Facile Construction of Hydantoin Scaffolds via a Post-Ugi Cascade Reaction

◊ These authors contributed equally to this work

Abstract

A small series of hydantoins was efficiently synthesized via a two-step Ugi/cyclization reaction sequence using alkyne group as a leaving group under basic conditions. This microwave-assisted one-pot cyclization strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like hydantoins.

Key words

hydantoins - multicomponent reactions (MCRs) - one-pot - alkyne group - leaving group

• References and Notes

• 1a Bowers EM, Yan G, Mukherjee C, Orry A, Wang L, Holbert MA, Crump NT, Hazzalin CA, Liszczak G, Yuan H, Larocca C, Saldanha SA, Abagyan R, Sun Y, Meyers DJ, Marmorstein R, Mahadevan LC, Alani RM, Cole PA. Chem. Biol. 2010; 17: 471
• 1b Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D, Digiammarino EL, Hansen TM, Risi RM, Frey R, Manaves V, Shaw B, Algire M, Hessler P, Lam LT, Uziel T, Faivre E, Ferguson D, Buchanan FG, Martin RL, Torrent M, Chiang GG, Karukurichi K, Langston JW, Weinert BT, Choudhary C, de Vries P, Van Drie JH, McElligott D, Kesicki E, Marmorstein R, Sun C, Cole PA, Rosenberg SH, Michaelides MR, Lai A, Bromberg KD. Nature 2017; 550: 128
• 1c May O, Nguyen PT, Arnold FH. Nat. Biotechnol. 2000; 18: 317
• 1d Martínez-López D, Yu M.-L, García-Iriepa C, Campos PJ, Frutos LM, Golen JA, Rasapalli S, Sampedro D. J. Org. Chem. 2015; 80: 3929
• 2 Nique F, Hebbe S, Peixoto C, Annoot D, Lefrançois J.-M, Duval E, Michoux L, Triballeau N, Lemoullec J.-M, Mollat P, Thauvin M, Prangé T, Minet D, Clément-Lacroix P, Robin-Jagerschmidt C, Fleury D, Guédin D, Deprez P. J. Med. Chem. 2012; 55: 8225
• 3 Spicer JA, Lena G, Lyons DM, Huttunen KM, Miller CK, O’Connor PD, Bull M, Helsby N, Jamieson SM. F, Denny WA, Ciccone A, Browne KA, Lopez JA, Rudd-Schmidt J, Voskoboinik I, Trapani JA. J. Med. Chem. 2013; 56: 9542
• 4 Park J.-H, Lee G.-E, Lee S.-D, Hien TT, Kim S, Yang JW, Cho J.-H, Ko H, Lim S.-C, Kim Y.-G, Kang K.-W, Kim Y.-C. J. Med. Chem. 2015; 58: 2114
• 5 Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li X.-N, Song Y. J. Med. Chem. 2015; 58: 6899
• 6 Wang C, Zhao Q, Vargas M, Jones JO, White KL, Shackleford DM, Chen G, Saunders J, Ng AC. F, Chiu FC. K, Dong Y, Charman SA, Keiser J, Vennerstrom JL. J. Med. Chem. 2016; 59: 10705
• 7 Muccioli GG, Wouters J, Charlier C, Scriba GK. E, Pizza T, Di Pace P, De Martino P, Poppitz W, Poupaert JH, Lambert DM. J. Med. Chem. 2006; 49: 872
• 8 Last-Barney K, Davidson W, Cardozo M, Frye LL, Grygon CA, Hopkins JL, Jeanfavre DD, Pav S, Qian C, Stevenson JM, Tong L, Zindell R, Kelly TA. J. Am. Chem. Soc. 2001; 123: 5643
• 9a Watanabe N, Hamano M, Todaka S, Asaeda T, Ijuin HK, Matsumoto M. J. Org. Chem. 2012; 77: 632
• 9b Bischoff AJ, Nelson BM, Niemeyer ZL, Sigman MS, Movassaghi M. J. Am. Chem. Soc. 2017; 139: 15539
• 9c Matthews J, Rivero RA. J. Org. Chem. 1997; 62: 6090
• 10 Boeijen A, Kruijtzer JA. W, Liskamp RM. J. Bioorg. Med. Chem. Lett. 1998; 8: 2375
• 11a Dömling A. Chem. Rev. 2006; 106: 17
• 11b Sharma UK, Sharma N, Vachhani DD, Van der Eycken EV. Chem. Soc. Rev. 2015; 44: 1836
• 11c Hulme C, Dietrich J. Mol. Diversity 2009; 13: 195
• 11d Wolkenberg SE, Boger DL. Chem. Rev. 2002; 102: 2477
• 11e Bass PD, Gubler DA, Judd TC, Williams RM. Chem. Rev. 2013; 113: 6816
• 11f Yan Z.-Y, Xiao Y, Zhang L. Angew. Chem. Int. Ed. 2012; 51: 8624
• 11g Muñoz III SB, Lee W.-T, Dickie DA, Scepaniak JJ, Subedi D, Pink M, Johnson MD, Smith JM. Angew. Chem. Int. Ed. 2015; 54: 10600
• 11h Maskill KG, Knowles JP, Elliott LD, Alder RW, Booker-Milburn KI. Angew. Chem. Int. Ed. 2013; 52: 1499
• 12a Olimpieri F, Volonterio A, Zanda M. Synlett 2008; 3016
