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CAS No. : | 70201-43-3 | MDL No. : | MFCD05864506 |
Formula : | C6H4BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NOBDKWLIAQKADB-UHFFFAOYSA-N |
M.W : | 186.01 | Pubchem ID : | 2762997 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.32 |
TPSA : | 29.96 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.72 cm/s |
Log Po/w (iLOGP) : | 1.33 |
Log Po/w (XLOGP3) : | 1.01 |
Log Po/w (WLOGP) : | 1.66 |
Log Po/w (MLOGP) : | 0.56 |
Log Po/w (SILICOS-IT) : | 2.2 |
Consensus Log Po/w : | 1.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.06 |
Solubility : | 1.63 mg/ml ; 0.00877 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.23 |
Solubility : | 11.0 mg/ml ; 0.0591 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.83 |
Solubility : | 0.278 mg/ml ; 0.00149 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.21 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H317-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 0.333333 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere |
To a solution of diisopropylamine (27.6 g, 273.0 mmol) in tetrahydrofuran (300 mL) was added dropwise a solution of n-butyllithium (91 mL, 228.0 mmol, 2.5 M) in tetrahydrofuran at —78 °C under nitrogen. The mixture was stirred at —78 °C for 1 h, followed by the dropwise addition of 3-bromopyridine (30.0 g, 190.0 mmol). The mixture was stirred at —78 °C for 20 mm before dimethylformamide (55.0 g, 760.0 mmol) was added dropwise. After addition, the reaction mixture was stirred at —78 °C for 1 h and was then warmed to ambient temperature before being quenched by addition of saturated aqueous ammonium chloride (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 3), the combined organic layers were concentrated in vacuo, and the resulting residue was purified by flash chromatography on Si02 to give the desired product (12.0 g, 34.0percent). ‘H NMR (400 MHz, CD3OD, ö): 10.37 (s, 1 H), 8.91 (s, 1 H), 8.80 — 8.61 (m, 1 H), 7.78 —7.63 (m, 1 H). LCMS (mlz): 187.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.25 h; Stage #2: at -70 - 20℃; |
n-BuLi (2 M in haxane, 24 mL, 48 mmol) was added to a solution of diisopropylamine (8 mL, 57 mmol) in anhydrous THF (80 mL) at -78 °C over 40 min and the resulting mixture was stirred at -78 °C for 1 hr. 3-Bromopyridine (9) (3.85 mL, 40 mmol) was then added over 5 min. After stirring for an additional 10 min, anhydrous methyl formate (10 mL, 160 mmol) was added drop-wise while the temperature was kept below -70 °C. The reaction mixture was warmed up to RT over 3 h. and quenched with saturated aqueous NaHCO3. After concentrated under reduced pressure, the residue was taken into ethyl acetate (100 mL) and water (75 mL). The aqueous layer was extracted with ethyl acetate (2 X 50 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate, 10:1) to give 10 (5.58 g, 75 percent) as a solid; mp. 81-82 °C (Lit.1 80-82 °C). 1H NMR (300 MHz, CDCl3): δ 10.38 (s, 1H), 8.92 (s, 1H), 8.70 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 5.4 Hz, 1H), 13C NMR (75 MHz, CDCl3): δ 190.7, 154.1, 149.5, 138.8, 123.0, 122.3. HRMS: m/e 184.9467, 186.9458 (Calcd for C6H4NOBr, 184.9469; C6H4NO81Br, 186.9450). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.25 h; Inert atmosphere Stage #2: at -78 - 20℃; for 2.33333 h; Inert atmosphere |
Under an N2 atmosphere, a 1.6 M solution of n-butyllithium in hexane (7.06 mL, 11.3 mmol) was added slowly to a cooled (-78 °C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol) in THF (25 mL). After 30 min stirring at 0 °C, the mixture was cooled to -78 °C and a solution of 3-bromopyridine 5c (1.63 g, 1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixture was stirred at -78 °C for 15 min, and then a solution of N-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was added slowly. The solution was stirred at -78 °C for 50 min. Then it was allowed to warm to room temperature and it was stirred for another 1.5 h. A satd. NH4Cl solution (40 mL) was added. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (60 mL) and dried over Na2SO4. Filtration and evaporation afforded crude product, which was purified by fc (5.5 cm, EtOAc:cyclohexane 1:4). Yellow solid (EtOAc:cyclohexane 2:1, Rf = 0.55), yield 914 mg (48percent). 1H NMR (600 MHz, CDCl3): δ (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72 (d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO). |
48% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.25 h; Inert atmosphere Stage #2: at -78℃; for 0.833333 h; Inert atmosphere |
Under an N2 atmosphere, a 1.6 M solution of n-butyllithium inhexane (7.06 mL, 11.3 mmol) was added slowly to a cooled(78 C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol)in THF (25 mL). After 30-min stirring at 0 C, the mixture wascooled to 78 C and a solution of 3-bromopyridine (5, 1.63 g,1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixturewas stirred at 78 C for 15 min, and then a solution ofN-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was addedslowly. The solution was stirred at 78 C for 50 min. Then itwas allowed to warm to room temperature and stirred for another1.5 h. Saturated NH4Cl solution (40 mL) was added. The aqueouslayer was extracted with EtOAc (3 30 mL). The combined organiclayers were washed with brine (60 mL) and dried over Na2SO4.Filtration and evaporation afforded crude product, which waspurified by fc (5.5 cm, EtOAc/cyclohexane 1:4). Yellow solid(EtOAc/cyclohexane2:1, Rf = 0.55), yield 914 mg (48percent). 1H NMR(600 MHz, CDCl3): d (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72(d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With n-butyllithium In tetrahydrofuran; water; N,N-dimethyl-formamide | The starting material was prepared as follows: A solution of di-isopropylamine (3.44 g, 34.1 mmol) was cooled to -78° C. and treated with n-butyl lithium 1.6M, 34.1 mmol). A solution of 3-bromopyridine (4.71 g, 30 mmol) in THF (5 ml) was added dropwise trying to keep the temperature below -70° C. The reaction was very exothermic, a solid precipitated and THF (2 ml) was added to improve stirring. The temperature rose to -45° C., after cooling to -60° C. and added remaining pyridine. DMF (2.49 g) in THF (15 ml) was added and the reaction stirred at -65° C. for 30 minutes. Water was added to quench the reaction and the reaction allowed to warm to ambient temperature. The reaction was partitioned between ethyl acetate/water and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated and the residue was subjected to chromatography (eluding with diethyl ether/hexane) to give 3-bromo-4-pyridinecarbaldehyde (1.4 g, 76percent). MS(CI+): 186 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.0 g | With hydrogen bromide In water at 20℃; for 0.5 h; | A mixture of crude 2-bromo-4-(diethoxymethyl)pyridine (162; 20.0 g,76.9 mmol) and aqueous HBr (100 mL) was stirred at room temperature for 30 mm, then neutralized with saturated NaHCO3 (50 mL) to pH 8-10 at 0 °C. The resulting mixture was extracted with CH2C12 (3 x 50 mL) and the combined organic layers were washed with brine, dried (Mg504) and concentrated. The residue was purified by silica gel column chromatographyto obtain 3-bromoisonicotinaldehyde (Compound 163; 15.0 g, quantitative) as a white solid. MS (ESI) calcd for C6H4BrNO:184.95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tetrahydroborate In methanol at 0℃; for 2 h; Inert atmosphere | [0068] To a solution of 3-bromo-4-pyridinecarboxaldehyde 3 (3.0 g, 16.2 mmol) in absolute methanol (40 mL) was added NaBH4 (0.736 g 19.5 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours under nitrogen. The solvent was then removed under vacuum. Water and ethyl acetate were added and the organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the compound 4 (3.021 g, 100percent) as a white powder. 1H NMR (CDCl3, 300 MHz, 298 K, δ ppm): 8.61 (s, 1 H), 8.51 (d, 1H, J = 4.8 Hz), 7.55 (d, 1H, J = 4.8 Hz), 4.76 (s, 2 H), 2.89 (s, 1H). 13C NMR (CDCl3, 75.5 MHz, 298 K, δ ppm): 151.14, 149.45, 148.54, 122.47, 119.90, 63.47. GC/MS (m/z): 188 IR (KBr, v, cm-1): 3152, 2894, 2829, 1593, 1447, 1401, 1333, 1223, 1170, 1070, 1024, 834, 705, 599 |
100% | With sodium tetrahydroborate In methanol at 0℃; for 2 h; Inert atmosphere | To a solution of 3 -bromo-4-pyridinecarboxaldehyde 3 (3.0 g, 16.2 mmol) in absolute methanol (40 mL) was added NaBH4 (0.736 g 19.5 mmol) at 0°C. The mixture was stirred at 0°C for 2 hoursunder nitrogen. The solvent was then removed under vacuum. Water and ethyl acetate were added and the organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the compound 4 (3.02 1 g, 100percent) as a white powder.‘H NN’IR (CDC13, 300 MHz, 298 K, S ppm): 8.61 (s, 1 H), 8.51 (d, 1H, J 4.8 Hz), 7.55 (d, 1H, J 4.8 Hz), 4.76 (s, 2 H), 2.89 (s, 1 H).‘3C NMR(CDC13, 75.5 MHz, 298 K, S ppm): 151.14, 149.45, 148.54, 122.47, 119.90, 63.47. GCIMS(m/z): 188IR (KBr, v, cm1): 3152, 2894, 2829, 1593, 1447, 1401, 1333, 1223, 1170, 1070, 1024, 834, 705, 599 |
