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'''Efficient and Convenient Synthesis of 1,2,3,3a-tetrahydro-pyrrolo[1,2- a]quinoxaline Under Microwave Irradiation '''Dr Suman Thummanagoti(Associate Research)* Laboratory of Combinatorial Drug Discovery, Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan. suman.ac96g@nctu.edu.tw Graphical abstract The present pyrrolo[1,2-a]quinoxalines has synthesized under microwave irradiation by taking the 4-fluro-3-nitrobenzoic acid has taken to esterification followed by the proline substituents with an hydroxyl substituent in an nucleophilic substitution pattern later on nitro functional group reduced to the amine to cyclise under reflux conditions froms the amide ring closure reaction. The pyrrolo[1,2-a]quinoxalines further amide bond convert to the sufide using an lowessons reagent; further it reduced to the sulfur alkylation; the hydroxyl terminal various isocyanides forms an two points of diversity all the reactions carried out under both conventional and microwave conditions. Introduction There is growing interest in designing and synthesizing pyrrolo[1,2-a]quinoxalines libraries based on privileged combinations of structures, especially focusing on structures, belong to a class of compounds with proven utility in medicinal chemistry97. The privileged pyrrolo[1,2-a]quinoxalines structure was a single molecular framework able to provide ligands for diverse receptors. Since then, many substructural (1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and 1,2,3,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine) and 2-phenyl benzanilide frameworks have been described as privileged structures associated with a wide range of biological activity98. These compounds exhibited a highly selective affnity for V2 receptor, and their stereochemical configuration had a great influence on V2 receptor binding99. The structure-activity relationships associated with the OPC-31260 indicated benzene-fused seven-membered ring system was significant for V2 (and V1a) antagonists; while the ortho substituents on the terminal benzoyl ring seemed to be important both for a high affinity for the V2 receptor and good oral activity100. The YM-087, nonpeptide antagonist of both V1a and V2 receptors biochemical and pharmacological properties of, and their systematically modified compounds clarified the structure features required for the binding affinity for vasopressin receptors101. The introduction of a lipophilic group such as 2-phenyl or 2-(4-substituted phenyl) on the terminal benzoyl ring exhibited more potent antagonistic activities than that of 2-methyl group in the in vivo tests towards both V1a and V2 receptors102. Figure 1.23: Pharmacologically active heterocyclic molecules. Scheme 1.11: Solution phase synthesis of pyyrolo[1,2-a]quinoxalines. To further decorate with unlimited combinations of annulated heterocyclic structures to obtain polycyclic skeletons with biological activity and rigid conformation was arsenal. To describe a useful protocol for the preparation of this pyrrolo[1,2-a]quinoxalines privileged structures, we report here rapid, reproducible, and scalable processes in high yield. Various synthetic methods to prepare the Pyrrolo[1,2-a]quinaxoline: Scheme 1.12: Synthetic scheme for the synthesis of pyrrolo[1,2-a]quinaxolines scaffolds. The preparation of various pyrrolo[1,2-a]quinaxoline have been done using the various synthetic methods. One of that is an efficient tandem process of hydroamination and hydroarylation using a gold catalyst to enable and study the reactions between pyrrole-substituted anilines and alkynes. The gold(I)-catalyzed reactions were achieved in toluene at 80 °C over a reaction time of 1−6 h. These reactions are applicable to a variety of aromatic amino compounds and both the terminal and internal alkynes. Substituted pyrrolo[1,2-a]quinoxalines were obtained in moderate to excellent yields. A presumed mechanism involving intermolecular C−N bond formation and intramolecular nucleophilic reaction via a cationic gold complex has been proposed on the basis