A Mild Hydration of Nitriles Catalysed by Copper(II) Acetate

Transcription

1 Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 205 SUPPRTING INFRMATIN A Mild Hydration of Nitriles Catalysed by Copper(II) Acetate Patricia Marcé, a James Lynch, a A. John Blacker b and Jonathan M. J. Williams a * a Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom b Institute of Process Research & Development, School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom

2 Table of Contents General Remarks...3 Influence of the Lewis acid in the formation of amidoxime...3 Conversion of amidoxime in amide using hydroxylamine and ammonia...3 Effect of additives in the formation of amidoxime...4 ptimization of the reaction conditions using N,N-diethylhydroxylamine as additive 5 NMR Experiment...6 Experiments using 8 -labelled water...6 Synthesis of N-hydroxy-4-methoxybenzimidamide...7 General procedure for the synthesis of amides...7 H-NMR and 3 C-NMR spectroscopic data...3

3 General Remarks All chemicals and solvents used were reagent grade and used as supplied unless otherwise specified. Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 glass or aluminium plates. rganic Compounds were visualized by UV (254 nm) irradiation. Flash column chromatography was carried out using forced flow or by gravity of the indicated solvent on Fluka silica gel 60 ( mesh). H and 3 C NMR spectra were recorded on Bruker AV 500, Bruker AV 300 or Bruker AV 250 spectrometer in CDCl 3 or d 6 -DMS as solvents. Chemical shifts (δ) were referenced internally to residual protic solvent signal for CDCl 3 (7.26 ppm) and d 6 -dmso (2.5 ppm). Multiplicities are presented as singlet (s), broad singlet (br s), doublet (d), triplet (t), triplet of triplets (tt), quadruplet (q) and, multiplet (m). Coupling constants, (J) were expressed in Hertz (Hz). HRMS-ESI were run on an Agilent 200 Series LC/MSD. Uncorrected melting points were determined using Stuart SMP0 melting point equipment using closed end glass capillary. Influence of the Lewis acid in the formation of amidoxime 4-Methoxybenzonitrile (0.30 g, mmol), hydroxylamine 50% in water solution ( ml) and the appropriate catalyst were added to a carousel tube (see table S). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum and the crude reaction was analysed by H-NMR. Table S Entry CN Catalyst (X mol%) H 2, rt + H + (Excess) Catalyst Loading (mol%) Time h 2 3 Conversion a (%) N Ratio :50 2 [IrCp*I 2 ] :50 3 Cu(Ac) :50 4 Zn(Ac) :50 5 FeCl :50 6 [RuCp*Cl 2 ] :50 a) Conversions were determined by analysis of the H-NMR spectra Conversion of amidoxime in amide using hydroxylamine and ammonia N-Hydroxy-4-methoxybenzimidamide (0.70 g, mmol) and water ( ml) were added in a carousel tube followed by the addition of the corresponding amount of additive. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum and the crude reactions were analysed by H NMR. 2:3 H S3

4 N H Additive (X equiv.) H 2, rt 3 2 Table S2 Entry Additive Conversion (%) a H ( equiv.) 0 2 H (2 equiv.) 0 3 H (3 equiv.) 2 4 H (5 equiv.) 3 5 H (0 equiv.) 3 6 H (20 equiv.) 3 7 NH 4 H (0 equiv.) 0 a) Conversions were determined by analysis of the H-NMR spectra Effect of additives in the formation of amidoxime 4-Methoxybenzonitrile (0.30 g, mmol) and hydroxylamine 50% in water solution ( ml) were added to a carousel tube. ml of HCl or NaH 2 M solution was added into the reaction mixture (see table S3). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum and the crude reaction was analysed by H-NMR. N H CN Additive + H 2 N H + H 2, rt, 24 h 2 3 Table S3 Ratio Entry Additive Notes Conversion (%) a 2:3 2 M HCl Added at the beginning of the reaction 00 50: M HCl Added after 24 hours 00 55: M NaH Added at the beginning of the reaction 00 60: M NaH Added after 24 hours 00 00:0 a) Conversions were determined by analysis of the H-NMR spectra S4

