4-BROMO-1-METHYLPYRIDIN-2(1H)-ONE

(0675) 4-Bromopyridin-2(1H)-one (1.0 g, 5.75 mmol) was dissolved in tetrahydrofuran (20 mL). Under the protection of nitrogen gas, the mixture was cooled to 0° C., and sodium hydride (mass percentage 60percent, 0.23 g, 5.75 mmol) was added. The mixture was warmed up to room temperature and stirred for 15 min. Iodomethane (1.10 mL, 17.24 mmol) was slowly added dropwisely. After the addition, the mixture was stirred at room temperature for 16 h. TLC detection showed that the reaction was finished. Water and ethyl acetate were added, and the water phase and the organic phase are separated. The organic phase was washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated to get the title compound (1.02 g, yield: 94.4percent).General procedure: In a dry Schlenk tube 6-methyl-2(1H)-pyridone (1) (3.43 g, 31.44 mmol) was dissolved in 50 mLof 1, 4-dioxane and KOt-Bu (8.69 g, 62.88 mmol) was added. The mixture was stirred at 100 °C for 2 h, then cooled down to rt, MeI (19.6 mL, 314.41 mmol) was added dropwise and the mixture was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the residue was separated between DCM and water. The extraction was performed using DCM (3×) and the combined organic phases were dried over MgSO4-bromopyridin-2 (1H) -one (3.0 g, 17.2 mmol) was dissolved in tetrahydrofuran (100 mL)Nitrogen protection down to 0 ° C, Sodium hydride (mass fraction 60percent, 0.69 g, 17.2 mmol) was added, The mixture was stirred at room temperature for 15 minutes, Methyl iodide (3.30 mL, 53.0 mmol) was slowly added dropwise, After completion of the dropwise addition, the mixture was stirred at room temperature for 16 hours, Water (80 mL) and ethyl acetate (80 mL) were added, The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (2.85 g, yield 88.2percent).To a solution of 4-bromo-2-hydroxypyridine (0.1O g, 0.57 mmol) in THF (5.0 mL) was added, portion wise, NaH (60percent dispersion in mineral oil, 0.02 g, 0.86 mmol). The resulting solution was stirred at room temperature for 5 min followed by addition of methyl iodide (0.11 mL, 1.72 mmol). The reaction mixture was then allowed to stir overnight at room temperature. After the completion of reaction, THF was distilled off, added water and extracted with ethyl acetate (3 x 25 mL). The combined organics was washed with water, brine, dried (NaTo a solution of 4-bromo-2-hydroxypyridine (0.55 g, 3.16 mmol) in DMF (8 mL) were added K2CO3 (0.874 g, 6.32 mmol) and Mel (0.23 mL, 3.64 mmol). The reaction mixture was stirred at rt over night. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine, dried over MgSCk The filtrate was concentrated in vacuo to give Intermediate 31A (white solid, 0.35 g, 1.89 mmol, 58percent yield). LC-MS Anal. Calc'd for CeHeBrNO 188.96, found [M+H] 188, 190.1. TTo a suspension of NaH (300 mg, 7.5 mmol) in THF (10 mL) was added 4-bromopyridin-2-ol (303 mg, 1.73 mmol) at 0° C. After the resulting mixture was stirred for 1 h, CHGeneral procedure: A Schlenk tube was charged with the 2-pyridone substrate (1.0 mmol) [in the case of a liquid substrate, this was added neat after the solvent], [Ir(cod)(OMe)]2 (6.6 mg, 0.01 equiv), 4, 4′-di-tert-butyl-2, 2′-dipyridyl (5.4 mg, 0.02 equiv) and bis(pinacolato)diboron (178 mg, 0.70 equiv). After purging with nitrogen, deoxygenated and anhydrous THF (1.4 mL) was added and the reaction mixture was heated at reflux for 48 h (in cases where full conversion occurred after 24 h, the reaction was halted at that time). The volatile materials were then removed under reduced pressure and the crude product was dissolved in MeOH (2.5 mL) and a solution of CuBr2 (670 mg, 3.0 mmol) in H2O (2.5 mL) was added. The reaction mixture was heated at 80 °C for 18 h under air, cooled to r.t., diluted with NH4OH (5 mL, 15percent aq) and extracted with CH2Cl2 (5 × 5 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude reaction mixture by flash column chromatography on silica gel afforded the desired product. Table 1 shows the product distributions of 2–5 but no attempt was