General Experimental Details
`
Supporting Information
Total Synthesis of (±)-Marinopyrrole A via CopperMediated N-Arylation Argyrios Kanakis, and Vasiliki Sarli* Aristotle University of Thessaloniki, Department of Organic Chemistry, Faculty of Chemistry, University Campus, 54124 Thessaloniki, Greece [email protected]
Table of Contents
General Experimental……………………………………………………………...S3 Experimental Procedures……………………………………….…….…………...S3 General Procedures for the N-Arylation……………….…….…………………...S3 3-bromo-1-tosyl-1H-pyrrole (6a)...………………………………………........…...S3 1'H-1,3΄-bipyrrole (8)-Method A ……………………….……..…....………...…...S4 3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (6b) ….……………....…………...…...S4 1'H-1,3΄-bipyrrole (8)-Method B ……………………….……..…....………...…...S4 tert-Butyl 3-bromo-1H-pyrrole-1-carboxylate (6c) ………………………….........S5 1'H-1,3΄-bipyrrole (8)-Method C ……………………….……..…....………...…...S5 1-(Triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (6d) ..…....………………...…...S5 Methyl 3-bromo-1-tosyl-1H-pyrrole-2-carboxylate (10)……………….……........ S5 Coupling of 1H-pyrrole-2-carboxylate (9) with methyl 3-bromo-1-tosyl-1H-pyrrole2-carboxylate (10)………………...…………………..…................... .…………...S6 N-methoxy-N-methyl-1H-pyrrole-2-carboxamide.…………………………...…....S6 N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (12)………………........S6 (2-Methoxyphenyl)(1-tosyl-1H-pyrrol-2-yl)methanone (14) ………………..........S7 (2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4)-Method A..…………............S7 (2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4)-Method B..…………....…....S8 3-Bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide.............................…...S8 3-bromo-N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (13) ………....S9 (3-bromo-1-tosyl-1H-pyrrol-2-yl)(2-methoxyphenyl)methanone (5)………….......S9 S1
` (2-methoxyphenyl)(1'-tosyl-1'H-1,3'-bipyrrol-2-yl)methanone (16) ….................S10 1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17)-Method A....S11 1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17)-Method B….S11 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-methoxyphenyl) methanone) (18) ……………...…………………..…..……...…….…………………………..S12 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-hydroxyphenyl)methano-ne) (±1)……………………..………….………………… …………………..……. ..S12 NMR spectra……………………………………………………………...……..... S14 1'H-1,3’-bipyrrole (8) ………………………………….……….……...…...…….S14 N-methoxy-N-methyl-1H-pyrrole-2-carboxamide…………………………...…...S15 N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (12)………………......S16 (2-Methoxyphenyl)(1-tosyl-1H-pyrrol-2-yl)methanone (14) ……………............S17 (2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4)..…………............................S18 3-Bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide...........................…...S19 3-bromo-N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (13) ...……...S20 (3-bromo-1-tosyl-1H-pyrrol-2-yl)(2-methoxyphenyl)methanone (5) ……...….....S21 (2-methoxyphenyl)(1'-tosyl-1'H-1,3'-bipyrrol-2-yl)methanone (16) ….................S22 1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17)…….....….....S23 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-methoxyphenyl) methanone) (18) …………………...……..……...…………………………………….……....S24 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-hydroxyphenyl)methanone) (±1)………………………….…………………… ……………………….……. .S25 References…………………………………………………………………..……. .S27
S2
`
Supporting information General Experimental Details All reactions were carried out under an atmosphere of Ar unless otherwise specified. Commercial reagents of high purity were purchased and used without further purification, unless otherwise noted. Reactions were monitored by TLC carried out on 0.25 mm E. Merck silica gel plates (60 F254) and using UV light as a visualizing agent and aqueous ceric sulfate/ phosphomolybdic acid, ethanolic p-anisaldehyde solution, potassium permanganate solution, and heat as developing agents. E. Merck silica gel 60 (230-400 mesh) was used for flash column chromatography. The 1H-NMR spectra were recorded at 300 (Bruker 300 AM spectrometer) and 500 MHz (Bruker Avance DRX) with tetramethylsilane as internal standard. 13C-NMR spectra were recorded at 75 MHz, on a Bruker 300 AM spectrometer. IR spectra were recorded on a Perkin– Elmer Spectrum 100 FT-IR spectrometer. Melting points (Mp) are uncorrected. Highresolution mass spectra (HRMS) were recorded on an Agilent ESITOF (time of flight) mass spectrometer at a 4000 V emitter voltage. Microwave reactions were carried out in a Biotage Initiator microwave system 2.0 (400W, operating at 2.45 GHz).
Experimental Procedures General procedure for the N-arylation: To a microwave vial charged with a magnetic stirring bar were added CuI (2 mmol), Cs2CO3 (3 mmol), compound bromopyrrole (1 mmol), and pyrrole (1.5 mmol) in 2.5 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for the appropriate time and temperature using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (2 mL, 3N) was added and the mixture was stirred for 5 min. Then, the mixture was extracted with CH2Cl2 (2 x 10 mL) and EtOAc (2 x 10 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography to afford the desired bipyrroles. Br N Ts 6a
3-bromo-1-tosyl-1H-pyrrole (6a) was synthesized in 75 % yield as per method described in the literature. 1
S3
` 1'H-1,3'-bipyrrole (8). Method A: To a microwave vial charged with a magnetic stirring bar were added CuI (378 mg, 2 mmol), Cs2CO3 (975 mg, 3 mmol), compound 6a (300.4 mg, 1 mmol), and pyrrole (100 mg, 1.5 mmol) in 2.5 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (2 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 10 mL) and EtOAc (2 x 10 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford 113 mg (86%) of bipyrrole 8 as a red oil. 1H NMR (300 MHz, CDCl3): 6.25 (t, J = 2.1 Hz, 2H), 6.30 (m, 1H), 6.73 (dd, J = 2.9, 5.1 Hz, 1H), 6.83 (dd, J = 2.2, 4.3Hz, 1H), 6.92 (t, J = 2.1 Hz, 2H), 8.07 (br, 1H); 13C NMR (75 MHz, CDCl3): 102.5, 107.8, 108.7, 117.5, 120.2; FT-IR: 1021, 1069, 1337, 1587, 1702, 2851, 2924, 3129, 3383; HRMS (ESI-TOF) m/z for C8H8N2 [M+H]+ calcd 133.076, found 133.0759. Br N TIPS 6b
3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (6b) was synthesized as per method described in the literature. 2
1'H-1,3'-bipyrrole (8) Method B: To a microwave vial charged with a magnetic stirring bar were added CuI (151 mg, 0.79 mmol), Cs2CO3 (389 mg, 1.19 mmol), compound 6b (120 mg, 0.4 mmol), and pyrrole (40 mg, 0.59 mmol) in 1 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (1 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford 47 mg (90%) of bipyrrole 8 as a red oil. The spectral data of 8 have been described above.
S4
` Br N Boc 6c
tert-Butyl 3-bromo-1H-pyrrole-1-carboxylate (6c) was synthesized as per method described in the literature. 3
1'H-1,3'-bipyrrole (8) Method C: To a microwave vial charged with a magnetic stirring bar were added CuI (151 mg, 0.79 mmol), Cs2CO3 (389 mg, 1.19 mmol), compound 6b (98 mg, 0.4 mmol), and pyrrole (40 mg, 0.59 mmol) in 1 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (1 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford 44 mg (85%) of bipyrrole 8 as a red oil. The spectral data of 8 have been described above.
