cyclopropylhydrazine

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclopropylhydrazine (2.71 g) (Step 17.2) was added to a solution of 5-(4-chlorophenyl)-3-hydroxy-4-(2-methoxyacetyl)-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (5 g, 12.4 mmol) (Step 130.2) in a mixture of EtOH and toluene (60 mL, 1:1, v/v). The reaction mixture was stirred 16 h at 115° C., concentrated, quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title compound (2.62 g) as a yellow solid. tR: 1.24 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1). concentrated quenched with a saturated aq. NaHCO3 solution extracted with EtOAc (2×100 mL) The combined organic layers were dried over Na2SO4 the solvent was evaporated off under reduced pressure The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%)

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 9:1). tR: 1.23 min (LC-MS 2); ESI-MS: 249.2 [M+H]+ (LC-MS 2); Rf=0.34 (hexane/EtOAc 9:1). The crude product was purified by silica gel column chromatography (hexane/EtOAc 9:1)

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (Hexane/EtOAc 9:1). tR: 1.10 min (LC-MS 2); ESI-MS: 249 [M+H]+ (LC-MS 2); Rf=0.17 (hexane/EtOAc 9:1). The crude product was purified by silica gel column chromatography (Hexane/EtOAc 9:1)

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 4-(dimethylamino)-2-oxobut-3-enoate at 125° C. for 8 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%). tR: 3.45 min (HPLC 1); tR: 0.74 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2); Rf=0.59 (hexane/EtOAc 1:1). The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%)

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

Procedure: The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 4-(Dimethylamino)-2-oxobut-3-enoate at 125° C. for 8 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%). tR: 4.40 min (HPLC 1); tR: 0.91 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2); Rf=0.85 (hexane/EtOAc 1:1). The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of cyclopropylhydrazine (Step 17.2) (4.90 g, 45.1 mmol) in toluene (30 mL) and EtOH (30 mL) was added ethyl 2,4-dioxavalerate (6.34 mL, 45.1 mmol). The reaction mixture was stirred for 1 hr at 100° C., quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%) to afford the title product (3.01 g, 15.50 mmol, 34% yield). tR: 4.70 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 195 [M+H]+ (LC-MS 2); Rf=0.33 (hexane/EtOAc 9:1). quenched with a saturated aq. NaHCO3 solution extracted with EtOAc The combined organic layers were washed with a saturated aq. NaHCO3 solution dried over Na2SO4 evaporated The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of cyclopropylhydrazine (Step 17.2) (4.90 g, 45.1 mmol) in toluene (30 mL) and EtOH (30 mL) was added ethyl 2,4-dioxavalerate (6.34 mL, 45.1 mmol). The reaction mixture was stirred for 1 hr at 100° C., quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc. The organic layers were combined and washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%) to afford the title product (3.74 g, 19.26 mmol, 43% yield). tR: 3.84 min (HPLC 1); tR: 0.84 min (LC-MS 2); ESI-MS: 195 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1). quenched with a saturated aq. NaHCO3 solution extracted with EtOAc washed with a saturated aq. NaHCO3 solution dried over Na2SO4 evaporated The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of cyclopropylhydrazine (Step 17.2) (4.90 g, 45.1 mmol) in toluene (30 mL) and EtOH (30 mL) was added ethyl 2,4-dioxavalerate (6.34 mL, 45.1 mmol). The reaction mixture was stirred for 1 hr at 100° C., quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc. The organic layers were combined and washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%) to afford the title product (3.74 g, 19.26 mmol, 43% yield). tR: 3.84 min (HPLC 1); tR: 0.84 min (LC-MS 2); ESI-MS: 195 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1). quenched with a saturated aq. NaHCO3 solution extracted with EtOAc washed with a saturated aq. NaHCO3 solution dried over Na2SO4 evaporated The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%)

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

Procedure: Following the procedure of Example 3, Step A, except that the o-dipropylbenzene of Example 3 is replaced by an equivalent amount of: 4-chloro-; 4-iodo-; and 4-bromo-1,2-dipropylbenzene and the methylhydrazine is replaced by an equivalent amount of propylhydrazine; cyclopropylhydrazine; and γ-THP-oxy-propylhydrazine, there is obtained 5-chloro, 5-iodo, and 5-bromo-2-propyl-1,3-diethylisoindole; 5-chloro-; 5-iodo-; and 5-bromo-2-cyclopropyl-1,3-diethylisoindole; and 5-chloro-; 5-iodo-; and 5-bromo-2-γ-THP-oxy-propyl-1,3-diethylisoindole, respectively; wherein THP represents tetrahydropyranyloxy.

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

Procedure: Acetic acid (1.71 mL, 29.9 mmol) was slowly added to a solution of cyclopropylhydrazine.HCl (2.5 g, 18.1 mmol) in H2O (30 mL), and was then quickly added dropwise to a solution of pyruvaldehyde (40%, 2.36 mL, 14.5 mmol) in H2O (240 mL). This solution was stirred overnight at room temperature. The aqueous layer was salted and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 1.04 g of crude product as a reddish oil. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of ethyl acetate/hexanes (25:75 to 50:50) to afford 637 mg (35%) of 2-oxopropanal cyclopropylhydrazone as a yellow solid. extracted with CH2Cl2 (4×) The combined organic extracts were dried (Na2SO4) concentrated under reduced pressure to give 1.04 g of crude product as a reddish oil The crude product was purified via flash chromatography (silica gel) eluting with a gradient of ethyl acetate/hexanes (25:75 to 50:50)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2Z)-3-amino-2-butenenitrile (903 mg, 11.00 mmol), cyclopropylhydrazine (1194 mg, 11 mmol) and triethylamine (3.07 mL, 22.00 mmol) were suspended in ethanol (100 mL) and heated to 70° C. for 16 hours. The solvent was removed in vacuo. The residue was suspended in 50 mL of saturated NaHCO3 and stirred for 10 minutes. The contents were extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0% to 100% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.13 (m, 4 H), 2.13 (s, 3 H), 3.06 (m, J=6.95, 6.95, 3.79, 3.54 Hz, 1 H), 3.76-3.88 (m, 2 H), 5.24 (s, 1 H). LCMS(ES) [M+H]+ 138.1 The solvent was removed in vacuo The contents were extracted with DCM dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel chromatography (eluent: 0% to 100% gradient EtOAc:Hex) The product was collected as 310 mg

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclopropylhydrazine (2.71 g) (Step 17.2) was added to a solution of 5-(4-chlorophenyl)-3-hydroxy-4-(2-methoxyacetyl)-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (5 g, 12.4 mmol) (Step 130.2) in a mixture of EtOH and toluene (60 mL, 1:1, v/v). The reaction mixture was stirred 16 h at 115° C., concentrated, quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title compound (2.62 g) as a yellow solid. tR: 1.24 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1). concentrated quenched with a saturated aq. NaHCO3 solution extracted with EtOAc (2×100 mL) The combined organic layers were dried over Na2SO4 the solvent was evaporated off under reduced pressure The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%)