Palladium Catalyzed [4+2] Cycloaddition of o-(silylmethyl)benzyl Esters with Ketones: An Equivalent to oxo-diels Alder Reaction of o-xylylenes

Transcription

1 Palladium Catalyzed [4+2] Cycloaddition of o-(silylmethyl)benzyl Esters with Ketones: An Equivalent to oxo-diels Alder Reaction of o-xylylenes Satoshi Ueno, Masakazu htsubo, and Ryoichi Kuwano* Department of Chemistry, Graduate School of Sciences, Kyushu University, Hakozaki, Higashi-ku, Fukuoka , Japan Supporting Information Table of Contents General and Materials Preparations of Ketonic Substrate 2 Palladum-Catalyzed [4+2] Cycloaddition of 1 or 4 with 2. ptimization of Reaction Parameters General Procedure Experimental Details of Scheme 1 Experimental Details of Table 1 Experimental Details of Table 2 References S1 S1 S2 S2 S3 S4 S4 S8 S18 1 H and 13 C { 1 H} NMR spectra of 2 S19 1 H and 13 C { 1 H} NMR spectra of 3 S21 1 H and 13 C { 1 H} NMR spectra of 5, 6, and related compounds S33

2 General and Materials. All NMR spectra were measured with Bruker AVANCE 400 (9.4 T magnet) spectrometer at ambient temperature. In 1 H NMR spectra, chemical shifts (ppm) referenced to internal tetramethylsilane (0.00 ppm, in CDCl 3 ). In 13 C NMR spectra, chemical shifts (ppm) referenced to the carbon signal of the deuterated solvents (77.0 ppm in CDCl 3 ). IR spectra and melting points were measured with JASC FT/IR-4100 and Büchi Melting Point B-545, respectively. High resolution mass spectroscopy (HRMS) and elemental analyses were conducted at Institute for Materials Chemistry and Engineering (IMCE) and Service Centre of Elementary Analysis of rganic Compounds in Kyushu University, respectively. All reactions were conducted under nitrogen atmosphere with dry solvent unless otherwise noted. Flash column chromatographies and medium-pressure liquid chromatographies (MPLC) were performed with silica gel 60 ( mesh, Merck) and C.I.G. pre-packed column CPS-223L-1 (Kusano, Tokyo, Japan), respectively. Dichloromethane (CH 2 Cl 2 ), pyridine, diethyl ether (Et 2 ) were dried with phosphorus(v) oxide, calcium hydride, and sodium-benzophenone ketyl, respectively. These dry solvent were distilled under nitrogen atmosphere before use. Tetrahydrofuran (THF) (HPLC grade, without inhibitor) was deoxidized by purging with nitrogen for 30 min and was dried with an alumina and copper column system (GlassContour Co.). Compounds 1, 1 2c, 2 2d, 2 2g, 3 2h, 4 2i, 5 4a, 6 4b, 1 4c, 6 4d, 6 4e, 1, 4b-d 2, 6 and Pd(η 3 -C 3 H 5 )Cp 7,8 were prepared according to literature procedures. Methyl benzoylformate (1a), ethyl benzoylformate (2a), benzil (2j), 2,2,2-trifluoro-1-phenylethanone (2k), dry N,N-dimethylformamide (DMF) (H 2 < 50 ppm, from Nacalai Tesque), bis[2-(diphenylphosphino)phenyl] ether (DPEphos), monomethyl oxalyl chloride, m-xylene, aluminum chloride, 1-bromonaphthalene, magnesium turnings, diethyl oxalate, 2,3-dimethylbenzoic acid, lithium aluminum deuteride, butyllithium, chlorotrimethylsilane, 4-(dimethylamino)pyridine, methyl chloroformate, and 4-methoxy-2-methylbenzoic acid were purchased and used without further purification. Preparations of Ketonic Substrates 2 Methyl 2-(2,4-Dimethylphenyl)-2-oxoethanoate (2e). Me C 2 Me Me 2e Aluminum chloride (2.56 g, 19 mmol) was placed in a 100 ml three-necked flask, which was equipped with a stirring bar, rubber septum, dropping funnel, and three-way stopcock. After the reaction vessel was evacuated and charged with nitrogen three times, dry CH 2 Cl 2 (13 ml) was added into the flask at 0 C. Monomethyl oxalyl chloride (2.34 g, 19 mmol) was added dropwise to the suspension of aluminum chloride for 10 min. After 20 min, m-xylene (1.06 g, 10 mmol) was added dropwise to the reaction mixture. After stirred at room temperature for 1 h, the resulting mixture was poured into a mixture of crushed ice (67 g) and conc. HCl aq. (22 ml), and then extracted three times with EtAc. The combined organic layer was washed with 0.1 N NaH aq., with brine, dried over Na 2 S 4, and then evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane = 1/10) to give 2e (1.50 g, 78%) as pale yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.37 (s, 3H), 2.57 (s, 3H), 3.94 (s, 3H), S1

3 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 21.4, 21.5, 52.5, 126.5, 128.3, 132.6, 133.1, 141.5, 144.9, 165.1, 188.0; IR (neat) 2957 w, 2927 w, 1740 s, 1681 s, 1610 s, 1564 m, 1437 m, 1381 w, 1321 m, 1285 m, 1205 s, 1136 m, 1000 s, 900 w, 830 w, 740 m, 685 w, 503 w, 480 m, 439 s cm 1 ; Anal. Calcd for: C 11 H 12 3 : C, 68.74; H, Found: C, 68.62; H, Ethyl 2-(1-Naphthyl)-2-oxoethanoate [ ] (2f) 3 C 2 Et 2f Magnesium turnings (545 mg, 22 mmol) were placed in a 100 ml three-necked flask, which was equipped with a stirring bar, rubber septum, dropping funnel, Dimroth condenser, and three-way stopcock. The magnesium was heated and stirred in vacuo with a mantle heater for 5 h, and then nitrogen was charged into the reaction vessel at room temperature. Dry THF (3.0 ml) and 1-bromonaphthalene (4.15 g, 20 mmol) were added into the flask and the dropping funnel, respectively. After ten drops of 1-bromonaphthalene were added to the suspension of the activated magnesium in THF, the mixture was vigorously stirred. When an exothermic reaction started in the vessel, the reaction mixture and the remaining 1-bromonaphthalene were diluted with dry THF (10 ml and 7 ml each). As the flask was cooled with an ice-bath, the solution of the bromonaphthalene was added dropwise to the reaction mixture for 30 min. The resulting mixture was stirred at room temperature for 1 h. Diethyl oxalate (7.30 g, 50 mmol) and dry THF (20 ml) were placed in another nitrogen-filled 100 ml three-necked flask, which was equipped with a stirring bar, rubber septum, dropping funnel, and three-way stopcock. The Grignard reagent prepared above was transferred through a cannula into the dropping funnel, and then added dropwise to the solution of diethyl oxalate at 78 C for 30 min. After warmed to room temperature gradually, the resulting mixture was diluted with saturated NH 4 Cl aq. (24 ml) and then extracted three times with EtAc. The combined organic layer was washed with brine, dried with MgS 4, and then evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane = 1/20), and then with vacuum distillation to give 2f (2.01 g, 44%) as pale yellow oil: bp 136 C (0.27 mmhg); 1 H NMR (400 MHz, CDCl 3, TMS) δ 1.44 (t, J = 7.2 Hz, 3H), 4.49 (q, J = 7.2 Hz, 2H), (m, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.99 (dd, J = 0.9, 7.3 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 9.04 (d, J = 8.6 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 13.8, 62.1, 124.0, 125.2, 126.7, 127.7, 128.5, 128.9, 130.6, 133.6, 133.8, 135.6, 164.4, Palladum-Catalyzed [4+2] Cycloaddition of 2-(Silylmethyl)benzyl Carbonates 1 or 4 with Ketones 2. Procedure for ptimizing Reaction Parameters for the [4+2] Cycloaddition of 1 with 2a. In a nitrogen-filled drybox, Pd(η 3 -C 3 H 5 )Cp (1.0 mg, 4.7 µmol), a ligand (10 µmol), and naphthalene (15 mg, as an internal standard for GC analysis) were placed in a 5 ml screw-capped vial equipped with a stirring bar. After dry solvent (1.0 ml) was added, the vial was sealed with a screw cap containing a PTFE/silicone septum and removed from the drybox. Methyl 2-[(trimethylsilyl)methyl]benzyl carbonate (1) (37.9 mg, S2

