Supporting Information

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1 Supporting Information N-Heterocyclic Carbene-Catalyzed Chemoselective Cross-Aza-Benzoin Reaction of Enals with Isatin-derived Ketimines: Access to Chiral Quaternary Aminooxindoles Jianfeng Xu 1, Chengli Mou 1,2, Tingshun Zhu 1, Bao-An Song 2 *, and Yonggui Robin Chi 1,2 * 1 Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore , Singapore; 2 Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang , China. robinchi@ntu.edu.sg Table of Contents I II III General information General procedure for the catalytic synthesis of products 3 X ray structure of product 3e References cited in the SI Characterization of products 1 H, 13 C NMR and HPLC spectra General Information Commercially available materials purchased from Alfa Aesar or Sigma-Aldrich were used as received. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Bruker BBFO (400 MHz) spectrometer. Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ 0.00) or chloroform ( = 7.26, singlet). 1 H NMR splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets); m (multiplet), and etc. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as m (multiplet) or br (broad). Carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Bruker BBFO (100 MHz) spectrometer. High resolution mass spectral analysis (HRMS) was performed on Finnigan MAT 95 XP mass spectrometer (Thermo Electron Corporation). The determination of er was performed via chiral HPLC analysis using Shimadzu LC-20AD HPLC workstation. X-ray crystallography analysis was performed on Bruker X8 APEX X-ray diffractionmeter. Optical rotations were measured using a 1 ml cell with a 1 dm path length on a Jasco P-1030 polarimeter and are reported as follows: [α] rt D (c in g per 100 ml solvent). Analytical thin-layer chromatography (TLC) was carried out on Merck 60 F254 pre-coated silica gel plate (0.2 mm thickness). Visualization was performed using a UV lamp. All substituted isatin-derived ketimines were synthesized according to literatures. 1

2 General procedure for the catalytic synthesis of products 3: A 10 ml dry Schlenk tube, equipped with a magnetic stir bar, was charged with chiral NHC catalyst F (0.01 mmol), KOAc (0.10 mmol) and 4 Å MS powder (100 mg). The tube was sealed with a septum, evacuated and refilled with nitrogen (3 cycles). CHCl 3 (1.0 ml), enal 1 (0.15 mmol), isatin-derived ketimine 2 (0.10 mmol) were then added successively and the reaction mixture was allowed to stir for 8 or 12 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography directly using hexane/etoac = 2/1 as eluent to afford the desired product 3. Note: The racemic catalyst that used for the preparation of the corresponding racemic products for HPLC analysis was synthesized by mixing the following two chiral NHC catalysts in a 1:1 ratio. Stereochemistry determination via X-ray crystallographic analysis: Absolute configurations of the products 3 were assigned based on the crystal X-ray structures of 3e. CCDC (3e, obtained as colorless needles via evaporation of a hexane/et 2 O solution) contains the supplementary X-ray crystallographic data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via References cited in the SI: 1. (a) Cali, P.; Begtrup, M. Synthesis 2002, 1, 63. (b) Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R. Org. Lett. 2012, 14, 2512.

3 Characterization of products: (R,E)-tert-butyl (3-cinnamoyl-1-methyl-2-oxoindolin-3-yl)carbamate (3a): 28.2 mg, 72% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 15.2 Hz, 1H), (m, 6H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.72 (br, 1H), 6.21 (d, J = 15.6 Hz, 1H), 3.39 (s, 3H), 1.37 (s, 6H), 1.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.8, 171.9, 153.4, 147.0, 144.9, 133.7, 131.2, 130.3, 128.9, 128.6, 126.1, 123.7, 123.4, 117.7, 108.9, 80.4, 71.5, 28.2, 27.2; HRMS (ESI, m/z): calcd. for C 23 H 24 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 97:3 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 27.9 min (major), 37.8 min (minor)]. (R,E)-tert-butyl (1-methyl-2-oxo-3-(3-(p-tolyl)acryloyl)indolin-3-yl)carbamate (3b): 30.9 mg, 76% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 15.6 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), (m, 4H), 6.99 (d, J = 7.6 Hz, 1H), 6.73 (br, 1H), 6.16 (d, J = 15.2 Hz, 1H), 3.39 (s, 3H), 2.33 (s, 3H), 1.37 (s, 6H), 1.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.7, 172.0, 153.4, 147.1, 144.9, 142.0, 131.0, 130.2, 129.6, 128.7, 126.3, 123.6, 123.4, 116.6, 108.8, 80.3, 71.4, 28.2, 27.1, 21.5; HRMS (ESI, m/z): calcd. for C 24 H 26 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 96:4 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 52.7 min (major), 75.3 min (minor)]. (R,E)-tert-butyl (3-(3-(4-methoxyphenyl)acryloyl)-1-methyl-2-oxoindolin-3-yl) carbamate (3c): 26.6 mg, 63% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 15.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.75 (br, 1H), 6.07 (d, J = 15.6 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H), 1.37 (s, 6H), 1.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 172.1, 162.2, 153.4, 146.8, 144.7, 130.6, 130.1, 126.5, 123.6, 123.3, 115.1, 114.4, 108.8, 80.3, 71.3, 55.4, 28.2, 27.1; HRMS (ESI, m/z): calcd. for C 24 H 26 N 2 O 5 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 97:3 er, [CHIRALPAK IC column; 0.9 ml/min; solvent