5 ptimization of the reaction conditions using N,N-diethylhydroxylamine as additive CN + NEt 2 H H Methoxybenzonitrile ( mmol) was added to a carousel tube followed by water ( ml), the amounts of N,N-diethylhydroxylamine and Lewis acid, as well as the temperature and the reaction time were modified according to table S4. The solvent was removed under vacuum and the crude was analysed by H-NMR. Table S4 Entry NEt 2 H Lewis acid (x equiv.) (2 mol%) Temp ( o C) Time (h) Conversion (%) a Cu(Ac) Zn(Ac) [IrCp*I 2 ] Cu(Ac) [IrCp*I 2 ] Cu(Ac) [IrCp*I 2 ] Cu(Ac) [IrCp*I 2 ] a) Conversions were determined by analysis of the H-NMR spectra S5

6 Effect of the solvent in the hydration of nitriles 4-Methoxybenzonitrile ( mmol) was added to carousel tube followed by the addition of solvent ( ml), N,N-diethylhydroxylamine (3 mmol) and copper acetate (2 mol%). The reaction mixture was heated at 35 o C for 3 hours. The solvent was removed under vacuum and the crude reaction was analysed by H- NMR using d 6 -DMS as deuterated solvent. CN NEt 2 H (3 equiv.) Cu(Ac) 2 (2 mol%) solvent, 35 o C, 3 h 2 Table S5 Entry Solvent Conversion (%) MeH 92 2 EtAc 89 3 DCE 84 4 THF 9 5 Toluene 84 6 Hexane 93 a) Conversions were determined by analysis of the H-NMR spectra S6

7 NMR Experiment 4-Methoxybenzonitrile (65 mg, 0.5 mmol) N,N-diethylhydroxylamine (33 mg,.5 mmol) and D 2 (0.5 ml) were added to a NMR tube. The tube was sealed and heated to 70 C in a Bruker Avance 500 (500 MHz). 3 C NMR spectra were taken every 5 minutes for 2 hours. Figure S. 3 C-NMR spectra of the reaction progress. CN 5 minutes after addition of NEt 2 H 30 minutes after addition of NEt 2 H 45 minutes after addition of NEt 2 H 60 minutes after addition of NEt 2 H 75 minutes after addition of NEt 2 H 2 hours after addition of NEt 2 H ppm Experiments using 8 -labelled water 8 CN + H N Cu(Ac) 2 (2 mol%) H 2 8, 35 o C, 3 h + 3 equiv. [ 8 ] Methoxybenzonitrile (3 mg, 0. mmol), N,N-diethylhydroxylamine (27 mg, 0.3 mmol), copper acetate (3.2 mg, 2 mol%) and 8 -labelled water ( ml) were added in a carousel tube. The reaction mixture was then stirred at room temperature for 24 hours. The final mixture was diluted in methanol and analysed by HRMS-ESI. A peak with m/z = was not detected, indicating that incorporation of 8 into the amide product had not occurred. This evidence supports that water does not act as nucleophile. S7

8 Figure S2. a) HRMS-ESI of the reaction mixture; b) comparison to the simulated peaks of the 8 -labelled amide a) reaction mixture b) 8 Synthesis of N-hydroxy-4-methoxybenzimidamide (3) N H 4-Methoxybenzonitrile (.300 g, 0 mmol) and hydroxylamine (0.600 g, 20 mmol) were dissolved in ethanol (50 ml) and heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The resulting residue was dissolved in ethyl acetate (20 ml) and washed with brine (2 x 20 ml). The organic layers were combined, dried over magnesium sulfate and filtered giving N-hydroxy-4-methoxybenzimidamide (.46 g, 90%) as a white solid. The product obtained was used without further purification. H NMR (300 MHz, CDCl 3 ) δ 7.67 (d, 2H, J = 7.6 Hz, aromatic), 6.94 (d, 2H, J = 7.6 Hz, aromatic), 4.89 (br s, 2H, ), 3.83 (s, 3H, CH 3 ); HRMS-ESI calcd for [C 8 H 0 N 2 2 ] + : [M+H] +. Found ; m.p C. General procedure for the synthesis of amides The appropriate nitrile ( mmol) was added to carousel tube followed by the addition of water ( ml), N,N-diethylhydroxylamine (3 mmol) and copper acetate (2 mol%). The reaction mixture was heated at 35 o C for 3 hours. The solvent was removed under vacuum and the crude reaction was purified over a short pad of silica (eluting with dichloromethane/methanol 95:5). S8

9 4-Methoxybenzamide (2) 4-Methoxybenzonitrile (0.30 g, mmol) was used as nitrile species. 4-Methoxybenzamide was recovered after purificacion by column chromatography as a white solid (0.47 g, 97%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ (m, 3H, aromatic and ), 7.20 (br s, H, ), 6.95 (d, J = 8.6 Hz, 2H, aromatic), 3.78 (s, 3H, CH 3 ); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 67.7, 6.9, 29.7, 26.8, 3.7, 55.6; HRMS-ESI calcd for [C 8 H 9 N 2 ] + : [M+H] +. Found ; FT-IR (neat) in cm - : 3393, 674; m.p C. Benzamide (4) 2 Benzonitrile (0.00 g, mmol) was used as nitrile species. Benzamide was recovered after purification by column chromatography as a white solid (0.9 g, 98%). H NMR (300 MHz, CDCl 3, 25 C) δ (m, 2H, aromatic), (m, 3H, aromatic), 6.33 (br s, 2H, ); 3 C NMR (75.5 MHz, CDCl 3, 25 C) δ 69.5, 33.2, 32., 28.6, 27.0; HRMS-ESI calcd for [C 7 H 6 N] - : [M-H] -. Found ; FT-IR (neat) in cm - : 2268, 659; m.p C. 4-Methylbenzamide (5) 4-Methylbenzonitrile (0.20 g, mmol) was used as nitrile species. 4-Methylbenzamide was recovered after purification by column chromatography as a white solid (0.32 g, 98%). H NMR (250 MHz, CDCl 3, 25 o C) δ (d, J = 8.3 Hz, 2H, aromatic), (d, J = 8.3 Hz, 2H, aromatic), 6.08 (br s, 2H, ), 2.33 (s, 3H, CH 3 ); 3 C NMR (75.5 MHz, CDCl3, 25 C) δ 69.5, 42.6, 30.4, 29.3, 27.4, 2.5; HRMS-ESI calcd for [C 8 H 9 NNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3303, 650; m.p C. 4-Fluorobenzamide (6) F 4-Fluorobenzonitrile (0.20 g, mmol) was used as nitrile species. 4-Fluorobenzamide was recovered after purification by column chromatography as a white solid (0.5 g, 92%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 7.99 (br s, H, ), 7.92 (dd, J = 5.6 Hz, J = 3.3 Hz, 2H, aromatics), 7.40 (s, H, ), 7.26 (t, J = 9.0 Hz, 2H, aromatic); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 67., 64.2 (d, J = Hz), 3.0, 30.5 (d, J = 9.0 Hz), 5.5 (d, J = 2. Hz); HRMS-ESI calcd for [C 7 H 5 NF] - : [M-H] -. Found ; FT-IR (neat) in cm - : 333, 674; m.p C4- (Trifluoromethyl)benzamide (7 F 3 C 4-(Trifluoromethyl)benzonitrile (0.85 g, mmol) was used as nitrile species. 4- (Trifluoromethyl)benzamide was recovered after purification by column chromatography as a white solid (0.76 g, 93%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 8.20 (br s, H, ), 8.05 (d, J = 7.9 Hz, 2H, aromatic), 7.82 (d, J = 8.3 Hz, 2H, aromatic), 7.63 (br s, H, ); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 67.0, 38.4, 3.7 S9