4 0.15 mmol) and methyl 2-oxo-2-phenylethanoate (2a) (29.5 mg, 0.18 mmol) were added into the vial through the septum by using a micro-syringe at room temperature. The solution was stirred at 120 or 100 C. The reaction was monitored by GC analysis with J&W capillary column DB-1 (0.53 mm φ 15 m, d f 1.5 µm). The selected results of the above reactions were summarized in Table S-1. Table S-1. ptimization of Reaction Parameters for the [4+2] Cycloaddition of 1 with 2a. entry Ligand solvent temp., C yield (3a), % a 1 DPPPent b DMF DPPPent b DMF DPPPent b toluene DPPPent b 1,4-dioxane DPPPent b CPME c DPPPent b DMS DPPPent b t-amyl alcohol DPPE d DMF DPPP e DMF DPPB f DMF DPPHex g DMF DPPF h DMF DPEphos i DMF Xantphos j DMF a Yields were measured at 1 h by GC analysis (average of two runs). b DPPPent = 1,5-bis(diphenylphosphino)pentane. c CPME = cyclopentyl methyl ether. d DPPE = 1,2-bis(diphenylphosphino)ethane. e f DPPP = 1,3-bis(diphenylphosphino)propane. g h DPPB = 1,4-bis(diphenylphosphino)butane. DPPHex = 1,6-bis(diphenylphosphino)hexane. DPPF = i j 1,1 -bis(diphenylphosphino)ferrocene. DPEphos = bis[2-(diphenylphosphino)phenyl] ether. Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. General Procedure for the [4+2] Cycloaddition of 1 or 4 with 2. In a nitrogen-filled drybox, Pd(η 3 -C 3 H 5 )Cp (2.9 mg, 14 µmol), DPEphos (16.0 mg, 30 µmol), and a ketone 2 (0.45 mmol) (if 2 is solid) were placed in a 5 ml screw-capped vial equipped with a stirring bar. After dry DMF (3.0 ml) was added, the vial was sealed with a screw cap containing a PTFE/silicone septum and removed from the drybox. Compounds 1 or 4 (0.68 mmol) and 2 (0.45 mmol) (if 2 is liquid) were added into the vial through the septum by using a micro-syringe at room temperature. The solution was stirred at 120 C until no 2 was detected in the capillary GC analysis of the reaction mixture. After cooled to room temperature, the resulting mixture was evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane) to give the desired cycloaddition product. Alternatively, it was purified with MPLC (EtAc/hexane) after passed through a short silica gel column. S3

5 Methyl 3-enyl-3-isochromanecarboxylate (3a) (Scheme 1). C 2 Me 3a The general procedure was followed with use of 1 (170 mg, 0.67 mmol) and 2a (73.2 mg, 0.45 mmol). The reaction was conducted for 3 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/20) to give 3a (108 mg, 90%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.30 (d, J = 16.3 Hz, 1H), 3.65 (s, 3H), 3.68 (d, J = 16.3 Hz, 1H), 4.87 (d, J = 15.5 Hz, 1H), 5.07 (d, J = 15.5 Hz, 1H), 6.97 (d, J = 6.3 Hz, 1H), (m, 3H), 7.29 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H), 7.57 (d, J = 7.3 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 35.7, 52.5, 64.7, 79.4, 123.9, 125.5, 126.4, 126.6, 128.0, 128.4, 128.5, 131.2, 133.1, 139.5, 172.3; IR (thin film) 3063 w, 3028 w, 2952 m, 2907 w, 2859 w, 1738 s, 1589 m, 1496 m, 1451 m, 1370 w, 1264 s, 1212 s, 1136 m, 1115 m, 1076 s, 1048 m, 1034 m, 911 m, 847 m, 812 w, 731 s, 698 m, 648 m cm 1 ; Anal. Calcd for C 17 H 16 3 : C, 76.10; H, Found: C, 76.05; H, Ethyl 3-enyl-3-isochromanecarboxylate (3b) (Table 1, entry 1). C 2 Et 3b The general procedure was followed with use of 1 (170 mg, 0.67 mmol) and ethyl 2-oxo-2-phenylethanoate (2b) (80.6 mg, 0.45 mmol). The reaction was conducted for 3 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/20) to give 3b (119 mg, 93%) as pale yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 1.11 (t, J = 7.1 Hz, 3H), 3.29 (d, J = 16.0 Hz, 1H), 3.68 (d, J = 16.0 Hz, 1H), 4.10 (dq, J = 10.8, 7.1 Hz, 1H), 4.13 (dq, J = 10.8, 7.1 Hz, 1H), 4.88 (d, J = 15.4 Hz, 1H), 5.10 (d, J = 15.4 Hz, 1H), 6.97 (d, J = 5.8 Hz, 1H), (m, 3H), 7.30 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 14.0, 36.0, 61.5, 64.9, 79.4, 124.0, 125.6, 126.4, 126.6, 128.0, 128.4, 128.6, 131.5, 133.3, 139.8, 171.8; IR (neat) 3029 w, 2979 m, 2906 m, 2864 w, 1733 s, 1496 m, 1450 m, 1368 w, 1261 m, 1208 s, 1135 m, 1066 s, 1047 m, 856 w, 748 m, 698 m, 643 m cm 1 ; Anal. Calcd for C 18 H 19 3 : C, 76.57; H, Found: C, 76.48; H, Ethyl 3-(4-Methoxyphenyl)-3-isochromanecarboxylate (3c) (Table 1, entry 2). Et 2 C Me 3c The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and ethyl 2-(4-methoxyphenyl)-2-oxoethanoate (2c) (94.2 mg, 0.45 mmol). The reaction was conducted for 12 h. The crude product was purified with MPLC (EtAc/hexane = 1/3) to give 3c (58.5 mg, 41%) as pale yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 1.12 (t, J = 7.1 Hz, 3H), 3.31 (d, J = 16.1 Hz, 1H), 3.63 (d, J = 16.1 Hz, 1H), 3.79 (s, 3H), 4.09 (dq, J = 10.7, 7.1 Hz, 1H), 4.13 (dq, J = 10.7, 7.1 Hz, 1H), 4.83 (d, J = 15.4 Hz, 1H), 5.08 (d, J = 15.4 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 6.3 Hz, 1H), (m, 3H), 7.49 (d, S4