4 system: i-proh/hexane = 30:70; retention times: 40.1 min (major), 60.2 min (minor)]. (R,E)-tert-butyl (3-(3-(3-fluorophenyl)acryloyl)-1-methyl-2-oxoindolin-3-yl) carbamate (3d): 23.4 mg, 57% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 15.6 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), (m, 1H), (m, 6H), 6.70 (br, 1H), 6.18 (d, J = 15.6 Hz, 1H), 3.40 (s, 3H), 1.38 (s, 6H), 1.10 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 171.8, (d, J C, F = 240 Hz), 153.3, 145.5, 144.8, (d, J C, F = 8 Hz), 130.5, (d, J C, F = 3 Hz), 124.9, (d, J C, F = 27 Hz), 118.9, (d, J C, F = 22 Hz), (d, J C, F = 21 Hz), 109.0, 80.4, 71.5, 28.2, 27.2; HRMS (ESI, m/z): calcd. for C 23 H 24 N 2 O 4 FH , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 98:2 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 25.8 min (major), 33.9 min (minor)]. BocHN O O N Me 3e Cl (R,E)-tert-butyl (3-(3-(4-chlorophenyl)acryloyl)-1-methyl-2-oxoindolin-3-yl) carbamate (3e): 31.1 mg, 73% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 15.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), (m, 4H), 7.15 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.70 (br, 1H), 6.17 (d, J = 15.6 Hz, 1H), 3.40 (s, 3H), 1.37 (s, 6H), 1.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.7, 171.9, 153.4, 145.5, 144.9, 137.3, 132.2, 130.4, 129.8, 129.2, 125.9, 123.8, 123.5, 118.1, 108.9, 80.4, 71.5, 28.2, 27.3; HRMS (ESI, m/z): calcd. for C 23 H 23 N 2 O 4 ClH , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 98:2 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 37.2 min (major), 54.0 min (minor)]. BocHN O O N Me 3f Br (R,E)-tert-butyl (3-(3-(4-bromophenyl)acryloyl)-1-methyl-2-oxoindolin-3-yl) carbamate (3f): 30.6 mg, 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 15.6 Hz, 1H), (m, 3H), (m, 4H), 7.01 (d, J = 8.0 Hz, 1H), 6.69 (br, 1H), 6.18 (d, J = 15.2 Hz, 1H), 3.39 (s, 3H), 1.37 (s, 6H), 1.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 171.8, 153.3, 145.6, 144.8, 132.6, 132.2, 131.6, 130.4, 129.9, 125.7, 123.7, 123.5, 118.1, 108.9, 80.4, 71.5, 28.2, 27.2; HRMS (ESI, m/z): calcd. for C 23 H 23 N 2 O 81 4 BrH , found [α] 21 D = (c = 1.0 in CHCl 3 );

