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1 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2019 Supporting Information Metal-free Difunctionalization of Alkynes to Access Tetrasubstituted Olefins through Spontaneous Selenosulfonylation of Vinylidene ortho-quinone Methide (VQM) Shengli Huang, a,b Zhili Chen, a Hui Mao, c Fangli Hu, a Dongmei Li, a Yu Tan, a Fengqing Yang b and Wenling Qin a* a Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing , P. R. China. b School of Chemistry and Chemical Engineering, Chongqing University, Chongqing , P. R. China. c Pharmaceutical and Material Engineering School, Jinhua Polytechnic, Jinhua, , Zhejiang Province, P. R. China. wenling.qin@cqu.edu.cn Contents I. General information...2 II. General procedure for the synthesis of o-alkynylnaphthols...2 III. General procedure for the synthesis of o-alkynylphenols...4 IV. General procedure for the synthesis of selenosulfonates...4 V. Optimization of the reaction conditions...6 VI. General procedure for the synthesis of compounds 3 or VII. General procedure for the synthesis of compounds 3t and 3u...8 VIII. Mechanistic studies...8 IX. Synthetic transformations...9 X. 1 H, 13 C NMR and HRMS data of compounds (1t, 1u, 3a-3u, 4a-4n, 7, 8, 9)...10 XI. HPLC traces of compound 3a...21 XII. 1 H and 13 C NMR spectra of compounds (1t, 1u, 3a-3u, 4a-4n, 7, 8, 9)...22 XIII. X-Ray Crystallographic information...62 XIV. Reference...63 S1

2 I. General information 1 H and 13 C NMR spectra were recorded on Agilent 400MR DD2 (400 MHz) spectrometer and Agilent 600MR DD2 (600 MHz) spectrometer. Chemical shifts were reported in parts per million (ppm), and tetramethylsilane or the residual solvent peak was used as an internal reference: CDCl 3 ( 1 H NMR δ 0.00, 13 C NMR δ 77.00). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz) and integration. High resolution mass spectra (HRMS) were performed on Bruker Solarix 7.0T. X-ray crystallography analysis of single crystal was performed on an Agilent SuperNova-CCD X-Ray diffractometer. Melting points were measured using SGWX-4A Microscopic melting point meter and are uncorrected. Enantiomeric excesses (ee) were determined by HPLC analysis on Hitachi Chromaster using DAICEL CHIRALCEL AD-H, 4.6 mm Ф 250 mml. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. II. General procedure for the synthesis of o-alkynylnaphthols The preparation of o-alkynylnaphthols were followed the literature procedure. 1, 2 Method A: (1a, 1b, 1c, 1e, 1f, 1p, 1q, 1r, 1s) Sulfuric acid (208.0 mmol) was added to a solution of 2-naphthol S (20.0 g, mmol) and potassium iodide (23.04 g, mmol) in methanol (400 ml) at 0 o C. A precipitate formed, and hydrogen peroxide (30% aqueous solution, mmol) was added. After 1.5 h of warming slowly to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH 2 Cl 2 (300 ml), washed with 25% sat.aq. Na 2 S 2 O 3 (250 ml) and water (200 ml), dried over Na 2 SO 4, and concentrated to provide a solid (26.32 g). This material was purified by column chromatography on silica gel (PE:EA = 20:1) to provide an orange solid S1 (34.0 g, 91%). Acetyl chloride (1.5 equiv.) was dropwise added to a solution of S1 (21.8 g, 80.7 mmol) and Et 3 N (22.4 ml, mmol) in CH 2 Cl 2 (200 ml) at 0 C under N 2. The reaction mixture was S2