6 J = 8.9 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 14.0, 35.7, 55.2, 61.4, 64.7, 79.0, 113.8, 123.9, 126.4, 126.6, 127.1, 128.6, , , 133.3, 159.3, 172.0; IR (neat) 2978 w, 2961 w, 2935 w, 2907 w, 2838 w, 1733 s, 1609 m, 1583 w, 1512 s, 1457 m, 1368 w, 1252 s, 1181 s, 1136 m, 1107 m, 1068 s, 1034 s, 907 w, 835 m, 797 w, 747 m, 661 w cm 1 ; Anal. Calcd for C 19 H 20 4 : C, 73.06; H, Found: C, 72.99; H, Ethyl 3-[4-(Trifluoromethyl)phenyl]-3-isochromanecarboxylate (3d) (Table 1, entry 3). Et 2 C CF 3 3d The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and ethyl 2-oxo-2-[4-(trifluoromethyl)phenyl]ethanoate (2d) (106 mg, 0.46 mmol). The reaction was conducted for 3 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/50) to give 3d (130 mg, 81%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 1.11 (t, J = 7.1 Hz, 3H), 3.23 (d, J = 16.0 Hz, 1H), 3.71 (d, J = 16.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.92 (d, J = 15.4 Hz, 1H), 5.13 (d, J = 15.4 Hz, 1H), (m, 1H), (m, 3H), 7.62 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 13.9, 36.2, 61.8, 65.0, 79.3, (q, J = 272 Hz), , (q, J = 4 Hz), 125.9, 126.7, 126.8, 128.6, (q, J = 32 Hz), 130.9, 133.0, 144.0, 171.2; IR (thin film) 3068 w, 2982 m, 2938 w, 2909 w, 2870 w, 1738 s, 1619 m, 1588 w, 1496 w, 1455 m, 1411 m, 1368 m, 1327 s, 1263 s, 1168 s, 1127 s, 1070 s, 1047 s, 1018 s, 909 w, 847 s, 746 s, 654 m, 603 w cm 1 ; Anal. Calcd for C 19 H 17 F 3 3 : C, 65.14; H, Found: C, 65.20; H,4.91. Methyl 3-(2,4-dimethylphenyl)-3-isochromanecarboxylate (3e) (Table 1, entry 4). Me Me 2 C Me 3e The general procedure was followed with use of 1 (172 mg, 0.68 mmol) and methyl 2-(2,4-dimethylphenyl)-2-oxoethanoate (2e) (86.4 mg, 0.45 mmol). The reaction was conducted for 24 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/5) to give 3e (47.1 mg, 35%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.25 (s, 3H), 2.38 (s, 3H), 3.45 (d, J = 16.4 Hz, 1H), 3.54 (d, J = 16.4 Hz, 1H), 3.75 (s, 3H), 4.33 (d, J = 15.3 Hz, 1H), 4.87 (d, J = 15.3 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.98 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), (m, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 20.1, 20.9, 35.3, 52.7, 63.7, 79.5, 123.9, , , 126.8, 128.1, 128.2, 131.5, 132.0, 132.9, 133.5, 137.4, 138.1, 173.5; IR (thin film) 3024 m, 2951 m, 2847 m, 1744 s, 1613 w, 1496 m, 1451 m, 1370 w, 1337 w, 1282 m, 1249 s, 1207 m, 1114 m, 1092 s, 1066 s, 1039 m, 911 m, 819 m, 787 m, 732 s, 679 m, 648 m, 586 w, 490 s cm 1 ; HRMS (FAB) Calcd for C 19 H 21 3 : Found: m/z = ([M+H] + ). S5

7 Ethyl 3-(1-Naphthyl)-3-isochromanecarboxylate (3f) (Table 1, entry 5). Et 2 C 3f The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and ethyl 2-(1-naphthyl)-2-oxoethanoate (2f) (104 mg, 0.46 mmol). The reaction was conducted for 3 h. The crude product was purified with MPLC (EtAc/hexane = 1/3) to give 3f (101 mg, 67%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 1.08 (t, J = 7.1 Hz, 3H), 3.62 (d, J = 16.5 Hz, 1H), 3.74 (d, J = 16.5 Hz, 1H), 4.11 (dq, J = 10.8, 7.1 Hz, 1H), 4.22 (dq, J = 10.8, 7.1 Hz, 1H), 4.28 (d, J = 15.5 Hz, 1H), 4.91 (d, J = 15.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), (m, 3H), 7.42 (d, J = 7.3 Hz, 1H), (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 8.60 (d, J = 8.2 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 14.0, 35.6, 61.6, 64.1, 79.8, 123.9, 124.6, 125.1, 125.7, 126.3, 126.4, (2C), 128.2, 128.8, 129.5, (2C), 132.6, 133.7, 134.2, 173.0; IR (thin film) 3051 w, 2979 w, 2902 w, 2848 w, 1744 m, 1509 w, 1450 m, 1367 w, 1289 m, 1238 s, 1206 m, 1113 s, 1077 s, 1052 m, 1037 m, 910 m, 780 s, 733 s, 648 w, 621 w, 557 w, 458 s cm 1 ; Anal. Calcd for C 22 H 20 3 : C, 79.50; H, Found: C, 79.29; H, Ethyl 3-(2-Naphthyl)-3-isochromanecarboxylate (3g) (Table 1, entry 6). Et 2 C 3g The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and ethyl 2-(2-naphthyl)-2-oxoethanoate (2g) (103 mg, 0.45 mmol). The reaction was conducted for 3 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/20) to give 3g (139 mg, 93%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 1.11 (t, J = 7.1 Hz, 3H), 3.40 (d, J = 16.1 Hz, 1H), 3.78 (d, J = 16.1 Hz, 1H), 4.11 (dq, J = 10.8, 7.1 Hz, 1H), 4.13 (dq, J = 10.8, 7.1 Hz, 1H), 4.92 (d, J = 15.4 Hz, 1H), 5.15 (d, J = 15.4 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), (m, 3H), (m, 2H), 7.72 (dd, J = 1.7, 8.7 Hz, 1H), (m, 3H), 8.04 (s, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 13.9, 35.9, 61.5, 64.9, 79.5, 123.3, 123.9, 124.9, 126.1, 126.3, 126.4, 126.6, 127.5, 128.2, 128.3, 128.6, 131.4, 132.9, 133.0, 133.2, 137.0, 171.7; IR (thin film) 3050 w, 2979 w, 2902 w, 2849 w, 1743 s, 1599 w, 1509 w, 1451 m, 1396 w, 1367 m, 1289 m, 1238 s, 1206 m, 1112 s, 1077 s, 1052 m, 1038 m, 909 m, 859 w, 779 s, 732 s cm 1 ; Anal. Calcd for C 22 H 20 3 : C, 79.50; H, Found: C, 79.26; H, Methyl 3-(2-Furyl)-3-isochromanecarboxylate (3h) (Table 1, entry 7). Me 2 C 3h S6

8 The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and methyl 2-(2-furyl)-2-oxoethanoate (2h) (69.7 mg, 0.45 mmol). The reaction was conducted for 4 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/10) to give 3h (108 mg, 93%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.49 (s, 2H), 3.77 (s, 3H), 4.66 (d, J = 15.3 Hz, 1H), 5.02 (d, J = 15.3 Hz, 1H), 6.30 (s, 2H), 6.95 (d, J = 6.3 Hz, 1H), (m, 3H), 7.40 (s, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 33.5, 52.9, 64.7, 75.7, 109.5, 110.3, 123.9, 126.4, 126.7, 128.4, 130.5, 132.9, 143.1, 150.9, 170.7; IR (thin film) 3120 m, 3028 w, 2953 m, 2850 w, 1744 s, 1590 m, 1496 m, 1453 m, 1437 m, 1370 w, 1289 s, 1266 s, 1208 s, 1155 m, 1117 s, 1065 s, 1014 m, 912 s, 813 m, 788 m, 739 s, 648 m, 599 w, 502 w cm 1 ; HRMS (FAB) Calcd for C 15 H 15 4 : Found: m/z = ([M+H] + ). 1-Benzylspiro[indoline-3,3 -isochromane]-2-one (3i) (Table 1, entry 8). CH 2 N 3i The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and 1-benzylindoline-2,3-dione (2i) (111 mg, 0.47 mmol). The reaction was conducted for 24 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/10) to give 3i (148 mg, 92%) as a brown solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.91 (d, J = 16.0 Hz, 1H), 3.49 (d, J = 16.0 Hz, 1H), 4.91 (d, J = 15.7 Hz, 1H), 4.95 (d, J = 15.7 Hz, 1H), 5.02 (d, J = 15.1 Hz, 1H), 5.24 (d, J = 15.1 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), (m, 3H), (m, 7H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 34.0, 43.6, 64.8, 75.3, 109.5, 122.7, 124.1, 124.3, 126.7, 127.0, 127.2, 127.6, 128.8, 129.0, 129.1, 129.6, 130.6, 134.2, 135.4, 142.5, 175.1; IR (thin film) 3030 w, 2930 w, 2854 w, 1725 s, 1613 m, 1489 m, 1467 m, 1366 m, 1301 w, 1262 w, 1193 m, 1095 m, 1033 m, 909 m, 733 s, 698 m, 646 w, 549 w, 494 m cm 1 ; HRMS (FAB) Calcd for C 23 H 19 N 2 : Found: m/z = (M + ). 3-Benzoyl-3-phenylisochromane (3j) (Table 1, entry 9). S7 3j The general procedure was followed with use of 1 (171 mg, 0.68 mmol) and benzil (2j) (94.1 mg, 0.45 mmol). The reaction was conducted for 6 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/50) to give 3j (120 mg, 85%) as a colorless solid: mp C; 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.95 (d, J = 16.2 Hz, 1H), 3.85 (d, J = 16.2 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 4.96 (d, J = 15.6 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), (m, 1H), 7.20 (d, J = 4.1 Hz, 2H), (m, 3H), 7.37 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.98 (d, J = 7.4 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 38.5, 65.4, 84.9, 123.8, 124.4, 126.1, 126.9, 127.6, 128.1,