100% | at 0℃; for 1 h; Inert atmosphere | Synthesis 2 (3-Bromo methanol A solution of 3-bromo-pyridine-4-carbaldehyde (5 mmol, 0.93 g) in methanol (10 mL) was cooled to 0 °C under nitrogen. This was treated with sodium borohydride (5.5 mmol, 0.200 g) portionwise, and allowed to stir at 0 °C for 1 hour, then slowly allowed to return to room temperature overnight. The reaction was quenched by the addition of saturated ammonium chloride (5 mL), then evaporated under reduced pressure. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was then separated and dried with MgSCU, filtered and evaporated to yield the title compound as a white solid. Yield: 0.94 g, 100percent. LCMS, analytical method 1 , TR= 2.18 mins, 100percent, Ml+H=188/190. H NMR (300 MHz, DMSO-d6) δ: 8.62 (1 H, m), 8.53 (1 H, d, J 4.9), 7.53 (1 H, dd, J 0.6, 4.9), 5.69 (1 H, t, J 5.6), 4.51 (2 H, dd, J 0.8, 5.6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | To a solution of diisopropylamine (27.6 g, 273.0 mmol) in tetrahydrofuran (300 mL) was added dropwise a solution of n-butyllithium (91 mL, 228.0 mmol, 2.5 M) in tetrahydrofuran at -78 C under nitrogen. The mixture was stirred at -78 C for 1 h, followed by the dropwise addition of 3-bromopyridine (30.0 g, 190.0 mmol). The mixture was stirred at -78 C for 20 mm before dimethylformamide (55.0 g, 760.0 mmol) was added dropwise. After addition, the reaction mixture was stirred at -78 C for 1 h and was then warmed to ambient temperature before being quenched by addition of saturated aqueous ammonium chloride (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL x 3), the combined organic layers were concentrated in vacuo, and the resulting residue was purified by flash chromatography on Si02 to give the desired product (12.0 g, 34.0%). ?H NMR (400 MHz, CD3OD, oe): 10.37 (s, 1 H), 8.91 (s, 1 H), 8.80 - 8.61 (m, 1 H), 7.78 -7.63 (m, 1 H). LCMS (mlz): 187.0 (M+1). | |
With lithium diisopropyl amide; In tetrahydrofuran; at -80℃;Inert atmosphere; | Tert-Butyl pyridine[4',5'-5,4]pyrrolo[2,3-c]pyridine-3-carboxylate (3) was synthesized from commercially available 3-bromopyridine-4-carbaldehyde (28) according to FIG. 9. Alternatively, 3-bromopyridine-4-carbaldehyde (28) may be prepared from 3-bromopyrimidine (27) as shown in FIG. 9. Commercially available reagents were used as received unless otherwise noted. Reactions requiring inert atmospheres were run under nitrogen unless otherwise noted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With zinc; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Zn powder (10 g, excess) was added to a solution of 10 (4.8 g, 25.8 mmol) and allylbromide (3.9 mL, 50 mmol) in DMF under N2 at RT. The resulting mixture was stirred at RT for 1 hr, DMF was then removed in vacuo and the residue was partitioned into saturated aqueous Na2CO3 and ethyl acetate (150 mL). The aqueous layer was further extracted with ethyl acetate and the combined organic extraction was dried over Na2SO4. After concentration, the residue was purified by chromatography (SiO2, hexane/ethyl acetate, 5:1) to afford 11 (5.35 g, 91 %) as a light yellowish oil. 1H NMR (300 MHz, CDCl3), delta 8.58 (s, 1H), 8.44 (d, J = 5.4 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 5.76-5.92 (m, 1H), 5.12-5.22 (m, 2H), 4.98-5.04 (m, 1H), 2.82-3.00 (br, 1H), 2.60-2.68 (m, 1H), 2.25-2.34 (m, 1H). 13C NMR (75 MHz, CDCl3), delta 152.3, 151.9, 488.3, 132.8, 122.5, 120.1, 118.8, 70.5, 40.9. HRMS: m/e 226.9937, 228.9923 (Calcd for C9H10NOBr, 226.9942; C9H10NO81Br, 228.9919). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With zinc In tetrahydrofuran at 20℃; for 3h; | |
82% | With zinc In tetrahydrofuran for 12h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,4-diaza-bicyclo[2.2.2]octane;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; for 1h; | Pd(PPh3)2Cl2 (1.07 g, 1.52 mmol), trimethylsilylacetylene (18.9 ml, 133 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (17.1 g, 152 mmol) and copper(I) iodide (145 mg, 0.76 mmol) were added in succession, under nitrogen, to a solution of <strong>[70201-43-3]3-bromo-4-pyridine carboxaldehyde</strong> (14.16 g, 76.1 mmol) in dry tetrahydrofuran (140 ml). The reaction mixture was stirred for 1 h, filtered off over Celite, washed with tetrahydrofuran and concentrated. The residue was purified by column chromatography (heptane/ethyl acetate, 9:1?9:2).Yield: 14.62 g (94%) |
46.2% | With copper(l) iodide; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); triethylamine; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | A mixture of 3-bromoisonicotinaldehyde (12.0 g, 64.5 mmol), ethynyltrimethylsilane (18.9 g, 193.5 mmol), Pd(dppf)C12 (1.0 g), CuT (500 mg), and triethylamine (9.8 g, 96.7 mmol) in dimethylformamide (60 mL) was stuffed at 80 C for 2 h under nitrogen. The reaction was diluted with water (100 mL) and the aqueous layer was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried and concentrated in vacuo. The resulting residue was purified by flash chromatography to give the desired product (6.0 g, 46.2%). LCMS (mlz): 204.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 5h; | 5H-pyrido[3',4':3,4]pyrrolo[1,2-a]indole-8-carboxylic acid, 11-cyclohexyl-5-hydroxy-, methyl ester A 2M aqueous solution of Na2CO3 (1.31 mL, 2.62 mmol) was added to a mixture of; methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (400 mg, 1.05 mmol), <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> (214 mg, 1.15 mmol) and LiCl (89 mg, 2.1 mmol), in ethanol (5 mL) and toluene (5 mL). The resultant mixture was degassed by the application of vacuum followed by flushing with N2. Pd(PPh3)4 (60.7 mg, 0.0525 mmol) was added and the reaction mixture was heated at 80 C. for 5 hr. It was then filtered and concentrated under reduced pressure. The residue was triturated with CH2Cl2 to give the title compound as a light yellow solid, (295 mg, 78% yield). MS m/z 363(MH+); 1H NMR (500 MHz, DMSO-D6) delta ppm 1.40-1.51 (m, 3 H) 1.75-1.97 (m, 7 H) 3.24 (m, 1 H) 3.89 (s, 3 H) 6.75 (d, J=8.85 Hz, 1 H) 7.55 (d, J=8.85 Hz, 1 H) 7.63-7.68 (m, 2 H) 7.68 (d, J=8.55 Hz, 1 H) 8.23 (s, 1 H) 8.63 (d, J=4.88 Hz, 1 H) 9.12 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With n-butyllithium; In tetrahydrofuran; water; N,N-dimethyl-formamide; | The starting material was prepared as follows: A solution of di-isopropylamine (3.44 g, 34.1 mmol) was cooled to -78 C. and treated with n-butyl lithium 1.6M, 34.1 mmol). A solution of 3-bromopyridine (4.71 g, 30 mmol) in THF (5 ml) was added dropwise trying to keep the temperature below -70 C. The reaction was very exothermic, a solid precipitated and THF (2 ml) was added to improve stirring. The temperature rose to -45 C., after cooling to -60 C. and added remaining pyridine. DMF (2.49 g) in THF (15 ml) was added and the reaction stirred at -65 C. for 30 minutes. Water was added to quench the reaction and the reaction allowed to warm to ambient temperature. The reaction was partitioned between ethyl acetate/water and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated and the residue was subjected to chromatography (eluding with diethyl ether/hexane) to give 3-bromo-4-pyridinecarbaldehyde (1.4 g, 76%). MS(CI+): 186 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydroxylamine hydrochloride; sodium acetate; In water; at 20 - 100℃; for 0.0833333h; | Step A: Preparation of (Z)-3-bromoisonicotinaldehyde oxime: 3-bromoisonicotinaldehyde (5073 mg, 27273 mumol) and sodium acetate (2797 mg, 34092 mumol) were suspended in 200 mL water and heated to 100 C. utilizing a condenser. H2NOH-HCl (5686 mg, 40910 mumol) was added to the reaction mixture, resulting in immediate heavy precipitation. The reaction mixture was removed from heat and stirred 5 minutes while cooling to room temperature, then cooled further to 0 C. on ice and filtered, rinsing with ice-cold water. The desired product was isolated as white fibrous crystalline material (5.096 g, 93%). MS(+) m/z=202.3. Product was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Heating / reflux; | Boronic acid (1-1, 2.0 g, 10.84 mmol), 3-bromo-4-pyridnecarboxaldehyde (2.01 g, 10.84 mmol), Na2CO3 (2M in H2O, 10.84 mL, 21.7 mmol) and Pd(PPh3)4 (0.62 g, 0.54 mmol) were suspended in dioxane (30 mL) and heated to reflux for 2h. Upon completion, the reaction was diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over MgSO4 and filtered. The solution was concentrated under reduced pressure and purified by flash column chromatography (Redisep column (12Og SiO2), 0-100% EtOAc/hexanes over 35 minutes at 40 mL/min) to provide 3-(5-chloro-2-formylphenyl)isonicotinaldehyde (1-3) as a white solid. 1H NMR (300 MHz, CDCl3) delta 9.90 (s, IH), 9.82 (s, IH), 8.93 (d, J = 5.2 Hz, IH), 8.67 (s, IH), 8.00 (d, J = 8.3 Hz, IH), 7.82 (d, J = 4.9 Hz, IH), 7.65 (d, J = 8.2 Hz, IH), 7.36 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Description 23: 1-(3-bromo-4-pyridinyl)-2,2,2-trifluoroethanol (D23); A solution of <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> (1.505g, 8.1 mmol) in tetrahydrofuran (50ml) was cooled in an ice/methanol bath with stirring under argon and was treated with (trifluoromethyl)trimethylsilane (1.15g, 1.2ml, 8.1 mmol) followed by the dropwise addition of tetrabutylammonium fluoride (TBAF, 1.0M in tetrahydrofuran, 0.8ml). The mixture was then allowed to warm up to room temperature and stirred for 2 hours. Aqueous hydrochloric acid (2M) was then added and the mixture stirred at room temperature for 18 hours. The reaction mixture was neutralised with saturated sodium bicarbonate solution <n="42"/>and extracted into ethyl acetate. The organic layer was separated, dried over sodium sulphate and the solvent removed by rotary evaporation to give a dark oil (1.53g) which was purified by flash column chromatography on a 2Og pre-packed isolute silica Sep- Pak column, eluting from 0-50% ethyl acetate in petroleum ether to give the title compound as a golden brown coloured oil (1.31g, 63%).LC/MS Retention time 2.22mins/(ES+) 256 & 258 (M+H, C7H5BrF3NO requires 255 & 257). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine In acetonitrile at 100℃; for 1h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine In acetonitrile at 100℃; for 1h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine In acetonitrile at 100℃; for 1h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A three-necked 250-mL, round-bottomed flask equipped with a condenser was charged with magnesium (0.92 g, 37.8 mmol), 1-bromo-4-(trifluoromethyl)-benzene (5.3 mL, 37.9 mmol) in THF (35 mL), and the suspension was stirred under nitrogen. Catalytic amount of iodine was added, the mixture was refluxed for 1.5 h, and allowed to cool to room temperature. The reaction mixture was treated with 3-bromoisonicotinaldehyde (3.5 g, 18.9 mmol) and stirred at room temperature for 2 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with DCM and the pure product was collected by filtration to give (3-bromopyridin-4-yl)-(4-(trifluoromethyl)phenyl)methanol (5.55 g) as an ivory colored solid. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 0.37 g of additional product. 1H NMR (400 MHz, CDCl3): delta 8.66 (s, 1H), 8.56 (d, J= 5.0 Hz, 1H), 7.53-7.64 (m, 5H), 6.17 (d, J= 3.7 Hz, 1H), 2.80 (d, J= 3.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium tetrahydroborate; In methanol; at 0℃; for 2h;Inert atmosphere; | [0068] To a solution of 3-bromo-4-pyridinecarboxaldehyde 3 (3.0 g, 16.2 mmol) in absolute methanol (40 mL) was added NaBH4 (0.736 g 19.5 mmol) at 0C. The mixture was stirred at 0C for 2 hours under nitrogen. The solvent was then removed under vacuum. Water and ethyl acetate were added and the organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the compound 4 (3.021 g, 100%) as a white powder. 1H NMR (CDCl3, 300 MHz, 298 K, delta ppm): 8.61 (s, 1 H), 8.51 (d, 1H, J = 4.8 Hz), 7.55 (d, 1H, J = 4.8 Hz), 4.76 (s, 2 H), 2.89 (s, 1H). 13C NMR (CDCl3, 75.5 MHz, 298 K, delta ppm): 151.14, 149.45, 148.54, 122.47, 119.90, 63.47. GC/MS (m/z): 188 IR (KBr, v, cm-1): 3152, 2894, 2829, 1593, 1447, 1401, 1333, 1223, 1170, 1070, 1024, 834, 705, 599 |
100% | With sodium tetrahydroborate; In methanol; at 0℃; for 2h;Inert atmosphere; | To a solution of 3 -bromo-4-pyridinecarboxaldehyde 3 (3.0 g, 16.2 mmol) in absolute methanol (40 mL) was added NaBH4 (0.736 g 19.5 mmol) at 0C. The mixture was stirred at 0C for 2 hoursunder nitrogen. The solvent was then removed under vacuum. Water and ethyl acetate were added and the organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the compound 4 (3.02 1 g, 100%) as a white powder.?H NN?IR (CDC13, 300 MHz, 298 K, S ppm): 8.61 (s, 1 H), 8.51 (d, 1H, J 4.8 Hz), 7.55 (d, 1H, J 4.8 Hz), 4.76 (s, 2 H), 2.89 (s, 1 H).?3C NMR(CDC13, 75.5 MHz, 298 K, S ppm): 151.14, 149.45, 148.54, 122.47, 119.90, 63.47. GCIMS(m/z): 188IR (KBr, v, cm1): 3152, 2894, 2829, 1593, 1447, 1401, 1333, 1223, 1170, 1070, 1024, 834, 705, 599 |
100% | With methanol; sodium tetrahydroborate; at 0℃; for 1h;Inert atmosphere; | Synthesis 2 (3-Bromo methanol A solution of 3-bromo-pyridine-4-carbaldehyde (5 mmol, 0.93 g) in methanol (10 mL) was cooled to 0 C under nitrogen. This was treated with sodium borohydride (5.5 mmol, 0.200 g) portionwise, and allowed to stir at 0 C for 1 hour, then slowly allowed to return to room temperature overnight. The reaction was quenched by the addition of saturated ammonium chloride (5 mL), then evaporated under reduced pressure. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was then separated and dried with MgSCU, filtered and evaporated to yield the title compound as a white solid. Yield: 0.94 g, 100%. LCMS, analytical method 1 , TR= 2.18 mins, 100%, Ml+H=188/190. H NMR (300 MHz, DMSO-d6) delta: 8.62 (1 H, m), 8.53 (1 H, d, J 4.9), 7.53 (1 H, dd, J 0.6, 4.9), 5.69 (1 H, t, J 5.6), 4.51 (2 H, dd, J 0.8, 5.6). |
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h; | To a solution of 3-bromo-pyridine-4-carbaldehyde (0.500 g, 2.68 mmol) in MeOH (5 ml_) at 0 C is added sodium borohydride (0.122 g, 3.22 mmol). The mixture is stirred at room temperature for 1 h followed by removal of the solvent in vacuo. The residue is <n="136"/>redissolved in DCM and washed with water twice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford (3-bromo-pyridin-4-yl)-methanol as a yellow oil. MS (ESI) m/z 189.9 (M+H)+ | |
To an ice-cold solution of 3-bromoisonicotinaldehyde (2.5 g, 13.44 mmol) in MeOH (Volume: 100 ml) was added sodium borohydride (1.017 g, 26.9 mmol) and the reaction mixture was stirred at that temperature for 1 hour. The reaction mixture was then quenched with satd. aHC03, filtered, and evaporated to remove MeOH. The aqueous layer was extracted with EtOAc (2X). The combined organics were washed with satd. aHC03 and brine, dried, and concentrated to give Intermediate 65A as a white solid. MS (ES): m/z = 189.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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A cooled (0 0C) suspension of <strong>[21406-61-1]n-pentyl-triphenylphosphonium bromide</strong> (Acros; 1200 mg;2.90 mmol) in anhydrous THF (20 mL) was slowly treated with a solution (1.6 M) of butyllithium in hexane (2 700 muL; 4.35 mmol). The mixture was stirred for 1 hour, then a solution of 3-bromo-4-pyridinecarboxaldehyde (Aldrich; 567 mg; 3.05 mmol) in anhydrous THF (10 mL) was added. After stirring for one hour, the reaction was quenched by addition of a saturated aqueous solution of ammonium chloride. After addition of EtOAc the phases were separated and the organic phase washed with brine, dried over MgSO4 and concentrated under vacuum to afford a crude product, which was purified by column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc to afford the title compound as a mixture of cis and trans isomers. MS (ESI"): 240.1. |
Yield | Reaction Conditions | Operation in experiment |
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A solution of methylmagnesium bromide (10,00 ml, 30.0 mmoi) was added dropwise to a solution of 3-Bromo-pyridine~4-carbaldehyde (1.860 g, 10.00 mmoi} in THF (30 ml) at - 78 0C. The resulting mixture was slowly warmed up to 0 0C over 3 h of period. The reaction was quenched by saturated NH4C. solution. After extraction with ethyl acetate {50 mL x 4), the combined extracts were dried over Na2SO4. After filtration and concentration, an oil residue was obtained, which turned into solid after standing (2.1 g), 1H NMR (400.3 MHz, COCi3): delta 0.23 (d. J = 8 Hz1 3H), 3.91 (m. 1H)1 6.29 (d, J 4 Hz1 1H)1 7.26 (d, J ~ 4 Hz, 1H)1 7.37 (s, 1H). | ||
2.1 g | In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 2h; | To a cooled (0 C.) solution of <strong>[70201-43-3]3-bromo-pyridine-4-carbaldehyde</strong> (2.0 g, 10.8 mmol) in dry THF (45 mL) is added methyl magnesium bromide solution in Et2O (3M; 3.9 mL, 11.8 mmol). The mixture is stirred at 0 C. for 1 h then warmed and stirred at room temperature for 1 h. Saturated aqueous NH4Cl solution is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to afford 2.1 g of 1-(3-bromo-pyridin-4-yl)-ethanol. |
