Supporting Information

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1 Supporting Information C F Bond Cleavage Enabled Redox-Neutral [4+1] Annulation via C H Bond Activation Cheng-Qiang Wang, Lu Ye, Chao Feng * and Teck-Peng Loh, * Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing , P.R. China Department of Chemistry, University of Science and Technology of China Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore iamcfeng@njtech.edu.cn teckpeng@ntu.edu.sg. Table of Contents General Information 2 Experimental Section 3 Substrate synthesis 3 Reaction conditions optimization 12 General procedure for the Rh(III)-catalyzed [4+1] annulation 13 Control experiments and synthetic elaborations 13 Gram-scale reaction 18 Characterization of structurally novel compounds 19 1 H and 13 C NMR spectra 39 Reference 87 Page S1

2 General Information [RhCp*Cl 2 ] 2 was purchased from Chemical Service and used as received. The molecular sieve was activated at 110 ºC for 2 h in the oven before using. All reactions were carried out under air without extra protection unless otherwise noted. Reactions were monitored through thin layer chromatography [Merck 60 F254 precoated silica gel plate (0.2 mm thickness)]. Subsequent to elution, spots were visualized using UV radiation (254 nm) on Spectroline Model ENF-24061/F 254 nm. Further visualization was possible using basic solution of potassium permanganate as stain. Flash chromatography was performed using Merck silica gel 60 with distilled solvents. HRMS spectra were recorded on a Waters Q TOF Permier Spectrometer. 1 H NMR and 13 C NMR spectra were recorded using Bruker Avance 400 MHz spectrometers. Chemical shifts for 1 H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublets of doublet); dt (doublets of triplet); dq (doublets of quartet); ddd (doublets of doublets of doublet); dddd (doublets of doublets of doublets of doublet); td (triplet of doublet), tt (triplets of triplet); tdd (triplets of doublets of doublet); m (multiplets) and etc. Coupling constants are reported as a J value in Hz. Carbon nuclear magnetic resonance spectra ( 13 C NMR) are reported as δ in units of parts per million (ppm) downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.0, triplet). S2

3 Experimental Section Substrate synthesis General reaction procedure for the synthesis of amide 1a-1z: 1) The acid was dissolved in anhydrous CH 2 Cl 2 (20 ml) and cooled with ice water. Oxalyl chloride (1.5 eq.) was added dropwise to the solution followed with the addition of catalytic amount of DMF (2 drops). The resulting mixture was allowed to stir at room temperature for additional two hours and the solvent was evaporated to afford crude acid chloride, which was used directly in the next step. 2) To a solution of K 2 CO 3 (2.0 eq.) in a mixture of EtOAc/H 2 O (30 ml, 2:1) was added O-methylhydroxylamine hydrochloride (1.2 eq.). The resulting solution was cooled to 0 ºC, followed by dropwise addition of the substituted benzoyl chloride (1.0 eq.) [Note: the substituted benzoyl chloride was dissolved in DCM (1 M) when it was solid]. The reaction mixture was warmed to rt and stirred overnight. The organic phase was separated and the aqueous phase was extracted with EtOAc (20 ml 3). The combined organic layers were dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. The pure products were obtained by flash column chromatography. S3

4 α,α-difluoromethylene alkyne 2 examined: Ph F F 2 2a Bu Ph F F F F Ph 2 2 Me 2b 2c Ph 2 Bu F F 2d Ph 2 F F Me 2e Bu Cy F F 2f Bu Ph F F F F Ph 2 2 OBn 2g 2h OPMB 3 Ph F F 2 2i OTHP 3 AcO F F 3 2j Bu HO F F 3 2k Bu Ph F F 2 2l OH 3 Ph F F 2 2m Cl 3 PhthN F F 3 2n Bu Ph F F 2o Bu F F F F Cl Cl F Ph Ph Me 3 Si F Bu OMe Bu OMe Bu 2p 2q 2r 2o 1, 2p 2 2s 3 was synthesized according to the previous literature. General reaction procedure for the synthesis of substrate 2: F 2s Ph 2 Synthetic procedure: a) To a solution of alkyne (1.1 eq.) in THF (20 ml) at -78 ºC was added dropwise n BuLi (2.5 M in hexane, 1.1eq.). After stirring 30 min, aldehyde (1.0 eq.) was added and the solution was warmed to rt. After the consumption of aldehyde, the solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to afford the crude propargylic alcohol, which could be used directly in the next step without further purification. b) The crude propargylic alcohol was dissolved in acetone (30 ml). A concentrated (2.7 M) solution of Jones reagent was added dropwise until S4

5 disappearance of the starting material (TLC analysis). After addition of isopropanol (5.0 eq.), the reaction mixture was filtered and the residues were washed with EA. The combined organic phases were dried over Na 2 SO 4, filtered and concentrated in vacuo and the residue was subjected to column chromatography on silica gel to deliver the corresponding ketone. c) To the ketone obtained above was added 1 drop of ethanol and DAST (2.5 eq.) was added in one portion at 0 ºC. After 30 min the reaction mixture was warmed to 60 ºC and stirred overnight. After coming back to rt, DCM (20 ml) was added, followed by slow addition of 20 ml sat. eq. NH 4 Cl. The organic phase was separated and the aqueous phase was extracted with DCM (2 20 ml) and dried over MgSO 4. The organic solvent was evaporated and the residue was subjected to column chromatography on silica gel to deliver the title compound. 2a, 2c, 2d, 2f and 2m were synthetized from the corresponding aldehydes and alkynes following the above synthetic procedure. General reaction procedure for the synthesis of 2b: Synthetic procedure: 1) To a solution of ethynyltrimethylsilane (1.1 eq.) in THF (20 ml) at -78 ºC n BuLi (2.5 M in hexane, 1.1 eq.) was added dropwise. After stirring 30 min, 3-phenylpropanal (1.0 eq.) was added and the solution warmed to 0 ºC. After the consumption of 3-phenylpropanal, the solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to afford the crude propargylic alcohol, which could be used directly in the next step without further purification. S5