9 128.5, 128.8, 130.0, 132.6, , , 134.7, 142.1, 199.0; IR (thin film) 3062 w, 3027 w, 2902 w, 2844 w, 1681 s, 1595 w, 1495 m, 1448 m, 1415 w, 1368 w, 1258 m, 1220 s, 1181 w, 1119 m, 1073 m, 1032 m, 954 m, 911 w, 745 s, 704 s, 622 m, 602 m cm 1 ; Anal. Calcd for C 22 H 18 2 : C, 84.05; H, Found: C, 83.84; H, enyl-3-(trifluoromethyl)isochromane (3k) (Table 1, entry 10). CF 3 3k The general procedure was followed with use of 1 (168 mg, 0.67 mmol) and 2,2,2-trifluoro-1-phenylethanone (2k) (77.6 mg, 0.45 mmol). The reaction was conducted for 24 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/100) to give 3k (116 mg, 93%) as pale yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.48 (d, J = 16.1 Hz, 1H), 3.55 (d, J = 16.1 Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 4.93 (d, J = 14.9 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), (m, 3H), (m, 3H), 7.52 (d, J = 7.0 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 30.7, 64.2, 77.7 (q, J = 29 Hz), 124.0, (q, J = 284 Hz), 126.5, 127.0, 128.1, , , 128.8, 130.2, 133.5, 134.1; IR (neat) 3065 w, 3031 w, 2862 w, 1496 w, 1451 m, 1309 m, 1274 m, 1251 m, 1167 s, 1121 m, 1080 m, 1059 s, 1037 m, 1002 m, 978 w, 896 w, 749 m, 725 m, 700 m, 632 w, 609 w, 589 w, 492 s, 472 m cm 1 ; Anal. Calcd for C 16 H 13 F 3 3 : C, 69.06; H, Found: C, 69.21; H, ,8-Diphenyl-3-(trifluoromethyl)isochromane (5a, 6b) [Containing 3,5-Diphenyl-3-(trifluoromethyl)isochromane (6a, 5b)] (Table 2, entries 1 and 2). CF 3 5a (= 6b) S8 CF 3 6a (= 5b) The general procedure was followed with use of methyl [6-phenyl-2-{(trimethylsilyl)methyl}phenyl]methyl carbonate (4a) (221 mg, 0.67 mmol) and 2k (78.3 mg, 0.45 mmol). The reaction was conducted for 24 h. The crude product contained the cycloadducts 5a and 6a in the ratio 85:15, which was determined with its 1 H NMR spectrum (Figure S-29). The crude product was purified with MPLC (EtAc/hexane = 1/20) to give a mixture of 5a and 6a (130 mg, 5a:6a = 89:11, 82%) as pale yellow oil. 5a: 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.49 (d, J = 15.9 Hz, 1H), 3.63 (d, J = 15.9 Hz, 1H), 4.67 (d, J = 14.9 Hz, 1H), 4.84 (d, J = 14.9 Hz, 1H), (13H). 6a (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.34 (d, J = 16.1 Hz, 1H), 3.40 (d, J = 16.1 Hz, 1H), 4.81 (d, 1H, overlapping with the peak at 4.84 ppm of 5a), 5.01 (d, J = 14.5 Hz, 1H). Alternatively, a mixture of compounds 5a and 6a was obtained with a similar molar ratio from the reaction of methyl [3-phenyl-2-{(trimethylsilyl)methyl}phenyl]methyl carbonate (4b) (221 mg, 0.67 mmol) with 2k (78.5 mg, 0.45 mmol). The reaction was conducted for 6 h. The crude product contained the cycloadducts 5b (= 6a) and 6b (= 5a) in the ratio 16:84, which was determined with its 1 H NMR spectrum (Figure S-31). The crude product was purified with MPLC (EtAc/hexane = 1/20) to give a mixture of 5b

10 and 6b (147 mg, 5b:6b = 14:86, 92%) as pale yellow oil. 5b (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.34 (d, J = 16.1 Hz, 1H), 3.40 (d, J = 16.1 Hz, 1H), 4.81 (d, 1H, overlapping with the peak at 4.84 ppm of 5a), 5.01 (d, J = 14.6 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 29.2, 64.8, 123.3, 126.2, 128.2, , , 128.6, 129.0, 134.3, 134.8, 140.1, b: 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.49 (d, J = 15.9 Hz, 1H), 3.63 (d, J = 15.9 Hz, 1H), 4.67 (d, J = 14.9 Hz, 1H), 4.85 (d, J = 14.9 Hz, 1H), (13H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 32.1, 63.1, 77.7 (q, J = 28 Hz), (q, J = 285 Hz), 127.1, , , 127.6, 128.0, (2C+1C), 128.7, 128.9, 131.2, 132.1, 135.5, 138.9, 139.5; IR (neat) 3061 w, 3030 w, 2859 w, 1955 m, 1888 m, 1813 m, 1593 w, 1496 w, 1450 m, 1301 m, 1275 m, 1168 s, 1125 m, 1082 m, 1057 s, 1033 m, 982 m, 909 m, 849 w, 793 m, 760 s, 731 s, 702 s, 651 m, 531 m, 500 m, 476 m cm 1 ; Anal. Calcd for C 22 H 17 F 3 : C, 74.57; H, Found: C, 74.89; H, The major product of the two above reactions was assigned to 5a or 6b through the reaction of dideuterio[3-phenyl-2-{(trimethylsilyl)methyl}phenyl]methyl methyl carbonate (4b-d 2 ) with 2k. SiMe 3 CMe D D 4b-d 2 + 2k CF 3 Pd(! 3 -C 3 H 5 )Cp (3.0%) DPEphos (3.3%) DMF, 120 C CF 3 D D CF 3 D D 5b-d 2 6b-d 2 The general procedure was followed with use of 4b-d 2 (223 mg, 0.68 mmol) and 2k (78.8 mg, 0.45 mmol). The reaction was conducted for 6 h. The crude product was purified with MPLC (EtAc/hexane = 1/5) to give a mixture of 5b-d 2 and 6b-d 2 (135 mg, 5b-d 2 :6b-d 2 = 14:86, 84%) as yellow oil. 5b-d 2 (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.34 (d, J = 16.1 Hz, 1H), 3.40 (d, J = 16.1 Hz, 1H). 6b-d 2 : 1 H NMR (400 MHz, CDCl 3, TMS) δ 4.67 (d, J = 14.9 Hz, 1H), 4.84 (d, J = 14.9 Hz, 1H), (13H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 31.5 (m), 63.1, 77.6 (q, J = 29 Hz), (q, J = 285 Hz), 127.1, , , 127.6, 128.0, (2C+1C), 128.7, 128.9, 131.1, 132.1, 135.4, 138.9, 139.5; IR (neat) 3061 w, 3031 w, 2859 w, 2317 w, 1955 w, 1888 w, 1815 w, 1679 w, 1592 w, 1496 w, 1450 m, 1301 m, 1173 s, 1094 m, 1022 m, 947 w, 910 m, 851 w, 760 s, 730 s, 702 s, 612 w, 484 s, 438 m cm 1. The major product of the above deuterium-labeled experiment has no signals in the range of ppm in its 1 H NMR spectrum. The observation indicates that the deuterium atoms locate at the 4-position of isochromane framework in the major product. It is concluded that the reactions of 4a and 4b with 2k produced 5a (= 6b) in preference to 6a (= 5b). 5-Methyl-3-phenyl-3-(trifluoromethyl)isochromane (6c, 5d) and 8-Methyl-3-phenyl-3-(trifluoromethyl)- isochromane (5c, 6d) (Table 2, entries 3 and 4). Me CF 3 6c (= 5d) S9 Me CF 3 5c (= 6d) The general procedure was followed with use of methyl [6-methyl-2-{(trimethylsilyl)methyl}phenyl]methyl carbonate (4c) (179 mg, 0.67 mmol) and 2k (79.6 mg, 0.46 mmol). The reaction was conducted for 24 h. The crude product contained the cycloadducts 5c and

