Tetrahedron Letters 53 (2012) 5483–5487

Contents lists available at SciVerse ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

CuCl catalyzed green and efficient one-pot synthesis of aminoindolizineframeworks via three-component reactions of aldehydes, secondary amines,and terminal alkynes in PEG

Sarita Mishra, Bikramaditya Naskar, Rina Ghosh ⇑Department of Chemistry, Jadavpur University, Kolkata 700 032, India

a r t i c l e i n f o

Article history:Received 14 June 2012Revised 23 July 2012Accepted 26 July 2012Available online 7 August 2012

Keywords:PEGHeterocyclesCyclizationCouplingAminoindolizidines

0040-4039/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2012.07.113

⇑ Corresponding author. Fax: +91 033 2414 6266.E-mail addresses: ghosh_rina@hotmail.com, ghosh

a b s t r a c t

CuCl catalyzes efficient synthesis of aminoindolizine scaffolds by one-pot reactions in PEG of pyridine- orquinoline-2-carboxaldehydes with secondary amines and terminal alkynes via tandem C–H activation,coupling, and cyclization reactions. The reactions are easy to perform, atom-economic, environmentfriendly, broad in scope, and allow the generation of a number of biologically potent aminoindolizineframeworks from readily accessible starting materials.

� 2012 Elsevier Ltd. All rights reserved.

N

CN

OON

N

N

O

MeO

O

N

HN

ON N

MeO5-HTIA receptor antagonist

The demand for protocol efficiency and green credentials in or-ganic synthesis can only be met through innovative research. Reac-tion procedures are expected to comprehensively address theissues of atom-economy, number of steps, and the avoidance ofauxiliary chemicals.1 Multi component reaction protocols in envi-ronmentally benign solvents coupled with the use of catalytic re-agent systems offer a suitable strategy to meet the greenrequirements while developing libraries of medicinal scaffolds.2

Polyethylene glycol happens to be one such solvent which meetsthe aforesaid requirements. This is on account of the fact that itis water soluble, thermally stable over a wide range of tempera-ture, insensitive to variation in catalytic systems, non-volatileand non-explosive by nature, commercially available, immisciblewith a number of organic solvents, and non-toxic.3 As a resultnumerous organic reactions utilizing PEG as solvent mediummay be found in the literature pertaining to syntheticmethodology.4

The indolizine nucleus is a noteworthy motif because it is foundas a key constituent in many bioactive compounds, some of whichare naturally occurring5,6 while others are only synthetically acces-sible. Besides, the indolizine nucleus has already established itselfas a potent pharmacophore exhibiting multiple pharmacologicalproperties7 (Fig. 1) like anti-inflammatory,7a anti-convulsant,7b

anti-tubercular,7c anti-leishmanial,7d herbicidal,7e anti-oxidant (li-

ll rights reserved.

rina@yahoo.com (R. Ghosh).

pid peroxidase inhibition),7f calcium entry blocker,7g histamineH3 receptor antagonist,7h and 5-HT1A receptor ligand.7i The nu-cleus has also been shown to have senescence delaying proper-ties,8a anti-HIV8b and anti-herpes8c activities. It even showsactive cardiovascular properties8d and is a CNS depression agent.8e

Indolizines have the ability to reverse multi-drug resistance8f andinduce apoptosis through a mitochondrial pathway against a broadrange of cancer cell lines.8g

Given the amount of applicability this framework commands onboth medicinal as well as industrial aspects. It is hardly an exagger-ation to state that considerable effort has already been devoted to-ward efficient synthesis of this nucleus. In this connection thesynthesis of amino indolizines has attracted much attention. Sev-eral synthetic protocols for the synthesis of indolizines have beenreported in the literature.9 Some of the methods worth notingare Chichibabin reaction of 1-(ethoxycarbonylmethyl)-2-meth-ylpyridinium chloride;9a 1,3 dipolar cycloaddition of a reactive

Anticonvulsant andantiinflammatory activity

OPDE5A inhibitor

N O N

histamine H3 receptor antagonist

Figure 1. Pharmacologically potent indolizine scaffolds.

NCHO

R3+ +NHR1

R2 PEG, 90 0C

(63-96 %)4a-4o

N

N

R3

R1R2

10 mol % CuCl

3-4 h, N21 2 3

Scheme 1. One-pot multicomponent synthesis of 1-aminoindolizines.

5484 S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487

dipole prepared from a substituted pyridinium salt and alkyne;9b

silver catalyzed cycloisomerization of propargyl heterocycles;9c

gold catalyzed migratory cycloisomerization of propargyl etherinto various types of 1,2-disubstituted N-fused heterocycles;9d

Pd-mediated coupling of aryl halide with propargylic esters orethers followed by cyclization;9e Cu-catalyzed reaction of pyridineand alkenyldiazoacetates;9f low temperature organo-copper medi-ated cross coupling/cycloisomerization of heterocyclic propargylmesylates;9g Pd/Cu activated sequential cross coupling/cycloiso-merization reactions of propargyl amines or amides with hetero-aryl bromide;9h Pd catalyzed intramolecular carbopalladation/cyclization of propargylic ethers or esters;9i microwave assistedthree-component reaction of acyl bromide, pyridine, and acety-lene9j and three-component coupling of pyridine-2-carboxalde-hyde, amine, and terminal alkyne (Au,10a AgBF4

10b or Fe(acac)3/TBAOH10c-catalyzed). One of the most convenient approachesamongst the aforesaid methods that attracted our attention wasthe three-component coupling of aldehydes, amines, and terminalacetylenes to form the highly potent aminoindolizines developedby Yan and Liu10a since such compounds are yet underexploredin terms of biological activities. It is indeed worth noting at thispoint that Cu-catalyzed reactions4f,11,12b have generated consider-able interest over the past decade for three-component coupling/cyclization of aldehydes, amines, and alkynes. In continuation ofour work on synthesis of heterocycles12 we report herein, an effi-cient, green, one pot method for the synthesis of 1-aminoindoli-zines and analogs via three-component coupling/cyclization ofaldehydes, secondary amines, and terminal alkynes catalyzed by

Table 1Screening of the catalyst and solvent in one-pot synthesis of 1-morpholinylindolizine

NCHO

Ph+ +NH

O

Entry Catalysta Solvent

1 FeCl3 Toluene2 In(OTf)3 Toluene3 Cu(OTf)2 Toluene4 Cu(OTf)2 PEG5 CuSO4 PEG6 CuI PEG7 CuCl PEG8 CuBr PEG9 CuCl2 PEG

10 CuO PEG11 Cu(OAc)2 PEG12 CuCl Toluene13 CuCl CH3CN14 CuCl DCE15 CuCl PEG16 CuClc PEG17 CuCl H2O

a 10 mol % of all the catalysts was used.b Standardization of reaction conditions: Pyridine-2-carboxaldehye (1.0 mmol), morpc 5 mol % CuCl was used.

CuCl in polyethylene glycol (PEG), and the results are summarizedin Scheme 1, Tables 1 and 2.

Keeping the coupling of pyridine-2-carboxaldehyde, morpho-line, and phenylacetylene as our model reaction a series of exper-iments were carried out with the aim of devising an improvedcatalyst system to reach the desired 1-aminoindolizine scaffold.We screened quite a few metal catalysts which included FeCl3, In(-OTf)3, and some salts of copper (I and II) such as its triflate, acetate,halides, and oxide (Table 1, entries 1–15). While FeCl3 in toluene(entry 1) altogether failed to yield the desired target, and In(OTf)3

in toluene afforded the corresponding product in 50% yield (Table 1,entry 2), Cu(OTf)2 and CuCl proved promising in their catalyticactivity keeping toluene as the reaction medium. In between thetwo aforesaid copper salts Cu(OTf)2 was found to give better yieldsof 1-aminoindolizine. In order to give due regard to the green cre-dentials as well as to the eco safety of the protocol we shifted oursolvent from toluene to PEG. We observed quite interestingly, thatCuCl surpassed Cu(OTf)2 in terms of the yield of the product gener-ated (entries 4 and 7). Alternative solvents like CH3CN and DCE(Table 1, entries 13 and14) were also tested (for the model reac-tion) but better results were obtained using 10 mol % of CuCl inPEG medium (entries 7 and 12–17). However, CuCl could not cat-alyze our model reaction at room temperature. Decreasing the cat-alyst load of CuCl from 10 to 5 mol % decreases the yield of 4bconsiderably (Table 1, entry 16).