1-(Triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (6d): was synthesized as per method described in the literature.2 Br O N Ts 10
O
Methyl 3-bromo-1-tosyl-1H-pyrrole-2-carboxylate (10): was synthesized as per method described in the literature. 4
S5
`
Coupling of 1H-pyrrole-2-carboxylate (9) with methyl 3-bromo-1-tosyl-1Hpyrrole-2-carboxylate: To a microwave vial charged with a magnetic stirring bar were added CuI (166 mg, 0.872 mmol), Cs2CO3 (426 mg, 1.308 mmol), methyl 1Hpyrrole-2-carboxylate 9 (60 mg, 0.479 mmol) and bromo-derivative 10 (156 mg, 0.436 mmol) in 1.1 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 240 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (1 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford compounds 11 (19 mg, 0.087 mmol) and 8 (17 mg, 0.131 mmol) in 20 and 30% yield respectively.
O LiHMDS, THF N H
O 9
MeNHOMe.HCl
O N H
N O
N-methoxy-N-methyl-1H-pyrrole-2-carboxamide: A stirred suspension of N,Odimethylhydroxylamine hydrochloride (507 mg, 5.19 mmol) and ester 9 (500 mg, 4 mmol) in 40 ml dry THF at -78 °C was treated with a 1M solution of LiHMDS (19.98 mmol, 20 mL). After 30 minutes stirring at -78 °C the reaction was quenched with a saturated aqueous solution of NH4Cl and warmed to room temperature. The mixture was extracted with AcOEt (4 x 50 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (gradient elution, 5:1, 4:1, 3:1 Hexane/EtOAc) to give 592 mg (96%) of Weinreb amide as a yellow solid. Mp: 67-69 °C; 1H NMR (300 MHz, CDCl3): δ 3.35 (s, 3H), 3.78 (s, 3H), 6.28 (m, 1H), 6.90 (m, 1H), 6.95 (m, 1H), 9.49 (br, 1H); 13 C NMR (75 MHz, CDCl3): 33.0, 61.0, 110.5, 114.6, 121.6, 123.7, 161.4; FT-IR: 991, 1425, 1602, 2821, 2936, 2972, 3287; HRMS (ESI-TOF) m/z for C7H10N2O2 [M+H]+ calcd 155.0815, found 155.0821.
N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (12): To a stirred solution of N-methoxy-N-methyl-1H-pyrrole-2-carboxamide (350 mg, 2.27 mmol) in THF (30 mL), NaH (182 mg, 60% in oil, 4.54 mmol) was added under nitrogen at 0 S6
` °C. After 10min, tosyl chloride (1.30 g, 6.81 mmol) was added and the mixture was allowed to warm at room temperature. After 5 hours stirring the reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 50 mL). The combined extracts were dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (3:2 Hexane/EtOAc) to give 630 mg (90%) of compound 12 as a yellow oil. Mp: 76-78 °C; 1H NMR (300 MHz, CDCl3): δ 2.37 (s, 3H), 3.29 (s, 3H), 3.64 (s, 3H), 6.24 (t, J = 3.30Hz, 1H), 6.47 (m, 1H), 7.29 (d, 2H, and 1H, overlapped), 7.91 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.3, 33.9, 60.9, 111.4, 115.3, 123.5, 126.1, 126.8, 127.7, 129.2, 129.4, 135.6, 144.8, 161.6; FT-IR: 1148, 1169, 1364, 1653, 2936, 2978, 3135; HRMS (ESI-TOF) m/z for C14H16N2O4S [M+H]+ calcd 309.0903, found 309.0905. O Mg Br O N N Ts O 12
O Et2O/THF
N Ts 14
O
(2-Methoxyphenyl)(1-tosyl-1H-pyrrol-2-yl)methanone (14): A solution of 2methoxyphenylmagnesium bromide (11.35 mmol) [prepared from 4.24 g (22.7 mmol) of 2-bromoanisole and 662 mg, (27.24 mmol) of magnesium turnings] in ether (15 mL) was added to a stirred solution of 12 (700 mg, 2.27 mmol) in 5 mL THF at -15 °C. The mixture was allowed to warm at room temperature and stirred for 30 min, and then another portion of Grignard reactant (11.35 mmol, in 15 mL ether) was added. After 30 min the reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 50 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (5:1 Hexane/EtOAc) to give 516 mg (64%) of (2-Methoxyphenyl)(1tosyl-1H-pyrrol-2-yl)methanone as a yellow oil. 1H NMR (300 MHz, CDCl3): 2.43 (s, 3H), 3.70 (s, 3H), 6.26 (t, J = 3.6 Hz, 1H), 6.57 (dd, J = 1.8, 3.6 Hz, 1H), 6.89-6.95 (m, 2H), 7.29 (dd, J = 1.8, 7.5 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.39 (m, 1H), 7.78 (dd, J = 1.8, 3.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.6, 55.7, 110.5, 111.6, 120.0, 126.2, 128.5, 128.7, 129.3, 129.8, 130.0, 132.1, 134.4, 135.9, 144.8, 157.5, 183.3 (two carbons are missing due to overlapping); FT-IR: 1112, 1172, 1205, 1620, 1723, 2858, 2930; HRMS (ESI-TOF) m/z for C19H17NO4S [M+H]+ calcd 356.0951, found 356.0954.
(2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4). Method A: To a solution of (2-methoxy phenyl)(1H-pyrrol-2-yl)methanone (310 mg, 0.87 mmol) in 2 mL EtOH and 4 mL THF, was added KOH (0.25 mL, 40% aqueous solution) and the solution
S7
` was stirred overnight. The mixture was neutralized with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 2 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (10:1 Hexane/EtOAc) to give 168 mg of 4 as a white solid in 96% yield. Mp: 137-139 °C; 1H NMR (300 MHz, CDCl3): 3.82 (s, 3H), 6.26 (m, 1H), 6.62 (m, 1H), 6.97-7.02 (m, 2H), 7.09 (m, 1H), 7.40-7.44 (m, 2H), 9.53 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.7, 110.7, 111.6, 119.8, 120.0, 125.4, 128.7, 129.4, 131.4, 132.5, 157.2, 184.6; FT-IR: 874, 1018, 1030, 1241, 1388, 1407, 1599, 1617, 2930, 2960, 3274; HRMS (ESI-TOF) m/z for C12H11NO2 [M+H]+ calcd 202.0863, found 202.0869.