6 2) The crude propargylic alcohol and K 2 CO 3 (0.3 eq.) was dissolved in MeOH (30 ml). After the consumption of the propargylic alcohol, the mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel to deliver 5-phenylpent-1-yn-3-ol. 3) To a solution of TBSCl (1.2 eq.) and DMAP (0.1 eq.) in DCM (40 ml) was added 5-phenylpent-1-yn-3-ol (1.0 eq.) and triethylamine (1.0 eq.) at 0 ºC. After the consumption of the alcohol starting material, the mixture was diluted with DCM, washed with 1 M HCl, sat. aq. NaHCO 3 and brine. The organic phase was separated and dried over MgSO 4. The volatiles were removed under reduce pressure. The silyl ether was purified by column chromatography. 4) To a solution of tert-butyldimethyl((5-phenylpent-1-yn-3-yl)oxy)silane (1.0 eq.) in THF (30 ml) at -78 ºC was added dropwise n BuLi (2.5 M in hexane, 2.0 eq.). After warmed to rt and stirred for 30 min, the mixture was cooled to 0 ºC and CH 3 I (3.5 eq.) was added dropwise. The mixture was allowed to warm to rt and stirred overnight. The next day, the solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to afford the crude tert-butyldimethyl((1-phenylhex-4-yn-3-yl)oxy)silane, which was purified by flash column chromatography. 5) To a solution of tert-butyldimethyl((1-phenylhex-4-yn-3-yl)oxy)silane (1.0 eq.) in THF (40 ml) at -78 ºC was added TBAF (1.2 eq.). After complete conversion of the starting material, the mixture diluted with EA, washed with sat. aq. NH 4 Cl and brine. The organic phase was dried over Na 2 SO 4, filtered, concentrated in vacuo and the residue was subjected to column chromatography on silica gel to deliver 1-phenylhex-4-yn-3-ol. (2b was synthetized from 1-phenylhex-4-yn-3-ol following the above synthetic procedure b and c) S6

7 General reaction procedure for the synthesis of 2e: Synthetic procedure: To a solution of hex-1-yne (1.0 eq.) in THF (30 ml) at -78 ºC was added dropwise n BuLi (2.5 M in hexane, 1.0 eq.). After stirring for 30 min, Ac 2 O (3.0 eq.) was added, then the solution was warmed to rt and stirred overnight. The solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure and the residue was purified by column chromatography. (2e was synthetized from oct-3-yn-2-one following the above synthetic procedure c). General reaction procedure for the synthesis of 2g: Synthetic procedure: To a suspension of NaH (1.1 eq.) in THF (30 ml) at 0 ºC was added prop-2-yn-1-ol (1.0 eq.) and the mixture was stirred at 0 ºC for 1 h. BnCl (1.1 eq.) was then added and the mixture was stirred overnight at rt. The mixture was quenched with sat. aq. NH 4 Cl at 0 ºC, extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel. (2g was synthetized from ((prop-2-yn-1-yloxy)methyl)benzene following the above synthetic procedure a, b and c) S7

8 General reaction procedure for the synthesis of 2h, 2l: Synthetic procedure: 1) To a suspension of NaH (1.1 eq.) in THF (30 ml) at 0 ºC was added pent-4-yn-1-ol (1.0 eq.) and the mixture was stirred at 0 ºC for 1 h. PMBCl (1.1 eq.) and n Bu 4 NI (0.1 eq.) were then added and the mixture was stirred overnight at rt. The mixture was quenched with sat. aq. NH 4 Cl at 0 ºC, extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel. (2h was synthetized from 1-methoxy-4-((pent-4-yn-1-yloxy)methyl)benzene following the above synthetic procedure a, b and c). 2) DDQ (1.5 eq.) was added to a solution of 2h (1.0 eq.) in DCM (30 ml) and water (3 ml) at 0 ºC. The reaction mixture was stirred 30 min at 0 ºC, then warmed to rt. After the consumption of 2h, the mixture was quenched with sat. aq. NaHCO 3, extracted with DCM, dried over MgSO 4, concentrated in vacuo and the residue was subjected to column chromatography on silica gel to deliver 2l. General reaction procedure for the synthesis of 2i: Synthetic procedure: 1) To a suspension of pent-4-yn-1-ol (1.0 eq.), camphorsulfonic acid (0.1 eq.) in DCM (30 ml) and 3,4-dihydro-2H-pyran(1.3 eq.) was added dropwise at 0 ºC and the S8

9 mixture was stirred overnight at rt. Then sat. aq. Na 2 CO 3 (20 ml) was added and the resulting mixture was stirred for an additional 20 min, extracted with DCM, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography. 2-((6,6-difluoro-8-phenyloct-4-yn-1-yl)oxy)tetrahydro-2H-pyran (2i) was synthetized from 2-(pent-4-yn-1-yloxy)tetrahydro-2H-pyran following the above synthetic procedure a, b and c. General reaction procedure for the synthesis of 2j, 2k and 2n: n Bu 1) n BuLi, THF, BF 3 Et 2 O dihydrofuran-2(3h)-one -78 ºC to rt 2) Ac 2 O, DMAP pyridine, DCM n Bu O OAc c n Bu 2j F F OAc K 2 CO 3 MeOH OH NPhth n Bu F F phthalimide PPh 3, DIAD THF, 0 ºC to rt n Bu F F 2k 2n Synthetic procedure: 1) To a solution of hex-1-yne (1.0 eq.) in THF (20 ml) at -78 ºC was added dropwise n BuLi (2.5 M in hexane, 1.0 eq.). After stirring for 30 min, BF 3 Et 2 O (1.1 eq.) was added dropwise and the mixture was stirred for another 30 min. Then dihydrofuran-2(3h)-one (1.2 eq.) was added dropwise, the mixture was warmed to rt and stirred overnight. The solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure and the residue was purified by column chromatography. 2) To a solution of 1-hydroxydec-5-yn-4-one (1.0 eq.) and DMAP (0.1 eq.) in DCM (40 ml) was added Ac 2 O (1.2 eq.) and pyridine (1.2 eq.) at rt. After the consumption of the alcohol starting material, the mixture was S9

10 diluted with DCM, washed with 1 M HCl, sat. aq. NaHCO 3 and brine. The organic phase was separated and dried over MgSO 4. The volatiles were removed under reduce pressure and the residue was purified by column chromatography. (2j was synthetized from 4-oxodec-5-yn-1-yl acetate following the above synthetic procedure c) 3) The 2j (1.0 eq.) and K 2 CO 3 (2.0 eq.) was dissolved in MeOH (30 ml). After the consumption of the 2j, the mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel to deliver 2k. 4) A solution of 2k (1.0 eq.), isoindoline-1,3-dione (1.2 eq.), and PPh 3 (1.2 eq.) in THF (30 ml) was cooled to 0 ºC and treated with DIAD (1.2 eq.) over 5 min. The reaction was warmed to and stirred overnight. The mixture was concentrated under reduced pressure and the residue was subjected to column chromatography on silica gel to deliver 2n. General reaction procedure for the synthesis of 2q: Synthetic procedure: To a solution of 2,2-difluoro-1-phenyloct-3-yn-1- ol 4 (1.0 eq.) in THF (2 ml) at 0 ºC was added NaH (60% in mineral oil, 1.5 eq.) in one portion. After stirring for 30 min, MeI (3 eq.) was added dropwise and the mixture was warmed to rt and stirred for 2 h. The solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure and 2q was obtained via column chromatography. General reaction procedure for the synthesis of 2r: S10

