Supporting information for Zinc Chloride Promoted Formal xidative Coupling of Aromatic Aldehydes and Isocyanides to α- Ketoamides Marinus Bouma, Géraldine Masson* and Jieping Zhu* Institut de Chimie des Substances aturelles, CRS, 91198 Gif-sur-Yvette Cedex, France masson@icsn.cnrs-gif.fr, zhu@icsn.cnrs-gif.fr S2: General information S3: General procedure S4-S12: Physical data of 1a-o and 7l S13-S34: Copies of 1 and 13 C MR spectra S35: PLC data of 1o S1
General Information: All reactions were carried out under argon atmosphere in dried glassware. All solvents were dried and distilled by standard procedures. Aldehydes and isocyanides were purchased from commercial suppliers and were used without further purification. All reactions were monitored by thin layer chromatography (TLC) plates (aluminium oxyde 60 F254, neutral) and analyzed with 254 nm UV light. Chromatography was performed using silica gel 60 (0.040-0.063 mm). ptical rotations were measured with a polarimeter (589 nm). Melting points were determined on recrystallized product and are uncorrected. 1 MR were recorded on a 500 Mz instrument and 13 C MR were recorded on a 75 Mz instrument. Chemical shifts (δ) were reported in ppm relative to residual CCl 3 as an internal reference ( 1 : 7.26 ppm, 13 C: 77 ppm). Coupling constants (J) were reported in ertz (z). Peak multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), b (broad) and m (multiplet). The RMS data were measured on MALDI-TF type of instrument for the high resolution mass spectra (RMS). Infrared spectra were recorded on IR spectrometer, and absorption frequencies were reported in reciprocal centimeters (cm -1 ). The known products were characterized by comparing the 1 MR, 13 C MR and melting points data with those reported in the literature. S2
General procedure for α-ketoamide synthesis from aldehyde and isocyanide: To a solution of freshly dried ZnCl 2 (3.0 eq.) and the aldehyde (1.0 eq.) in dry TF (1.0 M), was added -methyl hydroxylamine hydrochloride (1.6 eq.) and ac3 (1.6 eq.). The mixture was stirred for 30 min at room temperature. The isocyanide (2.0 eq.) and acetic acid (3.0 eq.) were then added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate and filtered, the solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica gel. S3
Compound 1a: Yield: 64% Aspect: White crystals Melting point: 77-78 C. IR (cm -1 ): 3310 (), 2969, 1666 (C), 1517, 1449, 1366, 1239, 751. MR 1 δ (500 Mz, CDCl 3, 293K): 8.32 (d, 2, J = 7.6z), 7.62 (t, 1, J = 7.4z,), 7.48 (dd, 2, J = 7.6z, J = 7.4z,), 6.95 (bs, 1), 1.47 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 188.5 (Cq), 161.1 (Cq), 134.1 (C), 133.4 (Cq), 131.1 (2x C), 128.3 (2x C), 51.6 (Cq), 28.3 (3x C 3 ). RMS (ESI): calculated for [M+a] +, C 12 15 2 a m/z = 228.1000, found m/z = 228.0991. S4
Compound 1b: Yield: 61% Aspect: White crystals Melting point: 49-51 C. IR (cm -1 ): 3324 (), 2969, 2930, 1660 (C), 1587, 1365, 1239, 1173, 1090, 1006, 838, 793. MR 1 δ (500 Mz, CDCl 3, 293K): 8.31 (d, 2, J = 8.6z), 7.45 (d, 2, J = 8.6z), 6.98 (bs, 1), 1.46 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 187.1 (Cq), 160.6 (Cq), 140.8 (Cq), 132.7 (2x C), 131.7 (Cq), 128.7 (2x C), 51.7 (Cq), 28.3 (3x C 3 ). RMS (ESI): calculated for [M+a] +, C 12 14 2 acl m/z = 262.0611, found m/z = 262.0602. S5
