Sultines as o-Quinodimethane Precursors in an Oxa-Diels–Alder Reaction: Synthesis of Functionalized Isochromans

Abstract

The development of an oxa-Diels–Alder reaction between sultines and carbonyl compounds is reported. o-Quinodimethanes, generated from sultines, undergo a [4+2]-cycloaddition with activated aldehydes or ketones in the presence of Cu(OTf)₂ to provide a variety of functionalized isochromans, including spiroisochromans, in up to 99% yield. The developed protocol demonstrates broad functional-group compatibility and tolerates unprotected isatins bearing free NH-functionalities.

Key words

quinodimethanes - oxa-Diels–Alder reaction - cycloaddition - sultines - isochromans

• References and Notes

• 1 Zhao Z, Kang K, Yue J, Ji X, Qiao H, Fan P, Zheng X. Eur. J. Med. Chem. 2021; 210: 113073
• 2 Cheng M, Li P, Jiang Y, Tang X, Zhang W, Wang Q, Li G. J. Nat. Prod. 2021; 84: 1345
• 3 Lakshminarayana N, Rajendra Prasad Y, Gharat L, Thomas A, Ravikumar P, Narayanan S, Srinivasan CV, Gopalan B. Eur. J. Med. Chem. 2009; 44: 3147
• 4 Larghi EL, Kaufman TS. Eur. J. Org. Chem. 2011; 2011: 5195
• 5 Muller C, Horký F, Vayer M, Golushko A, Lebœuf D, Moran J. Chem. Sci. 2023; 14: 2983

For reviews, see
• 6a Tamanna, Kumar M, Joshi K, Chauhan P. Adv. Synth. Catal. 2020; 362: 1907
• 6b Albano G, Aronica LA. Eur. J. Org. Chem. 2017; 2017: 7204

For some selected recent reports, see
• 7a Pandey G, Pal S, Laha R. Angew. Chem. Int. Ed. 2013; 52: 5146
• 7b Maity S, Parhi B, Ghorai P. Angew. Chem. Int. Ed. 2016; 55: 7723
• 7c Nickerson LA, Bergstrom BD, Gao M, Shiue Y.-S, Laconsay CJ, Culberson MR, Knauss WA, Fettinger JC, Tantillo DJ, Shaw JT. Chem. Sci. 2020; 11: 494
• 7d Jongcharoenkamol J, Jancharoen K, Batsomboon P, Ruchirawat S, Ploypradith P. Synthesis 2023; 55: 2757
• 8a Ngamnithiporn A, Chuentragool P, Ploypradith P, Ruchirawat S. Org. Lett. 2022; 24: 4192
• 8b Ngamnithiporn A, Chuentragool P, Ploypradith P, Ruchirawat S. Asian J. Org. Chem. 2023; 12: e202300366

For reviews on chemistry using sultines as masked; o-QDMs, see
• 9a Segura JL, Martín N. Chem. Rev. 1999; 99: 3199
• 9b Yang B, Gao S. Chem. Soc. Rev. 2018; 47: 7926
• 9c Kotha S, Khedkar P, Dommaraju Y. Tetrahedron Lett. 2019; 60: 631

For reviews on methods to prepare sultines, see
• 10a Zhu Z, Deng Z, Ouyang X, Shu C. Synlett 2023; 34: 1943
• 10b Zhang Y, Li H, Yang X, Zhou P, Shu C. Chem. Commun. 2023; 59: 6272
• 10c Bondarenko OB, Saginova LG, Zyk NV. Russ. Chem. Rev. 1996; 65: 147
• 11 Janssen-Müller D, Singha S, Olyschläger T, Daniliuc CG, Glorius F. Org. Lett. 2016; 18: 4444
• 12 Wang H, Chen X, Li Y, Wang J, Wu S, Xue W, Yang S, Chi YR. Org. Lett. 2018; 20: 333
• 13 Hu Y, Pan D, Cong L, Yao Y, Yu C, Li T, Yao C. ChemistrySelect 2018; 3: 1708
• 14 Mavroskoufis A, Rajes K, Golz P, Agrawal A, Ruß V, Götze JP, Hopkinson MN. Angew. Chem. Int. Ed. 2020; 59: 3190
• 15 Wurm T, Turnbull BW. H, Ambler BR, Krische MJ. J. Org. Chem. 2017; 82: 13751
• 16a Hentemann MF, Allen JG, Danishefsky SJ. Angew. Chem. Int. Ed. 2000; 39: 1937
• 16b Ueno S, Ohtsubo M, Kuwano R. Org. Lett. 2010; 12: 4332
• 16c Gao M, Ruiz JM, Jimenez E, Lo A, Laconsay CJ, Fettinger JC, Tantillo DJ, Shaw JT. Chem. Sci. 2023; 14: 6443
• 17 Attardo GG. Doctoral Dissertation. McGill University; Canada: 1990
• 18 See the Supporting Information for full results and analysis.
• 19 Jung F, Molin M, Van der Elzen R, Durst T. J. Am. Chem. Soc. 1974; 96: 935
• 20 See the Supporting Information for additional optimization results.
• 21 For the determination of isomeric ratios and analyses of the major and minor isomers, see the Supporting Information.
• 22 Attempts to perform the reaction in the absence of Cu(OTf)₂ resulted in no detectable amount of product, with methyl dimethoxyacetate remaining unreacted.
• 23 For a list of unsuccessful substrates, see the Supporting Information.
• 24 Yamazaki S. Org. Lett. 1999; 1: 2129
• 25 Isochromans 5aa–5am; General Procedure A flame-dried 25-mL round-bottomed flask equipped with a magnetic stirrer bar was charged with the appropriate sultine (0.4 mmol, 2 equiv) and Cu(OTf)₂ (0.01 mmol, 5 mol %). The flask was sealed with a septum then evacuated and backfilled with argon for three cycles. The appropriate aldehyde or ketone (0.2 mmol, 1 equiv) and DCE (2 mL) were added, and the septum was replaced with a Findenser equipped with an Ar balloon at the top. The mixture was stirred at 90 °C (preheated oil bath) for 18 h, then cooled to r.t., and filtered through a silica plug that was subsequently rinsed with EtOAc. The organic phase was then concentrated in vacuo, and the crude product was purified by column chromatography (silica gel; EtOAc–hexanes). Ethyl Isochroman-3-carboxylate (5aa) Prepared from sultine 3a (67.3 mg, 0.4 mmol) and a 47% solution of ethyl glyoxylate (polymer form) in toluene (42 μL, 0.2 mmol) by the general procedure, and purified by column chromatography (silica gel, 10% EtOAc/hexanes) as a pale-yellow oil; yield: 37.9 mg (92%). ¹H NMR (400 MHz, CDCl₃): δ = 7.22–7.17 (m, 2 H), 7.16–7.12 (m, 1 H), 7.04–6.98 (m, 1 H), 5.01 (d, J = 15.0 Hz, 1 H), 4.87 (d, J = 15.1 Hz, 1 H), 4.37 (dd, J = 8.8, 5.7 Hz, 1 H), 4.29 (q, J = 7.1 Hz, 2 H), 3.16–2.99 (m, 2 H), 1.33 (t, J = 7.1 Hz, 3 H). Ethyl 6,7-Dimethylisochroman-3-carboxylate (5ab) Prepared from sultine 3b and a 47% solution of ethyl glyoxylate (polymer form) in toluene (42 μL, 0.2 mmol) by the general procedure, and purified by column chromatography (silica gel, 10% EtOAc/hexanes) as a yellow oil; yield: 43.7 mg (93%). IR (UATR): 2924, 1734, 1451, 1186, 1117 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.91 (s, 1 H), 6.78 (s, 1 H), 4.95 (d, J = 14.8 Hz, 1 H), 4.81 (d, J = 14.8 Hz, 1 H), 4.36–4.31 (m, 1 H), 4.28 (q, J = 7.6 Hz, 2 H), 3.05–2.93 (m, 2 H), 2.22 (s, 3 H), 2.22 (s, 3 H), 1.32 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.4, 135.2, 135.0, 131.1, 129.9, 129.0, 125.3, 73.7, 67.9, 61.4, 30.6, 19.6, 14.5. HRMS (ESI-TOF); m/z [M + H]⁺ calcd for C₁₄H₁₉O₃: 235.1329; found: 235.1329.