3 stirred at 0 C for 30 min and then quenched with sat. aq. NH 4 Cl followed by extraction with CH 2 Cl 2. The organic phase was washed with brine and dried over Na 2 SO 4, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel to afford S2 (23.9 g, 95%). To a dry flask under N 2 containing S2 (5 mmol) was sequentially added Et 3 N (10 ml), appropriate alkynes (5 mmol), PdCl 2 (PPh 3 ) 2 (70 mg, 0.1 mmol), CuI (47.6 mg, 0.25 mmol). The mixture was stirred for 6 h at 50 C. Then the mixture was filtered through a pad of celite. Removal of solvent under reduced pressure afforded a residue which is purified by column chromatography on silica gel to afford S3. Hydrazine monohydrate (10 mmol) was dropwise added to a solution of S3 (2 mmol) in CH 3 CN (10 ml). After the resulted mixture was stirred at room temperature for 0.5 h, the mixture was treated with sat. aq. NH 4 Cl and extracted with CH 2 Cl 2 and dried over Na 2 SO 4. Removal of solvent under reduced pressure afforded a residue which is purified by column chromatography on silica gel to afford the compound 1. Method B: (1d, 1g-1o) Trimethylsilylacetylene (5.9 ml, 41.7 mmol) was dropwise added to a solution of S2 (10 g, 32.1 mmol), PdCl 2 (PPh 3 ) 2 (1.1 g, 1.6 mmol), CuI (609 mg, 3.2 mmol) and Et 3 N (13.4 ml, 96.1 mmol) in THF (50 ml) at room temperature under N 2. Then, the mixture was stirred for 12 h. The reaction mixture was treated with sat. aq. NH 4 Cl followed by extraction with CH 2 Cl 2. The combined organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA = 30:1) to afford S4 (7.3 g, 80% yield). To a solution of S4 (7.0 g, 24.8 mmol) in THF (75 ml) was added TBAF in THF (1 M, 12.4 ml, 12.4 mmol) dropwise at 0 C under N 2. Then the mixture was stirred for 1 h. The reaction mixture was treated with sat. aq. NH 4 Cl followed by extraction with CH 2 Cl 2. The combined organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA = 100:1) to afford S5 (3.9 g, 75% yield). S3

4 To a dry flask under N 2 containing the appropriate iodebenzenes (2.4 mmol) was sequentially added Et 3 N (5.0 ml), S5 (500 mg, 2.4 mmol), PdCl 2 (PPh 3 ) 2 (33.7 mg, mmol) and CuI (22.9 mg, 0.12 mmol). The mixture was stirred for 6 h at 50 C. Then the mixture was filtered through a pad of celite. Removal of solvent under reduced pressure afforded a residue which is purified by column chromatography on silica gel to afford S3. Hydrazine monohydrate (10 mmol) was dropwise added to a solution of S3 (2 mmol) in CH 3 CN (10 ml). After the resulted mixture was stirred at room temperature for 0.5 h, the mixture was treated with sat. aq. NH 4 Cl and extracted with CH 2 Cl 2, and dried over Na 2 SO 4. Removal of solvent under reduced pressure afforded a residue which is purified by column chromatography on silica gel afford the compound 1. III. General procedure for the synthesis of o-alkynylphenols To a dry flask under N 2 containing 2-iodophenol (10.0 mmol) was sequentially added THF (25 ml), diisopropylamine (10.0 mmol), appropriate alkynes (12.0 mmol), PdCl 2 (PPh 3 ) 2 (0.3 mmol), CuI (0.9 mmol). The resulting solution was stirred at room temperature for 3 h. Then the mixture was filtered through a pad of celite. Removal of solvent under reduced pressure afforded a residue which is purified by column chromatography on silica gel to afford appropriate o-alkynylphenols. IV. General procedure for the synthesis of selenosulfonates The preparation of compound S6 were followed the literature procedure. 3 To a stirred solution of Se 0 metal (10 mmol, 2.0 equiv.) and halides (5 mmol, 1.0 equiv.) in DMSO (10 ml) was added CuO nanoparticles (0.5 mmol, 0.1 equiv.) followed by KOH (10 mmol, 2.0 equiv.) under nitrogen atmosphere. The resulting reaction mixture was stirred at 90 C for 6 h. After the reaction was complete, the reaction mixture was allowed to cool, extraction with CH 2 Cl 2. The combined organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA = 100:1) to afford S6. S4

5 The preparation of compound 2 were followed the literature procedure. 4 A suspension of appropriate sodium benzenesulfinates (20 mmol, 4.0 equiv.) in CH 2 Cl 2 (50 ml) containing S6 (5 mmol, 1.0 equiv.) was cooled at 0 C and [bis(trifluoroacetoxy)iodo]benzene (5.5 mmol, 1.1 equiv.) in CH 2 Cl 2 (20 ml) was added dropwise. Then the mixture was stirred at room temperature for 3 h. The reaction mixture was washed with H 2 O, dried over anhydrous Na 2 SO 4. The solvent CH 2 Cl 2 was removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE:EA = 6:1) to afford compound 2. S5

