
ultrasound
+
ArCHO
+
H3C
OR
N
R1
CH3NO2
19 examples; 60-83% yield
2

Synthesis of substituted pyrroles via Amberlyst-15 mediated MCR under ultrasound
P. Radha Krishna Murthi,1 D. Rambabu,1,2 M. V. Basaveswara Rao,3,* Manojit Pal2,*
1Department of Chemistry, K L University, Vaddeswaram, Guntur-522502, Andhra Pradesh,
India.
2Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500 046, Andhra Pradesh, India.
3Department of Chemistry, Krishna University, Machilipatnam-521001, Andhra Pradesh, India.
--------------------------------------------------------------------------------------------------------------------
Abstract: A faster and efficient synthesis of polysubstituted pyrroles has been achieved via a
four-component reaction from β-ketoesters, benzylamines, aromatic aldehydes and nitromethane
in the presence of Amberlyst-15 under ultrasound. A variety of pyrrole derivatives were
synthesized by this simple and straightforward methodology in good yields.
Keywords: pyrrole, β-ketoester, benzylamine, nitromethane, aldehydes
---------------------------------------------------------------------------------------------------------------------
-------------------------------
*Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581;
E-mail: manojitpal@rediffmail.com.
3

Pyrroles, an important class of nitrogen containing heterocyclic compounds1 are widely
prevalent in nature,2 and used as valuable building blocks both in chemical and pharmaceutical
industries.3 The pyrrole framework is also considered as privileged structure in the area of new
drug discovery. Several pyrrole derivatives have shown promising biological activities such as
antimycobacterial, antibiotic, antioxidant properties and cytotoxicities.4
Due to their enormous importance pyrroles have attracted considerable interest in organic
synthesis and a number of synthetic methods have been developed for the construction of pyrrole
ring. These include5 well-known reactions such as Hantzsch,6,7 Knorr8,9 or Paal Knorr10,11
reaction. In spite of their effectiveness these classical methods suffer from several shortcomings
such as functional group compatibility, regiospecificity, harsh reaction conditions and multistep
synthetic operation. In recent time the multi-component reactions (MCRs) have emerged as
powerful tools in synthesizing complex bioactive molecules from readily available starting
materials in a single step. Advantages of this strategy include its simplicity, superior atom-
economy, low costs, high substrates variability and bond forming efficiency.12 The application of
this strategy in the synthesis of substituted pyrroles have also been explored which mainly
involved the MCR of β-diketones, aromatic aldehydes, primary amine and nitroalkane. Various
catalysts and/or reagents such as FeCl3,13 palladium,14 NiCl2⋅6H2O,15a CeCl3⋅7H2O (under
microwave),15b iodine,16 ionic liquid [Hbim]BF4 and solid-phase18 have been employed for this
17
purpose. All these methods though have their own merits many of them however, involve the use
of a metal catalyst the removal of which often require cumbersome workup and purifications.
The catalyst Amberlyst-15 has attracted considerable interest due to its non-hazardous nature and
efficiency in various organic transformations.19-21 Also it is inexpensive and commercially
available. Herein we report a metal-free synthesis of polysubstituted pyrroles via a four
4

component reaction catalyzed by Amberlyst-15 under ultrasound.22 Notably, the ultrasound
mediated reactions (known to be faster, convenient and high yielding process compared to the
traditional methods) have become increasingly popular and found wide applications in organic
synthesis.23-26
O
RO
Ar
O
O
Amberlyst-15
ultrasound
+ R1NH2 + ArCHO + CH3NO2
H3C
OR
H3C
N
4
3
2
5
1
R1
Scheme 1. Amberlyst-15 mediated synthesis of substituted pyrroles under ultrasound
In order to establish the optimized reaction condition, the MCR of methyl acetoacetate (1a),
benzylamine (2a) and 4-fluorobenzaldehyde (3a) in nitromethane (4) was carried out at room
temperature in the presence of Amberlyst-15 in a sonicator (using a regular laboratory ultrasonic
bath SONOREX SUPER RK 510H model producing irradiation of 35 KHz). The results of this
study are summarized in Table 1. It was observed that Amberlyst-15 (10% w/w) was found to be
optimum after varying the catalyst amount from 2.5% to 5% and then 10% (entries 1-3, Table 1).
While these reactions were performed for 12 h a decrease in reaction time to 6h did not change
the product yield significantly (entry 4, Table 1). However, further decrease in reaction time
decreased the product yield (entry 5, Table 1). The recyclability of the catalyst was also assessed
by recovering the catalyst through simple filtration followed by its reuse when 5a was isolated in
5

