Preparation of 2-Substituted 3-Methoxycarbonyl-4-methoxyfurans that Allow Access to Highly Functionalized Naphthalenes via Regioselective Cycloaddition with Alkoxybenzyne

Published as part of the ISHC Conference Special Section

Abstract

A facile synthetic method of 2-substituted 3-methoxycarbonyl-4-methoxyfurans has been developed, allowing construction of highly functionalized naphthalene derivatives via (1) regioselective benzyne [4+2] cycloaddition with α-alkoxybenzyne and (2) reductive aromatization.

Key words

natural products - cycloaddition - furans - benzyne

• References and Notes

• 1 Weber W. Zähner H. Siebers J. Schröder K. Zeeck A. Arch. Microbiol. 1979; 121: 111
• 2a Matsumoto N. Tsuchida T. Maruyama M. Kinoshita N. Homma Y. Iinuma H. Sawa T. Hamada M. Takeuchi T. J. Antibiot. 1999; 52: 269
• 2b Höltzel A. Dieter A. Schmid DG. Brown R. Goodfellow M. Beil W. Jung G. Fiedler H.-P. J. Antibiot. 2003; 56: 1058
• 3a Cameron DW. Bruyn PJ. Tetrahedron Lett. 1992; 33: 5593
• 3b Martin P. Rodier S. Mondon M. Renoux B. Pfeiffer B. Renard P. Pierré A. Gesson J.-P. Bioorg. Med. Chem. 2002; 10: 253
• 3c Kozhinov D. Behar V. J. Org. Chem. 2004; 69: 1378
• 3d Takikawa H. Nishii A. Suzuki K. Synthesis 2016; 48: 3331

For selected examples of benzyne–furan cycloaddition reaction, see:
• 4a Matsumoto T. Hosoya T. Katsuki M. Suzuki K. Tetrahedron Lett. 1991; 32: 6735
• 4b Matsumoto T. Hosoya T. Suzuki K. J. Am. Chem. Soc. 1992; 114: 3568
• 4c Hosoya T. Takashiro E. Matsumoto T. Suzuki K. J. Am. Chem. Soc. 1994; 116: 1004
• 4d Giles RG. F. Sargent MV. Sianipar H. J. Chem. Soc., Perkin Trans. 1 1991; 1571
• 4e Giles RG. F. Hughes AB. Sargent MV. J. Chem. Soc., Perkin Trans. 1 1991; 1581
• 4f Kaelin DE. Jr. Lopez OD. Martin SF. J. Am. Chem. Soc. 2001; 123: 6937
• 4g Apsel B. Bender JA. Escobar M. Kaelin DE. Jr. Lopez OD. Martin SF. Tetrahedron Lett. 2003; 44: 1075
• 5a Hayes DM. Hoffmann R. J. Phys. Chem. 1972; 76: 656
• 5b Inagaki S. Fukui K. Bull. Chem. Soc. Jpn. 1973; 46: 2240
• 5c Epiotis ND. Angew. Chem., Int. Ed. Engl. 1974; 13: 751
• 5d Inagaki S. Fujimoto H. Fukui K. J. Am. Chem. Soc. 1975; 97: 6108
• 5e Rondan NG. Domelsmith LN. Houk KN. Bowne AT. Levin RH. Tetrahedron Lett. 1979; 3237
• 6 Baker RW. Baker TM. Birkbeck AA. Giles RG. F. Sargent MV. Skelton BW. White AH. J. Chem. Soc., Perkin Trans. 1 1991; 1589
• 7a Hart H. Bashir-Hashemi A. Luo J. Meador MA. Tetrahedron 1986; 42: 1641
• 7b Hart H. Nwokogu G. J. Org. Chem. 1981; 46: 1251
• 7c Best WM. Collins PA. McCulloch RK. Wege D. Aust. J. Chem. 1982; 35: 843
• 7d Gribble GW. Kelly WJ. Sibi MP. Synthesis 1982; 143
• 8a Feist F. Ber. Dtsch. Chem. Ges. 1902; 3: 1545
• 8b Benary E. Ber. Dtsch. Chem. Ges. 1911; 14: 493
• 9a Gelin R. Galliaud A. Chantegrel B. Gelin S. Bull. Soc. Chim. Fr. 1974; 5: 1043
• 9b Gelin S. Hartmann D. J. Heterocycl. Chem. 1976; 13: 521
• 9c Moorthie VA. McGarrigle EM. Stenson R. Aggarwal VK. ARKIVOC 2007; (v): 139
• 9d Ünsal-tan O. Özden K. Rauk A. Balkan A. Eur. J. Med. Chem. 2010; 45: 2345
• 9e Ponoandian T. Muthusubramanian S. Tetrahedron 2013; 69: 527
• 10 Analytical Data for Compound 5 White solid; mp 57–59 °C. ¹H NMR (600 MHz, CDCl₃): δ = 2.51 (s, 3 H), 3.76 (s, 3 H), 3.85 (s, 3 H), 6.94 (s, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 14.7, 51.4, 58.4, 106.6, 121.3, 148.9, 159.7, 163.8. IR (ATR): 3144, 2952, 1698, 1616, 1446, 1288, 1105 cm^–1. ESI-HRMS: m/z calcd for C₈H₁₀NaO₄ [M + Na]⁺: 193.0471; found: 193.0466.
• 11 Experimental Procedure for [4+2] Cycloaddition To a mixture of o-iodoaryl triflate 6 (91.9 mg, 0.201 mmol) and furan 5 (48.3 mg, 0.284 mmol) in THF (1.9 mL) was dropwise added n-BuLi (0.57 M in hexane, 0.41 mL, 0.23 mmol) over 5 min at –95 °C. After stirring for 15 min, the reaction was quenched by adding water, and the products were extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/EtOAc = 4:1 to 3:1) to afford 1,4-epoxides 7 (56.3 mg, 80%) and 8 (3.3 mg, 5%) both as white solids.
• 12 Gilman H. Kyle RH. J. Am. Chem. Soc. 1952; 74: 3027
• 13a Guyot M. Molho D. Tetrahedron Lett. 1973; 14: 3433
• 13b Sammes PG. Wallace TW. J. Chem. Soc., Perkin Trans. 1 1975; 1377
• 13c Stevens RV. Bisacchi GS. J. Org. Chem. 1982; 47: 2393
• 13d Dodsworth DJ. Calcagno M.-P. Ehrmann U. Devadas B. Sammes PG. J. Chem. Soc., Perkin Trans. 1 1981; 2120
• 13e Townsend CA. Davis SG. Christensen SB. Link JC. Lewis CP. J. Am. Chem. Soc. 1981; 103: 6885

