Ethyl5-Oxo-4,5-dihydro-1H-pyrazole-3-carboxylate

Acetic acid (150 mL) was added drop-wise to a solution of sodium 1 , 4-diethoxy- (0282) 1 , 4-dioxobut-2-en-2-olate (30.0 g, 0.143 mol) in toluene (150 mL), and the mixture was stirred at room temperature for 30 minutes, whereupon hydrazine monohydrochloride (85percent, 17 g, 0.29 mol) was added. The reaction mixture was stirred for an additional 30 minutes at room temperature and subsequently heated at 100 °C overnight. It was then concentrated in vacuo and extracted with ethyl acetate (500 mL); the organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product as a yellow solid. Yield: 17 g, 0.1 1 mol, 77percent. Diethyloxalacetate, sodium salt (14. 53 g, 69. 15 mmol) was dissolved in 100 mL of benzene and stirred for 20 min. To the solution was added 100 ML of acetic acid and the reaction mixture was stirred for a further 30 min. Hydrazine monohydrochloride (9. 47 g, 138 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction was brought to reflux at 100 C for 24 h. The reaction was then removed from heat and cooled to room temperature and extracted with ethyl acetate and washed with 10percent hydrochloric acid, saturated sodium bicarbonate solution, water and then brine. The solvent was removed IN VACUO TO yield an oily solid which was then triturated with a 2 : 1 mixture of diethyl ether : hexanes to yield 3 (10. 00 g, 92percent) as an off-white solid : LRMS (electrospray) ; m/z [M+H1+ = 157.To a mixture of ethyl 5-hydroxy-1 H-pyrazole-3-carboxylate (10.0 g, 64.0 mmol, CAS 51986-17- 5) in DMF (300 ml) was added caesium carbonate (45.9 g, 141 mmol) and the mixture was stirred at room temperature for 10 min. The reaction was cooled down to 0C and iodomethane (8.2 ml, 130 mmol) was added and the mixture was stirred at room temperature overnight. For work-up, the reaction was concentrated under reduced pressure and the crude product was purified by flash chromatography (hexane /acetone gradient, 0% -> 100 % acetone) to give the title compound (1.46 g).A mixture of C1 3 (460 mg, 1 .1 mmol), C1 (600 mg, 3.8 mmol), cesium carbonate (0461) (1 .1 g, 3.4 mmol), and sodium iodide (140 mg, 0.93 mmol) in A/, A/-dimethylformamide (13 mL) was heated to 100 C for 3 hours. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were concentrated under reduced pressure and purified via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether); the product was isolated as a white solid. Yield: 220 mg, 0.95 mmol, 86%. 1H NMR (400 MHz, CDC ) delta 6.15 (s, 1 H), 4.59 (br t, JHF=12.4 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.36 (br t, JHF=10.4 HZ, 2H), 1 .40 (t, J=7.2 Hz, 3H).1 , 3-Dibromobutane (5.8 g, 27 mmol) was added to a suspension of C1 (4.0 g, 26 mmol) and potassium carbonate (14.1 g, 102 mmol) in acetonitrile (100 mL), and the reaction mixture was heated at reflux overnight. After it had cooled to room temperature, it was filtered, and the collected solids were washed with acetonitrile (3 x 30 mL). The combined filtrates were concentrated in vacuo to afford a mixture of P8 and P9 as a yellow oil. By 1H NMR, this was a roughly 2-3 to 1 mixture. 1 H NMR (400 MHz, CDCI3), minor component, presumed to be P8: delta 6.00 (s, 1 H), 4.42-4.14 (m, 5H), 2.25-2.17 (m, 1 H), 2.15-2.06 (m, 1 H), 1.48 (d, J=6.3 Hz, 3H), 1.39 (t, J=7.1 Hz, 3H); major component, presumed to be P9: delta 6.00 (s, 1 H), 4.49-4.22 (m, 5H), 2.37 (dddd, j=14.4, 7.4, 5.6, 3.1 Hz, 1 H), 2.01 (dddd, J=14.4, 7.8, 6.6, 3.1 Hz, 1 H), 1 .64 (d, J=6.5 Hz, 3H), 1.38 (t, J=7.1 Hz, 3H). This mixture was subjected to silica gel chromatography (Gradient: 17% to 67% ethyl acetate in petroleum ether) to afford the products. The indicated regiochemistry was assigned on the basis of NMR studies carried out on bromo derivatives C7 and C9 (see below). Yield of P8: 0.9 g, 4 mmol, 15%. Yield of P9: 1.7 g, 8.1 mmol, 31 %.A mixture of C4 (20 g, 50 mmol), C1 (8.2 g, 52 mmol), cesium carbonate (48.5 g, 149 mmol), and sodium iodide (7.5 g, 50 mmol) in /V, /V-dimethylformamide (150 mL) was heated at 100 C for 2 hours. Water (1 L) and ethyl acetate (500 mL) were added, and the organic layer was concentrated in vacuo; silica gel chromatography (Gradient: 1 % to 50% ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 8.0 g, 37 mmol, 74%. 1 H NMR (400 MHz, CDCI3) delta 6.10 (s, 1 H), [5.32-5.27 (m) and 5.21 -5.16 (m), JHF=46 Hz, 1 H], 4.67-4.54 (m, 2H), 4.48-4.32 (m, 1 H), 4.39 (q, J=7.1 Hz, 2H), 4.22 (br dd, J=36.6, 12.4 Hz, 1 H), 1.39 (t, J=7.1 Hz, 3H).