Application In Synthesis of 5-Bromonicotinaldehyde
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 2.5h;Heating / reflux;
IA. S-Phenyl-pyridine-3-carbaldehyde: A biphasic mixture of 5- bromo-3-formyl pyridine (0.500 g, 2.69 mmol), Pd(Ph3P)4 (0.155 g, 0.134 mmol), and phenyl boronic acid (0.492 g, 4.03 mmol) in degassed 2.0 M aqueous Na2CO3 (6.0 mL) and toluene (6.7 mL) was heated at reflux for 2.5 h. The reaction was cooled to rt, diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (Ix). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give an orange- brown oil weighing 0.848 g. Column chromatography on silica gel gave 0.447 g (91%) of the biaryl compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) delta: 10.19 (s, IH), 9.07 (s, IH), 9.04 (s, IH), 8.34 (s, IH), 7.62 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.47-7.44 (m, IH). MS 184.2 (M+H)+; 216.2 (M+CH3OH+H)+.
A flask is charged with Λ/-(tert-butoxycarbonyl)-6-chloro-1 H-indol-2-ylboronic acid (8.3 g, 28.1 mmol), 5-bromonicotinaldehyde (4.35 g, 23.4 mmol), K3PO4 (9.94 g, 46.8 mmol), s-Phos (0.480 g, 1.170 mmol) and Pd2(dba)3 (0.429 g, 0.468 mmol), and the flask is flushed with N2. Toluene (250 ml.) is added, and the mixture is heated to 85 0C for 1.5 h.The mixture is cooled to room temperature. Ethyl acetate (250 ml.) is added and the mixture is filtered through a pad of silica gel, which is washed with EtOAc. Silica gel is added to the combined filtrate, which is concentrated in vacuo. The residue is placed under high vacuum at 63 0C overnight, and after elution with ethyl acetate, 5-(6-chloro- <n="135"/>1 H-indol-2-yl)-pyridine-3-carbaldehyde is obtained. MS (ESI) m/z 257.0 and 258.9 (M+H)+.
A mixture of 5-bromonicotirsaSdehydbeta (1.860 g, 10 mrnof), ethanes utfonamtde (1.091 g, 10.00 mmo.) and titanium(iV) isopropoxide (5.86 mi, 20.00 mmoi) in Toluene (20 mL) was heated to reflux for 2 hr. After concentration, the residue was dissolved in THF (25 mL) and cooled to -40 0C. A solution of cyclopropyimagnesiurn bromide (50-0 ml, 25.00 mmoi) was added dropwise and the resuiting mixture was slowly warmed up to -20 0C and stirred at this temperature for 4 hr. After quenched by NH4C1 soiution, filtration, extraction with CH2C12, the solution was dried over Na2SO4, and concentrated, the residue was purified by flash column (ethyi acetate / heptane, v/v, 10percent-35percent) and yielded the title compound (1.5 g). 1H MMR (400.3 MHz, CDCf3); delta 0.2-0.3 (m, 1H)1 0.4-0.5 (m, IH)1 0.5-0.6 (m, 1H)1 0.6-0.7 (m, 1H), 1.0-1.1 (m, 1H)1 1.1-12 (m, 3H), 2.55-2.75 (m. 2H)1 3,6-3.7 <;m, 1 H), 4.51 (brd, J ~ 4.8 Hz, 1H)1 7.73 (s, 1H)r 8.42 (S, 1 H), 8.51 (S1 1H).
A mixture of 5-bromonicotinaldehyde (372 mg, 2 mmo.),<strong>[1520-70-3]ethanesulfonamide</strong> (273 mg, 2.500 mmol) and tttanium(IV) isopropoxide (1172 mul, 4.00 mmol) m toluene (20 mL) was heated to reflux for 2 h. After concentration, the residue was dissolved in THF (25 mL) and cooled to -400C. A solution of cyclopropyimagnesium bromide (10 mL, 5.00 mmol) was added dropwise and the resulting mixture was slowly warmed up to -200C and stirred at this temperature for 4 h. After quenching by saturated NH4CI solution, filtration, extraction with CH2CI7, the solution was dried over Na2SO4, and concentrated. The residue was purified by flash column (ethyl acetate / heptane, v/v, 10percent-35percent) and yielded the title product as oil (430 mg). 1H NMR (400 MHz, CDCI3): 80.2-0.3 (m, 1H)1 0.4-0.5 (m, 1H)1 0.5-0.6 (m. 1H), 0.6-0.7 (m, 1H), 1.0-1.1 (m, 1H), 1.1-1.2 (m, 3H). 2.55-2.75 (m,2H). 3.6-3.7 <;m, 1H)1 4.51 (brd. J = 4.8 Hz, 1H). 7.73 <;s, 1H). 8.42 (s, 1H), 8.51 (s, 1H).
