Friedel-Crafts Acylation of Pyrroles and Indoles using 1,5- Diazabicyclo[4.3.0]non-5-ene (DB) as a ucleophilic Catalyst James E. Taylor, Mathew D. Jones, Jonathan M. J. Williams, and Steven D. Bull * Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY Contents General Experimental Starting Material Compound Data rganocatalytic Acylation General Procedure rganocatalytic Acylation Compound Data Tolmetin Synthesis MR Spectra Mechanistic Studies Crystallographic Data References S2 S2 S7 S7 S15 S18 S64 S67 S68 S1
General Experimental All reactions were performed under a nitrogen atmosphere in oven-dried apparatus, unless otherwise stated. Anhydrous acetonitrile, toluene, and tetrahydrofuran were obtained from an Innovative Technology Inc. PS-400-7 solvent purification system. Petrol refers to the fraction of petroleum ether boiling at 40-60 C. Pyrrole and -methylpyrrole were distilled before use. All other commercially available compounds were used as obtained from the chemical suppliers. Analytical thin layer chromatography was performed using commercially available aluminium backed plates coated with Merck G/UV254 neutral silica. Plates were visualised under UV light (at 254 nm) or by staining with phosphomolybdic acid followed by heating. Flash chromatography was performed using chromatography grade, silica 60 Å particle size 35-70 microns from Fisher Scientific. 1 H MR spectra were recorded at 300 MHz and 13 C{ 1 H} spectra were recorded at 75 MHz on a Brüker Avance 300 spectrometer. Chemical shifts, δ, are quoted in parts per million and are referenced to the residual solvent peak. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; app., apparent and br, broad.. Coupling constants, J, are quoted to the nearest 0.1 Hz. High resolution mass spectra were recorded on a Brüker Daltonics microtf spectrometer with an electrospray source and external calibration. Masses were recorded in positive electrospray ionisation mode and were introduced by flow injection. Masses are accurate to 5 ppm and data was processed using DataAnalysis software from Brüker Daltonics. Infra red spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer, using a Universal ATR accessory for sampling, with only selected absorbances quoted as ν in cm -1. Starting Material Compound Data 1-Benzyl-1H-pyrrole Bn Based on a literature procedure, 1 sodium hydride (60% dispersion in mineral oil, 1.32 g, 33 mmol) was added to anhydrous DMF (30 ml) in a nitrogen purged two-neck round-bottom flask. The solution was cooled to 0 C and pyrrole (2.08 ml, 30 mmol) in anhydrous DMF (8 ml) was added dropwise. The solution was allowed to warm to room temperature and was stirred for 30 minutes before being cooled back to 0 C when benzyl bromide (3.57 ml, 30 mmol) was added dropwise. The solution was again allowed to warm to room temperature and was stirred for one hour. The solution was then added to H 2 and extracted with 1:1 hexane : Et 2. The combined organic layers were washed with H 2 before drying over MgS 4, filtering, and concentrating under reduced pressure. The crude product was purified by flash column chromatography (hexane : Et 2 (95:5), R f = 0.64), S2
yielding the title compound (3.60 g, 76%) as a yellow oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.39-7.27 (3H, m, ArH), 7.18-7.11 (2H, m, ArH), 6.72 (2H, app. t, J = 1.6 Hz, CH), 6.22 (2H, app. t, J = 1.6 Hz, CHCH), 5.09 (2H, s, CH 2 Ph); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 138.3, 128.8, 127.8, 127.1, 121.3, 108.6, 53.5. t-butyl 1H-pyrrole-1-carboxylate Boc Based on a literature procedure, 2 DMAP (0.12 g, 1 mmol) and di-t-butyl dicarbonate (2.62 g, 12 mmol) were added to a solution of pyrrole (0.69 ml, 10 mmol) in acetonitrile (10 ml) and the solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with Et 2 and washed with ahc 3 and then brine. The organic layer was then dried over MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol : EtAc (99:1), R f = 0.19), yielding the title compound (1.44 g, 86%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.24 (2H, t, J = 2.3 Hz, CH), 6.22 (2H, t, J = 2.3 Hz, CHCH), 1.60 (9H, s, C(CH 3 ) 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 149.1, 120.1, 112.0, 83.7, 28.1. 1-(4-Methoxybenzyl)-1H-pyrrole PMB Based on a literature procedure, 3 2,5-dimethoxytetrahydrofuran (1.30 ml, 10 mmol), 4- methoxybenzylamine (1.30 ml, 10 mmol), and glacial acetic acid (5 ml) were added to a carousel tube and heated at 115 C for 1.5 hours. The reaction was allowed to cool before being diluted with EtAc and quenched with ahc 3. The resulting layers were separated and the organics washed with brine before being dried over MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol : EtAc (95:5), R f = 0.44), yielding the title compound (0.98 g, 52%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.08 (2H, d, J = 8.5 Hz, ArH), 6.86 (2H, d, J = 8.6 Hz, ArH), 6.68 (2H, t, J = 1.9 Hz, CH), 6.18 (2H, t, J = 1.9 Hz, CHCH), 5.01 (2H, s, CH 2 ), 3.80 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 159.3, 130.3, 128.6, 121.1, 114.2, 108.5, 55.4, 53.0. S3