6 V. Optimization of the reaction conditions Table 1. Screening of solvent [a] entry solvent additive yield (%) [b] E:Z [c] 1 CH 2 Cl 2-73 >99:1 2 CH 3 OH - 69 >99:1 3 DCE - 85 >99:1 4 m-xylene - 60 >99:1 5 toluene - 63 >99:1 6 [d] toluene - 64 >99:1 7 CH 3 CN - 54 >99:1 8 CHCl 3-52 >99:1 9 THF - <5 >99:1 [a] Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol) in solvent (1.0 ml) at room temperature for 10 h. [b] Yield ratio was determined by column chromatography. [c] Determined by 1 H NMR analysis. [d] The reaction were carried out at 80 C. Table 2. Screening of additive [a] entry solvent additive yield (%) [b] E:Z [c] 1 DCE Et 3 N 67 >99:1 2 DCE K 2 CO 3 69 >99:1 3 DCE KF 73 >99:1 4 DCE DABCO 70 >99:1 5 DCE malonic acid 72 >99:1 6 DCE benzoic acid 54 >99:1 7 DCE citric acid 57 >99:1 8 DCE cinnamic acid 49 >99:1 9 DCE boric acid <5 >99:1 10 DCE AIBN 48 >99:1 [a] Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), additive (0.1 mmol) in DCE (1.0 ml) at room temperature for 10 h. [b] Yield ratio was determined by column chromatography. [c] Determined by 1 H NMR analysis. S6

7 Table 3. Screening of conditions for phenol derivatives [a] entry solvent base T ( C ) time (h) yield (%) [b] 1 DCE - r.t DCE - reflux toluene - reflux DMF - reflux DMSO - reflux DCE K 2 CO 3 r.t DCE KF r.t DCE Na 2 CO 3 r.t DCE KOH r.t DCE NaOH r.t DCE t-buok r.t DCE EtONa r.t DCE MeONa r.t DCE NaOAc r.t DCE DABCO r.t DCE DBU r.t DCE Et 3 N r.t 24 trace 18 toluene Et 3 N reflux [a] Unless otherwise noted, all reactions were carried out with 1t (0.2 mmol) and 2a (0.2 mmol) in 2.0 ml solvents loading at corresponding temperature and reaction time. [b] Isolated yield of 3t. S7

8 VI. General procedure for the synthesis of compounds 3 or 4 The substrate 1 (0.2 mmol) and selenosulfonate 2 (0.2 mmol) were added to a 10 ml flame-dried schlenk tube with a magnetic stirring bar. DCE (2.0 ml) was injected into the tube. After stirring at room temperature for 10 h, the mixture was evaporated and purified by column chromatography on silica gel (PE:EA = 4:1) to afford the products 3 or 4. VII. General procedure for the synthesis of compounds 3t and 3u The Et 3 N (1.0 mmol) was added to a solution of substrate 1t or 1u (1.0 mmol) and selenosulfonate 2a (1.0 mmol) in toluene (10 ml). After reflux for 16 h, The mixture was evaporated and purified by column chromatography on silica gel (PE:EA = 4:1) to afford the products 3t or 3u. VIII. Mechanistic studies The substrate 1a (0.1 mmol), selenosulfonate 2a (0.1 mmol) and (2,2,6,6-tetramethyl-1-piperidinyl)oxyl (TEMPO) (0.1 mmol) were added to a 10 ml flame-dried schlenk tube with a magnetic stirring bar. DCE (1.0 ml) was injected into the tube. After stirring at room temperature for 72 h, The mixture was evaporated and purified by column chromatography on silica gel (PE:EA = 4:1) to afford the product 3a. S8