In tetrahydrofuran; diethyl ether; at 0 - 65℃; for 3h; | A solution of MeMgBr in Et2O (54 mL, 3.0 M, 162 mmol) was added dropwise to a 65 C. solution of 3-bromoisonicotinaldehyde (10 g, 54 mmol) in THF (100 mL), and the resulting mixture was stirred and allowed to warm to 0 C. over 3 h. After this time, a saturated aqueous NH4Cl solution was added, and the resulting mixture was extracted three times with EtOAc. The organic extracts were combined, washed with brine, dried with anhydrous Na2SO4, filtered, and then concentrated to afford the title compound as a colorless solid. |
In tetrahydrofuran; diethyl ether; at -65 - 0℃; for 3h; | A solution of MeMgBr in Et2O (54 mL, 3.0 M, 160 mmol) was added dropwise to a -65 C. solution of 3-bromoisonicotinaldehyde (10 g, 54 mmol) in THF (100 mL), and the resulting mixture was stirred and allowed to warm to 0 C. over 3 h. After this time, a saturated aqueous NH4Cl solution was added, and the resulting mixture was extracted three times with EtOAc. The organic extracts were combined, washed with brine, dried with anhydrous Na2SO4, filtered, and then concentrated to afford the title compound as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydride; In dimethyl sulfoxide; at 20℃; | To a soiupsilontion of suifonium salt (7.39 g, 33.6 mrnol) in DMSO (40 ml) was added sodium hydride (60% in oil, 1.236 g, 30.9 mmol) at room temperature. After 15 min of stirring. 3- Bromo-pyridine-4-carbaSdehyde (930 mg, 5 mmo.) in DMSO (20 mL) was ae siowly at this temperature. After addition, the resulting mixture was stirred for another 30 min, and was subsequently quenched with brine. The mixture was extracted with ethyi acetate twice. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the title compound was obtained (200 mg). |
Yield | Reaction Conditions | Operation in experiment |
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A solution of 4-Ruoralphamagnesium bromide (2 M in ether, 8.3 rnL, 12.6 mmol) was added dralphapwise to a solution of 3-Bromo-pyridi?e-4-carbaldehyde (931 mg, 5 mmo.) in THF (15 mL) at -45 0C, The resulting mixture was stirred at this temperature for additional 2 h. The reaction was quenched by saturated NH4CI solution. After extraction with ethyl acetate (75 ml x 3), the combined extracts were dried over Na2SO*. After filtration and concentration, a yellow solid was obtained. (893mg). ESi-MS m/z: 284.0 [M-M]+, Retention time 1.17 min; |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; water; at 100℃; for 1h;Microwave irradiation; | A mixture of 3-Methy.-5-(4,4,5>;5-tetramethyl-[1,3,2]dioxaboroSan-2-y.)-3H~benzooxazo.-2- one (330 mg, 1.2 mmol), 3-Bromo-pyridine-4-carba.dehyde (188 mg, 1 mmo.}, polymer bound Pd(PPfIg)4 (842 mg, 0.0? mmol), Na2CO3 (2 M in water, 1 ml, 2 mmot) in N, N- Dimethytacetamide (9 mL) and wafer (1 ml) was heated Io 100 0C by microwave for 1 h. The reaction mixture was cooled to room temperature. The suspension was diluted with CH2Ci2 {15 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to reddish brown solid. This crude material was purified by flash column (0-10% CH3OH in CH2CI2, v/v) and afforded 152 mg of the desired product. ESi-MS mlz: 255.0[M+1]*, Retention time 1.03 min; 1HNMR (DIVISO, 400 342 MHz): delta 3.39 (s, 3H), 7.27 (dd. J " 8.2, 1.8 Hz, 1 H)1 7.50 Cd, J = 8.2 Hz, 1H), 7.57 (d, J - 1.8 Hz, 1H), 8.85 <;m, 2H)1 10.0 (s; 1 H), |
Yield | Reaction Conditions | Operation in experiment |
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98.2% | Example 176Preparation of 1-Benzothiazol-6-yl-3-(4-pyrrolidin-1-ylmethyl-pyridin-3-yl)-imidazolidin-2-one (176A) Step I. Synthesis of Intermediate 3-Bromo-4-pyrrolidin-1-ylmethyl-pyridine (I-176a) Acetic acid (0.1 mL) was added to a stirred solution of <strong>[70201-43-3]3-bromo-pyridine-4-carbaldehyde</strong> (220 mg, 1.18 mmol) and pyrrolidine (0.11 mL, 1.34 mmol) in DCE (15 mL) under nitrogen atmosphere and stirred at room temperature for 2 hours. This was followed by addition of NaBH(OAc)3 (342 mg, 1.612 mmol) at 0 C. over a period of 10 minutes. The resulting reaction mass was stirred for 12 hours at room temperature. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mixture was washed with NaHCO3 solution and extracted using ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to afford 275 mg of the product (98.2% yield).1H NMR (300 MHz, CDCl3): delta 8.63 (s, 1H), 8.46 (dd, 1H), 7.49 (d, 1H), 7.27 (d, 1H), 3.72 (s, 2H), 2.6 (m, 4H), 1.84 (m, 4H) | |
98.2% | Acetic acid (0.1 ml.) was added to a stirred solution of 3-bromo-pyridine-4- carbalilehydt' (220mg. 1.18mmol) and p> ?olidine (0. M mI J .34mmol) in DCF ( 15ml ) under nitrogen atmosphere and stirred at room temperature for 2 hours. This was followed b> addition of NaFiH(OAe); (342mg, 1.612mmalphal) at O0C over a period of 10 minutes. The resulting reaction mass was stirred for 12 hours ai room temperature. The reaction was monitored b> Tl C (30% ethyl acetate in hexuneV The reaction mixture was washed with NaI ICO* solution and extracted using eth) I acetate. The organic laver was dried over Na;SO4 and concentrated to afford 275mg of the product (98.2% yield).1I I NMR (300 MI b. CT)CU «5 8.63 (s, H IV 8.46 <dd. I l l), 7.49 (d, H IV 7.27 (d, I H). 3.72 (s, 2) ), 2.6 (m, 4HV 1.84 (m, 411) | |
96.52% | Catalytic amount of acetic acid (0.3mL) was added to a mixture of 3- bromoisonicotinaldehyde (200mg, 1.075mmol) and pyrrolidine (0.12mL, 1.34mmol) in DCE (20mL) under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 2.3 hours. This was followed by the addition of sodium triacetoxy-borohydride (342mg, 1.6l2mmol) at 0C. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (50%ethylacetate in hexane). The reaction mixture was washed with NaHC03 solution and separated the layers. The organic layer was dried over Na2S04 and concentrated to afford 250mg of the product (96.52% yield).'HNMR (300 MHz, CDC13): delta 8.65 (s, 1H), 8.5 (d, 1H), 7.5 (d, 1H), 3.7 (s, 2H), 2.65-2.55 (m, 4H), 1.90- 1.78 (m, 4H). |
96.52% | Preparation of Intermediate 3-Bromo-4-(pyrrolidin-1-ylmethyl)pyridine (I-52a) Catalytic amount of acetic acid (0.3 mL) was added to a mixture of 3-bromoisonicotinaldehyde (200 mg, 1.075 mmol) and pyrrolidine (0.12 mL, 1.34 mmol) in DCE (20 mL) under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 2.3 hours. This was followed by the addition of sodium triacetoxy-borohydride (342 mg, 1.612 mmol) at 0 C. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was washed with NaHCO3 solution and separated the layers. The organic layer was dried over Na2SO4 and concentrated to afford 250 mg of the product (96.52% yield). 1H NMR (300 MHz, CDCl3): delta 8.65 (s, 1H), 8.5 (d, 1H), 7.5 (d, 1H), 3.7 (s, 2H), 2.65-2.55 (m, 4H), 1.90-1.78 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
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96.3% | With toluene-4-sulfonic acid; at 75℃; for 3h; | p-Toluene sulphonic acid (PTSA) (613.5mg, 3.225mmol) was added to a stirred solution of 3-bromoisonicotinaldehyde (500mg, 2.688mmol) in methanol (20mL) and the resulting reaction mixture was stirred for 3 hours at 75C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was diluted with ice, basified using saturated NaHC03 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% ethyl acetate in hexane) afforded 600mg of the product (96.3% yield). |
96.3% | With toluene-4-sulfonic acid; at 75℃; for 3h; | Preparation of Intermediate 3-bromo-4-(dimethoxymethyl)pyridine (I-53a) p-Toluene sulphonic acid (PTSA) (613.5 mg, 3.225 mmol) was added to a stirred solution of 3-bromoisonicotinaldehyde (500 mg, 2.688 mmol) in methanol (20 mL) and the resulting reaction mixture was stirred for 3 hours at 75 C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was diluted with ice, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% ethyl acetate in hexane) afforded 600 mg of the product (96.3% yield). |
93.5% | With toluene-4-sulfonic acid; for 4h;Reflux; | Example 149Preparation of 1-Benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidin-2-one (149A) Step 1: Preparation of Intermediate 3-Bromo-4-dimethoxymethyl-pyridine (I-149a)PTSA (834 mg, 4.384 mmol) was added to a solution of <strong>[70201-43-3]3-bromo-pyridine-4-carbaldehyde</strong> (600 mg, 3.2256 mmol) in methanol (20 mL). The resulting mixture was heated to reflux for 4 hours. The reaction was monitored by TLC (20% ethylacetate in hexane). The reaction mixture was concentrated and basified with NaHCO3 solution. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine solution, dried over Na7SO4, filtered and the filtrate was concentrated to afford 700 mg of 3-Bromo-4-dimethoxymethyl-pyridine (93.5% yield).1H NMR (CDCl3, 300 MHz): delta 8.8-8.4 (m, 2H), 7.5 (s, 1H), 5.5 (s, 1H), 3.4 (s, 6H) |