Thus, under the optimized reaction condition pyridine-2-car-boxaldehyde (1a, 1.0 mmol), morpholine (1.2 mmol), and phenyl-acetylene (1.5 mmol) in the presence of 10 mol % of CuCl in PEGat 90 �C afforded the corresponding 1-aminoindolizine product(4a) in excellent yield (Table 2, entry 1). With the optimizedreaction conditions in hand, the generality of the protocol wasassessed by the synthesis of diversely substituted 1-aminoindoli-zines. This was achieved through variations (in the startingmaterials) between pyridine-2-carboxaldehyde (1a) and quino-line-2-carboxaldehyde (2b) and their reactions with various sec-ondary amines and a number of different terminal alkynes.Initially, keeping the first two components pyridine-2-carboxal-

NPh

NCatalystSolventTemp.

O

Condition Time (h) Yieldb (%)

Reflux 12 —Reflux 12 50Reflux 3 7590 �C 3 8290 �C 3 8090 �C 3 8090 �C 3 9690 �C 3 8290 �C 3 7090 �C 6 —90 �C 4 61Reflux 4 62Reflux 4 65Reflux 4 50rt 24 —90 �C 4 7090 �C 3 45

holine (1.2 mmol), and phenylacetylene (1.5 mmol) under N2 atmosphere.

Table 2One-pot synthesis of aminoindolizines13,14

NCHO

R3+ +NHR1

R2 PEG, 90 0C4

N

N

R3

R1R2

10 mol % CuCl

3-4 h, N21 2 3

Entry Aldehyde Amine Alkyne Product Time (h) Yielda,b (%)

1 N CHO1a

NH

O

2aPh 4a 3 96 (96,10a 91,10b 8310c)

2 1a 2a 4-Me-Ph 4b 3 92 (90,10b 8310c)3 1a 2a 4-F-Ph 4c 3 854 1a 2a 4-Cl-Ph 4d 3 895 1a 2a Biphenyl 4e 4 786 1a 2a C6H13 4f 4 73

7 1a NH2b

4-Cl-Ph 4g 3 85 (88,10a 7210c)

8 1a 2b C6H13 4h 3 70 (6610a)

9 1aNH2d

Ph 4i 3 85

10 1a NHPh

Me2e Ph 4j 4 71 (2810a)

11 1a 2e 4-Me-Ph 4k 4 81

12 1ac NHHN

2gPh 4ld 3 63 (52,10a 5710c)

13 N CHO1b

NH

O

2aPh 4m 4 90 (8810b)

14 1b 2a 4-Me-Ph 4n 3 92

15 1bNH2b

Ph 4o 4 90 (74,10a 7010c)

a Yield of isolated pure product.b Yield of reported compounds are listed in the parentheses with corresponding references.c 1a (2 equiv), 2g (1.2 equiv), and phenylacetylene (1.5 equiv).d Bis-indolizine.

S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487 5485

dehyde and morpholine of our model reaction intact, we variedthe substitution pattern on the phenyl group of the phenylacet-ylene. It was found that groups having +I effect (entry 2) or +Reffects (Table 2, entries 3 and 4) as well as �I effect (entry 5)led to the corresponding products in good to excellent yields.Aliphatic terminal alkyne like 1-octyne was found to reactuneventfully with pyridine-2-carboxaldehyde (1a) and morpho-line generating the corresponding product in 73% yield (Table 2,entry 6). Cyclic amines like piperidine coupled with pyridine-2-carboxaldehyde (1a) and terminal alkynes like 4-chlorophenyl-acetylene (entry 7) and 1-octyne (entry 8) to give the respectiveproducts, 4g in comparable yield to that reported earlier10a and4h in much improved yield in comparison to the reported one.10c

Both dicyclohexylamine (2d, entry 9) and methylphenylamine(2e, entry 10) reacted fruitfully with pyridine-2-carboxaldehyde(1a) and phenylacetylene pair to afford the corresponding prod-ucts in good yields; it is worthy to note that product 4j (entry10) was obtained in much better yield (71%) compared to that(28%) obtained before.10a Methylphenylamine (2e) also reactedsuccessfully with pyridine-2-carboxaldehyde and 4-methyl phen-

ylacetylene to produce the corresponding product in high yield(Table 2, entry 11). Of specific note was the coupling of pipera-zine with 1a and phenylacetylene resulting in the correspondingbis-indolizine moiety 4l in good yield (entry 12) which was bet-ter than those reported earlier.10a,c Similarly, quinoline-2-carbox-aldehyde was also coupled fruitfully under the optimizedprotocol with morpholine/piperidine (Table 2, entry 13/15) inthe presence of phenylacetylene to give the corresponding prod-ucts, 4m in comparable yield (entry 13) with respect to that pro-duced by the reported method based on morpholine10b but 4o inmuch better yield (entry 15) compared to those reported beforebased on piperidine.10a,c The yield of the product was not af-fected upon shifting to 4-methylphenylacetylene (Table 2, entry14).