Table 1. Effect of reaction conditions on the MCR of 1a, 2 and 3.a
O
CH3NO2 (4)
H3CO
H3C
C6H4F-p
O
O
Amberlyst-15
p-FC6H4CHO
+ PhCH2NH2 +
H3C
OCH3
ultrasound
N
2a
5a
3a
1a
PhH2C
Catalyst
Entry
Catalyst
Time (h)
Yield (%)b
amount (w/w)
1
2
3
4
5
6
7
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
--
2.5%
5%
12
12
12
6
17
46
78
10%
10%
10%
--
76 (70,63,61)c
4
55
0d
24
24
Amberlyst-15
10%
20e
aAll the reactions were carried out using 1a (1.1 mmol), 2a (1.0 mmol), 3a (1.0 mmol) and
Amberlyst-15 in CH3NO2 (4, 1 mL) under ultrasound irradiation (35 KHz) at room temperature.
c
d
bIsolated yield. Recovered Amberlyst-15 was used. The reaction was carried out under
ultrasound in the absence of catalyst. eThe reaction was carried out in the absence of ultrasound.
70, 63 and 61% yield after 1st, 2nd and 3rd recovery and reuse of the catalyst. To assess the role of
catalyst and ultrasound in the present MCR the reaction was performed in the absence of
Amberlyst-15 and ultrasound separately. The yield of 5a was decreased significantly in both the
cases (entry 6 and 7, Table 1) indicating the key role played by the catalyst and ultrasound. The
6

role of ultrasound was further supported by the fact that 5a was isolated in 46% yield when the
reaction was performed under thermal heating (60 °C for 24h).
Having optimized the reaction conditions27 the MCR was examined for its further scope and
utility. Thus a variety of substituted pyrroles (5) were synthesized in good yields by using this
methodology (Table 2). Various benzyl amine derivatives e.g. 2a-d participated well in the
present MCR and a range of aldehydes (3) including aryl and heteroaryl aldehydes containing
various substituents were employed. The β-ketoester (1) may contain a methoxy, ethoxy,
allyloxy or t-butyloxy ester moiety and was well tolerated during the MCR. We also examined
the use of aniline (2e) (in place of benzyl amine) that was reacted with ester 1b, benzaldehyde 3c
and nitromethane 4 under the condition of entry 4 of Table 1. While the reaction proceeded in
this case the desired product i.e. ethyl-2-methyl-1,4-diphenyl-1H-pyrrole-3-carboxylate15b (5t)
was isolated in 41% yield. It is worthy to mention that nitromethane played the role of a reactant
as well as solvent in the present MCR and therefore the reaction did not require the use of any
additional solvent. While all these reactions were performed at room temperature a marginal
increase of bath temperature (up to ~ 40 °C) was observed during ultrasound irradiation. Thus
the reaction temperature was maintained by adding cold water occasionally. All the compounds
synthesized were characterized by (NMR, IR and MS) spectra. For example, the compound 5a
was characterized by the appearance of a singlet at ~ δ 6.6 ppm in the 1H NMR spectra due to the
H-5 proton and a signal at ~ 110.9 ppm in the 13C NMR spectra due to the C-5 carbon atom.
Table 2. Synthesis of substituted pyrroles mediated by Amberlyst-15 under ultrasound
irradiation (Scheme 1).a
7

Entry
1; R
1a; CH3
1a
2; R1
3; Ar
3a; p-FC6H4
3b; p-ClC6H4
3c; Ph
Time (h) Products % yieldb
1
2
3
4
5
6
2a; CH2Ph
6
5
4
4
5
5
76
80
72
83
77
79
5a
5b
5c
5d
5e
5f
2a
1a
2a
3d; 2-Furanyl
3b
1a
2a
2b; CH2C6H4CH3-p
1a
1a
3c
2c; R (+)-α-
methylbenzyl
7
3e; p-CH3C6H4
3
3
5
4
4
6
6
4
4
4
5
71
80
70
60
80
75
73
77
69
70
65
1a
1a
2c
5g
5h
5i
8
3f; p-CH3OC6H4
2c
9
3g; p-NO2C6H4
1a
2c
10
11
12
13
14
15
16
17
3h; p-BrC6H4
1a
2c
5j
1a
2c
3a
5k
5l
3i; 2-Naphthyl
1a
2c
1b; C2H5
1b
2c
3a
5m
5n
5o
5p
5q
3j; m-HOC6H4
2c
1c; Allyl
1d; tButyl
1a
2c
3h
3h
3b
2c
2d; S(+)-α-
methylbenzyl
2d
18
19
5
5
68
67
1b
1b
3e
5r
5s
2d
3h
8

aAll the reactions were carried out using 1 (1.1 mmol), 2 (1.0 mmol), 3 (1.0 mmol) in CH3NO2
(4, 1 mL) in the presence of Amberlyst-15 (10% w/w) at room temperature under ultrasound.
bIsolated yield.
OR
R1NH2
Ar
CH3NO2
O
O
Ar
O
4
2
C O
H
NO2
T-2
H3C
OR
H+
(Amberlyst-15)
H+
(Amberlyst-15)
H
HN
R1
3
1
CH3
T-1
HO3S
(CHCH2)n
OR
Ar
H+
(Amberlyst-15)
O
OR
O
RO
H3C
Ar
O
H
Ar
O
H
H3C
N
OH
H3C
N
R1
OH
N
R1
N
N
R1
HN(OH)2
OH
T-3
T-4
5
Scheme 2. Proposed reaction mechanism for the Amberlyst-15 mediated MCR leading to
pyrroles under ultrasound irradiation.
A proposed mechanism for the Amberlyst-15 mediated MCR leading to pyrroles under
ultrasound irradiation is shown in Scheme 2. Amberlyst-15 being a macro reticular
polystyrene-based ion exchange resin possessing strongly acidic sulfonic groups (Scheme 2)
usually catalyzes various reactions involving carbonyl group via its activation. Thus, the
Amberlyst-15 facilitates the formation of β-enamino carbonyl compound (T-1) via the
reaction of β-ketoester (1) and the amine (2) in situ.28 Similarly, the formation of nitroalkene
(T-2) in situ was also facilitated by Amberlyst-15. Subsequent Michael type of reaction29,30
between T-1 and T-2 involving a nucleophilic attack by the enamino double bond (of T-1)
on the electron deficient double bond (of T-2) leads to the formation of T-3. An
9

intramolecular cyclization of T-3 involving the attack by the imine nitrogen to the nearby –
C=N(O)OH moiety affords T-4 which on subsequent aromatization provides the desired
pyrrole 5. While the precise role of ultrasound in the present MCR was not clearly undersood
possibly all the steps especially the formation of T-3 were accelerated in the presence of this
irradiation. Moreover, the results of entry 6 of Table 1 clearly suggests the need of
ultrasound irradiation in the present MCR.
In conclusion, we have described a practical synthesis of multisubstituted pyrroles via an MCR
involving the reaction of β-ketoesters, benzylamines, aromatic aldehydes and nitromethane.
Amberlyst-15 has been identified as a reusable catalyst and the MCR proceeds under ultrasound
irradiation at room temperature. The methodology was found to be general and a wide variety of
pyrrole derivatives were prepared in good yields. To the best of our knowledge this is the first
example of synthesizing multisubstituted pyrroles using Amberlyst-15 as a catalyst under
ultrasound. Overall, due to the operational simplicity, the use of a metal-free, inexpensive and
heterogeneous thereby recyclable catalyst, and good yields of products, the present method may
find wide usage in the rapid synthesis of pyrroles based library of small molecules useful for
chemical and pharmaceutical applications.
Acknowledgements. P. R. K. M. thanks K L University, Vaddeswaram, Guntur-522502, Andhra
Pradesh, India for encouragement and support.
References and notes
10