1-(2,4-Dimethoxybenzyl)-1H-pyrrole Based on a literature procedure, 3 2,5-dimethoxytetrahydrofuran (0.26 ml, 2 mmol), 2,4- dimethoxybenzylamine (0.30 ml, 2 mmol), and glacial acetic acid (2 ml) were added to a carousel tube and heated at 115 C for 1.5 hours. The reaction was allowed to cool before being diluted with EtAc and quenched with ahc 3. The resulting layers were separated and the organics washed with brine before being dried over MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol : EtAc (95:5), R f = 0.38), yielding the title compound (0.21 g, 49%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 6.81 (1H, d, J = 8.2 Hz, ArH), 6.71 (2H, t, J = 2.0 Hz, CH), 6.46 (1H, d, J = 2.4 Hz, ArH), 6.41 (1H, dd, J = 8.3, 2.4 Hz, ArH), 6.15 (2H, t, J = 2.0 Hz, CHCH), 5.00 (2H, s, CH 2 ), 3.83 (3H, s, CH 3 ), 3.79 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 160.7, 157.9, 129.5, 121.2, 119.3, 108.0, 104.2, 98.6, 55.6, 55.5, 48.0; IR (film, cm -1 ): ν max = 1613, 1589, 1508; HRMS: m/z (ES) 240.1003, C 13 H 15 a 2 [M+a] + requires 240.1000. 3-(1H-Pyrrol-1-yl)propanenitrile C Based on a literature procedure, 4 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 ml, 1 mmol) was added to a solution of pyrrole (1.39 ml, 20 mmol) and acrylonitrile (1.7 ml, 26 mmol) in a round-bottom flask. The solution was stirred at room temperature for 20 hours before being diluted with Et 2 and washed with H 4 Cl. The organics were dried with MgS 4, filtered, and concentrated under reduced pressure, to yield the title compound (2.15 g, 90%) as a pale yellow oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 6.71 (2H, t, J = 2.0 Hz, CH), 6.20 (2H, t, J = 2.0 Hz, CHCH), 4.19 (2H, t, J = 6.8 Hz, CH 2 ), 2.76 (2H, t, J = 6.8 Hz, CH 2 C); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 120.5, 117.3, 109.7, 45.2, 21.0. S4
1,2-Dimethyl-1H-pyrrole Based on a literature procedure, 5 -methylpyrrole (0.90 ml, 10 mmol) and THF (10 ml) were added to a nitrogen purged three-neck round-bottom flask and cooled to 78 C. nbuli (2.5 M in hexanes, 4 ml, 10 mmol) was added dropwise and the solution was stirred overnight, allowing to warm slowly to room temperature. The solution was again cooled to 78 C and methyl iodide (0.62 ml, 10 mmol) in THF (10 ml) was added in one portion. The reaction was stirred at 78 C for four hours and was then allowed to warm slowly for three hours. The reaction was quenched by adding H 2 (20 ml) and was then extracted with Et 2. The organics were dried with MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by Kugelrohr distillation (bp 140 C), yielding the title compound (0.57 g, 60%) as a yellow oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 6.56 (1H, t, J = 2.0 Hz, CH), 6.05 (1H, t, J = 3.0 Hz, CHCH), 5.91-5.88 (1H, m, CHC), 3.54 (3H, s, CH 3 ), 2.24 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 129.0, 121.0, 106.6, 106.5, 33.7, 12.0. 1,2-Dimethyl-1H-indole Based on a literature procedure, 6 sodium hydride (60% dispersion in mineral oil, 0.44 g, 11 mmol) was added portionwise to a solution of 2-methylindole (1.31 g, 10 mmol) in anhydrous DMF (16 ml). The solution was stirred at room temperature for 30 minutes before cooling to 0 C, when methyl iodide (0.68 ml, 11 mmol) was added. The reaction was stirred at 0 C for 30 minutes before warming to room temperature and stirring overnight. The reaction was quenched by adding H 2 and was extracted with 1:1 hexane : Et 2. The organics were washed with H 2, dried over MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol : EtAc (95:5), R f = 0.60) yielding the title compound (0.84 g, 58%) as a peach coloured solid. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.54 (1H, d, J = 7.6 Hz, ArH), 7.27 (1H, d, J = 7.6 Hz, ArH), 7.17 (1H, td, J = 7.0, 1.3 Hz, ArH), 7.08 (1H, td, J = 7.8, 1.3 Hz, ArH), 6.27 (1H, t, J = 0.9 Hz, CHC(CH 3 )), 3.68 (3H, s, CH 3 ), 2.44 (3H, d, J = 0.9 Hz, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 137.5, 136.9, 128.1, 120.6, 119.7, 119.4, 108.8, 99.7, 29.5, 12.9. S5
5-Methoxy-1-methyl-1H-indole Based on a literature procedure, 6 sodium hydride (60% dispersion in mineral oil, 0.29 g, 7.1 mmol) was added portionwise to a solution of 5-methoxyindole (0.7 g, 4.8 mmol) in anhydrous DMF (9.6 ml). The solution was stirred at room temperature for 30 minutes before cooling to 0 C, when methyl iodide (0.33 ml, 5.3 mmol) was added. The reaction was stirred at 0 C for 30 minutes before warming to room temperature and stirring overnight. The reaction was quenched by adding H 2 and was extracted with 1:1 hexane : Et 2. The organics were washed with H 2, dried over MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol : EtAc (90:10), R f = 0.65), yielding the title compound (0.59 g, 76%) as a white crystalline solid. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.22 (1H, d, J = 8.8 Hz, ArH), 7.11 (1H, d, J = 2.3 Hz, ArH), 7.03 (1H, d, J = 3.0 Hz, CH), 6.90 (1H, dd, J = 8.8, 2.4 Hz, ArH), 6.41 (1H, dd, J = 3.0, 0.8 Hz, CHCH), 3.87 (3H, s, CH 3 ), 3.78 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 154.1, 132.2, 129.3, 128.9, 111.9, 110.0, 102.6, 100.4, 55.9, 32.9; IR (film, cm -1 ): ν max = 1607, 1577, 1494, 1419; HRMS: m/z (ES) 162.0906, C 10 H 12 [M+H] + requires 162.0919. S6
rganocatalytic Acylation - General Procedure To a nitrogen purged Radleys carousel tube (150 24 mm fitted with gas-tight threaded PTFE caps with a suba-seal, sidearm and inlet valve) was added the appropriate -protected pyrrole or indole (1 mmol), toluene (0.11 ml, 1 mmol), 1,5-diazabicyclo[4.3.0]non-5-ene (DB) (0.018 ml, 0.15 mmol), and the acyl chloride (1.2 mmol). The sealed carousel tube was then heated at 115 C for four hours, before cooling to room temperature. The resulting mixture was diluted with CH 2 Cl 2 and washed with 1M HCl followed by 1M ah, before being dried with MgS 4, filtered, and concentrated under reduced pressure. The crude product was purified by either column chromatography or recrystallization. Conversions were obtained from the crude 1 H MR spectra using an internal standard of 2,5-dimethylfuran. rganocatalytic Acylation Compound Data (1-Methyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 2, entry 1) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (90:10), R f = 0.69), yielding the title compound (0.14 g, 73%) as a colourless oil with spectroscopic data in accordance to the literature. 7 1 H MR (300 MHz; CDCl 3 ): δ H = 7.82-7.79 (2H, m, ArH), 7.56-7.42 (3H, m, ArH), 6.92 (1H, app. t, J = 2.0 Hz, CH), 6.74 (1H, dd, J = 4.1, 1.7 Hz, CCH), 6.16 (1H, dd, J = 4.1, 2.5 Hz, CHCH), 4.04 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.3, 140.0, 131.6, 131.5, 130.6, 129.3, 128.2, 123.0, 108.2, 37.5; IR (film, cm -1 ): ν max = 1622 (C=); HRMS: m/z (ES) 186.0899, C 12 H 12 [M+H] + requires 186.0919. (1-Methyl-1H-pyrrol-2-yl)(4-nitrophenyl)methanone (Table 2, entry 2) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and 4-nitrobenzoyl chloride (0.22 g, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : EtAc (90:10), R f = 0.20), yielding the title compound (0.17 g, 74%) as yellow crystals with spectroscopic S7