Single crystal X-ray analysis conclusively confirmed the struc-ture of the isolated 1-aminoindolizine (4b) product.15 An ORTEPdiagram of 4b is shown in Figure 2.

The formation of aminoindolizine can be explained by a tenta-tive mechanism (Scheme 2) in which probably the activation ofC–H bond of phenylacetylene by CuCl is taking place and the cop-

Figure 2. ORTEP diagram of 4b.

Ph

Ph

Cu N

O

PhN5-endo digCyclisation

NPh

N

OCuCl

H

HPh

NCHO

+ NH

ON

O

N H2O

HCl

BA 1a

2aC

4a3a

NPh

N

O

H

CuCl

-H+

+H+D+CuCl

Cu

Cl-

Scheme 2. Proposed mechanism.

5486 S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487

per acetylide intermediate A is generated. A reacts with iminiumion B, in situ generated by the reaction of pyridine-2-carboxalde-hyde (1a) with morpholine (2a), producing the correspondingpropargylamine C. It then undergoes cyclization (5 endo-dig) togive finally 1-morpholinylindolizine product (4a).

In summary, a facile, economic, and green protocol for a one-potmulticomponent synthesis of the biologically potent indolizinescaffold has been described by the reaction of pyridine-2-carboxal-dehyde/quinoline-2-carboxaldehyde, secondary amines, and ter-minal alkynes. The salient features in favor of the presentprocedure being greater operational simplicity, low reaction time,and general high isolated yields of products. In addition, the useof a non-toxic and inexpensive catalytic system and a non-hazard-ous solvent system greatly augments the green credentials of thepresent protocol for its further ramification for large scale produc-tion of these pharmacologically potent heterocyclic compounds.Biological screening of some of the tailor-made aminoindolizinesand analogs is underway for future publication.

Acknowledgments

S.M. (SRF) and B.N. (JRF) are grateful to UGC and CSIR, India,respectively for their research fellowships. CAS-UGC and FIST-DST, New Delhi, India are acknowledged for supporting researchfacilities to the Department of Chemistry, Jadavpur University.

References and notes

1. (a) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010–3021; (b) Kumaravel, K.; Vasuki, G. Green Chem. 2009, 11, 1945–1947; (c)Gupta, A. K.; Kumari, K.; Singh, N.; Raghuvanshi, D. S.; Singh, K. N. TetrahedronLett. 2012, 53, 650–653; (d) Kumaravel, K.; Vasuki, G. Curr. Org. Chem. 2009, 13,1820–1841.

2. Reviews on one-pot multicomponent syntheses: (a) Armstrong, R. W.; Combs,A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123–131; (b) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (c) Zhu,J. Eur. J. Org Chem. 2003, 1133–1144; (d) Ramón, D. J.; Yus, M. Angew. Chem., Int.Ed. 2005, 44, 1602–1634; (e) Dömling, A. Chem. Rev. 2006, 106, 17–89; (f)Chapman, C. J.; Frost, C. G. Synthesis 2007, 1–21.

3. (a) Dickerson, T. J.; Reed, N. N.; Janada, K. D. Chem. Rev. 2002, 102, 3325–3344;(b) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green Chem. 2005, 7, 64–82; (c) Heldebrant, D.; Jessop, P. G. J. Am. Chem. Soc. 2003, 125, 5600–5601.

4. (a) Jain, S. L.; Singhal, S.; Sain, B. Green Chem. 2007, 9, 740–741; (b) Suryakiran,S.; Reddy, T. S.; Ashalatha, K.; Lakshman, M.; Venkateswarlu, Y. TetrahedronLett. 2006, 47, 3853–3856; (c) Smith, C. B.; Raston, C. L.; Sobolev, A. N. GreenChem. 2005, 7, 650–654; (d) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S.;Reddy, N. R. Chem. Commun. 2003, 1716–1717; (e) Smith, N. M.; Raston, C. L.;Smith, C. B.; Sobolev, A. N. Green Chem. 2007, 9, 1185–1190; (f) Zhang, Q.; Chen,J.-X.; Ding, J.-C.; Wu, H.-Y. Appl. Organomet. Chem. 2010, 24, 809–812; (g)Verma, S.; Jain, S. L.; Sain, B. Beil. J. Org. Chem. 2011, 7, 1334–1341.