1. Jones, R. A. The Chemistry of Heterocyclic Compounds, Pyrroles; John Wiley & Sons,
Canada, 1990.
2. Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron Lett. 2003,
44, 4443.
3. Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891.
4. Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264.
5. Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. 2010, 39, 4402.
6. Kaupp, G.; Schmeyers, J.; Kuse, A.; Atfeh, A. Angew. Chem., Int. Ed. 1999, 38, 2896.
7. Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Y. V.; Pidlypnyi, N. I.
Chem. Heterocycl. Compd. 2004, 40, 1218.
8. Manley, J. M.; Kalman, M. J.; Conway, B. G.; Ball, C. C.; Havens, J. L.; Vaidyanathan,
R. J. Org. Chem. 2003, 68, 6447.
9. Shiner, C. M.; Lash, T. D. Tetrahedron 2005, 61, 11628.
10. Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367.
11. Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 24, 5277.
12. Dömling, A. Chem. Rev. 2006, 106, 17.
13. Maiti, S.; Biswas, S.; Jana, U. J. Org. Chem. 2010, 75, 1674.
14. Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Reddy, L. S.; Kumar, P. M.;
Krishna, G. R.; Reddy, C. M.; Rambabu, D.; Kapavarapu, R.; Lakshmi, C.; Meda, T.;
Priya, K. K.; Parsa, K. V. L.; Pal, M. Chem. Comm. 2011, 47, 7779.
15. (a) Khan, A. T.; Lal, M.; Bagdi, P. R.; Basha, R. S.; Saravanan, P.; Patra, S. Tetrahedron
Lett. 2012, 53, 4145. (b) Silveira, C. C.; Mendes, S. R. Martins, G. M.; Schlösser, S. C.;
Kaufman, T. S. Tetrahedron 2013, 69, 9076.
11

16. Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Pal, M. RSC Adv. 2012, 2, 3387.
17. Meshram, H. M.; Babu, B. M.; Kumar, G. S.; Thakur, P. B.; Bangade, V. M. Tetrahedron
Lett. 2013, 54, 2296.
18. Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263.
19. Coppola, G. M. Synthesis 1984, 1021.
20. Ramesh, C.; Banerjee, J.; Pal, R.; Das, B. Adv. Synth. Catal. 2003, 345, 557.
21. Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.; Sekar, D. G. Synthesis 2001, 6, 885.
22. For our earlier effort on the use of Amberlyst-15 under ultrasound, see: Rambabu, D.;
Kumar, S. K.; Sreenivas, B. Y.; Sandra, S.; Kandale, A.; Misra, P.; Rao, M. V. B.; Pal,
M. Tetrahedron Lett. 2013, 54, 495.
23. (a) Luche, J. L. Synthetic Organic Sonochemistry, Plenum Press, New York, 1998. (b) Li,
J. T.; Han, J. F.; Yang, J. H.; Li, T. S. Ultrason. Sonochem. 2003, 10, 119.
24. Mcnulty, J.; Steere, J. A.; Wolf, S. Tetrahedron Lett. 1998, 39, 8013.
25. Li, J. T.; Wang, S. X.; Chen, G. F.; Li, T. S. Curr. Org. Synth. 2005, 2, 415.
26. Ratoarinoro, N.; Wilhelm, A. M.; Berlan, J.; Delmas, H. Chem. Eng. J. 1992, 50, 27.
27. (a) General procedure for the preparation of compounds 5: A mixture of
compound 1 (1.1 mmol), 2 (1.0 mmol), 3 (1.0 mmol) and Amberlyst-15 (10%, w/w)
in CH3NO2 (4, 1 mL) was irradiated with ultrasound (35 KHz) continuously at room
temperature for the time indicated in Table 2 [a marginal increase of bath temperature
(up to ~ 40 °C) was observed during ultrasound irradiation and therefore the reaction
temperature was maintained by occasional addition of cold]. After completion of the
reaction (indicated by TLC) the mixture was treated with EtOAc (15 mL). After
stirring for 10 min the mixture was filtered to remove the insoluble catalyst. The
12

filtrate was collected and concentrated under vacuum. The crude product isolated was
purified by silica gel column (hexane / ethylacetate, 10:1) to give the desired product.
(b) Recovery of the catalyst: The recovered Amberlyst-15 obtained by filtering off
the reaction mixture, was washed successively with THF (5 mL) and EtOAc (5 mL)
thrice and dried at 100 °C for 2 h. The efficiency of the catalyst was not changed
significantly on using for additional three consecutive times in the model reaction as
shown in Table 1.
28. Narsaiah, A. V.; Reddy, A. R.; Reddy, B. V. S.; Yadav, J. S. The Open Cat. J. 2011, 4,
43.
29. For the first example of Michael-type addition of 1-nitropropene to the N-substituted
esters of β-aminocrotonic acid leading to N-substituted 2,4-dimethyl-4-carbethoxy-
pyrroles, see: Grob, C. A.; Camenisch, K. Helv. Chim. Acta. 1953, 36, 49.
30. Guan, Z.-H.; Li, L.; Ren, Z.-H.; Li, J.; Zhao, M.-N. Green. Chem. 2011, 13, 1664.
13