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Method 4; Preparation of 6-bromo-5-methylnicotinaldehyde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 C. The solution was stirred for 2 hours at 0 C. and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound (3.0 g, 74%); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, 1H), 8.73 (s, 1H), 10.09 (s, 1H).
74%
Method 3; Preparation of 6-bromo-5-methvmicotmaldehvde; 2,5-Dibromo-3-picoline (5.1 g, 20.30 mmol) in tetrahydrofuran (25 ml) was added dropwise to a 2M solution of isopropylmagnesium chloride (10.7 ml, 21.3 mmol) in tetrahydrofuran at 0 0C. The solution was stirred for 2 hours at 0 0C and then for 1 hour at ambient temperature. A solution of 4-formylmorpholine (2.1 ml, 20.3 mmol) in tetrahydrofuran (25 ml) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and the solution concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 10 % ethyl acetate in isohexane, to give the title compound (3.0 g, 74 %); NMR Spectrum: (DMSO-d6) 2.44 (s, 3H), 8.19 (s, IH), 8.73 (s, IH), 10.09 (s, IH).
Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to -78 C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0 C. over 30 minutes, followed by stirring at 0 C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).
8.58g of t-Butyl N-(3-bromobenzyl)carbamate was dissolved in 100 ml of tetrahydrofuran, and the mixture was cooled to -78C under nitrogen atmosphere. 41 ml of butyl lithium (1.56 M solution in hexane) was added. After stirring was continued for 30 minutes, 6.91 g of N-formylmorpholine was added. After stirring was continued at -78C for 30 minutes, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off, and the residue was purified by silica gel column chromatography, to give 4.762 g of the title compound in the 3:1 ? 3:2 hexane-ethyl acetate fraction.1H-NMR (CDCl3) delta : 1.44 (s, 9H) 4.40 (d, J=6.0Hz, 2H) 4.95 (br, 1H) 7.50 (m, 1H) 7.56-7.59 (m, 1H) 7.78-7.80 (m, 1H) 7.80 (s, 1H) 10.01 (s, 1H)
As depicted in Scheme 25 below, <strong>[3704-41-4]2-(4-nitrophenyl)thiazole</strong> (19.9 mmol) dissolved in ether (20 ml) is added dropwise over 1 hour to a stirred and cooled (-78 C.) solution of butyl lithium (1.5 M) in n-hexane (20 ml, 29.9 mmol), diluted with ether (50 ml). The mixture is stirred at -78 C. for 30 minutes and then a solution of N-formylmorpholine (29.9 mmol) in ether (30 ml) is added dropwise over a time period of 15 minutes. After 30 minutes at -78 C., the mixture is washed with saturated aqueous NaHCO3 (30 ml) and extracted with ether (2*20 ml). The organic phase is dried over Na2SO4 and the solvent is removed under reduced pressure to give the crude <strong>[3704-41-4]2-(4-Nitro-phenyl)-thiazol</strong>e-5-carbaldehyde.
5-chloro-2-fluoropyridine-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Formation of 5-chloro-2-fluoronicotinaldehyde (27)To a cold (0 °C) solution of diisopropylamine (12.8 mL, 91.2 mmol) in THF (100 mL) was added butyllithium (31.9 mL of 2.5 M, 79.8 mmol) over 5 min. After 5 min, the reaction was cooled to -78 °C for 15 min. Then <strong>[1480-65-5]5-chloro-2-fluoro-pyridine</strong> (10.0 g, 76.0 mmol) was slowly added over 5 min. The reaction was kept at -78 °C for an additional 1.5 hr. Then, morpholine-4- carbaldehyde (17.5 g, 152.1 mmol) was added rapidly. The mixture was stirred for a further 2 min and quenched with 10percent citric acid and the mixture was allowed to warm to room temperature. The pH was adjusted to 5-6 with additional citric acid solution. The mixture was extracted with dichloromethane (3 x 200 mL) and the combined organic layers were dried over Na2S04, filtered and concentrated. Flash chromatography (Si02, 0-25percent EtOAc-Hexanes, gradient eiution) provided the desired product as an off-white crystaiine solid (8.95 g, 74percent yield). LC-MS shows the mass for the desired product and the corresponding hydrate: NMR (300 MHz, CDC13) 5 10.28 (d, J = 8.4 Hz, 1 H), 8.41 (t, J= 1.4 Hz, 1 H) and 8.25 (dd, J = 2.7, 7.8 Hz, 1H) ppm; LC/MS Gradient 10-90percent, 0.1percent formic 5min, C 18/ACN, RT = 2.45 min, (M+H) 159.91.
To a stirred solution of 5chloro-24luoropyridine (15 g,114.5 mmcl) in THE (150 mL) was added LDA (85.8 mL, 171.7 mmcl) drop wise at 78 °C. After stirred for 1.5 h, the morpholine4-carbaldehyde was added to the above solution and the mixture solution was stirred at 78 °C for another 2 h. After TLC (petroleum ether: EtOAc = 5:1) showed the. . Z 1 L.. IL.. f?OIcomp.euu UI LI reauu I, Lie iedclur VY uenci eu uy lIe uuIuuI UI 1 U /0 iLi i NU.The reaction mixture was then allowed to warm up to room temperature and adjusted to pH = 5-6. The mixture was extracted with DCM (100 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4,filtered and concentrated in vacuo to give a crude title compound (2.8 g, 15percent yield) as a while solid. MS: 160.0 [M±H]. This crude product wasused directly in the next step without tudher purification.
General procedure: The reaction was carried out in a sealed tube under N2 using THF (4 mL) as the solvent. To the solution of tert-butyl 2-bromothiazole-4-carboxylate 1a (0.397 mmol), iPrMgCl·LiCl (1.3 M, 0.52 mmol) was added dropwise at -78 C. After 15 min the corresponding aldehyde (0.79-0.99 mmol) or N-formyl-morpholine (in the case of 2-formylthiazoles 3a-b) was added dropwise under stirring and the reaction mixture was stirred at -78 C for 10 min, then 1.5 h at 0 C. Saturated aqueous NH4Cl was added and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with 5% aqueous HCl (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mixture of EtOAc:P (petroleum ether) as eluent (see below) to give tert-butyl 2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2a-h.
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