• 12b Olimpieri F, Bellucci MC, Marcelli T, Volonterio A. Org. Biomol. Chem. 2012; 10: 9538
• 13 Sañudo M, García-Valverde M, Marcaccini S, Torroba T. Tetrahedron 2012; 68: 2621
• 14a Song G, Li S, Yang Z, Yuan J, Wang M, Zhu J, Chen Z, Xu Z. Tetrahedron Lett. 2015; 56: 4616
• 14b Li S, Gao H, Lei J, Wang J, Xu J, Chen Z, Xu Z. RSC Adv. 2016; 6: 8461
• 14c Liao W, Li S, Wang J, Zhang Z, Yang Z, Xu D, Xu C, Lan H, Chen Z, Xu Z. ACS Comb. Sci. 2016; 18: 65
• 14d Li Y, Lei J, Chen Z, Tang D, Yuan H, Wang M, Zhu J, Xu Z. Eur. J. Org. Chem. 2016; 34: 5770
• 15 Ignacio JM, Macho S, Marcaccini S, Pepino R, Torroba T. Synlett 2005; 3051
• 16 CCDC 1853754 contains the supplementary crystallographic data for 7h. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 17a Abdelraheem EM. M, Kurpiewska K, Kalinowska-Tłuścik J, Dömling A. J. Org. Chem. 2016; 81: 8789
• 17b Kreye O, Tóth T, Meier M. J. Am. Chem. Soc. 2011; 133: 1790
• 17c Paravidino M, Scheffelaar R, Schmitz RF, de Kanter FJ. J, Groen MB, Ruijter E, Orru RV. A. J. Org. Chem. 2007; 72: 10239
• 17d Maeda S, Komagawa S, Uchiyama M, Morokuma K. Angew. Chem. Int. Ed. 2011; 50: 644
• 17e Reza KazemizadehA, Ramazani A. Curr. Org. Chem. 2012; 16: 418
• 18a Liepouri F, Bernasconi G, Petasis NA. Org. Lett. 2015; 17: 1628
• 18b Mundal DA, Lutz KE, Thomson RJ. J. Am. Chem. Soc. 2012; 134: 5782
• 18c Muncipinto G, Moquist PN, Schreiber SL, Schaus SE. Angew. Chem. Int. Ed. 2011; 50: 8172
• 19a Dong Y, Li R, Lu J, Xu X, Wang X, Hu Y. J. Org. Chem. 2005; 70: 8617
• 19b Thinnes CC, Tumber A, Yapp C, Scozzafava G, Yeh T, Chan MC, Tran TA, Hsu K, Tarhonskaya H, Walport LJ, Wilkins SE, Martinez ED, Müller S, Pugh CW, Ratcliffe PJ, Brennan PE, Kawamura A, Schofield CJ. Chem. Commun. 2015; 51: 15458
• 20a Cheng X, Goddard R, Buth G, List B. Angew. Chem. Int. Ed. 2008; 47: 5079
• 20b Bhagat S, Chakraborti AK. J. Org. Chem. 2007; 72: 1263
• 20c Joly GD, Jacobson EN. J. Am. Chem. Soc. 2004; 126: 4102
• 21a Xu L.-W, Xia C.-G, Li L. J. Org. Chem. 2004; 69: 8482
• 21b Kobayashi S, Kiyohara H, Yamaguchi M. J. Am. Chem. Soc. 2011; 133: 708
• 21c Hayashi Y, Tsuboi W, Ashimine I, Urushima T, Shoji M, Sakai K. Angew. Chem. Int. Ed. 2003; 42: 3677
• 21d Jiang J, Xu H.-D, Xi J.-B, Ren B.-Y, Lv F.-P, Guo X, Jiang L.-Q, Zhang Z.-Y, Hu W.-H. J. Am. Chem. Soc. 2011; 133: 8428
• 22 General Procedure for the Preparation of Hydantoin Compound 7A solution of aniline (1.0 mmol), propiolic acid (1.0 mmol), benzaldehyde (1.0 mmol), and isonitrile (1.0 mmol) were mixed in methanol with stirring overnight at room temperature. The reaction mixture was monitored by TLC. When no isonitrile was left, the solvent was removed under a gentle stream of nitrogen. Then, the residue was diluted with CH₃CN (5.0 mL) and K₂CO₃ (1.0 mmol) was added. The reaction mixture was treated in microwave at 100 °C for 10 min. After the microwave vial was cooled to room temperature, the reaction mixture was diluted with EtOAc (25 mL) and washed with water and brine. Then the organic layer was dried with Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography using a gradient of EtOAc/hexane (15–30%) to afford the relative targeted product 7.Analytical Data for Compound 7aWhite solid, 75%. ¹H NMR (400 MHz, CDCl₃): δ = 4.71–4.83 (q, J = 14.4 Hz, 2 H), 5.46 (s, 1 H), 7.05–7.09 (t, J = 7.6 Hz, 1 H), 7.23–7.27 (m, 2 H), 7.27–7.35 (m, 8 H), 7.43–7.47 (t, J = 8.8 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.59, 160.24, 154.41, 136.47, 135.75, 134.35, 130.37, 129.11, 128.74, 128.07, 124.75, 120.20, 119.01, 114.73, 112.21, 64.26, 42.90. HRMS (ESI): m/z calcd for C₂₂H₁₈N₂O₂ ⁺ [M + H]⁺: 343.14465; found: 343.14431.