3-chloro-4,4-dimethylpent-2-enenitrile

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium selenide (4.39 g, 34.84 mmol, prepared from 2.78 g of selenium as described above) in DMF (35 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5.0 g, 34.84 mmol) in DMF (13 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (2.2 mL, 34.84 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.88 g, 34.84 mmol) in dry methanol (22 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 30 min. The precipitated solid was filtered and washed with water. The solid was recrystallized from chloroform-hexane to give the product as a brown color solid (5.2 g, 65%), mp 110-112° C. 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s, H-4), 4.46 (2H, br s, —NH2), 1.33 (9H, s, tert-butyl); LC-MS (negative ion mode): m/z 225, 227 (M−H)−. again stirred at 60-70° C. for 2 h stirring was continued for 1 h at the same temperature was allowed to room temperature (rt) stirred for 30 min The precipitated solid was filtered washed with water The solid was recrystallized from chloroform-hexane

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium selenide (4.39 g, 34.84 mmol, prepared from 2.78 g of selenium as described above) in DMF (35 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5.0 g, 34.84 mmol) in DMF (13 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (2.2 mL, 34.84 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.88 g, 34.84 mmol) in dry methanol (22 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 30 min. The precipitated solid was filtered and washed with water. The solid was recrystallized from chloroform-hexane to give the product as a brown color solid (5.2 g, 65%), mp 110-112° C. 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s, H-4), 4.46 (2H, br s, —NH2), 1.33 (9H, s, tert-butyl); LC-MS (negative ion mode): m/z 225, 227 (M−H)−. again stirred at 60-70° C. for 2 h stirring was continued for 1 h at the same temperature was allowed to room temperature (rt) stirred for 30 min The precipitated solid was filtered washed with water The solid was recrystallized from chloroform-hexane

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium selenide (4.4 g, 34.84 mmol, prepared from 2.78 g of selenium as described above) in DMF (35 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5 g, 34.84 mmol) in DMF (10 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then ethyl chloroacetate (3.71 mL, 34.84 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.88 g, 34.84 mmol) in methanol (25 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into ice cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (6.2 g, 65%), mp 66-68° C. 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s, H-4), 5.52 (2H, br s, —NH2), 4.24 (2H, q, J=7.1 Hz, —COOCH2CH3), 1.33 (9H, s, tert-butyl), 1.31 (3H, t, J=7.1 Hz, —COOCH2CH3). again stirred at 60-70° C. for 2 h stirring was continued for 1 h at the same temperature was allowed to rt poured into ice cold water stirred for 15 min The precipitated solid was filtered washed with water dried

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium selenide (4.4 g, 34.84 mmol, prepared from 2.78 g of selenium as described above) in DMF (35 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5 g, 34.84 mmol) in DMF (10 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then ethyl chloroacetate (3.71 mL, 34.84 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.88 g, 34.84 mmol) in methanol (25 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into ice cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (6.2 g, 65%), mp 66-68° C. 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s, H-4), 5.52 (2H, br s, —NH2), 4.24 (2H, q, J=7.1 Hz, —COOCH2CH3), 1.33 (9H, s, tert-butyl), 1.31 (3H, t, J=7.1 Hz, —COOCH2CH3). again stirred at 60-70° C. for 2 h stirring was continued for 1 h at the same temperature was allowed to rt poured into ice cold water stirred for 15 min The precipitated solid was filtered washed with water dried

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice cold (0-5° C.) dimethylformamide (6.2 mL, 80 mmol) was added phosphorous oxychloride (3.75 mL, 40 mmol) dropwise with stirring for 15 min. To this cold mixture, tert-butyl methyl ketone (2.0 g, 20 mmol) was added dropwise maintaining the temperature of the reaction mixture between 45-55° C. for 10 min. The reaction mixture was slowly allowed to room temperature (rt) and stand for 30 min. To the reaction mixture, 1 mL of a total solution of hydroxylamine hydrochloride (5.56 g, 80 mmol) in dry DMF (8 mL) was added and the mixture was stirred at 70-80° C. for 5 min. Then the remaining solution of hydroxylamine hydrochloride in DMF was added thereafter at such a rate that the temperature of the reaction mixture rise above 145-155° C. After completion of the addition, the reaction mixture was allowed to rt for 30 min and diluted with cold water (200 mL). The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel using hexane-ethyl acetate (98:2) as eluent to give the product as a light green color oil (1.0 g, 35%). 1H NMR (400 MHz, CDCl3): δ 5.56 (1H, s, ═CH), 1.24 (9H, s, tert-butyl). was slowly allowed to room temperature (rt) stand for 30 min the mixture was stirred at 70-80° C. for 5 min rise above 145-155° C After completion of the addition the reaction mixture was allowed to rt for 30 min The solution was extracted with chloroform (3×100 mL) the combined chloroform layer was washed with water, brine dried over sodium sulfate The solution was filtered evaporated the solvent The residue was chromatographed over silica gel

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

Procedure: The 3-amino-5-(tert-butyl)selenophene-2-carbonitrile is prepared starting from the 3-chloro-4,4-dimethylpent-2-enenitrile, sodium selenide and chloroacetonitrile, which on diazotization with sodium nitrite followed by treatment with dimethylamine gave the required 3-[(dimethylamino)diazenyl]-5-(tert-butyl)selenophene-2-carbonitrile (compound 11).

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

Procedure: The reaction of 3-chloro-4,4-dimethylpent-2-enenitrile, sodium selenide and bromonitromethane as described earlier gave the product as a yellow color solid, mp 112-114° C. 1H NMR (400 MHz, DMSO-d6): δ 8.28 (2H, br s), 6.76 (1H, s), 1.28 (9H, s). as described earlier gave the product as a yellow color solid, mp 112-114° C

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice cold (0-5° C.) dimethylformamide (6.2 mL, 80 mmol) was added phosphorous oxychloride (3.75 mL, 40 mmol) dropwise with stirring for 15 min. To this cold mixture, tert-butyl methyl ketone (2.0 g, 20 mmol) was added dropwise maintaining the temperature of the reaction mixture between 45-55° C. for 10 min. The reaction mixture was slowly allowed to room temperature (rt) and stand for 30 min. To the reaction mixture, 1 mL of a total solution of hydroxylamine hydrochloride (5.56 g, 80 mmol) in dry DMF (8 mL) was added and the mixture was stirred at 70-80° C. for 5 min. Then the remaining solution of hydroxylamine hydrochloride in DMF was added thereafter at such a rate that the temperature of the reaction mixture rise above 145-155° C. After completion of the addition, the reaction mixture was allowed to rt for 30 min and diluted with cold water (200 mL). The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel using hexane-ethyl acetate (98:2) as eluent to give the product as a light green color oil (1.0 g, 35%). 1H NMR (400 MHz, CDCl3): δ 5.56 (1H, s), 1.24 (9H, s). was slowly allowed to room temperature (rt) stand for 30 min the mixture was stirred at 70-80° C. for 5 min rise above 145-155° C After completion of the addition the reaction mixture was allowed to rt for 30 min The solution was extracted with chloroform (3×100 mL) the combined chloroform layer was washed with water, brine dried over sodium sulfate The solution was filtered evaporated the solvent The residue was chromatographed over silica gel

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

Procedure: The 3-chloro-3-tert-butylprop-2-enenitrile is reacted with sodium selenide, bromonitromethane in the presence of a base to provide 3-amino-5-tert-butyl-2-nitroselenophene.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of NaH (5.98 g, 0.24 mol, 2.6 equiv) in anh. DME (800 mL) at 0° C. was added methyl glycolate (23.0 g, 0.26 mol, 2.8 equiv) over 20 min. The mixture was stirred for 1 h at room temp. and a solution of 3-chloro-4,4-dimethyl-2-pentenenitrile (13.1 g, 0.091 mol) in DME (100 mL) was added. The resulting solution was heated to 85° C. for 42 h, cooled to room temp., and treated with H2O (100 mL). The resulting mixture was separated between H2O (200 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The residual oil was purified by flash chromatography (300 g SiO2, gradient from 50% CH2Cl2/hexane to 20% EtOAc/CH2Cl2) to give methyl 3-amino-5-tert-butylfuran-2-carboxylate as a yellow solid (2.98 g, 17%): mp 91-2° C.; TLC (20% EtOAc/hexane) Rf0.36; 1H NMR (CDCl3) δ1.26 (s, 9H), 3.84 (s, 3H), 4.54 (br s, 2H), 5.75 (s, 1H); 13C NMR (CDCl3) δ28.5 (3C), 33.0, 50.7, 98.5, 128.8, 131.0, 160.7, 168.3. cooled to room temp. The resulting mixture was separated between H2O (200 mL) and EtOAc (300 mL) The aqueous layer was extracted with EtOAc (2×200 mL) The combined organic layers were washed with a saturated NaCl solution dried (Na2SO4) concentrated under reduced pressure The residual oil was purified by flash chromatography (300 g SiO2, gradient from 50% CH2Cl2/hexane to 20% EtOAc/CH2Cl2)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Chloro-4,4dimethyl-2-pentenenitrile was prepared following a literature procedure (Hatcher et al. J. Heterocycl. Chem. 1989, 26, 1575). POCl3 (22.4 mL), 0.24 mol, 2.4 equiv) was slowly added to a 0° C. solution of DMF (20.2 mL, 0.26 mol, 2.6 equiv) keeping the temp. under 20° C. The resulting pink solid was heated to 40° C., pinacolone (12.5 mL, 0.10 mol) was added to the resulting red solution, and this mixture was heated to 55° C. for 2 h and 75° C. for 2 h. NH2OH.HCl (16.7 g, 0.24 mol, 2.4 equiv) was added to the 75° C. mixture slowly (<100 mg portions; CAUTION gas evolution and foaming). The resulting solution was heated to 85° C. for 2 h, then allowed to cool to room temp. overnight. The resulting yellow gel was separated between H2O (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure to give 3-chloro-4,4-dimethyl-2-pentenenitrile as a brown oil (13.2 g, 93%): 1H NMR (CDCl3) δ1.23 (s, 9H), 5.56 (s, 1H); GC-LRMS m/z (rel abundance) 143 (28%), 145 (11%). This material was used in the next step without further purification. 3-Chloro-4,4dimethyl-2-pentenenitrile was prepared under 20° C this mixture was heated to 55° C. for 2 h and 75° C. for 2 h The resulting solution was heated to 85° C. for 2 h to cool to room temp. overnight The resulting yellow gel was separated between H2O (500 mL) and EtOAc (300 mL) The aqueous layer was extracted with EtOAc (2×200 mL) The combined organic layers were washed with a saturated NaCl solution dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium selenide (3.51 g, 27.87 mmol) in DMF (28 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (4.0 g, 27.87 mmol; Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Yamaguchi, T.; Tomishima, Y.; Futaki, N.; Toda, Y.; Saito, S. Bioorg. Med. Chem., 2008, 16, 1111-1124) in DMF (10 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (1.76 mL, 27.87 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.5 g, 27.87 mmol) in dry methanol (18 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into cold water and stirred for 30 min. The precipitated solid was filtered and washed with water. The solid was recrystallized from chloroform-hexane to give the product as a brown color solid (3.8 g, 60%), mp 110-112° C. (Thomae, D.; Kirsch, G.; Seck, P. Synthesis, 2008, 1600-1606). 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s), 4.46 (2H, br s), 1.33 (9H, s); LC-MS (negative ion mode): m/z 225, 227 (M−H)−. again stirred at 60-70° C. for 2 h stirring was continued for 1 h at the same temperature was allowed to rt stirred for 30 min The precipitated solid was filtered washed with water The solid was recrystallized from chloroform-hexane to give the product