9 The substrate 5 (0.1 mmol) and selenosulfonate 2a (0.1 mmol) were added to a 10 ml flame-dried schlenk tube with a magnetic stirring bar. DCE (1.0 ml) was injected into the tube. Then the mixture was stirring at room temperature for 72 h. The substrate 1a (0.2 mmol), sodium 4-methy-benzenesulfinate (0.2 mmol) and diphenyl diselenide (0.2 mmol) were added to a 10 ml flame-dried schlenk tube with a magnetic stirring bar. CH 2 Cl 2 (2.0 ml) was injected into the tube. After stirring at room temperature for 12 h, The mixture was evaporated and purified by column chromatography on silica gel (PE:EA = 4:1) to afford the compound 6 (20% yield). IX. Synthetic transformations The preparation of compound 7 were followed the literature procedure. 5 m-cpba (0.6 mmol, 1.2 equiv.) was dissolved in 5 ml of CHCl 3 and added to a solution of 3a (0.5 mmol, 1 equiv.) in 20 ml of CHCl 3. After standing for 10 min at room temperature, the solvent CHCl 3 was removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE:EA = 1:10) to afford compound 7 (254.0 mg, 89%). A solution of KOH (6.34 mmol) in 5 ml of water was added dropwise to 7 (0.2 mmol) in 10 ml of THF. After 5 h at room temperature, the mixture was extracted with EA. The combined organic layers were dried with anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA = 4:1) to afford 8. S9

10 m-cpba (1.2 mmol, 2.4 equiv.) was dissolved in 5 ml of CHCl 3 and added to a solution of 3t (0.5 mmol, 1 equiv.) in 20 ml of CHCl 3. After standing for 10 min at room temperature, the solvent was removed under reduced pressure to afford a residue. Then the residue was dissolved by 20 ml of THF and 5 ml of 1 M aqueous KOH solution was added dropwise. After 1.5 h at room temperature, the mixture was extracted with EA. The combined organic layers were dried with anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA = 15:1) to afford 9 (132.0 mg, 76%). The substrate 1a (0.1 mmol), selenosulfonate 2a (0.1 mmol) and cat.-a (10 mol%) were added to a 10 ml flame-dried schlenk tube with a magnetic stirring bar. CH 2 Cl 2 (1.0 ml) was injected into the tube. After stirring at 40 C for 5 h, the mixture was evaporated and purified by column chromatography on silica gel (PE:EA = 4:1) to afford the product 3a. X. 1 H, 13 C NMR and HRMS data of compounds (1t, 1u, 3a-3u, 4a-4n, 7, 8, 9) 1 H NMR (600 MHz, CDCl 3 ): δ (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), (m, 3H), 7.26 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 5.86 (s, 1H). 13 C NMR (150 MHz, CDCl 3 ): δ , , , , , , , , , , 96.31, HRMS (ESI) m/z Calcd for [C 14 H 10 NaO, M + Na] + : , Found: Physical properties: yellow solid; Yield: 95%, 1.84 g; M. p ºC S10

11 1 H NMR (600 MHz, CDCl 3 ): δ 7.44 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), (m, 3H), 5.93 (s, 1H), 3.78 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ): δ , , , , , , , , , , 96.32, 81.66, HRMS (ESI) m/z Calcd for [C 15 H 12 NaO 2, M + Na] + : , Found: Physical properties: yellow solid; Yield: 90%, 1.75 g; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 8.3 Hz, 1H), (m, 6H), (m, 8H), (m, 4H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 24 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 85%, 94.4 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), (m, 6H), (m, 5H), (m, 6H), 2.23 (s, 3H), 2.18 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 21.37, HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 44%, 50.1 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), (m, 6H), (m, 5H), (m, 4H), 6.62 (d, J = 8.5 Hz, 2H), 3.73 (s, 3H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , 55.18, HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 4 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 76%, 89.0 mg; M. p ºC S11

12 1 H NMR (400 MHz, CDCl 3 ): δ 7.83 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), (m, 6H), 7.02 (t, 3H), (m, 4H), 6.85 (q, 4H), 2.20 (s, 3H), 1.21 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , 34.39, 31.20, Found: HRMS (ESI) m/z Calcd for [C 35 H 32 NaO 3 SSe, M + Na] + : , Physical properties: white solid; Yield: 53%, 61.4 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): 7.81 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), (m, 6H), (m, 3H), 7.02 (d, J = 7.1 Hz, 2H), (m, 4H), 6.78 (t, J = 8.3 Hz, 2H), 2.20 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ (d, J = Hz), , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 FNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 81%, 92.9 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (d, J = 8.9 Hz, 1H), 7.73 (q, J = 9.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), (m, 7H), (m, 6H), (m, 4H), 2.20 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 ClNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 47%, 55.5 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.99 (s, 2H), 7.85 (d, J = 8.5 Hz, 1H), (m, 1H), 7.40 (s, 1H), (m, 8H), (m, 3H), (m, 4H), 2.21 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , S12

