Synthesis of functionalized pyrroles and fused pyrroles through intermolecular [3?+?2] cycloaddition reaction

Article abstract of DOI:10.1080/00397911.2018.1433301

A facile and efficient synthesis of pyrrole and pyrrole-fused heterocyclic compounds has been demonstrated. The current protocol involves the in situ generation of azomethine ylides which undergoes intermolecular cycloaddition reaction and subsequent treatment with DDQ provides the pyrrole and fused heterocyclic compounds in good yields.

Full text of DOI:10.1080/00397911.2018.1433301

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of functionalized pyrroles and
fused pyrroles through intermolecular [3 + 2]
cycloaddition reaction
Pulaganti Vijaya Prasad, Medi Shanker, Avudoddi Venkanna, Marapala
Kumara Swamy, K. Gopichand & Pallapothula Venkateswar Rao
To cite this article: Pulaganti Vijaya Prasad, Medi Shanker, Avudoddi Venkanna, Marapala
Kumara Swamy, K. Gopichand & Pallapothula Venkateswar Rao (2018): Synthesis of
functionalized pyrroles and fused pyrroles through intermolecular [3 + 2] cycloaddition reaction,
Synthetic Communications, DOI: 10.1080/00397911.2018.1433301
To link to this article: https://doi.org/10.1080/00397911.2018.1433301
View supplementary material
Published online: 27 Mar 2018.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2018.1433301
Synthesis of functionalized pyrroles and fused pyrroles
through intermolecular [3 + 2] cycloaddition reaction
Pulaganti Vijaya Prasad, Medi Shanker, Avudoddi Venkanna, Marapala Kumara Swamy,
K. Gopichand, and Pallapothula Venkateswar Rao
Department of Chemistry, Osmania University, Tarnaka, Hyderabad, Telangana, India
ABSTRACT
ARTICLE HISTORY
Received 23 December 2017
A
facile and efficient synthesis of pyrrole and pyrrole-fused
heterocyclic compounds has been demonstrated. The current
protocol involves the in situ generation of azomethine ylides which
undergoes intermolecular cycloaddition reaction and subsequent
treatment with DDQ provides the pyrrole and fused heterocyclic
compounds in good yields.
KEYWORDS
1,3-Dipolar intermolecular
cycloaddition; azomethine
ylides; Baylis–Hillman
adducts; DDQ
GRAPHICAL ABSTRACT
Introduction
The cycloaddition reactions have emerged as a powerful synthetic strategy in modern
organic synthesis as it provides an easy access for the rapid construction of complex
carbocyclic and heterocyclic molecular architectures.[1] In particular, the dipolar [3 þ 2]
cycloadditions had attracted much attention in the recent years due to their wide range
of applications in the synthesis of diversely functionalized five-membered heterocyclic
compounds of biological importance.[2] The azomethine ylides generated in situ undergoes
1,3 dipolar cycloaddition reaction with the reactive partners to afford the corresponding
pyrrolidine derivatives, which can also be further modified chemically to obtain pyrrole
derivatives.[3]
Pyrrole and pyrrole-fused heterocyclic compounds constitute a significant class of
heterocyclic compounds owing to their occurrence in various natural products and
bioactive synthetic molecules.[4] These compounds are used as intermediates in the syn-
thesis of natural products[5] and functionalized heterocyclic derivatives.[6] Furthermore,
they also exhibit various promising biological activities such as cytotoxic,[7] anticancer,[8]
antimicrobial activity.[9] Therefore, the development of novel, simple, and efficient
synthetic strategies for synthesis of pyrrole and its derivatives have been of continuous
interest. Herein we wish to report a facile protocol for the synthesis of pyrrole and
CONTACT Pallapothula Venkateswar Rao
pallapothulavrao@gmail.com
Department of Chemistry, Osmania
University, Tarnaka, Hyderabad, Telangana 500007, India.
Supplemental data (Full experimental detail, H, 13C NMR, FT-IR, mass spectra and elemental analysis data of pyrroles
and fused pyrroles) can be accessed on the publisher’s website.
1
© 2018 Taylor & Francis