Compound 1c: Yield: 53% Aspect: Colourless oil IR (cm -1 ): 3317 (), 2970, 1666 (C), 1514, 1365, 1232, 1195, 751. MR 1 δ (500 Mz, CDCl 3, 293K): 8.47 (s, 1), 8.28 (d, 1, J = 7.8z), 7.74 (d, 1, J = 7.9z), 7.33-7.38 (m, 1), 6.97 (bs, 1), 1.47 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 187.0 (Cq ), 160.3 (Cq), 136.8 (C), 135.0 (Cq), 133.9 (C), 129.9 (C), 129.8 (C), 122.4 (Cq), 51.7 (Cq), 28.3 (3x C 3 ). RMS (ESI): calculated for [M+a] +, C 12 14 Br 2 a 79 Br = 306.0106, found m/z = 306.0106; calculated for [M+a] +, C 12 14 Br 2 a 81 Br = 308.0086, found m/z = 308.0085. S6
Compound 1d: Yield: 58% Aspect: Colourless oil IR (cm -1 ): 3286 (), 2980, 1680, 1647 (C), 1606, 1555, 1449, 1364, 1242, 1221, 1173, 1009, 857, 779, 668. MR 1 δ (500 Mz, CDCl 3, 293K): 8.23 (d, 2, J = 8.2z), 7.26 (d, 2, J = 8.2z), 6.97 (bs, 1), 2.41 (s, 3), 1.46 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 188.0 (Cq), 161.4 (Cq), 145.2 (Cq), 131.2 (2x C), 130.9 (Cq), 129.0 (2x C), 51.5 (Cq), 28.4 (3x C 3 ), 21.7 (C 3 ). RMS (ESI): calculated for [M+a] +, C 13 17 2 a m/z = 242.1157, found m/z = 242.1159. S7
Compound 1e: Yield: 50% Aspect: White crystals Melting point: 38-39 C. IR (cm -1 ): 3334 (), 2964, 1650 (C), 1601, 1531, 1453, 1362, 1240, 1176, 1054, 1007, 861, 841, 804, 724. MR 1 δ (500 Mz, CDCl 3, 293K): 8.24 (d, 2, J = 8.4z), 7.32 (d, 1, J = 8.4z), 6.95 (bs, 1), 2.96 (td, 1, J = 13.8z, J = 6.9z), 1.46 (s, 9), 1.26 (d, 6). MR 13 C δ (75 Mz, CDCl 3, 293K): 188.1 (Cq), 161.4 (Cq), 155.8 (Cq), 131.4 (2x C), 131.2 (Cq), 126.5 (2x C), 51.5 (Cq), 34.3 (C), 28.3 (3xC 3 ), 23.5 (2x C 3 ). RMS (ESI): calculated for [M+a] +, C 15 21 2 a m/z = 270.1470, found m/z = 270.1463. S8
Compound 1f: Yield: 46% Aspect: White crystals Melting point: 84 C. IR (cm -1 ): 3328 (), 2972, 2355, 1655 (C), 1624, 1515, 1458, 1366, 1227, 1175, 1126, 804, 744, 668. MR 1 δ (500 Mz, CDCl 3, 293K): 9.19 (s, 1), 8.19 (d, 1, J = 8.7z), 8.01 (d, 1, J = 8.1z), 7.84-7.90 (m, 2), 7.60-7.64 (m, 1), 7.53-7.57 (m, 1), 7.08 (bs, 1), 1.51 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 188.0 (Cq), 161.2 (Cq), 135.9 (Cq), 134.7 (C), 132.3 (Cq), 130.5 (Cq), 130.2 (C), 129.1 (C), 128.1 (C), 127.6 (C), 126.7 (C), 125.4 (C), 51.6 (Cq), 28.4 (3x C 3 ). RMS (ESI): calculated for [M+a] +, C 16 17 2 a m/z = 278.1157, found m/z = 278.1151. S9
Compound 1g: Yield: 52% Aspect: White crystals Melting point: 59-63 C. IR (cm -1 ): 3316 (), 2969, 2925, 1660 (C), 1516, 1250, 1218, 1165, 772, 750. MR 1 δ (500 Mz, CDCl 3, 293K): 8.09-8.13 (m, 2), 7.43 (d, 1, J = 7.6z), 7.36 (dd, 1, J = 7.6z, J = 7.6z), 6.95 (bs, 1), 2.41 (s, 3), 1.47 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 188.7 (Cq), 161.2 (Cq), 138.1 (Cq), 134.9 (C), 133.3 (Cq), 131.5 (C), 128.4 (C), 128.2 (C), 51.6 (Cq), 28.3 (3x C 3 ), 21.3 (C 3 ). RMS (ESI): calculated for [M+a] +, C 13 17 2 a = 242.1157, found m/z = 242.1156. S10
