Nihat Çelebi, Selçuk Gümüş, Lemi Türker, Mustafa Kemal Bayazıt

An experimental and theoretical approach to synthesis of novel indolizine type heterocycles

Indolizine derivatives are interesting due to their anti-inflammatory and antioxidant properties as well astheir known fluorescent properties. Theoretical studies supported by the experimental evidences can shedlight on the fundamental understanding of the versatility of the synthetic approaches. Herein, 1,3-dipolarcycloaddition reactions of three pyridinium ylides with seven dipolarophiles was studied theoretically atFMO level (PM3-RHF calculations) for the first time. The theoretical studies suggested a more probablereaction of pyridinium ylides with the dipolarophiles such as vinyl acetate and vinylene carbonate.However, the ylides have reacted only with dimethyl acetylenedicarboxylate and diethyl acetylenedicarboxylate, indicative of the effect of other reaction parameters (e.g. solvent, temperature etc.).Experimentally, only six indolizine heterocycles, two of which are not reported previously (18 and 19),were synthesized and theoretical predictions were further compared with experimental findings. Thestructural analysis of synthesized indolizine compounds was performed by 1H NMR, FTIR, GC-MS andelemental analysis.

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[1]. Attalah, KM, Abdalla AN, Aslam A, Ahmed M, Abourehab MAS, ElSawy NA, Gouda AM. 2020. Ethyl benzoate bearing pyrrolizine/indolizine moieties: Design, synthesis and biological evaluation of anti-inflammatory and cytotoxic activities. Bioorganic Chemistry; 94.
[2]. Venugopala, KN, Tratrat C, Pillay M, Mahomoodally FM, Bhandary S, Chopra D, Morsy MA, Haroun M, Aldhubiab BE, Attimarad M, Nair AB, Sreeharsha N, Venugopala R, Chandrashekharappa S, Alwassil OI, Odhav B. 2019. AntiTubercular Activity of Substituted 7-Methyl and 7- Formylindolizines and In Silico Study for Prospective Molecular Target Identification. Antibiotics-Basel; 8.
[3]. Liu, YS, Shao EX, Zhang ZY, Yang DJ, Li GT, Cao H, Huang HL. 2019. A Novel Indolizine Derivative Induces Apoptosis Through the Mitochondria p53 Pathway in HepG2 Cells. Frontiers in Pharmacology; 10.
[4]. Gayton, J, Autry SA, Meador W, Parkin SR, Hill GA, Hammer NI, Delcamp JH. 2019. Indolizine-Cyanine Dyes: Near Infrared Emissive Cyanine Dyes with Increased Stokes Shifts. Journal of Organic Chemistry; 84: 687-697.
[5]. Sung, J, Lee Y, Cha JH, Park SB, Kim E. 2017. Development of fluorescent mitochondria probe based on 1,2-dihydropyrrolo 3,4-b indolizine-3-one. Dyes and Pigments; 145: 461-468.
[6]. Ge, YQ, Liu AK, Dong J, Duan GY, Cao XQ, Li FY. 2017. A simple pH fluorescent probe based on new fluorophore indolizine for imaging of living cells. Sensors and Actuators BChemical; 247: 46-52.
[7]. Bayazit, MK, Coleman KS. 2009. Fluorescent Single-Walled Carbon Nanotubes Following the 1,3-Dipolar Cycloaddition of Pyridinium Ylides. Journal of the American Chemical Society; 131: 10670-10676.
[8]. Bayazit, MK, Coleman KS. 2014. Synthesis and characterization of a substituted indolizine and investigation of its photoluminescence quenching via electron-deficient nitroaromatics. Arkivoc: 362-371.
[9]. Bayazit, MK, Palsson LO, Coleman KS. 2015. Sensing properties of light-emitting single walled carbon nanotubes prepared via click chemistry of ylides bound to the nanotube surface. Rsc Advances; 5: 36865-36873.
[10]. Bode, ML, Kaye PT, George R. 1994. Indolizine studies. Part 3. Synthesis and dynamic NMR analysis of indolizine-2- carboxamides. Journal of the Chemical Society, Perkin Transactions 1: 3023-3027.
