J. Chem. Sci. Ó (2020) 132:76 Indian Academy of Sciences https://doi.org/10.1007/s12039-020-01772-7Sadhana(0123456789().,-volV)FT3](0123456789().,-volV) REGULAR ARTICLE Highly efficient endo’- selective synthesis of (dispiro 3,20- pyrrolidinyl) bisoxindoles containing three contiguous chiral stereocenters with two contiguous quaternary spirostereocenters PANNEERSELVAM YUVARAJa,* , HUIDROM BIRKUMAR SINGHa, ARUN PRASATH LINGAM KANDAPALAMb, DEVARAJAN KATHIRVELANc and SANKARANARAYANAN NAGARAJANd aCSIR-North East Institute of Science and Technology, Branch Laboratory, Imphal, Manipur 795004, India bDepartment of Chemistry, Kamaraj College, Thoothukudi, Tamil Nadu 628003, India cDepartment of Chemistry, Indian Institute of Technology-Hyderabad, Kandi, Telangana 502285, India dDepartment of Chemistry, National Institute of Technology Manipur, Imphal 795004, India E-mail: [email protected]; [email protected] MS received 15 November 2019; revised 6 January 2020; accepted 9 January 2020 Abstract. An efficient, atom economical, one-pot synthesis of endo’- selective (dispiro 3,20-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved by three-component reaction of isatins, malononitrile (cyanoacetic ester) and 1,3- dicarbonyl compounds in water in the presence of L-proline. One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst have also been achieved in good yields. This new methodology offers many advantages of catalyst-free, mild reaction conditions, shorter reaction time, environmental friendliness, regio- and stereoselective processes in higher yields. Keywords. 1,3-Dipolar cycloaddition; Endo-Selectivity; Dispiro-bis-oxindoles; HOMO-LUMO interaction. 1. Introduction Heck reaction are only known to achieve this chal- lenging goal.6 Spirocyclic oxindole has been an elegant target of a Multi-step synthesis poses many drawbacks such as synthetic chemist owing to prevalence in several decreased yield, time-consuming and use of toxic 1 natural alkaloids. Spirotryprostatin A has been iso- solvents. To overcome these hurdles, 1, 3 dipolar lated from the fermentation broth of aspergillus cycloaddition reactions are considered as the most fumigates and identified as a novel inhibitor of widely used methodology for the construction of many microtubule assembly, muscarinic serotonin receptors biologically active heterocyclic systems. It also offers 2 as well as medicinally relevant compounds. Among many advantages such as atom economical, eco- 3 the different, the spirooxindoles, the pyrrolidinyl friendly solvent, less time consuming, stereospeci- spirooxindole framework has recently drawn the ficity, stereoselectivity and regioselectivity.7,8 The attention of a synthetic chemist because of its sig- reaction pathway concludes that the cycloaddition nificant bioactivities such as anti-microbial, anti-tu- reactions proceed via a concerted mechanism. The mour, anti-inflammatory and acetylcholinesterase mechanism was first suggested by Huisgen,9 and it has 4 (AChE) inhibitory activities (Figure 1). Particularly, been specified as one pot, five-centre, and involves 4p stereocontrolled synthesis of such compounds instal- electrons from the 1,3-dipole and 2p electrons from ling the spiro-quaternary stereocenter at 3- position, the dipolarophile. 5 poses a great synthetic challenge. A few venerable In the continuation of our previous reports to syn- asymmetric transformations such as cycloaddition or thesize spirooxindoles10 via 1,3-dipolar cycloaddition *For correspondence Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-01772-7) contains supplementary material, which is available to authorized users. 76 Page 2 of 8 J. Chem. Sci. (2020) 132:76 Cl For 4a: White solid. M.p.: 240–243 °C. Rf 0.25 (50% 1 N EtOAc/Petroleum ether). HNMR(500 MHz, CDCl3): d O S 2.21 (s, 3H), 2.96 (s, 3H), 3.27 (s, 3H), 3.51 (t, J = 18 Hz, O O O O 1H), 3.98 (t, J = 17 Hz, 1H), 4.38 (t, J = 18 Hz, 1H), O N 6.55–6.59 (m, 2H), 6.83 (t, J = 14.5 Hz, 1H), 6.82 (t, N N O2N J = 14.5 Hz, 1H), 7.12–7.14 (m, 2H), 7.30 (d, J = 8 Hz, O O N 1H), 7.40 (d, J = 8 Hz, 1H) and 7.70 (s, 1H). 