93.5% | With toluene-4-sulfonic acid; for 4h;Reflux; | ITSA (834 ing. 4.384 mmol) was added to a solution of 3-biotaorm>-pyridine-4- carbaldchjde (600 mg, 3.2,756 mmol) in methanol (20 ml.). The resulting mixture was heated to reflux for 4 hours. The reaction was monitored by TI C (20% elh> (acetate in hcxanc). The reaction mixture was concentrated and hasified with NaI ICO< solution. Hie reaction mixture was partitioned between water and OCM. T he organic laser was washed with brine solution, dried over Na^SOo, filtered and the filtrate waj> concentrated to afford 700 mg of 3-Bromo-4-dimetho.>'melhyl-pyridine <93.5% yield).1I I NMR (COCH, 300 MHz): delta 8.8-8.4 (in. 2H), 7.5 (s, I H). 5.5 <s, IH). 3.4 (s. 611) |
Yield | Reaction Conditions | Operation in experiment |
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75% | n-BuLi (2 M in haxane, 24 mL, 48 mmol) was added to a solution of diisopropylamine (8 mL, 57 mmol) in anhydrous THF (80 mL) at -78 C over 40 min and the resulting mixture was stirred at -78 C for 1 hr. 3-Bromopyridine (9) (3.85 mL, 40 mmol) was then added over 5 min. After stirring for an additional 10 min, anhydrous methyl formate (10 mL, 160 mmol) was added drop-wise while the temperature was kept below -70 C. The reaction mixture was warmed up to RT over 3 h. and quenched with saturated aqueous NaHCO3. After concentrated under reduced pressure, the residue was taken into ethyl acetate (100 mL) and water (75 mL). The aqueous layer was extracted with ethyl acetate (2 X 50 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate, 10:1) to give 10 (5.58 g, 75 %) as a solid; mp. 81-82 C (Lit.1 80-82 C). 1H NMR (300 MHz, CDCl3): delta 10.38 (s, 1H), 8.92 (s, 1H), 8.70 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 5.4 Hz, 1H), 13C NMR (75 MHz, CDCl3): delta 190.7, 154.1, 149.5, 138.8, 123.0, 122.3. HRMS: m/e 184.9467, 186.9458 (Calcd for C6H4NOBr, 184.9469; C6H4NO81Br, 186.9450). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 28: Synthesis of 2-chloro-4-{4-(oxetan-2-yl)pyridin-3-yl)benzonitrile 28a 28 Step 1·. 3-bromo-4-(oxetan-2-yl)pyridine (28a) A 500 mL round-bottomed flask was charged with trimethylsulfoxonium iodide (1 1.83 g, 53.8 mmol) in DMSO (80 ml), sodium hydride (1.989 g, 49.7 mmol) was added. After stirring for 15min, a solution of 3-biOmoisonicotinaldehyde (5g, 26.9 mmol) in DMSO (20 ml) was added slowly to the reaction. After 10min, The reaction mixture was diluted with water and EtOAc. The mixture was washed with H20 and brine. The organic was dried over Na2S04, filtered and concentrated to give crude intermediate 2.69g without further purification.A 100 mL round-bottomed flask was charged with trimetylsulfoxonium iodide (5.92 g, 26.9 mmol) in t-BuOH (20 ml). Potassium tert-butoxide (3.02 g, 26.9 mmol) was added. After stirring for 15min at 50C, a solution of the above intermediate (2.69g) in DMSO (20 ml) was added slowly to the reaction. After 16h, the reaction mixture was diluted with water and EtOAc. The mixture was extracted with ethyl acetate and washed with H20 and brine to give 462mg of crude title compound. ESI-MS mlz. 216.1 [M+1]+, Retention time 1.01 min;1HNMR (CDCI3, 400.342 MHz) delta ppm 2.50-2.59 (m, 1 H), 3.31-3.39 (m, 1 H), 4.65-4.70 (m, 1H), 4.87-4.92 (m, 1 H), 5.91 (t, J =8 Hz, 1H), 7.95 (d, J = 8 Hz, 1 H), 8.68 (d, J = 8 Hz, 1H), 8.73 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 120℃; for 3h; | Example 40: Synthesis of 4-(4-(cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2- methoxy be nzon itrileStep 1: 4-(4-formylpyridin-3-yl)-2-methoxybenzonitrile (40a) A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (259 mg, 1 mmol), 3-bromoisonicotinaldehyde (186 mg, 1.000 mmol), a solution of sodium carbonate (2M in water, 1.000 ml, 2.000 mmol), bis(triphenylphosphine)palladium(ll) chloride (17.55 mg, 0.025 mmol) in DMF (6 mL, dry) was heated to 120 C for 3 hrs. After concentration, the residue was dissolved into CH2CI2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH-CH2CI2, v/v, 0.5% - 1%) yielded colorless solid (170 mg). 1H NMR (400.3 MHz, CDCI3): delta 3.99 (s, 3H), 6.98 (d, J = 1.32 Hz, 1H), 7.05 (dd, J = 1.48, 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1 H), 7.81 (d, J = 5 Hz, 1 H), 8.81 (s, 1 H), 8.90 (d, J = 5 Hz, 1 H), 10.04 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 100℃; for 2h; | Step 2: 4-(4-formylpyridin-3-yl)-2-methylbenzonitrile (1b) A mixture of 1a (430 mg, 1.769 mmol), <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> (299 mg, 1.608 mmol), sodium carbonate (2N in water, 1.608 ml_, 3.22 mmol),bis(triphenylphosphine)palladium(ll) chloride (28.2 mg, 0.040 mmol) in DMF (6.432 mL) was heated to 100 C for 2 hrs. The mixture was quenched with saturated NaHC03 and extracted with EtOAc two times, dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage (0-50% EtOAc/heptane; 25 column) giving compound 1b as white solid (280 mg, 78%). LC-MS (M+1) 223.1 , t = 1.28 min. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 120℃; for 3h; | Example 20: Synthes -chloro-4-(4-(1-hydroxyethyl)pyridin-3-yl)benzonitrile 20a Step 1: 2-chloro-4-(4-formylpyridin-3-yl)benzonitrile (20a) A mixture of 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.264 g, 1 mmol), 3-bromoisonicotinaldehyde (0. 86 g, 1.000 mmol), sodium carbonate (1.000 ml, 2.000 mmoi), bis(triphenylphosphine)palladium(ll) chloride (0.018 g, 0.025 mmol) in DMF (6 mL, dry) was heated to 120 C for 3 hrs. After concentration, the residue was dissolved into CH2CI2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH- CH2CI2, v/v, 0.5% - 1 %) yielded 2-chloro-4-(4-formylpyridin-3-yl)benzonitrile (20a) as colorless solid (170 mg) 1H NMR (400.3 MHz, CDCI3): delta 7.63 (d, J = 8.0 Hz, 1H), 7.79 (s,1H), 7.83 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 9.07 (s, 1 H), 9.15 (s, 1H), 10.22 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 0℃; for 2h; | To a stirred solution of 3-bromoisonicotinaldehyde (100 mg, 0.538 mmol) in CH2CI2 (5 mL) at 0 C was added dropwise [bis(2-methoxyethyl)amino]sulfur trifluoride (0.38 mL, 2.06 mmol). The reaction mixture was stirred at 0 C for 2 hours, quenched with saturated aqueous sodium bicarbonate (3 mL) and extracted with CH2CI2 (2 x 5 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Intermediate 41 (78 mg, 70% yield). MS (ES): m/z=208.2) [M+H] |
67% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0℃; for 2h; | To a solution of 3-bromoisonicotinaldehyde (200 mg, 1.08 mmol) in dichloromethane (10 mL) was added dropwise DAST (693 mg, 4.3 mmol) at 0 C. The mixture was stirred at 0 C. for 2 hours. The reaction mixture was quenched with aqueous saturated NaHCO3 (5 mL) and extracted with dichloromethane (50 mL*3). The organic extracts were combined, concentrated and purified by silica gel flash chromatography (petroleum ether/ethyl acetate=10:1 to 3:1) to give 3-bromo-4-(difluoromethyl)pyridine (150 mg, 67% yield) as a colorless oil. LCMS (ESI): [M+H]+=208.2. |
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 0℃; for 2h; | Deoxo-Fluor (24.0 g, 108 mmol) was added to a 0 C. solution of 3-bromoisonicotinaldehyde (5.0 g, 27 mmol) in DCM (50 mL), and the reaction mixture was stirred at 0 C. for 2 h. After this time, a saturated aqueous NaHCO3 solution was added, and the resulting mixture was extracted twice with DCM. The organic extracts were combined, washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (5?20% petroleum ether/EtOAc) to afford the title compound as a yellow oil. |