[11]. Hagishita, S, Yamada M, Shirahase K, Okada T, Murakami Y, Ito Y, Matsuura T, Wada M, Kato T, Ueno M, Chikazawa Y, Yamada K, Ono T, Teshirogi I, Ohtani M. 1996. Potent Inhibitors of Secretory Phospholipase A2: Synthesis and Inhibitory Activities of Indolizine and Indene Derivatives. Journal of Medicinal Chemistry; 39: 3636-3658.
[12]. Sharma, V, Kumar V. 2014. Indolizine: a biologically active moiety. Medicinal Chemistry Research; 23: 3593-3606.
[13]. Dohmen, C, Ihmels H, Kreienmeier R, Patrick BO. 2019. Synthesis of a crystallochromic indolizine dye by a base- and catalyst-free photochemical route. Chemical Communications; 55: 11071-11074.
[14]. Bertallo, CRD, Arroio TR, Toledo M, Sadler SA, Vessecchi R, Steel PG, Clososki GC. 2019. C-H Activation/Metalation Approaches for the Synthesis of Indolizine Derivatives. European Journal of Organic Chemistry; 2019: 5205-5213.
[15]. Padwa, A. 1,3-Dipolar cycloaddition chemistry; John Wiley and Sons: New York, 1986; pp 817.
[16]. Katritzky, AR, Qiu G, Yang B, He H-Y. 1999. Novel Syntheses of Indolizines and Pyrrolo[2,1-a]isoquinolines via Benzotriazole Methodology. The Journal of Organic Chemistry; 64: 7618-7621.
[17]. Ramesh, V, Devi NS, Velusamy M, Shanmugam S. 2019. Catalyst free Synthesis of Highly Functionalized Indolizines from In Situ Generated Pyridinium Ylides via One-Pot Multicomponent Reaction. Chemistryselect; 4: 3717-3721.
[18]. 18. Zhang, D, Lin LL, Yang J, Liu XH, Feng XM. 2018. Asymmetric Synthesis of Tetrahydroindolizines by Bimetallic Relay Catalyzed Cycloaddition of Pyridinium Ylides. Angewandte Chemie-International Edition; 57: 12323-12327.
[19]. 19. Katritzky, AR, Grzeskowiak NE, Alvarezbuilla J. 1981. Preparation of Tetrahydroindolizines From Pyridinium and Isoquinolinium Ylides. Journal of the Chemical Society-Perkin Transactions 1: 1180-1185.
[20]. 20. Tan, J, Yang Y, Chen J, Kuang C. 2015. A facile approach for the synthesis of 1,3-di- and 1,2,3-tri-substituted indolizines. Canadian Journal of Chemistry; 93: 542-545.
[21]. 21. Day, J, Uroos M, Castledine RA, Lewis W, McKeeverAbbas B, Dowden J. 2013. Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of pyridinium ylides. Organic & Biomolecular Chemistry; 11: 6502-6509.
[22]. Henrick, C, Ritchie E, Taylor W. 1967. Pyridinium ylids in synthesis. III. Synthesis of indolizines. Australian Journal of Chemistry; 20: 2467-2477.
[23]. Chen, R, Zhao Y, Sun H, Shao Y, Xu Y, Ma M, Ma L, Wan X. 2017. In Situ Generation of Quinolinium Ylides from Diazo Compounds: Copper-Catalyzed Synthesis of Indolizine. The Journal of Organic Chemistry; 82: 9291-9304.
[24]. Bayazıt, MK. 1,3-Dipolar Cycloaddition Reactions of Some Azomethine Imines and Azomethine Ylides [MSc. Thesis]. Bolu: Abant İzzet Baysal University; 2005.
[25]. Sun, J, Hu H, Wang F, Wu H, Liu Y. 2014. Copper(ii)- catalyzed cleavage of carbon–carbon triple bond to synthesize 1,2,3-triesterindolizines. Rsc Advances; 4: 36498-36501.
[26]. Stewart, JJP. 1989. Optimization of parameters for semiempirical methods I. Method. Journal of Computational Chemistry; 10: 209-220.
[27]. Stewart, JJP. 1989. Optimization of parameters for semiempirical methods II. Applications. Journal of Computational Chemistry; 10: 221-264.
[28]. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; John Wiley and Sons: Chichester, United Kingdom, 1976; pp 249.
[29]. Froimowitz, M. 1993. HyperChem: a software package for computational chemistry and molecular modeling. BioTechniques; 14: 1010-1013.
[30]. Otohiko, T, Shuji K, Shigeori T. 1985. Stereochemical Study on 1,3-Dipolar Cycloaddition Reactions of Heteroaromatic NYlides with Symmetrically Substituted cis and trans Olefins. Bulletin of the Chemical Society of Japan; 58: 3137-3157.