(2-Methoxyphenyl)(1H-pyrrol-2-yl)methanone (4). Method B: Methyl iodide (2.95 g, 20.8 mmol) in dry ether (10 ml) was added to a stirred mixture of magnesium turnings (500 mg, 20.8 mmol) in (5 ml) at such a rate that gentle reflux was maintained. After completion of the addition the mixture was stirred at r.t. for 30 min and then pyrrole (1.4 g, 20.87 mmol) was added at such a rate that gentle reflux was maintained. After completion of the addition the mixture was heated under reflux with stirring for 30 minutes and then cooled to 0 °C. A solution of 2-methoxybenzoyl chloride (3.56 g, 20.87 mmol) in dry toluene 20 mL was added dropwise with stirring and the resulting black mixture was heated to 40 °C for 30 minutes. The mixture was cooled and a solution of saturated ammonium chloride 10 mL was added. The mixture was extracted with diethyl ether (4 x 50 mL). The combined extracts were dried over Na2SO4, and evaporated. The crude product was purified by column chromatography (4:1 Hexane/EtOAc) to give 3.317g (79%) of 4 as a white solid. Mp: 137-139 °C; 1H NMR (300 MHz, CDCl3): 3.82 (s, 3H), 6.26 (m, 1H), 6.62 (m, 1H), 6.97-7.02 (m, 2H), 7.09 (m, 1H), 7.40-7.44 (m, 2H), 9.53 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.7, 110.7, 111.6, 119.8, 120.0, 125.4, 128.7, 129.4, 131.4, 132.5, 157.2, 184.6; FTIR: 874, 1018, 1030, 1241, 1388, 1407, 1599, 1617, 2930, 2960, 3274; HRMS (ESITOF) m/z for C12H11NO2 [M+H]+ calcd 202.0863, found 202.0869.
3-Bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide: A stirred suspension of N,O-dimethylhydroxylamine hydrochloride (245 mg, 2.51 mmol) and ester 10 (297
S8
` mg, 0.829 mmol) in 8 ml dry THF at -78 °C was treated with a 1M solution of LiHMDS (20 mmol, 20 mL). After 30 minutes stirring at -78 °C the reaction was quenched with a saturated aqueous solution of NH4Cl and warmed to room temperature. The mixture was extracted with AcOEt (4 x 20 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (2:1 Hexane/EtOAc) to give 126 mg (65%) of weinreb amide as a yellow solid. Mp: 98 °C; 1H NMR (300 MHz, CDCl3): 3.36 (s, 3H), 3.71 (s, 3H), 6.33 (t, J = 2.9 Hz, 1H), 6.81 (t, J = 2.9 Hz, 1H), 9.64 (br, 1H); 13C NMR (75 MHz, CDCl3): 33.9, 61.5, 104.0, 114.1, 120.8, 120.9, 160.0; FT-IR: 1106, 1199, 1367, 1416, 1524, 1608, 2924, 2972, 3117, 3365; HRMS (ESI-TOF) m/z for C7H9BrN2O2 [M+H]+ calcd 232.992, found 232.9928.
3-bromo-N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (13): To a stirred solution of 3-bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide (140 mg, 0.6 mmol) in THF (14 mL), NaH (72 mg, 40% in oil, 1.2 mmol) was added under nitrogen at 0 °C. After 10 min, tosyl chloride (172 mg, 0.9 mmol) was added and the mixture was allowed to warm at room temperature. After 5 hours stirring the reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 10 mL). The combined extracts were dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (5:1 Hexane/EtOAc) to give 209 mg (90%, based on recovered starting material) of compound 13 as a colorless oil. 13: Mixture of rotamers, 1H NMR (300 MHz, 40 °C, CDCl3): 2.39 (s, 3H), 3.33 (br, 3H), 3.70 (br, 3H), 6.26 (d, J = 3.4 Hz, 1H), 7.13 (br, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, 40 °C, CDCl3): 21.4, 33.8, 61.1, 65.6, 101.7, 115.0, 122.2, 125.7, 128.0, 129.8, 129.9, 135.1, 145.6, 160.9; FT-IR: 1197, 1376, 1656, 2930, 2978, 3057, 3123, 3141; HRMS (ESITOF) m/z for C15H15BrN2O4S [M+H]+ calcd 387.0009, found 387.0012.
(3-bromo-1-tosyl-1H-pyrrol-2-yl)(2-methoxyphenyl)methanone (5): Under an argon atmosphere, a hexane solution of n-butyllithium (1 mL, 1.56 mmol, 1.6 M,) was added dropwise to a solution of diisopropylamine (0.3 mL, 2.08 mmol) in 5mL THF at 0 °C. After being stirred for 15 min at 0 °C and the mixture was cooled to -78 °C, a solution of compound 10 (250 mg, 0.833 mmol) in 2 mL THF was added dropwise. After been stirred for 1 h a solution of 2-methoxybenzoyl chloride (320 mg, 1.87
S9
` mmol) in 6mL toluene was added dropwise. After been stirred for 5 hours at the same temperature the mixture was quenched with saturated aqueous NH4Cl. The mixture was extracted with diethyl ether (4 x 20 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (10:1 Hexane/EtOAc) and the product was recrystalized from a mixture of DCM/hexane to give 5 (245 mg) as a white solid in 82% yield. Mp: 127129 °C; 1H NMR (300 MHz, CDCl3): δ 2.42 (s, 3H), 3.73 (s, 3H), 6.29 (d, J = 3.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.447.50 (m, 2H), 7.54 (dd, J = 1.3, 7.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.6, 56.1, 106.0, 111.8, 114.9, 120.5, 125.2, 127.9, 128.2, 129.6, 131.1, 132.0, 134.1, 135.8, 145.2, 159.2, 185.1 (two carbons are missing due to overlapping); IR (KBr) : 1018, 1130, 1175, 1247, 1373, 1464, 1593, 1638, 2930, 3117, 3135; HRMS (ESI-TOF) m/z for C19H16BrNO4S [M+H]+ calcd 434.0056, found 434.0052.
(2-methoxyphenyl)(1'-tosyl-1'H-1,3'-bipyrrol-2-yl)methanone (16): To a microwave vial charged with a magnetic stirring bar were added CuI (63 mg, 0.33 mmol), Cs2CO3 (161 mg, 0.495 mmol), compound 4 (50 mg, 0.248 mmol) and bromo-derivative 6a (50 mg, 0.165 mmol) in 0.5 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (0.4 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (6:1 Hexane/EtOAc) to afford compound 16 (20.5 mg, 20% isolated yield, 60% based on recovered 4) and recovered compound 4 (39 mg). 1H NMR (300 MHz, CDCl3): 2.41 (s, 3H), 3.77 (s, 3H), 6.19 (dd, J = 2.6, 3.9 Hz, 1H), 6.42 (dd, J = 1.6, 3.3 Hz, 1H), 6.61 (dd, J = 1.6, 3.9 Hz, 1H), 6.90-6.96 (m, 3H), 7.08 (t, J = 2.6 Hz, 1H), 7.30-7.40 (m, 5H), 7.79 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.6, 55.7, 109.4, 111.4, 112.4, 114.5, 119.5, 119.9, 123.6, 127.0, 129.3, 129.8, 130.0, 130.1, 131.2, 131.3, 132.4, 135.9, 145.2, 157.2, 184.4 (two carbons are missing due to overlapping); FT-IR: 874, 1042, 1060, 1169, 1247, 1355, 1370, 1410, 1596, 1626, 2851, 2918, 3057, 3135; HRMS (ESITOF) m/z for C23H20N2O4S [M+H]+ calcd 421.1216, found 421.1222
S10
`
1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17): Method A: To a microwave vial charged with a magnetic stirring bar were added CuI (568 mg, 2.98 mmol), Cs2CO3 (1.456 g, 4.47 mmol), compound 4 (300 mg, 1.49 mmol) and bromo-derivative 15 (647 mg, 1.49 mmol) in 3.8 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (3 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 15 mL) and EtOAc (2 x 15 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (3:2 Hexane/EtOAc) to afford compounds 17 (143 mg, 24%), 14 (100 mg, 19%) and recovered starting material 4 (198 mg). Method B: To a microwave vial charged with a magnetic stirring bar were added Cu(OAc)2 (48 mg, 265.05 μmol), DBU (80.7 mg, 530 μmol), compound 4 (80 mg, 398 μmol), and 15 (115.1 mg, 265 μmol) in 1.6 mL DMF. The reaction vessel was sealed and heated under microwave irradiation for 2 h at 200 °C. After cooling, the reaction vessel was uncapped, a solution of HCl (0.5 mL, 3N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (4 x 2 mL) and EtOAc (4 x 2 mL), dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (3:2 Hexane/EtOAc) to afford 46 mg (43%) of bipyrrole 17, and 54.5 mg of recovered 4 and 18 mg (50.65 μmol, 19%) of 14. 1H NMR (300 MHz, CDCl3): δ 3.70 (s, 3H), 3.77 (s, 3H), 5.79 (m, 1H), 6.28-6.32 (m, 2H), 6.63 (m, 1H), 6.66-6.71 (m, 2H), 6.906.95 (m, 2H), 7.03 (t, J = 3.1 Hz, 1H), 7.13-7.21 (m, 3H), 7.35 (t, J = 7.8 Hz, 1H), 9.66 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.4, 55.6, 108.4, 110.6, 110.7, 111.4, 119.6, 120.0, 122.8, 123.1, 126.0, 128.1, 128.7, 129.4, 129.8, 130.8, 130.9, 131.2, 132.31, 132.38, 156.5, 157.2, 183.4, 183.8; IR (KBr) : 1021, 1160, 1247, 1404, 1620, 2845, 2930, 2966, 3444; HRMS (ESI-TOF) m/z for C24H20N2O4 [M+H]+ calcd 401.1496, found 401.1505.