13 HRMS (ESI) m/z Calcd for [C 31 H 23 NNaO 5 SSe, M + Na] + : , Found: Physical properties: yellow solid; Yield: 61%, 73.3 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 8.9 Hz, 1H), (m, 3H), (m, 4H), (m, 5H), (m, 2H), 6.94 (t, J = 7.5 Hz, 3H), 6.87 (d, J = 8.0 Hz, 2H), 2.16 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 BrNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 47%, 59.6 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (d, J = 9.4 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 8.9 Hz, 2H), (m, 4H), (m, 3H), 7.09 (t, J = 8.3 Hz, 3H), 6.93 (t, J = 7.5 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 2.13 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , (q, J = 30.0 Hz), (q, J = 5.0 Hz), , (q, J = Hz), , , , , , HRMS (ESI) m/z Calcd for [C 32 H 23 F 3 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 30%, 37.4 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.84 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 10.0 Hz, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), (m, 1H), (m, 6H), (m, 2H), 6.94 (t, J = 7.5 Hz, 2H), 6.86 (d, J = 7.9 Hz, 2H), 2.16 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , (q, J = Hz), , , , HRMS (ESI) m/z Calcd for [C 32 H 23 F 3 NaO 4 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 55%, 70.4 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), (m, 1H), (m, 6H), (m, 5H), (m, 5H), 6.67 (s, 1H), 2.20 (s, 3H), 2.11 (s, 3H). S13

14 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 21.37, HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 51%, 56.7 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), (m, 2H), (m, 9H), 6.97 (t, J = 7.4 Hz, 2H), 6.85 (d, J = 7.8 Hz, 2H), 2.13 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , (q, J = 31.0 Hz), , (q, J = 5.0 Hz), , , (q, J = Hz) , , , HRMS (ESI) m/z Calcd for [C 32 H 22 ClF 3 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 31%, 40.8 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), (m, 1H), (m, 5H), 7.04 (t, J = 7.3 Hz, 1H), (m, 2H), 6.91 (d, J = 7.8 Hz, 4H), 6.63 (s, 1H), 6.57 (s, 2H), 2.22 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): , , , , , , , , , , , , , , , , , , , , , , , , 21.35, HRMS (ESI) m/z Calcd for [C 33 H 28 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 43%, 50.2 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (t, J = 7.8 Hz, 2H), (m, 2H), 7.44 (t, J = 7.2 Hz, 2H), (m, 5H), 7.22 (d, J = 8.9 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), (m, 6H), 2.25 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , (q, J = 33.0 Hz), , , , , , , , , , (q, J = Hz), , (t, J = 4.0 Hz), , , HRMS (ESI) m/z Calcd for [C 33 H 22 F 6 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 46%, 63.6 mg; M. p ºC S14

15 1 H NMR (400 MHz, CDCl 3 ):δ 7.85 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), (m, 10H), 7.11 (t, J = 7.4 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 2.20 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , Found: HRMS (ESI) m/z Calcd for [C 31 H 19 F 5 NaO 3 SSe, M + Na] + : , Physical properties: white solid; Yield: 61%, 78.8 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.77 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), (m, 3H), (m, 2H), (m, 1H), 7.16 (d, J = 4.5 Hz, 1H), (m, 3H), (m, 3H), 6.90 (d, J = 7.5 Hz, 2H), (m, 1H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 29 H 22 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 46%, 51.7 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.75 (dd, J = 8.1, 4.6 Hz, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.0 Hz, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 6.3 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), (m, 4H), (m, 5H), 6.67 (d, J = 4.8 Hz, 1H), 2.21 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 29 H 22 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 62%, 69.6 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.89 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), (m, 2H), (m, 3H), (m, 6H), 6.99 (d, J = 7.5 Hz, 2H), (m, 4H), 2.23 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , S15

