id2143625 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com OOrrggaanniicc ISSN: 0974 - 7516 Volume 8 Issue 3 CCHHEEMMAn IIInSSdiTTan RRJouYrYnal Trade Science Inc. Full Paper OCAIJ, 8(3), 2012 [94-102] Facile synthesis of 3-spiropyrrolizidine oxindoles and 3-spirotetrahydroquinoline oxindoles via [3+2] and [4+2] cycloaddition reactions A.Sudhakara1, H.C.Kiran Kumar2, H.Jayadevappa1, K.M.Mahadevan2* 1Department of Chemistry, Sahyadri Science College, Shimoga, Karnataka, 577 203, (INDIA) 2Department of Postgraduate Studies and Research in Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, Karnataka, 577 451, (INDIA) E-mail: [email protected] Received: 22nd June, 2011 ; Accepted: 22nd July, 2011 ABSTRACT KEYWORDS A rapid and efficient synthesis of a number of functionalized 3- Isatin; spiropyrrolizidine oxindoles from [3+2] cycloaddition of azomethine ylide Imino Diels-Alder; and 3-spirotetrahydroquinoline oxindoles from [4+2] imino Diels-Alder re- Antimony(III)chloride; action; catalyzed by Antimony(III)chloride in excellent yields are reported. Spiropyrrolizidine oxindoles; 2012 Trade Science Inc. - INDIA Spirotetrahydroquinoline- oxindoles. INTRODUCTION sor for the synthesis of biologically active indole de- rivatives and natural products[2]. The Spirooxindoles core Heterocyclic compounds containing isatin (1H-in- is featured in a number of natural products and recently dole-2, 3-dione) scaffold have a wide range of biologi- has been the subject of significant synthetic interest[3]. cal activities[1] and also serves as an important precur- Oxindoles derivatized like Spirotryprostatin B, Horsfiline O Me H H O NH MeO N Me N N H MeO O H O O N N N O Me H H Spirotryprostatin B Horsfiline Alstonisine Spirooxindole alkaloid natural products Figure 1 : Spirotryprostatin B, horsfiline and alstonisine are alkaloids present in nature and are elegant targets in the organic synthesis due to their significant biological activities. OCAIJ, 8(3) 2012 K.M.Mahadevan et al. 95 Full Paper and Alstonisine are alkaloids present in nature and are explored the [3+2] cycloaddition reaction of elegant targets in the organic synthesis due to their sig- azomethine ylide derived from decarboxylative con- nificant biological activities[4,5] (Figure 1). densation between isatin and proline. And [4+2] imino Classical preparations of oxindoles have involved Diels-Alder cycloaddition reaction was also been stud- carboline oxidative rearrangement[6], intramolecular ied to obtain structurally diversified spirotetra- Mannich and radical cyclization approach[7,8]. The tran- hydroquinoline oxindoles. Our work in cycloaddition sition metal catalyst mediated methods have also been reaction in the synthesis of nitrogen heterocycles developed and have become the part of elegant total catalysed by Antimony(III)chloride[24], prompted us synthesis of oxindole derivatized at C3 as spirocarbo to use Antimony(III)chloride as a catalyst in the syn- and heterocyclics, spirolactones and spirocyclic ethers thesis of spiropyrrolizidine oxindoles and are main targets in organic synthesis due to their sig- spirotetrahydroquinoline oxindoles. Thus the current nificant biological activities[9]. These derivatives have method provides a rapid route for access to stereo been served as potential synthons for the synthesis of chemically distinct spirooxindoles and this method will alkaloids, drug intermediates and clinical pharmaceu- lead to library synthesis for biological evaluation. Here- ticals. Azomethine ylides are a class of powerful re- with we are reporting our findings. agents to utilized in the dipolar cycloaddition reac- tions[4,10], which generally afford a range of pharma- RESULTS AND DISCUSSION cologically important heterocyclic compounds[11]. The synthetic versatility of isatin and its derivatives has led The synthetic strategy for the construction of to the extensive use of this compound in synthetic or- spiropyrrolizidine oxindoles is as shown in Scheme ganic chemistry[12,13]. With the ongoing discovery of 1. Accordingly, the spiropyrrolizidine oxindoles de- new natural compounds containing Spirocenters, the rivative (4a) could be synthesized from [3+2] cy- synthesis of these structures will remain an active area cloaddition reaction of isatin (1), proline (2) and vari- of research. As part of our research in the area of ous unsymmetrical dipolarophiles (3a-g) (TABLE 3) novel synthesis of bioactive heterocycles[14-24], we have in one pot. H H O HOOC H3CO2C H COOCH3 MeOH O + + N N O N H H H SbCl3 / rt H N H 1 2 3a 4a Scheme 1 : The synthetic strategy for the construction of spiropyrrolizidine oxindoles. In a typical experiment, the three component one 7'a pot reaction of isatin (1), proline (2) and methyl acry- H 1' H late (3a) in methanol proceeds