5. (a) Pyne, S. G. Curr. Org. Synth. 2005, 2, 39–57; (b) Honda, T.; Namiki, H.;Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035–3058; (c) Wei, L.;Drossi, A.; Morris-Natschke, S. L.; Bastow, K. F.; Lee, K. H. In Studies in NaturalProducts Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York, 2008; Vol. 34, pp3–34; (d) Toyooka, N.; Zhou, D.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly,W.; John, W. Beil. J. Org. Chem. 2007, 3, 29; (e) Marsden, S. P.; McElhinney, A. D.Beil. J. Org. Chem. 2008, 4, 8; (f) Zumino, F.; Kotchevar, A. T.; Waring, M.; Daoudi,M.; Larbi, N. B.; Mimouni, M.; Sam, N.; Zahidi, A.; Ben-Hadda, T. Molecules 2002,7, 628–640; (g) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A. E. J. Org.Chem. 2006, 65, 6966–6972; (h) Diederich, M.; Nubbemeyer, U. Synthesis 1999,286–289; (i) Chalard, P.; Remuson, R.; Mialhe, Y. G.; Gramain, J. C.; Canet, I.Tetrahedron Lett. 1999, 40, 1661–1664; (j) Park, S. H.; Kang, H. J.; Ko, S.; Park, S.;Chang, S. Tetrahedron: Asymmetry 2001, 12, 2621–2624.

6. (a) Facompré, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.; Manzanares, I.;Cuevas, C.; Baily, C. Cancer Res. 2003, 63, 7392–7399; (b) Vanhuyse, M.; Kluza,J.; Tardy, C.; Otero, G.; Cuevas, C.; Bailly, C.; Lansiaux, A. Cancer Lett. 2005, 221,165–175.

7. (a) Dawood, K.; Abdel-Gawad, H.; Ellithey, M.; Mohamed, H. A.; Hegazi, B. Arch.Pharm. 2006, 339, 133–140; (b) Krall, R. L.; Penry, J. K.; White, B. G.; Kupferberg,H. J.; Swinyard, E. A. Epilepsia 1978, 19, 409–428; (c) Gundersen, L.-L.; Negussie,A. H.; Rise, F.; Østby, O. B. Arch. Pharm. Pharm. Med. Chem. 2003, 336, 191–195;(d) Gunderson, L.-L.; Charnock, C.; Negussie, A. H.; Rise, F. Eur. J. Pharm. Sci.2007, 30, 26–35; (e) Smith, S. C.; Clarke, E. D.; Ridley, S. M.; Bartlett, D.;Greenhow, D. T.; Glithro, H.; Klong, A. Y.; Mitchell, G.; Mullier, G. W. PestManag. Sci. 2005, 61, 16–24; (f) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise,F.; Bast, A.; Haenen, G. R. M. Eur. J. Org. Chem. 2000, 3763–3769; (g) Poty, C.;Gibon, V.; Evrard, G.; Norberg, B.; Vercauteren, D. P.; Gubin, J.; Chatelain, P.;Durant, F. Eur. J. Org. Chem. 1994, 29, 911–923; (h) Chai, W.; Breitenbucher, J.G.; Kwok, A.; Li, X.; Wong, V.; Carruthers, T. W.; Lovenberg, T. W.; Mazur, C.;Wilson, S. J.; Axe, F. U.; Jones, T. K. Bioorg. Med. Chem. Lett. 2003, 13, 1767–1770;(i) Gmeiner, P.; Huebner, H.; Bettinetti, L.; Schlotter, K. PCT Int. Appl. WO015737, 2006.

