Supporting Information Enantioselective rganocatalyzed Direct α-thiocyanation of Cyclic β-ketoesters by N-Thiocyanatophthalimide Jiashen Qiu, Di Wu, Pran Gopal Karmaker, Hongquan Yin, and Fu-Xue Chen* School of Chemistry & Chemical Engineering, Beijing Institute of Technology, 5 South Zhongguancun Street, Haidian district, Beijing 100081, China fuxue.chen@bit.edu.cn Contents 1. General Information... S2 2. Preparation of the Catalysts.... S3 3. Preparation of the Substrates and Reagents... S5 4. Asymmetric Reactions and Copies of HPLC Chromatograms... S6 4.1 General Procedure for the Synthesis of 4... S6 4.2 Scale-up reaction of 4d S26 5. X-Ray Structure of 4e (CCDC 1576837)... S28 6. References... S35 7. Copies of 1 H and 13 C NMR Spectra... S36 S1
1. General information All reactions were carried out with oven dried glassware under argon atmosphere, unless otherwise stated. All chemicals were purchased from Acros, Alfa, Aladdin, or InnoChem and used as it comes unless otherwise stated. TLC was performed on silica gel F254 TLC glass plates and visualized with UV light. All the HPLC columns were purchased from Daicel Chemical Industries. Solvent of petroleum ether (PE) and ethyl acetate (EA) were used directly in column chromatography. Toluene, THF were dried over sodium (diphenyl ketone) and distilled; CH2Cl2 were distilled over CaH2 before use. 1 H NMR spectra were recorded on a Brucker Avance400 (400 MHz) spectrometer in chloroform-d, all signals are reported in ppm with the internal chloroform signal at 7.26 ppm as the standard. 13 C{ 1 H} NMR spectra were recorded with 1 H-decoupling on a Brucker Avance400/700 (100/146 MHz) spectrometer in chloroform-d, all signals are reported in ppm with the internal chloroform signal at 77.0 ppm as the standard. The data is reported as (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, coupling constant(s) in Hz, integration, assignment). ther analyses were carried out on the following instruments. Infrared spectrometer: Bruker ALPHA FT-IR-Spektrometer. High resolution mass spectrum: AGILENT 7890A/5975C. Rotation polarity: Krüss P8000. High Performance Liquid Chromatography: Shimadzu LC-20A. Melting point detector:binocular microscope XT4A melting point apparatus (without correct). S2
Scheme S1. Lewis Acid-Catalyzed α-thiocyanation 2. Preparation of Catalysts. Catalysts 3a-3d were purchased from Sigma Aldrich and used without further purification. Catalysts 3e-k and QN-1 were prepared according to known literature procedures. 1 Figure S1. Structure of Catalysts Evaluated in This Study General Procedure for the Preparation of 3e-k (by using Quinidine as the starting material) and QN-1 (by using Quinine as the starting material): S3
3j was obtained as a yellowish powder with two steps (302.5 mg, 72% yield). TLC: eluent EA/MeH/Et3N (10/1/0.01, v/v/v), Rf = 0.50. [α] 20 D = +165.3 (c 0.30, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 10.25 (br, 1H), 8.70 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.94 (s, 1H), 7.48 (br, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.80 (s, 2H), 5.85-5.76 (m, 1H), 5.60 (br, 1H), 4.90-4.88 (m, 2H), 4.45-4.35 (m, 2H), 3.45 (br, 1H), 2.97-2.76 (m, 4H), 2.24-2.18 (m, 10H), 1.72 (br, 1H), 1.50-1.42 (m, 2H), 1.30-1.20 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 156.8, 146.4, 144.6, 143.7, 139.7, 137.8, 137.7, 131.3, 131.1, 128.9, 128.1, 123.2, 114.8, 106.8, 66.1, 59.6, 49.7, 48.7, 39.6, 31.6, 28.1, 26.1, 22.1, 21.0, 19.7 ppm. IR (KBr) 2300-3500 (br.), 2935, 2872, 1616, 1508, 1458, 1242, 1051, 732 cm -1. HRMS (ESI): calc. for C29H35N22 [M+H] + : 443.2693 found: 443.2703. 3k was obtained as a yellowish powder with two steps (350.3 mg, 67% yield). TLC: eluent EA/MeH/Et3N (10/1/0.01, v/v/v), Rf = 0.55. [α] 20 D = +117.3 (c 0.45, CH2Cl2). [lit. [2] [ ] 25 D = + 157.4 (c 0.11, CHCl3)]. 1 H NMR (400 MHz, CDCl3) δ 9.68 (br, 1H), 8.71 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.94-7.93 (m, 1H), 7.50 (br, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.99 (s, 2H), 5.76-5.70 (m, 1H), 5.70 (br, 1H), 4.90-4.70 (m, 2H), 4.55-4.40 (m, 2H), 3.53 (br, 1H), 3.25 (br, 2H), 2.97-2.76 (m, 5H), 2.26-2.14 (m, 2H), 1.72 (s, 2H), 1.43-1.30 (m, 2H), 1.25-1.16 (m, 19H); 13 C NMR (100 MHz, CDCl3) δ 156.8, 149.0, 148.5, 146.4, 144.4, 143.9, 139.5, S4
131.4, 128.6, 128.1, 123.1, 114.8, 106.8, 64.4, 59.5, 49.7, 48.6, 39.4, 34.4, 31.6, 29.3, 28.1, 27.0, 26.0, 25.2, 24.1 ppm. IR (KBr): 2400-3300 (br.), 2958, 2868, 1616, 1508, 1458, 1242, 1050, 854 cm -1. HRMS (ESI): calc. for C35H47N22 [M+H] + : 527.3632 found: 527.3649. QN-1 was obtained as a yellowish powder with two steps (274.2 mg, 62% yield). TLC: eluent EA/MeH/Et3N (10/1/0.01, v/v/v), Rf = 0.50. [α] 20 D = -90.7 (c 0.60, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.01 (br, 1H), 7.98-7.82 (m, 1H), 7.94 (s, 1H), 7.45 (br, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.80 (s, 2H), 5.99-5.90 (m, 1H), 5.69 (br, 1H), 5.02-4.88 (m, 2H), 4.43-4.32 (m, 2H), 3.50 (br, 1H), 3.19-3.10 (m, 2H), 2.77-2.72 (m, 2H), 2.24-2.19 (m, 10H), 1.83 (br, 1H), 1.74-1.72 (m, 2H), 1.60-1.54 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 157.7, 146.4, 145.6, 144.7, 140.8, 139.6, 137.8, 131.3, 131.0, 128.1, 122.9, 120.0, 115.5, 115.0, 106.9, 65.9, 61.5, 48.9, 48.5, 39.8, 39.3, 31.6, 27.8, 27.6, 26.3, 22.7, 21.0, 19.7 ppm. IR (KBr) 2300-3400 (br.), 2914, 2852, 1616, 1051, 754 cm -1. HRMS (ESI): calc. for C29H35N22 [M+H] + : 443.2693 found: 443.2684. 3. Preparation of the Substrates and Reagents Substrates 2a-b, 2k-m were prepared according to known literature procedures. 3 Substrates 2c-j, 2n-p were prepared according to known literature procedures. 4 Experimental procedure for synthesis of 1c: To a solution of N-chlorophthalimide (1.82 g, 10 mmol. 1.0 equiv) in 40 ml of dry acetonitrile under Ar was added cuprous thiocyanate (1.46 g, 12 mmol, 1.2 equiv) in S5
