3-(BENZYLOXY)-5-BROMOPYRIDINE

White solid

3-(Benzyloxy)-5-bromopyridine [1099] (Zhu. G.-D. et al., Bioorg. Med. Chem. Lett. 2006, 16, 3150-3155) [1100] A 500 mL three-necked flask was charged with sodium hydride (60percent dispersion in oil; 9.6 g, 240 mmol, 2.0 equiv.) and fitted out with stir bar, dropping funnel, NBenzylalcohol (10 mL, 96 mmol) was dissolved in dry DMF (30 mL) and sodium hydride (60percent suspension in mineral oil) (2.5 g, 62.50 mmol) was slowly added. When no more gas evolved, 3, 5-dibromopyridine (10 g, 42.21 mmol) was added and the reaction mixture was stirred at 180 °C for 2 h. After addition of water, the aqueous phase was extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by column chromatography eluting with an 8/2 mixture of petroleum ether and diethyl ether and then a second column chromatography eluting with a 9/1 mixture of CHBenzyl alcohol (4.60 g, 42.6 mmol) was slowly added to a stirred solution of NaH (60percent disp., 1.70 g, 42.5 mmol) in DMF (50 mL). The reaction was heated to 60 To a solution of benzyl alcohol (1.04g, 9.66mmol) in anhydrous DMF (80mL) was slowly added 60percent NaH (0.58g, 14.49mmol). The mixture was allowed to react at room temperature for 30min then it was heated to reflux for 1h. 3, 5-dibromopyridine (2.41g, 10.17mmol) was added and the reaction was continued for 12h. After cooling down to room temperature, the mixture was poured in water and extracted with ethyl acetate. The organic phase was washed with brine, dried on MgSOCaesium carbonate (6.52 g, 20.0 mmol) was added to a stirred solution of 5-bromopyridin-3-ol (1.74 g, 10 mmol) in DMF (25 mL). The reaction mixture was stirred at 60 °C for 30 minutes, then benzyl bromide (2.05 g, 1.43 mL, 12 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and partitioned between diethyl ether (100 mL) and water (50 mL). The organic phase was separated, dried and evaporated. The residue was purified by chromatography on silica gel eluting with dichloromethane to give 3-(benzyloxy)-5- bromopyridine (1.17 g, 4.43 mmol, 44.3percent yield) as an orange solid. LCMS (2 min, Formic Acid): Rt = 1.15 min, MHStep 1 (0839) To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 hour and then cooled to 25° C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and ethyl acetate extraction. The product was purified by ISCO column eluted with 40-100percent EtOAc-Hexanes. The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8percent yield) was obtained as yellow oil. MS: 266.1. ESIMS found for CStep 1 To a solution of 5-bromopyridin-3-ol (LI) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 hour and then cooled to 25°C. The (bromomethyl)benzene (LV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and ethyl acetate extraction. The product was purified by ISCO column eluted with 40- 100percent EtOAc-Hexanes. The 3-(benzyloxy)-5-bromopyridine (LVI) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil.. MS: 266.1. ESIMS found for CTo a solution of 5-bromopyridin-3-ol (XLIX) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIII) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LIV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C12H10BrNO mlz 266.1 (M+H).To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C, 2H, oBrNO mlz 266.1 (M+H).To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C12H10BrNO mlz 266.1 (M+H).j0674j To a solution of 5-bromopyridin-3-ol (LXVII) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LXXI) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LXXII) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C12H10BrNO mlz 266.1 (M+H).To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25 °C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for Ci[0674] To a solution of 5-bromopyridin-3-ol (LXVII) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LXXI) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25 °C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LXXII) ( 105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 inL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25 °C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (LXVII) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25 °C. The (bromomethyl)benzene (LXXI) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25 °C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40- 100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LXXII) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil.To a solution of 5-bromopyridin-3-ol (LXVII) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LXXI) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25 °C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LXXII) ( 105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5 -bromopyridin-3 -ol (XLIX) ( 174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIII) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LIV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiStep 1 [0654] To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 inL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) ( 171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40- 100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) ( 171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40- 100percent EtOAc-hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C12H10BrNO m/z 266.1 (M+H).Step 1 [0655] To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 inL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for Ci[0651] To a solution of 5-bromopyridin-3-ol (XLIX) (174 mg, 1.0 mmol) in DMF (3 inL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIII) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LIV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 inL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAc- hexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for CiTo a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C12H10BrNO mlz 266.1 (M+H).To a solution of 5-bromopyridin-3-ol (LXV) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 hour and then cooled to 25° C. The (bromomethyl)benzene (LXIX) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and ethyl acetate extraction. The product was purified by ISCO column eluted with 40-100percent EtOAc-Hexanes. The 3-(benzyloxy)-5-bromopyridine (LXX) (105 mg, 0.398 mmol, 39.8percent yield) was obtained as yellow oil. MS: 266.1. ESIMS found for CStep 1 Preparation of intermediate 3-(benzyloxy)-5-bromopyridine (LV) is depicted below in Scheme 11. Step 1 (0839) To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 hour and then cooled to 25° C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and ethyl acetate extraction. The product was purified by ISCO column eluted with 40-100percent EtOAc-Hexanes. The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8percent yield) was obtained as yellow oil. MS: 266.1. ESIMS found for CStep 1 (0842) To a solution of 5-bromopyridin-3-ol (L) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 hour and then cooled to 25° C. The (bromomethyl)benzene (LIV) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and ethyl acetate extraction. The product was purified by ISCO column eluted with 40-100percent EtOAc-Hexanes. The 3-(benzyloxy)-5-bromopyridine (LV) (105 mg, 0.398 mmol, 39.8percent yield) was obtained as yellow oil. MS: 266.1. ESIMS found for CStep 1 (0863) To a solution of 5-bromopyridin-3-ol (LXV) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90° C. for 1 hour and then cooled to 25° C. The (bromomethyl)benzene (LXIX) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25° C. overnight. The reaction was worked-up using a saturated sodium bicarbonate and ethyl acetate extraction. The product was purified by ISCO column eluted with 40-100percent EtOAc-Hexanes. The 3-(benzyloxy)-5-bromopyridine (LXX) (105 mg, 0.398 mmol, 39.8percent yield) was obtained as yellow oil. MS: 266.1. ESIMS found for Cj0651j To a solution of 5-bromopyridin-3-ol (XLIX) (174 mg, 1.0 mmol) in DMF (3 mL) was added potassium carbonate (415 mg, 3.0 mmol). The slurry was heated at 90°C for 1 h and then cooled to 25°C. The (bromomethyl)benzene (LIII) (171 mg, 1.0 mmol) was added and the mixture was stirred at 25°C overnight. The reaction was worked-up using a saturated sodium bicarbonate and EtOAc extraction. The product was purified by ISCO column (40-100percent EtOAchexanes). The 3-(benzyloxy)-5-bromopyridine (LIV) (105 mg, 0.398 mmol, 39.8 percent yield) was obtained as yellow oil. ESIMS found for C, 2H, oBrNO mlz 266.1 (M+H).5-bromopyridin-3-ol (100 mg, 0.575 mmol), silver carbonate (475 mg, 1.724 mmol), and benzyl bromide (68.4 μL, 0.575 mmol) were dissolved in CHClTo a suspension of 5-bromo-pyridin-3-ol (1.9 g, 10.9 mmol) in acetonitrile (152 mL) is added bromomethyl-benzene (2.1 g, 12.0 mmol) and potassium carbonate (4.5 g, 32.8 mmol). The resultant mixture is stirred at room temperature for 16 h. The crude product is purified by silica gel column to afford 3-benzyloxy-5-bromo-pyridine (1.0 g).Synthesis of 3-Benzyloxy-5-bromo-pyridine

Molecular Weight:264.12
XLogP3:3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:262.99458
Monoisotopic Mass:262.99458
Topological Polar Surface Area:22.1
Heavy Atom Count:15
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes