5-diazoimidazole-4-carboxamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Isocyanatomethyl-carbamic acid 9H-fluoren-9-ylmethyl ester (1.13 g, 3.83 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the pouring onto crushed ice. The resultant precipitate was collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a white solid (600 mg, 33.9%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.86 (1H, s), 8.61 (1H, t-broad), 7.89-7.26 (9H, m), 5.55 (2H, t, J=6.8 Hz), 4.40-4.19 (5H, m), 2.01 (2H, s). The reaction was quenched by the pouring onto crushed ice The resultant precipitate was collected by filtration washed with Et2O (3 reaction volumes) dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Isocyanatomethyl-phosphonic acid diethyl ester (953 mg, 6.95 mmol) in EtOAc (10 mL) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (10 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into Et2O and the resultant collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a solid (1.14 g, 50%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.91 (1H, s), 7.88 (1H, s), 7.74 (1H, s), 4.85 (2H, t, J=11.2 Hz), 4.12 (4H, m), 1.25 (6H, t, 7.2). the resultant collected by filtration washed with Et2O (3 reaction volumes) dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Isocyanato-methanesulfonyl-methane (250 mg, 1.85 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (210 mg, 1.53 mmol) in dry DMSO (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 72 hours. The reaction was quenched by the pouring onto crushed ice. The resultant precipitate was collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a white solid (283 mg, 68%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.94 (1H, s), 7.90 (1H, s), 7.75 (1H, s), 5.82 (2H, s), 3.15 (3H, s). The reaction was quenched by the pouring onto crushed ice The resultant precipitate was collected by filtration washed with Et2O (3 reaction volumes) dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-diazoimidazole-4-carboxamide (0.5 g, 12.0 mmol) in dry DMSO (5 mL) was added 1-Isocyanato-2-methanesulfonyl-ethane (1.04 g, 3.65 mmol). The mixture was stirred at room temperature for 16 hours, whereupon it was poured onto crushed ice and the resultant precipitate collected by filtration. The filter cake was washed with Et2O (3×1 reaction volume) and dried to give the title compound as an off white solid (990 mg, 95%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.89 (1H, s), 7.84 (1H, s), 7.71 (1H, s), 4.73 (2H, t, J=6.8 Hz), 3.70 (2H, t, j=6.8 Hz), 2.44 (3H, s). was poured onto crushed ice the resultant precipitate collected by filtration The filter cake was washed with Et2O (3×1 reaction volume) dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-isocyanato-2-methyl-propionic acid methyl ester (510 mg, 1.86 mmol) in dry DMSO (1.5 mL) was added 5-diazoimidazole-4-carboxamide (135 g, 0.98 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 2 hours whereupon it was poured onto crushed ice. The resultant white precipitate was collected by vacuum filtration. The filter cake was washed with water (2×1 reaction volume), EtOAc (1 reaction volume) and then Et2O (1 reaction volume) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-(8-carbamoyl-4-oxo-imidazo[5,1-d][1,2,3,5]tetrazin-3-yl)-2-methyl-propionic acid methyl ester as a pale off white solid (140 mg, 34%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.96 (CH, s, 1H), 7.91 (CONH2, s, 1H), 7.77 (CONH2, s, 1H), 5.77 (CH, dd, J=8.8 Hz, 5.6 Hz, 1H), 4.36 (CH2, dd, J=10.6 Hz, 5.6 Hz, 1H), 4.23 (CH2, dd, J=10.6 Hz, 8.8 Hz, 1H), 3.72 (CO2CH3, s, 3H), 0.72 (SiC(CH3)3, s, 9H), 0.03 (SiCH3, s, 3H), −0.06 (SiCH3, s, 3H). was poured onto crushed ice The resultant white precipitate was collected by vacuum filtration The filter cake was washed with water (2×1 reaction volume), EtOAc (1 reaction volume)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Isocyanato-2-methylsulfanyl-ethane (1.09 g, 9.31 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (brown) was removed by filtration, washed with Et2O, and purified using flash chromatography (SiO2) using MeCN:CH2Cl2 (0-100% MeCN) Yield: 52 mg, 26%. 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.87 (1H, s), 7.80 (1H, s), 7.66 (1H, s), 4.48 (2H, t), 2.94 (2H, t). The reaction was quenched by the addition of ice the solid product (brown) was removed by filtration washed with Et2O purified

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Isocyanatomethyl-3-methyl-isoxazole (735 mg, 5.32 mmol) was diluted in DMSO (1.5 mL) and added to a solution of 5-diazoimidazole-4-carboxamide (250 mg, 1.83 mmol) in 2 mL DMSO. The reaction mixture was stirred at room temperature for 16 hours before the addition of sufficient ice water to cause precipitation of the crude product which was collected by vacuum filtration and washed with Et2O (1 reaction volume title compound as a yellow solid (503 mg, 98% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.86 (1H, s), 7.84 (1H, s), 7.71 (1H, s), 6.51 (1H, s), 5.64 (2H, s), 2.21 (3H, s). precipitation of the crude product which was collected by vacuum filtration washed with Et2O (