11 Synthetic procedure: 1) To a solution of 2,2-dichloro-1-phenylhept-3- yn-1-one 5 (1.0 eq.) in MeOH (20 ml) at 0 ºC was added NaBH 4 (3 eq.) in one portion. After the consumption of the ketone, the mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel to deliver the 2,2-dichloro-1-phenylhept-3- yn-1-ol. 2) To a solution of 2,2-dichloro-1-phenylhept-3-yn-1-ol (1.0 eq.) in THF (2 ml) at 0 ºC was added NaH (60% in mineral oil, 1.5 eq.) in one portion. After stirring for 30 min, MeI (3 eq.) was added dropwise and the mixture was warmed to rt and stirred for 2 h. The solution was quenched with sat. aq. NH 4 Cl, the mixture was extracted with EA, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure and 2r was obtained via column chromatography. General reaction procedure for the synthesis of 2t: Synthetic procedure: To a solution of 1-phenylnon-4-yn-3-one (1.0 eq.) and TsOH (0.05 eq.) in MeOH (10 ml) at 0 ºC was added CH(OMe) 3 (20 eq.). After stirring for 1.5 h at 0 ºC, the mixture was warmed to rt and stirred for 1 h. After neutralizing the TsOH with NaHCO 3 solid, the mixture was filtered, and concentrated under reduced pressure and 2t was obtained via flash column chromatography on silica gel [which was steeped in Et 3 N: PE (1:99) overnight before use]. General reaction procedure for the synthesis of 2u: Synthetic procedure: To a solution of DAST (1.2 eq.) in dry DCM (10 ml) at -78 ºC was added 1-phenylnon-4-yn-3-ol (1 M in dry DCM) dropwise under nitrogen. After the consumption of the alcohol, the S11

12 mixture was quenched with sat. aq. NH 4 Cl, extracted with DCM, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure and 2u was obtained via column chromatography. Reaction conditions optimization Table S1. Optimization studies a entry additive 1 additive 2 yield b 1 NaOAc NaOAc 3Å MS 80 3 NaOAc 4Å MS 70 4 NaOAc 5Å MS 78 5 KOAc 3Å MS 84 6 K 2 CO 3 3Å MS 53 7 c KOAc 3Å MS 86(82) 8 c AcOH 3Å MS 70 9 c,d KOAc 3Å MS ND 10 c - 3Å MS 12 S12

13 11 c,e KOAc 3Å MS 15 a All of the experiments were performed at relevant temperature with 1a (0.1 mmol), 2a (0.12 mmol), additive 1 (0.03 mmol), additive 2 (100 mg), [RhCp*Cl2]2 (0.002 mmol) in MeOH (0.5 ml) for 12 hours. b NMR yield using tetrachloroethane as internal standard; isolated yield was indicated in the parentheses. c The reaction was carried out at 40 C. d In the absence of [Rh] catalyst. e 2.0 equivalents of KOAc was added. General procedure for the Rh(III)-catalyzed [4+1] annulation Experiment procedure: An oven-dried 10 ml Schlenk Tube was charged with 1 (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol), KOAc (0.03 mmol) and oven activated 3Å MS (100 mg) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2 (0.12 mmol) through syringe. The resulting reaction mixture was stirred at 40 ºC for 12 h and then diluted with CH 2 Cl 2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired annulation product 3. Control experiments and synthetic elaborations Experiment procedure: An oven-dried 10 ml Schlenk Tube was charged with 6 (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol), KOAc (0.03 mmol) and oven activated 3Å MS (100 mg) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2a (0.12 mmol) through syringe. The S13

14 resulting reaction mixture was stirred at 80 ºC for 12 h and no title compound was detected via the TLC and crude NMR analysis. Experiment procedure: An NMR Tube was charged with a stir bar, 1d (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol) or [RhCp*(OAc) 2 ] (0.004 mmol), KOAc (0.03 mmol) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2a (0.12 mmol) and (CHCl 2 ) 2 (0.1 mmol) through syringe. The resulting reaction mixture was stirred at 60 ºC and monitored by crude NMR when reaction proceeded 5 min, 45 min, 3 h 15 min, 7 h 15 min, 9 h, 12h, 20 h. a) [RhCp*Cl 2 ] 2 (0.002 mmol) was used as the catalyst; b) [RhCp*(OAc) 2 ] (0.004 mmol) was used as the catalyst. S14

15 Experiment procedure: An oven-dried 10 ml Schlenk Tube was charged with 1d (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol), KOAc (0.03 mmol) and oven activated 3Å MS (100 mg) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2q or 2r (0.12 mmol) through syringe. The resulting reaction mixture was stirred at 80 ºC for 12 h and then diluted with CH 2 Cl 2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired annulation product. Experiment procedure: An oven-dried 10 ml Schlenk Tube was charged with 1d (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol), KOAc (0.03 mmol) and oven activated 3Å MS (100 mg) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2s (0.12 mmol) through syringe. The resulting reaction mixture was stirred at 80 ºC for 12 h and then diluted with CH 2 Cl 2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired annulation product 5. S15

16 Experiment procedure: An oven-dried 10 ml Schlenk Tube was charged with 1d (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol), KOAc (0.03 mmol) and oven activated 3Å MS (100 mg) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2t (0.12 mmol) through syringe. The resulting reaction mixture was stirred at 80 ºC for 12 h and the reaction was messy via the TLC and crude NMR analysis. Experiment procedure: An oven-dried 10 ml Schlenk Tube was charged with 1d (0.1 mmol), [RhCp*Cl 2 ] 2 (0.002 mmol), KOAc (0.03 mmol) and oven activated 3Å MS (100 mg) in sequence, followed by adding anhydrous MeOH (0.5 ml), 2u (0.12 mmol) through syringe. The resulting reaction mixture was stirred at 80 ºC for 12 h and no reaction was occurred via the TLC and crude NMR analysis. Experiment procedure: An oven-dried 15 ml glass tube was charged with 3d (0.1 mmol). After purging with nitrogen three times, SmI 2 (0.1 M in THF, 5 eq.) was added dropwise at 0 o C and then the mixture was warmed to rt and stirred for 6 h. After that the mixture was quenched with 5 ml saturated aqueous Na 2 S 2 O 3 and extracted with DCM, dried S16

17 over Na 2 SO 4, filtered, and concentrated under reduced pressure and 4a was obtained in 80% yield via column chromatography. Experiment procedure: An oven-dried 15 ml glass tube was charged with 3d (0.1 mmol), anhydrous AlCl 3 (0.2 mmol) and THF (0.5 ml), then LiAlH 4 (0.5 mmol) was added in one portion at 0 o C and the mixture was warmed to rt. After the consumption of 3d, the mixture was quenched with sat. aq. NH 4 Cl, extracted with DCM, dried over Na 2 SO 4, filtered, and concentrated under reduced pressure and 4b was obtained in 96% yield via column chromatography. Experiment procedure: 1) An oven-dried 15 ml glass tube was charged with 3ao (0.1 mmol), K 2 CO 3 (0.2 mmol) and MeOH (0.5 ml) at rt. After the consumption of 3ao, the mixture was concentrated under reduced pressure and 6 was obtained in quantitative yield via column chromatography. 2) An oven-dried 15 ml glass tube was charged with 6 (0.1 mmol), RuCp*Cl(COD) (0.01 mmol). After purged with nitrogen three times dry S17

18 toluene (0.5 ml) and (2-azidoethyl)benzene (0.2 mmol) was added via syringe. The mixture was stirred at 40 o C for 12 h. Then the mixture was purified by column chromatography and 4c was obtained in 98% yield. Experiment procedure: An oven-dried 15 ml glass tube was charged with Au(PPh 3 )Cl (0.01 mmol), AgOTf (0.15 mmol) and 3Å MS(100 mg). Then dry toluene (0.5 ml) was added via syringe and the mixture was stirred at rt for 5 min. After that 3ak in 0.5 ml dry toluene was added and the resulting mixture was stirred at 60 o C for 12 h. Purification the reaction mixture by column chromatography gave 4d in 91% yield. Gram-scale reaction An oven-dried 50 ml RBF was charged with 1d (4.0 mmol), [RhCp*Cl 2 ] 2 (0.08 mmol), KOAc (1.2 mmol) and oven activated 3Å MS (4.0 g) in sequence, followed by adding anhydrous MeOH (20.0 ml), 2a (4.8 mmol) through syringe and then equipped with a reflux condenser. The resulting reaction mixture was stirred at 80 ºC for 30 h and then diluted with CH 2 Cl 2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded 1.02 g the desired annulation product 3d. S18

19 Characterization of structurally novel compounds (3, 3-Difluoronon-4-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), (m, 2H), (m, 4H), (m, 2H), (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.3, 5.1 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 140.1, 128.6, 128.3, 126.3, (t, J = Hz), 89.2 (t, J = 6.6 Hz), 73.7 (t, J = 40.3 Hz), 41.3 (t, J = 26.9 Hz), 29.9 (t, J = 1.8 Hz), 29.3 (t, J = 4.0 Hz), 21.9, 18.1 (t, J = 2.2 Hz), (3, 3-Difluorohex-4-yn-1-yl)benzene F F 1 H NMR (400 MHz, CDCl3): δ (m, 2H), b 7.18 (m, 3H), (m, 2H), (m, 2H), (t, J = 5.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ -( ) (m) ppm; 13 C NMR (100 MHz, CDCl3): δ 140.1, 128.6, 128.3, 126.3, (t, J = Hz), 84.9 (t, J = 6.7 Hz), 73.0 (t, J = 40.8 Hz), 41.1 (t, J = 26.7 Hz), 29.2 (t, J = 3.9 Hz), (5, 5-Difluorohept-3-yne-1,7-diyl)dibenzene 1 H NMR (400 MHz, CDCl3): δ (m, 4H), (m, 6H), 2.88 (t, J = 7.4 Hz, 2H), (m, 2H), 2.59 (tt, J = 7.5, 4.9 Hz, 2H), (m, 2H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.2, 4.9 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 140.0, 139.8, 128.5, 128.4, 128.3, 126.6, 126.3, (t, J = Hz), 88.2 (t, J = 6.8 Hz), 74.5 (t, J = 39.8 Hz), 41.1 (t, J = 26.8 Hz), 34.1 (t, J = 2.0 Hz), 29.2 (t, J = 4.0 Hz), 20.6 (t, J = 2.1 Hz). (5,5-Difluoronon-3-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 2.72 (t, J = 7.5 Hz, 2H), 2.42 (ddd, J = 7.5, 5.0, 2.6 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), 0.81 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.6, 4.8 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 139.9, 128.5, 128.4, 126.6, (t, J = Hz), 87.5 (t, J = 6.7 Hz), 74.9 (t, J = 40.5 Hz), 39.2 (t, J = 26.3 Hz), 34.2 (t, J = 2.0 Hz), 25.0 (t, J = 3.6 Hz), 22.2, 20.6 (t, J = 2.4 Hz), , 2-Difluorooct-3-yne 1 H NMR (400 MHz, CDCl3): δ 2.26 (tt, J = 7.1, 5.0 Hz, 1H), 1.84 (t, J = 17.1 Hz, 1H), (m, 1H), 1.42 (tdd, J = 14.0, 8.5, 5.8 Hz, 1H), 0.92 (t, J = 7.3 Hz, 2H) ppm; 19 F NMR S19

20 (376 MHz, CDCl3): δ -( ) (m) ppm; 13 C NMR (100 MHz, CDCl3): δ (t, J = Hz), 87.8 (t, J = 6.6 Hz), 74.7 (t, J = 40.2 Hz), 29.8 (t, J = 1.8 Hz), 27.1 (t, J = 29.4 Hz), 21.9, 18.0 (t, J = 2.2 Hz), (1,1-Difluorohept-2-yn-1-yl)cyclohexane 1 H NMR (400 MHz, CDCl3): δ 2.28 (tt, J = 7.1, 5.1 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 4H), 0.93 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 10.8, 5.4 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ (t, J = Hz), 89.0 (t, J = 6.9 Hz), 73.2 (t, J = 40.4 Hz), 46.2 (t, J = 24.8 Hz), 29.9 (t, J = 1.9 Hz), 26.0 (t, J = 3.2 Hz), 25.9, 25.3, 21.9, 18.1 (t, J = 2.3 Hz), (6-(Benzyloxy)-3, 3-difluorohex-4-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 7H), (m, 3H), 4.62 (s, 3H), 4.27 (t, J = 4.3 Hz, 2H), (m, 2H), (m, 2H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.5, 4.2 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 139.7, 136.8, 128.6, 128.6, 128.3, 128.1, 126.4, (t, J = Hz), 83.6 (t, J = 6.6 Hz), 79.3 (t, J = 40.7 Hz), 72.0, 56.7, 41.0 (t, J = 26.2 Hz), 29.8 (t, J = 1.8 Hz), 29.0 (t, J = 3.9 Hz). 1-(((6, 6-Difluoro-8-phenyloct-4-yn-1-yl)oxy)methyl)-4-methoxybenzene 1 H NMR (400 MHz, CDCl3): δ (m, 7H), (m, 2H), 4.45 (s, 2H), 3.79 (s, 3H), 3.53 (t, J = 6.0 Hz, 2H), (m, 2H), 2.41 (tt, J = 7.1, 5.0 Hz, 2H), 2.31 (dddd, J = 17.1, 14.3, 10.3, 6.6 Hz, 2H), (m, 2H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.3, 5.0 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 159.2, 140.0, 130.4, 129.3, 128.6, 128.3, 126.3, (t, J = Hz), 113.8, 88.5 (t, J = 6.6 Hz), 74.0 (t, J = 40.2 Hz), 72.7, 68.0, 55.3, 41.2 (t, J = 26.8 Hz), 29.2 (t, J = 3.9 Hz), 28.1 (t, J = 2.2 Hz), 15.3 (t, J = 2.0 Hz). 2-((6, 6-Difluoro-8-phenyloct-4-yn-1-yl)oxy)tetrahydro-2H-pyran 1 H NMR (400 MHz, CDCl3): δ (m, F F 2i 2H), (m, 3H), (m, 1H), 3.85 Ph OTHP (tt, J = 12.4, 4.8 Hz, 2H), 3.49 (dq, J = 9.9, 5.7 Hz, 2H), (m, 2H), (m, 4H), 1.83 (qd, J = 13.0, 7.0 Hz, 3H), 1.72 (ddd, J = 12.0, 5.9, 3.1 Hz, 1H), (m, 4H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.3, 5.0 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 140.0, 128.6, 128.3, 126.3, (t, J = Hz), 98.9, 88.5 (t, J = 6.7 Hz), 74.0 (t, J = 39.2 Hz), 65.6, 62.3, 41.2 (t, J = 26.8 Hz), 30.6, 29.2 (t, J = 4.0 Hz), 28.1 (t, J = 1.8 Hz), 25.4, 19.5, 15.4 (t, J = 2.2 Hz). S20

