Diastereo- and Enantioselective Propargylation of Benzofuranones. Catalyzed by Pybox-Copper Complex

Transcript

1 Diastereo- and Enantioselective Propargylation of Benzofuranones Catalyzed by Pybox-Copper Complex Long Zhao, Guanxin Huang, Beibei Guo, Lijun Xu, Jie Chen, Weiguo Cao, Gang Zhao, *, Xiaoyu Wu *, Department of Chemistry, College of Sciences, Shanghai University 99 Shangda Rd, Shanghai , China Key Laboratory of Synthetic rganic Chemistry of Natural Substances, Shanghai Institute of rganic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai , China General Information S1 Experimental procedure for propargylation of benzofuranones s1 Screening of bases and solvents s2 1 H NMR, 13 C NMR, MS, HPLC and specific rotation data of S2-8 Procedure for cyclization of alkyne products with 1-azido-4-bromobenzene S7 xidation of the terminal alkyne into a methyl ketone S8 1 H NMR, 13 C NMR, MS, HPLC and specific rotation data of S8 Single-crystal X-ray analysis of 3a S9 Single-crystal X-ray analysis of 3ag S9 1 H NMR, 13 C NMR, MS, HPLC and specific rotation data of 8 and S9-10 General procedure for preparation of 2-substituted benzofuran-3(2h)-ones S10 1 H NMR, 13 C NMR, MS data of 2-substituted benzofuran-3(2h)-ones S11-12 General Procedure for preparation of propargylic acetates S12 1 H NMR, 13 C NMR, MS data of propargylic acetates S H NMR, 13 C NMR and HPLC spectra of isolated compounds S15-65 General Information: Thin-layer chromatography (TLC) carried out on 0.25 mm silica gel plates visualized with UV light and/or by staining with ethanolic phosphomolybdic acid (PMA) or iodine. Flash column chromatography was performed on silica gel ( mesh). NMR spectras were recorded on Bruker AM500 (500MHz). Chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hz. ptical rotations were taken on JASC P1030. High-resolution mass spectra were recorded on Bruker ApeXIII 7.0 TESLA FTMS. Enantiomeric excesses were determined by chiral HPLC using a Shimadzu instrument. Experimental procedure for propargylation of benzofuranones: Ac CuBr (5%), ligand A (6%) CEt + Ph DIPEA (2equ), MeH 20 C 1a 2a 3a Ph CEt In a 25 ml Schlenk flask was placed CuBr (1.5 mg, mmol) and A (3.9 mg, mmol) under N 2. Anhydrous MeH (2 ml) was added, and the mixture was magnetically stirred at 20 C for 15 min. Then propargylic acetate 2a (0.2 mmol) and a solution of benzofuranones 1a (0.4 mmol) and diisopropylethylamine (0.07ml, 0.4mmol) in MeH (1.5 ml) were added dropwise successively. The reaction flask was kept at 20 C for 0.5 h. After complete comsumption of 2a as N N A N 1

2 followed by TLC the reaction was quenched with H 2. The product was then extracted three times with diethyl ether (30 ml). The combined organic layer was dried over Na 2 S 4. Solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to afford pure 3a (60 mg, 0.19 mmol) as a white solid in a yield of 94%. Screening of bases and solvents a Ac CuBr (5%), ligand A (6%) CEt + Ph Base (2equ), solvent 20 C 1a 2a 3a Ph CEt entry base solvent time yield% b ee c dr c 1 DIPEA MeH 0.5 h :2 2 d DBU MeH 0.25 h :6 3 TEA MeH 0.5 h :4 4 DMAP MeH 0.5 h :50 5 Cs 2 C 3 MeH 24 h - e DIPEA EtH 0.5 h :28 7 DIPEA THF 0.5 h :50 8 DIPEA DCM 0.5 h :64 9 DIPEA DMF 24 h - e DIPEA CH 3 CN 0.5 h :50 N N A N a Genreal conditions: 1a (0.4 mmol), 2a (0.2 mmol), CuBr (5 mol%), ligand A (6 mol%) and DIPEA (2 equiv) in methanol (4 ml) at 20 o C. b Yield referred to isolated 3a and its diastereoismer. c Enantiomeric excess and diastereoselectivity of 3a was determined by chiral HPLC analysis. d Reaction performed at 0 o C. e No formation of desired product was observed. Ph 3a CEt Compound 3a: white solid, actual mass 60 mg, yield 94%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 4H), (m, 4H), (m, 1H), 4.90 (s, 1H), (m, 2H), 2.42(s, 1H), (m, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 193.0, 172.5, 164.3, 138.7, 132.5, 129.6, 128.1, 128.0, 124.5, 122.5, 119.5, 113.1, 92.7, 80.6, 72.9, 63.2, 42.8, HRMS (ESI) calcd. for (C 20 H 16 4 Na) , found [α] D (c 1.1, CHCl 3 ). 2

3 HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 9 : 1, Flow rate = 1.0 ml/min, λ = 220 nm): t R = 7.46 min (minor enantiomer), t R = 6.89 min (major enantiomer). Me 3b CEt Compound 3b: light yellow oil, actual mass 61 mg, yield 91%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 1H), (m, 3H), (m, 3H), 4.87 (m, 1H), (m, 2H), 2.39 (s, 1H), 2.13 (s, 3H), (m, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 193.0, 172.5, 164.4, 138.5, 137.7, 129.4, 129.2, 128.7, 124.9, 124.5, 122.5, 119.6, 113.2, 92.8, 80.8, 72.7, 63.1, 42.3, 20.9, HRMS (ESI) calcd. for (C 21 H 18 4 Na) , found [α] D (c 0.85, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 49 : 1, Flow rate = 0.5 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Me 3c CEt Compound 3c: light yellow oil liquid, actual mass 64 mg, yield 91%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), 3.62 (s, 3H), 2.40 (s, 1H), 1.32 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 193.1, 172.5, 164.3, 159.2, 138.6, 130.5, 124.5, 122.6, 119.6, 113.5, 92.9, 80.9, 72.8, 63.1, 55.1, 41.9, HRMS (ESI) calcd. for (C 21 H 18 5 Na) , found [α] D (c 0.78, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 49 : 1, Flow rate = 0.5 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Cl CEt 3d Compound 3d: light yellow oil, actual mass 64 mg, yield 90%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 1.33 (t, J = 7.0 Hz, 3H). 3

4 13 C NMR (125 MHz, CDCl 3 ) δ 192.9, 172.5, 164.2, 138.9, 134.1, 131.1, 130.9, 129.5, 128.3, 124.7, 122.8, 122.5, 119.3, 116.7, 113.2, 92.5, 80.6, 72.9, 63.3, 41.9, HRMS (ESI) calcd. for (C 20 H 15 Cl 4 Na) , found [α] D (c 1.13, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 49 : 1, Flow rate = 0.5 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). CF 3 3e CEt Compound 3e: light yellow oil liquid, actual mass 61 mg, yield 79%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 3H), (m, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.7, 172.4, 164.1, 138.9, 136.7, 130.4, 130.0, 125.0, 124.7, 122.9, 119.3, 113.1, 92.4, 79.8, 73.6, 63.3, 42.2, HRMS (ESI) calcd. for (C 21 H 15 F 3 4 Na) , found [α] D (c 0.9, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 49 : 1, Flow rate = 0.5 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). F 3 C CF 3 3f CEt Compound 3f: light yellow oil liquid, actual mass 71 mg, yield 78%. 1 H NMR (500 MHz, CDCl 3 ): δ 7.83 (s, 2H), 7.57 (s, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 5.01 (s, 1H), 4.36 (q, J = 7.0 Hz, 2H), (m, 1H), 1.33 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.4, 172.1, 163.5, 139.1, 137.6, 135.4, 131.6, (q, J = 33 Hz, 2C), 129.8, 124.6, 123.2, (q, J = 272 Hz, 2C), 122.1, 119.2, 113.2, 91.8, 91.3, 78.8, 74.4, 63.4, 42.2, HRMS (ESI) calcd. for (C 22 H 14 F 6 4 Na) , found [α] D (c 1.0, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 17 : 3, Flow rate = 1.0 ml/min, λ = 220 nm): t R = 6.77 min (minor enantiomer), t R = min (major enantiomer). Br 3g CEt Compound 3g: light yellow solid, actual mass 72 mg, yield 90%. 1 H NMR (500 MHz, CDCl 3 ): δ 4

5 (m, 1H), (m, 1H), 7.22 (s, 4H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 1.33 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.8, 172.4, 164.1, 138.9, 132.3, 131.6, 129.5, 128.1, 124.7, 122.8, 122.3, 119.7, 117.2, 113.1, 92.4, 80.0, 73.3, 63.2, 42.0, HRMS (ESI) calcd. for (C 20 H 15 Br 4 Na) , found [α] D (c 0.78, CHCl 3 ). HPLC (Daicel CHIRALPAK D-H, Hexane : Isopropanol = 99 : 1, Flow rate = 0.3 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). 3h CEt Compound 3h: light yellow solid, actual mass 69 mg, yield 93%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.42 (br, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), 2.42 (s, 1H), 1.39 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.2, 172.4, 164.6, 138.4, 133.6, 130.8, 129.1, 128.9, 128.3, 126.4, 126.1, 125.6, 124.8, 124.6, 122.9, 122.4, 119.3, 112.9, 92.7, 81.5, 72.3, 63.3, HRMS (ESI) calcd. for (C 24 H 18 4 Na) , found [α] D (c 0.53, CHCl 3 ). HPLC (Phenomenex cellulose-1, Hexane : Isopropanol = 24 : 1, Flow rate = 0.8 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). 3i CEt Compound 3i: light yellow oil liquid, actual mass 27 mg, yield 45%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 2.21 (s, 1H), (m, 1H), (m, 2H), 1.28 (t, J = 7.08 Hz, 3H), (m, 3H), (m, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 193.8, 172.8, 164.5, 138.8, 124.9, 122.8, 122.6, 119.9, 113.6, 93.0, 81.2, 72.2, 62.9, 37.2, 29.3, 27.3, 22.0, 14.0, HRMS (ESI) calcd. for (C 18 H 20 4 Na) , found [α] D (c 0.53, CHCl 3 ). HPLC (Phenomenex cellulose-1, Hexane : Isopropanol = 24 : 1, Flow rate = 0.8 ml/min, λ = 220 nm): t R = 7.69 min (minor enantiomer), t R = 7.10 min (major enantiomer). 3j CEt 5

6 Compound 3j: light yellow oil, actual mass 22 mg, yield 40%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 1H), (m, 1H), 4.24 (q, J = 7.06 Hz, 2H), 2.08 (s, 1H), 1.49 (s, 3H), 1.53 (s, 3H), 1.25 (t, J = 7.06 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 193.8, 171.9, 164.1, 138.3, 124.6, 122.5, 120.8, 113.1, 91.7, 86.1, 70.4, 62.5, 38.3, 24.6, 23.9, HRMS (ESI) calcd. for (C 16 H 16 4 Na) , found [α] D (c 0.48, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 49 : 1, flow rate = 0.5 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Ph CMe 3ab Compound 3ab: white solid, actual mass 56 mg, yield 91%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 3H), (m, 4H), (m, 1H), 4.90 (s, 1H), 3.87 (s, 3H), 2.42 (s, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.8, 172.4, 164.9, 138.6, 134.6, 132.3, 129.5, 128.2, 128.1, 124.6, 122.6, 119.4, 113.2, 92.8, 80.5, 73.0, 53.8, HRMS (ESI) calcd. for (C 19 H 14 4 Na) , found [α] D (c 0.73, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 99 : 1, Flow rate = 0.8 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Br Ph 3ac CEt Compound 3ac: white solid, actual mass 72 mg, yield 91%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 4H), (m, 3H), (m, 1H), (m, 2H), (m, 1H), 1.35 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 191.4, 168.1, 163.1, 142.7, 134.1, 132.0, 129.4, 128.5, 128.3, 125.8, 122.1, 115.2, 107.4, 94.0, 79.9, 73.3, 63.4, 42.8, HRMS (ESI) calcd. for (C 20 H 15 Br 4 Na) , found [α] D (c 0.93, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 19 : 1, Flow rate = 0.8 ml/min, λ = 220 nm): t R = 7.77 min (minor enantiomer), t R = 8.09 min (major enantiomer). Ph Me CEt 3ad Compound 3ad: light yellow oil liquid, actual mass 63 mg, yield 90%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 1H), (m, 3H), (m, 1H),