one portion. The dark brown reaction mixture was stirred at rt for 1-2 h. The resulting suspension was concentrated in vacuum directly. The resulting residues were dissolved and washed with DCM/PE (3:1, 40 ml x 2, v/v) and filtered through a layer of Celite, Filtrate was concentrated in vacuum to provide the title compound as a white solid (1.77 g, 87% yield) including 7% of a phthalimide product, which was used for the asymmetric reaction without further purification. The reagent 1c was stored in the dark at -15 o C under Ar. MP: 104-106 o C. TLC: eluent PE/EA (5/1, v/v), Rf = 0.20. 1 H NMR (400 MHz, CDCl3) δ 8.03-8.01 (m, 2H, Ar-H), 7.90-7.88 (m, 2H, Ar- H) ppm. 13 C NMR (100 MHz, CDCl3) δ 164.6, 135.7, 131.5, 124.9, 109.0 (SCN) ppm. IR (KBr): 2981, 2160 (SCN), 1751, 1273, 866 cm -1. MS (DART): Calc. for C9H8N32S [M+NH4] + : 222.0332 found: 222.0320. Calc. for [SCN] + : 57.9746 found: 57.9750. Calc. for C8H4N2 [M-SCN] + : 146.0248 found: 146.0213. 4. Asymmetric reactions and copies of HPLC chromatograms 4.1 General procedure for the synthesis of 4 General procedure: In a screw-capped reaction tube, substrate 2a (0.05 mmol, 1.0 equiv) and catalyst 3j (2.2 mg, 10 mol %) were dissolved in a solvent (1.0 ml) for 5 min, then the reaction mixture was cooled to 78 o C. The N-thiocyanatophthalimide (1c, 0.075 mmol, 1.5 equiv) was added in one portion at 78 o C. The resulting solution was stirred at the same temperature until the reaction was completed (monitored by TLC). The crude reaction mixture was directly charged on silica gel and purified by column chromatography (EtAc/PE = 1:10, v/v) to afford the desired product 4a. 1-Adamantanyl (R)-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2-carboxylate (4a) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol, 10 mol%), 1c (15.5 mg, 0.075 mmol, 1.5 equiv), and 2a (15.5 mg, 0.05 mmol) in 1,1- dichloroethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The S6
crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (18.2 mg, 99% yield, 94% ee). MP: 99-101 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.54. [α] 20 D = -69.3 (c 0.15, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 1H, Ar-H), 7.51 (dt, J = 7.6, 1.2 Hz, 1H, Ar-H), 7.52-7.46 (m, 2H, Ar-H), 4.04 (Jab = 18.0 Hz, 1H, CH2), 3.62 (Jab = 18.0 Hz, 1H, CH2), 2.16 (s, 3H, Ad-H), 2.05 (s, 6H, Ad-H), 1.62 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 195.1, 164.8, 151.1, 136.7, 133.2, 128.8, 126.2, 125.8, 109.8 (SCN), 86.2, 64.4, 40.9, 40.5, 35.8, 31.0 ppm. IR (KBr): 2912, 2850, 2156 (SCN), 1732, 1716, 1450 cm -1. HRMS (ESI): calc. for C21H25N23S [M+NH4] + : 385.1586 Found 385.1570. HPLC: on D-H column (n-hexane/iso-propanol 95:5, v/v, 1.0 ml min 1, 254 nm), tr(major) = 11.0 min, t S(minor) = 12.4 min. Peak time area area/% 1 10.427 5290386 49.944 2 11.698 5302344 50.056 total 10592730 100.000 Peak time area area/% 1 11.008 1280956 96.997 2 12.480 39657 3.003 total 1320613 100.000 S7
Ethyl (R)-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2-carboxylate (4b) was synthesized following the General procedure, using 3j (4.4 mg, 0.01 mmol), 1c (30.5 mg, 0.15 mmol), and 2b (20.4 mg, 0.10 mmol) in 1,1-dichloroethane (2.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 5 : 1 to 3 : 1, v/v) to provide the title compound as a white solid (22.7 mg, 87% yield, 75% ee). MP: 65-66 o C. TLC: eluent PE/EA (5/1, v/v), Rf = 0.20. [α] 20 D = -64.7 (c 0.70, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 1H, Ar-H), 7.51 (t, J = 7.6 Hz, 1H, Ar-H), 7.54-7.48 (m, 2H, Ar-H), 4.28 (dd, J = 14.0, 7.2 Hz, 2H, CH2), 4.10 (Jab = 18.0 Hz, 1H, CH2), 3.64 (Jab = 18.0 Hz, 1H, CH2), 1.26 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 194.5, 166.3, 150.9, 137.0, 133.0, 129.0, 126.3, 126.0, 109.3(SCN), 64.2, 63.5, 40.4, 13.9 ppm. IR (KBr) 2983, 2158 (SCN), 1747, 1714, 1604 cm -1. HRMS (ESI): calc. for C13H15N23S [M+NH4] + : 279.0798 found: 279.0798. HPLC: on D-H column (n-hexane/iso-propanol 95:5, v/v, 1.0 ml min 1, 254 nm), tr(major) = 16.6 min, ts(minor) = 18.0 min. Peak time area area/% 1 16.653 5509005 49.763 2 18.029 5561486 50.237 total 11070491 100.000 S8
Peak time area area/% 1 16.629 595177 87.003 2 18.029 88910 12.997 total 684087 100.000 tert-butyl (R)-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2-carboxylate (4c) was synthesized following the General procedure, using 3j (4.4 mg, 0.01 mmol), 1c (30.5 mg, 0.15 mmol), and 2c (23.2 mg, 0.10 mmol) in 1,1-dichloroethane (2.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (28.6 mg, 99% yield, 93% ee). MP: 88-89 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.50. [α] 20 D = -62.4 (c 0.50, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 1H, Ar-H), 7.72 (t, J = 7.6 Hz, 1H, Ar-H), 7.53-7.47 (m, 2H, Ar-H), 4.04 (Jab = 18.0 Hz, 1H, CH2), 3.61 (Jab = 18.0 Hz, 1H, CH2), 1.44 (s, 9H, tbu-h). 13 C NMR (100 MHz, CDCl3) δ 195.0, 165.1, 151.0, 136.8, 133.1, 128.8, 126.2, 125.8, 109.7 (SCN), 86.1, 64.2, 40.4, 27.7 ppm. IR (KBr) 2985, 2150 (SCN), 1705, 1149 cm -1. HRMS (ESI): calc. for C15H19N23S [M+NH4] + : 307.1111 found: 307.1114. HPLC: on AD-H column (n-hexane/iso-propanol 98:2, v/v, 1.0 ml min 1, 254 nm), tr(major) = 11.9 min, ts(minor) = 12.9 min. S9