16 HRMS (ESI) m/z Calcd for [C 31 H 23 BrNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 76%, 94.4 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ):δ 8.07 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.47 (t, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.25 (s, 2H), (m, 5H), (m, 6H), 6.56 (s, 1H), 4.06 (s, 3H), 2.28 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , 55.99, HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 4 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 72%, 84.3 mg; M. p ºC 1 H NMR (600 MHz, CDCl 3 ): δ 7.48 (s, 4H), 7.40 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), (m, 3H), (m, 3H), 6.58 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.50 (t, J = 7.4 Hz, 1H), 5.62 (s, 1H), 2.35 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 27 H 22 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 20%, mg; M. p ºC 1 H NMR (600 MHz, CDCl 3 ): δ (m, 2H), (m, 2H), 7.13 (d, J = 7.6 Hz, 2H), 7.07 (t, J = 7.2 Hz, 3H), 7.00 (d, J = 8.3 Hz, 2H), 6.92 (dt, J = 18.7, 7.1 Hz, 3H), 6.59 (d, J = 8.1 Hz, 1H), 6.50 (q, J = 7.7 Hz, 2H), 5.52 (s, 1H), 3.88 (s, 3H), 2.35 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , 55.30, HRMS (ESI) m/z Calcd for [C 28 H 24 NaO 4 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 26%, mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.79 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), (m, 3H), 7.34 (t, J = 7.5 Hz, 1H), (m, 3H), (m, 10H), 6.89 (t, J = 7.5 Hz, 2H). S16

17 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 30 H 22 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 59%, 63.9 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 3H), (m, 2H), 7.25 (d, J = 8.5 Hz, 1H), (m, 8H), 6.90 (t, J = 7.6 Hz, 2H), 6.75 (t, J = 8.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ (d, J = Hz), , , , (d, J = 2.0 Hz), , , , , , , , , , , , , , , , , , (d, J = 22.0 Hz), HRMS (ESI) m/z Calcd for [C 30 H 21 FNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 64%, 71.6 mg; M. p ºC , , H NMR (400 MHz, CDCl 3 ): δ 7.82 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), (m, 3H), (m, 1H), 7.18 (s, 1H), (m, 7H), 7.01 (d, J = 7.7 Hz, 3H), 6.90 (t, J = 7.5 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 30 H 21 ClNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 76%, 87.6 mg; M. p ºC , , H NMR (400 MHz, CDCl 3 ): δ 7.79 (t, J = 7.7 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), (m, 3H), (m, 3H), (m, 8H), 6.88 (t, J = 7.5 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 30 H 21 BrNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 70%, 86.9 mg; M. p ºC S17

18 1 H NMR (400 MHz, CDCl 3 ): δ 7.79 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), (m, 5H), 7.07 (s, 5H), 6.86 (d, J = 7.6 Hz, 4H), 6.68 (d, J = 7.7 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , 21.36, HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 56%, 63.8 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.79 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), (m, 4H), 7.24 (s, 1H), (m, 5H), (m, 2H), 6.88 (d, J = 7.9 Hz, 2H), 6.57 (t, J = 8.5 Hz, 2H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ (d, J = Hz), , , , , , , , , , , , , , , , , , , (d, J = 3.0 Hz), , (d, J = 22.0 Hz), , , HRMS (ESI) m/z Calcd for [C 31 H 23 FNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 65%, 74.6 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.79 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 5H), (m, 5H), (m, 6H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 ClNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 75%, 88.5 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), (m, 5H), (m, 6H), 6.96 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.2 Hz, 3H), 6.71 (t, J = 7.6 Hz, 1H), 2.18 (s, 3H), 2.16 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , 23.21, S18

19 HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 61%, 69.5 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.79 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), (m, 7H), (m, 5H), 6.97 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 7.9 Hz, 2H), 6.77 (t, J = 7.5 Hz, 1H), 2.18 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 ClNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 66%, 77.9 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), (m, 9H), 7.15 (d, J = 7.6 Hz, 1H), (m, 3H), 6.87 (d, J = 7.9 Hz, 3H), 6.82 (t, J = 7.5 Hz, 1H), 2.19 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 BrNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 54%, 68.5 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), (m, 5H), 7.07 (s, 5H), (m, 6H), 2.18 (s, 3H), 2.02 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , 21.36, HRMS (ESI) m/z Calcd for [C 32 H 26 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 79%, 90.0 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), (m, 5H), (m, 5H), 7.02 (d, 1H), 6.96 (s, 1H), 6.89 (t, J = 8.4 Hz, 3H), 6.83 (t, J = 7.8 Hz, 1H), 2.20 (s, 3H). S19