7 (m, 1H), (m, 1H), (m, 2H), 3.78 (s, 3H), (m, 1H), 1.33 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 191.1, 190.3, 175.5, 175.0, 168.8, 168.6, 164.6, 163.9, 135.0, 132.6, 129.5, 129.3, 128.4, 128.0, 126.0, 125.6, 112.7, 112.5, 112.3, 96.1, 95.8, 93.5, 93.1, 80.7, 79.2, 73.2, 72.7, 63.0, 62.7, 55.9, 55.8, 42.4, 14.0, HRMS (ESI) calcd. for (C 21 H 18 5 Na) , found [α] D (c 0.88, CHCl 3 ). HPLC (Daicel CHIRALPAK D-H, Hexane : Isopropanol = 49 : 1, Flow rate = 0.5 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Me Ph 3ae CEt Compound 3ae: light yellow oil liquid, actual mass 63 mg, yield 90%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 1H), (m, 3H), 6.93 (s, 1H), (m, 1H), 4.89 (s, 1H), (m, 2H), (m, 1H), 2.33 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 192.2, 173.0, 164.5, 150.9, 134.9, 132.6, 129.6, 128.1, 124.2, 124.1, 117.1, 113.1, 92.9, 80.7, 72.7, 63.1, 42.5, 22.5, HRMS (ESI) calcd. for (C 21 H 18 4 Na) , found [α] D (c 0.58, CHCl 3 ). HPLC (Phenomenex cellulose-1, Hexane : Isopropanol = 99 : 1, Flow rate = 0.3 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Ph 3af CN Compound 3af: light yellow oil liquid, actual mass 41 mg, yield 75%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 5H), (m, 4H), (m, 1H), (m, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 190.3, 171.4, 139.5, 132.6, 130.5, 129.7, 129.4, 129.1, 128.9, 128.7, 128.3, 125.2, 123.7, 118.5, 113.4, 113.0, 82.2, 78.6, 74.9, HRMS (ESI) calcd. for (C 18 H 11 N 2 Na) , found [α] D (c 0.45, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 99 : 1, Flow rate = 0.3 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Procedure for cyclization of alkyne products with 1-azido-4-bromobenzene: Ph CH 3 crude product from propargylation reaction cyclization conditions Ph CH 3 3ag N N N Br 7