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 0℃; for 3h; | Deoxo-Fluor (5.9 mL, 32 mmol) was added to a 0 C. solution of <strong>[70201-43-3]3-bromopyridine-4-carboxaldehyde</strong> (3.0 g, 16 mmol) in DCM (70 mL). After stirring for 3 h at 0 C., a saturated aqueous NaHCO3 solution was added, and the mixture was allowed to warm to rt. The layers were separated, and the aqueous layers was extracted with DCM. The organics were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexanes) to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 90℃; for 16h;Inert atmosphere; sealed tube; | To a solution of Intermediate 51 (1.50 g, 4.58 mmol) and 3- bromoisonicotinaldehyde (1.023 g, 5.50 mmol) in a mixture of DME (20 mL), ethanol (10 mL), and water (10 mL) was added a2C03 (1.944 g, 18.34 mmol). This suspension was degassed with a stream of 2 for 10 minutes and then tetrakis(triphenylphosphine) palladium(O) (0.265 g, 0.229 mmol) was added followed by degassing for 10 minutes. The tube was then sealed and heated at 90 C for 16 hours. The reaction mixture was cooled to room temperature and diluted with MeOH. The resulting suspension was filtered and washed with methanol and the filtrate concentrated to a brown sludge. The crude material used without purification. HPLC Ret. time1: 1.02 min. MS (ES): m/z = 307.1 [M+H]+. Intermediate 63 was used in the synthesis of Example 253. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 150℃; for 0.75h;microwave irradiation; | To a solution of <strong>[70201-43-3]3-bromo-pyridine-4-carbaldehyde</strong> (726mg), N-(4-fluoro-phenyl)- malonamic acid ethyl ester (lg), Pd2(dba)3 (112mg) and Xantphos (225mg) in toluene (18ml) was added caesium carbonate (3.18g). The reaction mixture was heated in a microwave at 150C for 45minutes, then diluted with dichloromethane and filtered through a pad of celite. The filtrate was evaporated under reduced pressure and the residue purified by flash chromatography (silica; ethyl acetate/hexane) to give the required product as an orange solid (586mg).1 H MR (CDC13) 6: 8.49 (1 H, d), 8.41 (1 H, s), 8.15 (1 H, s), 7.55 (1 H, d), 7.31 (2 H, s), 7.30 (2 H, s), 4.43 (2 H, q), 1.40 (3 H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 60℃; | General procedure: To a solution of CH3CN (5 mL), PdCl2(PPh3)2 (2 mol %), Et3N (2 equiv), 1.0 mmol of ortho halo aldehyde and 1.2 mmol of terminal alkyne was added and stirring was continued for another 5 min before flushing with N2 and the then flask was sealed. The reaction mixture was allowed to stir at 60 C for 1-2 h and the resulting solution was filtered and washed with saturated aq NaCl solution and extracted with ethyl acetate (2 x 10 mL). The combined organic fractions was dried over anhydrous Na2SO4 and concentrated under vacuum to yield the crude product. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred suspension of methyltriphenylphosphonium bromide in dry tetrahydrofuran (15 mL) at 0 C was added n-butyl lithium (3.87 mL, 3.87 mmol) with constant stirring, yellow colour was observed. The yellow colour suspension was allowed to stir at room temperature for 40 min. After 40 min, the reaction mixture was cooled to 0 C and 3-bromoisonicotinaldehyde (0.6 g, 3.23 mmol) in tetrahydrofuran (5 mL) was added drop wise, the yellow colour was disappeared. Reaction mass was allowed to stir at0 C to room temperature for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ether (3 x 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by columnchromatography to obtain the title compound. 1H NMR (400 MHz, CDC13) delta: 8.69 (s, 1 H), 8.45 (d, J= 4.8 Hz, 1 H), 7.41 (d, J= 4.8 Hz, 1 H), 7.02-6.95 (m, 1 H), 5.95-5.91 (d, J= 17.6 Hz, 1 H), 5.60-5.57 (d, J= 10.8 Hz, 1 H). MS (M+2): 185.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; (S,S)-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane; at 150℃; for 2.5h;Microwave irradiation; Inert atmosphere; | Cul (190 mg, 1 mmol), (lS,2S)-cyclohexane-l,2-diamine (228 mg, 2 mmol) and CS2CO3 (6.5 g, 20 mmol) were added to a solution of 6-chloro-3,4-dihydro-2H-isoquinolin-l-one (1.82 g, 10 mmol, intermediate A-2) and 5-bromo-pyridine-4-carbaldehyde (3.72 g, 20 mmol) in dioxane (15 mL). The reaction mixture was heated to 150 C using microwave for 2.5 hours before it was poured into H20 (50 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product (2.0 g, 70%) as brown oil. MS: 287.0 (M+H+). | |
With copper(l) iodide; (S,S)-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane; at 150℃; for 2.5h;Microwave irradiation; | [A] 5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-3-carbaldehyde CuI (190 mg, 1 mmol), (1S,2S)-cyclohexane-1,2-diamine (228 mg, 2 mmol) and Cs2CO3 (6.5 g, 20 mmol) were added to a solution of <strong>[22246-02-2]6-chloro-3,4-dihydro-2H-isoquinolin-1-one</strong> (1.82 g, 10 mmol, intermediate A-2) and 5-bromo-pyridine-4-carbaldehyde (3.72 g, 20 mmol) in dioxane (15 mL). The reaction mixture was heated to 150 C. using microwave for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2*20 mL). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (2.0 g, 70%) as brown oil. MS: 287.0 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of (i-Pr)2NH (0.3 mL, 2.2 mmol) at 0C in dry THF (15 mL) was added n-BuLi (1.22 M solution in hexane, 2.7 mL, 2.2 mmol), the mixture was stirred for 15 mm at this temperature, after which the 6,7-dimethoxy-1 -tetralone (0.4 12 g, 2 mmol) in dry THF (7 mL) was slowly added at-78C. After 30 mm at this temperature, <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> (0.446 g, 2.4 mmol) indry THF (7 mL) was slowly added and the solution was stirred for 30 mm at -78C before allowedto reach room temperature and being stirred for a night. Then, the mixture was hydrolyzed by HC1 iN and extracted by AcOEt to eliminate the possible excess of tetralone. The aqueous layer was neutralized by NaHCO3 and the compound was extracted by CH2C12 three times. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified bycolumn chromatography on Si02 (gradient of EtOAc in petroleum ether) to afford the expected product 84 (Yield 598,7 mg, 80%).111 NMR (300 MRz, CDC13, 8): 2.87-2.93 (m, 4H), 3.95 (s, 6H), 6.68 (s, 1H), 7.20 (d, 1H, J= 4.8 Hz), 7.64 (s, 2H), 8.54 (d, 1H, J= 5.1 Hz), 8.79 (s, 1H).?3C NMR (75 Mhz, CDC13, 8): 27.8, 28.7, 56.2, 56.3, 109.7, 110.1, 122.6, 124.6, 126.9, 131.6,138.8, 144.6, 147.6, 148.6, 151.7, 152.4, 154.2, 185.7.MS (ESfl: 374.03 (M+1I?) | |
57% | With sodium hydroxide; In ethanol; at 35℃; for 4h; | General procedure: At 35 C, to a solution of NaOH (0.39 g, 9.7 mmol) in EtOH(12 mL) were added in one portion a mixture of 6,7-dimethoxy-1-tetralone 1c (1.0 g, 4.85 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong>2 (0.9 g, 4.85 mmol). The reaction mixture was then stirredfor 4 h at the same temperature. The resulting precipitate was filtered off then rinsed twice with cold diethyl ether to afford thetitle compound 3c as a pale yellow solid. (Yield 1.80 g, 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With toluene-4-sulfonic acid; In toluene; for 4h;Dean-Stark; Reflux; | To a solution of 5-methoxy-1-indanone (0.32 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> (0.36 g, 2 mmol) in toluene (30 mL) was added p-toluenesulfonic acid (0.45 g, 2.4 mmol). After heated atreflux using a Dean-Stark for 4h, the mixture was cooled to room temperature and the solvent was removed in vacuum, then 5% sodium bicarbonate solution was added until pH 8. After extraction with dichloromethane (4x), the organic layer was dried over magnesium sulfate and concentrated to dryness. The residue was taken up with EtOAc and the solid was filtered, rinsed with EtOAc to afford the title compound 91 as a yellow solid (Yield 330 mg, 50%).1fl NMR (300 MHz, CDC13, 6): 3.91 (br s, 5H), 6.96-7.00 (m, 2H), 7.49 (d, 1H, J 5,1 Hz), 7.74(t, 1H, J= 2.4 Hz), 7.87 (d, 1H, J= 8.4 Hz), 8.58 (d, 1H, J= 5.1 Hz), 8.82 (s, 1H).?3C NMR (75 MHz, CDCI3, 6): 31.7, 55.8, 109.8, 115.8, 123,5, 126.7, 128.2, 131.1, 141.2, 143.1, 148.3, 152.3, 153.0, 165.8, 191.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Under an N2 atmosphere, a 1.6 M solution of n-butyllithium in hexane (7.06 mL, 11.3 mmol) was added slowly to a cooled (-78 C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol) in THF (25 mL). After 30 min stirring at 0 C, the mixture was cooled to -78 C and a solution of 3-bromopyridine 5c (1.63 g, 1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixture was stirred at -78 C for 15 min, and then a solution of N-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was added slowly. The solution was stirred at -78 C for 50 min. Then it was allowed to warm to room temperature and it was stirred for another 1.5 h. A satd. NH4Cl solution (40 mL) was added. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (60 mL) and dried over Na2SO4. Filtration and evaporation afforded crude product, which was purified by fc (5.5 cm, EtOAc:cyclohexane 1:4). Yellow solid (EtOAc:cyclohexane 2:1, Rf = 0.55), yield 914 mg (48%). 1H NMR (600 MHz, CDCl3): delta (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72 (d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO). | |