8. (a) Wang, P.; Zhang, Z.; Ma, X.; Huang, Y.; Liu, X.; Tu, P.; Tong, T. Mech. AgeingDev. 2003, 124, 1025–1034; (b) Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson,P.; Perez, C.; Manzanares, I.; Cuevas, C.; Baily, C. Cancer Res. 2003, 63, 7392–7399; (c) Foster, C.; Ritchie, M.; Selwood, D. L.; Snowden, W. Antivir. Chem.Chemother. 1995, 6, 289–297; (d) Gubin, J.; Descamps, M.; Chatelain, P.; Nisato,D. Eur. Pat. Appl. EP 235111, 1987.; (e) Harrell, W. B. J. Pharm. Sci. 1970, 59,275–277; (f) Pla, D.; Marchal, A.; Olsen, C. A.; Francesch, A.; Cuevas, C.;Albericio, F.; Alvarez, M. J. Med. Chem. 2006, 49, 3257–3268; (g) Ballot, C.;Kluza, J.; Martoriati, A.; Nyman, U.; Formstecher, P.; Joseph, B.; Bailly, C.;Marchetti, P. Mol. Cancer Ther. 2009, 8, 3307–3317.

9. (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. In Comprehensive HeterocyclicChemistry; Pergamon: Oxford, 1996; Vol. 8, pp 237–257.; (b) Gandaségui, M. T.;Alvarez-Builla, J. J. Chem. Res. 1986, 74–75; (c) Seregin, I. V.; Schammel, A. W.;Gevorgyan, V. Org. Lett. 2007, 9, 3433–3436; (d) Seregin, I. V.; Gevorgyan, V. J.Am. Chem. Soc. 2006, 128, 12050–12051; (e) Chernyak, D.; Skontos, C.;Gevorgyan, V. Org. Lett. 2010, 12, 3242–3245; (f) Barluenga, J.; Lonzi, G.;Riesgo, L.; López, L. A.; Tomás, M. J. Am. Chem. Soc. 2010, 132, 13200–13202; (g)Chernyak, D.; Gadamsetty, S. B.; Gevorgyan, V. Org. Lett. 2008, 10, 2307–2310;(h) Liu, Y.; Song, Z.; Yan, B. Org. Lett. 2007, 9, 409–412; (i) Chernyak, D.;

S. Mishra et al. / Tetrahedron Letters 53 (2012) 5483–5487 5487

Gevorgyan, V. Org. Lett. 2010, 12, 5558–5560; (j) Bora, U.; Saikia, A.; Boruah, R.C. Org. Lett. 2003, 5, 435–438.

10. (a) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323–4326; (b) Bai Gorityala, B. K.; Liu, X.-W. J. Comb. Chem. 2010, 12, 696–699; (c) Patil, S. S.; Patil, S. V.; Bobade, V. D.Synlett 2011, 2379–2383.

11. (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743–2746; (b)Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107–1110; (c) Park, S. B.; Alper,H. Chem. Commun. 2005, 1315–1317; (d) Patil, M. K.; Keller, M.; Reddy, B. M.;Pale, P.; Sommer, J. Eur. J. Org. Chem. 2008, 26, 4440–4445; (e) Kantam, M. L.;Bhargava, S. Tetrahedron Lett. 2008, 49, 3083–3086.

12. (a) Mishra, S.; Ghosh, R. Tetrahedron Lett. 2011, 52, 2857–2861; (b) Mishra, S.;Ghosh, R. Synthesis 2011, 3463–3470; (c) Mishra, S.; Ghosh, R. Synth. Commun.2011, 42, 2229–2244; (d) Mishra, S.; Ghosh, R. Indian J. Chem. 2011, 50B, 1630–1636; (e) Ghosh, R.; Chakraborty, A.; Maiti, D. K.; Puranik, V. G. Org. Lett. 2006,6, 1061–1064; (f) Roy, S.; Chakraborty, A.; Chattopadhyay, B.; Bhattacharya, A.;Mukherjee, A. K.; Ghosh, R. Tetrahedron 2010, 66, 8512–28521.

13. Typical experimental procedure: Pyridine-2-carboxaldehye (107.12 mg,1.0 mmol), CuCl (9.9 mg, 0.1 mmol), morpholine (104.5 mg, 1.2 mmol), andphenylacetylene (153.2 mg, 0.16 mL, 1.5 mmol) were sequentially taken in a10 mL flask followed by PEG (2 mL). The resulting reaction mixture was thenstirred at 90 �C in oil bath under N2 atmosphere until completion of thereaction (3 h, as monitored by TLC). Cold water (40 mL) was added to thereaction mixture, and the product was extracted with ethyl acetate(3 � 20 mL). The organic layer was washed with water, dried over anhydrousNa2SO4, and then the solvent was evaporated under vacuum. The crudeproduct obtained was purified by flash chromatography on silica gel column(230–400 mesh) using ethyl acetate-petroleum ether as eluent to afford thepure indolizine product (4a, 267 mg, 96% yield). Spectroscopic data (IR, 1HNMR, 13C NMR and HRMS) are in good agreement with the product structure.This procedure was followed for the synthesis of all other 1-amino indolizinederivatives and their analogs (4b–4o), Table 2).Characterization data of some representative compounds:3-(4-Flurophenyl)-1-(morpholin-4-yl)indolizine (4c): Yellow solid; mp 78–80 �C.

