iodomethyl ethylsulfanylformate

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

Procedure: Crude 5b (23.6 g, 96 mmol) is added during 30 min to a stirred suspension of sodium butanoate (10.5 g, 96 mmol) in dry DMF (125 mL) at -20° C. followed by stirring overnight at ambient temperature. After filtration and washing with DMF (5 mL) and Et2O (10 mL),Et2O (250 mL) and ice-cold H2O (100 mL) are added to the combined filtrates. The aqueous phase is separated and extracted with Et2O (100 mL). The combined organic phases are washed (all solutions ice-cold) with 5% aqueous NaHCO3 (50 mL), H2O (50 mL), 0.01N HCl (100 mL), and H2O (2×50 mL). After drying (MgSO4) and evaporation of solvents the residue is distilled to yield 15.0 g (76%) of 6db, bp 75°-80° C./0.5 mbar. After filtration washing with DMF (5 mL) and Et2O (10 mL),Et2O (250 mL) and ice-cold H2O (100 mL) are added to the combined filtrates The aqueous phase is separated extracted with Et2O (100 mL) The combined organic phases are washed (all solutions ice-cold) with 5% aqueous NaHCO3 (50 mL), H2O (50 mL), 0.01N HCl (100 mL), and H2O (2×50 mL) After drying (MgSO4) and evaporation of solvents the residue is distilled

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

Procedure: Furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid), (10) (Aldrich) (0.050 mole) is added to a stirred solution of sodium bicarbonate (0.100 mole) and tetrabutylammonium hydrogen sulfate (0.050 mole) in water (100 mL) at ambient temperature. After 10 minutes 1,2-dichloroethane (100 mL) is added and then after 30 minutes O-iodomethyl S-ethyl carbonothioate (0.050 mole) in 1,2-dichloroethane (25 mL) is added over 15 minutes. The mixture is stirred for 1 hour at ambient temperature. The organic layer is separated, washed with water (50 mL), dried (magnesium sulfate), and the solvent is evaporated. The residue is stirred with diethyl ether (100 mL), insoluble material is filtered off and washed with diethyl ether. The combined ether phases is evaporated, and the residue may be crystallized to give O-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl) S-ethyl carbonothioate (1005). See eg., Folkmann, et al., Synthesis, 1159 (1990), Method D. The organic layer is separated washed with water (50 mL) dried (magnesium sulfate) the solvent is evaporated The residue is stirred with diethyl ether (100 mL), insoluble material is filtered off washed with diethyl ether The combined ether phases is evaporated the residue may be crystallized

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

Procedure: Finely powdered potassium N-acetylglycinate (5.8 g, 37 mmol) and TBA I (1.2 g, 3.4 mmol) are thoroughly mixed and shaken for 5 min with 5b (8.3 g, 34 mmol). The mixture is left for 48 h at room temperature and then extracted with Et2O (4×40 mL). The combined extracts are filtered and evaporated. The residue (6.4 g) is thoroughly extracted with pentane (4×25 mL) to remove unreacted 5b. The residue is freed from remaining traces of pentane by evaporation leaving 3.7 g of 6tb (46%). extracted with Et2O (4×40 mL) The combined extracts are filtered evaporated The residue (6.4 g) is thoroughly extracted with pentane (4×25 mL) to remove unreacted 5b by evaporation leaving 3.7 g of 6tb (46%)

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

Procedure: Redistilled 2-oxopropanoic acid (12.6 ml, 0.18 mol) is added to a vigorously stirred mixture of NaHCO3 (30.6 g, 0.36 mol), TBA HSO4 (61.2 g, 0.18 mol), H2O (360 mL), and CH2Cl2 (360 mL) in an open Erlenmeyer flask. Following stirring for 10 min 5b (44.0 g, 0.18 mol) in CH2Cl2 (400 mL) is added during 3 h at 25° C. together with CH2Cl2 (500 mL) in portions to compensate for the evaporation. In this way the formation of sulfurous by-products is minimized. The mixture is extracted with CH2Cl2 (300-200 mL). The combined organic phases are washed with H2O (2×200 mL); dried (MgSO4) and evaporated. The residue is triturated with Et2O (600 mL). After filtration the filtrate is treated with charcoal, evaporated, and the residue crystallized from pentane at -70° C. to yield 6ob, melting below room temperature. to compensate for the evaporation The mixture is extracted with CH2Cl2 (300-200 mL) The combined organic phases are washed with H2O (2×200 mL) dried (MgSO4) evaporated The residue is triturated with Et2O (600 mL) After filtration the filtrate is treated with charcoal evaporated the residue crystallized from pentane at -70° C. to yield 6ob melting below room temperature

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

Procedure: To a stirred solution of NaHCO3 (45 g, 536 mmol) in H2O (540 ml) is added TBA HSO4 (91.2 g, 268 mmol), propanoic acid (20.1 mL, 268 mmol), and CH2Cl2 (540 ml). Following stirring for 1 h at room temperature a solution of 5b (49.2 g, 200 mmol) in CH2Cl2 (100 mL) is added during 45 min keeping the temperature below 30° C. The stirring is continued for 11/2 h. The organic phase is separated, washed with H2O (200 mL), dried (MgSO4), and evaporated. The residue is stirred in Et2O (800 mL) during the night, filtered, and washed with Et2O (50 mL). The filtrate is evaporated and distilled to yield 38.0 g (98%) of 6cb, bp 71°-73° C./0.3 mbar. is added during 45 min the temperature below 30° C 2 h The organic phase is separated washed with H2O (200 mL) dried (MgSO4) evaporated filtered washed with Et2O (50 mL) The filtrate is evaporated distilled

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

Procedure: 2-Furancarboxylic acid (5.6 g, 50 mmol) is added to a stirred solution of NaHCO3 (8.4 g, 100 mmol) and TBA HSO4 (17.0 g, 50 mmol) in H2O (100 mL) at room temperature. After stirring for 10 min 1,2-dichloroethane (100 mL) is added and the stirring continued for 30 min. 5b (12.5 g, 50 mmol) in 1,2-dichloroethane (25 mL) is added over 15 min. The mixture is stirred for 60 min at room temperature. The organic phase is separated, washed with H2O (50 mL), dried (MgSO4), and evaporated. The residue is stirred with Et2O (100 mL), insoluble material filtered off and washed with Et2O. The combined Et2O-phases are evaporated and the residue crystallized from ice-cold pentane to yield 8.5 g (74%) of 6mb, mp 37.2°-38.4° C. is added The organic phase is separated washed with H2O (50 mL) dried (MgSO4) evaporated The residue is stirred with Et2O (100 mL), insoluble material filtered off washed with Et2O The combined Et2O-phases are evaporated the residue crystallized from ice-cold pentane to yield 8.5 g (74%) of 6mb, mp 37.2°-38.4° C.

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

Procedure: To a mixture of 3-(diethylphosphono)propanoic acid (79, 1.0 g, 4.76 mmol) in H2O (12 mL) and CH2Cl2 (12 mL) was added NaHCO3 (1.0 g, 11.9 mmol) and TBAHSO4 (1.62 g, 4.76 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (1.17 g, 4.76 mmol) in CH2Cl2 (2 mL) was added. The biphasic reaction was stirred vigorously for 4 h 20 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using EtOAc as the eluent, to yield compound 80 (1.29 g, 83%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.30-1.65 (m, 9H), 2.03-2.12 (m, 2H), 2.64-2.71 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 4.06-4.14 (m, 4H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 30.45 (s). The biphasic reaction was stirred vigorously for 4 h 20 min The layers were separated the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution dried over MgSO4 filtered concentrated to dryness The crude product was triturated with Et2O the solids were removed by filtration rinsed with small portions of Et2O After concentration the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system