48% | Under an N2 atmosphere, a 1.6 M solution of n-butyllithium inhexane (7.06 mL, 11.3 mmol) was added slowly to a cooled(78 C) solution of diisopropylamine (1.25 g, 1.73 mL, 12.4 mmol)in THF (25 mL). After 30-min stirring at 0 C, the mixture wascooled to 78 C and a solution of 3-bromopyridine (5, 1.63 g,1.00 mL, 10.3 mmol) in THF (5 mmol) was added slowly. The mixturewas stirred at 78 C for 15 min, and then a solution ofN-formylpiperidine (5.24 g, 5.14 mL, 46.4 mmol) was addedslowly. The solution was stirred at 78 C for 50 min. Then itwas allowed to warm to room temperature and stirred for another1.5 h. Saturated NH4Cl solution (40 mL) was added. The aqueouslayer was extracted with EtOAc (3 30 mL). The combined organiclayers were washed with brine (60 mL) and dried over Na2SO4.Filtration and evaporation afforded crude product, which waspurified by fc (5.5 cm, EtOAc/cyclohexane 1:4). Yellow solid(EtOAc/cyclohexane2:1, Rf = 0.55), yield 914 mg (48%). 1H NMR(600 MHz, CDCl3): d (ppm) = 7.22 (d, J = 4.9 Hz, 1H, 5-H-Py), 8.72(d, J = 4.9 Hz, 1H, 6-H-Py), 8.92 (s, 1H, 2-H-Py), 10.37 (s, 1H, CHO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With toluene-4-sulfonic acid; In methanol; water; for 14.5h;Reflux; | A solution of 6c (233 mg, 1.25 mmol), p-TsOH·H2O (262 mg, 1.38 mmol) and trimethyl orthoformate (0.15 mL) in CH3OH (10 mL) was heated to reflux for 14.5 h. After concentration of the mixture in vacuo, the residue was partitioned between satd. NaHCO3 solution (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried over Na2SO4. Filtration and evaporation afforded crude product, which was purified by fc (2 cm, EtOAc:cyclohexane 1:2). Colorless oil (EtOAc:cyclohexane 2:1, Rf = 0.54), yield 259 mg (89%). 1H NMR (600 MHz, CD3OD): delta (ppm) = 3.40 (s, 6H, OCH3), 5.51 (s, 1H, PyCH), 7.61 (d, J = 5.0 Hz, 1H, 5-H-Py), 8.56 (d, J = 5.0 Hz, 1H, 6-H-Py), 8.75 (s, 1H, 2-H-Py). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 2h;Inert atmosphere; Microwave irradiation; | General procedure: A mixture of the appropriate o-haloaldehyde (1 eq, 2.60mmol), methyl propargyl ether (1.2 eq, 3.12mmol), Pd(PPh3)2Cl2 (0.04 eq, 0.10mmol), CuI (0.075 eq, 0.19mmol), Et3N (1.5 eq, 3.90mmol), in dry DMF (12mL), was stirred under nitrogen atmosphere, at room temperature for 1h. The mixture was quenched with H2O and the product was extracted with Et2O. The combined organic layers were washed with water, brine, dried over Na2SO4, and evaporated. The crude product was purified by FC (petroleum ether/AcOEt 6:4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | General procedure: A mixture of the appropriate o-haloaldehyde (1 eq, 2.60mmol), methyl propargyl ether (1.2 eq, 3.12mmol), Pd(PPh3)2Cl2 (0.04 eq, 0.10mmol), CuI (0.075 eq, 0.19mmol), Et3N (1.5 eq, 3.90mmol), in dry DMF (12mL), was stirred under nitrogen atmosphere, at room temperature for 1h. The mixture was quenched with H2O and the product was extracted with Et2O. The combined organic layers were washed with water, brine, dried over Na2SO4, and evaporated. The crude product was purified by FC (petroleum ether/AcOEt 6:4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium <i>tert</i>-butylate In tetrahydrofuran at -50 - 20℃; for 0.833333h; Inert atmosphere; Overall yield = 64 %; Overall yield = 217 mg; | 3 3-Bromo-4-(2-methoxyvinyl)pyridine (7) Under an N2 atmosphere, (Ph3PCH2OCH3)Cl was suspended inTHF (12 mL). The suspension was cooled to 50 C, and then 1 Mt-BuOK solution in THF (2.39 mL, 2.39 mmol) was added. After3-min stirring at 50 C, 6 (295 mg, 1.59 mmol) in THF (2 mL)was added. The solution was stirred at 50 C for 30 min. Then itwas allowed to warm to room temperature and stirred for another20 min. The reaction mixture was partitioned between water(12 mL) and EtOAc (10 mL). The aqueous layer was extracted withEtOAc (3 6 mL). The combined organic layers were washed withbrine (10 mL) and dried over Na2SO4. Filtration and evaporationafforded crude product, which was purified by fc (2 cm, EtOAc/cyclohexane 1:2 to EtOAc/cyclohexane 1:1). Pale yellow liquid ((E):(Z) = 70:30, EtOAc/cyclohexane 2:1, Rf = 0.52 and 0.46), yield217 mg (64%). 1H NMR (600 MHz, CDCl3): d (ppm) = 3.79 (s,3 0.7H, OCH3, (E)), 3.90 (s, 3 0.3H, OCH3, (Z)), 5.61 (d,J = 7.1 Hz, 0.3H, PyCH = CH, (Z)), 6.02 (d, J = 12.9 Hz, 0.7H,PyCH = CH, (E)), 6.51 (d, J = 7.1 Hz, 0.3H, PyCH = CH, (Z)), 7.25 (d,J = 5.3 Hz, 0.7H, 5-H-Py, (E)), 7.28 (d, J = 12.9 Hz, 0.7H, PyCH = CH,(E)), 8.02 (d, J = 5.4 Hz, 0.3H, 5-H-Py, (Z)), 8.32 (d, J = 5.3 Hz, 0.7H,6-H-Py, (E)), 8.37 (d, J = 5.4 Hz, 0.3H, 6-H-Py, (Z)), 8.62 (s, 0.7H,2-H-Py, (E)), 8.64 (s, 0.3H, 2-H-Py, (Z)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a mixture of 3-bromoisonicotinaldehyde (163; 5.0 g, 27.2 mmol) and K2C03 (5.3 g,38.0 mmol) in DMF (100 ml) was added mercapto-acetic acid ethyl ester (3.3 g, 27.2mmol) at room temperature. The reaction mixture was stirred overnight, then diluted with water (100 mL), extracted with CH2C12 (3 x 100 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na2504), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography toobtain ethyl thieno[2,3-c]pyridine-2-carboxylate (Compound 164; 2.1 g, 35%). MS (ESI) calcd for C10H9N025: 207.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.0 g | With hydrogen bromide; In water; at 20℃; for 0.5h; | A mixture of crude 2-bromo-4-(diethoxymethyl)pyridine (162; 20.0 g,76.9 mmol) and aqueous HBr (100 mL) was stirred at room temperature for 30 mm, then neutralized with saturated NaHCO3 (50 mL) to pH 8-10 at 0 C. The resulting mixture was extracted with CH2C12 (3 x 50 mL) and the combined organic layers were washed with brine, dried (Mg504) and concentrated. The residue was purified by silica gel column chromatographyto obtain 3-bromoisonicotinaldehyde (Compound 163; 15.0 g, quantitative) as a white solid. MS (ESI) calcd for C6H4BrNO:184.95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 20h; Inert atmosphere; | 4.4. General procedure A for the synthesis of indazoles (3b-m) General procedure: In a Schlenk tube under nitrogen atmosphere at room temperature were added BINAP (5.5 mol %), Pd(OAc)2 (5 mol %) and Cs2CO3 (1.4 equiv) and toluene (10 mL per mmol of 1bem). The suspension was heated at 80° C for 10 min and benzophenonehydrazone (2.1 equiv) and the chosen substituted starting material 1b-m (1 equiv) were added. The resulting mixture was heated at100° C for the time depicted in Tables 1 and 2. The mixture was poured in water (20 mL per mmol of 1bem) and CH2Cl2 (20 mL per mmol of 1b-m), filtrated on a short pad of Celite, andextracted with CH2Cl2 (320 mL per mmol of 1bem). The combined organic layers were washed with water (320 mL per mmolof 1bem), dried over MgSO4, filtrated and evaporated. The crude product was eluted on a short pad of silica gel using CH2Cl2 aseluent and evaporated. The crude was introduced in a microwavevial with p-toluenesulfonic acid (2 or 3 equiv see Tables 1 and 2) and solvents (see Tables 1 and 2, 10 mL per mmol of 1b-m). The vial was sealed and the suspension was heated at 100° C for the time depicted in Tables 1 and 2. The resulting mixture was poured in water (20 mL per mmol of 1b-m) and extracted with EtOAc (320 mL per mmol of 1bem). The combined layers were driedon MgSO4, filtrated, evaporated purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 120℃; for 5h; | Ethyl acrylate (0.88 mL, 8.06 mmol) and Et3N (1.14 mL, 8.06 mmol) were added to a solution of 3-bromoisonicotinaldehyde (1.00 g, 5.38 mmol), Pd(OAc)2 (121 mg, 0.54 mmol, 10.0 mol%) and (o-Tol)3P (327 mg, 1.08 mmol, 20.0 mol%) in DMF. The reaction was heated to 120 C and stirred for 5 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether (25 mL). The resulting slurry was filtered through Celite, dried (MgSO4), and the solvent removed under vacuum to give the crude product as a brown oil. The crude product was purified by column chromatography (eluent: cyclohexane/EtOAc (80:20)) and recrystallisation from Et2O: cyclohexane. The title compound was isolated as a cream solid in 16% yield (187 mg, 0.88 mmol). m.p. 55-56 C; 1H NMR (400 MHz, CDCl3) deltaH: 10.37 (1H, s, CHO), 8.96 (1H, s, ArH), 8.87 (1H, d, J = 5.1 Hz, ArH), 8.36 (1H, d, J = 15.9 Hz, ArCH=CH), 7.70 (1H, d, J = 5.1 Hz, ArH), 6.48 (1H, d, J = 15.9 Hz, ArCH=CH), 4.32 (2H, q, J = 7.1 Hz, CH2CH3), 1.37 (3H, t, J = 7.2 Hz, CH2CH3); 13C{1H} NMR (100 MHz CDCl3) deltaC: 190.8, 165.6, 151.5, 149.8, 138.5, 137.4, 130.0, 125.1, 123.0, 61.1, 14.3; I.R (thinfilm) nu max (cm-1): 1703 (C=O), 1637 (C=C); HRMS (ESI): m/z calculated for C11H12NO3: requires: 206.0817 for [M+H]+; found: 206.0811. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In toluene at 95℃; for 5h; | 3.2.4 Example 3.2.4: Preparation of 2-(cyclopropylmethoxy)-N-(3-fluoro-4-methoxybenzyl)-5-(3- formylpyridine-2-yl)benzamide (IC10) The crude compound IC9 was re-dissolved in toluene (500 mL) and 3-bromo-4- formylpyridine (ICc) (19.1 g, 0.101 mol), Pd(dppf)Cl2 (3.5 g, 0.0043 mol), 2N(aq.) and sodium carbonate (86 ml, 0.172 mol) were added. The resulting mixture was heated to 95 °C. After refluxing for 5 H, the reaction was diluted with water. The aqueous portion was separated and extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to obtain a crude material, which was purified by silica gel chromatography and subsequent recrystallization to afford 2-(cyclopropylmethoxy)-N-(3-fluoro-4-methoxybenzyl)-5-(3- formylpyridine-2-yl)benzamide (24 g, 65%) as an off-white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium metabisulfite; In dimethyl sulfoxide; at 120℃; for 2h; | j9388j 2-Amino-5-methoxybenzene-1-thiol (80%, 1 g, 5.15 mmol, described in J. Med. Chem., (2003) 46, 2740), 3-bromopyridine-4-carbaldehyde (0.98 g, 5.26 mmol) and sodium metabisulfite (1 g, 5.26 mmol) were dissolved in anhydrous dimethylsulfoxide (5 mL). The reaction mixture was stirred at 120 C for 2 hours. The mixture was cooled to room temperature and water (100 mL) was added. The resulting black precipitate was filtered and washed with water. The precipitate was dissolved in dichloromethane. The suspension was passed through a pad of silica. The pad was washed with diebloromethane to give the title compound 1.123 g (68% yield) as a purple solid. dnNMR (500 MHz, DMSO) 8.99 (s, 1H), 8.71 (d, I = 5.0 Hz, 1H), 8.13 (d, J = 5.0 Hz, 1H), 8.07 (d, I = 9.0 Hz, 1H), 7.83 (d, I = 2.0 Hz, IH), 7.23 (dd, I = 8.9, 2.2 Hz, IR), 3.88 (s, 3H). Tr(MET-uHPLC-AB-l01) = 3.57 mm, (ESt) (M+H)t 32 1/323. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