1H NMR (500 MHz, C6D6): d 7.72 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 9.0 Hz,1H), 7.07(dd, J = 5.5 Hz, 8.0 Hz, 2H), 6.83 (d, J = 5.1 Hz, 2H), 6.55 (s, 1H), 6.36 (dd,J = 6.5 Hz, 8.5 Hz, 1H), 6.06 (t, J = 6.5 Hz, 1H), 3.77 (t, J = 4.5 Hz, 4H), 2.88 (t,J = 4.5 Hz, 4H). 13C NMR (125 MHz, C6D6): d = 130.3, 129.8, 129.7, 128.84,128.82, 125.8, 121.6, 121.4, 118.0, 115.9, 115.8, 114.7, 111.0, 106.2, 67.3, 54.5.IR (KBr) (mmax/cm�1): 2978, 2863, 2826, 1627, 1517, 1451, 1431, 1306, 1222,1111. ESI-HRMS: Calcd for C18H18FN2O [M+H]+: 297.1403. Found: 297.1398.3-(Biphenyl)-1-(morpholin-4-yl)indolizine (4e): Yellow solid, mp 168–169 �C.1H NMR (500 MHz, C6D6): d 7.98 (d, J = 7.0 Hz, 1H), 7.52 (q, J = = 8.0 Hz, 4H),7.45 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.26 (t, J = = 7.5 Hz, 2H), 7.16–7.18 (m, 1H), 6.72 (s, 1H), 6.36 (dd, J = 6.5 Hz, 8.5 Hz, 1H), 6.08 (t, J = 7.0 Hz,1H), 3.76 (t, J = 4.5 Hz, 4H), 2.89 (t , J = 4.0 Hz, 4H). 13C NMR (125 MHz, C6D6): d140.9, 139.7, 131.8, 130.6, 128.97, 128.3, 127.4, 127.1, 126.2, 122.5, 121.8,118.1, 114.8, 111.0, 106.3, 63.4, 54.5. IR (KBr) (mmax/cm�1): 2948, 2976, 2863,2806, 1608, 1527, 1432, 1258, 1111, 1074. ESI-HRMS: Calcd for C24H22N2O[M]+: 354.1732. Found: 354.1733.N-Methyl-N-phenyl-[3-(4-methylphenyl)-indolizin-1-yl]amine (4l): Yellow solid;mp 91 �C 1H NMR (500 MHz, C6D6): d 7.96 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz,2H), 7.17 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.82(d, J = 8.0 Hz, 2H), 6.77 (t, J = 7.0 Hz, 1H), 6.68 (s, 1H), 6.26 (dd, J = 6.5 Hz,8.5 Hz, 1H), 6.00 (t, J = 6.8 Hz, 1H), 3.11 (s, 3H), 2.12 (s, 3H). 13C NMR (125 MHz,C6D6): d 150.5, 136.6, 129.62, 129.55, 129.0, 128.4, 128.1, 124.0, 123.3, 122.0,117.6, 117.1, 116.2, 113.4, 111.9, 110.6, 40.4, 20.9. IR (KBr) (mmax/cm�1): 3098,3058, 2994, 2806, 2363, 1925, 1596, 1523, 1499, 1432, 1345, 1297, 1109. ESI-HRMS: Calcd for C22H20N2 [M]+: 312.1626. Found: 312.1627.

14. The aminoindolizines and analogs (4a–4o) were found to decompose at roomtemperature, indicated by a change of coloration from yellow to brown whenexposed to air.

15. Crystallographic data (excluding structure factor) for 4b have been depositedwith the Cambridge Crystallographic Data Centre as SupplementaryPublication No. CCDC 886132. Copies of the data can be obtained, free ofcharge, on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (fax:+44 (0) 1223336033 or e-mail: deposit@ccdc.cam.ac.UK).