21 4, 4-Difluorodec-5-yn-1-yl acetate 1 H NMR (400 MHz, CDCl3): δ 4.12 (t, J = 6.4 Hz, F F 2j AcO 2H), (m, 2H), (m, 5H), 1.90 (dt, J = 13.5, 6.5 Hz, 2H), (m, 2H), (m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.5, 5.1 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 171.0, (t, J = Hz), 89.2 (t, J = 6.6 Hz), 73.6 (t, J = 40.1 Hz), 63.3, 36.3 (t, J = 27.5 Hz), 29.8, 22.5 (t, J = 3.7 Hz), 21.9, 20.9, 18.0 (t, J = 2.2 Hz), , 4-Difluorodec-5-yn-1-ol 1 H NMR (400 MHz, CDCl3): δ 3.71 (t, J = 6.4 Hz, 2H), 2.27 (tt, J = 7.1, 5.1 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 3H), 0.92 (t, J = 7.2 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.7, 5.0 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ (t, J = Hz), 88.9 (t, J = 6.7 Hz), 73.7 (t, J = 40.1 Hz), 61.8, 36.0 (t, J = 27.2 Hz), 29.8, 26.2 (t, J = 3.4 Hz), 21.9, 18.0 (t, J = 2.1 Hz), , 6-Difluoro-8-phenyloct-4-yn-1-ol 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 3.76 (t, J = 5.8 Hz, 2H), (m, 2H), 2.43 (tt, J = 7.0, 5.0 Hz, 2H), (m, 2H), (m, 2H), 1.63 (s, 1H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.3, 5.0 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 140.0, 128.6, 128.3, 126.3, (t, J = Hz), 88.3 (t, J = 6.6 Hz), 74.2 (t, J = 40.5 Hz), 61.2, 41.2 (t, J = 26.8 Hz), 30.5 (t, J = 1.8 Hz), 29.2 (t, J = 3.9 Hz), 14.9 (t, J = 2.2 Hz). (8-Chloro-3,3-difluorooct-4-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 3.65 (t, J = 6.2 Hz, 2H), (m, 2H), 2.51 (tt, J = 7.0, 4.9 Hz, 2H), (m, 1H), 2.02 (p, J = 6.6 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tq, J = 14.5, 4.8 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 139.9, 128.6, 128.3, 126.4, (t, J = Hz), 87.0 (t, J = 6.6 Hz), 74.8 (t, J = 40.3 Hz), 43.3, 41.2 (t, J = 26.7 Hz), 30.5 (t, J = 2.0 Hz), 29.2 (t, J = 3.9 Hz), 15.9 (t, J = 2.2 Hz) ppm. 2-(4, 4-Difluorodec-5-yn-1-yl)isoindoline-1,3-dione 1 H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 5.5, 3.0 Hz, 2H), 7.73 (dd, J = 5.4, 3.1 Hz, 2H), 3.76 (t, J = 7.0 Hz, 2H), 2.25 (tt, J = 7.1, 5.0 Hz, 2H), (m, 2H), (m, 2H), 1.51 (ddd, J = S21

22 12.2, 7.1, 4.0 Hz, 2H), (m, 2H), 0.90 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (tt, J = 14.2, 5.0 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ 168.3, 134.0, 132.0, 123.3, (t, J = Hz), 89.3 (t, J = 6.6 Hz), 73.5 (t, J = 40.0 Hz), 37.2, 37.1 (t, J = 27.7 Hz), 29.8, 22.5 (t, J = 3.5 Hz), 21.9, 18.0, 13.5 ppm. 2-(4, 4-Difluorodec-5-yn-1-yl)isoindoline-1,3-dione 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 2.36 (dtd, J = 10.1, 7.0, 4.6 Hz, 2H), (m, 2H), (m, 2H), 0.95 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ (t, J = 5.1 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ (t, J = 28.4 Hz), (t, J = 1.8 Hz), , (t, J = 4.6 Hz), (t, J = Hz), (t, J = 6.0 Hz), (t, J = 41.1 Hz), (t, J = 1.9 Hz), (t, J = 2.3 Hz) ppm. 2-(4, (1,1-Difluorohept-2-yn-1-yl)trimethylsilane 1 H NMR (400 MHz, CDCl3): δ 2.31 (p, J = 6.9 Hz, 2H), (m, 2H), (m, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.21 (s, 9H) ppm; 19 F NMR (376 MHz, CDCl3): δ (t, J = 6.7 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ (t, J = Hz), 93.0 (t, J = 9.0 Hz), 74.4 (t, J = 31.0 Hz), 30.1 (t, J = 2.7 Hz), 21.84, 18.4 (t, J = 3.1 Hz), 13.5, -5.0 (t, J = 1.4 Hz) ppm. (2,2-Difluoro-1-methoxyoct-3-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 4.42 (t, J = 8.6 Hz, 1H), 3.42 (s, 3H), 2.26 (tt, J = 7.1, 5.3 Hz, 2H), (m, 2H), (m, 2H), 0.90 (t, J = 7.3 Hz, 3H) ppm; 19 F NMR (376 MHz, CDCl3): δ -( ) (m) ppm; 13 C NMR (100 MHz, CDCl3): δ (t, J = 2.9 Hz),129.0, 128.6, 128.1, (t, J = Hz), 91.2 (t, J = 6.5 Hz), 85.3 (t, J = 29.5 Hz), 71.9 (t, J = 38.2 Hz), 58.2, 29.7 (t, J = 2.0 Hz), 21.8, 18.2 (t, J = 2.4 Hz), 13.5 ppm. (2,2-dichloro-1-methoxyoct-3-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 4.45 (s, 1H), 3.31 (s, 3H), 2.18 (t, J = 7.1 Hz, 2H), (m, 2H), (m, 2H), 0.80 (t, J = 7.3 Hz, 3H) ; 13 C NMR (100 MHz, CDCl3): δ 134.9, 129.6, 129.1, 127.7, 93.5, 91.0, 78.0, 77.2, 58.4, 29.8, 21.9, 18.6, 13.6 ppm. (3,3-dimethoxynon-4-yn-1-yl)benzene 1 H NMR (400 MHz, CDCl3): δ (m, 2H), (m, 3H), 3.32 (s, 6H), (m, 2H), 2.28 (t, J = 6.9 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), 0.93 (t, J = 7.2 Hz, 3H) S22

