Synlett, Table of Contents Synlett 2017; 28(04): 471-474DOI: 10.1055/s-0036-1588348 letter © Georg Thieme Verlag Stuttgart · New YorkAn Expedient Synthesis of 2-Aryl-1,4-benzoxazin-3-ones via Tandem Anionic Cyclisation/Alkylation Reactions of N-Boc-O-benzyl-2-aminophenols Authors Author Affiliations Olga Bodero Department of Chemistry, South Kensington Campus, Imperial College London, SW7 2AZ, UK Email: a.c.spivey@imperial.ac.uk Alan C. Spivey* Department of Chemistry, South Kensington Campus, Imperial College London, SW7 2AZ, UK Email: a.c.spivey@imperial.ac.uk Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) Abstract A one-pot, tandem anionic cyclization/alkylation reaction of N-Boc-O-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-ones is described. The Boc protecting group plays a crucial role in the process, as the tert-butoxide liberated in the cyclisation step facilitates the benzylic deprotonation necessary for the subsequent alkylation. The reaction gives expedient access to a range of substitution patterns in 1,4-benzoxazin-3-ones of potential biological relevance. Key words Key words1,4-benzoxazin-3-one - cyclization - alkylation - reagent recycling - DIBOA Full Text References References and Notes 1a Macias FA, Marin D, Oliveros-Bastidas A, Molinillo JM. G. Nat. Prod. Rep. 2009; 26: 478 1b Hashimoto Y, Shudo K. Phytochemistry 1996; 43: 551 2 Hamilton RH, Bandurski RS, Reusch WH. Cereal Chem. 1962; 39: 107 3 Bravo HR, Lazo W. J. Agric. Food Chem. 1996; 44: 1569 4a Friebe A, Vilich V, Hennig L, Kluge M, Sicker D. Appl. Environ. Microbiol. 1998; 64: 2386 4b Macchiarulo A, Costantino G, Fringuelli D, Vecchiarelli A, Schiaffella F, Fringuelli R. Bioorg. Med. Chem. 2002; 10: 3415 5 Frechette R, Beach M. PCT Int Appl WO9728167 A1, 1997 6a Dudley DA, Bunker AM, Chi L, Cody WL, Holland DR, Ignasiak DP, Janiczek-Dolphin N, McClanahan TB, Mertz TE, Narasimhan LS, Rapundalo ST, Trautschold JA, Van Huis CA, Edmunds JJ. J. Med. Chem. 2000; 43: 4063 6b Huang W, Zhang P, Zuckett JF, Wang L, Woolfrey J, Song Y, Jia ZJ, Clizbe LA, Su T, Tran K, Huang B, Wong P, Sinha U, Park G, Reed A, Malinowski J, Hollenbach SJ, Scarborough RM, Zhu B.-Y. Bioorg. Med. Chem. Lett. 2003; 13: 561 7a Meguro K, Nishikawa K. Eur. Patent EP0233728 A1, 1987 7b Powell NA, Ciske FL, Cai C, Holsworth DD, Mennen K, Van Huis CA, Jalaie M, Day J, Mastronardi M, McConnell P, Mochalkin I, Zhang E, Ryan MJ, Bryant J, Collard W, Ferreira S, Gu C, Collins R, Edmunds JJ. Bioorg. Med. Chem. 2007; 15: 5912 8 Ilaš J, Anderluh PŠ, Dolenc MS, Kikelj D. Tetrahedron 2005; 61: 7325 9 Özden S, Murat Öztürk A, Göker H, Altanlar N. Farmaco 2000; 55: 715 10a Xing X, Wu J, Feng G, Dai W.-M. Tetrahedron 2006; 62: 6774 10b Martinand-Lurin E, El Kaïm L, Grimaud L. Tetrahedron Lett. 2014; 55: 5144 11 Ylijoki KE. O, Kundig EP. Chem. Commun. 2011; 47: 10608 12 Chen D, Shen G, Bao W. Org. Biomol. Chem. 2009; 7: 4067 13 Bayly AR, White AJ. P, Spivey AC. Eur. J. Org. Chem. 2013; 2013: 5566 14 Maggi R, Schlosser M. J. Org. Chem. 1996; 61: 5430 15a Zhou J, Zeng X.-P In Multicatalyst System in Asymmetric Catalysis . John Wiley & Sons; New York: 2014: 633-670 15b Zhu F, Xu P.-W, Zhou F, Wang C.-H, Zhou J. Org. Lett. 2015; 17: 972 16 Kinoshita T, Okada S, Park S.-R, Matsunaga S, Shibasaki M. Angew. Chem. Int. Ed. 2003; 42: 4680 17 Brindisi M, Gemma S, Alfano G, Kshirsagar G, Novellino E, Campiani G, Butini S. Tetrahedron Lett. 2013; 54: 5387 18 General Procedure; Anionic Cyclisation/Alkylation Reaction: To a solution of the appropriate N-Boc-O-benzyl-2-aminophenol (0.3 mmol) in anhyd THF (1 mL) under nitrogen atmosphere cooled at –78 °C, a solution of t-BuLi was added dropwise (1.7 M in pentane, 0.39 mL, 0.66 mmol). The solution immediately turned orange. It was stirred at –78 °C for 10 min, then 2 h at –20 °C. Then the corresponding electrophile was added (0.6 mmol) and the resulting mixture was stirred for an additional 2 h at 20 °C before being quenched with H2O (5 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL) and the combined organic extracts washed with H2O (20 mL) and brine (20 mL), dried over MgSO4 and filtered. The product was purified by flash chromatography eluting with hexane–EtOAc (9:1 → 8:2). Data for selected products (for all data, see Supporting Information) follows. 2a: mp 110–111 °C. 1H NMR (400 MHz, CDCl3): δ = 8.88 (br s, 1 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.20–7.35 (m, 3 H), 7.09–7.18 (m, 1 H), 7.00 (td, J = 7.8, 1.5 Hz, 1 H), 6.90 (td, J = 7.7, 1.3 Hz, 1 H), 6.73 (dq, J = 7.9, 1.4 Hz, 1 H), 4.65–5.13 (m, 2 H), 3.21 (d, J = 14.7 Hz, 1 H), 2.84 (d, J = 14.7 Hz, 1 H), 1.81 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 167.3, 142.9, 140.5, 139.0, 128.3, 128.0, 126.1, 125.6, 124.1, 122.4, 120.7, 117.5, 115.5, 115.4, 84.7, 46.8, 28.7, 28.3, 24.5. HRMS (ES): m/z [M + H+] calcd for C18H18NO2: 280.13318; found: 280.1335. IR: 1680, 1502, 1448, 1370, 1155, 1057 cm–1. 2g: mp 150–155 °C. 1H NMR (400 MHz, CDCl3): δ = 9.56 (s, 1 H), 7.56 (d, J = 6.8 Hz, 2 H), 7.22–7.36 (m, 3 H), 7.17 (d, J = 7.9 Hz, 1 H), 7.02 (td, J = 7.8, 1.4 Hz, 1 H), 6.91 (td, J = 7.8, 1.4 Hz, 1 H), 6.81 (dd, J = 7.8, 1.4 Hz, 1 H), 2.38 (dd, J = 14.5, 6.8 Hz, 1 H), 2.12 (dd, J = 14.5, 6.8 Hz, 1 H), 0.98–1.08 (m, 1 H), 0.35–0.57 (m, 2 H), 0.19–0.33 (m, 1 H), 0.00–0.08 (m, 1 H). 13C NMR (101 MHz, CDCl3): δ = 168.2, 143.3, 139.3, 128.3, 127.9, 126.3, 125.7, 124.4, 122.2, 117.3, 115.6, 84.9, 44.6, 6.0, 4.6, 4.4. HRMS (ES): m/z [M + H+] calcd for C18H18NO2: 280.1338; found: 280.1345, IR: 1688, 1502, 1428, 1368, 1124, 1045 cm–1. 2h: mp 123–126 °C. 1H NMR (400 MHz, CDCl3): δ = 9.35 (s, 1 H), 8.54 (s, 1 H), 8.40–8.50 (m, 1 H), 7.58 (d, J = 12 Hz, 1 H), 7.46 (dd, J = 6.1, 1.8 Hz, 2 H), 7.22–7.35 (m, 3 H), 7.06–7.18 (m, 2 H), 6.97 (ddd, J = 7.9, 6.1, 1.8 Hz, 1 H), 6.88 (ddd, J = 7.9, 6.1, 1.8 Hz, 1 H), 6.72 (dt, J = 7.9, 1.8 Hz, 1 H), 3.72 (dd, J = 14.1, 1.6 Hz, 1 H), 3.40 (dd, J = 14.1, 1.6 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 166.6, 152.1, 147.9, 142.7, 138.7, 138.0, 131.3, 128.5, 128.4, 126.1, 125.7, 124.1, 122.8, 122.6, 117.5, 115.5, 84.1, 43.0, 28.2. HRMS (ES): m/z [M + H+] calcd for C20H17N2O2: 317.1290; found: 317.1302. IR: 1682, 1502, 1448, 1372, 1128, 1031 cm–1. Supplementary Material Supplementary Material Supporting Information (PDF)