11 6c in the ratio 35:65, which was determined with its 1 H NMR spectrum (Figure S-36). The crude product was purified with MPLC (EtAc/hexane = 1/20) to give a mixture of 5c and 6c (115 mg, 5c:6c = 35:65, 86%) as pale yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.03 (s, 1.1H), 2.35 (s, 1.9H), 3.32 (d, J = 16.3 Hz, 0.6H), (m, 1.4H), 4.60 (d, J = 15.5 Hz, 0.4H), 4.71 (d, J = 14.8Hz, 0.6H), (m, 1H), (m, 0.6H), 6.92 (d, J = 6.9 Hz, 0.4H), (m, 2H), (m, 3H), (m, 2H). Alternatively, a mixture of compounds 5c and 6c was obtained with a similar molar ratio from the reaction of methyl [3-methyl-2-{(trimethylsilyl)methyl}phenyl]methyl carbonate (4d) (179 mg, 0.67 mmol) with 2k (78.6 mg, 0.45 mmol). The reaction was conducted for 6 h. The crude product contained the cycloadducts 5d (= 6c) and 6d (= 5c) in the ratio 68:32, which was determined with its 1 H NMR spectrum (Figure S-38). The crude product was purified with MPLC (EtAc/hexane = 1/15) to give a mixture of 5d and 6d (105 mg, 5d:6d = 66:34, 80%) as pale yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.03 (s, 1H), 2.35 (s, 2H), 3.32 (d, J = 16.3 Hz, 0.6H), (m, 1.4H), 4.60 (d, J = 15.6 Hz, 0.3H), 4.71 (d, J = 14.8Hz, 0.7H), (m, 1H), (m, 0.7H), 6.92 (d, J = 7.0 Hz, 0.3H), (m, 2H), (m, 3H), (m, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ (17.7), 18.9, 27.4, (30.3), (62.5), 64.2, [77.4 (q, J = 29 Hz)], 78.0 (q, J = 28 Hz), 121.7, [124.8 (q, J = 284 Hz)], (q, J = 285 Hz), 126.0, (126.2), (126.6), 127.8, (128.1), (128.27), , , , , (128.85), (129.7), (131.2), (132.9), 133.3, (133.4), 134.4, (chemical shifts in parentheses might be assigned to the minor regioisomer 6d); IR (neat) 3031 w, 2942 w, 2861 w, 1743 m, 1599 w, 1474 m, 1451 m, 1347 w, 1304 m, 1275 s, 1254 m, 1166 s, 1127 m, 1080 s, 1037 m, 1017 m, 978 m, 914 w, 874 w, 768 m, 727 s, 701 s, 627 m, 608 w cm 1 ; Anal. Calcd for C 17 H 15 F 3 : C, 69.85; H, Found: C, 69.92; H, The major product of the two above reactions was assigned to 6c or 5d through the reaction of dideuterio[3-methyl-2-{(trimethylsilyl)methyl}phenyl]methyl methyl carbonate (4d-d 2 ) with 2k. labeled substrate 4d-d 2 was prepared as shown in the following scheme. Me Me C 2 H LiAlD 4 THF, reflux Me Me CD 2 H 1. BuLi, Et 2 reflux 2. Me 3 SiCl 78 C to r.t. Me SiMe 3 CD 2 H ClC 2 Me, pyridine, cat. DMAP CH 2 Cl 2, r.t. Me SiMe 3 CMe D D 4d-d 2 A solution of 2,3-dimethylbenzoic acid (1.06 g, 7.0 mmol) in THF (11 ml) was added dropwise to a mixture of lithium aluminum deuteride (294 mg, 7.0 mmol) in THF (7.0 ml) at 0 C for 30 min. After hydrogen evolution ceased, the reaction mixture was stirred under reflux for 11 h. After the reaction vessel was cooled with ice bath, H 2 and 10% H 2 S 4 aq. were carefully added to the resulting mixture. The mixture was extracted three times with EtAc. The combined organic layer was washed with saturated Na 2 C 3 aq., with brine, dried with Na 2 S 4, and then evaporated under reduced pressure to give the crude The S10

12 dideuterio(2,3-dimethylphenyl)methanol (979 mg, >99%) as a colorless solid: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.28 (s, 3H), 2.30 (s, 3H), (m, 2H), 7.19 (dd, J = 2.1, 6,7 Hz, 1H). A solution of butyllithium in hexane (1.4 M, 12 ml, 17 mmol) was added dropwise to a solution of the crude benzylic alcohol (979 mg, 7.0 mmol) in dry Et 2 (14 ml) at 0 C for 30 min. After stirred under reflux for 24 h, the reaction mixture was cooled to 78 C. Chlorotrimethylsilane (2.3 ml, d g/ml, 18 mmol) was added dropwise to the resulting solution for 15 min. The mixture was stirred at room temperature for 3 h, and then 10% H 2 S 4 aq. (7.0 ml) was carefully added to it. After stirred at room temperature for 1 h, the mixture was extracted three times with EtAc. The combined organic layer was washed with brine, dried with Na 2 S 4, and then evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane = 1/10) to give dideuterio[3-methyl-2-{(trimethylsilyl)methyl}phenyl]methanol (1.02 g, 69%) as colorless oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 0.02 (s, 9H), 2.25 (s, 5H), 7.01 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H). The silylated compound (927 mg, 4.4 mmol) and 4-(dimethylamino)pyridine (5.5 mg, 45 µmol) was dissolved in dry CH 2 Cl 2 (5.0 ml). After dry pyridine (0.57 ml, d g/ml, 7.0 mmol) was added, methyl chloroformate (584 mg, 6.2 mmol) was added dropwise to the solution at 0 C for 15 min. The mixture was stirred at room temperature for 3 h. After 1 N HCl aq. was added, the resulting mixture was extracted three times with CH 2 Cl 2. The combined organic layer was washed with brine, dried with Na 2 S 4, and then evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane = 1/10) to give 4d-d 2 (1.09 g, 92%) as colorless oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 0.02 (s, 9H), 2.24 (s, 2H), 2.25 (s, 3H), 3.79 (s, 3H), 7.00 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 0.5, 19.4, 20.9, 54.6, 67.9 (quintet, J = 23 Hz), 123.9, 127.6, 130.6, 131.5, 135.3, 136.7, 155.7; IR (thin film) 3066 w, 3005 w, 2955 m, 2182 w, 2145 w, 1933 w, 1748 s, 1593 w, 1442 m, 1289 s, 1258 s, 1198 w, 1153 w, 1093 w, 1050 m, 1002 w, 928 m, 847 s, 790 m, 771 m, 691 w, 504 m, 476 s, 449 s, 418 s cm 1. Me D D 4d-d 2 SiMe 3 CMe + 2k CF 3 Pd(! 3 -C 3 H 5 )Cp (3.0%) DPEphos (3.3%) DMF, 120 C S11 Me CF 3 D D CF 3 D D Me 5d-d 2 6d-d 2 The general procedure was followed with use of 4d-d 2 (182 mg, 0.68 mmol) and 2k (78.8 mg, 0.45 mmol). The reaction was conducted for 6 h. The crude product was purified with MPLC (EtAc/hexane = 1/5) to give a mixture of 5d-d 2 and 6d-d 2 (112 mg, 5d-d 2 :6d-d 2 = 66:34, 85%) as yellow oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.03 (s, 1H), 2.36 (s, 2H), 3.31 (d, J = 16.3 Hz, 0.7H), 3.50 (d, J = 16.3 Hz, 0.7H), 4.60 (d, J = 15.5 Hz, 0.3H), 4.88 (d, J = 15.5 Hz, 0.3H), 6.76 (dd, J = 2.7, 6.1 Hz, 0.7H), 6.93 (dd, J = 7.3 Hz, 0.3H), (m, 2H), (m, 3H), (m, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ (17.7), 18.9, 27.4, [29.6 (m)], (62.5), 63.6 (quintet, J = 23 Hz), 77.9 (q, J = 28 Hz), 121.7, [124.8 (q, J = 284 Hz)], (q, J = 284 Hz), 126.0, (126.2), (126.6), 127.8, (128.1), (128.27), , , , , (128.86), (129.6), (131.2), (132.9), 133.1, (133.4), 134.4, 135.6; IR (neat) 3031 w, 2922 w, 2855 w, 2219 w, 2089 w,