smoothly at room tem- 7' perature for 1hr in presence of Antimony(III)chloride MeO2C 2' 5 3' 4' 6' (20 mol%) to afford the corresponding spiropyrrolizi- 4 N 3 5' dineoxindole derivative (4a) in >90% yield (TABLE 6 1 O 2 3, entry 1). Thus the reaction of proline, isatin, and 7 N H methyl acrylate occur regio and stereo specifically Figure 2 : Structure 1 to give (4a)[9,26] in good yield. The relative stereo ’ ’ 1 chemistry of the 2 -H and 7a -H, protons was es- Hence, based on the spectral analysis such as H tablished by NOE studies and stereo chemical as- NMR and Mass spectral analysis and in comparison of ’ these results with earlier report[26], the regio and stere- signment at C2 was later confirmed by a single crys- tal X-ray structure[25]. ochemistry of the products have been established Organic CHEAMn InIdiSanT JoRurnYal 96 Facile synthesis of 3-spiropyrrolizidine oxindoles and 3-spirotetrahydroquinoline oxindoles OCAIJ, 8(3) 2012 Full Paper HOOC O .. 2 H N + O H MeOH N N O O O N SbCl3 / rt N H O- H H O O 1 -CO N 2 H H H H H3COOC H O- H CO C + 3 2 3a H N N O N O 4a N H H A Scheme 2 : Regio and stereochemistry of the products (TABLE 3, Scheme 2). dihydro-2H-pyran, N-vinyl pyrrolidin-2-one (NVP) and Further by adopting established reaction condition N-vinyl caprolactum (NVC) (TABLE 3). The predomi- we attempted to carry out analogous reactions of nate products (85-90%) arise from azomethine ylide azomethine ylide with various dipolarophiles i.e. acry- via an endo-transition state with regiospecificity is as lates (3a-g) and electron rich dienophiles such as 3,4- shown in Scheme 3 and products are summarize in HOOC 2 O .. H N N O H MeOH + N O SbCl / rt N H O O 3 N H H O O- N O 1 H -CO 2 O O N H H 3i _ N O N N + O N H O N H 4i A A Scheme 3 : The predominate products (85-90%) arise from azomethine ylide via an endo-transition state with regiospecificity TABLE 3. spiropyrrolizidineoxindole in 85-90% yield respectively. Initially the one pot reaction carried out as a model Further we set out to establish the optimal amount of reaction in various solvents to investigate the solvent Antimony(III) chloride, finding that reaction with a 10 effect. The results are summarized in TABLE 1. Metha- mol% catalyst loading gave a 75% yield after 1.5 hr nol, ethanol and acetonitrile were found to be better (entry 1), however the best result (90%) was found solvents for this transformation. However, the best re- which corresponds to the use of 20 mol% catalyst (en- sults were achieved by carrying out the reaction in try 2) and the reaction time reduced to 1hr. The in- MeOH at room temperature to afford creasing amount of the catalyst did not change the re- Organic CHEAMn IIndSiaTn JRournYal OCAIJ, 8(3) 2012 K.M.Mahadevan et al. 97 Full Paper TABLE 1 : Screening of the catalytic activity in various sol- spirooxindolyl compounds and impressed by the suc- vents for the synthesis of 3-spiroxindoles cess in synthesizing various spiropyrrolizidineoxindoles Catalysta Yieldb (4a-j), further we thought to exploit the utilization of Entry Solvent Time/hr Load mol% (%) C=O group of isatin in [4+2] cycloaddition reaction to 1 MeOH 10 1.5 75 obtain various structurally diversified spirotetra- 2 MeOH 20 1.0 90 hydroquinolineoxindole compounds (2a-c). Similarly, 3 EtOH 20 1.3 80 the isatin underwent smooth condensation with 4- 4 CH3CN 20 4.0 80 methoxyaniline to produce corresponding imines in an 5 DMF 20 12 38 excellent yield. Since the imines are known to undergo 6 Ether 20 14 30 imino Diels-Alder reaction with electron rich 7 Toluene 20 24 Trace dienophiles[24], the imine thus generated was subse- 8 Hexane 20 24 No reaction quently made to react with 2,3-dihydro furan/3,4- 8 EtOAc 20 9 25 dihydro-2H-pyran, and N-vinyl pyrrolidin-2-one 9 CH2Cl2 20 7 30 (NVP) dienophiles to obtain various spirotetra- a20 mol % of catalyst used; bIsolated yield. hydroquinolineoxindole derivatives (2a), (2b)[27], (2c) action time whereas isolated yield was found to be less O in nature. OCH3 Similarly, the spiropyrrolizidineoxindole derivatives + + O O (4a-j) could be synthesized from the three component N N H N one pot reaction between isatin (1), proline (2a) and H 2 dipolarophiles (3a-g). The dipole azomethine ylide (A) could be generated in situ from isatin and proline by O H3CO N thermal decarboxylation reaction which immediately underwent [3+2] cycloaddition reaction with dipolarophiles as shown in Scheme 2. SbCl3 (20 mole %) N In order to test the scope of this [3+2] cycloaddi- MeOH / r t tion reaction, various dipolarophiles (TABLE 3) have O been examined. In addition to these dipolarophiles, elec- N A H tron rich dienophiles such as 3,4-dihydro-2H-pyran, N-vinyl pyrrolidin-2-one (NVP) and N-vinyl caprolactum were also tested along with dipolarophiles.