10 (q, J = 3.7 Hz), 24.6, 27. (q, J = 3.74 Hz), 25.6 (q, J = Hz); HRMS-ESI calcd for [C 8 H 6 F 3 NNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3373, 654; m.p C. 4-Chlorobenzamide (8) Cl 4-Chlorobenzonitrile (0.37 g, mmol) was used as nitrile species. 4-Chlorobenzamide was recovered after purification by column chromatography as a white solid (0.49 g, 96%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 8.07 (br s, H, ), 7.88 (d, J = 8.6 Hz, 2H, aromatic), (m, 3H, aromatic and ); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 3.3, 38.2, 59.6, 68.3; HRMS- ESI calcd for [C 7 H 5 ClN] - : [M-H] -. Found ; FT-IR (neat) in cm - : 3370, 653; m.p C. 4-Nitrobenzamide (9) 3 2 N 4-Nitrobenzonitrile (0.50 g, mmol) was used as nitrile species. 4-Nitrobenzonitrile was recovered after purification by column chromatography as a white solid (0.34 g, 8%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 8.32 (d, J = 8.3 Hz, 3H, aromatic and ), 8. (d, J = 9.0 Hz, 2H, aromatic), 7.72 (br s, H, ); 3 C NMR (75 MHz, d 6 -DMS, 25 o C) δ 66.5, 49.4, 40.3, 29.3, 23.8; HRMS-ESI calcd for [C 7 H 6 N 2 3 ] - : [M-H] -. Found ; FT-IR (neat) in cm - : 3367, 656; m.p C. 3-Methylbenzamide (0) 3 3-Methylbenzonitrile (0.20 g, mmol) was used as nitrile species. 3-Methylbenzamide was recovered after purification by column chromatography as a white solid (0.26 g, 93%). H NMR (300 MHz, CDCl 3, 25 C) δ 7.65 (s, H, aromatic), (m, H, aromatic), (m, 2H, aromatic), 6.33 (br s, 2H, ), 2.39 (s, 3H, CH 3 ); 3 C NMR (75.5 MHz, CDCl 3, 25 C) δ 69.9, 38.5, 33.6, 32.7, 28.5, 28., 24.3, 2.3; HRMS-ESI calcd for [C 8 H 9 NNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3375, 649; m.p C. 3-Chlorobenzamide () 4 Cl 3-Chlorobenzonitrile (0.40 g, mmol) was used as nitrile species. 3-Chlorobenzamide was recovered after purification by column chromatography as a white solid (0.5 g, 94%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 8.09 (br s, H, ), 7.90 (s, H, aromatic), 7.8 (d, J = 7.9 Hz, H, aromatic), 7.52 (m, 3H, aromatic and ); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 66.7, 36.6, 33.4, 3.4, 30.6, 27.6, 26.5; HRMS-ESI calcd for [C 7 H 5 ClN] - : [M-H] -. Found ; FT-IR (neat) in cm - : 3359, 659; m.p C. 2-Methylbenzamide (2) 4 2-Methylbenzonitrile (0.20 g, mmol) was used as nitrile species. 2-Methylbenzamide was recovered after purification by column chromatography as a white solid (0.28 g, 95%). S0

11 H NMR (300 MHz, CDCl 3, 25 o C) δ 7.35 (d, J = 8. Hz, H, aromatic), (m, H, aromatic), 7.5 (m, 2H, aromatic), 2.43 (s, 3H, CH 3 ); 3 C NMR (75.5 MHz, CDCl 3, 25 o C) δ 72.3, 36.3, 35.2, 3.2, 30.3, 26.9, 25.7, 9.9; HRMS-ESI calcd for [C 8 H 9 NNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3370, 65; m.p C. 2-Chlorobenzamide (3) 4 Cl 2-Chlorobenzonitrile (0.37 g, mmol) was used as nitrile species. 2-Chlorobenzamide was recovered after purification by column chromatography as a white solid (0.43 g, 92%). H NMR (300 MHz, CDCl 3, 25 o C) δ 7.76 (dd, J = 8. Hz, J =.2 Hz, H, aromatic), (m, 3H, aromatic), 6.32 (br s, 2H, ); 3 C NMR (75.5 MHz, CDCl 3, 25 o C) δ 68.2, 33.8, 3.8, 30.8, 30.7, ; HRMS-ESI calcd for [C 7 H 6 ClNNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3363, 65; m.p C. 2-Hydroxybenzamide (4) 3 H 2-Hydroxybenzonitrile (0.20 g, mmol) was used as nitrile species. 2-Hydroxybenzamide was recovered after purification by column chromatography as a white solid (0.37 g, 85%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 3.0 (s, H, H), 8.40 (br s, H, ), 7.80 (br s, H, ), 7.85 (d, J = 8.2 Hz, H, aromatic), 7.42 (t, J = 8.2 Hz, H, aromatic), (m, 2H, aromatic); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 72.5, 6.5, 34.4, 28.4, 8.7, 7.8, 4.7; HRMS-ESI calcd for [C 7 H 7 N 2 ] - : [M-H] -. Found ; FT-IR (neat) in cm - : 3420, 685; m.p C. 2,4-Dichlorobenzamide (5) 3 Cl Cl 2,4-Dichlorobenzonitrile (0.70 g, mmol) was used as nitrile species. 2,4-Dichlorobenzamide was recovered after purification by column chromatography as a white solid (0.095 g, 50%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 7.9 (br s, H, ), (m, 2H, and aromatic), 7.47 (d, J =.2 Hz, 2H, aromatic); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 67.6, 36.3, 34.6, 3.2, 30.4, 29.5, 27.6; HRMS-ESI calcd for [C 7 H 4 Cl 2 N] - : [M-H] -. Found ; FT-IR (neat) in cm - : 3376, 65; m.p C. S