Compound 1h: Yield: 31% Aspect: Yellow oil IR (cm -1 ): 3388 (), 2971, 2926, 1673 (C), 1612, 1531, 1349, 1235, 1098, 750. MR 1 δ (500 Mz, CDCl 3, 293K): 9.18 (s, 1), 8.71 (d, 1, J = 7.7z), 8.48 (d, 1, J = 8.3z), 7.69 (dd, 1, J = 7.7z, J = 8.3z), 7.03 (bs, 1), 1.49 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 186.1 (Cq), 159.8 (Cq), 148.1 (Cq), 136.9 (C), 134.6 (Cq), 129.5 (C), 128.1 (C), 126.1 (C), 52.0 (Cq), 28.3 (3x C 3 ). RMS (ESI): calculated for [M+a] +, C 12 14 2 4 a = 273.0852, found m/z = 273.0862. S11
Compound 1i: Yield: 31% Aspect: Colourless oil IR (cm -1 ): 3327 (), 2968, 2360, 1671 (C), 1517, 1455, 1366, 1238, 1216, 1005, 846, 750, 666. MR 1 δ (500 Mz, CDCl 3, 293K): 7.89 (d, 1), 7.44 (dd, 1, J = 7.6z, J = 7.6z), 7.27-7.31 (m, 2), 6.93 (bs, 1), 2.49 (s, 3), 1.48 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 192.3 (Cq), 161.2 (Cq), 139.7 (Cq), 133.0 (Cq), 132.4 (C), 131.7 (C), 131.5 (C), 125.2 (C), 51.6 (Cq), 28.3 (3x C 3 ), 20.7 (C 3 ). RMS (ESI): calculated for [M+a] +, C 13 17 2 a = 242.1157, found m/z = 242.1155. S12
Compound 1j: Yield: 61% Aspect: Pale yellow oil IR (cm -1 ): 3178 (), 3026, 1660 (C), 1592, 1510, 1469, 1260, 1216, 1162, 1026, 745, 666. MR 1 δ (500 Mz, CDCl 3, 293K): 8.48-8.53 (m, 3), 7.13-7.21 (m, 3), 7.00 (d, 2, J = 9.0z), 3.93 (s, 3), 2.32 (s, 6). MR 13 C δ (75 Mz, CDCl 3, 293K): 185.6 (Cq), 164.9 (Cq), 160.4 (Cq), 135.1 (2x Cq), 134.1 (2x C), 132.6 (Cq), 128.3 (2x C), 127.7 (C), 126.3 (Cq), 114.0 (2x C), 55.6 (C 3 ), 18.5 (2x C 3 ). RMS (ESI): calculated for [M+a] +, C 17 17 3 a m/z = 306.1106, found m/z =306.1100. S13
Compound 1k: Yield: 50% Aspect: Yellow crystals Melting point: 117 C. IR (cm -1 ): 3178 (), 3042, 1682 (C), 1626, 1540, 1469, 1426, 1217, 1189, 1075, 896, 735, 702. MR 1 δ (500 Mz, CDCl 3, 293K) 8.42-8.47 (m, 2), 8.37 (d, 1, J = 7.8z), 7.65 (d, 1, J = 8.0z), 7.48 (dd, J = 7.8z, J = 8.0z, 1), 2.31 (s, 6). MR 13 C δ (75 Mz, CDCl 3, 293K) 186.3 (Cq), 159.1 (Cq), 135.0 (2x Cq), 134.8 (Cq), 134.6 (Cq), 134.5 (C), 132.2 (Cq), 131.2 (C), 130.0 (C), 129.6 (C), 128.4 (2x C), 127.9 (C), 18.5 (2x C 3 ). RMS (ESI): calculated for [M+a] +, C 16 14 2 acl = 310.0611, found m/z = 310.0620. S14
Compound 1l: Yield: 44% Aspect: Colourless oil IR (cm -1 ): 3390 (), 2954, 1659 (C), 1597, 1514, 1262, 1241, 1215, 1168, 1031, 754. MR 1 δ (500 Mz, CDCl 3, 293K): 8.41 (d, 2, J = 9.0z), 7.08 (bs, 1), 6.94 (d, 2, J = 9.0z), 3.89 (s, 3), 1.83 (s, 2), 1.52 (s, 6), 1.05 (s, 9). MR 13 C δ (75 Mz, CDCl 3, 293K): 186.5 (Cq), 164.5 (Cq), 161.3 (Cq), 133.9 (2x C), 126.4 (Cq), 113.7 (2x C), 55.5 (C 3 ), 55.3 (Cq), 51.6 (C 2 ), 31.7 (Cq), 31.4 (3x C 3 ), 28.7 (2x C 3 ). RMS (ESI): calculated for [M+a] +, C 17 25 3 a m/z = 314.1732, found m/z = 314.1731. S15
Compound 1m: Yield: 58% Aspect: White crystals Melting point: 113-114 C. IR (cm -1 ): 3302 (), 2904, 2846, 1668 (C), 1643, 1599, 1573, 1537, 1453, 1265, 1218, 1169, 1092, 1026, 854, 799, 790. MR 1 δ (500 Mz, CDCl 3, 293K): 8.39 (d, 2, J = 9.0z), 6.93 (d, 2, J = 9.0z), 6.86 (bs, 1), 3.89 (s, 3), 2.09-2.15 (m, 9), 1.72-1.75 (m, 6). MR 13 C δ (75 Mz, CDCl 3, 293K): 186.5 (Cq), 164.4 (Cq), 161.4 (Cq), 133.9 (2x C), 126.4 (Cq), 113.6 (2x C), 55.5 (C 3 ), 51.2 (Cq), 41.1 (3x C 2 ), 36.2 (3x C), 29.3 (3x C 3 ). RMS (ESI): calculated for [M+a] +, C 19 23 3 a m/z = 336.1576, found m/z = 336.1584. S16
Compound 1n: Yield: 67% Aspect: White crystals Melting point: 96-97 C. IR (cm -1 ): 3318 (), 3063, 2928, 1659 (C), 1595, 1518, 1449, 1218, 1177, 746, 688. MR 1 δ (500 Mz, CDCl 3, 293K): 8.37 (d, 2, J = 7.4z), 7.63 (t, 1, J = 7.4z), 7.49 (dd, 2, J = 7.4z, J = 7.4z), 7.42 (bs, 1), 7.29-7.39 (m, 5), 4.58 (d, 2, J = 6.0z). MR 13 C δ (75 Mz, CDCl 3, 293K): 187.5 (Cq), 161.6 (Cq), 137.1 (Cq), 134.4 (C), 133.3 (Cq), 131.2 (2x C), 128.8 (2x C), 128.4 (2x C), 127.8 (2x C), 127.8 (Cq), 43.4 (C 2 ). RMS (ESI): calculated for [M+a] +, C 15 13 2 a m/z = 262.0844, found m/z = 262.0851. S17
Compound 1o: Yield: 35% Aspect: Yellow oil IR (cm -1 ): 3294 (), 3064, 3030, 2975, 2926, 1660 (C), 1566, 1514, 1211, 760, 698. MR 1 δ (500 Mz, CDCl 3, 293K): 8.37 (s, 1), 8.28 (d, 1, J = 7.8z), 7.60 (d, 1, J = 7.1z), 7.37-7.45 (m, 6), 7.33 (dd, J = 7.8z, J = 7.1z, 1), 5.16-5.23 (m, 1), 1.63 (d, 3, J = 6.9z). MR 13 C δ (75 Mz, CDCl 3, 293K): 186.2 (Cq), 160.1 (Cq), 142.1 (Cq), 134.8 (Cq), 134.7 (Cq), 134.3 (C), 131.1 (C), 129.7 (C), 129.4 (Cq), 128.8 (2x C), 127.7 (C), 126.1 (2x C), 49.2 (C), 21.6 (C 3 ). RMS (ESI): calculated for [M+a] +, C 16 14 2 acl = 310.0611, found m/z = 310.0599. S18
Compound 1a 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (f1) 150 100 50 S19
Compound 1b Cl 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 Cl 150 100 50 S20
Compound 1c Br 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 Br ppm (f1) 200 150 100 50 0 S21
Compound 1d ppm (f1) 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (f1) 150 100 50 S22
Compound 1e 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (f1) 150 100 50 S23
Compound 1f 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (f1) 150 100 50 S24
Compound 1g 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 150 100 50 S25
Compound 1h 2 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 2 150 100 50 S26
Compound 1i 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (f1) 150 100 50 S27
Compound 1j 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 150 100 50 S28
Compound 1k Cl 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 Cl ppm (f1) 150 100 50 S29
Compound 1l 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 150 100 50 S30
Compound 1m 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 150 100 50 S31
Compound 1n 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 150 100 50 S32
Compound 1o Cl 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 Cl 150 100 50 S33
Compound 7l 2 ppm (f1) 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 2 150 100 50 S34
PLC Chromatograms of compound 1o 1000 1000 800 800 600 600 mau mau 400 400 2 1 200 200 0 0 5 10 15 20 25 Minutes DAD-C1 254 nm Results Pk # Retention Time Area Area % 1 11.23 33557855 47.09 2 19.05 37703529 52.91 0 1000 1000 800 800 600 600 mau 1 mau 400 400 200 200 0 0 5 10 15 20 25 30 Minutes DAD-C1 254 nm Results Pk # Retention Time Area Area % 23.51 112250642 100.00 23.51 112250642 100.00 0 S35