8 The crude product obtained from propargylation step was dissolved in DCM and H 2 (v/v = 1:1, 3 ml), Cu(Ac) 2 (0.2 equiv), L-(+)-sodium ascorbate (0.4 equiv), 1-azido-4-bromobenzene (1.5 equiv) were added successively. The mixture was stirred at room temperature for 3 h. The product was then extracted with DCM (10 ml x 2). The combined organic layer was dried over Na 2 S 4. Solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to afford pure compound (66 mg, 0.14 mmol) as a white solid in a yield of 72%. Ph CH 3 3ag N N N Br Compound 3ag: white solid, actual mass 66 mg, yield 72%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.21 (s, 1H), (m, 4H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 1H), 4.82 (s, 1H), 1.52 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 202.5, 171.4, 147.2, 138.0, 136.2, 136.0, 132.9, 129.4, 128.7, 127.3, 124.4, 122.3, 121.9, 121.7, 120.7, 120.4, 113.0, 91.2, 49.1, HRMS (ESI) calcd. for (C 24 H 18 BrN 3 2 Na) , found [α] D (c 0.38, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 9 : 1, Flow rate = 1.0 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). xidation of the terminal alkyne into a methyl ketone: Ph Ph Hg(TFA) 2 (5 mol%) C 2 Et TFA (3 equiv), C 2 Et 3a DCM, rt, 2 h 4 98% ee, 98:2 dr 84% yield >98% ee, 99:1 dr To a solution of 3a (64 mg, 0.2 mmol) in 2mL DCM, Hg(TFA) 2 (4.3 mg, 0.01 mmol) and TFA (30 μl, 0.4 mmol) was added successively while stirring. The reaction mixture was stirred for 2 h at room temperature. Then the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to afford pure 4 (57 mg, 0.17 mmol) as a white solid in a yield of 84%. 4 Ph C 2 Et Compound 4: white solid, actual mass 57 mg, yield 84%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 3H), (m, 5H), (m, 1H), 5.00 (s, 1H), (m, 2H), 2.09 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 204.4, 195.0, 173.0, 165.4, 138.6, 137.7, 130.4, 130.3, 129.1, 128.7, 128.6, 128.4, 124.5, 122.4, 120.8, 119.1, 113.3, 90.7, 63.1, 62.8, 28.5,

9 HRMS (ESI) calcd. for (C 20 H 18 5 Na) , found [α] D (c 0.61, CHCl 3 ). HPLC (Daicel CHIRALPAK IA, Hexane : Isopropanol = 9 : 1, Flow rate = 1.0 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). Single-crystal X-ray analysis of 3a: Single-crystal X-ray analysis of 3ag: Ph N NN C 2 Et 8 Br Compound 8: pale yellow solid, actual mass 79 mg, yield 77%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 5H), (m, 2H), (m, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 4H), 1.05 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 201.3, 169.5, 154.9, 149.2, 137.5, 136.0, 135.3, 134.9, 132.9, 130.0, 128.1, 127.3, 127.2, 126.0, 124.5, 122.2, 121.7, 120.5, 65.9, 61.9, 45.4, 34.1, HRMS (ESI) calcd. for (C 27 H 22 BrN 3 3 Na) , found [α] D (c 0.55, CHCl 3 ). HPLC (Daicel CHIRALPAK IC, Hexane : Isopropanol = 95 : 5, Flow rate = 1.0 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). 9