S11
`
(4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-methoxyphenyl) methano ne) (18): To a stirred solution of compound 17 (16.7 mg, 41.7 μmol) in acetonitrile (1 mL), 22.2 mg (166.8 μmol) of NCS were added. After 36 hours the mixture was evaporated. The residue was partitioned between water (1 mL) and CH2Cl2 (5 mL). The aqueous layer was separated and extracted with CH2Cl2 (4 x 5mL). The combined extracts were washed with water, dried over Na2SO4, and evaporated. The crude product was purified by column chromatography (10:1 DCM/EtOAc) to give 20.0 mg (89%) of 18 as a yellow solid. Mp: 192-194 °C; 1H NMR (300 MHz, CDCl3): δ 3.73 (s, 3H), 3.80 (s, 3H), 6.31 (s, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.8 Hz, 2H), 7.17-7.25 (m, 3H), 7.40 (td, J = 1.6, 7.8 Hz, 1H), 9.94 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.6, 55.7, 109.6, 110.6, 111.6, 119.8, 119.88, 120.3, 120.5, 121.8, 124.0, 124.8, 125.7, 126.5, 128.0, 128.6, 129.3, 131.0, 131.4, 131.7, 156.7, 157.2, 182.2, 182.4; IR (KBr) : 1021, 1250, 1413, 1629, 2845, 2942, 3015, 3202; HRMS (ESI-TOF) m/z for C24H16Cl4N2O4 [M+H]+ calcd 536.9937, found 536.9942.
O
HO
Cl O Cl
N Cl O
Cl
N H 18
Cl O Cl
N Cl O
Benzene O
AlCl3
Cl
N H
OH
(±)-1
(4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-hydroxyphenyl)methanone) (±)-1: A solution of 18 (20 mg, 37.2 μmol ) in 2 mL benzene was added to a stirred suspension of aluminum trichloride (248 mg, 1.86 mmol) in 10 mL benzene and the mixture was stirred overnight at room temperature. Then the mixture was poured into HCl (10 mL, 3 N) and left stirred for 40 minutes. The mixture was extracted with diethyl ether (1 x 20 mL) and CH2Cl2 (3 x 20 mL). The combined extracts were dried over Na2SO4, and evaporated. The crude product was purified by column chromatography with CH2Cl2 to give 17.7 mg of (±)-1 in 94% yield. 1H NMR (300 MHz, CDCl3): δ 6.49 (t, J = 7.5 Hz, 1H), 6.68 (s, 1H), 6.82-6.90 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 7.34 (td, J = 1.5, 7.8 Hz, 1H), 7.44-7.52 (m, 2H), 7.56 (dd, J = 1.5, 8.0 Hz, 1H), 9.68 (br, 1H), 10.3 (s, 1H), 11.1 (s, 1H); 1H NMR (500 MHz, CDCl3): δ 6.51 (t, J = 7.8 Hz, 1H), 6.71 (s, 1H), 6.88-6.92 (m, 2H), 7.02 (d, J = 7.8
S12
` Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 9.85 (s, 1H), 10.41 (s, 1H), 11.18 (s, 1H); 13C NMR (75 MHz, CDCl3): 110.8, 112.7, 117.8, 118.4, 118.6, 118.9, 119.00, 19.02 119.9, 120.2, 122.9, 124.0, 124.1, 129.0, 130.1, 131.8, 136.0, 136.2, 161.2, 162.5, 185.5, 186.8; IR (KBr): 702, 738, 759, 892, 934, 1012, 1151, 1241, 1355, 1413, 1482, 1593, 1620, 2851, 2924, 2954, 3238; HRMS (ESI-TOF) m/z for C22H12Cl4N2O4 [M+H]+ calcd 508.9624, found 508.9637.
S13
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 8 in CDCl3:
N N H 8
S14
`
1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of N-methoxy-N-methyl1H-pyrrole-2-carboxamide in CDCl3: O N H
N
O
S15
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 12 in
S16
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 14 in
S17
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 4 in CDCl3: O N H
O
4
S18
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 3-bromo-Nmethoxy-N-methyl-1H-pyrrole-2-carboxamide in CDCl3: Br O N H
N O
S19
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 13 in CDCl3: Mixture of rotamers. The spectra were measured at 40 °C. Br O N N Ts O 13
S20
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 5 in CDCl3:
S21
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 16 in
S22
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 17 in
O O
N O N H
O
17
S23
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 18 in
S24
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound (±)-1 in
S25
`
1
H NMR (500 MHz) spectrum of compound (±)-1 in CDCl3:
S26
`
References (1) Zonta, C.; Fabris, F.; De Lucchi O.; Org. Lett., 2005, 7, 1003–1006. (2) Alvarez, A.; Guzmh, A.; Ruiz, A.; Velarde, E.; Muchowski, J. M.; J. Org. Chem. 1992, 57, 1653-1656. (3) Leroy, J.; Poriel, E.; Bondon, A.; Tetrahedron 2002, 58, 6713-6722. (4) Ohta, T.; Fukuda, T.; Ishibashi, F.; Iwao, M.; J. Org. Chem. 2009, 74, 8143–8153.