data in accordance with the literature. 8 mp: 151-153 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 8.31 (2H, d, J = 8.7 Hz, ArH), 7.92 (2H, d, J = 9.0 Hz, ArH), 6.99 (1H, app. t, J = 1.8 Hz, CH), 6.68 (1H, dd, J = 4.2, 1.6 Hz, CCH), 6.19 (1H, dd, J = 4.2, 2.5 Hz, CHCH), 4.06 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 183.8, 149.4, 145.5, 132.9, 130.0, 123.8, 123.5, 109.0, 37.7; IR (film, cm -1 ): ν max = 1623 (C=); HRMS: m/z (ES) 231.0744, C 12 H 11 2 3 [M+H] + requires 231.0770. (4-Methoxyphenyl)(1-methyl-1H-pyrrol-2-yl)methanone (Table 2, entry 3) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and 4-methoxybenzoyl chloride (0.16 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (90:10), R f = 0.09), yielding the title compound (0.14 g, 66%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.86-7.81 (2H, m, ArH), 6.97-6.92 (2H, m, ArH), 6.89 (1H, app. t, J = 2.0 Hz, CH), 6.72 (1H, dd, J = 4.0, 1.7 Hz, CCH), 6.15 (1H, dd, J = 4.0, 2.5 Hz, CHCH), 4.01 (3H, s, CH 3 ), 3.87 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 185.3, 162.6, 132.6, 131.6, 130.8, 122.0, 113.4, 108.0, 55.5, 37.3; IR (film, cm -1 ): ν max = 1623 (C=); HRMS: m/z (ES) 216.1004, C 13 H 14 2 [M+H] + requires 216.1025. (1-Methyl-1H-pyrrol-2-yl)(m-tolyl)methanone (Table 2, entry 4) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and m-toluoyl chloride (0.16 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (90:10), R f = 0.25), yielding the title compound (0.12 g, 58%) as a yellow oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.62-7.56 (2H, m, ArH), 7.36-7.30 (2H, m, ArH), 6.91 (1H, app. t, J = 2.0 Hz, CH), 6.74 (1H, dd, J = 4.0, 1.7 Hz, CCH), 6.16 (1H, dd, J = 4.0, 2.5 Hz, CHCH), 4.04 (3H, s, CH 3 ), 2.42 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.5, 140.1, 137.9, 132.2, 131.5, 130.8, 129.8, 128.0, S8
126.5, 122.9, 108.1, 37.5, 21.5; IR (film, cm -1 ): ν max = 1623 (C=); HRMS: m/z (ES) 200.1068, C 13 H 14 [M+H] + requires 200.1075. (1-Methyl-1H-pyrrol-2-yl)(o-tolyl)methanone (Table 2, entry 5) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and o-toluoyl chloride (0.16 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (95:5), R f = 0.19), yielding the title compound (0.13 g, 63%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.30-7.21 (2H, m, ArH), 7.17-7.09 (2H, m, ArH), 6.80 (1H, app. t, J = 2.0 Hz, CH), 6.39 (1H, dd, J = 4.1, 1.8 Hz, CCH), 6.00 (1H, dd, J = 4.1, 2.6 Hz, CHCH), 3.99 (3H, s, CH 3 ), 2.28 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 188.3, 140.3, 136.2, 131.9, 131.5, 130.8, 129.5, 128.2, 124.9, 123.7, 108.3, 37.6, 19.7; IR (film, cm -1 ): ν max = 1619 (C=); HRMS: m/z (ES) 200.1072, C 13 H 14 [M+H] + requires 200.1075. (4-Bromophenyl)(1-methyl-1H-pyrrol-2-yl)methanone (Table 2, entry 6) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and 4-bromobenzoyl chloride (0.22 g, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (95:5), R f = 0.24), yielding the title compound (0.18 g, 70%) as a white solid. mp: 72-73 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 7.67 (2H, dt, J = 8.6, 2.0 Hz, ArH), 7.58 (2H, dt, J = 8.6, 2.0 Hz, ArH), 6.93 (1H, app. t, J = 2.0 Hz, CH), 6.70 (1H, dd, J = 4.1, 1.7 Hz, CCH), 6.16 (1H, dd, J = 4.2, 2.5 Hz, CHCH), 4.02 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 184.9, 138.8, 131.9, 131.4, 130.8, 130.3, 126.2, 122.9, 108.4, 37.5; IR (film, cm -1 ): ν max = 1624 (C=); HRMS: m/z (ES) 264.0027, C 12 H 11 Br [M+H] + requires 264.0024. S9
2,2-Dichloro-1-(1-methyl-1H-pyrrol-2-yl)ethanone (Table 2, entry 7) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and dichloroacetyl chloride (0.12 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. o purification was required and the title compound (0.15 g, 80%) was obtained as a yellow solid with spectroscopic data in accordance with the literature. 9 mp: 65-66 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 7.14 (1H, dd, J = 4.3, 1.5 Hz, CCH), 6.98 (1H, app. t, J = 1.7 Hz, CH), 6.58 (1H, s, CHCl 2 ), 6.23 (1H, dd, J = 4.3, 2.4 Hz, CHCH), 3.98 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 176.7, 134.0, 125.3, 121.3, 109.4, 68.1, 38.0; IR (film, cm -1 ): ν max = 1654 (C=); HRMS: m/z (ES) 191.9969, C 7 H 8 Cl 2 [M+H] + requires 191.9983. 1-(1-Methyl-1H-pyrrol-2-yl)-3-phenylpropan-1-one (Table 2, entry 8) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and hydrocinnamoyl chloride (0.18 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (90:10), R f = 0.24), yielding the title compound (0.15 g, 70%) as a yellow oil with spectroscopic data in accordance with the literature. 10 1 H MR (300 MHz; CDCl 3 ): δ H = 7.25-7.08 (5H, m, ArH), 6.86 (1H, dd, J = 4.1, 1.7 Hz, CCH), 6.71 (1H, app. t, J = 1.9 Hz, CH), 6.02 (1H, dd, J = 4.1, 2.5 Hz, CHCH), 3.86 (3H, s, CH 3 ), 3.05-3.00 (2H, m, CH 2 Ph), 2.96-2.90 (2H, m, CH 2 CH 2 Ph); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 190.3, 141.6, 131.1, 130.7, 128.6, 128.5, 126.1, 119.1, 108.0, 40.8, 37.8, 31.0; IR (film, cm -1 ): ν max = 1643 (C=); HRMS: m/z (ES) 214.1217, C 14 H 16 [M+H] + requires 214.1232. 1-(1-Methyl-1H-pyrrol-2-yl)heptan-1-one (Table 2, entry 9) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and heptanoyl chloride (0.19 ml, 1.2 mmol) were heated at 115 C for four hours according to the general S10
procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (90:10), R f = 0.38), yielding the title compound (0.16 g, 82%) as a yellow oil with spectroscopic data in accordance with the literature. 11 1 H MR (300 MHz; CDCl 3 ): δ H = 6.95 (1H, dd, J = 4.1, 1.7 Hz, CCH), 6.78 (1H, app. t, J = 2.0 Hz, CH), 6.11 (1H, dd, J = 4.1, 2.5 Hz, CHCH), 3.94 (3H, s, CH 3 ), 2.75 (2H, t, J = 7.5 Hz, CCH 2 ), 1.69 (2H, app. p, J = 7.5 Hz, CCH 2 CH 2 ), 1.38-1.26 (6H, m, (CH 2 ) 3 CH 3 ), 0.89 (3H, t, J = 6.8 Hz, CH 2 CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 191.9, 130.9, 119.0, 107.9, 39.3, 37.8, 31.8, 29.3, 25.4, 22.7, 14.2; IR (film, cm -1 ): ν max = 1646 (C=); HRMS: m/z (ES) 216.1363, C 12 H 19 a [M+a] + requires 216.1364. 2,2-Dimethyl-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (Table 2, entry 10) -Methylpyrrole (0.09 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and trimethylacetyl chloride (0.15 ml, 1.2 mmol) were heated at 115 C for six hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (90:10), R f = 0.36), yielding the title compound (0.08 g, 49%) as a colourless oil with spectroscopic data in accordance with the literature. 12 1 H MR (300 MHz; CDCl 3 ): δ H = 7.03 (1H, dd, J = 4.2, 1.6 Hz, CCH), 6.74 (1H, t, J = 2.0 Hz, CH), 6.11 (1H, dd, J = 4.2, 2.5 Hz, CHCH), 3.90 (3H, s, CH 3 ), 1.36 (9H, s, C(CH 3 ) 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 198.0, 129.9, 128.7, 118.8, 107.2, 43.9, 38.7, 29.0; IR (film, cm -1 ): ν max = 1636 (C=); HRMS: m/z (ES) 166.1225, C 10 H 16 [M+H] + requires 166.1232. (1-Benzyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 1) -Benzylpyrrole (0.15 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (hexane : Et 2 (95:5), R f = 0.20), yielding the title compound (0.15 g, 56%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.70-7.66 (2H, m, ArH), 7.44-7.29 (3H, m, ArH), 7.23-7.08 (5H, m, ArH), 6.91 (1H, dd, J = 2.5, 1.8 Hz, CH), 6.68 (1H, dd, J = 4.1, 1.7 Hz, CCH), 6.11 (1H, dd, J = 4.1, 2.5 Hz, CHCH), 5.57 (2H, s, CH 2 Ph); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.3, 140.0, 138.4, 131.5, 131.0, 130.3, 129.3, S11
128.7, 128.1, 127.6, 127.3, 123.6, 108.8, 52.5; IR (film, cm -1 ): ν max = 1616 (C=); HRMS: m/z (ES) 262.1227, C 18 H 16 [M+H] + requires 262.1231. (1-(4-Methoxybenzyl)-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 2) 1-(4-Methoxybenzyl)-1H-pyrrole (0.19 g, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (95:5), R f = 0.27), yielding the title compound (0.23 g, 79%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.80-7.77 (2H, m, ArH), 7.55-7.40 (3H, m, ArH), 7.18 (2H, d, J = 8.7 Hz, ArH), 7.01 (1H, app. t, J = 2.0 Hz, CH), 6.85 (2H, d, J = 8.7 Hz, ArH), 6.76 (1H, dd, J = 4.0, 1.7 Hz, CCH), 6.19 (1H, dd, J = 4.0, 2.6 Hz, CHCH), 5.60 (2H, s, CH 2 Ar), 3.78 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.3, 159.2, 140.1, 131.5, 130.7, 130.4, 130.2, 129.4, 129.0, 128.1, 123.7, 114.2, 108.7, 55.4, 52.0; IR (film, cm -1 ): ν max = 1624 (C=); HRMS: m/z (ES) 292.1323, C 19 H 18 2 [M+H] + requires 292.1338. (1-(2,4-Dimethoxybenzyl)-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 3) 1-(2,4-Dimethoxybenzyl)-1H-pyrrole (0.12 g, 0.5 mmol), toluene (0.05 ml, 0.5 mmol), DB (0.009 ml, 0.075 mmol), and benzoyl chloride (0.08 ml, 0.7 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (90:10), R f = 0.32), yielding the title compound (0.10 g, 62%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.81-7.78 (2H, m, ArH), 7.55-7.40 (3H, m, ArH), 7.04-7.01 (2H, m, ArH, CH), 6.72 (1H, dd, J = 4.0, 1.7 Hz, CCH), 6.46 (1H, d, J = 2.4 Hz, ArH), 6.40 (1H, dd, J = 8.3, 2.4 Hz, ArH), 6.14 (1H, dd, J = 4.0, 2.5 Hz, CHCH), 5.62 (2H, s, CH 2 Ar), 3.82 (3H, s, CH 3 ), 3.78 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.4, 160.7, 158.3, 140.3, 133.9, 131.4, 131.3, 130.3, 130.1, 129.4, 128.6, 128.1, 123.5, 119.3, 108.2, 104.2, 98.5, 55.5, 55.4, 47.1; IR (film, cm -1 ): ν max = 1691 (C=); HRMS: m/z (ES) 322.1434, C 20 H 20 3 [M+H] + requires 322.1443. S12
3-(2-Benzoyl-1H-pyrrol-1-yl)propanenitrile (Table 3, entry 4) Ph C 3-(1H-Pyrrol-1-yl)propanenitrile (0.12 g, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (80:20), R f = 0.32), yielding the title compound (0.16 g, 73%) as a colourless solid. mp: 88-89 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 7.80-7.76 (2H, m, ArH), 7.59-7.44 (3H, m ArH), 7.11 (1H, dd, J = 2.4, 1.8 Hz, CH), 6.84 (1H, dd, J = 4.1, 1.7 Hz, CCH), 6.25 (1H, dd, J = 4.1, 2.6 Hz, CHCH), 4.62 (2H, t, J = 6.3 Hz, CH 2 ), 3.03 (2H, t, J = 6.3 Hz, CH 2 C); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.4, 139.6, 131.8, 131.6, 129.7, 129.3, 128.3, 124.5, 117.7, 109.5, 45.7, 20.6; IR (film, cm -1 ): ν max = 2253 (C), 1608 (C=); HRMS: m/z (ES) 225.1030, C 14 H 13 2 [M+H] + requires 225.1028. (1,5-Dimethyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 5) 1,2-Dimethyl-1H-pyrrole (0.10 g, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (90:10), R f = 0.42), yielding the title compound (0.13 g, 63%) as a pale yellow oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.80-7.76 (2H, m, ArH), 7.53-7.40 (3H, m, ArH), 6.65 (1H, d, J = 4.0 Hz, C(CH 3 )CHCH), 5.96 (1H, dd, J = 4.0, 0.6 Hz), 3.94 (3H, s, CH 3 ), 2.30 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 185.6, 140.6, 139.6, 131.1, 130.6, 129.2, 128.0, 123.4, 108.4, 33.0, 12.7; IR (film, cm -1 ): ν max = 1615 (C=); HRMS: m/z (ES) 200.1072, C 13 H 14 [M+H] + requires 200.1075. S13