5 HPLC analysis: 98:2 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 31.5 min (major), 45.6 min (minor)]. (R,E)-tert-butyl (3-(3-(furan-2-yl)acryloyl)-1-methyl-2-oxoindolin-3-yl) carbamate (3g): 19.9 mg, 52% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, J = 15.2 Hz, 1H), (m, 2H), (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.73 (br, 1H), 6.64 (d, J = 3.2 Hz, 1H), (m, 1H), 6.08 (d, J = 15.2 Hz, 1H), 3.39 (s, 3H), 1.37 (s, 6H), 1.08 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 172.0, 153.3, 150.6, 145.7, 144.9, 132.4, 130.2, 126.1, 123.6, 123.3, 118.1, 115.0, 112.9, 108.9, 80.3, 71.3, 28.2, 27.1; HRMS (ESI, m/z): calcd. for C 21 H 22 N 2 O 5 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 92:8 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 36.3 min (major), 46.7 min (minor)]. (R,E)-tert-butyl (1-methyl-2-oxo-3-(3-(thiophen-2-yl)acryloyl)indolin-3-yl) carbamate (3h): 21.1 mg, 53% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 15.2 Hz, 1H), (m, 2H), 7.23 (d, J = 3.6 Hz, 1H), (m, 2H), (m, 2H), 6.71 (br, 1H), 5.98 (d, J = 15.2 Hz, 1H), 3.38 (s, 3H), 1.37 (s, 6H), 1.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.4, 171.9, 161.5, 153.3, 144.8, 139.2, 133.0, 130.2, 130.0, 128.5, 126.1, 123.7, 123.3, 116.4, 108.8, 80.3, 71.3, 28.2, 27.1; HRMS (ESI, m/z): calcd. for C 21 H 22 N 2 O 4 SH , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 97:3 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 39.5 min (major), 50.3 min (minor)]. BocHN O Me O N Me 3i (R,E)-tert-butyl (3-(but-2-enoyl)-1-methyl-2-oxoindolin-3-yl)carbamate (3i): 15.8 mg, 48% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (s, 1H), (m, 3H), 6.96 (d, J = 6.8 Hz, 1H), 6.67 (br, 1H), 5.66 (d, J = 15.2 Hz, 1H), 3.37 (s, 3H), 1.76 (d, J = 6.4 Hz, 3H), 1.36 (s, 6H), 1.07 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.4, 172.0, 153.3, 148.3, 144.9, 130.1, 126.0, 123.5, 123.3, 123.0, 108.8, 80.3, 71.0, 28.2, 27.1, 18.5; HRMS (ESI, m/z): calcd. for C 18 H 22 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 92:8 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 24.1 min (major),

6 36.6 min (minor)]. (R,E)-tert-butyl (3-(hex-2-enoyl)-1-methyl-2-oxoindolin-3-yl)carbamate (3j): 17.9 mg, 50% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (t, J = 6.4 Hz, 1H), (m, 3H), 6.95 (d, J = 7.2 Hz, 1H), 6.65 (br, 1H), 5.63 (d, J = 15.2 Hz, 1H), 3.35 (s, 3H), (m, 2H), (m, 8H), 1.07 (s, 3H), 0.80 (t, J = 7.6 Hz, 3H),; 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 171.9, 153.3, 152.8, 144.8, 130.1, 126.1, 123.5, 123.3, 121.5, 108.8, 80.3, 71.1, 34.6, 28.2, 27.1, 20.9, 13.4; HRMS (ESI, m/z): calcd. for C 20 H 26 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 93:7 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 19.7 min (major), 24.0 min (minor)]. (R,E)-tert-butyl (1-allyl-3-cinnamoyl-2-oxoindolin-3-yl)carbamate (3k): 25.9 mg, 62% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 15.6 Hz, 1H), (m, 6H), 7.16 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.72 (br, 1H), 6.30 (d, J = 15.6 Hz, 1H), (m, 1H), 5.49 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 9.6 Hz, 1H), 4.63 (br, 1H), 4.38 (br, 1H), 1.38 (s, 6H), 1.10 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.7, 171.6, 153.3, 147.0, 144.0, 133.8, 131.2, 131.1, 130.1, 128.9, 128.6, 126.1, 123.6, 123.5, 118.7, 117.8, 109.7, 80.3, 71.5, 43.2, 28.2; HRMS (ESI, m/z): calcd. for C 25 H 26 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 97:3 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 22.7 min (major), 32.6 min (minor)]. (R,E)-tert-butyl (1-benzyl-3-cinnamoyl-2-oxoindolin-3-yl)carbamate (3l): 27.2 mg, 58% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 15.6 Hz, 1H), (m, 2H), (m, 7H), (m, 5H), 6.77 (br, 1H), 6.13 (d, J = 15.2 Hz, 1H), 5.39 (br, 1H), 4.73 (br, 1H), 1.40 (s, 6H), 1.11 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 171.8, 153.4, 147.0, 144.0, 135.6, 133.5, 131.2, 130.1, 129.1, 128.8, 128.6, 128.0, 127.9, 126.1, 123.6, 123.5, 117.8, 109.7, 80.4, 71.5, 44.8, 28.2; HRMS (ESI, m/z): calcd. for C 29 H 28 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 97:3 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 22.6 min (major), 37.6 min (minor)].

7 (R,E)-tert-butyl (3-cinnamoyl-2-oxo-1-phenylindolin-3-yl)carbamate (3m): 25.0 mg, 55% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 15.2 Hz, 1H), (m, 13H), 6.95 (s, 1H), 6.78 (br, 1H), 6.50 (d, J = 15.6 Hz, 1H), 1.40 (s, 6H), 1.15 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.6, 171.4, 153.5, 147.1, 145.1, 134.5, 133.7, 131.3, 130.1, 129.8, 129.0, 128.6, 128.4, 126.7, 126.5, 124.1, 123.7, 117.8, 110.0, 80.4, 71.6, 28.2; HRMS (ESI, m/z): calcd. for C 28 H 26 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 93:7 er, [CHIRALPAK IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 21.1 min (major), 31.9 min (minor)]. (R,E)-tert-butyl (3-cinnamoyl-1,5-dimethyl-2-oxoindolin-3-yl)carbamate (3n): 26.8 mg, 66% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 15.6 Hz, 1H), (m, 5H), 7.19 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.71 (br, 1H), 6.22 (d, J = 15.6 Hz, 1H), 3.38 (s, 3H), 2.29 (s, 3H), 1.39 (s, 6H), 1.10 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.9, 171.8, 153.3, 146.8, 142.4, 133.7, 133.3, 131.2, 130.6, 128.9, 128.6, 125.9, 124.1, 117.7, 108.6, 80.3, 71.5, 28.2, 27.2, 21.0; HRMS (ESI, m/z): calcd. for C 24 H 26 N 2 O 4 H , found [α] 21 D = -7.2 (c = 1.0 in CHCl 3 ); HPLC analysis: 96:4 er, [CHIRALPAK IC column; 0.9 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 31.3 min (major), 48.8 min (minor)]. (R,E)-tert-butyl (3-cinnamoyl-5-methoxy-1-methyl-2-oxoindolin-3-yl)carbamate (3o): 30.0 mg, 71% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 15.6 Hz, 1H), (m, 5H), 6.92 (s, 2H), 6.76 (s, 1H), 6.72 (br, 1H), 6.24 (d, J = 15.6 Hz, 1H), 3.75 (s, 3H), 3.37 (s, 3H), 1.39 (s, 6H), 1.12 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.7, 171.5, 156.7, 153.4, 147.0, 138.2, 133.7, 131.3, 128.9, 128.7, 127.2, 117.6, 114.5, 110.3, 109.4, 80.4, 71.8, 55.7, 28.2, 27.3; HRMS (ESI, m/z): calcd. for C 24 H 26 N 2 O 5 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 97:3 er, [CHIRALCEL OD-H column; 0.5 ml/min; solvent system: i-proh/hexane = 5:95; retention times: 29.6 min (minor), 34.5 min (major)].

8 (R,E)-tert-butyl (3-cinnamoyl-1,7-dimethyl-2-oxoindolin-3-yl)carbamate (3p): 30.0 mg, 74% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 15.6 Hz, 1H), (m, 5H), 7.12 (s, 1H), 6.97 (s, 2H), 6.72 (br, 1H), 6.24 (d, J = 15.6 Hz, 1H), 3.65 (s, 3H), 2.67 (s, 3H), 1.38 (s, 6H), 1.13 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.8, 172.7, 153.3, 147.0, 142.6, 134.1, 133.8, 131.2, 128.9, 128.7, 126.6, 123.6, 121.4, 120.4, 117.7, 80.2, 71.0, 30.6, 28.2, 19.1; HRMS (ESI, m/z): calcd. for C 24 H 26 N 2 O 4 H , found [α] 21 D = (c = 1.0 in CHCl 3 ); HPLC analysis: 98:2 er, [CHIRALCEL IC column; 1.0 ml/min; solvent system: i-proh/hexane = 30:70; retention times: 35.3 min (major), 49.9 min (minor)].

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