Peak time area area/% 1 11.943 1764783 49.969 2 12.939 1766973 50.031 total 3531757 100.000 Peak time area area/% 1 12.117 156391 96.392 2 13.144 5854 3.608 total 162245 100.000 1-Adamantanyl (R)-5-fluoro-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4d) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2d (16.4 mg, 0.05 mmol) in 1,1- dichloroethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (18.8 mg, 98% yield, 90% ee). MP: 127-129 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.47. [α] 20 D = -52.4 (c 0.75, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.90-7.87 (m, 1H, Ar-H), 7.21-7.19 (m, 2H, Ar- H), 4.04 (Jab = 18.4 Hz, 1H, CH2), 3.60 (Jab = 18.0 Hz, 1H, CH2), 2.17 (s, 3H, Ad-H), 2.05 (s, 6H, Ad-H), 1.63 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 193.2, 168.2 (d, 1 JC-F = 258.9 Hz), 164.4, 154.06 (d, 3 JC-F = 10.6 Hz), 129.6, 128.3 (d, 3 JC-F = 10.7 Hz), 117.4 (d, 2 JC-F = 23.8 Hz), 113.1 (d, 2 JC-F = 23.0 Hz), 109.7 (SCN), 86.5, 64.6, 40.9, 40.3 (d, 4 JC- F = 2.1 Hz), 35.8, 31.0 ppm. IR (KBr): 2914, 2854, 2156 (SCN), 1716, 1614, 1251 cm -1. HRMS (ESI): calc. for C21H24FN23S [M+NH4] + : 403.1486 found: 403.1487. HPLC: on D-H column (n-hexane/iso-propanol, 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.2 min, ts(minor) = 8.6 min. S10
Peak time area area/% 1 7.055 2751863 50.169 2 8.317 2733320 49.831 total 5485183 100.000 Peak time area area/% 1 7.254 1629001 94.886 2 8.621 87800 5.114 total 1716801 100.000 1-Adamantanyl (R)-5-chloro--1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4e) was synthesized following the General procedure, using 3j (3.3 mg, 0.0075 mmol), 1c (15.5 mg, 0.075 mmol), and 2e (17.2 mg, 0.05 mmol) in 1,1- dichloroethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (19.6 mg, 98% yield, 90% ee). MP: 140 142 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.55. [α] 20 D = -55.6 (c 0.30, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H, Ar-H), 7.51 (s, 1H, Ar- H), 7.46 (dd, J = 8.0, 1.2 Hz, 1H, Ar-H), 4.02 (Jab = 18.0 Hz, 1H, CH2), 3.59 (Jab = 18.0 Hz, 1H, CH2), 2.17 (s, 3H, Ad-H), 2.05 (s, 6H, Ad-H), 1.62 (s, 6H, Ad-H). S11
13 C NMR (100 MHz, CDCl3) δ 193.7, 164.4, 152.4, 143.6, 131.7, 129.7, 126.8, 126.5, 109.6(SCN), 86.5, 64.5, 40.9, 40.1, 35.8, 31.0 ppm. IR (KBr) 2914, 2852, 2156 (SCN), 1739, 1597, 1456 cm -1. HRMS (ESI): calc. for C21H24ClN23S [M+NH4] + : 419.1196 Found 419.1200. HPLC: on D-H column (n-hexane/iso-propanol, 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.0 min, ts(minor) = 8.5 min. Peak time area area/% 1 7.471 2192564 94.784 2 9.270 120670 5.216 total 162245 100.000 Peak time area area/% 1 7.533 4632501 50.195 2 9.335 4596539 49.805 total 9229040 100.000 1-Adamantan-yl (R)-5-bromo-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4f) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2f (19.4 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (20.5 mg, 92% yield, 84% ee). S12
MP: 136-139 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.55. [α] 20 D = -26.9 (c 0.75, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.73-7.71 (m, 1H, Ar-H), 7.63 (d, J = 8.4 Hz, 1H, Ar-H), 4.02 (Jab = 18.0 Hz, 1H, CH2), 3.59 (Jab = 18.0 Hz, 1H, CH2), 2.17 (s, 3H, Ad-H), 2.05 (s, 6H, Ad-H), 1.63 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 194.0, 164.3, 152.4, 132.57, 132.52, 132.1, 129.5, 126.8, 109.6 (SCN), 86.6, 64.4, 40.9, 40.1, 35.8, 31.0 ppm. IR (KBr): 2916, 2850, 2156 (SCN), 1732 cm -1. HRMS (ESI): calc. for C21H24Br 79 N23S [M+NH4] + : 463.0686 found: 463.0690. calc. for C21H24Br 81 N23S [M+NH4] + : 465.0665 found: 465.0669. HPLC: on D-H column (n-hexane/iso-propanol 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.5 min, ts(minor) = 9.5 min. Peak time area area/% 1 7.226 230956 50.596 2 9.068 225516 49.404 total 456472 100.000 Peak time area area/% 1 7.515 1501642 91.992 2 9.562 130983 8.008 total 1635625 100.000 1-Adamantanyl (R)-6-bromo-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- S13
carboxylate (4g) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2g (19.4 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (18.2 mg, 82% yield, 80% ee). MP: 108-110 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.52. [α] 20 D = -38.8 (c 0.80, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H, Ar-H), 7.81 (d, J = 8.0 Hz, 1H, Ar- H), 7.41 (t, J = 8.4 Hz, 1H, Ar-H), 3.98 (Jab = 18.4 Hz, 1H, CH2), 3.56 (Jab = 18.0 Hz, 1H, CH2), 2.17 (s, 3H, Ad-H), 2.05 (s, 6H, Ad-H), 1.63 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 193.8, 164.3, 149.6, 139.5, 135.0, 128.6, 127.7, 123.0, 109.6(SCN), 86.6, 64.6, 40.9, 40.2, 35.8, 31.0 ppm. IR (KBr) 2914, 2852, 2158 (SCN), 1732, 1257 cm -1. HRMS (ESI): calc. for C21H24Br 79 N23S [M+NH4] + : 463.0686 found: 463.0689. calc. for C21H24Br 81 N23S [M+NH4] + : 465.0665 found: 465.0670. HPLC: on D-H column (n-hexane/iso-propanol 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.9 min, ts(minor) = 8.9 min. Peak time area area/% 1 7.559 4483031 49.773 2 8.397 4523974 50.227 total 9007004 100.000 Peak time area area/% 1 7.910 642534 90.011 2 8.927 71304 9.989 total 713838 100.000 S14