(1-Methyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 6) Ph 1-Methyl-1H-indole (0.12 ml, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (dichloromethane (neat), R f = 0.21), yielding the title compound (0.13 g, 54%) as a colourless oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 8.46-8.41 (1H, m, Ph-H), 7.82 (2H, app. dt, J = 6.5, 1.7 Hz, indole- H 2 ), 7.56-7.45 (4H, m, indole-h 2, Ph-H, CH), 7.39-7.33 (3H, m, Ph-H 3 ), 3.85 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 190.9, 141.0, 138.0, 137.7, 131.2, 128.8, 128.4, 127.3, 123.8, 122.9, 122.8, 115.7, 109.7, 33.6; IR (film, cm -1 ): ν max = 1611 (C=); HRMS: m/z (ES) 236.1073, C 16 H 14 [M+H] + requires 236.1075. (1,2-Dimethyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 7) Ph 1,2-Dimethyl-1H-indole (0.15 g, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (80:20), R f = 0.35), yielding the title compound (0.22 g, 88%) as a peach coloured solid. mp: 139-141 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 7.76 (2H, dt, J = 6.9, 1.6 Hz, ArH), 7.55 (1H, tt, J = 7.3, 1.4 Hz, ArH), 7.48-7.42 (2H, m, ArH), 7.34-7.30 (2H, m, ArH), 7.22 (1H, td, J = 7.2, 1.2 Hz, ArH), 7.07 (1H, td, J = 7.2, 1.0 Hz, ArH), 3.74 (3H, s, CH 3 ), 2.59 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 193.0, 144.8, 141.6, 136.7, 131.6, 129.2, 128.4, 127.2, 122.2, 121.5, 121.1, 113.8, 109.3, 29.8, 12.7; IR (film, cm -1 ): ν max = 1608 (C=); HRMS: m/z (ES) 250.1240, C 17 H 16 [M+H] + requires 250.1232. S14
(5-Methoxy-1-methyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 8) 5-Methoxy-1-methyl-1H-indole (0.16 g, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (80:20), R f = 0.26), yielding the title compound (0.10 g, 40%) as a pale yellow oil. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.88 (1H, d, J = 2.4 Hz, ArH), 7.70 (2H, dt, J = 6.5, 1.5 Hz, ArH), 7.46-7.35 (4H, m, ArH, CH), 7.14 (1H, d, J = 8.9 Hz, ArH), 6.88 (1H, dd, J = 8.9, 2.5 Hz, ArH), 3.82 (3H, s, CH 3 ), 3.68 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 191.0, 156.7, 141.1, 138.1, 132.6, 131.1, 128.7, 128.4, 128.1, 115.3, 114.3, 110.6, 104.0, 55.9, 33.8; IR (film, cm -1 ): ν max = 1612 (C=); HRMS: m/z (ES) 266.1192, C 17 H 16 2 [M+H] + requires 266.1181. Tolmetin Synthesis 2-(1-Methyl-1H-pyrrol-2-yl)-2-oxoacetic acid Based on a literature procedure, 13 oxalyl chloride (4.30 ml, 50 mmol) and CH 2 Cl 2 (20 ml) were added to a three-neck round-bottom flask and cooled to -10 C under a nitrogen atmosphere. - Methylpyrrole (4.44 ml, 50 mmol) in CH 2 Cl 2 (40 ml) was added dropwise via a dropping funnel, maintaining the temperature below 0 C. The resulting solution was stirred at 0 C for one hour before sufficient 20% KH(aq) was added to make the solution ph 10. The solution was stirred for 30 minutes and then diluted with H 2. The two layers were separated and the aqueous layer extracted with CH 2 Cl 2. To the combined organic layers was added 20% H 2 S 4 (aq) until a white precipitate formed and the solution was stirred for 30 minutes. The solid was filtered, washing with cold H 2, before being dried under reduced pressure to yield the title compound (5.28 g, 69%) as a pale yellow solid. mp: 140-141 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 8.05 (1H, dd, J = 4.4, 1.6 Hz, CCH), 7.10 (1H, app. t, J = 1.8 Hz, CH), 6.28 (1H, dd, J = 4.4, 2.4 Hz, CHCH), 3.99 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 170.5, 160.5, 136.7, 128.9, 126.7, 111.1, 38.3; IR (film, cm -1 ): ν max = 2739 (-H), 1718 (C=); HRMS: m/z (ES) 154.0503, C 7 H 8 3 [M+H] + requires 154.0504. S15
2-(1-Methyl-1H-pyrrol-2-yl)acetic acid Based on a literature procedure, 13 2-(1-methyl-1H-pyrrol-2-yl)-2-oxoacetic acid (3.08 g, 20 mmol), hydrazine monohydrate (2.00 ml, 40 mmol), and 20% KH(aq) (40 ml) were added to a two-neck round-bottom flask fitted with a reflux condenser under a nitrogen atmosphere. The resulting solution was refluxed at 100 C for eight hours. After cooling to room temperature, 2M HCl was added to make the solution ph 2. The mixture was extracted with CH 2 Cl 2 and the organics were washed with H 2, before drying with MgS 4 and filtering. The solvent was removed under reduced pressure and the crude recrystallized from Et 2 and petrol to yield the title compound (1.88 g, 68%) as a yellow solid. mp: 107-108 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 6.61 (1H, app. t, J = 2.3 Hz, CH), 6.10-6.06 (2H, m, CHCH, CCH), 3.67 (2H, s, CH 2 C 2 H), 3.59 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 176.9, 124.1, 122.9, 109.3, 107.3, 34.0, 32.4; IR (film, cm -1 ): ν max = 2919 (-H), 1688 (C=); HRMS: m/z (ES) 140.0712, C 7 H 10 2 [M+H] + requires 140.0712. Methyl 2-(1-methyl-1H-pyrrol-2-yl)acetate (11) 2-(1-Methyl-1H-pyrrol-2-yl)acetic acid (1.14 g, 8 mmol) and p-toluenesulfonic acid (0.47 g, 2 mmol) were added to a two-neck round-bottom flask fitted with a reflux condenser under a nitrogen atmosphere. MeH (20 ml) was added and the reaction refluxed at 70 C for eight hours. After cooling to room temperature, the methanol was removed under reduced pressure and the crude was diluted with CH 2 Cl 2 before being washed with brine. The organics were dried with MgS 4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (petrol : EtAc (90:10), R f = 0.38), yielding the title compound 11 (0.98 g, 80%) as a colourless oil with spectroscopic data in accordance with the literature. 13 1 H MR (300 MHz; CDCl 3 ): δ H = 6.60 (1H, app. t, J = 2.1 Hz, CH), 6.09-6.04 (2H, m, CCH, CHCH), 3.71 (3H, s, CH 3 ), 3.64 (2H, s, CH 2 C 2 Me), 3.58 (3H, s, CH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 171.1, 124.9, 122.7, 108.9, 107.1, 52.2, 34.0, 32.6; IR (film, cm -1 ): ν max = 1733 (C=); HRMS: m/z (ES) 154.0862, C 8 H 12 2 [M+H] + requires 154.0868. S16