of the deuterium labeling studies reported by the hong lui. (Acs. Comb. Sci. 2011, 13 (3), pp 209-213)103. Scheme 1.13: Synthetic scheme for the synthesis of pyrrolo[1,2-a]quinaxoline. Another synthetic method described by the Dawei Ma; CuI-catalyzed coupling of 2-halotrifluoroacetanilides with L-proline or pipecolinic acid in DMSO at 90-110 °C followed by in situ hydrolysis at 100 °C afforded tetrahydropyrrolo[1,2-a]quinoxalines or tetrahydropyrido[1,2-a]quinoxalines104. Scheme 1.14: Synthetic scheme for the synthesis of pyrrolo[1,2 Tetrahedron Letters volume Pyrrolo[1,2-a]quinaxaline has been synthesized in the presence of base, ethyl 2,2-dihydropoly(per)fluoroalkanoate( N-phenacyl benzimidazole and N-ethoxycarbonylmethyl pyrrolo[1,2-a]quinoxaline derivatives( Wei-Yuan Huang. However the various synthetic methods described to synthesize the pyrrolo[1,2-a]quinoxaline due consume to prepare the various analogues and the lack of scalability led us to prepare the scaffolds in a way to satisfy the above functionalization requirements under fast and rapid way in the microwave synthetic process 1,2-a]quinoxalines. 38, 27, 4827-4830. 2) reacted with bromide(1a–1b),N-acetonyl benzimidazolebromide( benzimidazole bromide(1d) in DMF to give 3ae-3dg) respectively has been reported by to the lack of the various functionalization and the time rowave process105. ) bromide(1c) ) ) Figure 1.24: 1H NMR monitoring for the pyrrolo[1,2 The synthesis of the present library carried by taking the then it was attached to the ionic liquid support. This reaction was done in the presence of DCC coupling reagent and the catalytic amount of DMAP to form the ester bond in the acetonitrile as solvent. This reaction was carryout for about 10 min at 100oC. After the reaction the product washed by the cold ether. And the precipitated compound has been dissolved in acetonitrile and evacuated. Further the subsequent nucleophic substitution reaction with carried out in the presence of triethylamine and in high boiling point solvent such as ethylenedichloride under microwave irradiation for about 15 min at 80 as the solvent. After the reaction the crude several times with cold ether to remove the byproducts. After the crude product handed the subsequent reduction followed by the amide bond formation led cyclization has been carried out in Zn and the appropriate amou reaction temperature and 20 min of reaction time. The same reaction at high temperature and the same acidic conditions; it took 5 min of microwave irradiation at the 80oC of reaction temperature. The insoluble Zinc has b support substrate has been washes several times under cold ether. After the substrate filtration and rinced with acetonitrile; and dried. The dried substrate has been taken into the toluene as solvent and the addition of app H 1,2-a]quinoxalines scaffold. 4-Fluoro-3-nitrobenzoicacid under the microwave irradiation C. 4-hydroxy proline-2 80oC in acetonitrile product has been taken taken and washed amount of acetic acid for about 50 C been filtered and the Il support appropriate amount of lawesson’s reagent the 2-ester has been C nt 50oC of een ropriate to made the thio amide from the amide, this reaction was carried out in microwave irradiation for about 150oC of reaction temperature and 20 min of reaction time. The formation of the thioamide has been identified from the proton and the carbon 13 and the IR studies. The thioamide functional group rearranges to form a resonance heterocyclic moiety leading to the substrate allowed to functional derivatives by t halides; through the alkylation of mercapto functional group. This reaction has been carried out by taking the various halides and an organic base under the microwave irradiation for about 15 min of reaction time an Afyter completion of the reaction the substrate has been taken and the hydroxyl functional group having moiety has been derivatives by taking various isocyanates and isothiocyanates. This reaction has been carried out an C by the pattern of spectrum available –SH bond. Then this taking the various aliphatic and aromatic and the 100oC of reaction temperature. in the presence of isocyanates and aking C Figure 1.25: 1H (300 MHz) NMR monitoring for the pyrrolo[1,2 organic base under the microwave irradiation for about 10 and 15 min of reaction time. After functionalizing the target molecule the ionic liquid attached substrate has been cleaved by using the sodium methoxide in methanol under microwave irradiation at 120 been purified and analyzed by the appropriate analytical techniques. Figure 1.26: 1H NMR monitoring for the pyrrolo[1,2 intermediate. H 1,2-a]quinoxalines. 