1-Adamantanyl (R)-4-bromo-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4h) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2h (19.4 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (22.2 mg, 99% yield, 92% ee). MP: 101-103 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.52. [α] 20 D = -21.2 (c 1.00, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H, Ar-H), 7.82 (d, J = 7.6 Hz, 1H, Ar-H), 7.88 (t, J = 8.0 Hz, 1H, Ar-H), 3.96 (Jab = 18.4 Hz, 1H, CH2), 3.52 (Jab = 18.4 Hz, 1H, CH2), 2.17 (s, 3H, Ad-H), 2.06 (s, 6H, Ad-H), 1.63 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 194.5, 164.3, 150.7, 139.4, 135.2, 130.5, 124.6, 121.4, 109.4(SCN), 86.6, 64.1, 41.5, 40.9, 35.8, 31.0 ppm. IR (KBr): 2914, 2852, 2158 (SCN), 1747, 1714, 1597 cm -1. HRMS (ESI): calc. for C21H24Br 79 N23S [M+NH4] + : 463.0686 found: 463.0688. calc. for C21H24Br 81 N23S [M+NH4] + : 465.0665 found: 465.0670. HPLC: on D-H column (n-hexane/iso-propanol, 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 9.5 min, ts(minor) = 10.5 min. Peak time area area/% 1 9.524 3707956 49.866 2 10.398 3727818 50.134 total 7435774 100.000 S15
Peak time area area/% 1 9.548 1295153 95.719 2 10.595 57919 4.281 total 1353072 100.000 1-Adamantanyl (R)-6-methyl-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4i) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1 (15.5 mg, 0.075 mmol), and 2i (16.2 mg, 0.05 mmol) in 1,1- dichloroethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (19.0 mg, 99% yield, 84% ee). MP: 138-139 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.52. [α] 20 D = -41.1 (c 0.90, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H, Ar-H), 7.52 (d, J = 8.0 Hz, 1H, Ar- H), 7.39 (t, J = 7.6 Hz, 1H, Ar-H), 3.98 (Jab = 17.6 Hz, 1H, CH2), 3.56 (Jab = 18.0 Hz, 1H, CH2), 2.43 (s, 3H, Me), 2.16 (s, 3H, Ad-H), 2.05 (s, 6H, Ad-H), 1.62 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 195.1, 164.9, 148.5, 139.0, 138.1, 133.4, 125.8, 125.7, 109.9(SCN), 86.0, 64.7, 40.9, 40.3, 35.9, 31.0, 21.2 ppm. IR (KBr) 2912, 2852, 2156 (SCN), 1732, 1253, 1045 cm -1. HRMS (ESI): calc. for C22H27N23S [M+NH4] + : 399.1737 found: 399.1744. HPLC: on D-H column (n-hexane/iso-propanol 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.3 min, ts(minor) = 8.3 min. S16
Peak time area area/% 1 7.146 572577 49.801 2 7.938 577153 50.199 total 1149730 100.000 Peak time area area/% 1 7.360 5183161 91.982 2 8.380 451792 8.018 total 5634953 100.000 1-Adamantanyl (R)-1,1-dimethyl-3-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4j) was synthesized following the General procedure, using 3j (4.4 mg, 0.01 mmol), 1c (15.5 mg, 0.075 mmol), and 2j (16.9 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a colorless oil (18.5 mg, 95% yield, 87% ee). TLC: eluent PE/EA (10/1, v/v), Rf = 0.50. [α] 20 D = +26.0 (c 0.60, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H, Ar-H), 7.70 (t, J = 7.6 Hz, 1H, Ar-H), 7.49-7.44 (m, 2H, Ar-H), 2.13 (s, 3H, Ad-H), 1.99 (s, 6H, Ad- H), 1.59 (s, 6H, Me), 1.58 (s, 6H, Ad-H). 13 C NMR (100 MHz, CDCl3) δ 194.2, 164.8, 159.9, 136.3, 132.6, 128.6, 125.0, 123.0, 110.0(SCN), 86.1, 75.9, 48.3, 41.0, 35.8, 30.9, 30.0, 25.1 ppm. IR (KBr) 2156 (SCN), 1730, 1704, 1452 cm -1. HRMS (ESI): calc. for C23H23N23S [M+NH4] + : 407.1424 found: 407.1417. HPLC: on AD-H column (n-hexane / iso-propanol 90:10, 1.0 ml min 1, 254 nm), ts(minor) = 7.3 min, tr(major) = 7.9 min. S17
Peak time area area/% 1 7.455 858529 49.612 2 8.067 871971 50.388 total 1730500 100.000 Peak time area area/% 1 7.226 38243 6.674 2 7.807 534806 93.326 total 573049 100.000 tert-butyl (R)-6-chloro-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2-carboxylate (4k) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2k (13.3 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (15.0 mg, 93% yield, 83% ee). MP: 73-74 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.50. [α] 20 D = -56.8 (c 0.50, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H, Ar-H), 7.68 (d, J = 8.4 Hz, 1H, Ar- H), 7.47 (d, J = 8.4 Hz, 1H, Ar-H), 4.01 (d, J = 18.4 Hz, 1H, CH2), 3.58 (d, J = 18.0 Hz, 1H, CH2), 1.45 (s, 9H, tbu-h). S18
13 C NMR (175 MHz, CDCl3) δ 193.9, 164.7, 149.1, 136.8, 135.3, 134.6, 127.4, 125.4, 109.5(SCN), 86.5, 64.5, 40.0, 27.7 ppm. IR (KBr) 2922, 2156 (SCN), 1716, 1147 cm -1. HRMS (ESI): calc. for C15H18ClN23S [M+NH4] + : 341.0721 found: 341.0732. HPLC: on AS-H column (n-hexane/iso-propanol 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 8.7 min, ts(minor) = 9.7 min. Peak time area area/% 1 8.750 541397 50.027 2 9.763 540809 49.973 total 1082206 100.000 Peak time area area/% 1 8.797 2625100 91.259 2 9.794 251433 8.741 total 2876533 100.000 tert-butyl (R)-1-oxo-5-phenyl-2-thiocyanato-2,3-dihydro-1H-indene-2-carboxylate (4l) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2l (15.4 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (17.3 mg, 95% yield, 74% ee). MP: 150-151 o C. S19
TLC: eluent PE/EA (10/1, v/v), Rf = 0.50. [α] 20 D = -42.3 (c 0.50, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 1H, Ar-H), 7.72-7.70 (m, 2H, Ar-H), 7.64 (d, J = 7.6 Hz, 1H, Ar-H), 7.52-7.43 (m, 3H, Ar-H), 4.09 (Jab = 18.0 Hz, 1H, CH2), 3.67 (Jab = 18.0 Hz, 1H, CH2), 1.45 (s, 9H, tbu-h). 13 C NMR (100 MHz, CDCl3) δ 194.5, 165.2, 151.7, 149.9, 139.5, 131.9, 129.1, 129.0, 128.2, 127.6, 126.2, 124.5, 109.8(SCN), 86.2, 64.6, 40.5, 27.7 ppm. IR (KBr) 2918, 2850, 2156 (SCN), 1707, 1145 cm -1. HRMS (ESI): calc. for C21H23N23S [M+NH4] + : 383.1424 found: 383.1420. HPLC: on D-H column (n-hexane/iso-propanol 90:10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 10.5 min, ts(minor) = 13.6 min. Peak time area area/% 1 10.536 439040 50.205 2 13.603 435452 49.795 total 874491 100.000 Peak time area area/% 1 10.459 536422 87.053 2 13.567 79780 12.947 total 616202 100.000 tert-butyl (R)-1-oxo-6-(phenylethynyl)-2-thiocyanato-2,3-dihydro-1H-indene-2- carboxylate (4m) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2m (16.6 mg, 0.05 mmol) in S20
dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (19.3 mg, 98% yield, 87% ee). MP: 84-87 o C. TLC: eluent PE/EA (10/1, v/v), Rf = 0.50. [α] 20 D = -120.0 (c 0.35, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H, Ar-H), 7.85 (d, J = 8.0 Hz, 1H, Ar- H), 7.55-7.50 (m, 3H, Ar-H), 7.38-7.37 (m, 3H, Ar-H), 4.05 (Jab = 18.4 Hz, 1H, CH2), 3.62 (Jab = 18.4 Hz, 1H, CH2), 1.45 (s, 9H, tbu-h). 13 C NMR (100 MHz, CDCl3) δ 194.3, 164.9, 150.4, 139.5, 133.4, 131.8, 128.9, 128.6, 128.5, 126.2, 124.5, 122.5, 109.6(SCN), 91.4, 87.4, 86.3, 64.4, 40.4, 27.7 ppm. IR (KBr) 2980, 2926, 2156 (SCN), 1718, 1496, 1147 cm -1. HRMS (ESI): calc. for C23H23N23S [M+NH4] + : 407.1424 found: 407.1417. HPLC: on D-H column (n-hexane/iso-propanol 90:10, v/v, 1.0 ml min 1, 254 nm), ts(minor) = 9.1 min, tr(major) = 10.7 min. Peak time area area/% 1 9.180 5938771 49.894 2 10.775 5963926 50.106 total 11902697 100.000 Peak time area area/% 1 9.110 10.3624 6.466 2 10.687 1498904 93.534 total 1602528 100.000 S21
1-Adamantanyl (R)-7-bromo-1-oxo-2-thiocyanato-1,2,3,4-tetrahydronaphthalene -2-carboxylate (4n) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2n (20.1 mg, 0.05 mmol) in 1,1- dichloroethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a white solid (17.8 mg, 78% yield, 65% ee). After recrystallization, 50% yield, 90% ee. MP: 134 136 o C TLC: eluent PE/EA (10/1, v/v), Rf = 0.60. [α] 20 D = +96.8 (c 0.50, CH2Cl2, 90% ee). 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.2 Hz, 1H, Ar-H), 7.66 (dd, J = 8.2, 2.2 Hz, 1H, Ar-H), 7.17 (d, J = 8.2 Hz, 1H, Ar-H), 3.13-3.07 (m, 3H), 2.59-2.51 (m, 1H), 2.16 (s, 3H), 2.06 (s, 6H), 1.62 (s, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ 188.4, 164.8, 141.3, 137.6, 132.1, 130.8, 130.7, 121.5, 110.2 (SCN), 85.9, 65.9, 40.9, 35.9, 33.9, 30.9, 26.7 ppm. IR (KBr) 2912, 2852, 2156 (SCN), 1728, 1693, 1589 cm -1. HRMS (ESI): calc. for C22H23BrN3S [M + H] + : 460.0582; Found 460.0587. HPLC: on AD-H column (n-hexane/iso-propanol, 98 : 2, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.5 min, ts(minor) = 8.4 min. Peak time area area/% 1 7.580 787932 50.124 2 8.454 784026 49.876 total 1571959 100.000 S22
After recrystallization Peak time area area/% 1 7.544 500081 82.251 2 8.412 107911 17.749 total 607992 100.000 Peak time area area/% 1 8.015 1689611 94.759 2 9.172 93452 5.241 total 1783063 100.000 1-Adamantanyl (R)-5-oxo-6-thiocyanato-6,7,8,9-tetrahydro-5Hbenzo[7]annulene-6-carboxylate (4o) was synthesized following the General procedure, using 3j (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2o (16.9 mg, 0.05 mmol) in 1,1-dichloroethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title compound as a colorless oil (18.5 mg, 94% yield, 36% ee). TLC: eluent PE/EA (10/1, v/v), Rf = 0.55. [α] 20 D = +22.3 (c 0.70, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.6, 0.8 Hz, 1H, Ar-H), 7.45-7.41 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H, Ar-H), 7.18 (d, J = 7.2 Hz, 1H, Ar-H), 3.04 2.97 (m, 2H), 2.93 2.86 (m, 1H), 2.33 2.26 (m, 1H), 2.18 2.02 (m, 5H), 1.89 (m, 6H), 1.57 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 197.6, 164.7, 139.7, 136.7, 132.5, 130.7, 129.9, 126.6, 110.8 (SCN), 84.9, 72.2, 40.6, 35.9, 33.9, 30.8, 26.9, 24.9 ppm. IR (KBr) 2912, 2852, 2154 (SCN), 1737, 1682, 1597 cm -1. HRMS (ESI): calc. for C23H26N3S [M + H] + : 352.1656 found: 352.1653. HPLC: on D-H column (n-hexane/iso-propanol, 90 : 10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.1 min, ts(minor) = 7.6 min. S23
Peak time area area/% 1 7.161 1860421 49.290 2 7.681 1914010 50.710 total 3774431 100.000 Peak time area area/% 1 7.184 585636 67.940 2 7.698 276348 32.060 total 861984 100.000 1-Adamantanyl (R)-2-chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (5a) was synthesized following the General procedure, using 3j (3.3 mg, 0.0075 mmol), N- chlorophthalimide (14.5 mg, 0.075 mmol), and 2a (15.5 mg, 0.05 mmol) in dichloromethane (1.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 15 : 1, v/v) to provide the title compound as a yellow oil (17.4 mg, 99% yield, 86% ee). TLC: eluent PE/EA (15/1, v/v), Rf = 0.65. S24
[α] 20 D = -20.4 (c 0.85, CH2Cl2). [lit. [5] [α] 20 D = -22.0 (c 1.01, CHCl3) for 90% ee for R structure]. 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H, Ar-H), 7.68 (t, J = 7.2 Hz, 1H, Ar-H), 7.47-7.43 (m, 1H, Ar-H), 7.18 (d, J = 7.2 Hz, 1H, Ar-H), 4.02 (Jab = 17.6 Hz, 1H), 3.53 (Jab = 18.0 Hz, 1H), 2.14 (s, 3H), 2.05 (s, 6H), 1.62 (s, 6H). The 1 H NMR data was accorded with the literature. 4 HPLC: on D-H column (n-hexane/iso-propanol, 90 : 10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 6.5 min, ts(minor) = 7.8 min. Peak time area area/% 1 6.598 2350238 49.952 2 7.983 2354763 50.048 total 4705001 100.000 Peak time area area/% 1 6.499 1478013 92.768 2 7.810 115220 7.232 total 1593233 100.000 1-Adamantanyl (S)-1-oxo-2-thiocyanato-2,3-dihydro-1H-indene-2-carboxylate ((S)-4a) was synthesized following General procedure, using QN-1 (2.2 mg, 0.005 mmol), 1c (15.5 mg, 0.075 mmol), and 2a (15.5 mg, 0.05 mmol) in CH2Cl2 (1.5 ml), and the reaction mixture was stirred for 1 h at -78 o C. The crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide the title S25
compound as a white solid (18.2 mg, 99% yield, 85% ee). TLC: eluent PE/EA (10/1, v/v), Rf = 0.54. ptical value: [α] 20 D = +62.4 (c 0.15, CH2Cl2). HPLC: on D-H column (n-hexane/iso-propanol, 90 : 10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 8.9 min, t S(minor) = 10.0 min. Peak time area area/% 1 8.952 97845 7.663 2 10.065 1178969 92.337 total 1276814 100.000 4.2 Scale-up reaction of 4d Peak time area area/% 1 8.912 3721895 49.664 2 10.021 3772251 50.336 total 7494146 100.000 The scale-up reaction was carried out on 1.17 mmol scale following the General procedure, using 3j (44.1 mg, 0.1 mmol, 8.5 mol %), 1c (384 mg, 1.17 mmol), and 2d (320 mg, 1.57 mmol, 1.3 equiv) in CH2Cl2 (20.0 ml), and the reaction mixture was stirred for 1 h at -78 o C. After removing solvent under reduced pressure the crude product was purified by flash column chromatography (PE : EtAc = 10 : 1, v/v) to provide 4d as a white solid (446 mg, 99% yield, 88% ee). HPLC: D-H column (n-hexane/iso-propanol, 90 : 10, v/v, 1.0 ml min 1, 254 nm), tr(major) = 7.97 min, ts(minor) = 9.76 min. S26
Peak time area area/% 1 7.981 243234 50.396 2 9.744 239407 49.604 total 482642 100.000 Peak time area area/% 1 7.973 411459 93.796 2 9.758 27218 6.204 total 438676 100.000 S27
5. X-Ray Structure of 4e (CCDC 1576837) Table S1. Crystal data and structure refinement for 4e. Identification code data_1 Empirical formula C21 H20 Cl N 3 S Formula weight 401.89 Temperature 296(2) K Wavelength 0.71073 Crystal system orthorhombic Space group P 21 21 21 and P 2ac 2ab Unit cell dimensions a = 6.313(2) Å α = 90 b = 13.256(4) Å β = 90 c = 23.840(8) Å γ = 90 Volume 1995.1(11) Å 3 Z 4 Density (calculated) 1.338 g/cm 3 Absorption coefficient 0.317 mm -1 F(000) 840 Crystal size 0.30 0.15 0.10 mm 3 Theta range for data collection 1.708 to 31.651 Index ranges -9<=h<=9, -19<=k<=18, -34<=l<=34 Reflections collected 27140 Independent reflections 6149 [R int = 0.0249] Completeness to theta = 25.242 100% Max. and min. transmission 0.883 and 0.549 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6149 / 0 / 244 Goodness-of-fit on F 2 1.034 Final R indices [I>2σ(I)] R1 = 0.0455, wr2 = 0.1132 R indices (all data) R1 = 0.0562, wr2 = 0.1200 S28
Table S2. Atomic coordinates and equivalent isotropic displacement parameters (Å 2 ) for 4e. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) S1 S -0.00969(14) 0.34295(5) 0.41617(3) 0.0582(2) Cl1 Cl 0.6273(2) 0.64582(10) 0.62335(4) 0.1062(4) 3 0.3080(3) 0.54305(14) 0.33551(7) 0.0471(4) 2 0.0536(4) 0.42882(17) 0.31486(8) 0.0721(7) 1-0.1304(4) 0.57740(18) 0.42244(12) 0.0752(7) C12 C 0.3332(3) 0.58322(16) 0.27728(8) 0.0343(4) C17 C 0.1730(4) 0.68777(19) 0.20231(11) 0.0449(5) H17A H 0.0448 0.7236 0.1906 0.054 C3 C 0.3528(4) 0.52611(17) 0.48869(9) 0.0410(5) C11 C 0.1671(4) 0.4728(2) 0.34704(10) 0.0474(5) C4 C 0.1670(4) 0.58013(17) 0.48581(10) 0.0444(5) C18 C 0.1341(3) 0.63834(17) 0.25972(9) 0.0387(4) H18A H 0.0987 0.6895 0.2873 0.046 H18B H 0.0167 0.5913 0.2572 0.046 C9 C 0.3723(4) 0.45008(19) 0.44178(10) 0.0450(5) H9A H 0.3966 0.3829 0.4566 0.054 H9B H 0.4879 0.4676 0.4168 0.054 C8 C 0.1575(4) 0.45560(17) 0.41083(9) 0.0405(5) C19 C 0.3896(5) 0.50125(19) 0.23514(11) 0.0487(6) H19A H 0.2753 0.4526 0.2325 0.058 H19B H 0.5167 0.4661 0.2471 0.058 C20 C 0.4267(4) 0.5516(2) 0.17748(11) 0.0522(6) H20A H 0.4615 0.4997 0.1497 0.063 C21 C 0.2253(4) 0.6069(2) 0.15933(10) 0.0496(6) H21A H 0.2466 0.6375 0.1228 0.060 H21B H 0.1088 0.5594 0.1565 0.060 C7 C 0.0373(4) 0.54591(18) 0.43833(11) 0.0471(5) C2 C 0.4988(5) 0.5453(2) 0.53138(11) 0.0540(6) H2A H 0.6249 0.5093 0.5340 0.065 C13 C 0.5154(4) 0.6572(2) 0.28312(10) 0.0474(5) H13A H 0.6418 0.6222 0.2956 0.057 H13B H 0.4805 0.7084 0.3107 0.057 C14 C 0.5555(4) 0.7069(2) 0.22552(12) 0.0541(7) H14A H 0.6730 0.7549 0.2286 0.065 C16 C 0.3551(5) 0.7626(2) 0.20720(14) 0.0613(7) H16A H 0.3200 0.8143 0.2345 0.074 H16B H 0.3789 0.7952 0.1713 0.074 S29
C5 C 0.1188(5) 0.6559(2) 0.52498(13) 0.0589(7) H5A H -0.0068 0.6922 0.5226 0.071 C15 C 0.6104(4) 0.6260(3) 0.18213(12) 0.0646(8) H15A H 0.6362 0.6573 0.1460 0.078 H15B H 0.7380 0.5907 0.1934 0.078 C6 C 0.2641(6) 0.6748(2) 0.56731(13) 0.0673(9) H6A H 0.2370 0.7244 0.5940 0.081 C10 C -0.0014(7) 0.3276(2) 0.48667(12) 0.0691(9) C1 C 0.4487(6) 0.6197(2) 0.56953(12) 0.0610(7) N1 N 0.0019(9) 0.3128(3) 0.53349(13) 0.1177(17) Table S3. Bond lengths [Å] and angles [ o ] for 4e. S1 C10 1.694(3) S1 C8 1.833(2) Cl1 C1 1.743(3) 3 C11 1.317(3) 3 C12 1.495(3) 2 C11 1.201(3) 1 C7 1.199(3) C12 C18 1.513(3) C12 C13 1.518(3) C12 C19 1.522(3) C17 C21 1.520(4) C17 C16 1.523(4) C17 C18 1.537(3) C17 H17A 0.9800 C3 C4 1.376(4) C3 C2 1.396(3) C3 C9 1.511(3) C11 C8 1.539(3) C4 C5 1.404(4) C4 C7 1.469(4) C18 H18A 0.9700 C18 H18B 0.9700 C9 C8 1.545(3) C9 H9A 0.9700 C9 H9B 0.9700 C8 C7 1.562(4) C19 C20 1.546(4) C19 H19A 0.9700 C19 H19B 0.9700 S30
C20 C15 1.527(4) C20 C21 1.530(4) C20 H20A 0.9800 C21 H21A 0.9700 C21 H21B 0.9700 C2 C1 1.379(4) C2 H2A 0.9300 C13 C14 1.544(4) C13 H13A 0.9700 C13 H13B 0.9700 C14 C16 1.529(4) C14 C15 1.530(5) C14 H14A 0.9800 C16 H16A 0.9700 C16 H16B 0.9700 C5 C6 1.386(5) C5 H5A 0.9300 C15 H15A 0.9700 C15 H15B 0.9700 C6 C1 1.377(5) C6 H6A 0.9300 C10 N1 1.134(4) C10 S1 C8 98.55(12) C11 3 C12 121.16(17) 3 C12 C18 109.89(17) 3 C12 C13 103.03(16) C18 C12 C13 110.06(18) 3 C12 C19 112.55(18) C18 C12 C19 110.89(18) C13 C12 C19 110.2(2) C21 C17 C16 110.3(2) C21 C17 C18 109.5(2) C16 C17 C18 109.3(2) C21 C17 H17A 109.2 C16 C17 H17A 109.2 C18 C17 H17A 109.2 C4 C3 C2 120.3(2) C4 C3 C9 112.3(2) C2 C3 C9 127.4(2) 2 C11 3 127.8(2) 2 C11 C8 122.4(2) 3 C11 C8 109.72(19) S31
C3 C4 C5 121.6(2) C3 C4 C7 110.7(2) C5 C4 C7 127.8(3) C12 C18 C17 108.60(17) C12 C18 H18A 110.0 C17 C18 H18A 110.0 C12 C18 H18B 110.0 C17 C18 H18B 110.0 H18A C18 H18B 108.4 C3 C9 C8 104.5(2) C3 C9 H9A 110.8 C8 C9 H9A 110.8 C3 C9 H9B 110.8 C8 C9 H9B 110.8 H9A C9 H9B 108.9 C11 C8 C9 116.4(2) C11 C8 C7 108.7(2) C9 C8 C7 105.20(19) C11 C8 S1 102.23(15) C9 C8 S1 115.69(16) C7 C8 S1 108.38(17) C12 C19 C20 108.3(2) C12 C19 H19A 110.0 C20 C19 H19A 110.0 C12 C19 H19B 110.0 C20 C19 H19B 110.0 H19A C19 H19B 108.4 C15 C20 C21 110.0(2) C15 C20 C19 109.2(2) C21 C20 C19 109.4(2) C15 C20 H20A 109.4 C21 C20 H20A 109.4 C19 C20 H20A 109.4 C17 C21 C20 109.1(2) C17 C21 H21A 109.9 C20 C21 H21A 109.9 C17 C21 H21B 109.9 C20 C21 H21B 109.9 H21A C21 H21B 108.3 1 C7 C4 128.9(3) 1 C7 C8 124.3(3) C4 C7 C8 106.8(2) C1 C2 C3 117.4(3) C1 C2 H2A 121.3 S32