10 C 2 Et 9a N N N Br Compound 9a: white solid, actual mass 92 mg, yield 86%. 1 H NMR (500 MHz, CDCl 3 ): δ 7.92 (s, 1H), (m, 1H), (m, 2H), (m, 4H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), 5.27 (d, J = 12 Hz, 1H), 5.11 (s, 1H), 4.84 (d, J = 12 Hz, 1H), (m, 2H), 0.94 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 188.5, 168.0, 160.9, 147.7, 137.1, 136.1, 135.9, 132.8, 130.8, 128.3, 127.9, 127.6, 122.2, 121.8, 121.7, 121.6, 120.7, 117.7, 71.9, 61.9, 61.3, 44.9, HRMS (ESI) calcd. for (C 27 H 22 BrN 3 4 Na) , found HPLC (Phenomenex cellulose-1, Hexane : Isopropanol = 9 : 1, Flow rate = 1.0 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). CH 3 C 2 Et 9b N N N Br Compound 9b: a white solid, actual mass 80 mg, yield 73%. 1 H NMR (500 MHz, CDCl 3 ): δ 7.90 (s, 1H), (m, 1H), (m, 6H), (m, 1H), (m, 2H), (m, 2H), 5.27 (d, J = 12.5 Hz, 1H), 5.10 (s, 1H), 4.86 (d, J = 12.5 Hz, 1H), (m, 2H), 2.28 (s, 3H), 0.94 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 188.5, 168.0, 160.9, 147.9, 137.3, 136.1, 135.9, 134.0, 132.8, 130.6, 129.0, 127.9, 122.2, 121.7, 121.6, 120.6, 117.7, 71.8, 61.8, 61.3, 44.4, 21.0, HRMS (ESI) calcd. for (C 28 H 24 BrN 3 4 Na) , found [α] D (c 0.44, CHCl 3 ). HPLC (Phenomenex cellulose-1, Hexane : Isopropanol = 9 : 1, Flow rate = 1.0 ml/min, λ = 220 nm): t R = min (minor enantiomer), t R = min (major enantiomer). General procedure for preparation of 2-substituted benzofuran-3(2h)-ones 1: H CH t-buk THF,0 C EtH,H 2 S 4 reflux 1a CEt H CEt Br K 2 C 3,acetone reflux CEt To a solution of 2-hydroxybenzoic acid (5.0 g, 36.2 mmol) in anhydrous EtH (150 ml) was added 98% H 2 S 4 (4 ml). The mixture was refluxed for 4 h and concentrated. The residue was extracted with CH 2 Cl 2 dried over Na 2 S 4 and evaporated. The residue was purified by flash chromatography on silica gel to afford pure ethyl 2-hydroxybenzoate (6 g, 36 mmol) as colorless oil in a yield of 99%. To a solution of ethyl-2-hydroxybenzoate (6 g, 36 mmol) in acetone (50 ml) was added 10

11 potassium carbonate (9.95 g, 72 mmol) and ethyl bromoacetate (4.78 ml, 43.2 mmol). The reaction mixture was stirred at 60 C for 3 h. The white solid was removed by filtration and the filtrate concentrated under reduced pressure, yielding the desired product as orange oil (10.5 g, 96% yield). Under the atmosphere of nitrogen, a 100 ml flask was charged with potassium tert-butoxide (3.88 g, 69 mmol), 50 ml THF was added and the resulting solution was cooled with ice bath. The mixture was stirred for 30 min. A solution of ethyl 2-(2-ethoxy-2-oxoethoxy)benzoate in 20 ml THF was added dropwise while stirring. The resulting solution was stirred for 0.5 h. After the reaction was complete, the reaction was quenched with NH 4 Cl (satd. aq.) and extracted three times with EA. The organic layer was washed with NH 4 Cl (satd. aq.) and dried over Na 2 S 4. Solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to afford pure 1a (5.1 g, 24.9 mmol) as a white solid in a yield of 75%. ethyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate: white solid, actual mass 5.1 g, yield 85%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.12 (br, 1H), 7.66 (d, J = 7.88 Hz, 1H), (m, 2H), (m, 1H), 4.41 (q, J = 7.09 Hz, 2H), 1.39 (t, J = 7.09 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 153.5, 129.1, 126.0, 122.9, 120.4, 120.1, 112.4, 61.2, HRMS (ESI) calcd. for (C 11 H 11 4 ) , found methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate: white solid, actual mass 3.2g, yield 82%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.07 (br, 1H), 7.71 (d, J = 7.89 Hz, 1H), (m, 2H), (m, 1H), 3.98 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 153.6, 129.3, 125.9, 123.1, 120.6, 120.0, 112.5, HRMS (ESI) calcd. for (C 10 H 9 4 ) , found ethyl 5-bromo-3-oxo-2,3-dihydrobenzofuran-2-carboxylate: pale yellow solid, actual mass 2g, yield 80%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.11 (br, 1H), (m, 2H), 4.49 (q, J = 7.06 Hz, 2H), 1.45 (t, J = 7.06 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 149.3, 134.2, 127.9, 122.7, 122.3, 116.2, 106.4, 61.8, HRMS (ESI) calcd. for (C 11 H 10 Br 4 ) , found

12 ethyl 6-methoxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate: pale yellow solid, actual mass 2.3 g, yield 85%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.19 (br, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 3H), (m, 3H). HRMS (ESI) calcd. for (C 12 H 13 5 ) , found ethyl 5-methyl-3-oxo-2,3-dihydrobenzofuran-2-carboxylate: white solid, actual mass 2.8 g, yield 87%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), (m, 2H), (m, 2H), 3.95 (s, 1H), 2.43 (s, 3H), (m, 3H). HRMS (ESI) calcd. for (C 12 H 13 4 ) , found oxo-2,3-dihydrobenzofuran-2-carbonitrile: prepared according to a literature procedure (J. Chem. Soc. 1965, 2361); yellow solid, actual mass 2 g, yield 76%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H). 1g CH 3 2-methylbenzofuran-3(2H)-one: prepared according to a literature procedure (Synth. Commun. 2012, 42, 989); oily liquid, actual mass 1.5 g, yield 83%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 4.57 (q, J = 7.24 Hz, 1H), 1.46 (d, J = 7.24 Hz, 3H). General Procedure for preparation of propargylic acetates 2: Br Mg, I2 MgBr CH H Ac 2,Et 3 N Ac THF THF,-78 C DCM, rt 2a A freshly prepared Grignard reagent (40.0 mmol) in 50 ml THF under nitrogen atomosphere in a 250 ml flask was cooled to -78 C. Propargyl aldehyde (1.5 g, 27.8 mmol) was added dropwise while stirring. The resulting solution was stirred for min. The reaction was quenched with NH 4 Cl (satd. aq.), the organic layer was separated, and the aqueous layer was then extracted three times with EA. The combined organic layer was dried over Na 2 S 4. Solvent was removed under 12

13 reduced pressure. The residue was purified by flash chromatography on silica gel to afford pure 1-phenylprop-2-yn-1-ol (3.3 g, 25 mmol) as pale yellow oil in a yield of 90%. A 100 ml flask was charged with 50 ml DCM, 1-phenylprop-2-yn-1-ol (3.3 g, 25 mmol) and Et 3 N (3.8 ml, 27.5 mmol). The solution was cooled with ice bath, followed by dropwise addition of acetic anhydride (2.83 ml, 30 mmol). The solution was gradually warmed to room temperature and stirred for 3 h at this temperature. After complete consumption of 1-phenylprop-2-yn-1-ol as followed by TLC, solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to afford pure 2a (3.7g, 21.3 mmol) as as a pale yellow oil in a yield of 85%. Ac 2a 1-phenylprop-2-ynyl acetate: known compound (J. rg. Chem. 2011, 76, 500); a pale yellow oil liquid, actual mass 3.7g, yield 85%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 3H), 6.45 (s, 1H), 2.65 (s, 1H), 2.11 (s, 3H). 1-p-tolylprop-2-ynyl acetate: known compound (J. rg. Chem. 2011, 76, 500); a pale yellow oil liquid, actual mass 2.3g, yield 87%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), (m, 1H), 2.64 (s, 1H), 2.36 (s, 3H), 2.10 (s, 3H). 1-(4-methoxyphenyl)prop-2-ynyl acetate: known compound (Chem. Eur. J. 2011, 21, 5921); a pale yellow oil liquid, actual mass 2.1g, yield 82%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), (m, 1H), 3.80 (s, 3H), 2.66 (s, 1H), 2.08 (s, 3H). 1-(4-chlorophenyl)prop-2-ynyl acetate: known compound (J. rg. Chem. 2011, 76, 500); a pale yellow oil liquid, actual mass 2.8g, yield 83%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 6.41 (m, 1H), 2.67 (s, 1H), 2.10 (s, 3H). 1-(4-(trifluoromethyl)phenyl)prop-2-ynyl acetate: known compound (Angew. Chem. Int. Ed. 2008, 47, 3777); a pale yellow oil liquid, actual mass 3.8g, yield 89%. 1 H NMR (500 MHz, CDCl 3 ): δ 13