For our contributions, see:
• 13f Hosoya T. Hasegawa T. Kuriyama Y. Matsumoto T. Suzuki K. Synlett 1995; 177
• 13g Hosoya T. Hasegawa T. Kuriyama Y. Suzuki K. Tetrahedron Lett. 1995; 36: 3377
• 13h Hosoya T. Hamura T. Kuriyama Y. Matsumoto T. Suzuki K. Synlett 2000; 520
• 13i Hamura T. Hosoya T. Yamaguchi H. Kuriyama Y. Tanabe M. Miyamoto M. Yasui Y. Matsumoto T. Suzuki K. Helv. Chim. Acta 2002; 85: 3589

For a recent interpretation of the regioselectivity, see:
• 14a Medina JM. Mackey JL. Garg NK. Houk KN. J. Am. Chem. Soc. 2014; 136: 15798
• 14b Picazo E. Houk KN. Garg NK. Tetrahedron Lett. 2015; 56: 3511
• 15 The density functional theory (DFT) calculation was performed using Jaguar (version 8.8, Schrödinger Inc., LLC. New York, 2015). The HOMO of 5 was calculated at the B3LYP/6-31G (d) level.
• 16a Guinn DE. Summers JB. Heyman HR. Conway RG. Rhein DA. Albert DH. Magoc T. Carter GW. J. Med. Chem. 1992; 35: 2055
• 16b Sasaki I. Toyoda T. Yoshinaga H. Natsutani I. Takahashi Y. WO 2012008528, 2012
• 16c Dockerty P. Edens JG. Tol MB. Angeles DM. Domenech A. Hirsch AK. H. Veening J.-W. Scheffers D.-J. Witte MD. Org. Biomol. Chem. 2017; 15: 894
• 17 Use of 2 equiv of NaH gave lower yield of 11 (27% yield).