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

Procedure: To a mixture of acid 73 (519 mg, 1.01 mmol) in H2O (3 mL) and CH2Cl2 (3 mL) was added NaHCO3 (176 mg, 2.09 mmol) and TBAHSO4 (342 mg, 1.01 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (192 mg, 0.77 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 3 h and was diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 20-60% EtOAc in CH2Cl2 as eluent, to furnish compound 74 (351 mg, 72%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.94-1.98 (m, 6H), 2.20-2.24 (m, 6H), 2.43 (t, J=6.9 Hz, 2H), 2.70 (t, J=6.9 Hz, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.81 (s, 2H), 5.98 (s, 1H). The biphasic reaction was stirred vigorously for 3 h The layers were separated the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution dried over MgSO4 filtered concentrated to dryness The crude product was triturated with Et2O the solids were removed by filtration rinsed with small portions of Et2O After concentration the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system

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

Procedure: To a mixture of dipeptide 51 (969 mg, 1.69 mmol) in H2O (3.25 mL) and CH2Cl2 (3.25 mL) was added NaHCO3 (294 mg, 3.50 mmol) and TBAHSO4 (572 mg, 1.69 mmol). After stirring for 15 min, S-ethyl O-iodomethyl carbonothioate (322 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 2.5 h and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using a gradient of 0-50% EtOAc in CH2Cl2 as eluent to provide compound 52 (818 mg, 91%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.30-1.53 (m, 8H), 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.60-1.75 (m, 2H), 1.82-1.90 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 3.06-3.14 (m, 4H), 4.04-4.10 (m, 1H), 4.58-4.64 (m, 1H), 4.70 (bs, 2H), 5.18-5.21 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.90 (d, J=5.6 Hz, 1H) 6.67 (bd, J=6.8 Hz, 1H). The biphasic reaction was stirred vigorously for 2.5 h The layers were separated the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution dried over MgSO4 filtered concentrated to dryness The crude product was triturated with Et2O the solids were removed by filtration rinsed with small portions of Et2O After concentration the combined filtrates were purified by flash chromatography on silica gel

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

Procedure: S-Ethyl O-iodomethyl carbonothioate (423 mg, 1.72 mmol) was added to a stirring mixture of 31 (1.13 g, 1.71 mmol), NaHCO3 (298 mg, 3.55 mmol) and tetrabutylammonium hydrogensulfate (588 mg, 1.73 mmol) in CH2Cl2/H2O (1:1, 17 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (80 mL) and the aqueous layer was discarded. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaCl, dried over Na2SO4 then concentrated under reduced pressure. The residue was resuspended in Et2O, filtered and again concentrated under reduced pressure. The crude material was purified by silica gel chromatography (25%-60% EtOAc in hexanes over 10 column volumes) to give the colourless liquid 32 (1.23 g, 92%): 1H NMR (400 MHz, CDCl3): δ 1.32 (t, J=7.3, 3H), 1.41-1.47 (m, 40H), 1.61-1.75 (m, 4H), 2.89 (q, J=7.3, 2H), 3.10-3.31 (m, 12H), 3.92 (s, 4/7 of 2H, rotamer A), 4.01 (s, 3/7 of 2H, rotomer B), 5.84 (s, 2H). The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaCl dried over Na2SO4 then concentrated under reduced pressure filtered again concentrated under reduced pressure The crude material was purified by silica gel chromatography (25%-60% EtOAc in hexanes over 10 column volumes)

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

Procedure: To a mixture of acid 1 (1.0 g, 5.74 mmol) in H2O (14.5 mL), and CH2Cl2 (14.5 mL) was added NaHCO3 (1.00 g, 11.9 mmol) and TBAHSO4 (1.95 g, 5.74 mmol). After stirring for 25 min, S-ethyl O-iodomethyl carbonothioate (1.10 g, 4.42 mmol, prepared according to Synthesis 1990, 1159) in CH2Cl2 (5 mL) was added. The biphasic reaction was stirred vigorously for 2 h 35 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with water, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over Na2SO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using 20% EtOAc in hexanes as eluent to furnish compound 2 (1.06 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 9H), 2.54-2.58 (m, 2H), 2.63-2.66 (m, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.62 (s, 2H). The biphasic reaction was stirred vigorously for 2 h 35 min The layers were separated the organic layer was washed with water, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution dried over Na2SO4 filtered concentrated to dryness The crude product was triturated with Et2O the solids were removed by filtration rinsed with small portions of Et2O After concentration the combined filtrates were purified by flash chromatography on silica gel