Methyl 2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetate (12) Methyl 2-(1-methyl-1H-pyrrol-2-yl)acetate (11) (0.46 g, 3 mmol), toluene (0.33 ml, 3 mmol), DB (0.054 ml, 0.45 mmol), and p-toluoyl chloride (0.48 ml, 3.6 mmol) were heated at 115 C for four hours according to the general procedure. The crude product was purified by flash column chromatography (petrol : EtAc (80:20), R f = 0.38) yielding the title compound (12) (0.54 g, 66%) as a pale yellow solid with spectroscopic data in accordance with the literature. 13 mp: 116-117 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 7.63 (2H, d, J = 8.1 Hz, ArH), 7.16 (2H, d, J = 7.9 Hz, ArH), 6.59 (1H, d, J = 4.0 Hz, CHCC), 6.02 (1H, d, J = 4.0 Hz, CHCCH 2 ), 3.86 (3H, s, CH 3 ), 3.66 (3H, s, CH 3 ), 3.64 (2H, s, CH 2 C 2 Me), 2.34 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.0, 169.9, 142.0, 137.4, 134.5, 131.6, 130.3, 129.5, 129.3, 128.8, 122.4, 109.6, 52.6, 33.3, 32.8,, 21.6; IR (film, cm -1 ): ν max = 1722 (C=), 1622 (C=); HRMS: m/z (ES) 272.1277, C 16 H 18 3 [M+H] + requires 272.1287. 2-(1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetic acid, Tolmetin (13) Methyl 2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetate (12) (0.40 g, 1.5 mmol), H 2 (4.2 ml), and 2.5 M ah(aq) (0.72 ml, 1.8 mmol) were added to a round-bottom flask and stirred at room temperature for 48 hours, until all the solid had dissolved. The solution was acidified with 2M HCl until a precipitate was formed. The mixture was diluted with CH 2 Cl 2 and the layers were separated, washing the organics with brine, before drying with MgS 4, filtering, and concentrating under reduced pressure. The crude was purified by stirring with Et 2 and filtering, yielding the title compound (13) (0.30 g, 78%) as a white solid with spectroscopic data in accordance with the literature. 13 mp: 156-157 C; 1 H MR (300 MHz; CDCl 3 ): δ H = 7.70 (2H, d, J = 7.9 Hz, ArH), 7.23 (2H, d, J = 7.9 Hz, ArH), 6.67 (1H, d, J = 3.8 Hz, CHCC), 6.12 (1H, d, J = 3.7 Hz, CHCCH 2 ), 3.93 (3H, s, CH 3 ), 3.75 (2H, s, CH 2 C 2 H), 2.41 (3H, s, CCH 3 ); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 186.3, 175.1, 142.2, 137.2, 133.9, 131.7, 129.6, 128.9, 122.6, 109.9, 33.4, 32.7, 21.7; IR (film, cm -1 ): ν max = 3199 (-H), 1731 (C=), 1698 (C=); HRMS: m/z (ES) 258.1126, C 15 H 16 3 [M+H] + requires 258.1130. S17
(1-methyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 2, entry 1) 7.79 7.82 7.56 7.42 6.73 6.73 6.74 6.75 6.92 6.92 6.93 7.26 6.15 6.16 6.16 6.17 4.04 Ph 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm 2.04 3.15 1.00 1.00 1.00 3.08 S18
(1-methyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 2, entry 1) 186.35 123.03 128.16 129.30 130.62 131.51 131.62 140.03 108.22 76.74 77.16 77.58 37.52 Ph 75 MHz, CDCl 3 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm S19
(1-methyl-1H-pyrrol-2-yl)(4-nitrophenyl)methanone (Table 2, entry 2) 8.29 8.32 7.90 7.93 7.26 6.99 6.67 6.68 6.69 6.69 6.18 6.19 6.20 6.21 4.06 2 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm 2.08 2.08 1.00 1.00 1.03 3.06 S20
(1-methyl-1H-pyrrol-2-yl)(4-nitrophenyl)methanone (Table 2, entry 2) 2 183.83 149.44 145.53 132.90 129.96 123.80 123.47 109.00 77.16 37.68 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 ppm S21
(4-methoxyphenyl)(1-methyl-1H-pyrrol-2-yl)methanone (Table 2, entry 3) 7.81 7.86 6.14 6.15 6.15 6.16 6.71 6.72 6.73 6.73 6.88 6.89 6.90 6.92 6.97 7.26 3.87 4.01 Me 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm 2.03 1.01 2.07 1.01 1.00 3.03 3.14 S22
(4-methoxyphenyl)(1-methyl-1H-pyrrol-2-yl)methanone (Table 2, entry 3) 185.26 162.57 130.78 131.00 131.57 132.59 122.00 113.43 107.98 77.16 55.52 37.25 Me 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 ppm S23
(1-methyl-1H-pyrrol-2-yl)(m-tolyl)methanone (Table 2, entry 4) 6.14 6.15 6.16 6.17 6.73 6.73 6.74 6.75 6.91 6.91 6.92 7.26 7.30 7.36 7.56 7.62 4.04 2.42 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 2.02 2.07 1.00 1.01 1.00 3.05 3.07 S24
(1-methyl-1H-pyrrol-2-yl)(m-tolyl)methanone (Table 2, entry 4) 186.54 122.88 126.54 127.98 129.80 130.76 131.47 132.24 137.93 140.08 108.14 77.16 37.45 21.50 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S25
(1-methyl-1H-pyrrol-2-yl)(o-tolyl)methanone (Table 2, entry 5) 5.99 6.00 6.01 6.02 6.38 6.38 6.39 6.40 6.80 6.81 6.81 7.09 7.17 7.21 7.30 3.99 2.28 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 2.17 2.03 1.01 1.00 1.00 3.08 3.08 S26
(1-methyl-1H-pyrrol-2-yl)(o-tolyl)methanone (Table 2, entry 5) 188.30 123.65 124.93 128.15 129.54 130.75 131.50 131.93 136.16 140.27 108.32 77.16 37.62 19.72 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S27
(4-bromophenyl)(1-methyl-1H-pyrrol-2-yl)methanone (Table 2, entry 6) 7.57 7.60 7.66 7.69 7.26 6.69 6.70 6.70 6.71 6.92 6.93 6.93 6.15 6.15 6.16 6.17 4.02 Br 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm 2.01 2.02 1.02 1.00 1.00 3.08 S28
(4-bromophenyl)(1-methyl-1H-pyrrol-2-yl)methanone (Table 2, entry 6) Br 184.94 138.79 131.92 131.40 130.82 130.26 126.23 122.94 108.43 77.16 37.45 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 ppm S29
2,2-dichloro-1-(1-methyl-1H-pyrrol-2-yl)ethanone (Table 2, entry 7) 6.97 6.98 6.98 7.13 7.14 7.15 7.15 6.58 6.21 6.22 6.23 6.24 3.98 Cl Cl 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm 1.02 0.99 0.99 1.00 3.09 S30
2,2-dichloro-1-(1-methyl-1H-pyrrol-2-yl)ethanone (Table 2, entry 7) Cl Cl 176.73 134.02 125.27 121.35 109.42 77.16 68.07 38.02 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S31
1-(1-methyl-1H-pyrrol-2-yl)-3-phenylpropan-1-one (Table 2, entry 8) 6.70 6.71 6.71 6.85 6.85 6.86 6.87 7.08 7.25 6.01 6.02 6.02 6.03 3.86 2.90 2.96 3.00 3.05 Ph 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 5.55 1.00 1.05 1.00 3.09 2.12 2.13 S32
1-(1-methyl-1H-pyrrol-2-yl)-3-phenylpropan-1-one (Table 2, entry 8) 190.27 141.64 119.10 126.14 128.51 128.58 130.71 131.07 108.01 77.16 37.79 40.84 30.97 75 MHz, CDCl 3 Ph 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S33