13C NMR N N (125 MHz, CDCl3): 26.4, 29.8, 36.3, 48.6, 51.5, 54.1, 61.7, 107.6, 109.5, 122.2, 122.5, 124.5, 125.1, 126.6, 126.9, Figure 1. Bioactive compounds containing 3,20-pyrro- 129.0, 129.8, 141.6, 143.8, 170.6 and 177.1. LC-MS: lidinyl spirooxindoles framework. Calcd. for C22H21N3O4 is m/z = 391.14 [M?1]. Found: m/ z = 392.2. reaction, we wish to accomplish the synthesis of 3,20- For 5a: White solid. M.p.: 238–240 °C. Rf 0.25 (50% pyrrolidinyl spirooxindoles via more convenient 1,3- 1 EtOAc/Petroleum ether). HNMR(500 MHz, CDCl3): d dipolar cycloaddition reaction. It is noteworthy to 2.21 (s, 3H), 3.00 (s, 3H), 3.17 (s, 3H), 3.71 (t, J = 20 Hz, mention that the method reported herein appears to be 1H), 3.98–4.01 (m, 1H), 4.71–4.72 (m, 1H), 6.16 (d, J =8 excellent for the construction of a series of complex Hz, 1H), 6.52 (t, J = 15 Hz, 1H), 6.66 (t, J = 14.5 Hz, 2H), bis-spirooxindole derivatives with three contiguous 7.00 (t, J = 15 Hz, 1H), 7.12 (t, J = 15.5 Hz, 1H), 7.29 (t, stereocenters including two spiro-quaternary chiral J = 15.5 Hz, 1H), 7.57 (s, 1H) and 7.66 (d, J = 7.5 Hz, 1H). 13 carbon atoms. Moreover, the method reported here- C NMR (125 MHz, CDCl3): 26.3, 35.3, 49.5, 51.5, 54.5, in is an effective extension of the Huisgen synthesis 62.5, 77.4, 107.4, 109.6, 121.1, 121.8, 122.3, 123.3, 126.0, for dispiroheterocycles11,12 without using any catalyst. 126.6, 127.7, 129.2, 129.7, 141.9, 144.0, 170.6 and 176.5. LC-MS: Calcd. for C22H21N3O4 is m/z = 391.14 [M?1]. Found: m/z = 392.2. 2. Experimental 2.1 Materials and Physical measurements 3. Results and Discussion All chemicals and solvents required for the reactions were 3.1 Synthesis and characterization purchased from Sigma-Aldrich, Merck, and used without further purification. All reactions were carried out in oven- Primarily, investigation of isatin 1, sacrosine 2 and dried glassware. Progress of reactions was monitored by 2-oxindole-3-ylidene 3 in THF as a solvent at 60 °C thin-layer chromatography (TLC), while column chro- affords the functionalized dispiropyrrolidine bis-oxin- matography was utilized for purification of crude com- 1 13 dole 4a and 5a with two spirocentres in 55% combined pounds by using silica gel (100–200 mesh). H and C yields (Scheme 1). This strategy would provide access NMR spectra were recorded on Bruker 500 MHz and 125 to a fast, one-pot synthesis of dispiroheterocycles, spectrometers respectively in CDCl3 with tetramethylsilane (TMS) as an internal standard. The chemical shifts are which are otherwise accessible only through multi- expressed in ppm and coupling **constants are given in Hz. step synthesis. The data for 1H NMR are recorded as follows: chemical shift (d, ppm), multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; p = pentet; m = multiplet; br = broad), 3.2 Structure of compounds 4a and 5a coupling constant (Hz), integration. Mass spectra were recorded using 6495C Triple Quadrupole LC/MS. The structure of the two regioisomers 4a and 5a were confirmed by various spectroscopic analyses such as 1H, 13C, and DEPT-135 and mass spectroscopy. The 0 2.2 Synthesis of (dispiro 3,2 -pyrrolidinyl) 1H NMR spectrum of compound 4a exhibited four bisoxindoles characteristic singlets at d 2.21, 2.96, 3.23 and 7.70 due to the presence of – NCH3 protons of pyrrolidine, A mixture of isatin (1a-k) (1.0 mmol), sacrosine 2 (1.5 –NCH protons of oxindoles, –OCH protons of mmol) and 2-oxindole-3-ylidene 3 (1.1 mmol) in acetoni- 3 3 methyl ester and –NH proton of oxindole, respec- trile was refluxed until the completion of the reaction as tively. The 1H NMR data confirm the incorporation of monitored by TLC and then cooled to room temperature. 13 The solid formed in the reaction mixture was filtered and two spiro oxindole rings. In C NMR spectrum, the dried under vacuum. The solid crude product was purified spirocarbon atoms appeared at d 54.0 and 61.6 ppm, by preparative HPLC and the pure products (4a-k) and (5a- respectively. The shifts at d 170.6 and 177.0 ppm k) obtained in good yields (80–99%). representing ester carbonyl and amide carbonyl J. Chem. Sci. (2020) 132:76 Page 3 of 8 76 O O O CO Me CO Me O 2 2 O N N R1 N H [3+2] cycloaddition 1 O N N THF, 60 0C N O N O N O H 3 O N H H OH Endo-4a Exo-5a 2 Scheme 1. Synthesis of dispiropyrrolidine oxindoles 4a and 5a. Figure 2. ORTEP view of compounds 4a13 and 5a14. groups, respectively. The DEPT-135 spectrum showed The 1H NMR spectrum of compound 5a exhibited a chemical shift at 54.1 ppm corresponds to one -CH2 characteristic four singlets appeared at d 2.22, 3.00, carbon atom. These observed chemical shift values are 3.18 and 7.57 representing –NCH3 protons of pyrro- in accordance with the structure of the compound 4a. lidine, –NCH3 protons of oxindole, –OCH3 protons of Moreover, the presence of a molecular ion peak at m/z methyl ester and –NH proton of oxindole, respec- 391 (M?1) in the mass spectrum confirmed the tively.