2
P. V. PRASAD ET AL.
pyrrole-fused derivatives through the intermolecular dipolar [3 þ 2] cycloaddition
reaction.
Results and discussion
Baylis–Hillman adducts are versatile synthons, which are successfully used as intermediates
in the synthesis of various natural and synthetic organic molecules.[10] From the literature,
it is clear that the Baylis–Hillman adducts were also exploited effectively in the cycloaddi-
tion reactions.[11] We envisioned that the (E)-2-formyl-3-phenylacrylonitrile (1a), which
can be synthesized easily from the corresponding Baylis–Hillman alcohol[12], can
participate in the [3 þ 2] cycloaddition reaction with sarcosine, proline, and diethyl
aminomalonate hydrochloride. Accordingly, we synthesized the substrates 1a–c following
the procedure reported in the literature.[12] Initially we performed a model reaction, where
the substrate 1a and sarcosine were dissolved in CH3CN, allowed heat to reflux in presence
of 4 Ǻ molecular sieves (MS) for 6 h. After completion of reaction as shown by TLC, DDQ
was added and heated to reflux for further 2 h. The reaction mixture was subjected to usual
workup and purification of crude reaction mixture by silica gel column chromatography
afforded the desired functionalized pyrrole derivative 2a in 88% yield (Scheme 1). The
1
product thus obtained was confirmed by H and 13C NMR analysis.
Encouraged with preliminary result, we proceeded to explore the reactivity of 1b and 1c
with sarcosine under the standard reaction conditions, both the reactions underwent
smoothly to obtain the products 2b and 2c in 85 and 83% yields, respectively. Further,
we focused on investigating the reactivity of 1a–c with proline under similar conditions.
The reaction of 1a with proline underwent effectively to obtain the pyrrole-fused derivative
3a in 84% yield. The reactions of 1b and 1c with proline also delivered the expected
products in 79 and 81% yields, respectively (Scheme 2).
To explore the applicability of current protocol, we have also examined the reactivity of
1a and 1b with diethyl aminomalonate hydrochloride. The reaction of 1a with diethyl
aminomalonate hydrochloride in acetonitrile was performed at reflux temperature for
5 h, we were pleased to observe that the reaction proceeded cleanly and afforded the
desired product 4a in 76% yield. Under similar reaction conditions, 1b reacted with diethyl
Scheme 1. Synthesis of functionalized pyrroles through intermolecular 1,3-dipolar cycloaddition
a
reactiona,b. Note: All the reactions were performed with 1.0 mmol (1a,b&c), 1.0 mmol (sarcosine, proline,
b
and diethyl aminomalonate hydrochloride) in 5 mL of aceto nitrile. Yields of pure and isolated product
after column chromatography.

SYNTHETIC COMMUNICATIONS®
3
Scheme 2. Synthesis of functionalized fused pyrroles through intermolecular 1,3-dipolar cycloaddition
a
reactiona,b. Note: All the reactions were performed with 1.0 mmol (1a,b&c), 1.0 mmol (sarcosine, proline,
b
and diethyl aminomalonate hydrochloride) in 5 mL of aceto nitrile. Yields of pure and isolated product
after column chromatography.
Scheme 3. Synthesis of functionalized pyrroles through intermolecular 1,3-dipolar cycloaddition
a
reactiona,b. Note: All the reactions were performed with 1.0 mmol (1a&b), 1.0 mmol (sarcosine, proline,
b
and diethyl aminomalonate hydrochloride) in 5 mL of aceto nitrile. Yields of pure and isolated product
after column chromatography.
aminomalonate hydrochloride also delivered the expected product in 80% yield,
1
respectively (Scheme 3). All the products are confirmed by analysis of IR, H, 13C NMR,
and mass spectral data.
Conclusion
We have successfully developed a clean and facile protocol for the synthesis of densely
functionalized pyrrole and pyrrole-fused heterocyclic compounds through 1,3 dipolar
intermolecular cycloaddition reactions from the Baylis–Hillman adducts. The current pro-
tocol is easy to handle and can be performed under catalyst-free reaction conditions.
Experimental section
General information: All starting materials were purchased from Sigma-Aldrich and Fluka
was used without any further purification. All experiments were performed under air. Col-
umn chromatography was performed with silica gel 60–120-sized mesh using hexane and
ethylacetate as eluents. Analytical TLC was performed with silica gel 60 F254 plates