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An aqueous solution of NaNO2 (84 mg, 1.2 mmol) was added to a cooled (0° C.) solution of (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid hydrazide (1.02 mmol) in a 1:1 mixture of CH2Cl2:1M HCl (1.5 mL). The reaction mixture was stirred at this temperature for 5 minutes before being poured onto crushed ice. The crude azide was extracted with CH2Cl2 and then dried (MgSO4), filtered and concentrated in vacuo. Toluene (1.5 mL) was added to the crude residue and the resultant mixture heated to 80° C. for 1 hour whereupon it was cooled and concentrated in vacuo to give a crude orange residue corresponding to 5-isocyanatomethyl-3-methyl-[1,2,4]oxadiazole (quantitative yield assumed) (1H NMR (400 MHz, CDCl3) δ ppm: 4.56 (2H, s), 2.36 (3H, s). IR (μmax, cm−1): 2260.7 (s, N═C═O), 1593.3 (m), 1494.9 (m), 1435.1 (w), 1325.1 (m)) which was then diluted in DMSO (1.5 mL) and added to a solution of 5-diazoimidazole-4-carboxamide (355 mg, 2.58 mmol) in 3.5 mL DMSO. The reaction mixture was stirred at room temperature for 10 minutes before the addition of sufficient ice water to cause precipitation of the crude product which was collected by vacuum filtration and washed with EtOH (1 reaction volume and then Et2O (1 reaction volume) to give the title compound as a yellow solid (56% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.92 (1H, s), 7.88 (1H, s), 7.74 (1H, s), 5.89 (2H, s), 2.34 (3H, s). precipitation of the crude product which was collected by vacuum filtration washed with EtOH ( 1 reaction volume

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thiophen-2-ylmethyl isocyanate (0.350 g, 2.5 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.314 g, 2.3 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) was removed by filtration, washed with water and ethyl acetate and air dried to give the title compound. Yield: 0.405 g, 64%. IR vmax/cm−1 3094, 1732, 1690, 1607. 1H NMR δH (DMSO-d6) 5.68 (2H, s, CH2Ar), 7.03 (1H, dd, J=5.1, 3.5, ArH), 7.25 (1H, dd, J=3.5, 1.0, ArH), 7.55 (1H, dd, J=5.1, 1.0, ArH), 7.71 (1H, br s, NH), 7.83 (1H, br s, NH), 8.85 (1H, s, 6-H). The reaction was quenched by the addition of ice the solid product (off-white) was removed by filtration washed with water and ethyl acetate and air dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thiophen-3-ylmethyl isocyanate (0.306 g, 2.2 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) removed by filtration, washed with water and ethyl acetate and air dried. Yield: 0.235 g, 42%. IR vmax/cm−1 3094, 1728, 1688, 1604. 1H NMR δH (DMSO-d6) 5.50 (2H, s, CH2Ar), 7.17 (1H, dd, J 4.9, 1.3, ArH), 7.55-7.58 (2H, m, ArH), 7.70 (1H, br s, NH), 7.83 (1H, br s, NH), 8.85 (1H, s, 6-H). δC (DMSO-d6) 48.0, 124.4, 127.3, 128.0, 129.5, 131.4, 134.9, 136.7, 139.5, 162.0. The reaction was quenched by the addition of ice the solid product (off-white) removed by filtration washed with water and ethyl acetate and air dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 3,4-dimethoxybenzyl isocyanate (4 mmol) was added to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product was removed by filtration and purified by column chromatography to give the title compound as a white solid. Yield: 0.068 g, 10%. IR vmax/cm−1 1734, 1686, 1616. 1H NMR δH (DMSO-d6) 3.73 (3H, s, OMe), 3.74 (3H, s, OMe), 5.42 (2H, s, CH2Ar), 6.91-6.98 (2H, m, ArH), 7.03 (1H, d, J=1.9, ArH), 7.70 (1H, br s, NH), 7.82 (1H, br s, NH), 8.83 (1H, s, 6-H). δC (DMSO-d6) 52.2, 56.0, 56.0, 112.1, 112.4, 121.1, 128.3, 129.4, 131.3, 134.9, 139.6, 149.1, 149.2, 162.0. The reaction was quenched by the addition of ice the solid product was removed by filtration purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-dimethoxybenzyl isocyanate (0.717 g, 4.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.548 g, 4 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (purple) removed by filtration, washed with water and ethyl acetate and recrystallised from chloroform/hexane to give the title compound. Yield: 0.613 g, 46%. IR vmax/cm−1 3473, 3121, 1734, 1697, 1605, 1589. 1H NMR δH (DMSO-d6) 3.76 (3H, s, OMe), 3.80 (3H, s, OMe), 5.37 (2H, s, CH2Ar), 6.48 (1H, dd, J=8.4, 2.4, ArH), 6.60 (1H, d, J=2.4, ArH), 7.22 (1H, d, J=8.4, ArH), 7.68 (1H, br s, NH), 7.80 (1H, br s, NH), 8.81 (1H, s, 6-H). δC (DMSO-d6) 47.5, 55.8, 56.1, 98.9, 105.1, 115.9, 129.3, 130.7, 131.2, 134.8, 139.4, 158.5, 161.1, 162.0. The reaction was quenched by the addition of ice the solid product (purple) removed by filtration washed with water and ethyl acetate recrystallised from chloroform/hexane