20 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 ClNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 61%, 72.0 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.38 (s, 1H), (m, 5H), (m, 7H), 6.96 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.78 (t, J = 7.8 Hz, 1H), 2.20 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 23 BrNaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 76%, 96.4 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 7.81 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), (m, 6H), (m, 5H), 6.89 (d, J = 7.9 Hz, 2H), (m, 2H), (m, 1H), 2.20 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ (d, J = Hz), , (d, J = Hz), , , , , , , , , , , , , , , , , (d, J = 8.0 Hz), (d, J = 7.0 Hz), (d, J = 8.0 Hz), (d, J = 8.0 Hz), , HRMS (ESI) m/z Calcd for [C 31 H 22 F 2 NaO 3 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 64%, 75.7 mg; M. p ºC 1 H NMR (400 MHz, CDCl 3 ): δ 8.01 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), (m, 7H), (m, 5H), 6.94 (d, J = 8.0 Hz, 3H), 6.80 (d, J = 7.7 Hz, 2H), 2.25 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 31 H 24 NaO 4 SSe, M + Na] + : , Found: Physical properties: white solid; Yield: 89%, mg; M. p ºC S20

21 1 H NMR (400 MHz, CDCl 3 ): δ 9.15 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), (m, 4H), 7.66 (d, J = 8.9 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), (m, 4H), 7.14 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 25 H 18 NaO 3 S, M + Na] + : , Found: Physical properties: white solid; Yield: 95%, 76.0 mg; M. p ºC 1 H NMR (600 MHz, CDCl 3 ): δ (m, 1H), 7.82 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), (m, 4H), (m, 2H), 7.05 (d, J = 8.1 Hz, 2H), 2.21 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , HRMS (ESI) m/z Calcd for [C 21 H 16 NaO 3 S, M + Na] + : , Found: Physical properties: white solid; Yield: 76%, mg; M. p ºC XI. HPLC traces of compound 3a (3a ) HPLC analysis: Chiralcel AD-H (Hexane/i-PrOH = 80:20), flow rate = 1.0 ml/min, wave length = 254 nm, t R = min (minor), t R = min (major). S21

22 XII. 1 H and 13 C NMR spectra of compounds (1t, 1u, 3a-3u, 4a-4n, 7, 8, 9) S22

23 S23

24 S24

25 S25

26 S26

27 S27

28 S28

29 S29

30 S30

31 S31

32 S32

33 S33

34 S34

35 S35

36 S36

37 S37

38 S38

39 S39

40 S40

41 S41

42 S42

43 S43

44 S44

45 S45

46 S46

47 S47

48 S48

49 S49

50 S50

51 S51

52 S52

53 S53

54 S54

55 S55

56 S56

57 S57

58 S58

59 S59

60 S60

61 S61

62 XIII. X-Ray Crystallographic information Bond precision: C-C = A Wavelength = Cell: a = (4) b = (3) c = (5) alpha = 90 beta = (3) gamma = 90 Temperature: 295 K Calculated Reported Volume (15) (15) Space group P 21/c P 1 21/c 1 Hall group : -P 2ybc -P 2ybc Moiety formula C31 H23 Br O3 S Se [+ solvent] C31 H23 Br O3 S Se Sum formula C31 H23 Br O3 S Se [+ solvent] C24 H17 Br O3 S Se Mr Dx,g cm Z 4 4 Mu (mm-1) F F h, k, lmax 18, 16, 21 18, 16, 21 Nref Tmin, Tmax 0.352, , Tmin Correction method= # Reported T Limits: Tmin=0.691 Tmax=1.000 AbsCorr = MULTI-SCAN Data completeness = Theta(max) = R(reflections) = ( 4724) wr2(reflections) = ( 6378) S = Npar = 336 S62

63 XIV. Reference 1 S. Jia, Z. Chen, N. Zhang, Y. Tan, Y. Liu, J. Deng and H. Yan, J. Am. Chem. Soc., 2018, 140, D. Li, Y. Tan, L. Peng, S. Li, N. Zhang, Y. Liu and H. Yan, Org. Lett., 2018, 20, D. Singh, A. M. Deobald, L. R. S. Camargo, G. Tabarelli, O. E. D. Rodrigues and A. L. Braga, Org. Lett., 2010, 12, S. Luo, N. Zhang, Z. Wang and H. Yan, Org. Biomol. Chem., 2018, 16, T. G. Back, S. Collins and R. G. Kerr, J. Org. Chem., 1983, 48, S63