0.59 g
Step A: To a mixture of 5-bromonicotinaldehyde (0.50 g, 2.69 mmol) and <strong>[1520-70-3]ethanesulfonamide</strong> (0.37 g, 3.36 mmol) in 9.0 mL of toluene is added titanium(IV) isopropoxide (1.59 mL, 5.4mmol). The reaction mixture is stined at 120°C for 3 hours after which time it is concentrated to dryness. The remaining residue is dissolved in 10 mL of THF and cooled to -40°C. Cyclopropylmagnesium bromide (16.13 mL, 8.1 mmol) is added drop-wise and the reaction mixture is allowed to gradually warm to room temperature. After 16 hours, the reaction mixture is diluted with EtOAc and washed with saturated aqueous NH4C1 solution then brine. The organic layer is dried (Mg504), filtered and concentrated. The remaining residue is purified via silica gel flash column chromatography eluting with 0-5percent MeOH/DCM to give 0.59 g of ethanesulfonic acid [(5-bromo-pyridin-3-yl)-cyclopropyl-methyl] -amide.
Intermediate A- 11Ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amideA flask was charged with 5-bromonicotinaldehyde (2.55 g, 13.7 mmol),<strong>[1520-70-3]ethanesulfonamide</strong> (2.99 g, 27.4 mmol) and toluene (250 mL), then titanium isopropoxide (5.84 g, 20.6 mmol) was added dropwise. The reaction mixture was heated to 115 °C over night and then concentrated in vacuo. The residue was taken up in DCM (200 mL) and MeOH (200 mL) and NaBH4 (1.04 g, 27.4 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then poured into water (100 mL) and the resulting suspension was filtered through a pad of Dicalite and washed with DCM (3 x 100 mL). The aqueous layer was separated and extracted with DCM (2 x 200 mL).Combined organics were dried over Na2S04, filtered and preadsorbed on silica gel. The residue was purified by silica gel flash chromatography eluting with a 0 to 5percent MeOH- DCM gradient to give the title compound (3.01 g, 79percent) as an orange solid. MS: 279.0, 281.0 (M+H+).
79%
A flask was charged with 5-bromonicotinaldehyde (2.55 g, 13.7 mmol),<strong>[1520-70-3]ethanesulfonamide</strong> (2.99 g, 27.4 mmol) and toluene (250 mL), then titanium isopropoxide (5.84 g, 20.6 mmol) was added dropwise. The reaction mixture was stirred at 115 °C over night and then concentrated in vacuo. The residue was taken up in DCM (200 mL) and MeOH (200 mL) and NaBH4 (1.04 g, 27.4 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then poured into water (100 mL) and the resulting suspension was filtered through a pad of dicalite. The dicalite layer was washed with DCM (3x 100 mL). The resulting aqueous layer was separated and extracted with DCM (500 mL). Combined organics were dried over Na2S04, filtered and preadsorbed on silica gel. The residue was purified by silica gel flash chromatography eluting with a 0 to 5percent MeOH-DCM gradient to give the title compound (3.01 g, 79percent) as an orange solid. MS: 279.0, 281.0 (M+H+).