1-(1-methyl-1H-pyrrol-2-yl)heptan-1-one (Table 2, entry 9) 6.10 6.11 6.11 6.12 6.78 6.78 6.79 6.94 6.94 6.95 6.96 7.26 3.94 2.73 2.75 2.78 0.86 0.89 0.91 1.26 1.38 1.64 1.66 1.69 1.71 1.74 5 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1.00 1.02 1.01 3.08 2.09 2.07 6.06 3.06 S34
1-(1-methyl-1H-pyrrol-2-yl)heptan-1-one (Table 2, entry 9) 5 191.93 130.87 118.98 107.85 77.16 39.31 37.81 31.84 29.30 25.42 22.68 14.20 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S35
2,2-dimethyl-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (Table 2, entry 10) 6.10 6.11 6.12 6.12 6.74 6.74 6.75 7.02 7.02 7.03 7.04 7.26 3.90 1.36 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1.04 1.01 1.00 3.09 9.05 S36
2,2-dimethyl-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (Table 2, entry 10) 197.97 129.89 128.70 118.77 107.21 77.16 43.85 38.67 29.00 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S37
(1-benzyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 1) 7.66 7.70 6.67 6.67 6.68 6.69 6.90 6.91 6.91 6.91 7.08 7.23 7.29 7.44 6.10 6.11 6.11 6.12 5.57 Ph Bn 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 ppm 1.97 3.09 5.22 1.01 1.00 0.98 2.01 S38
(1-benzyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 1) 186.26 108.76 123.62 127.30 127.59 128.08 128.73 129.33 130.25 130.97 131.50 138.37 140.03 77.16 52.49 Ph Bn 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S39
(1-(4-methoxybenzyl)-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 2) 6.18 6.19 6.20 6.20 6.75 6.76 6.77 6.77 6.84 6.86 7.00 7.01 7.01 7.16 7.19 7.26 7.40 7.55 7.77 7.80 5.60 3.78 Ph PMB 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 2.04 3.09 2.05 1.02 2.06 1.01 1.00 2.08 3.03 S40
(1-(4-methoxybenzyl)-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 2) 186.32 159.16 114.15 123.71 128.10 128.95 129.36 130.19 130.39 130.74 131.49 140.12 108.67 77.16 52.02 55.36 Ph PMB 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm S41
(1-(2,4-dimethoxybenzyl)-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 3) 5.62 6.13 6.14 6.14 6.15 6.38 6.39 6.41 6.42 6.46 6.46 6.71 6.72 6.72 6.73 7.02 7.04 7.26 7.40 7.55 7.78 7.81 3.78 3.82 Ph DMB 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 2.03 3.08 2.04 1.00 1.07 1.04 1.00 2.05 3.03 3.01 S42
(1-(2,4-dimethoxybenzyl)-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 3) 186.36 158.29 160.66 119.25 123.51 128.06 128.60 129.41 130.13 130.31 131.27 131.41 133.87 140.30 104.21 108.23 98.53 77.16 55.46 55.47 47.10 Ph DMB 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm S43
3-(2-benzoyl-1H-pyrrol-1-yl)propanenitrile (Table 3, entry 4) 6.24 6.25 6.26 6.27 6.83 6.83 6.84 6.85 7.11 7.11 7.11 7.12 7.26 7.44 7.59 7.76 7.80 4.60 4.62 4.64 3.01 3.03 3.05 Ph C 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 2.03 3.09 1.01 1.01 1.00 2.08 2.07 S44
3-(2-benzoyl-1H-pyrrol-1-yl)propanenitrile (Table 3, entry 4) 186.44 117.73 124.47 128.33 129.26 129.71 131.55 131.84 139.62 109.47 77.16 45.65 20.59 Ph C 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S45
(1,5-dimethyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 5) 7.26 7.40 7.53 7.76 7.80 6.64 6.66 5.96 5.96 5.97 5.97 3.94 2.30 Ph 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 2.04 3.15 1.00 1.00 3.03 3.09 S46
(1,5-dimethyl-1H-pyrrol-2-yl)(phenyl)methanone (Table 3, entry 5) 185.63 123.26 128.02 129.21 130.56 131.12 139.62 140.56 108.39 77.16 33.02 12.69 Ph 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S47
(1-methyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 6) 8.41 8.46 7.26 7.33 7.39 7.45 7.56 7.80 7.81 7.81 7.82 7.83 7.83 3.85 Ph 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 ppm 1.00 2.03 4.06 3.07 3.05 S48
(1-methyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 6) 190.94 109.73 115.70 122.80 122.83 123.75 127.31 128.37 128.76 131.16 137.66 138.00 141.04 77.16 33.64 Ph 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S49
(1,2-dimethyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 7) 10 9 8 7 6 5 4 3 ppm 2 7.04 7.05 7.07 7.07 7.09 7.10 7.19 7.19 7.21 7.22 7.24 7.24 7.26 7.30 7.34 7.42 7.48 7.52 7.53 7.53 7.54 7.55 7.56 7.57 7.57 7.58 7.74 7.75 7.76 7.77 7.77 7.78 3.74 2.59 Ph 300 MHz, CDCl 3 1.04 1.04 2.03 2.08 1.04 2.00 3.08 3.05 S50
(1,2-dimethyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 7) 193.01 144.83 141.61 136.69 131.55 129.17 128.35 127.21 122.16 121.54 121.11 113.76 109.25 77.16 29.81 12.65 Ph 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm S51
(5-methoxy-1-methyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 8) 6.86 6.87 6.89 6.90 7.12 7.15 7.35 7.46 7.68 7.69 7.70 7.71 7.71 7.71 7.88 7.89 3.68 3.82 Me Ph 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 ppm 1.00 2.05 4.07 1.04 1.01 3.03 3.08 S52
(5-methoxy-1-methyl-1H-indol-3-yl)(phenyl)methanone (Table 3, entry 8) 190.95 156.71 128.13 128.35 128.65 131.05 132.63 138.11 141.08 110.59 114.26 115.25 103.95 77.16 55.90 33.79 Me Ph 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm S53
2-(1-methyl-1H-pyrrol-2-yl)-2-oxoacetic acid 8.04 8.05 8.06 8.06 7.10 7.26 6.27 6.28 6.28 6.29 3.99 C 2 H 300 MHz, CDCl 3 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 1.01 1.01 1.00 3.08 S54
2-(1-methyl-1H-pyrrol-2-yl)-2-oxoacetic acid C 2 H 170.53 160.47 136.66 128.92 126.73 111.13 77.16 38.25 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm S55
2-(1-methyl-1H-pyrrol-2-yl)acetic acid 7.26 6.61 6.61 6.62 6.06 6.10 3.59 3.67 C 2 H 300 MHz, CDCl 3 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 ppm 1.01 2.00 3.03 2.05 S56
2-(1-methyl-1H-pyrrol-2-yl)acetic acid C 2 H 176.86 124.12 122.94 109.26 107.30 77.16 34.03 32.40 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm S57