S27
Supporting Information
Total Synthesis of (±)-Marinopyrrole A via CopperMediated N-Arylation Argyrios Kanakis, and Vasiliki Sarli* Aristotle University of Thessaloniki, Department of Organic Chemistry, Faculty of Chemistry, University Campus, 54124 Thessaloniki, Greece [email protected]
Table of Contents
General Experimental……………………………………………………………...S3 Experimental Procedures……………………………………….…….…………...S3 General Procedures for the N-Arylation……………….…….…………………...S3 3-bromo-1-tosyl-1H-pyrrole (6a)...………………………………………........…...S3 1'H-1,3΄-bipyrrole (8)-Method A ……………………….……..…....………...…...S4 3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (6b) ….……………....…………...…...S4 1'H-1,3΄-bipyrrole (8)-Method B ……………………….……..…....………...…...S4 tert-Butyl 3-bromo-1H-pyrrole-1-carboxylate (6c) ………………………….........S5 1'H-1,3΄-bipyrrole (8)-Method C ……………………….……..…....………...…...S5 1-(Triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (6d) ..…....………………...…...S5 Methyl 3-bromo-1-tosyl-1H-pyrrole-2-carboxylate (10)……………….……........ S5 Coupling of 1H-pyrrole-2-carboxylate (9) with methyl 3-bromo-1-tosyl-1H-pyrrole2-carboxylate (10)………………...…………………..…................... .…………...S6 N-methoxy-N-methyl-1H-pyrrole-2-carboxamide.…………………………...…....S6 N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (12)………………........S6 (2-Methoxyphenyl)(1-tosyl-1H-pyrrol-2-yl)methanone (14) ………………..........S7 (2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4)-Method A..…………............S7 (2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4)-Method B..…………....…....S8 3-Bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide.............................…...S8 3-bromo-N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (13) ………....S9 (3-bromo-1-tosyl-1H-pyrrol-2-yl)(2-methoxyphenyl)methanone (5)………….......S9 S1
` (2-methoxyphenyl)(1'-tosyl-1'H-1,3'-bipyrrol-2-yl)methanone (16) ….................S10 1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17)-Method A....S11 1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17)-Method B….S11 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-methoxyphenyl) methanone) (18) ……………...…………………..…..……...…….…………………………..S12 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-hydroxyphenyl)methano-ne) (±1)……………………..………….………………… …………………..……. ..S12 NMR spectra……………………………………………………………...……..... S14 1'H-1,3’-bipyrrole (8) ………………………………….……….……...…...…….S14 N-methoxy-N-methyl-1H-pyrrole-2-carboxamide…………………………...…...S15 N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (12)………………......S16 (2-Methoxyphenyl)(1-tosyl-1H-pyrrol-2-yl)methanone (14) ……………............S17 (2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4)..…………............................S18 3-Bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide...........................…...S19 3-bromo-N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (13) ...……...S20 (3-bromo-1-tosyl-1H-pyrrol-2-yl)(2-methoxyphenyl)methanone (5) ……...….....S21 (2-methoxyphenyl)(1'-tosyl-1'H-1,3'-bipyrrol-2-yl)methanone (16) ….................S22 1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17)…….....….....S23 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-methoxyphenyl) methanone) (18) …………………...……..……...…………………………………….……....S24 (4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-hydroxyphenyl)methanone) (±1)………………………….…………………… ……………………….……. .S25 References…………………………………………………………………..……. .S27
S2
`
Supporting information General Experimental Details All reactions were carried out under an atmosphere of Ar unless otherwise specified. Commercial reagents of high purity were purchased and used without further purification, unless otherwise noted. Reactions were monitored by TLC carried out on 0.25 mm E. Merck silica gel plates (60 F254) and using UV light as a visualizing agent and aqueous ceric sulfate/ phosphomolybdic acid, ethanolic p-anisaldehyde solution, potassium permanganate solution, and heat as developing agents. E. Merck silica gel 60 (230-400 mesh) was used for flash column chromatography. The 1H-NMR spectra were recorded at 300 (Bruker 300 AM spectrometer) and 500 MHz (Bruker Avance DRX) with tetramethylsilane as internal standard. 13C-NMR spectra were recorded at 75 MHz, on a Bruker 300 AM spectrometer. IR spectra were recorded on a Perkin– Elmer Spectrum 100 FT-IR spectrometer. Melting points (Mp) are uncorrected. Highresolution mass spectra (HRMS) were recorded on an Agilent ESITOF (time of flight) mass spectrometer at a 4000 V emitter voltage. Microwave reactions were carried out in a Biotage Initiator microwave system 2.0 (400W, operating at 2.45 GHz).
Experimental Procedures General procedure for the N-arylation: To a microwave vial charged with a magnetic stirring bar were added CuI (2 mmol), Cs2CO3 (3 mmol), compound bromopyrrole (1 mmol), and pyrrole (1.5 mmol) in 2.5 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for the appropriate time and temperature using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (2 mL, 3N) was added and the mixture was stirred for 5 min. Then, the mixture was extracted with CH2Cl2 (2 x 10 mL) and EtOAc (2 x 10 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography to afford the desired bipyrroles. Br N Ts 6a
3-bromo-1-tosyl-1H-pyrrole (6a) was synthesized in 75 % yield as per method described in the literature. 1
S3
` 1'H-1,3'-bipyrrole (8). Method A: To a microwave vial charged with a magnetic stirring bar were added CuI (378 mg, 2 mmol), Cs2CO3 (975 mg, 3 mmol), compound 6a (300.4 mg, 1 mmol), and pyrrole (100 mg, 1.5 mmol) in 2.5 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (2 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 10 mL) and EtOAc (2 x 10 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford 113 mg (86%) of bipyrrole 8 as a red oil. 1H NMR (300 MHz, CDCl3): 6.25 (t, J = 2.1 Hz, 2H), 6.30 (m, 1H), 6.73 (dd, J = 2.9, 5.1 Hz, 1H), 6.83 (dd, J = 2.2, 4.3Hz, 1H), 6.92 (t, J = 2.1 Hz, 2H), 8.07 (br, 1H); 13C NMR (75 MHz, CDCl3): 102.5, 107.8, 108.7, 117.5, 120.2; FT-IR: 1021, 1069, 1337, 1587, 1702, 2851, 2924, 3129, 3383; HRMS (ESI-TOF) m/z for C8H8N2 [M+H]+ calcd 133.076, found 133.0759. Br N TIPS 6b
3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (6b) was synthesized as per method described in the literature. 2
1'H-1,3'-bipyrrole (8) Method B: To a microwave vial charged with a magnetic stirring bar were added CuI (151 mg, 0.79 mmol), Cs2CO3 (389 mg, 1.19 mmol), compound 6b (120 mg, 0.4 mmol), and pyrrole (40 mg, 0.59 mmol) in 1 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (1 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford 47 mg (90%) of bipyrrole 8 as a red oil. The spectral data of 8 have been described above.
S4
` Br N Boc 6c
tert-Butyl 3-bromo-1H-pyrrole-1-carboxylate (6c) was synthesized as per method described in the literature. 3
1'H-1,3'-bipyrrole (8) Method C: To a microwave vial charged with a magnetic stirring bar were added CuI (151 mg, 0.79 mmol), Cs2CO3 (389 mg, 1.19 mmol), compound 6b (98 mg, 0.4 mmol), and pyrrole (40 mg, 0.59 mmol) in 1 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (1 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford 44 mg (85%) of bipyrrole 8 as a red oil. The spectral data of 8 have been described above.
1-(Triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (6d): was synthesized as per method described in the literature.2 Br O N Ts 10
O
Methyl 3-bromo-1-tosyl-1H-pyrrole-2-carboxylate (10): was synthesized as per method described in the literature. 4
S5
`
Coupling of 1H-pyrrole-2-carboxylate (9) with methyl 3-bromo-1-tosyl-1Hpyrrole-2-carboxylate: To a microwave vial charged with a magnetic stirring bar were added CuI (166 mg, 0.872 mmol), Cs2CO3 (426 mg, 1.308 mmol), methyl 1Hpyrrole-2-carboxylate 9 (60 mg, 0.479 mmol) and bromo-derivative 10 (156 mg, 0.436 mmol) in 1.1 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 240 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (1 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (10:1 Hexane/EtOAc) to afford compounds 11 (19 mg, 0.087 mmol) and 8 (17 mg, 0.131 mmol) in 20 and 30% yield respectively.
O LiHMDS, THF N H
O 9
MeNHOMe.HCl
O N H
N O
N-methoxy-N-methyl-1H-pyrrole-2-carboxamide: A stirred suspension of N,Odimethylhydroxylamine hydrochloride (507 mg, 5.19 mmol) and ester 9 (500 mg, 4 mmol) in 40 ml dry THF at -78 °C was treated with a 1M solution of LiHMDS (19.98 mmol, 20 mL). After 30 minutes stirring at -78 °C the reaction was quenched with a saturated aqueous solution of NH4Cl and warmed to room temperature. The mixture was extracted with AcOEt (4 x 50 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (gradient elution, 5:1, 4:1, 3:1 Hexane/EtOAc) to give 592 mg (96%) of Weinreb amide as a yellow solid. Mp: 67-69 °C; 1H NMR (300 MHz, CDCl3): δ 3.35 (s, 3H), 3.78 (s, 3H), 6.28 (m, 1H), 6.90 (m, 1H), 6.95 (m, 1H), 9.49 (br, 1H); 13 C NMR (75 MHz, CDCl3): 33.0, 61.0, 110.5, 114.6, 121.6, 123.7, 161.4; FT-IR: 991, 1425, 1602, 2821, 2936, 2972, 3287; HRMS (ESI-TOF) m/z for C7H10N2O2 [M+H]+ calcd 155.0815, found 155.0821.
N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (12): To a stirred solution of N-methoxy-N-methyl-1H-pyrrole-2-carboxamide (350 mg, 2.27 mmol) in THF (30 mL), NaH (182 mg, 60% in oil, 4.54 mmol) was added under nitrogen at 0 S6
` °C. After 10min, tosyl chloride (1.30 g, 6.81 mmol) was added and the mixture was allowed to warm at room temperature. After 5 hours stirring the reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 50 mL). The combined extracts were dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (3:2 Hexane/EtOAc) to give 630 mg (90%) of compound 12 as a yellow oil. Mp: 76-78 °C; 1H NMR (300 MHz, CDCl3): δ 2.37 (s, 3H), 3.29 (s, 3H), 3.64 (s, 3H), 6.24 (t, J = 3.30Hz, 1H), 6.47 (m, 1H), 7.29 (d, 2H, and 1H, overlapped), 7.91 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.3, 33.9, 60.9, 111.4, 115.3, 123.5, 126.1, 126.8, 127.7, 129.2, 129.4, 135.6, 144.8, 161.6; FT-IR: 1148, 1169, 1364, 1653, 2936, 2978, 3135; HRMS (ESI-TOF) m/z for C14H16N2O4S [M+H]+ calcd 309.0903, found 309.0905. O Mg Br O N N Ts O 12
O Et2O/THF
N Ts 14
O
(2-Methoxyphenyl)(1-tosyl-1H-pyrrol-2-yl)methanone (14): A solution of 2methoxyphenylmagnesium bromide (11.35 mmol) [prepared from 4.24 g (22.7 mmol) of 2-bromoanisole and 662 mg, (27.24 mmol) of magnesium turnings] in ether (15 mL) was added to a stirred solution of 12 (700 mg, 2.27 mmol) in 5 mL THF at -15 °C. The mixture was allowed to warm at room temperature and stirred for 30 min, and then another portion of Grignard reactant (11.35 mmol, in 15 mL ether) was added. After 30 min the reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 50 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (5:1 Hexane/EtOAc) to give 516 mg (64%) of (2-Methoxyphenyl)(1tosyl-1H-pyrrol-2-yl)methanone as a yellow oil. 1H NMR (300 MHz, CDCl3): 2.43 (s, 3H), 3.70 (s, 3H), 6.26 (t, J = 3.6 Hz, 1H), 6.57 (dd, J = 1.8, 3.6 Hz, 1H), 6.89-6.95 (m, 2H), 7.29 (dd, J = 1.8, 7.5 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.39 (m, 1H), 7.78 (dd, J = 1.8, 3.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.6, 55.7, 110.5, 111.6, 120.0, 126.2, 128.5, 128.7, 129.3, 129.8, 130.0, 132.1, 134.4, 135.9, 144.8, 157.5, 183.3 (two carbons are missing due to overlapping); FT-IR: 1112, 1172, 1205, 1620, 1723, 2858, 2930; HRMS (ESI-TOF) m/z for C19H17NO4S [M+H]+ calcd 356.0951, found 356.0954.
(2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (4). Method A: To a solution of (2-methoxy phenyl)(1H-pyrrol-2-yl)methanone (310 mg, 0.87 mmol) in 2 mL EtOH and 4 mL THF, was added KOH (0.25 mL, 40% aqueous solution) and the solution
S7
` was stirred overnight. The mixture was neutralized with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 2 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (10:1 Hexane/EtOAc) to give 168 mg of 4 as a white solid in 96% yield. Mp: 137-139 °C; 1H NMR (300 MHz, CDCl3): 3.82 (s, 3H), 6.26 (m, 1H), 6.62 (m, 1H), 6.97-7.02 (m, 2H), 7.09 (m, 1H), 7.40-7.44 (m, 2H), 9.53 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.7, 110.7, 111.6, 119.8, 120.0, 125.4, 128.7, 129.4, 131.4, 132.5, 157.2, 184.6; FT-IR: 874, 1018, 1030, 1241, 1388, 1407, 1599, 1617, 2930, 2960, 3274; HRMS (ESI-TOF) m/z for C12H11NO2 [M+H]+ calcd 202.0863, found 202.0869.
(2-Methoxyphenyl)(1H-pyrrol-2-yl)methanone (4). Method B: Methyl iodide (2.95 g, 20.8 mmol) in dry ether (10 ml) was added to a stirred mixture of magnesium turnings (500 mg, 20.8 mmol) in (5 ml) at such a rate that gentle reflux was maintained. After completion of the addition the mixture was stirred at r.t. for 30 min and then pyrrole (1.4 g, 20.87 mmol) was added at such a rate that gentle reflux was maintained. After completion of the addition the mixture was heated under reflux with stirring for 30 minutes and then cooled to 0 °C. A solution of 2-methoxybenzoyl chloride (3.56 g, 20.87 mmol) in dry toluene 20 mL was added dropwise with stirring and the resulting black mixture was heated to 40 °C for 30 minutes. The mixture was cooled and a solution of saturated ammonium chloride 10 mL was added. The mixture was extracted with diethyl ether (4 x 50 mL). The combined extracts were dried over Na2SO4, and evaporated. The crude product was purified by column chromatography (4:1 Hexane/EtOAc) to give 3.317g (79%) of 4 as a white solid. Mp: 137-139 °C; 1H NMR (300 MHz, CDCl3): 3.82 (s, 3H), 6.26 (m, 1H), 6.62 (m, 1H), 6.97-7.02 (m, 2H), 7.09 (m, 1H), 7.40-7.44 (m, 2H), 9.53 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.7, 110.7, 111.6, 119.8, 120.0, 125.4, 128.7, 129.4, 131.4, 132.5, 157.2, 184.6; FTIR: 874, 1018, 1030, 1241, 1388, 1407, 1599, 1617, 2930, 2960, 3274; HRMS (ESITOF) m/z for C12H11NO2 [M+H]+ calcd 202.0863, found 202.0869.