100oC of reaction temperature 120oC and 15 of reaction temperature. All the substrates has 1,2-a]quinoxalines scaffold C ature. O O F NO2 NH HO COOCH3 HCl Et3N Reflux O O N NO2 OH COOCH3 H NH N O OH O O N N O OH O O NH N S OH O R O 1 NaH; R1X Lawesson's reagent Mitsunobu reaction Et3N, RX N N S OH O O R Mitsunobu reaction R1OH N N S OR1 O O R Acknowledgement: We gratefully acknowledge National Science Council, Taiwan; for the financially supported and the authorities of National Chiao Tung University. Supporting Information Available: The detailed experimental procedures and analytical data (1H, 13C NMR, MS, and IR) for all compounds will available free of charge via the Internet at http: //pubs.acs.org. Conclusion In this paper Microwave-assisted organic synthesis pyrrolo[1,2-a]quinoxalines scaffold has carried out. One of the most valuable advantages of using controlled microwave dielectric heating for chemical synthesis is the dramatic reduction in reaction times: from days and hours to minutes and seconds. As will be explained in this tutorial review, there are many more good reasons why organic chemists are nowadays incorporating dedicated microwave reactors into their daily work routine. References 1. Guillon, J.; Grellier, P.; Labaied, M.; sonnet, P.; Leger, J-M.; Poulain, R-D. J. Med. Chem., 2004, 47, 1997-2009. 2. Yamamura, Y.; Ogawa, H.; Chihara, T.; Kondo, K.; Onogawa, T.; Nakamura, S.; Mori, T.; Tominaga, M.; Yabuuchi, Y. Science, 1991, 252, 572-574. 3. Ogawa, H.; Yamamura, Y.; Yamamoto, H.; Kondo, K.; Yamashita, H.; Nakaya, K.; Chihara, T.; Mori, T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem., 1993, 36, 2011-2017. 4. Ogawa, H.; Yamashita, H.; Kondo, K.; Yamamura, Y.; Miyamoto, H.; Kan, K.; Kitano, K.; Tanaka, M.; Nakaya, K.; Nakamura, S.; Mori, T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem., 1996, 39, 3547-3555. 5. Tahara, A.; Tamura, Y.; Wada, K.; Kusayama, T.; Tsukada, J.; Takanashi, M.; Yatsu, T.; Uchida, W.; Tanaka, A. J. Pharmacol. Exp. Ther., 1997, 282, 301-308.(101) 6. Matsuhisa, A.; Tanaka, A.; Kikuchi, K.; Shimada, Y.; Yatsu, T.; Yanagisawa, I. Chem. Pharm. Bull., 1997, 45, 1870-1874. Efficient and Convenient Synthesis of 1,2,3,3a-tetrahydro -pyrrolo[1,2- a]quinoxaline Under Microwave Irradiation Laboratory of Combinatorial Drug Discovery, Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan. Experimental SectionPreparation of (4S)-methyl 4-hydroxy-1- (4-(methoxycarbonyl)-2-nitrophenyl) pyrrolidine-2-carboxylate By taking the appropriate amount of methyl 4-fluoro-3-nitrobenzoate and the (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate in the presence of Triethylamine as the organic base the reaction mixture refluxed for about 10 hr in EDC as the solvent. The same reaction was carried out under microwave irradiation for about 15 min of reaction time at 120 C. Then the reaction medium was reduced under the reduced pressure. Then the crude reaction mixture subjected to the column chromatography. Preparation of (2S,3aR)-methyl 2-hydroxy-4-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline-7- carboxylate Taking the above obtained compound and then the reaction mixture submitted to reduce the nitrofunctional group to the amine and subsequent amide bond formation cyclization under the same reaction conditions. This reaction has been done using the same cat. amount of aetic acid and Zn in methanol as a solvent. The same reaction has been done using the microwave irradiation for about 10 min reaction time at 80 C reaction