13 1598 w, 1473 w, 1450 m, 1308 m, 1272 m, 1205 m, 1169 s, 1100 m, 1076 m, 1034 m, 1001 m, 763 m, 725 m, 699 m, 472 m cm 1. In the 1 H NMR spectrum of the mixture obtained from the above deuterium-labeled experiment, the peaks in the ranges of and ppm appeared in the ratio 66:34. The observation indicates that the deuterium atoms locate at the 1-position of isochromane framework in the major product. It is concluded that the reactions of 4c and 4d with 2k produced 6c (= 5d) in preference to 5c (= 6d). Methyl 3,5-Diphenyl-3-isochromanecarboxylate (5e) and Methyl 3,8-diphenyl-3-isochromanecarboxylate (6e) (Table 2, entry 5). C 2 Me 5e C 2 Me The general procedure was followed with use of 4b (225 mg, 0.69 mmol) and 2a (74.4 mg, 0.45 mmol). The reaction was conducted for 4 h. The crude product contained the cycloadducts 5e and 6e in the ratio 52:48, which was determined with its 1 H NMR spectrum (Figure S-45). The crude product was purified with MPLC (EtAc/hexane = 1/3) to give 5e (47.2 mg, 30%) and 6e (51.7 mg, 33%). 5e: colorless oil; 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.12 (d, J = 16.5 Hz, 1H), 3.58 (d, J = 16.5 Hz, 1H), 3.62 (s, 3H), 4.95 (d, J = 15.4 Hz, 1H), 5.14 (d, J = 15.4 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 7.3 Hz, 1H), (m, 11H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 34.5, 52.6, 65.2, 79.9, 123.2, 125.5, 126.1, 127.2, , , 128.3, 128.4, , , 133.6, 139.7, 140.5, 141.8, 172.5; IR (neat) 3060 w, 3027 w, 2951 w, 2907 w, 2855 w, 1737 s, 1495 w, 1452 m, 1270 m, 1216 m, 1142 w, 1061 m, 910 w, 762 m, 730 m, 700 s, 647 w cm 1 ; Anal. Calcd for C 23 H 20 3 : C, 80.21; H, Found: C, 79.90; H, e: colorless oil; 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.33 (d, J = 16.2 Hz, 1H), 3.66 (s, 3H), 3.80 (d, J = 16.2 Hz, 1H), 4.72 (d, J = 15.8 Hz, 1H), 4.94 (d, J = 15.8 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), (m, 10H), 7.57 (d, J = 7.2 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 36.4, 52.7, 64.0, 79.3, 125.4, 126.7, 127.3, 127.7, 128.0, 128.1, 128.3, 128.5, 128.7, 131.1, 131.9, 139.0, 139.8, 140.1, 172.6; IR (neat) 3060 w, 3028 w, 2952 w, 2906 w, 2854 w, 1737 s, 1591 w, 1495 m, 1448 m, 1369 w, 1272 m, 1205 s, 1141 m, 1082 m, 1060 m, 910 m, 818 w, 791 m, 761 m, 731 s, 701 s, 649 w, 508 m cm 1 ; Anal. Calcd for C 23 H 20 3 : C, 80.21; H, Found: C, 79.91; H, The phenyl substituent at the 5- or 8-position of the isochromane 5e or 6e is expected to affect the chemical shifts of the protons at 1- and 4-positions. The protons would be placed over the phenyl ring, because the aryl plane should be perpendicular to the isochromane framework. Therefore, the peaks of the protons at 4-position of 5e appears in upfield as compared to 6e. Similarly, the chemical shifts of the protons at 1-position of 6e are lower than those of 5e. 6e S12

14 Methyl 5-Methyl-3-phenyl-3-isochromanecarboxylate (6f, 5g) [Containing Methyl 8-Methyl-3-phenyl-3- isochromanecarboxylate (5f, 6g)] (Table 2, entries 6 and 7). Me C 2 Me 6f (= 5g) S13 Me C 2 Me 5f (= 6g) The general procedure was followed with use of 4c (181 mg, 0.68 mmol) and 2a (75.8 mg, 0.46 mmol). The reaction was conducted for 24 h. The crude product contained the cycloadducts 5f and 6f in the ratio 13:87, which was determined with its 1 H NMR spectrum (Figure S-50). The crude product was purified with MPLC (EtAc/hexane = 1/5) to give a mixture of 5f and 6f (97.1 mg, 5f:6f = 11:89, 74%) as colorless oil. 5f (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.11 (s, 3H), 3.31 (d, J = 16.1 Hz, 1H), 3.65 (s, 3H), 4.79 (d, 1H, overlapping with the peak at 4.83 ppm of 6f), 5.01 (d, J = 15.0 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H). 6f: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.34 (s, 3H), 3.13 (d, J = 16.5 Hz, 1H), 3.60 (d, J = 16.5 Hz, 1H), 3.68 (s, 3H), 4.83 (d, J = 15.4 Hz, 1H), 5.03 (d, J = 15.4 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), (m, 2H), (m, 3H), 7.56 (d, J = 7.2 Hz, 2H). Alternatively, a mixture of compounds 5f and 6f was obtained with a similar molar ratio from the reaction of 4d (177 mg, 0.67 mmol) with 2a (74.6 mg, 0.45 mmol). The reaction was conducted for 20 h. The crude product contained the cycloadducts 5g (= 6f) and 6g (= 5f) in the ratio 90:10, which was determined with its 1 H NMR spectrum (Figure S-52). The crude product was purified with MPLC (EtAc/hexane = 1/3) to give a mixture of 5g and 6g (96.2 mg, 5g:6g = 90:10, 75%) as colorless oil. 5g: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.33 (s, 3H), 3.12 (d, J = 16.5 Hz, 1H), 3.59 (d, J = 16.5 Hz, 1H), 3.66 (s, 3H), 4.83 (d, J = 15.5 Hz, 1H), 5.03 (d, J = 15.5 Hz, 1H), 6.80 (d, J = 6.0 Hz, 1H), (m, 2H), (m, 3H), 7.56 (d, J = 7.3 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 18.9, 33.1, 52.64, 64.9, 79.7, 121.6, 125.3, 125.9, 128.0, 128.1, , 129.8, 132.9, 136.0, 140.0, 172.6; IR (neat) 3062 w, 3027 w, 2951 m, 2905 w, 2859 w, 1736 s, 1598 w, 1495 m, 1449 m, 1434 m, 1366 w, 1336 w, 1273 s, 1219 s, 1144 m, 1074 s, 1049 m, 1032 m, 1004 w, 912 w, 813 m, 711 m, 729 m, 699 s, 671 m, 643 m, 577 w cm 1 ; Anal. Calcd for C 18 H 18 3 : C, 76.57; H, Found: C, 76.32; H, g (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.09 (s, 3H), 3.30 (d, J = 16.1 Hz, 1H), 3.63 (s, 3H), 4.78 (d, 1H, overlapping with the peak at 4.83 ppm of 5g), 5.01 (d, J = 15.6 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 17.7, 35.9, 52.56, 63.7, 79.1, 124.2, 125.2, 125.5, 126.2, 126.4, , 130.9, 131.3, 133.1, 139.6, a. The major product of the two above reactions was assigned to 6f or 5g through the reaction of 4d-d 2 with Me SiMe 3 CMe D D 4d-d 2 + 2a C 2 Me Pd(! 3 -C 3 H 5 )Cp (3.0%) DPEphos (3.3%) DMF, 120 C Me C 2 Me D D Me 5g-d 2 6g-d 2 D D C 2 Me The general procedure was followed with use of 4d-d 2 (183 mg, 0.68 mmol) and 2a (73.9 mg, 0.45 mmol). The reaction was conducted for 3 h. The crude product was purified with MPLC (EtAc/hexane = 1/3) to give a mixture of 5g-d 2 and 6g-d 2 (114 mg, 5g-d 2 :6g-d 2 = 92:8, 89%) as pale yellow oil. 5g-d 2 : 1 H NMR