3-Bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide: A stirred suspension of N,O-dimethylhydroxylamine hydrochloride (245 mg, 2.51 mmol) and ester 10 (297
S8
` mg, 0.829 mmol) in 8 ml dry THF at -78 °C was treated with a 1M solution of LiHMDS (20 mmol, 20 mL). After 30 minutes stirring at -78 °C the reaction was quenched with a saturated aqueous solution of NH4Cl and warmed to room temperature. The mixture was extracted with AcOEt (4 x 20 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (2:1 Hexane/EtOAc) to give 126 mg (65%) of weinreb amide as a yellow solid. Mp: 98 °C; 1H NMR (300 MHz, CDCl3): 3.36 (s, 3H), 3.71 (s, 3H), 6.33 (t, J = 2.9 Hz, 1H), 6.81 (t, J = 2.9 Hz, 1H), 9.64 (br, 1H); 13C NMR (75 MHz, CDCl3): 33.9, 61.5, 104.0, 114.1, 120.8, 120.9, 160.0; FT-IR: 1106, 1199, 1367, 1416, 1524, 1608, 2924, 2972, 3117, 3365; HRMS (ESI-TOF) m/z for C7H9BrN2O2 [M+H]+ calcd 232.992, found 232.9928.
3-bromo-N-methoxy-N-methyl-1-tosyl-1H-pyrrole-2-carboxamide (13): To a stirred solution of 3-bromo-N-methoxy-N-methyl-1H-pyrrole-2-carboxamide (140 mg, 0.6 mmol) in THF (14 mL), NaH (72 mg, 40% in oil, 1.2 mmol) was added under nitrogen at 0 °C. After 10 min, tosyl chloride (172 mg, 0.9 mmol) was added and the mixture was allowed to warm at room temperature. After 5 hours stirring the reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (4 x 10 mL). The combined extracts were dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (5:1 Hexane/EtOAc) to give 209 mg (90%, based on recovered starting material) of compound 13 as a colorless oil. 13: Mixture of rotamers, 1H NMR (300 MHz, 40 °C, CDCl3): 2.39 (s, 3H), 3.33 (br, 3H), 3.70 (br, 3H), 6.26 (d, J = 3.4 Hz, 1H), 7.13 (br, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, 40 °C, CDCl3): 21.4, 33.8, 61.1, 65.6, 101.7, 115.0, 122.2, 125.7, 128.0, 129.8, 129.9, 135.1, 145.6, 160.9; FT-IR: 1197, 1376, 1656, 2930, 2978, 3057, 3123, 3141; HRMS (ESITOF) m/z for C15H15BrN2O4S [M+H]+ calcd 387.0009, found 387.0012.
(3-bromo-1-tosyl-1H-pyrrol-2-yl)(2-methoxyphenyl)methanone (5): Under an argon atmosphere, a hexane solution of n-butyllithium (1 mL, 1.56 mmol, 1.6 M,) was added dropwise to a solution of diisopropylamine (0.3 mL, 2.08 mmol) in 5mL THF at 0 °C. After being stirred for 15 min at 0 °C and the mixture was cooled to -78 °C, a solution of compound 10 (250 mg, 0.833 mmol) in 2 mL THF was added dropwise. After been stirred for 1 h a solution of 2-methoxybenzoyl chloride (320 mg, 1.87
S9
` mmol) in 6mL toluene was added dropwise. After been stirred for 5 hours at the same temperature the mixture was quenched with saturated aqueous NH4Cl. The mixture was extracted with diethyl ether (4 x 20 mL). The combined extracts were dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (10:1 Hexane/EtOAc) and the product was recrystalized from a mixture of DCM/hexane to give 5 (245 mg) as a white solid in 82% yield. Mp: 127129 °C; 1H NMR (300 MHz, CDCl3): δ 2.42 (s, 3H), 3.73 (s, 3H), 6.29 (d, J = 3.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.447.50 (m, 2H), 7.54 (dd, J = 1.3, 7.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.6, 56.1, 106.0, 111.8, 114.9, 120.5, 125.2, 127.9, 128.2, 129.6, 131.1, 132.0, 134.1, 135.8, 145.2, 159.2, 185.1 (two carbons are missing due to overlapping); IR (KBr) : 1018, 1130, 1175, 1247, 1373, 1464, 1593, 1638, 2930, 3117, 3135; HRMS (ESI-TOF) m/z for C19H16BrNO4S [M+H]+ calcd 434.0056, found 434.0052.
(2-methoxyphenyl)(1'-tosyl-1'H-1,3'-bipyrrol-2-yl)methanone (16): To a microwave vial charged with a magnetic stirring bar were added CuI (63 mg, 0.33 mmol), Cs2CO3 (161 mg, 0.495 mmol), compound 4 (50 mg, 0.248 mmol) and bromo-derivative 6a (50 mg, 0.165 mmol) in 0.5 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (0.4 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 5 mL) and EtOAc (2 x 5 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (6:1 Hexane/EtOAc) to afford compound 16 (20.5 mg, 20% isolated yield, 60% based on recovered 4) and recovered compound 4 (39 mg). 1H NMR (300 MHz, CDCl3): 2.41 (s, 3H), 3.77 (s, 3H), 6.19 (dd, J = 2.6, 3.9 Hz, 1H), 6.42 (dd, J = 1.6, 3.3 Hz, 1H), 6.61 (dd, J = 1.6, 3.9 Hz, 1H), 6.90-6.96 (m, 3H), 7.08 (t, J = 2.6 Hz, 1H), 7.30-7.40 (m, 5H), 7.79 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): 21.6, 55.7, 109.4, 111.4, 112.4, 114.5, 119.5, 119.9, 123.6, 127.0, 129.3, 129.8, 130.0, 130.1, 131.2, 131.3, 132.4, 135.9, 145.2, 157.2, 184.4 (two carbons are missing due to overlapping); FT-IR: 874, 1042, 1060, 1169, 1247, 1355, 1370, 1410, 1596, 1626, 2851, 2918, 3057, 3135; HRMS (ESITOF) m/z for C23H20N2O4S [M+H]+ calcd 421.1216, found 421.1222
S10
`
1'H-1,3'-bipyrrole-2,2'-diylbis((2-methoxyphenyl)methanone) (17): Method A: To a microwave vial charged with a magnetic stirring bar were added CuI (568 mg, 2.98 mmol), Cs2CO3 (1.456 g, 4.47 mmol), compound 4 (300 mg, 1.49 mmol) and bromo-derivative 15 (647 mg, 1.49 mmol) in 3.8 mL DMF. The reaction vessel was sealed and the mixture ultrasonicated (1-2 min) to affect solution. The vial was transferred to the microwave synthesizer and after pre-stirring 15 s, irradiated for 2 h at 200 °C using a power setting of "Very High". After cooling, the reaction vessel was uncapped, a solution of HCl (3 mL, 3 N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (2 x 15 mL) and EtOAc (2 x 15 mL) dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (3:2 Hexane/EtOAc) to afford compounds 17 (143 mg, 24%), 14 (100 mg, 19%) and recovered starting material 4 (198 mg). Method B: To a microwave vial charged with a magnetic stirring bar were added Cu(OAc)2 (48 mg, 265.05 μmol), DBU (80.7 mg, 530 μmol), compound 4 (80 mg, 398 μmol), and 15 (115.1 mg, 265 μmol) in 1.6 mL DMF. The reaction vessel was sealed and heated under microwave irradiation for 2 h at 200 °C. After cooling, the reaction vessel was uncapped, a solution of HCl (0.5 mL, 3N) was added and the solution was stirred for 5 min. The mixture was extracted with CH2Cl2 (4 x 2 mL) and EtOAc (4 x 2 mL), dried over Na2SO4, and concentrated via rotary evaporation. The crude mixture was purified by column chromatography on silica gel (3:2 Hexane/EtOAc) to afford 46 mg (43%) of bipyrrole 17, and 54.5 mg of recovered 4 and 18 mg (50.65 μmol, 19%) of 14. 1H NMR (300 MHz, CDCl3): δ 3.70 (s, 3H), 3.77 (s, 3H), 5.79 (m, 1H), 6.28-6.32 (m, 2H), 6.63 (m, 1H), 6.66-6.71 (m, 2H), 6.906.95 (m, 2H), 7.03 (t, J = 3.1 Hz, 1H), 7.13-7.21 (m, 3H), 7.35 (t, J = 7.8 Hz, 1H), 9.66 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.4, 55.6, 108.4, 110.6, 110.7, 111.4, 119.6, 120.0, 122.8, 123.1, 126.0, 128.1, 128.7, 129.4, 129.8, 130.8, 130.9, 131.2, 132.31, 132.38, 156.5, 157.2, 183.4, 183.8; IR (KBr) : 1021, 1160, 1247, 1404, 1620, 2845, 2930, 2966, 3444; HRMS (ESI-TOF) m/z for C24H20N2O4 [M+H]+ calcd 401.1496, found 401.1505.
S11
`
(4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-methoxyphenyl) methano ne) (18): To a stirred solution of compound 17 (16.7 mg, 41.7 μmol) in acetonitrile (1 mL), 22.2 mg (166.8 μmol) of NCS were added. After 36 hours the mixture was evaporated. The residue was partitioned between water (1 mL) and CH2Cl2 (5 mL). The aqueous layer was separated and extracted with CH2Cl2 (4 x 5mL). The combined extracts were washed with water, dried over Na2SO4, and evaporated. The crude product was purified by column chromatography (10:1 DCM/EtOAc) to give 20.0 mg (89%) of 18 as a yellow solid. Mp: 192-194 °C; 1H NMR (300 MHz, CDCl3): δ 3.73 (s, 3H), 3.80 (s, 3H), 6.31 (s, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.8 Hz, 2H), 7.17-7.25 (m, 3H), 7.40 (td, J = 1.6, 7.8 Hz, 1H), 9.94 (br, 1H); 13C NMR (75 MHz, CDCl3): 55.6, 55.7, 109.6, 110.6, 111.6, 119.8, 119.88, 120.3, 120.5, 121.8, 124.0, 124.8, 125.7, 126.5, 128.0, 128.6, 129.3, 131.0, 131.4, 131.7, 156.7, 157.2, 182.2, 182.4; IR (KBr) : 1021, 1250, 1413, 1629, 2845, 2942, 3015, 3202; HRMS (ESI-TOF) m/z for C24H16Cl4N2O4 [M+H]+ calcd 536.9937, found 536.9942.
O
HO
Cl O Cl
N Cl O
Cl
N H 18
Cl O Cl
N Cl O
Benzene O
AlCl3
Cl
N H
OH
(±)-1
(4,4',5,5'-tetrachloro-1'H-1,3'-bipyrrole-2,2'-diyl)bis((2-hydroxyphenyl)methanone) (±)-1: A solution of 18 (20 mg, 37.2 μmol ) in 2 mL benzene was added to a stirred suspension of aluminum trichloride (248 mg, 1.86 mmol) in 10 mL benzene and the mixture was stirred overnight at room temperature. Then the mixture was poured into HCl (10 mL, 3 N) and left stirred for 40 minutes. The mixture was extracted with diethyl ether (1 x 20 mL) and CH2Cl2 (3 x 20 mL). The combined extracts were dried over Na2SO4, and evaporated. The crude product was purified by column chromatography with CH2Cl2 to give 17.7 mg of (±)-1 in 94% yield. 1H NMR (300 MHz, CDCl3): δ 6.49 (t, J = 7.5 Hz, 1H), 6.68 (s, 1H), 6.82-6.90 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 7.34 (td, J = 1.5, 7.8 Hz, 1H), 7.44-7.52 (m, 2H), 7.56 (dd, J = 1.5, 8.0 Hz, 1H), 9.68 (br, 1H), 10.3 (s, 1H), 11.1 (s, 1H); 1H NMR (500 MHz, CDCl3): δ 6.51 (t, J = 7.8 Hz, 1H), 6.71 (s, 1H), 6.88-6.92 (m, 2H), 7.02 (d, J = 7.8
S12
` Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 9.85 (s, 1H), 10.41 (s, 1H), 11.18 (s, 1H); 13C NMR (75 MHz, CDCl3): 110.8, 112.7, 117.8, 118.4, 118.6, 118.9, 119.00, 19.02 119.9, 120.2, 122.9, 124.0, 124.1, 129.0, 130.1, 131.8, 136.0, 136.2, 161.2, 162.5, 185.5, 186.8; IR (KBr): 702, 738, 759, 892, 934, 1012, 1151, 1241, 1355, 1413, 1482, 1593, 1620, 2851, 2924, 2954, 3238; HRMS (ESI-TOF) m/z for C22H12Cl4N2O4 [M+H]+ calcd 508.9624, found 508.9637.
S13
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 8 in CDCl3:
N N H 8
S14
`
1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of N-methoxy-N-methyl1H-pyrrole-2-carboxamide in CDCl3: O N H
N
O
S15
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 12 in
S16
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 14 in
S17
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 4 in CDCl3: O N H
O
4
S18
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 3-bromo-Nmethoxy-N-methyl-1H-pyrrole-2-carboxamide in CDCl3: Br O N H
N O
S19
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 13 in CDCl3: Mixture of rotamers. The spectra were measured at 40 °C. Br O N N Ts O 13
S20
` 1
H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra of compound 5 in CDCl3:
S21
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 16 in
S22
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 17 in
O O
N O N H
O
17
S23
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound 18 in
S24
` 1
H NMR (300 MHz) and CDCl3:
13
C NMR (75.5 MHz) spectra of compound (±)-1 in
S25
`
1
H NMR (500 MHz) spectrum of compound (±)-1 in CDCl3:
S26
`
References (1) Zonta, C.; Fabris, F.; De Lucchi O.; Org. Lett., 2005, 7, 1003–1006. (2) Alvarez, A.; Guzmh, A.; Ruiz, A.; Velarde, E.; Muchowski, J. M.; J. Org. Chem. 1992, 57, 1653-1656. (3) Leroy, J.; Poriel, E.; Bondon, A.; Tetrahedron 2002, 58, 6713-6722. (4) Ohta, T.; Fukuda, T.; Ishibashi, F.; Iwao, M.; J. Org. Chem. 2009, 74, 8143–8153.
S27