C3 C2 H2A 121.3 C12 C13 C14 108.55(18) C12 C13 H13A 110.0 C14 C13 H13A 110.0 C12 C13 H13B 110.0 C14 C13 H13B 110.0 H13A C13 H13B 108.4 C16 C14 C15 109.5(2) C16 C14 C13 108.9(2) C15 C14 C13 109.9(2) C16 C14 H14A 109.5 C15 C14 H14A 109.5 C13 C14 H14A 109.5 C17 C16 C14 109.3(2) C17 C16 H16A 109.8 C14 C16 H16A 109.8 C17 C16 H16B 109.8 C14 C16 H16B 109.8 H16A C16 H16B 108.3 C6 C5 C4 118.1(3) C6 C5 H5A 121.0 C4 C5 H5A 121.0 C20 C15 C14 109.3(2) C20 C15 H15A 109.8 C14 C15 H15A 109.8 C20 C15 H15B 109.8 C14 C15 H15B 109.8 H15A C15 H15B 108.3 C1 C6 C5 119.5(3) C1 C6 H6A 120.3 C5 C6 H6A 120.3 N1 C10 S1 176.8(3) C6 C1 C2 123.3(3) C6 C1 Cl1 118.1(2) C2 C1 Cl1 118.6(3) S33
Table S4. Anisotropic displacement parameters (Å 2 ) for 4e. U11 U22 U33 U23 U13 U12 S1 0.0833(5) 0.0515(3) 0.0399(3) 0.0062(2) -0.0095(3) -0.0283(3) Cl1 0.1172(9) 0.1263(9) 0.0751(6) -0.0356(6) -0.0343(6) -0.0269(8) 3 0.0491(9) 0.0570(10) 0.0352(8) 0.0100(7) -0.0099(7) -0.0173(8) 2 0.0942(17) 0.0813(14) 0.0409(9) 0.0108(9) -0.0140(10) -0.0498(13) 1 0.0589(13) 0.0727(14) 0.0941(17) -0.0026(12) -0.0213(12) 0.0109(11) C12 0.0312(9) 0.0377(10) 0.0341(9) 0.0046(8) -0.0038(8) -0.0043(8) C17 0.0293(10) 0.0490(12) 0.0564(13) 0.0166(10) -0.0070(9) -0.0007(9) C3 0.0488(12) 0.0388(10) 0.0354(10) 0.0027(8) -0.0036(9) -0.0100(9) C11 0.0534(13) 0.0522(13) 0.0366(10) 0.0070(9) -0.0057(10) -0.0154(11) C4 0.0518(13) 0.0375(10) 0.0439(11) 0.0040(9) 0.0003(10) -0.0068(10) C18 0.0262(9)0.0427(11) 0.0470(11) 0.0000(9) -0.0002(8) -0.0009(8) C9 0.0501(13) 0.0466(12) 0.0384(10) -0.0008(9) -0.0084(10) 0.0016(10) C8 0.0461(11) 0.0408(10) 0.0346(9) 0.0041(8) -0.0060(9) -0.0095(9) C19 0.0513(14) 0.0412(11) 0.0535(13) -0.0005(10) -0.0035(11) 0.0106(11) C20 0.0445(13) 0.0687(16) 0.0434(12) -0.0068(11) 0.0052(10) 0.0065(12) C21 0.0367(11) 0.0744(17) 0.0378(11) 0.0084(11) -0.0037(9) -0.0092(11) C7 0.0490(13) 0.0419(11) 0.0505(12) 0.0068(9) -0.0034(11) -0.0039(10) C2 0.0567(15) 0.0602(14) 0.0451(12) -0.0012(10) -0.0104(12) -0.0101(13) C13 0.0324(10) 0.0610(13) 0.0487(12) 0.0033(10) -0.0082(9) -0.0138(11) C14 0.0335(11) 0.0693(16) 0.0596(15) 0.0142(13) -0.0052(10) -0.0210(11) C16 0.0539(15) 0.0504(14) 0.0795(19) 0.0251(13) -0.0082(14) -0.0166(12) C5 0.0679(17) 0.0461(13) 0.0625(15) -0.0050(12) 0.0065(14) -0.0006(13) C15 0.0309(11) 0.111(3) 0.0525(14) 0.0116(15) 0.0053(11) -0.0022(14) C6 0.097(3) 0.0511(15) 0.0539(15) -0.0154(12) 0.0066(16) -0.0152(16) C10 0.100(3) 0.0627(16) 0.0442(13) 0.0079(12) -0.0036(16) -0.0366(18) C1 0.0755(19) 0.0613(15) 0.0463(13) -0.0097(11) -0.0089(13) -0.0229(15) N1 0.187(4) 0.119(3) 0.0470(14) 0.0139(16) -0.004(2) -0.083(3) S34
6. References [1] Y. Wang, X. F. Liu, and L. Deng, J. Am. Chem. Soc. 2006, 128, 3928-3930. [2] T. Sekikawa, H. Kitaura, T. Kitaguchi, T. Minami, Y. Hatanaka, Tetrahedron Lett. 2016, 57, 2985-2989. [3] J. S. Qiu, Y. F. Wang, G.R. Qi, P. G. Karmaker, H. Q. Yin, and F. X. Chen, Chem. Eur. J. 2017, 23, 1775-1778. [4] X. Gu, Y. Zhang, Z. J. Xu, and C. M. Che. Chem. Commun., 2014, 50, 7870-7873. [5] J. Li, W. Pan, Z. Wang, X. M. Zhang and K. L. Ding. Adv. Synth. Catal. 2012, 354, 1980-1986. S35
7. Copies of 1 H and 13 C NMR spectra 7.876 7.857 7.735 7.732 7.716 7.698 7.695 7.524 7.504 7.502 7.482 7.464 7.260 4.065 4.020 3.636 3.591 2.162 2.053 1.622 4a CAd SCN 6.11 6.09 3.08 1.04 1.05 2.01 1.04 1.00 ppm (t1) 5.0 0.0 S36
195.055 164.755 151.061 136.709 133.219 128.788 126.174 125.843 109.804 86.175 77.373 77.056 76.738 64.370 40.912 40.507 35.844 30.974 4a CAd SCN 200 ppm (t1) 150 100 50 0 S37
7.886 7.867 7.756 7.737 7.718 7.541 7.520 7.500 7.481 7.260 4.305 4.287 4.270 4.252 4.123 4.078 3.656 3.611 1.280 1.262 1.245 4b CEt SCN 3.03 1.00 1.01 2.02 1.95 0.99 1.00 ppm (t1) 5.0 0.0 S38
194.509 166.280 150.924 136.972 132.953 128.980 126.300 125.998 109.348 77.395 77.078 76.760 64.206 63.485 40.382 13.926 4b CEt SCN 200 ppm (t1) 150 100 S39 50 0
7.874 7.855 7.736 7.718 7.699 7.527 7.507 7.483 7.465 7.260 4.063 4.018 3.634 3.589 1.439 CtBu 4c SCN 9.19 1.03 1.04 2.11 1.03 1.00 ppm (t1) 5.0 S40 0.0
195.005 165.138 151.018 136.768 133.148 128.830 126.202 125.847 109.714 86.110 77.390 77.072 76.754 64.224 40.414 27.683 4c CtBu SCN 200 ppm (t1) 150 100 S41 50 0
7.902 7.889 7.879 7.867 7.260 7.206 7.191 4.056 4.010 3.629 3.583 2.170 2.053 1.627 F 4d CAd SCN 6.02 5.99 3.12 1.02 1.01 1.92 1.00 ppm (t1) 5.0 S42 0.0
193.225 169.527 166.938 164.415 154.121 154.015 129.621 128.375 128.268 117.497 117.259 113.248 113.018 109.672 86.486 77.367 77.049 76.732 64.618 40.919 40.313 40.292 35.820 30.984 F 4d CAd SCN 200 ppm (t1) 150 100 S43 50 0
7.803 7.783 7.514 7.470 7.467 7.450 7.260 4.040 3.995 3.611 3.566 2.165 2.046 1.621 Cl 4e CAd SCN 6.21 6.29 3.37 1.06 1.05 1.00 1.01 ppm (t1) 5.0 S44 0.0
193.728 164.364 152.415 143.566 131.677 129.727 126.824 126.471 109.608 86.536 77.401 77.083 76.765 64.464 40.912 40.135 35.811 30.984 Cl CAd SCN 4e 200 ppm (t1) 150 100 S45 50 0
7.731 7.708 7.703 7.636 7.615 7.260 4.044 3.999 3.618 3.572 2.169 2.047 1.625 Br 4f CAd SCN 6.17 6.17 3.28 1.07 1.10 0.94 2.00 ppm (t1) 5.0 S46 0.0
193.980 164.327 152.435 132.579 132.520 132.078 129.541 126.840 109.592 86.569 64.358 40.919 40.060 35.814 30.988 Br 4f CAd SCN 200 ppm (t1) 150 100 S47 50 0