15 (400 MHz, CDCl 3, TMS) δ 2.33 (s, 3H), 3.12 (d, J = 16.5 Hz, 1H), 3.60 (d, J = 16.5 Hz, 1H), 3.67 (s, 3H), 6.81 (dd, J = 2.1, 6.4 Hz, 1H), (m, 2H), (m, 3H), 7.56 (d, J = 7.6 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 19.0, 33.1, 52.7, 64.3 (m), 79.7, 121.6, 125.4, 125.9, 128.0, 128.1, 128.5, 129.9, 132.8, 136.0, 140.0, 172.6; IR (neat) 3062 w, 3027 w, 2952 w, 2901 w, 1737 s, 1597 w, 1494 w, 1449 m, 1380 w, 1270 s, 1225 m, 1151 m, 1100 m, 1074 s, 1020 m, 959 w, 911 m, 803 w, 762 m, 732 s, 699 m, 661 m, 512 w, 494 m, 459 s cm 1. 6g-d 2 (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.10 (s, 3H), 3.64 (s, 3H), 4.78 (d, J = 15.8 Hz, 1H), 5.01 (d, J = 15.8 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H). The major product of the above deuterium-labeled experiment has no resonances in the range of ppm in its 1 H NMR spectrum. The observation indicated that the deuterium atoms located at the 1-position of isochromane framework in the major product. It is concluded that the reactions of 4c and 4d with 2a produced 6f (= 5g) in preference to 5f (= 6g). 1-Benzyl-5 -methylspiro[indoline-3,3 -isochromane]-2-one (5h) [Containing 1-Benzyl-8 -methylspiro- [indoline-3,3 -isochromane]-2-one (6h)] (Table 2, entry 8). Me CH 2 N S14 CH 2 N 5h Me 6h The general procedure was followed with use of 4d (182 mg, 0.68 mmol) and 2i (107 mg, 0.45 mmol). The reaction was conducted for 24 h. The crude product contained the cycloadducts 5h and 6h in the ratio 91:9, which was determined with its 1 H NMR spectrum (Figure S-57). The crude product was purified with a flash column chromatography (EtAc/hexane = 1/10) to give a mixture of 5h and 6h (110 mg, 5h:6h = 93:7, 69%) as a brown solid. 5h: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.21 (s, 3H), 2.85 (d, J = 16.4 Hz, 1H), 3.30 (d, J = 16.4 Hz, 1H), 4.91 (d, J = 15.7 Hz, 1H), 4.95 (d, J = 15.7 Hz, 1H), 5.02 (d, J = 15.2 Hz, 1H), 5.22 (d, J = 15.2 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), (m, 2H), 6.99 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), (m, 2H), (m, 5H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 18.8, 31.0, 43.6, 64.6, 75.3, 109.5, 121.6, 122.6, 124.2, 126.1, 127.2, 127.5, 128.2, 128.7, 128.9, 129.1, 129.6, 133.6, 135.4, 136.3, 142.4, 175.1; IR (thin film) 3061 w, 3031 w, 2925 w, 2857 w, 1725 s, 1612 s, 1488 s, 1468 s, 1365 s, 1301 w, 1259 w, 1202 m, 1173 m, 1108 m, 1079 m, 1049 m, 992 w, 910 s, 844 w, 732 s, 700 s, 674 w, 646 m, 594 w, 550 w, 504 m, 482 s, 463 m cm 1 ; HRMS (FAB) Calcd for C 24 H 22 N 2 : Found: m/z = ([M+H] + ). 6h (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.24 (s, 3H), 2.91 (d, J = 16.1 Hz, 1H), 3.48 (d, J = 16.1 Hz, 1H), 5.16 (d, J = 16.0 Hz, 1H). The major product of the above reactions was assigned to 5h through the reaction of 4d-d 2 with 2i. Me SiMe 3 CMe D D 4d-d 2 CH 2 N + 2i Pd(! 3 -C 3 H 5 )Cp (3.0%) DPEphos (3.3%) DMF, 120 C Me D D 5h-d 2 CH 2 N Me D D 6h-d 2 CH 2 N

16 The general procedure was followed with use of 4d-d 2 (120 mg, 0.45 mmol) and 2i (70.9 mg, 0.30 mmol). The reaction was conducted for 24 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/10) to give a mixture of 5h-d 2 and 6h-d 2 (86.6 mg, 5h-d 2 :6h-d 2 = 93:7, 81%) as brown oil. 5h-d 2 : 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.21 (s, 3H), 2.85 (d, J = 16.4 Hz, 1H), 3.29 (d, J = 16.4 Hz, 1H), 4.91 (d, J = 15.8 Hz, 1H), 4.95 (d, J = 15.8 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), (m, 2H), 6.99 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), (m, 2H), (m, 5H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 18.9, 31.2, 43.8, 75.4, 109.6, 121.8, 122.8, 124.3, 126.2, 127.3, 127.7, 128.4, 128.8, 129.1, 129.3, 129.7, 133.7, 135.5, 136.5, 142.6, 175.3; IR (neat) 3032 w, 2924 w, 2089 w, 1725 s, 1611 m, 1467 m, 1364 m, 1299 w, 1262 w, 1173 w, 1106 w, 1076 w, 1015 w, 909 w, 855 w, 734 m, 701 m, 645 w, 551 w cm 1. 6h-d 2 (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.24 (s, 3H), 5.15 (d, J = 15.6 Hz, 1H). The major product of the above deuterium-labeled experiment has only resonances of the N-benzyl protons in the range of ppm in its 1 H NMR spectrum. The observation indicated that the deuterium atoms located at the 1-position of isochromane framework in the major product. It is concluded that the reaction of 4d with 2i produced 5h in preference to 6h. 3-Benzoyl-5-methyl-3-phenylisochromane (5i) [Containing 3-Benzoyl-8-methyl-3-phenylisochromane (6i)] (Table 2, entry 9). Me 5i Me The general procedure was followed with use of 4d (179 mg, 0.67 mmol) and 2j (95.9 mg, 0.46 mmol). The reaction was conducted for 6 h. The crude product contained the cycloadducts 5i and 6i in the ratio 88:12, which was determined with its 1 H NMR spectrum (Figure S-62). The crude product was purified with MPLC (EtAc/hexane = 1/5) to give a mixture of 5i and 6i (109 mg, 5i:6i = 86:14, 73%) as a colorless solid. 5i: 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.21 (s, 3H), 2.70 (d, J = 16.5 Hz, 1H), 3.82 (d, J = 16.5 Hz, 1H), 4.70 (d, J = 15.5 Hz, 1H), 4.92 (d, J = 15.5 Hz, 1H), (m, 1H), (m, 2H), (m, 3H), 7.39 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.58 (d, J = 7.5 Hz, 2H), 7.99 (d, J = 7.4 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 18.9, 35.8, 65.5, 85.1, 121.4, 124.3, 125.6, 127.6, , , 128.8, 130.0, 131.2, 132.4, 132.8, 134.6, 136.1, 142.5, 199.1; IR (thin film) 3062 w, 3027 w, 2943 w, 2902 w, 2847 w, 1681 s, 1597 w, 1493 w, 1473 w, 1447 m, 1414 w, 1365 w, 1334 w, 1259 m, 1226 m, 1182 w, 1126 m, 1072 m, 1032 m, 1002 w, 969 w, 942 m, 910 m, 848 w, 768 s, 733 s, 704 s, 663 m, 615 m cm 1 ; Anal. Calcd for C 23 H 20 2 : C, 84.12; H, Found: C, 83.96; H, i (partially assigned): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.02 (s, 3H), 2.95 (d, J = 16.1 Hz, 1H), 4.58 (d, J = 15.9 Hz, 1H), 4.95 (d, J = 15.9 Hz, 1H), 6.95 (d, J = 7.1 Hz, 1H). The major and minor products of the reaction of 4d with 2j were assigned to 5i and 6i with their analogy with 5g and 6g in 1 H NMR spectra, respectively. 6i S15