4
P. V. PRASAD ET AL.
1
(Merck), and the products were visualized by UV detection. H-NMR and 13C-NMR were
recorded on Bruker Avance 400 MHz. All the spectra were recorded in CDCl3 using TMS
as internal standard. Chemical shifts (δ) are reported in ppm and spin–spin coupling con-
stants (J) are in Hz. Melting points were determined on a Fischer-Johns melting point
apparatus. IR was recorded on a Thermo Nicolet Nexus 670 FTIR spectrometer and Fin-
negan MAT 1020 mass spectrometer operating at 70 eV.
General procedure: The substrates (E)-2-formyl-3-phenylacrylonitrile (1a) (1.0 mmol)
and sarcosine (1.0 mmol) were dissolved in CH3CN (5 mL) and allowed heat to reflux in
presence of 4 Ǻ molecular sieves (MS) for 6 h. After completion of reaction as shown by
TLC, DDQ was added and heated to reflux for further 2 h. The reaction mixture was
subjected to usual workup and purification of crude reaction mixture by silica gel
column chromatography afforded the desired functionalized pyrrole derivative 1-methyl-
4-phenyl-1H-pyrrole-3-carbonitrile (2a) in 88% yield (Scheme 1). NMR data and
elemental analysis data of the 1-methyl-4-phenyl-1H-pyrrole-3-carbonitrile (2a) were pro-
1
vided as follows: H NMR (400 MHz, CDCl3):7.64-7.57 (m, 2H), 7.39 (t, J ¼ 7.7 Hz, 2H),
7.30-7.26 (m, 1H), 7.14 (d, J ¼ 2.2 Hz, 1H), 6.79 (d, J ¼ 2.2 Hz, 1H), 3.70 (s, 3H)ppm; 13C
NMR (100 MHz, CDCl3): 36.99, 91.13, 116.87, 120.23, 126.41, 127.12, 127.66, 128.87,
130.22, 132.78.ppm; Anal. Calcd for C12H10N2: C, 79.10; H, 5.53; N, 15.37. Found: C,
79.21; H, 5.58; N, 15.29.
Funding
The authors thank the Council of Scientific and Industrial Research New Delhi, India and University
Grants Commission New Delhi, India for financial assistance.
References
[1] a) Gandeepan, P.; Cheng, C.-H. Acc. Chem. Res. 2015, 48, 1194.
[2] a) Mathusalini, S.; Arasakumar, T.; Lakshmi, K.; Lin, C.-H.; Mohan, P. S.; Ramnath, M. G.;
Thirugnanasampandan, R. New J. Chem. 2016, 40, 5164. b) Sankar, U.; Kumar, C. V. S.
Subramanian, V.; Balasubramanian, K. K.; Mahalakshimi, S. J. Org. Chem. 2016, 81, 2340. c)
Kacprzak, K.; Skiera, I.; Piasecka, M,; Paryzek, Z. Chem. Rev. 2016, 116, 5689. d) Fraile, A.;
Alemán, J. Synlett 2015, 26, 1940. e) Nájera, C.; Sansano, J. M.; Yus, M. Org. Biomol. Chem.
2015, 13, 8596. f) Lima, C. G. S.; Ali, A.; van Berkel, S. S.; Westermann, B.; Paixão, M. W.
Chem. Commun. 2015, 51, 10784. g) Seidel, D. Acc. Chem. Res. 2015, 48, 317. h) Alonso, F.;
Moglie, Y.; Radivoy, G. Acc. Chem. Res. 2015, 48, 2516. i) Kumar, I. RSC Adv. 2014, 4, 16397.
[3] a) Kumari, S.; Singh, H.; Khurana, J. M. Tetrahedron Lett. 2016, 57, 3081. b) Jones, B.; Proud,
M.; Sridharan, V. Tetrahedron Lett. 2016, 57, 2811. c) Rajkumar, V.; Babu, S. A.; Padmavathi, R.
Tetrahedron 2016, 72, 5578. d) Ghandi, M.; Zarezadeh, N.; Abbasi, A. RSC Adv. 2016, 6, 67805.
e) Singh, M. S.; Chowdhury, S.; Koley, S. Tetrahedron 2016, 72, 1603. f) Ryan, J. H. ARKIVOC
2015, i, 160. g) Mantelingu, K.; Lin, Y.; Seidel, D. Org. Lett. 2014, 16, 5910. h) Lashgari, N.;
Ziarani, G. M. ARKIVOC 2012, i, 277.
[4] a) Nelli, M. R. Scheerer, J. R. J. Nat. Prod. 2016, 79, 1189. b) Han, L.; Gao, C.; Jiang, Y.; Guan,
P.; Liu, J.; Li, L.; Xu, L.; Huang, X. J. Nat. Prod. 2014, 77, 2605. c) Jansen, R.; Sood, S.; Mohr, K.
I.; Kunze, B.; Irschik, H.; Stadler, M.; Müller, R. J. Nat. Prod. 2014, 77, 2545. d) Patiño C, L. P.;
Muniain, C.; Knott, M. E.; Puricelli, L.; Palermo, J. A. J. Nat. Prod. 2014, 77, 1170.
[5] a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. b) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
[6] Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667.
[7] a) Kumar, R.; Lown, J. W. Eur. J. Med. Chem. 2005, 40, 641. b) Reddy, S. M.; Srinivasulu, M.;
Satyanarayana, N.; Kondapi, A. K.; Venkateswarlu, Y. Tetrahedron 2005, 61, 9242.

SYNTHETIC COMMUNICATIONS®
5
[8] Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S. Bioorg. Med. Chem. 2006, 14, 8162.
[9] Raimondi, M. V.; Cascioferro, S.; Schillaci, D.; Petruso, S. Eur. J. Med. Chem. 2006, 41, 1439.
[10] a) Santos, M. S.; Coelho, F.; Lima-Junior, C. G.; Vasconcellos, M. L. A. A. Curr. Org. Synth.
2015, 12, 830. b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447.
c) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005. d) Declerck, V.; Martinez, J.; Lamaty, F.
Chem. Rev. 2009, 109, 1. e) Xie, P.; Huang, Y. Org. Biomol. Chem. 2015, 13, 8578.
[11] a) Bakthadoss, M.; Srinivasan, J. RSC Adv. 2015, 5, 67206. b) Bakthadoss, M.; Vinayagam, V.
Org. Biomol. Chem. 2015, 13, 10007. c) Bakthadoss, M.; Kannan, D.; Srinivasan, J.; Vinayagam,
V. Org. Biomol. Chem. 2015, 13, 2870. d) Bakthadoss, M.; Devaraj, A. Tetrahedron Lett. 2015,
56, 3954. e) Bakthadoss, M.; Sivakumar, N.; Devaraj, A. Tetrahedron Lett. 2015, 56, 4980.
[12] Basavaiah, D; Kumaragurubaran, N.; Padmaja, K. Synlett, 1999, 10, 1630.