Metal-Free Mild Synthesis of Novel 1′H-Spiro[Cycloalkyl-1,2′-quinazolin]-4′(3′H)-ones by an Organocatalytic Cascade Reaction

Abstract

A concise organocatalytic method for the facile synthesis of some novel 1′H-spiro[cycloalkyl-1,2′-quinazolin]-4′(3′H)-ones via a one-pot, three-component condensation of isatoic anhydride, aryl or aliphatic amines and a cyclic ketone is described.

Key words

spiro compounds - quinazolinones - isatoic anhydride - amines - cycloalkanones - multicomponent reactions

• References and Notes

• 1a Corey EJ. Cheng X.-M. The Logic of Chemical Synthesis . Wiley; New York: 1989: 1
• 1b Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2006
• 1c Trost BM. Science 1991; 254: 1471
• 1d Nicolaou KC. Vourloumis D. Winssinger N. Baran PS. Angew. Chem. Int. Ed. 2000; 39: 44
• 1e Nicolaou KC. Hale CR. H. Nilewski C. Ioannidou HA. Chem. Soc. Rev. 2012; 41: 5185
• 2a Tseng M.-C. Chu Y.-W. Tsai H.-P. Lin C.-M. Hwang J. Chu Y.-H. Org. Lett. 2011; 13: 920
• 2b Liu J.-F. Ye P. Zhang B.-L. Bi G. Sargent K. Yu L.-B. Yohannes D. Baldino CM. J. Org. Chem. 2005; 70: 6339
• 2c Foley P. Eghbali N. Anastas PT. J. Nat. Prod. 2010; 73: 811
• 3 Rambabu D. Kiran Kumar S. Sreenivas BY. Sandra S. Kandale A. Misra P. Basaveswara Rao MV. Pal M. Tetrahedron Lett. 2013; 54: 495
• 4a Yale HL. Kalkstin M. J. Med. Chem. 1967; 10: 334
• 4b Peet NP. Sunder S. Cregge RJ. J. Org. Chem. 1976; 41: 2733
• 4c Jiang JB. Hesson DP. Dusak BA. Dexter DL. Kang GL. Hamel E. J. Med. Chem. 1990; 33: 1721
• 4d Ozaki K.-i. Yamada Y. Oine T. Ishizuka T. Iwasawa Y. J. Med. Chem. 1985; 28: 568
• 5 Safari J. Gandomi-Ravandi S. J. Mol. Catal. A: Chem. 2014; 390: 1
• 6 Hour M.-J. Huang L.-J. Kuo S.-C. Xia Y. Bastow K. Nakanishi Y. Hamel E. Lee K.-H. J. Med. Chem. 2000; 43: 4479
• 7 Birch HL. Buckley GM. Davies N. Dyke HJ. Frost EJ. Gilbert PJ. Hannah DR. Haughan AF. Madigan MJ. Morgan T. Pitt WR. Ratcliffe AJ. Ray NC. Richard MD. Sharpe A. Taylor AJ. Whitworth JM. Williams SC. Bioorg. Med. Chem. Lett. 2005; 15: 5335
• 8 Bonola G. Da Re P. Magistretti MJ. Massarani E. Setnikar I. J. Med. Chem. 1968; 11: 1136
• 9 Bolger JW. US 3257397, 1966
• 10 Okumura K. Oine T. Yamada Y. Hayashi G. Nakama M. J. Med. Chem. 1968; 11: 348
• 11 Cohen E. Klarberg B. Vaughan JR. Jr. J. Am. Chem. Soc. 1959; 81: 5508
• 12 Alagarsamy V. Solomon VR. Murugan M. Bioorg. Med. Chem. 2007; 15: 4009
• 13 Levin JI. Chan PI. Bailey T. Katocs AS. Jr. Venkatesan AM. Bioorg. Med. Chem. Lett. 1994; 4: 1141
• 14 Beau de Loménie G. Armengaud A. Houssard G. FR 1893(M), 1963
• 15 Schipper ES. US 3265697, 1966
• 16 Hirose N. Kuriyama S. Sohda S. Sakaguchi K. Yamamoto H. Chem. Pharm. Bull. 1973; 21: 1005
• 17 Mustazza C. Borioni A. Sestili I. Sbraccia M. Rodomonte A. Ferretti R. Del Giudice MR. Chem. Pharm. Bull. 2006; 54: 611
• 18 Schramm S. Schmitz E. Grundemann E. J. Prakt. Chem. 1984; 326: 279
• 19 Michael JP. Nat. Prod. Rep. 2008; 25: 166
• 20 Imagawa J. Sakai K. Eur. J. Pharmacol. 1986; 131: 257
• 21 Dempcy RQ. Skibo EB. Biochemistry 1991; 30: 8480
• 22 Gackenheimer SL. Schaus JM. Gehlert DR. J. Pharmacol. Exp. Ther. 1995; 274: 1558
• 23 Molamas MS. Miller J. J. Med. Chem. 1991; 34: 1492
• 24a Ramesh R. Lalitha A. RSC Adv. 2015; 5: 51188
• 24b Ramesh R. Lalitha A. Res. Chem. Intermed. 2015; 41: 8009
• 24c Ramesh R. Maheswari S. Murugesan S. Sandhiya R. Lalitha A. Res. Chem. Intermed. 2015; 41: 8233
• 24d Ramesh R. Vadivel P. Maheswari S. Lalitha A. Res. Chem. Intermed. 2016; 42: 7625
• 24e Ramesh R. Lalitha A. ChemistrySelect 2016; 1: 2085
• 24f Ramesh R. Madhesh R. Malecki JG. Lalitha A. ChemistrySelect 2016; 1: 5196
• 24g Ramesh R. Nagasundaram N. Meignanasundar D. Lalitha A. Res. Chem. Intermed. 2017; 43: 1767
• 25 1′ H-Spiro[cycloalkyl-1,2′-quinazolin]-4′(3′ H)-ones 4a– l and 6a–l; General Procedure A 50 mL round-bottomed flask was charged with MeOH (5 mL), isatoic anhydride (2; 3 mmol), the appropriate amine 1 (3 mmol), and AcOH (10 mol%), and the mixture was stirred at r.t. for about 5 min. Cyclohexanone or cyclopentanone (3 mmol) in MeOH (5 mL) was added, and the resulting mixture was stirred at the reflux temperature until the reaction was complete [TLC; EtOAc–hexane (3:7); see Tables 2 and 3]. The mixture was allowed to cool to r.t., and the resulting solid was collected by filtration. The crude product was purified by crystallization from EtOH.
• 26 3′-(4-Isopropylphenyl)-1′ H-spiro[cyclohexane-1,2′-quinazolin]-4′(3′ H)-one (4b) Colorless crystals; yield: 914 mg (91%); mp 208–210 °C. ¹H NMR (400 MHz, DMSO-d₆ ): δ = 0.91 (d, J = 12.0 Hz, 1 H, CH₂), 1.23 (d, J = 6.8 Hz, 6 H, CH₂), 1.29 (d, J = 12.4 Hz, 2 H, CH₂), 1.55 (m, 5 H, CH₂), 2.01 (d, J = 12.0 Hz, 2 H, CH), 2.91 (m, 1 H, CH), 6.68 (s, 1 H, ArH), 6.70 (s, 1 H, NH), 7.03 (m, 3 H, ArH), 7.27 (d, J = 6.8 Hz, 3 H, ArH), 7.63 (t, J = 7.2 Hz, 1 H, ArH). ¹³C NMR (100 MHz, DMSO-d₆ ): δ = 21.1, 23.7, 24.0, 32.9, 34.5, 72.9, 115.1, 115.6, 117.1, 126.4, 127.5, 130.0, 132.9, 135.7, 145.5, 147.3, 162.8. Anal. Calcd for C₂₂H₂₆N₂O (334.45): C 79.0, H 7.84, N 8.38; Found: C 79.44, H 8.15, N 8.76.
• 27 Crystals of compounds 4a, 4e, and 6e were mounted on a Gemini A Ultra Oxford Diffraction automatic diffractometer equipped with a CCD detector. Data were collected with graphite-monochromated MoKα radiation (λ = 0.71073 Å) at 295(2) K with an ω scan mode. Lorentz, polarization, and empirical absorption corrections using spherical harmonics implemented in the SCALE3 ABSPACK scaling algorithm were applied.³⁰ The structure was solved by direct methods and subsequently completed by difference Fourier recycling. Nonhydrogen atoms were refined anisotropically by using the full-matrix least-squares technique. Hydrogen atoms were found by difference Fourier synthesis after four cycles of anisotropic refinement, and refined as riding on the adjacent carbon atom with an individual isotropic temperature factor equal to 1.2 times the value of equivalent temperature factor of the parent atom. Olex2³¹ and SHELXS, SHELXL³² programs were used for all the calculations.
• 28 CCDC 1543174, 1543282, and 1543283 contains the supplementary crystallographic data for compounds 4a, 4e, and 6e, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 29 3′-(4-Isopropylphenyl)-1′ H-spiro[cyclopentane-1,2′-quinazolin]-4′(3′ H)-one (6b) Colorless crystals; yield: 907 mg (94%); mp 244–246 °C. ¹H NMR (400 MHz, DMSO-d₆ ): δ = 1.22 (d, J = 6.8, 6 H, CH₃), 1.43 (s, 2 H, CH₂), 1.71 (d, J = 7.6 Hz, 4 H), 1.89 (s, 2 H, CH₂), 2.91 (m, 1 H, CH), 6.71 (t, J = 7.2 Hz, 1 H, ArH), 6.86 (d, J = 8.0 Hz, 1 H, ArH), 6.93 (s, 1 H, NH), 7.10 (d, J = 8.0 Hz, 2 H, ArH), 7.28 (d, J = 7.6 Hz, 3 H, ArH), 7.67 (d, J = 7.2 Hz, 1 H, ArH). ¹³C NMR (100 MHz, DMSO-d₆ ): δ = 21.2, 23.7, 32.9, 36.2, 81.6, 114.9, 115.6, 117.1, 126.5, 127.8, 129.7, 132.9, 136.1, 146.4, 147.4, 163.0. Anal. Calcd for C₂₁H₂₄N₂O (320.43): C 78.71, H 7.55, N 8.74; Found: C 79.26, H 7.89, N 9.03.
• 30 CrysAlis RED . ; Version 1.171.37.35g Oxford Diffraction Ltd; London:
• 31 Dolomanov OV. Bourhis LJ. Gildea RJ. Howard JA. K. Puschmann H. J. Appl. Crystallogr. 2009; 42: 339
• 32 Sheldrick GM. Acta Crystallogr., Sect. A 2008; 64: 112