With sodium tris(acetoxy)borohydride; acetic acid; triethylamine; In 1,1-dichloroethane; at 20℃; for 3h;
To a solution of 5-bromo-3-pyndmecarboxaldehyde (CASNo. 113118-81-3, 450 mg, 2 4 mmol) in dichloroethane (15 mL) was added <strong>[1520-70-3]ethanesulfonamide</strong> (CASNo. 1520-70-3, 175 mg, 1 6 mmol), acetic acid (0 18 mL 3.2 mmol), triethylamtne (0.45 mL, 3 2 mmol) and sodium triacetoxyborohydride (1.0g, 4 8 mmol) The reaction was stirred at room temperature for 3 hours, at which time it was diluted with dichloromethane and saturated aqueous sodium bicarbonate The layers were separated and the aqueous layer was extracted two additional times with dichloromethane The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated The resulting residue was purrfied by silica gel flash chromatography (ethyl acetate-heptane, 10 to 100percent) to provide ethanesulfonic acid (5-bromo-pyridm-3-ylmethyl)-arnide, MS (ES+) m/z 278 9 (M+H)
A mixture of 5-bromonicotinaidehyde (930 mg, 5 mmol),<strong>[1520-70-3]ethanesulfonamide</strong> (546 mg, 5.00 mmol) and titanium(IV) isopropoxide (2930 mul, 10.00 mmoi) in toluene (20 mL) was heated to refiux for 4 h. After concentration, the residue was dissolved in THF (25 mL) and cooled to -400C. A solution of cyclopentylmagnesium bromide (2M in THF, 6.25 mL, 12.5 mmol) was added dropwise and the resulting mixture was slowly warmed up to 0 0C over 4 h. The reaction was quenched with a saturated NH4CI solution. The mixture was filtered, separated, and extracted with CH2CI2. The organic pahse was dried over Na2SO4. filtered and concentrated, and the residue was purified by flash column (ethyl acetate / heptane, v/v, 10percent- 30percent) to give a yellow oil (480 mg). ESi-MS mlz: 348.9 [M+1}+; 1H NMR (400 MHz, CDCI3): delta 1.13-1.80 (m, 7H). 1.26 (t, J * 7.4 Hz, 3H), 1.97- 2.0delta (m, 1H), 2.20-2.29 (m, 1H). 2.67-2.92 (m, 2H). 4.27 (t, J * 8.8 Hz, 1H), 5.59 (brs, 1H), 7.87 (s, 1H), 8.56 (s, 1H), 8.68 (s, 1H).
A mixture of 5~bromo-pyridine-3-carbaidehyde (0.930 g, S mmol). <strong>[1520-70-3]ethanesulfonamide</strong> (0,682 g, 6.25 mmol) and titanium(IV) isopropoxide (2.93 ml. 10.00 mmol) in toluene (10 ml.) was heated to 100 °C for 4 h. After concentration, the residue was dissolved in THF (12.5 ml), and (4-fluorophenyl)magnesium bromide (1 M in THF, 12.50 mL, 12.50 mmol) was added dropwise at -78 0C. The mixture was stirred at -78 0C for 45 min. The mixture was quenched with saturated NH4CI and extracted with EtOAc two times, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via Biotage (10-40percent AcOEt/heptane; SNAP25 column) giving the title compound (986 mg. 53percent) as a beige solid, LC-MS (M-H) 375.0.
A flask was charged with 5-bromonicotinaldehyde (0.5 g, 2.69 mmol), <strong>[1520-70-3]ethanesulfonamide</strong> (0.367 g, 3.36 mmol) and toluene (25 mL), then titanium tetra-isopropoxide (1.53 g, 5.38 mmol) was added dropwise. The reaction mixture was heated to 110° C. over night and then concentrated in vacuo. The residue was dissolved in THF (25 mL) and cooled down to ?40° C. A 3 M solution of ethylmagnesium bromide in ether (2.24 mL, 6.72 mmol) was added dropwise at this temperature and the resulting mixture was slowly warmed up to ?20° C. and stirred for 2.5 h. The mixture was poured into a saturated NH4Cl solution (15 mL), the resulting suspension was filtered and the filtrate was extracted with DCM (2×50 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5percent MeOH-DCM gradient to give the title compound (0.5 g, 56percent) as light yellow oil. MS: 307.1 and 308.9
56%
Intermediate A-38 (rac)-N-(l-(5-Bromopyridin-3-yl)propyl)<strong>[1520-70-3]ethanesulfonamide</strong>A flask was charged with 5-bromonicotinaldehyde (0.5 g, 2.69 mmol), <strong>[1520-70-3]ethanesulfonamide</strong> (0.367 g, 3.36 mmol) and toluene (25 mL), then titanium tetra-isopropoxide (1.53 g, 5.38 mmol) was added dropwise. The reaction mixture was heated to 110 °C over night and then concentrated in vacuo. The residue was dissolved in THF (25 mL) and cooled down to -40 °C. A 3 M solution of ethylmagnesium bromide in ether (2.24 mL, 6.72 mmol) was added dropwise at this temperature and the resulting mixture was slowly warmed up to -20 °C and stirred for 2.5 h. The mixture was poured into a saturated NH4C1 solution (15 mL), the resulting suspension was filtered and the filtrate was extracted with DCM (2 x 50 mL). Combined organics were dried over Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5percent MeOH- DCM gradient to give the title compound (0.5 g, 56percent) as light yellow oil. MS: 307.1 and 308.9.