made to optimise monosubstitution (vs. disubstitution) in the case of 1b or 1c. According to General Procedure 1, analysis of the 1H NMR spectrum ofthe crude reaction mixture showed a conversion of 100percent. Products 5-bromo-1-methylpyridin-2(1H)-one (3b), 4-bromo-1-methylpyridin-2(1H)-one (2b), 4, 6-dibromo-1- methylpyridin-2(1H)-one (4b) and 3, 5-dibromo-1-methylpyridin-2(1H)-one (5b) were generated in a 35:5:39:21 ratio. Purification by flash column chromatography on silica gel (n-hexane–EtOAc, 70:30 to EtOAc, 100percent) gave an inseparable 95:5 mixture of 5-bromo-1-methylpyridin-2(1H)-one (3b) and 4-bromo-1-methylpyridin-2(1H)-one (2b) (71 mg, 38percent) as an orange oil. 2b (minor component) Rf = 0.24 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 7.5 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 6.28 (dd, J = 2.0, 7.5 Hz, 1 H), 3.50 (s, 3 H). The spectroscopic properties of this compound were consistent with data available in literature. 3b (major component) Rf = 0.24 (EtOAc).1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 2.5 Hz, 1 H), 7.33 (dd, J = 2.5, 9.5 Hz, 1 H), 6.46 (d, J = 9.5 Hz, 1 H), 3.50 (s, 3 H). The spectroscopic properties of this compound were consistent with data availablein literature.19a4, 6-Dibromo-1-methylpyridin-2(1H)-one (4b) Yield: 58 mg (22percent); off-white solid; Rf = 0.59 (EtOAc). IR (neat): 3111, 2922, 2851, 1650, 1566, 1495 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.75 (s, 1 H), 6.66 (s, 1 H), 3.68 (s, 3 H).13C NMR (100 MHz, CDCl3): δ = 161.5, 134.8, 128.3, 120.7, 114.4, 36.4.HRMS-ESI: m/z [M + H]+ calcd for C6H679Br2NO: 265.8811; found:265.8799.3, 5-Dibromo-1-methylpyridin-2(1H)-one (5b)Yield: 28 mg (11percent); white solid; Rf = 0.51 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 2.0 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 3.58 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 158.0, 143.8, 137.5, 117.4, 96.5, 39.0. The spectroscopic properties of this compound were consistent withthe data available in literature.4-bromo-1-methylpyridin-2(1H)-one (17a)Step 8: To the mixture from Step 7, was added 2 M aqueous K2CO3 (0.1 mL), Pd X-Phos G3 (4.0 mg, 0.05 mmol) and 4-bromo-l-methylpyridin-2(lH)-one (20.0 mg, 0.11 mmol). The reaction was then heated at 100 C for 12 h. The crude product was purified by column chromatography on silica gel, eluting with a MeOH/CH2Cl2 gradient (0-30% MeOH) to yield 4-(4-(3-((3S, 4S)-3- fluoro-2, 2, 6, 6-tetramethylpiperidin-4-yl)-37/-[l, 2, 3]triazolo[4, 5-c]pyridazin-6-yl)-3- (methoxymethoxy)phenyl)-l-methylpyridin-2(lH)-one (35 mg, 75% yield). MS m/z 522.4 [M+H]+General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.General procedure: To a 50mL round-bottom flask under a nitrogen atmosphere 7 (10.0 mmol), bispinacolatodiboron (10.0 mmol), PdCl2(dppf)2 (0.5 mmol), potassium acetate (15 mmol) and 1, 4-dioxane (20 mL) were added. The reaction mixture was stirred at 80 C for 8 h. After the completion of the reaction, Cs2CO3 (15 mmol), PdCl2(dppf)2 (0.5 mmol), 3 (11.0 mmol) and 0.5 mL H2O were added to the above mixture. The reaction was stirred at 110 C overnight. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with DCM for 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 8a-8l.To an ice-cold solution of 2-hydroxy-4-bromopyridine (5.75 mmol) in THF was added NaH (5.75 mmol) portion-wise. The reaction mixture was stirred in an ice-bath for 15 min followed by addition of halide or iodine (17.24 mmol). The resulting reaction mixturewas stirred at room temperature for 16 h. After the completion of the reaction, 20 mL of H2O was added and the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was collected and rinsed with brine. The mixture was evaporated to obtain the crude product and purified by silica gel for 3a-3d. 4.1.2.1.

Molecular Weight:188.02
XLogP3:0.8
Hydrogen Bond Acceptor Count:1
Exact Mass:186.96328
Monoisotopic Mass:186.96328
Topological Polar Surface Area:20.3
Heavy Atom Count:9
Complexity:195
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes