pent-4-enal

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) (2 g, 6.96 mmol) in DCE (35 ml) was added pent-4-enal (2.061 ml, 20.88 mmol) and the mixture was stirred at RT overnight. A further portion of sodium triacetoxyborohydride (4.43 g, 20.88 mmol) was added and the mixture was stirred at RT for 2.5 hours under an atmosphere of nitrogen. Water was added and the mixture was extracted with EtOAc (3×60 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound; the mixture was stirred at RT for 2.5 hours under an atmosphere of nitrogen the mixture was extracted with EtOAc (3×60 ml) The combined organic extracts were dried over MgSO4 filtered concentrated in vacuo The crude material was purified by chromatography on silica eluting with EtOAc/iso-hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an oven-dried 1 L round-bottomed flask pent-4-enal (11.3 g, 134 mmol) was dissolved in toluene (300 mL) to give a colorless solution. After cooling to 0° C., nitromethane (72.4 mL, 1343 mmol) and 1,1,3,3-tetramethylguanidine (1.685 mL, 13.43 mmol) were added. After the mixture was stirred at 0° C. for 60 min, TLC showed a major product (4:1 hexane/ethyl acetate). Methanesulfonyl chloride (15.7 mL, 202 mmol) and triethylamine (28 mL, 202 mmol) were added. The cooling bath was removed and the mixture was stirred at r.t. for 1 h. After 1 h, a further 0.5 equiv. of methanesulfonyl chloride (5.2 mL) and triethylamine (9.3 mL) were added to the mixture and the reaction continued for another h. It was quenched with saturated sodium bicarbonate solution and diluted with diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated under high vacuum to give a tan oil. The residue was purified by flash column chromatography up to 20% ethyl acetate/hexanes. The major uv-active fraction was pooled and concentrated to a light yellow oil (further dried under house vac over 3 days: 12.30 g, 72%): 1H NMR (4.00 MHz, CHLOROFORM-d) δ ppm 7.24 (ddd, J=13.74, 7.15, 6.96 Hz, 1H) 6.98 (d, J=13.55 Hz, 1H) 5.67-5.86 (m, 1H) 4.98-5.14 (m, 2H) 2.37 (q, J=7.03 Hz, 2H) 2.27 (q, J=6.94 Hz, 2H); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 140.82-141.82 (m, 1C) 139.50 (d, J=10.02 Hz, 1C) 135.60 (d, J=10.02 Hz, 1C) 115.56-116.67 (m, 1C) 30.49-31.82 (m, 1C) 26.73-27.94 (m, 1C). to give a colorless solution The cooling bath was removed the mixture was stirred at r.t. for 1 h After 1 h It was quenched with saturated sodium bicarbonate solution diluted with diethyl ether The layers were separated the aqueous layer was extracted with diethyl ether The combined organic layers were washed with brine dried with sodium sulfate concentrated under high vacuum to give a tan oil The residue was purified by flash column chromatography up to 20% ethyl acetate/hexanes concentrated to a light yellow oil (further dried under house vac over 3 days: 12.30 g, 72%)

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

Procedure: Boron trifluoride diethyl etherate (0.2 mL) was added, with stirring, to a solution of 4-pentenal (Cherif, A.; Farquhar, D. N-(5,5-diacetoxypent-1-yl)doxorubicin: A new intensely potent doxorubicin analogue. J. Med. Chem. 35, 3208-3214 (1992)) (2.5 g, 29.8 mmol) in ethanol (150 mL). The mixture was refluxed for 10 min under nitrogen, then the ethanol was removed under reduced pressure. The residue was taken up in dichloromethane (25 mL), and the solution was washed with 10% sodium acetate solution (15 mL) and water (2×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated. The residue was chromatographed on a column of silica gel using chloroform/methanol (97:3) as eluent. 4-Pentenal diethyl acetal was obtained as an oil (4.5 g, 96%). 1H NMR (CDCl3) δ 5.88-5.61 (m, 1 H, H4), 5.03-4.87 (m, 2 H, H5), 4.38 (t, 1 H, J=7, H1), 3.30-3.61(m, 4 H, 2×CH2), 2.07-1.96 (m, 2 H, H2), 1.64-1.53 (m, 2 H, H3), 1.09 (t, 6 H, J=7, 2×CH3). The mixture was refluxed for 10 min under nitrogen the ethanol was removed under reduced pressure the solution was washed with 10% sodium acetate solution (15 mL) and water (2×10 mL) dried over anhydrous sodium sulfate evaporated The residue was chromatographed on a column of silica gel

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 4-pentenal (8.4 g., 0.1 mol) was added dropwise to the Grignard reagent from magnesium turnings (2.88 g., 0.12 mol) and 1-bromohexane (19.8 g., 0.12 mol) in ether (120 ml). The reaction mixture was then refluxed for 2 hours cooled, and quenched with ammonium chloride solution. After layers were separated, ether solution was evaporated and the residue distilled to give 1-undecen-5-ol (15.0 g., 88% yield, b.p. 93°-96°/1.2 torr). The reaction mixture was then refluxed for 2 hours cooled quenched with ammonium chloride solution After layers were separated ether solution was evaporated the residue distilled