23 ppm; 13 C NMR (100 MHz, CDCl3): δ 141.9, 128.5, 128.4, 125.8, 99.2, 86.9, 76.8, 49.9, 39.3, 30.8, 30.6, 22.0, 18.2, 13.6 ppm. 3-Butyl-2-methoxy-5-methyl-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3a was obtained in 82% yield; 1 H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.8 Hz, 1H), (m, 6H), 7.12 (s, 1H), 4.00 (s, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.46 (s, 3H), 2.08 (dddd, J = 40.2, 13.8, 11.9, 4.5 Hz, 2H), (m, 2H), (m, 1H), 0.78 (t, J = 7.4 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.5, 144.7, 143.4, 140.2, 129.7, 128.5, 128.3, 126.4, 126.0, 123.4, 122.5, 84.4, 79.1, 64.9, 62.2, 38.7, 34.6, 25.1, 22.3, 22.1, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3b was obtained in 85% yield; 1 H NMR (400 MHz, CDCl3): δ 7.77 (dt, J = 7.5, 1.0 Hz, 1H), 7.54 (td, J = 7.6, 1.2 Hz, 1H), 7.43 (td, J = 7.5, 1.0 Hz, 1H), 7.31 (dt, J = 7.6, 0.9 Hz, 1H), (m, 2H), (m, 3H), 3.98 (s, 3H), 2.78 (t, J = 7.3 Hz, 2H), 2.50 (t, J = 7.3 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 0.74 (t, J = 7.3 Hz, 3H), 0.67 (dddd, J = 14.9, 6.6, 3.9, 2.0 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.1, 144.4, 140.2, 132.5, 128.7, 128.7, 128.5, 128.4, 126.4, 123.6, 122.1, 84.6, 78.9, 64.9, 62.3, 38.6, 34.6, 25.1, 22.3, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-6-methyl-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3c was obtained in 76% yield; 1 H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 1.7 Hz, 1H), 7.37 (dt, J = 8.2, 1.2 Hz, 1H), (m, 4H), (m, 2H), 3.99 (s, 3H), 2.79 (t, J = 7.3 Hz, 2H), 2.51 (t, J = 7.3 Hz, 2H), 2.42 (s, 3H), 2.06 (qdd, J = 13.8, 11.5, 4.7 Hz, 2H), (m, 2H), 1.02 (dddd, J = 16.7, 8.4, 4.0, 1.8 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.3, 141.7, 140.2, 138.9, 133.5, 128.7, 128.5, 128.4, 126.4, 123.8, 121.9, 84.4, 79.1, 64.8, 62.2, 38.6, 34.6, 25.1, 22.3, 21.4, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S23

24 5-(Tert-butyl)-3-butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3d was obtained in 70% yield; 1 H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.2 Hz, 1H), 7.50 (dt, J = 8.1, 1.6 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), (m, 2H), (m, 3H), 4.00 (d, J = 1.4 Hz, 3H), 2.83 (t, J = 7.3 Hz, 2H), 2.55 (dd, J = 8.2, 6.7 Hz, 2H), 2.08 (ddd, J = 11.1, 9.0, 5.0 Hz, 1H), 1.36 (d, J = 1.4 Hz, 9H), 1.18 (pd, J = 7.0, 2.7 Hz, 1H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.4, 156.7, 144.4, 140.3, 128.5, 128.4, 126.4, 126.1, 125.9, 123.2, 118.7, 84.5, 79.1, 64.9, 62.4, 38.7, 35.5, 34.7, 31.4, 25.2, 22.2, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)-2,3,5,6,7,8-hexahydro-1H-benzo[f]i soindol-1-one Following the general experiment procedure, 3e was obtained in 69% yield; 1 H NMR (400 MHz, CDCl3): δ 7.49 (s, 1H), (m, 2H), (m, 3H), 7.01 (s, 1H), 4.00 (s, 3H), 2.84 (dt, J = 20.3, 6.5 Hz, 6H), 2.53 (t, J = 7.3 Hz, 2H), (m, 2H), 1.83 (d, J = 4.7 Hz, 4H) (m, 2H), (m, 1H), (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.6, 142.7, 141.5, 140.3, 138.2, 128.5, 128.3, 126.4, 125.9, 123.9, 122.4, 84.2, 79.4, 64.8, 62.1, 38.8, 34.7, 30.3, 29.5, 25.2, 22.9, 22.8, 22.3, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2,5-dimethoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3f was obtained in 63% yield; 1 H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 1H), (m, 2H), (m, 3H), 6.97 (dd, J = 8.4, 2.3 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.08 (dddd, J = 51.3, 13.8, 12.1, 4.4 Hz, 2H), (m, 1H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), 0.70 (dddd, J = 12.9, 11.2, 5.2, 3.2 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.6, 163.5, 146.7, 140.2, 128.5, 128.4, 126.4, 125.2, 121.0, 114.9, 107.3, 84.5, 79.1, 64.9, 62.2, 55.7, 38.7, 34.6, 25.0, 22.3, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S24

25 3-Butyl-2-methoxy-1-oxo-3-(4-phenylbut-1-yn-1-yl)isoindolin-5-yl acetate Following the general experiment procedure, 3g was obtained in 68% yield; 1 H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.2 Hz, 1H), (m, 2H), (m, 4H), (m, 1H), 3.99 (s, 3H), 2.81 (t, J = 7.3 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.35 (s, 3H), (m, 2H), (m, 2H), (m, 1H), (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3): δ 168.7, 163.4, 154.1, 145.9, 140.2, 128.5, 128.4, 126.4, 126.0, 124.9, 122.5, 115.8, 85.0, 78.3, 64.9, 62.2, 38.6, 34.5, 25.1, 22.2, 21.2, 20.7, 13.7 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2,4,6-trimethoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure (reaction temperature was 80 ºC), 3h was obtained in 77% yield; 1 H NMR (400 MHz, CDCl3): δ (m, 2H), 7.18 (ddt, J = 7.5, 3.1, 1.2 Hz, 3H), 6.92 (d, J = 2.1 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 4.01 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 2.79 (t, J = 7.4 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), 0.76 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 163.9, 161.9, 155.1, 140.4, 131.3, 128.5, 128.3, 126.3, 123.3, 103.7, 98.0, 83.1, 78.5, 64.8, 61.4, 55.8, 55.7, 35.5, 34.7, 25.0, 22.1, 20.9, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-6-methoxy-7-(4-phenylbut-1-yn-1-yl)-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]i soindol-5-one Following the general experiment procedure, 3i was obtained in 72% yield; 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 7.9 Hz, 1H), (m, 2H), (m, 3H), 6.91 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 1.4 Hz, 1H), 6.07 (d, J = 1.4 Hz, 1H), 3.99 (s, 3H), 2.81 (t, J = 7.3 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3): δ 163.7, 151.8, 140.2, 128.5, 128.4, 128.3, 126.3, 123.8, 123.1, 118.3, 109.1, 102.5, 84.6, 77.6, 64.9, 60.3, 37.0, 34.6, 25.3, 22.3, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S25