With titanium(IV) isopropylate; In toluene; at 115℃;
A flask was charged with 5-bromonicotinaldehyde (2.55 g, 13.7 mmol), <strong>[1520-70-3]ethanesulfonamide</strong> (2.99 g, 27.4 mmol) and toluene (250 mL), then titanium isopropoxide (5.84 g, 20.6 mmol) was added dropwise. The reaction mixture was heated to 115° C. over night and then concentrated in vacuo. The residue was taken up in DCM (200 mL) and MeOH (200 mL) and NaBH4 (1.04 g, 27.4 mmol) was added portionwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then poured into water (100 mL) and the resulting suspension was filtered through a pad of Dicalite and washed with DCM (3×100 mL). The aqueous layer was separated and extracted with DCM (2×200 mL). Combined organics were dried over Na2SO4, filtered and preadsorbed on silica gel. The residue was purified by silica gel flash chromatography eluting with a 0 to 5percent MeOH-DCM gradient to give the title compound (3.01 g, 79percent) as an orange solid. MS: 279.0, 281.0 (M+H+).
To a vial is added 5-bromonicotinaldehyde (300 mg, 1.61 mmol) and <strong>[1520-70-3]ethanesulfonamide</strong> (220 mg, 2.02 mmol) in 6 ml of toluene, followed by the addition of titanium(IV) isopropoxide (1 ml, 3.23 mmol). The reaction mixture is stirred at 120° C. for 6 hours. The reaction mixture is concentrated. The residue is dissolved in 5 ml of THF and is cooled to ?40° C., methylmagnesium bromide, 3M in ether (1.6 ml, 4.84 mmol) is added dropwise. The reaction mixture is warm up and stirred at room temperature for 18 hours. The reaction mixture is diluted with EtOAc, washed with saturated NH4Cl, (aq.) brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 130 mg of ethanesulfonic acid [1-(5-bromo-pyridin-3-yl)-ethyl]-amide.
5-(6-chloro-1-Boc-1H-indol-2-yl)nicotinaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.9%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; In toluene; at 40 - 45℃; for 3.0h;Inert atmosphere;
Was added to the reaction flask under nitrogen 17.0 g of <strong>[352359-22-9](N-Boc-6-chloro-1H-indol-2-yl)boronic acid</strong>, 10.2 g of 5-bromo-3-pyridinecarboxaldehyde, 1.02 g S-phos, 14.1 g of potassium acetate, 141 g of toluene, 0.85 g of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3). Stirred and reacted at 40 to 45 C for 3 hours. To the reaction solution was added 85 g of water, followed by stirring for 20 minutes. The reaction solution was filtered (pad 5.6 g of diatomaceous earth) 14g toluene. The filtrate is separated, The organic layer was washed with 51 g of water, and then the organic layer was concentrated under reduced pressure to obtain a solid. The solid was refluxed with 42.5 g of methyl tert-butyl ether, filtered, filtered, dried, To give a pale yellow solid (17.2 g) of 5-(6-chloro-1-Boc-1H-indol-2-yl)nicotinaldehyde was obtained. HPLC purity 98.9% yield 83.9%.
2-(5-bromopyridin-3-yl)-2,3-dihydrofuro[3,2-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With tetrabutyl ammonium fluoride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃;
General procedure: To a stirred mixture of 1.00 mmol of nitropicoline 35 or 63, 1.20 mmol of the appropriate benzaldehyde, and 1.5 mmol of Huenig's base in THF (7 mL/g of nitropicoline 35/63) was added 1.3 mmol of a 1 M THF solution of TBAF. The resulting mixture was heated 60 C for 1.5e2.0 h in the case of 2,3-dihydrofuro[3,2-c] pyridines or for 18 h in the case of 2,3-dihydrofuro[2,3-b]pyridines. After cooling to room temperature, the reactions were quenched with sat. aqueous NH4Cl. The solution was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography as specified above.