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-2-vinylbenzene (2.8146 g, 15.38 mmol) was azeotropped by dry benzene twice before taken up in THF (50 ml). The solution was cooled to −78° C. BuLi (6.77 ml, 16.91 mmol) was added to the reaction mixture at −78° C. and stirred for 20 min at this temperature. pent-4-enal (1.670 ml, 16.91 mmol) was added to the reaction mixture and stirred for 4 hours while the bath temperature gradually warmed up. Chlorotriisopropylsilane (3.58 ml, 16.91 mmol) was added to the reaction mixture and the reaction was stirred overnight while the reaction was warmed up to room temperature. The solvent was mostly removed via vacuum and the crude was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The product was obtained by flash column eluted with ether in hexane from 0 to 30% (3.9 g, 74% yield). MS (ESI)[M+H+]=346.46. stirred for 4 hours while the bath temperature gradually warmed up the reaction was stirred overnight while the reaction was warmed up to room temperature The solvent was mostly removed via vacuum the crude was partitioned between ethyl acetate and water The ethyl acetate layer was separated dried (Na2SO4) filtered concentrated The product was obtained by flash column eluted with ether in hexane from 0 to 30% (3.9 g, 74% yield)

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

Procedure: To 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.220 g; 0.72 mmol), dissolved in DCE (4 mL), is added pent-4-enal (0.060 mg; 0.72 mmol) followed by sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture stirred for 18 h at RT. The reaction mixture was diluted with CH2Cl2, washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to afford 2-methyl-2-(2-pent-4-enylaminoindan-5-ylsulfanyl)propionic acid tert-butyl ester as a crude oil. washed with H2O, brine dried over Na2SO4 filtered the solvent evaporated under reduced pressure

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

Procedure: 0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 0.414 ml of pent-4-enal (3.75 mmol) were dissolved in 7.5 ml methanol at rt and then refluxed for 1.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2¼ h. After cooling down to rt again 114 mg of sodium borohydride were added and the mixture was again refluxed for additional 1¼ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 172 mg light yellow oil (29%). MS (ISP) 232.3 (M+H)+. refluxed for 1.5 h the reaction mixture was then refluxed for 2¼ h were added the mixture was again refluxed for additional 1¼ h After cooling down to rt concentrated in vacuo The residue was diluted with water/EtOAc After separation of the organic phase the aqueous phase was extracted with EtOAc the combined organic phases were washed with brine dried with magnesium sulfate filtered off concentrated in vacuo The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Pentenal (4.45 g, 51.4 mmol) and malonic acid (6.41 g, 61.6 mmol) were dissolved in pyridine (9.9 mL). To the solution, piperidine (1.9 mL) was added, and the mixture was then stirred at 90° C. for 5 hours. The mixture was allowed to cool and then made acidic by the addition of 2 N hydrochloric acid, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the filtrate was then concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain the compound of interest as a colorless oil substance (3 mmHg, 110-116° C., 3.27 g, 50%). to cool followed by extraction with diethyl ether The organic layer was washed with saturated saline dried over anhydrous magnesium sulfate the filtrate was then concentrated under reduced pressure The residue was distilled under reduced pressure to obtain the compound of interest as a colorless oil substance (3 mmHg, 110-116° C., 3.27 g, 50%)

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

Procedure: A solution of 1-methyl-4-nitro-1H-pyrazole (9.7 g, 76.7 mmol) and 4-pentenal (10 g, 84.4 mmol) in dry THF (250 mL) was cooled to −78° C. and stirred under nitrogen. A solution of LiHMDS (1 M in THF, 192 mL, 191.7 mmol) was added dropwise over a period of 3 hr. The reaction mixture was allowed to warm and to −40° C. and stirred for 2 hr, quenched by dropwise addition of saturated ammonium chloride solution (100 mL), warmed to room temperature and diluted with EtOAc (200 mL). The organic layer was washed with saturated ammonium chloride solution (50 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel chromatography (0-100% EtOAc/DCM) followed by silica gel chromatography (0-100% EtOAc/isohexane) to gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pent-4-en-1-ol as a pale yellow oil (5.75 g, 36%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.85-5.78 (m, 1H), 5.32-5.26 (m, 1H), 5.12-5.04 (m, 2H), 3.98 (s, 3H), 3.45 (d, J=8.7 Hz, 1H), 2.92-2.09 (m, 3H), 1.90-1.86 (m, 1H). stirred for 2 hr quenched by dropwise addition of saturated ammonium chloride solution (100 mL) warmed to room temperature diluted with EtOAc (200 mL) The organic layer was washed with saturated ammonium chloride solution (50 mL) separated dried over MgSO4 the solvent removed under reduced pressure Purification via silica gel chromatography (0-100% EtOAc/DCM)