26 3-Butyl-2-methoxy-5-(methylthio)-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3j was obtained in 62% yield; 1 H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.0 Hz, 1H), (m, 3H), (m, 3H), (m, 1H), 4.00 (d, J = 0.8 Hz, 3H), 2.81 (t, J = 7.2 Hz, 2H), (m, 5H), 2.07 (dddd, J = 48.3, 13.8, 12.1, 4.5 Hz, 2H), 1.18 (pd, J = 7.1, 4.0 Hz, 2H), 1.03 (tdd, J = 12.8, 8.3, 5.0 Hz, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.1, 145.2, 145.1, 140.2, 128.5, 128.4, 126.4, 125.7, 125.1, 123.8, 118.8, 84.7, 78.8, 64.9, 62.2, 38.7, 34.6, 25.1, 22.3, 20.8, 15.3, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-5-phenyl-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure (reaction temperature was 80 ºC), 3k was obtained in 66% yield; 1 H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 7.9, 0.6 Hz, 1H), 7.69 (dd, J = 7.9, 1.6 Hz, 1H), (m, 2H), (m, 3H), (m, 1H), (m, 5H), 4.04 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.1, 145.9, 145.1, 140.2, 140.2, 129.0, 128.5, 128.3, 128.3, 127.9, 127.5, 127.4, 126.4, 124.0, 120.7, 84.7, 78.9, 64.9, 62.5, 38.7, 34.6, 25.2, 22.3, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)-2,3-dihydro-1H-benzo[f]isoindol-1- one Following the general experiment procedure (reaction temperature was 80 ºC and PivOH was used instead of KOAc), 3l was obtained in 76% yield; 1 H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.61 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.56 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H), (m, 6H), 4.07 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 4H) ppm; 13 C NMR (100 MHz, CDCl3): δ 163.7, 140.2, 139.7, 135.5, 133.1, 129.5, 128.5, 128.4, 128.3, 127.9, 126.7, 126.5, 126.4, 124.1, 121.2, 84.5, 79.5, 64.9, 62.3, 39.2, 34.6, 25.2, 22.3, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S26

27 Ethyl (E)-3-(3-butyl-2-methoxy-1-oxo-3-(4-phenylbut-1-yn-1-yl)isoindolin-5-yl)acrylate Following the general experiment procedure, 3m O was obtained in 42% yield; 1 H NMR (400 MHz, N OMe CDCl3): δ 7.80 (d, J = 7.9 Hz, 1H), 7.72 (d, J = EtO 2 C 16.1 Hz, 1H), 7.60 (dd, J = 7.9, 1.5 Hz, 1H), Bu 7.41 (d, J = 1.5 Hz, 1H), (m, 3H), 3m Ph (m, 2H), 6.52 (d, J = 16.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.10 (dddd, J = 36.2, 13.9, 11.9, 4.6 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.19 (ddd, J = 11.4, 9.7, 5.8 Hz, 2H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 166.4, 163.3, 143.3, 140.1, 138.7, 130.1, 128.6, 128.5, 128.4, 126.5, 124.1, 121.4, 120.7, 85.0, 78.4, 64.9, 62.3, 60.8, 38.6, 34.5, 25.1, 22.2, 20.7, 14.3, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Acetyl-3-butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure (reaction temperature was 80 ºC and PivOH was used instead of KOAc), 3n was obtained in 44% yield; 1 H NMR (400 MHz, CDCl3): δ 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.97 (dd, J = 1.5, 0.7 Hz, 1H), 7.90 (dd, J = 7.9, 0.7 Hz, 1H), (m, 2H), (m, 3H), 4.01 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.67 (s, 3H), 2.54 (t, J = 7.1 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 0.76 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 197.2, 162.7, 144.7, 140.5, 140.1, 132.7, 129.1, 128.4, 128.4, 126.4, 123.9, 121.8, 85.2, 78.1, 64.9, 62.5, 38.5, 34.5, 27.0, 25.1, 22.2, 20.8, 13.7 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Methyl 3-butyl-2-methoxy-1-oxo-3-(4-phenylbut-1-yn-1-yl)isoindoline-5-carboxylate O Following the general experiment procedure (reaction temperature was 80 ºC), 3o was obtained in 64% N OMe yield; 1 H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = MeO 2 C 7.9, 1.4 Hz, 1H), 8.07 (dd, J = 1.4, 0.7 Hz, 1H), 7.87 Bu (dd, J = 8.0, 0.7 Hz, 1H), (m, 2H), o Ph 7.15 (m, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 2.81 (t, J = 7.3 Hz, 2H), 2.54 (t, J = 7.1 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 0.76 (t, J = 7.4 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 166.2, 162.7, 144.4, 140.1, 134.0, 132.7, 130.1, 128.4, 128.4, 126.4, S27

28 123.6, 123.4, 85.2, 78.1, 64.9, 62.4, 52.6, 38.4, 34.5, 25.1, 22.2, 20.8, 13.7 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-1-oxo-3-(4-phenylbut-1-yn-1-yl)isoindoline-5-carbonitrile O Following the general experiment procedure (reaction temperature was 80 ºC and reaction time was 24 h), 3p N OMe was obtained in 56% yield; 1 H NMR (400 MHz, NC CDCl3): δ 7.90 (dd, J = 7.8, 0.7 Hz, 1H), 7.75 (dd, J = Bu 7.8, 1.3 Hz, 1H), 7.52 (dd, J = 1.4, 0.8 Hz, 1H), p Ph 7.25 (m, 3H), (m, 2H), 4.01 (s, 3H), 2.82 (t, J = 7.1 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 161.8, 145.0, 139.9, 132.7, 128.5, 128.4, 126.7, 126.1, 124.4, 117.9, 116.0, 85.9, 77.4, 65.0, 62.2, 38.4, 34.3, 25.1, 22.2, 20.6, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-5-nitro-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure (reaction temperature was 80 ºC and reaction time was 24 h), 3q was obtained in 62% yield; 1 H NMR (400 MHz, CDCl3): δ 8.34 (ddd, J = 8.2, 2.0, 0.9 Hz, 1H), (m, 1H), 7.97 (d, J = 8.3 Hz, 1H), (m, 2H), (m, 3H), 4.02 (d, J = 0.9 Hz, 3H), 2.82 (t, J = 7.2 Hz, 2H), (m, 2H), (m, 2H), 1.20 (tdd, J = 13.2, 9.4, 5.6 Hz, 2H), (m, 1H), 0.78 (td, J = 7.3, 0.9 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 161.4, 150.7, 145.4, 139.9, 134.3, 128.4, 128.4, 126.5, 124.8, 124.4, 117.9, 86.1, 77.2, 65.0, 62.5, 38.4, 34.3, 25.1, 22.2, 20.7, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)-5-(trifluoromethyl)isoindolin-1-one Following the general experiment procedure, 3r was obtained in 56% yield; 1 H NMR (400 MHz, CDCl3): δ (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 3H), 4.02 (s, 3H), 2.82 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.11 (dddd, J = 35.2, 13.9, 11.9, 4.6 Hz, 2H), (m, 1H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), 0.68 (dddd, J = 14.8, 7.0, 3.7, 1.7 Hz, 1H) ppm; 19 F NMR (376 MHz, CDCl3): δ ppm; 13 C NMR (100 MHz, CDCl3): δ 162.3, 144.8, 140.0, (q, J = 32.6 Hz), 132.1, 128.4, 128.4, 126.5, (q, J = 3.6 Hz), 124.2, (q, J = Hz), (q, J = 3.7 Hz), 85.5, 77.8, 65.0, 62.4, 38.5, 34.4, 25.1, 22.2, 20.8, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S28

29 3-Butyl-5-fluoro-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3s was obtained in 76% yield; 1 H NMR (400 MHz, CDCl3): δ 7.79 (dd, J = 8.4, 5.0 Hz, 1H), (m, 2H), (m, 1H), (m, 3H), 6.99 (dd, J = 8.0, 2.3 Hz, 1H), 4.00 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.07 (dddd, J = 44.4, 13.9, 12.1, 4.5 Hz, 2H), (m, 2H), 1.01 (ddd, J = 12.3, 6.2, 3.0 Hz, 1H), 0.78 (t, J = 7.3 Hz, 3H), 0.70 (dddd, J = 12.2, 7.7, 5.9, 1.4 Hz, 1H) ppm; 19 F NMR (376 MHz, CDCl3): δ (td, J = 8.4, 4.9 Hz) ppm; 13 C NMR (100 MHz, CDCl3): δ (d, J = Hz), 163.3, (d, J = 9.5 Hz), 140.1, 128.5, 128.4, 126.5, (d, J = 9.5 Hz), (d, J = 2.5 Hz), (d, J = 23.3 Hz), (d, J = 24.3 Hz), 85.1, 78.4, 64.9, 62.1 (d, J = 2.5 Hz), 38.6, 34.5, 25.1, 22.2, 20.7, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-5-chloro-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3t was obtained in 72% yield; 1 H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 7.9, 1.8 Hz, 1H), (m, 3H), (m, 3H), 4.00 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.07 (dddd, J = 44.2, 14.0, 12.0, 4.5 Hz, 2H), 1.19 (dtd, J = 14.0, 10.3, 8.8, 5.5 Hz, 2H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 163.1, 145.9, 140.1, 138.8, 129.4, 128.5, 128.4, 127.1, 126.5, 124.9, 122.6, 85.2, 78.2, 64.9, 62.1, 38.5, 34.5, 25.1, 22.2, 20.7, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Bromo-3-butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3u was obtained in 46% yield; 1 H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.1 Hz, 1H), 7.60 (dt, J = 8.1, 1.3 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), (m, 2H), (m, 3H), 4.00 (s, 3H), 2.82 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), (m, 2H), 1.20 (dtd, J = 14.0, 9.7, 8.5, 5.2 Hz, 2H), 1.02 (dtt, J = 14.9, 7.5, 3.6 Hz, 1H), 0.79 (t, J = 7.3 Hz, 3H), 0.71 (dt, J = 13.0, 7.2 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 163.2, 146.0, 140.1, 132.3, 128.5, 128.4, 127.6, 127.2, 126.5, 125.5, 125.1, 85.2, 78.2, 64.9, 62.0, 38.6, 34.5, 25.1, 22.2, 20.7, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S29

30 3-Butyl-6-iodo-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3v was obtained in 44% yield; 1 H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.0, 1.7 Hz, 1H), (m, 3H), (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 2.80 (t, J = 7.2 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.06 (dddd, J = 33.9, 13.9, 11.8, 4.6 Hz, 2H), 1.19 (tdd, J = 7.6, 6.3, 4.4 Hz, 2H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 162.3, 143.7, 141.3, 140.1, 132.6, 130.7, 128.5, 128.4, 126.4, 124.0, 93.9, 85.0, 78.2, 64.9, 62.3, 38.3, 34.5, 25.1, 22.2, 20.7, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-5-(hydroxymethyl)-2-methoxy-3-(4-phenylbut-1-yn-1-yl)isoindolin-1-one Following the general experiment procedure, 3w was obtained in 61% yield; 1 H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.6 Hz, 1H), (m, 1H), 7.37 (dq, J = 1.5, 0.7 Hz, 1H), (m, 2H), (m, 3H), 4.81 (s, 2H), 4.00 (s, 3H), 2.81 (t, J = 7.3 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.09 (dddd, J = 34.9, 13.8, 11.9, 4.6 Hz, 2H), (m, 2H), (m, 1H), 0.77 (t, J = 7.3 Hz, 3H), (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3): δ 164.1, 146.3, 144.8, 140.2, 128.5, 128.4, 127.8, 127.1, 126.4, 123.7, 120.1, 84.7, 78.8, 64.9, 64.8, 62.4, 38.6, 34.6, 25.1, 22.3, 20.7, 13.8 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: Butyl-2-methoxy-3-(4-phenylbut-1-yn-1-yl)-5-(trimethylsilyl)isoindolin-1-one Following the general experiment procedure, 3x was obtained in 63% yield; 1 H NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 7.5, 0.8 Hz, 1H), 7.62 (dd, J = 7.5, 0.9 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.27 (ddd, J = 6.1, 5.0, 3.0 Hz, 2H), (m, 3H), 4.01 (s, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.55 (t, J = 7.3 Hz, 2H), 2.10 (ddd, J = 11.0, 9.3, 5.0 Hz, 2H), (m, 2H), (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), (m, 1H), 0.32 (s, 9H) ppm; 13 C NMR (100 MHz, CDCl3): δ 165.3, 146.8, 143.5, 140.2, 133.5, 129.0, 128.4, 128.3, 126.4, 126.4, 122.5, 84.6, 78.9, 64.8, 62.4, 38.6, 34.6, 25.1, 22.2, 20.8, 13.8, -1.2 ppm; HRMS (ESI, m/z): calculated for [M+Na] + : , found: S30