14 7.65 (s, 4H), 6.48 (s, 1H), 2.69 (s, 1H), 2.12 (s, 3H). 1-(3,5-bis(trifluoromethyl)phenyl)prop-2-ynyl acetate: a pale yellow oil liquid, actual mass 3.2g, yield 86%. 1 H NMR (500 MHz, CDCl 3 ): δ 7.99 (s, 2H), 7.89 (s, 1H), 6.52 (s, 1H), 2.74 (s, 1H), 2.15 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 139.0, (q, J = 33.6 Hz, 2C), (q, J = 2.75 Hz, 2C), (q, J = Hz, 2C), (m, 1C), 78.7, 76.9, 68.3, HRMS (ESI) calcd. for (C 13 H 9 F 6 2 ) , found Ac Br 2g 1-(4-bromophenyl)prop-2-ynyl acetate: known compound (J. rg. Chem. 2011, 76, 500); a pale yellow oil liquid, actual mass 1.2 g, yield 73%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 6.39 (s, 1H), 2.67 (s, 1H), 2.10 (s, 3H). 1-(naphthalen-1-yl)prop-2-ynyl acetate: known compound (Angew. Chem. Int. Ed. 2008, 47, 3777); a pale yellow oil, actual mass 1.5 g, yield 72%. 1 H NMR (500 MHz, CDCl 3 ): δ 8.16 (d, J = 8.43 Hz, 1H), (m, 3H), (m, 3H), 7.08 (s, 1H), 2.71 (s, 1H), 2.13 (s, 3H). hept-1-yn-3-yl acetate: known compound (Angew. Chem. Eng. Ed. 2013, 52, 3277); a pale yellow oil, actual mass 1.5 g, yield 71%. 1 H NMR (500 MHz, CDCl 3 ): δ (m, 1H), 2.44 (s, 1H), 2.08 (s, 3H), (m, 2H), (m, 4H), 0.91 (t, J = 7.15 Hz, 3H). 2-methylbut-3-yn-2-yl acetate: known compound (Adv. Synth. Catal. 2004, 346, 483); prepared from commercially available 2-methylbut-3-yn-2-ol following the general procedure; colorless oil, actual mass 1.2 g, yield 56%. 1 H NMR (500 MHz, CDCl 3 ): δ 2.50 (s, 1H), 2.00 (s, 3H), 1.64 (s, 6H). 14

15 Ph 3a CEt 15

16 Ph 3a CEt 16

17 Me 3b CEt 17

18 Me 3b CEt 18

19 Me 3c CEt 19

20 Me 3c CEt 20

21 Cl CEt 3d 21

22 Cl CEt 3d 22

23 CF 3 3e CEt 23

24 CF 3 3e CEt 24

25 F 3 C CF 3 CEt 3f 25

26 F 3 C CF 3 CEt 3f 26

27 Br 3g CEt 27

28 Br 3g CEt 28

29 3h CEt 29

30 3h CEt 30

31 3i CEt 31

32 3i CEt 32

33 3j CEt 33

34 3j CEt 34

35 Ph CMe 3ab 35

36 Ph CMe 3ab 36

37 Br 3ac Ph CEt 37

38 Br 3ac Ph CEt 38

39 Ph Me 3ad CEt 39

40 Ph Me 3ad CEt 40

41 Me 3ae Ph CEt 41

42 Me 3ae Ph CEt 42

43 Ph 3af CN 43

44 Ph 3af CN 44

45 Ph CH 3 3ag N N N Br 45

46 Ph CH 3 3ag N N N Br 46

47 4 Ph C 2 Et 47

48 4 Ph C 2 Et 48

49 Ph N NN C 2 Et 8 Br 49

50 Ph N NN C 2 Et 8 Br 50

51 Ph N N N C 2 Et 9a Br 51

52 Ph N N N C 2 Et 9a Br 52

53 CH 3 C 2 Et 9b N N N Br 53

54 CH 3 C 2 Et 9b N N N Br 54

55 55

56 56

57 57

58 58

59 59

60 60

61 61

62 62

63 63

64 64

65 65