temperature. After the completion of the reaction the reaction mixture submitted to the column chromatography for the further purification. Process for the preparation of (R)-1-(4-(methoxycarbonyl)-2-nitrophenyl)pyrrolidine-2-carboxylic acid By taking the appropriate amount of the methyl 4-fluoro-3-nitrobenzoate and proline reagents in a reaction vessel and the triethyl amine as orgainic base the reaction mixture submitted to the reflux for about 10 hr in EDC as the solvent. The formation of the product has been confirmed by the TLC. However the same reaction has been doen using the same reactents in a microwave vessel. The reaction mixture exposed to the microwave vessel for about 15 min of reaction time at 80 C of reaction temperature. After the completion of the reaction, the reaction mixture submitted to the reduced pressure and then the crude reaction mixture submitted to the column chromatography. Preparation of (S)-methyl 4-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline-7-carboxylat e By taking the above obtained product and appropriate amount of Zn and acetic acid in methanol as a solvent. Further the reaction mixture has been submitted to the reflux for about an hour in order to reduce the nitro functional group and then the subsequent cyclization leads to the amide bond formation. However the same reaction under the microwave irradiation conditions it took for about 15 min of rection time. After the confirming the reaction product it has further subjected to the column chromatography. Process for the preparation of (2S,4S)-methyl 4-(benzoyloxy)-1-(4-(methoxycarbonyl)-2-nitrophenyl)pyrrolidine-2 -carboxylate O O NO2 N O O O O By taking the above obtained compound then it was dissolved in DCM and then it has been added the appropriate amount if the benzoic acid and the coupling reagent DCC and DMAP. The reaction mixture was allowed to stir at room temperature for about 10 hr. The formation of the product has been confirmed by the TLC. However the same reaction under microwave irradiation conditions it took 15 of raction time at 100 C reaction temperature. Then the reaction mixture submitted to the reduced pressure, followed by the column chromatography. Preparation for the process of (2S,4R)-methyl 4-(benzoyloxy)-1-(4-(methoxycarbonyl)-2-nitrophenyl)pyrrolidine-2-carboxylat e By taking the above sample of this compound the chirality of the compound has been changed to form the ester bond through the mitsunobu reaction conditions. This reaction has been done by taking the THF as the solvent and the Ph3P and DEAD reangent following benzoic acid. The completion of the reaction has been confirmed by the TLC. The reaction mixture submitted to the rotavapour and subsequently to the column chromatography. At last the product has been confirmed by the 1H NMR spectroscopy. Process for the preparation of (2S,4S)-methyl 4-((4-fluoro-3-nitrobenzoyl)oxy)-1-(4-(methoxycarbonyl)-2-nitrophenyl)pyrroli dine-2-carboxylate. By taking the above obtained compound then it was dissolved in DCM and then it has been added the appropriate amount if the 4-fluoro-3-nitrobenzoic acid and the coupling reagent DCC and DMAP. The reaction mixture was allowed to stir at room temperature for about 10 hr. The formation of the product has been confirmed by the TLC. However the same reaction under microwave irradiation conditions it took 15 of raction time at 100 C reaction temperature. Then the reaction mixture submitted to the reduced pressure, followed by the column chromatography. Process for the preparation of (3S,5S)-5-(methoxycarbonyl)-1-(4-(methoxycarbonyl)-2-nitrophenyl)pyrrolidin3- yl 2-(3,3-diphenylpropyl)-2H-indazole-6-carboxylate By taking the appropriate amount of (4S)-methyl 4-hydroxy-1-(4-(methoxycarbonyl)-2-nitrophenyl)pyrrolidine-2-carboxylate and indazole having terminal carboxylic acid in the presence of PYBOP and the Et3N in THF as the solvent. After the completion of the reaction the reaction has been subjected to the rotavapour and then column chromatography. The formation of the product has been confirmed by the 1H NMR spectroscopy.