Direct Propargylation of ortho-Quinone Methides with Alkynyl Zinc Reagents: An Application to the One-Pot Synthesis of 2,3-Disubstituted Benzofurans

Abstract

A transition-metal-free propargylation of ortho-quinone methides (o-QMs) with alkynyl zinc reagents was achieved. A conjugate alkynylation of an o-QM and subsequent cyclization sequence in the presence of KOt-Bu for the synthesis of 2,3-disubstituted benzofurans in one pot was developed. This efficient strategy exhibits good functional-group compatibility and gives moderate to good yields. The present reaction might serve as an attractive method for the synthesis of polysubstituted benzofurans.

Key words

propargylation - ortho-quinone methides - alkynyl zinc reagents - benzofurans

• References and Notes


For recent reviews on the synthesis of 1-benzofurans, see:
• 1a Hou X.-L, Yang Z, Wong HN. C. Prog. Heterocycl. Chem. 2003; 15: 167
• 1b Dell CP. In Science of Synthesis, Vol. 10. Thomas JE. Thieme; Stuttgart: 2001. Chap. 10.1, 11
• 1c McCallion GD. Curr. Org. Chem. 1999; 3: 67

For recent selected examples of syntheses of 2,3-disubstituted benzofurans, see:
• 2a Chen C.-y, Dormer PG. J. Org. Chem. 2005; 70: 6964
• 2b Hu Y, Yang Z. Org. Lett. 2001; 3: 1387
• 2c Kao C.-L, Chern J.-W. J. Org. Chem. 2002; 67: 6772
• 2d Inoue M, Carson MW, Frontier AJ, Danishefsky SJ. J. Am. Chem. Soc. 2001; 123: 1878
• 2e Baralle A, Otsuka S, Guérin V, Murakami K, Yorimitsu H, Osuka A. Synlett 2015; 26: 327
• 2f Katritzky AR, Ji Y, Fang Y, Prakash I. J. Org. Chem. 2001; 66: 5613
• 2g Nakamura I, Mizushima Y, Yamamoto Y. J. Am. Chem. Soc. 2005; 127: 15022
• 2h Nakamura I, Mizushima Y, Yamagishi U, Yamamoto Y. Tetrahedron 2007; 63: 8670
• 2i Kim K.-O, Tae J. Synthesis 2005; 387
• 2j Ma X, Wu F, Yi X, Wang H, Chen W. Chem. Commun. 2015; 51: 6862
• 2k Agasti S, Maity S, Szabo KJ, Maiti D. Adv. Synth. Catal. 2015; 357: 2331
• 2l Lu B, Wang B, Zhang Y, Ma D. J. Org. Chem. 2007; 72: 5337
• 2m Reddy CR, Krishna G, Kavitha N, Latha B, Shin D.-S. Eur. J. Org. Chem. 2012; 5381
• 3 Shirota O, Pathak V, Sekita S, Satake M, Nagashima Y, Hirayama Y, Hakamata Y, Hayashi T. J. Nat. Prod. 2003; 66: 1128
• 4 Wallez V, Durieux-Poissonnier S, Chavatte P, Boutin JA, Audinot V, Nicolas J.-P, Bennejean C, Delagrange P, Renard P, Lesieur D. J. Med. Chem. 2002; 45: 2788
• 5 Malamas MS, Sredy J, Moxham C, Katz A, Xu W, McDevitt R, Adebayo FO, Sawicki DR, Seestaller L, Sullivan D, Taylor JR. J. Med. Chem. 2000; 43: 1293

For conjugated propargylations using transition metals as catalysts, see:
• 6a Nikishin GI, Kovalev IP. Tetrahedron Lett. 1990; 31: 7063
• 6b Lerum RV, Chisholm JD. Tetrahedron Lett. 2004; 45: 6591
• 6c Zhou L, Chen L, Skouta R, Jiang H.-f, Li C.-J. Org. Biomol. Chem. 2008; 6: 2969
• 6d Chen L, Li C.-J. Chem. Commun. 2004; 2362
• 6e Picquet M, Bruneau C, Dixneuf PH. Tetrahedron 1999; 55: 3937
• 6f Chang S, Na Y, Choi E, Kim S. Org. Lett. 2001; 3: 2089
• 6g Nishimura T, Washitake Y, Nishiguchi Y, Maeda Y, Uemura S. Chem. Commun. 2004; 1312
• 6h Nishimura T, Washitake Y, Uemura S. Adv. Synth. Catal. 2007; 349: 2563
• 7a Trost BM, Weiss AH. Adv. Synth. Catal. 2009; 351: 963
• 7b Rossiter BE, Swingle NM. Chem. Rev. 1992; 92: 771
• 7c Harutyunyan SR, den HartogT, Geurts K, Minnaard AJ, Feringa BL. Chem. Rev. 2008; 108: 2824
• 7d Alexakis A, Bäckvall JE, Krause N, Pàmies O, Diéguez M. Chem. Rev. 2008; 108: 2796
• 7e Fagnou K, Lautens M. Chem. Rev. 2003; 103: 169

For recent reviews of o- and p-quinone methides, see:
• 8a Willis NJ, Bray CD. Chem. Eur. J. 2012; 18: 9160
• 8b Singh MS, Nagaraju A, Anand N, Chowdhury S. RSC Adv. 2014; 4: 55924
• 8c Caruana L, Fochi M, Bernardi L. Molecules 2015; 20: 11733
• 8d Parra A, Tortosa M. ChemCatChem 2015; 7: 1524
• 8e Osipov DV, Osyanin VA, Klimochkin YN. Russ. Chem. Rev. 2017; 86: 625
• 8f Bai W.-J, David JG, Feng Z.-G, Weaver MG, Wu K.-L, Pettus TR. R. Acc. Chem. Res. 2014; 47: 3655
• 8g Pathak TP, Sigman MS. J. Org. Chem. 2011; 76: 9210
• 8h Nielsen CD-T, Abas H, Spivey AC. Synthesis 2018; 50: 4008
• 9a Liu X, Wang K, Guo W, Liu Y, Li C. Chem. Commun. 2019; 55: 2668
• 9b Lai Z, Wang Z, Sun J. Org. Lett. 2015; 17: 6058
• 9c Osipov DV, Osyanin VA, Voskressensky LG, Klimochkin YN. Synthesis 2017; 49: 2286
• 9d Guo W, Wu B, Zhou X, Chen P, Wang X, Zhou Y.-G, Liu Y, Li C. Angew. Chem. Int. Ed. 2015; 54: 4522
• 9e Chen M.-W, Cao L.-L, Ye Z.-S, Jiang G.-F, Zhou Y.-G. Chem. Commun. 2013; 49: 1660
• 9f El-Sepelgy O, Haseloff S, Alamsetti SK, Schneider C. Angew. Chem. Int. Ed. 2014; 53: 7923
• 9g Hsiao C.-C, Liao H.-H, Rueping M. Angew. Chem. Int. Ed. 2014; 53: 13258
• 9h Izquierdo J, Orue A, Scheidt KA. J. Am. Chem. Soc. 2013; 135: 10634
• 9i Wu B, Gao X, Yan Z, Huang W.-X, Zhou Y.-G. Tetrahedron Lett. 2015; 56: 4334
• 10 Miao M, Yin W, Wang L, Chen Z, Xu J, Ren H. J. Org. Chem. 2018; 83: 10602
• 11a Fisher KM, Bolshan Y. J. Org. Chem. 2015; 80: 12676
• 11b Hu J, Liu L, Wang X, Hu Y, Yang S, Liang Y. Green Sustainable Chem. 2011; 1: 165
• 11c Liu C.-R, Li M.-B, Yang C.-F, Tian S.-K. Chem. Eur. J. 2009; 15: 793
• 11d Liu Z, Liu L, Shafiq Z, Wu Y.-C, Wang D, Chen Y.-J. Synthesis 2007; 1961
• 11e Xu X, Liu J, Liang L, Li H, Li Y. Adv. Synth. Catal. 2009; 351: 2599
• 11f Pareek A, Dada R, Rana M, Sharma A, Yaragorla S. RSC Adv. 2016; 6: 89732
• 11g Rajesh M, Singam MK. R, Gadi RK, Reddy MS. ACS Omega 2018; 3: 17155
• 11h Rajesh M, Thirupathi N, Reddy TJ, Kanojiya S, Reddy MS. J. Org. Chem. 2015; 80: 12311
• 11i Zhang M, Yang J, Xu Q, Dong C, Han L.-B, Shen R. Adv. Synth. Catal. 2018; 360: 334
• 12 Li W.-T, Nan W.-H, Luo Q.-L. RSC Adv. 2014; 4: 34774
• 13 4-Fluoro-2-[1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl]phenol (2b); Typical ProcedureA 2.5 M solution of BuLi in hexanes (1.5 mmol) was added dropwise to a solution of ethynylbenzene (1.5 mmol) in anhyd THF (2 mL) at –20 °C under N₂, and the mixture was stirred for 30 min at –20 °C. A 1.0 M solution of ZnBr₂ in THF (1.5 mL) was added, and the resulting mixture was stirred for about 15 min at 0 °C. 4-fluoro-2-((4-methoxyphenyl)(tosyl)methyl)phenol 1b (193 mg, 0.5 mmol) was then added, and the mixture was stirred at rt for 15 h until the reaction was complete. The reaction was then quenched by adding sat. aq NH₄Cl (5 mL) and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with H₂O (3 × 10 mL), dried (Na₂SO₄), concentrated in vacuo, and purified by flash chromatography (silica gel, petroleum ether/EtOAc = 5:1) to give a yellow solid; yield: 140 mg (84%); mp 89–90 °C (PE–EtOAc); R_f = 0.66 (PE–EtOAc, 3:1). IR (neat): 3380, 2221, 1605, 1512, 1234, 1182, 1024 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.46 (m, 2 H), 7.37 (d, J = 8.8 Hz, 2 H), 7.32–7.30 (m, 3 H), 7.14–7.11 (m, 1 H), 6.89–6.82 (m, 3 H), 6.76–6.73 (m, 1 H), 5.37 (s, 1 H), 5.29 (s, 1 H), 3.79 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.6 (d, J_{C –F} = 40 Hz), 156.0, 149.1, 131.7, 131.6, 129.4, 129.3, 128.8, 128.3, 128.2, 122.7, 117.4 (d, J_{C –F} = 7.9 Hz), 115.7 (d, J_{C –F} = 24 Hz), 114.7 (d, J_C-F = 22.8 Hz), 114.2, 88.5, 85.4, 55.3, 37.7. HRMS (ES⁺-TOF): m/z [M + H]⁺ calcd for C₂₂H₁₈FO₂: 333.1291; found: 333.1288.