7.987 7.822 7.802 7.418 7.397 7.260 4.004 3.958 3.576 3.531 2.170 2.045 1.625 Br 4g CAd SCN 5.95 6.01 3.19 1.04 1.08 1.04 1.00 0.99 ppm (t1) 5.0 S48 0.0
193.838 164.284 149.604 139.501 134.991 128.564 127.650 122.981 109.557 86.608 77.372 77.054 76.737 64.566 40.917 40.166 35.810 30.987 Br 4g CAd SCN 200 ppm (t1) 150 100 S49 50 0
7.888 7.868 7.834 7.815 7.417 7.397 7.378 7.260 3.976 3.930 3.541 3.495 2.174 2.061 1.630 Br 4h CAd SCN 6.01 5.99 3.09 1.01 1.03 1.00 1.00 0.93 ppm (t1) 5.0 S50 0.0
194.478 164.253 150.748 139.360 135.178 130.515 124.573 121.409 109.425 86.643 77.373 77.056 76.738 64.098 41.490 40.914 35.818 30.998 Br 4h CAd SCN 200 ppm (t1) 150 100 S51 50 0
7.650 7.534 7.514 7.401 7.382 7.260 4.007 3.963 3.580 3.535 2.430 2.158 2.050 1.619 4i CAd SCN 6.39 6.37 3.19 3.20 1.05 1.07 0.96 1.00 1.00 ppm (t1) 5.0 S52 0.0
195.100 164.894 148.539 138.980 138.063 133.370 125.817 125.650 109.897 86.045 77.382 77.065 76.747 64.730 40.912 40.267 35.854 30.971 21.155 Me 4i CAd SCN 200 ppm (t1) 150 100 S53 50 0
7.830 7.810 7.718 7.699 7.680 7.488 7.470 7.454 7.435 7.260 2.125 1.990 1.592 1.582 CAd SCN 4j 11.90 6.02 3.48 2.08 1.05 1.00 ppm (t1) 5.0 S54 0.0
194.199 164.839 159.869 136.288 132.626 128.620 124.966 122.973 111.039 86.050 77.376 77.059 76.741 75.919 48.266 40.992 35.843 30.915 29.791 25.078 CAd SCN 4j 200 ppm (t1) 150 100 S55 50 0
7.830 7.689 7.668 7.485 7.464 7.263 4.031 3.986 3.605 3.560 1.448 Cl C t Bu 4k SCN 9.73 1.11 1.12 1.06 1.10 1.00 ppm (t1) 5.0 S56 0.0
193.932 164.688 149.089 136.805 135.317 134.631 127.375 125.456 109.473 86.518 77.233 77.051 76.870 64.535 40.009 27.677 Cl 4k C t Bu SCN 200 ppm (f1) 150 100 S57 50 0
7.936 7.917 7.718 7.697 7.654 7.635 7.519 7.500 7.482 7.464 7.446 7.429 7.260 4.117 4.072 3.689 3.644 1.465 Ph 4l C t Bu SCN 8.67 0.99 0.99 2.91 2.00 1.96 1.00 ppm (t1) 5.0 S58 0.0
194.470 165.211 151.728 149.946 139.462 131.918 129.141 128.975 128.243 127.603 126.222 124.518 109.814 86.153 77.370 77.053 76.735 64.569 40.465 27.721 Ph 4l C t Bu SCN 200 ppm (t1) 150 100 S59 50 0
8.009 7.859 7.839 7.553 7.546 7.539 7.533 7.523 7.502 7.380 7.375 7.261 4.074 4.028 3.650 3.604 1.451 Ph 4m C t Bu SCN 9.02 1.01 1.01 2.95 3.00 1.00 0.97 10.0 ppm (t1) 5.0 S60 0.0
194.299 164.895 150.363 139.488 133.410 131.766 128.869 128.590 128.492 126.212 124.533 122.504 109.585 91.361 87.435 86.338 77.364 77.047 76.729 64.382 40.393 27.692 Ph 4m C t Bu SCN 200 ppm (t1) 150 100 S61 50 0
8.144 8.139 7.671 7.665 7.650 7.645 7.260 7.179 7.159 3.134 3.125 3.117 3.093 3.077 3.072 2.590 2.574 2.568 2.564 2.550 2.541 2.534 2.517 2.511 2.160 2.059 1.621 Br CAd SCN 4n 6.54 5.93 3.44 1.17 3.27 1.00 1.07 1.00 ppm (t1) 5.0 S62 0.0
188.398 164.811 141.267 137.589 132.067 130.845 130.653 121.481 110.181 85.938 77.389 77.071 76.754 65.945 40.893 35.849 33.856 30.935 26.681 Br 4n CAd SCN 200 ppm (t1) 150 100 S63 50 0
S64 ppm (t1) 0.0 5.0 7.567 7.565 7.548 7.452 7.449 7.434 7.431 7.415 7.412 7.331 7.312 7.294 7.260 7.190 7.172 3.039 3.006 2.994 2.986 2.974 2.922 2.908 2.900 2.868 2.331 2.299 2.264 2.217 2.209 2.197 2.098 2.056 2.047 2.012 1.999 1.958 1.930 1.859 1.831 1.572 1.00 1.01 0.99 0.98 2.09 1.03 1.09 1.31 1.15 3.15 3.09 3.08 5.68 CAd SCN 4o
197.567 164.719 139.715 136.748 132.517 130.682 129.924 126.602 110.800 84.894 77.390 77.072 76.755 72.178 40.576 35.873 35.181 33.912 30.824 26.947 24.853 CAd SCN 4o 200 ppm (t1) 150 100 S65 50 0
S66 ppm (t1) 0.0 5.0 10.0 10.247 8.695 8.026 8.003 7.936 7.484 7.316 7.294 7.260 6.804 5.847 5.827 5.804 5.783 5.781 5.761 5.595 4.897 4.879 4.382 3.450 2.967 2.940 2.828 2.759 2.235 1.724 1.503 1.423 1.267 1.00 1.96 1.02 1.86 0.93 1.52 1.82 0.91 4.02 1.09 2.27 0.95 0.67 1.92 9.97 0.99 N H N H 9 6 QD-6, 3j
156.795 146.399 144.585 143.728 139.734 137.787 137.719 131.257 131.107 128.905 128.127 123.228 114.827 106.786 77.392 77.074 76.757 66.090 59.589 49.670 48.716 39.563 31.628 28.089 26.062 22.697 21.008 19.773 6 H N 9 H N QD-6, 3j 200 ppm (t1) 150 100 S67 50 0
S68 ppm (t1) 0.0 5.0 10.0 9.679 8.707 8.041 8.019 7.935 7.926 7.500 7.333 7.311 7.260 6.993 5.757 5.755 5.738 5.718 5.700 4.785 4.459 3.538 3.499 3.247 2.948 2.886 2.870 2.853 2.757 2.226 2.207 1.718 1.427 1.249 1.231 1.178 1.164 1.00 2.00 0.93 0.95 1.87 1.31 1.65 1.85 0.80 2.07 5.00 1.71 0.99 19.07 1.19 2.03 N H N H 9 6 i Pr i Pr i Pr QD-7, 3k
156.757 149.035 148.475 146.403 144.350 143.891 139.492 131.406 128.635 128.079 123.078 120.844 114.826 106.775 77.380 77.062 76.745 64.419 59.534 49.735 48.605 39.381 34.382 29.737 29.255 28.128 26.952 26.025 25.163 24.050 i Pr i Pr H 6 i Pr N 9 H QD-7, 3k N 200 ppm (t1) 150 100 S69 50 0
S70 ppm (f1) 0.0 5.0 10.0 8.708 7.980 7.947 7.858 7.823 7.533 7.454 7.259 7.103 7.081 6.798 5.937 5.689 5.016 4.973 4.929 4.908 4.883 4.368 3.502 3.187 3.149 3.098 2.770 2.717 2.242 2.188 1.899 1.873 1.826 1.738 1.601 1.571 1.541 2.00 1.03 2.01 1.22 1.11 0.62 2.43 2.28 1.13 2.13 2.26 10.28 2.03 2.06 1.30 1.33 0.56 H N N 6 9 QN-1
157.693 146.480 145.679 144.743 140.779 139.576 137.845 131.393 131.031 128.963 122.806 120.067 115.491 115.012 106.930 77.368 77.050 76.733 65.859 60.997 48.875 48.532 43.127 39.846 39.333 27.779 27.575 26.251 22.721 21.011 19.699 N 9 QN-1 H N 6 ppm (f1) 150 100 S71 50 0
1c 8.031 8.024 8.018 8.010 7.899 7.891 7.885 7.878 7.260 1.604 N SCN 2.02 1.99 8.100 ppm (t1) 8.050 8.000 7.950 7.900 7.850 2.02 2.00 ppm (t1) 5.0 S72 0.0
1c 164.552 135.709 131.492 124.947 108.988 77.364 77.047 76.729 N SCN 200 ppm (t1) 150 100 S73 50 0
5c 7.859 7.839 7.696 7.677 7.659 7.472 7.453 7.434 7.260 4.035 3.991 3.548 3.503 2.143 2.049 2.043 1.618 Cl Ad 6.31 6.22 3.22 1.97 1.02 1.00 ppm (t1) 5.0 S74 0.0