methyl 2-(1-methyl-1H-pyrrol-2-yl)acetate (11) 7.26 6.60 6.60 6.61 6.04 6.09 3.58 3.64 3.71 C 2 Me 300 MHz, CDCl 3 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 1.00 2.03 3.01 2.04 3.03 S58
methyl 2-(1-methyl-1H-pyrrol-2-yl)acetate (11) C 2 Me 171.13 124.90 122.66 108.85 107.13 77.16 52.24 34.01 32.57 75 MHz, CDCl 3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm S59
methyl 2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetate (12) 7.62 7.64 7.15 7.17 6.59 6.60 6.02 6.03 3.64 3.66 3.86 2.34 C 2 Me 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 2.04 2.52 1.00 1.00 2.01 3.04 3.02 3.05 S60
methyl 2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetate (12) 186.02 169.93 122.36 128.79 129.28 129.54 130.30 131.56 134.49 137.42 142.01 109.55 77.16 52.55 32.83 33.28 21.63 75 MHz, CDCl 3 C 2 Me 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm S61
2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetic acid, Tolmetin (13) 7.68 7.71 7.22 7.24 7.26 6.66 6.67 6.11 6.12 3.93 3.75 2.41 C 2 H 300 MHz, CDCl 3 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 2.01 2.05 1.05 1.00 3.09 2.06 3.05 S62
2-(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl)acetic acid, Tolmetin (13) 186.26 175.05 122.58 128.85 129.62 131.66 133.94 137.23 142.20 109.87 77.16 32.69 33.39 21.68 75 MHz, CDCl 3 C 2 H 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm S63
Kinetic Experiments -Benzyl-D 4 -pyrrole Firstly, D 5 -pyrrole was synthesised in accordance to a literature procedure. 14 Pyrrole (2 ml, 29 mmol), acetic acid-d 1 (1.83 ml, 32 mmol), and D 2 (4 ml) were equilibrated at room temperature for eight hours in the absence of light. Anhydrous CH 2 Cl 2 was added and the solution neutralised with K 2 C 3. The layers were then separated and the organics dried over MgS 4, filtered, and the solvent was allowed to evaporate slowly. The procedure was then repeated. -Benzyl-D 4 -pyrrole was then synthesised based on the literature procedure used previously. 1 Sodium hydride (60% dispersion in mineral oil, 0.17 g, 4.13 mmol) was added to anhydrous DMF (3.75 ml) in a nitrogen purged two-neck round-bottom flask. The solution was cooled to 0 C before pyrrole-d 5 (0.27 g, 3.75 mmol) in anhydrous DMF (1 ml) was added dropwise. The solution was allowed to warm to room temperature and was stirred for 30 minutes before cooling back to 0 C and benzyl bromide (0.45 ml, 3.75 mmol) was added dropwise. The solution was again allowed to warm to room temperature and was stirred for one hour. The solution was then added to H 2 and extracted with 1:1 hexane : Et 2. The combined organic layers were washed with H 2 before drying over MgS 4, filtering, and concentrating under reduced pressure. The crude product was purified by flash column chromatography (petrol : ethyl acetate (95:5), R f = 0.65) yielding the title compound (0.50 g, 83%) as a colourless oil with 85% deuterium incorporation, as determined by analysis of the 1 H MR spectra. 1 H MR (300 MHz; CDCl 3 ): δ H = 7.40-7.29 (3H, m, ArH), 7.15-7.12 (2H, m, ArH), 5.09 (2H, s, CH 2 Ph); 13 C{ 1 H} MR (75 MHz, CDCl 3 ): δ C = 138.3, 128.8, 127.8, 127.1, 53.4. -Benzyl-D 4 -pyrrole (0.16 g, 1 mmol), toluene (0.11 ml, 1 mmol), DB (0.018 ml, 0.15 mmol), and benzoyl chloride (0.14 ml, 1.2 mmol) were heated at 115 C according to the general procedure. Aliquots of 0.01 ml were taken every hour up to 6 hours and analysed using 1 H MR. The procedure was then repeated with -benzylpyrrole (0.16 g, 1 mmol). Comparison of the data showed essentially no difference in the rate of acylation between the deuterated and non-deuterated pyrroles, suggesting that re-aromatisation is not the rate determining step. S64
90 80 70 60 Conversion / % 50 40 30 20 10 0 0 50 100 150 200 250 300 350 400 t / m Benzylpyrrole Benzyl D4 pyrrole The kinetic experiment was again repeated for -benzylpyrrole, taking aliquots at shorter time intervals to investigate whether there is a change in mechanism during the reaction. The smooth curve obtained suggests that a single mechanism operates throughout the reaction. 90 80 70 60 Conversion / % 50 40 30 20 10 0 0 50 100 150 200 250 300 350 400 t / m S65
Acyl-DB Intermediate Analysis Benzoyl chloride (1) Cl 1 H MR (500 MHz; CDCl 3 ): δ H = 8.13 (2H, dd, J = 8.4, 1.2 Hz, o-arh), 7.69 (1H, tt, J = 7.4, 1.2 Hz, p-arh), 7.52 (2H, dd, J = 8.3, 7.6 Hz, m-arh); 13 C{ 1 H} MR (125 MHz, CDCl 3 ): δ C = 168.6, 135.5, 133.4, 131.6, 129.1. IR (film, cm -1 ): ν max = 1770 (C=), 1730, 1595, 1582. 1,5-Diazabicyclo[4.3.0]non-5-ene (DB) 7 6 5 8 9 4 1 3 2 1 H MR (500 MHz; CDCl 3 ): δ H = 3.27 (2H, t, J = 5.5 Hz, H 2 ), 3.21 (2H, t, J = 6.8 Hz, H 6 ), 3.12 (2H, t, J = 6.0 Hz, H 4 ), 2.38 (2H, t, J = 7.8 Hz, H 8 ), 1.86 (2H, p, J = 7.3 Hz, H 7 ), 1.72 (2H, p, J = 5.8 Hz, H 3 ); 13 C{ 1 H} MR (125 MHz, CDCl 3 ): δ C = 160.7 (C 9 ), 51.5 (C 6 ), 44.1 (C 2 ), 43.2 (C 4 ), 31.5 (C 8 ), 20.9 (C 3 ), 19.7 (C 7 ). -Acyl-DB Cl Intermediate (8) 7 6 5 8 9 4 3 2 1 Cl Ph Benzoyl chloride (0.12 ml, 1 mmol) was added dropwise to a solution of DB (0.12 ml, 1 mmol) in CDCl 3. The solution turns yellow upon the addition of benzoyl chloride; after stirring at room temperature for two hours the colour had dissipated and complex 8 was formed in quantative yield, as shown by 1 H MR spectroscopy. The solution can be concentrated under reduced pressure to give a hygroscopic pale yellow powder. 1 H MR (500 MHz; CDCl 3 ): δ H = 7.88-7.86 (2H, m, o-arh), 7.50-7.45 (1H, m, p-arh), 7.39-7.36 (2H, m, m-arh), 3.96 (2H, t, J = 7.5 Hz, H 6 ), 3.92-3.89 (2H, m, H 2 ), 3.77-3.73 (2H, br. s, H 4 ), 3.39-3.33 (2H, m, H 8 ), 2.25-2.17 (2H, m, H 7 ), 2.15-2.10 (2H, m, H 3 ); 13 C{ 1 H} MR (125 MHz, CDCl 3 ): δ C = 170.9, 167.9, 133.5, 131.2, 129.6, 128.9, 55.4, 46.4, 44.6, 34.3, 19.7, 18.6; IR S66