17 6-Methoxy-3-phenyl-3-(trifluoromethyl)isochromane (5j) (Table 2, entry 10). CF Me 3 5j The general procedure was followed with use of [4-methoxy-2-{(trimethylsilyl)methyl}phenyl]methyl methyl carbonate (4e) (191 mg, 0.68 mmol) and 2k (78.4 mg, 0.45 mmol). The reaction was conducted for 9 h. No formation of 6j was observed in the 1 H NMR spectrum of the crude product (Figure S-65). The crude product was purified with a flash column chromatography (EtAc/hexane = 1/100) to give 5j (96.5 mg, 70%) as colorless oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.43 (d, J = 16.1 Hz, 1H), 3.52 (d, J = 16.1 Hz, 1H), 3.77 (s, 3H), 4.67 (d, J = 14.4 Hz, 1H), 4.88 (d, J = 14.4 Hz, 1H), 6.68 (dd, J = 2.4, 8.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), (m, 3H), 7.52 (d, J = 7.2 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 31.1, 55.2, 63.9, 77.6 (q, J = 28 Hz), 112.4, 113.4, (q, J = 285 Hz), 125.1, 125.6, 128.0, 128.3, 128.8, 131.6, 134.3, 158.5; IR (neat) 3014 w, 2952 w, 2935 w, 2906 w, 2862 w, 2836 w, 1614 w, 1506 m, 1450 m, 1322 m, 1296 m, 1275 m, 1253 s, 1193 s, 1163 s, 1110 m, 1077 m, 1056 m, 1033 m, 977 w, 910 w, 850 w, 816 w, 767 w, 732 w, 703 m cm 1 ; Anal. Calcd for C 22 H 17 F 3 : C, 66.23; H, Found: C, 66.35; H, The product was assigned to 5j through the reaction of dideuterio[4-methoxy-2-{(trimethylsilyl)methyl}phenyl]methyl methyl carbonate (4e-d 2 ) with 2k. The labeled substrate 4e-d 2 was prepared as shown in the following scheme. 1. BuLi, Et 2 Me Me LiAlD Me Me 4 reflux Me SiMe 3 C 2 H THF, reflux CD 2 H 2. Me 3 SiCl 78 C to r.t. CD 2 H ClC 2 Me, pyridine, cat. DMAP CH 2 Cl 2, r.t. S16 Me SiMe 3 CMe D D 4e-d 2 A solution of 4-methoxy-2-methylbenzoic acid (2.49 g, 15 mmol) in THF (44 ml) was added dropwise to a mixture of lithium aluminum deuteride (637 mg, 15 mmol) in THF (44 ml) at 0 C for 30 min. After hydrogen evolution ceased, the reaction mixture was stirred under reflux for 18 h. After the reaction vessel was cooled with ice bath, H 2 and 10% H 2 S 4 aq. were carefully added to the resulting mixture. The mixture was extracted three times with EtAc. The combined organic layer was washed with saturated Na 2 C 3 aq., with brine, dried with Na 2 S 4, and then evaporated under reduced pressure to give the crude dideuterio(4-methoxy-2-methylphenyl)methanol (2.24 g, 97%): 1 H NMR (400 MHz, CDCl 3, TMS) δ 2.37 (s, 3H), 3.79 (s, 3H), (m, 2H), 7.23 (d, J = 8.2 Hz, 1H). A solution of butyllithium in hexane (1.6 M, 21 ml, 34 mmol) was added dropwise to a solution of the crude benzylic alcohol (2.24 mg, 15 mmol) in dry Et 2 (30 ml) at 0 C for 30 min. After stirred under reflux for 24 h, the reaction mixture was cooled to 78 C. Chlorotrimethylsilane (4.8 ml, d g/ml, 38 mmol) was added dropwise to the resulting solution for 15 min. The mixture was stirred at room

18 temperature for 3 h, and then 10% H 2 S 4 aq. (15 ml) was carefully added to it. After stirred at room temperature for 16 h, the mixture was extracted three times with EtAc. The combined organic layer was washed with brine, dried with Na 2 S 4, and then evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane = 1/10) to give dideuterio[4-methoxy-2-{(trimethylsilyl)methyl}phenyl]methanol (799 mg, 24%) as colorless oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 0.04 (s, 9H), 2.21 (s, 2H), 3.79 (s, 3H), 6.58 (d, J = 2.6 Hz, 1H), 6.65 (dd, J = 2.6, 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H). The silylated compound (691 mg, 3.1 mmol) and 4-(dimethylamino)pyridine (4.2 mg, 34 µmol) was dissolved in dry CH 2 Cl 2 (3.0 ml). After dry pyridine (0.37 ml, d g/ml, 4.6 mmol) was added, methyl chloroformate (352 mg, 3.7 mmol) was added dropwise to the solution at 0 C for 15 min. The mixture was stirred at room temperature for 2 h. After 1 N HCl aq. was added, the resulting mixture was extracted three times with EtAc. The combined organic layer was washed with brine, dried with Na 2 S 4, and then evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtAc/hexane = 1/20) to give 4e-d 2 (705 mg, 81%) as colorless oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 0.02 (s, 9H), 2.18 (s, 2H), 2.25 (s, 3H), 3.78 (s, 6H), 6.56 (d, J = 2.6 Hz, 1H), 6.63 (dd, J = 2.6, 8.3 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 1.5, 23.5, 54.7, 55.1, 67.4 (m), 109.6, 114.7, 124.0, 132.0, 141.9, 155.8, 159.7; IR (thin film) 3002 w, 2955 m, 2901 w, 2837 w, 2181 w, 1746 s, 1609 m, 1575 m, 1503 m, 1442 m, 1295 s, 1253 s, 1191 w, 1165 m, 1135 m, 1070 m, 1046 m, 1026 m, 923 m, 852 s, 793 m, 694 w cm 1. Me SiMe 3 CMe D D 4e-d 2 + 2k CF 3 Pd(! 3 -C 3 H 5 )Cp (3.0%) DPEphos (3.3%) DMF, 120 C 5j-d 2 D D CF 3 The general procedure was followed with use of 4e-d 2 (189 mg, 0.67 mmol) and 2k (78.9 mg, 0.45 mmol). The reaction was conducted for 18 h. The crude product was purified with a flash column chromatography (EtAc/hexane = 1/50) to give 5j-d 2 (129 mg, 91%) as colorless oil: 1 H NMR (400 MHz, CDCl 3, TMS) δ 3.43 (d, J = 16.1 Hz, 1H), 3.52 (d, J = 16.1 Hz, 1H), 3.77 (s, 3H), 6.67 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), (m, 3H), 7.52 (d, J = 7.1 Hz, 2H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 31.0, 55.2, 63.2 (quintet, J = 22 Hz), 77.5 (q, J = 28 Hz), 112.4, 113.4, (q, J = 284 Hz), 125.1, 125.5, 128.0, 128.3, 128.8, 131.6, 134.3, 158.6; IR (neat) 3002 w, 2955 m, 2901 w, 2837 w, 2181 w, 1746 s, 1609 m, 1575 m, 1503 m, 1442 m, 1295 s, 1253 s, 1191 w, 1165 m, 1135 m, 1070 m, 1046 m, 1026 m, 923 m, 852 s, 793 m, 694 w cm 1. The product of the above deuterium-labeled experiment has no resonances in the range of ppm in its 1 H NMR spectrum. The observation indicated that the deuterium atoms located at the 1-position of isochromane framework in the product. It is concluded that the reaction of 4e with 2k produced 5j with no formation of 6j. Me S17