12 Pentafluorobenzamide (6) 5 F F F F F Pentafluorobenzonitrile (0.200 g, mmol) was used as nitrile species. Pentafluorobenzamide was recovered after purification by column chromatography as a white solid (0.20 g, 92%) H NMR (500 MHz, d 6 -DMS, 25 C) δ 8.2 (br s, H, ), 8.6 (br s, H, ); 9 F NMR (470 MHz, d 6 - DMS, 25 C) δ (m, 2F), (t, J = 2 Hz, F), (m, 2F); HRMS-ESI calcd for [C 7 H F 5 N] - : [M-H] -. Found ; FT-IR (neat) in cm - : 339, 672; m.p C. Butyramide (7) Butyronitrile (70 mg, mmol) was used as nitrile species. Butyramide was recovered after purification by column chromatography as a white solid (70 mg, 79%). H NMR (250 MHz, CDCl 3, 25 C) δ 5.35 (br s, 2H, ), 2.4 (t, J = 7.5 Hz, 2H, CH 2 CH 2 C()),.60 (sextet, J = 7.5 Hz, 2H, CH 3 CH 2 CH 2 ), 0.90 (t, J = 7.5 Hz, 3H, CH 3 ); 3 C NMR (75.5 MHz, CDCl 3, 25 C) δ 75.5, 37.3, 9.0, 3.7; HRMS-ESI calcd for [C 4 H 0 N] + : [M+H] +. Found ; FT-IR (neat) in cm - : 3360, 632; m.p. 5-7 C. Propionamide (8) 6 Propionitrile (55 mg, mmol) was used as nitrile species. Propionamide was recovered after purification by column chromatography as a white solid (58 mg, 80%). H NMR (300 MHz, CDCl 3, 25 o C) δ 6.3 (br s, H, ), 5.92 (br s, H, ), 2.20 (q, J = 7.3 Hz, 2H, CH 2 ),.09 (t, J = 7.3 Hz, 3H, CH 3 ); 3 C NMR (75.5 MHz, CDCl 3, 25 o C) δ 77.3, 28.9, 9.5; HRMS-ESI calcd for [C 3 H 6 N] - : [M-H] -. Found ; FT-IR (neat) in cm - : 626; m.p C. Cyclohexane amide (9) 2 Cyclohexanecarbonitrile (0.0 g, mmol) was used as nitrile species. Cyclohexane amide was recovered after purification by column chromatography as a white solid (0.3 g, 89%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 7.3 (br s, H, ), 6.62 (br s, H, ), (m, H, CH), (m, 5H, CH 2 ), (m, 5H, CH 2 ); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 77.7, 44.0, 28.5 (2C), 25.9, 25.7 (2C); HRMS-ESI calcd for [C 7 H 3 NNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3340, 66; m.p C. Benzenepropanamide (20) 2 Benzenepropanonitrile (0.30 g, mmol) was used as nitrile species. Benzenepropanamide was recovered after purification by column chromatography as a white solid (0.27 g, 85%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ (m, 5H, aromatic), 5.98 (br s, H, ), 5.60 (br s, H, ), 2.95 (t, J = 6.2 Hz, 2H, CH 2 ), 2.5 (t, J = 6.2 Hz, 2H, CH 2 ); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 74.9, 40,7, 28.5, 28.4, 26.3, 37.5, 3.4; HRMS-ESI calcd for [C 9 H NNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3389, 649; m.p C. S2

13 Cinnamamide (2) Cinnamonitrile (0.3 g, mmol) was used as nitrile species. Cinnamamide was recovered after purification by column chromatography as an off-white solid (0.27 g, 85%). H NMR (300 MHz, CDCl 3, 25 o C) δ 7.66 (d, J = 5.9 Hz, H, CH=CH), (m, 2H, aromatic), (m, 3H, aromatic), 6.5 (d, J = 5.4 Hz, H, CH=CH), 5.86 (br s, 2H, ); 3 C NMR (75.5 MHz, CDCl 3, 25 C) δ 68.3, 42.7, 34.4, 30., 28.9, 28.0, 22.7; HRMS-ESI calcd for [C 9 H 0 N] + : [M+H] +. Found ; FT-IR (neat) in cm - : 3382, 66; m.p C. Furan-2-carboxylic acid amide (22) 3 2-Furonitrile (0.090 g, mmol) was used as nitrile species. 2-Furanamide was recovered after purification by column chromatography as a brown solid (0. g, 92%). H NMR (300 MHz, CDCl3, 25 o C) δ 7.4 (dd, J =.5 Hz, J = 0.7 Hz, H, CH), 7.09 (dd, J = 2.6 Hz, 0.7 Hz, H, CH), 6.44 (dd, J = 3.7 Hz, J =.5 Hz, H, CH), 6.7 (br s, 2H, NH2); 3 C NMR (75.5 MHz, CDCl 3, 25 o C) δ 60.3, 47.4, 44.4, 5.2, 2.3; HRMS-ESI calcd for [C 5 H 6 N 2 ] + : [M+H] +. Found 2.04; FT-IR (neat) in cm - : 3352, 625; m.p C. Thiophene-2-carboxylic acid amide (23) S 2-Thiophenecarbonitrile (0.0 g, mmol) was used as nitrile species. 2-Thiophenecarboxamide was recovered after purification by column chromatography as a white solid (0.0 g, 79%). H NMR (300 MHz, d 6 -DMS, 25 o C) δ 7.98 (br s, H, ), (m, 2H, CH), 7.40 (br. s, H, ), 7. (t, J = 4.2 Hz, H, CH); 3 C NMR (75.5 MHz, d 6 -DMS, 25 o C) δ 63.2, 40.4, 3.2, 28.8, 28.; HRMS-ESI calcd for [C 5 H 4 NSNa] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3366, 654; m.p C. 2-Phenyl-malonamic acid ethyl ester (24) 7 Cyano-phenylacetic acid ethyl ester (0.90 g, mmol) was used the nitrile species. 2-Phenyl-malonamic acid ethyl ester was recovered after purification by column chromatography as a white solid (0.66 g, 80%). H NMR (300 MHz, CDCl 3, 25 o C) δ (m, 5H, aromatic), 6.8 (br s, H, ), 5.7 (br s, H, ), 4.44 (s, H, CH), (m, 2H, CH 2 ),.2 (t, J = 6 Hz, 3H, CH 3 ); 3 C NMR (75.5 MHz, CDCl 3, 25 o C) δ 70.6, 69.6, 33.9, 29., 28.3, 28.2, 62.0, 58.4, 3.9; HRMS-ESI calcd for [C H 3 N 3 Na] + : [M+Na] +. Found ; FT-IR (neat) in cm - : 3394, 655; m.p C. R. hmura, M. Takahata and H. Togo, Tetrahedron Lett., 200, 5, 4378 S3

14 2 S. K. Sharma, S. D. Bishopp, C. L. Allen, R. Lawerence, M. J. Bamford, A. A. Lapkin, P. Plucinski, R. J. Watson and J. M. J Williams, Tetrahedron Lett., 20, 52, Z. Li, L. Wang and X. Zhou, Adv. Synth. Catal., 202, 354, C. C. Hughes and D. Trauner, Angew. Chem. Int. Ed., 2002, 4, E. Tomás-Mendivil, F. J. Suárez, J. Díez and V. Cadierno, Chem. Commun., 204, 50, K. Y. Koltunor, J. Sommer and S. Walspurger, Eur. J. rg. Chem., 2009, 9, M. C. Kozlowski, E. S. Divirgilio, K. Malolananasimham and A. Carol, Tetrahedron: Asymmetry, 2005, 6, 3599 S4

15 H-NMR and 3 C-NMR spectroscopic data S5

16 S6

17 S7

18 S8

19 F S9

20 F 3 C S20

21 Cl S2

22 2 N S22

23 S23

24 Cl S24

25 S25

26 Cl S26

27 H S27

28 Cl Cl S28

29 F F F F F S29

30 S30

31 S3

32 S32

33 S33

34 S34

35 S35

36 S S36

37 S37