245 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 150℃; for 1h; | The compound (557 mg) produced in Example 18 was dissolved in toluene (10 mL). To the resulting solution,3-bromopyridine-4-carboxaldehyde (500 mg), tris(dibenzylideneacetone)dipalladium (0) (123 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (155 mg), and cesium carbonate (1751 mg) were added. The resulting mixture was stirredat 150C for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organiclayer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue waspurified by chromatography on silica gel (ethyl acetate) to obtain the title compound (245 mg) having the followingphysical property values.TLC: Rf 0.23 (hexane : ethyl acetate = 1:1);1H-NMR (CDCl3): delta 1.41, 4.43, 7.29 7.33, 7.52-7.65, 8.13, 8.41, 8.47 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With caesium carbonate In dimethyl sulfoxide at 120℃; for 0.25h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (60%, 476 mg, 19.83 mmol, 1.10 equiv) in tetrahydrofuran (70 mL). To this was added a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.36 g, 12.96 mmol, 1.20 equiv) in tetrahydrofuran (70 mL). The resulting solution was stirred for 30 min at 0 C., then to this was added a solution of 3-bromopyridine-4-carbaldehyde (2 g, 10.75 mmol, 1.00 equiv) in tetrahydrofuran (60 mL). The resulting solution was allowed to react with stirring for 2 h at room temperature. Then was poured into 100 mL of water, extracted with 100 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The collected fraction was concentrated under vacuum to give (E)-methyl 3-(3-bromopyridin-4-yl)acrylate (1.5 g, 58%) as a white solid. MS: (ES, m/z): 242[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 1h; Inert atmosphere; Microwave irradiation; | B.1 Procedure B.2 - microwave heating 3-Bromo-4-pyridinecarboxaldehyde (200 mg, 1 .07 mmol), (1 -tritylimidazol-4-yl)boronic acid (500 mg, 1.41 mmol), potassium carbonate (297 mg, 215 mmol) and [1,1-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (88 mg, 0.11 mmol) were loaded in a microwave vial. The vial was capped and the mixture degased under nitrogen. A 2:1 mixture of 1 ,4-dioxane and water (9 mL) - preliminarily degased under nitrogen - was added to the solid mixture and the resulting suspension was degased under nitrogen for another 5 minutes. The mixture was submitted to microwave irradiations at 120°C for 1 hour. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and washed with a saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with ethyl acetate (50 mL) and the organic layers were combined, dried over sodium sulphate filtered and concentrated in vacuo. The product was isolated via column chromatography with a 0-40% ethylacetate in petroleum ethergradient. 1H NMR (CDCI3, 400 MHz) O: 10.70 (5, 1H), 8.94 (d, J0.8 Hz,1 H), 8.66 (dd, J 5.1, 0.6 Hz, 1 H), 7.68 (dd, J 5.1, 0.7 Hz, 1 H), 7.62 (d, J 1.3 Hz, 1 H), 7.36-7.40 (m,9H), 7.18-7.22 (m, 6H), 6.85 (d, J 1.2 Hz, 1H). LCMS purity >95%, [M+H] = 416, 1.88 mm(analytical short). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Under nitrogen, to 4-iodo-l-trit l-imidazole (2.18 g, 5.00 mmol, 1.00 equiv) in THF (10 mL) at 0 C was added z-PrMgCl (2.0 M, 2.63 mL, 5.3 mmol, 1.1 equiv). After stirring for 1.5 hr at 0 C, -Bu3SnCl (1.56 mL, 5.75 mmol, 1.15 equiv) was added and the reaction mixture was warmed to 23 C. After stirring for 20 min at 23 C, 3-bromopyridine- 4-carbaldehyde (930 mg, 5.00 mmol, 1.00 equiv), Pd(PPh3)4 (1.16 g, 1.00 mmol, 0.200 equiv), Cul (95.2 mg, 0.500 mmol, 0.100 equiv), and LiCl (2.12 g, 50.0 mmol, 10.0 equiv) were added and the reaction mixture was heated to 70 C. After stirring for 21 hr at 70 C, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH to afford 1.0 g of 3-(l-trityl-lH-imidazol-4-yl)isonicotinaldehyde (48% yield). [00272] NMR Spectroscopy: lH NMR (300 MHz, CDC13, 23 C, delta): 10.66 (s, 1H), 8.90 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.40-7.08 (m, 16H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With toluene-4-sulfonamide; In toluene; at 120℃; for 12h;Inert atmosphere; | A solution of <strong>[1078-28-0]6-methoxy-2-methylquinoline</strong> (200 mg, 1.15 mmol), p-toluenesulfonamide (197 mg, 1.15 mmol) and 3-bromoisonicotinaldehyde (214 mg, 1.15 mmol) in toluene (5 mL) was refluxed at 120 C. for 12 h in a reaction tube under N2. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. Then the concentrate was purified by column chromatography with EtOAc/DCM (1:4, v/v) on silica gel, affording TZ-36-46 as a yellow solid (247 mg, 63%). 1H NMR (400 MHz, CDCl3) delta 8.76 (t, J=3.6 Hz, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.17 (d, J=8.6 Hz, 2H), 7.89-7.60 (m, 4H), 7.43 (d, J=9.2 Hz, 1H), 7.11 (s, 1H), 3.95 (d, J=2.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
250 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 150℃; for 1h; | 27 Example 27: ethyl 2-oxo-1-phenyl-1,2-dihydro-1,7-naphthyridine-3-carboxylate Example 27 ethyl 2-oxo-1-phenyl-1,2-dihydro-1,7-naphthyridine-3-carboxylate The compound (560 mg) produced in Example 26 was dissolved in toluene (10 mL), 3-bromopyridine-4-carbaldehyde (500 mg), tris(dibenzylideneacetone)dipalladium(0) (120 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (160 mg), and cesium carbonate (1800 mg) were added. The mixture was stirred at 150°C for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (250 mg) having the following physical property values. TLC: Rf 0.23 (hexane: ethyl acetate =1:1); 1H-NMR (CDCl3): δ 1.41, 4.43, 7.29-7.33, 7.52-7.65, 8.13, 8.41, 8.47. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonamide; In toluene; for 12h;Inert atmosphere; Reflux; | General procedure: A solution of commercially available quinoline derivatives (1equiv.), p-toluenesulfonamide (1equiv.) and aldehyde (1equiv.) in toluene (1 M) was refluxed at 120C for 12h in a reaction tube under N2. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. Then the residue was purified by silica gel column chromatography to afford the vinyl quinoline derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bismuth (III) nitrate pentahydrate; In ethanol; at 80℃; | General procedure: To a 50 mL round-bottomed flask charged with pentahydratedbismuth nitrate (0.032 g, 0.065 mmol) in ethanol(20 mL) were added thiobarbituric acid (0.144 g, 1.0 mmol) and aromatic aldehydes (1.0 mmol). The reaction mixturewas stirred for 10-20 min at 80 C, when thin layer chromatographyanalyzes revealed it was completed. Aftercompletion the precipitated product was separated by filtration,dried, and recrystallized from ethanol. Full physicaland spectroscopic data and yields for all compounds arepresented in the supporting information (SI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With 18-crown-6 ether; potassium carbonate; In dichloromethane; at 65℃; for 96h; | A suspension of compound 28 (1.64 g, 2.75 mmol), 3-bromoisonicotinaldehyde(465 mg, 2.5 mmol), solid K2CO3 (3.46 g,25.0 mmol) and 18-crown-6 (100.0 mg, 0,38 mmol) in dichloromethane(125 mL) was stirred at 65 C (external temperature) for 4days. The resulting mixture was cooled at room temperature andfiltered off. The filtrate was concentrated under vaccum and thecrude residue was then purified by chromatography on silica gel(gradient of EtOAc in petroleum ether) to afford the title compound29 as a pale yellow solid. (E/Z mixture, Yield 0.54 g, 57%). Rf 0.27(EtOAc/petroleum ether 1:1). 1H NMR (300 MHz, CDCl3, d):2.61e2.77 (m, 2H), 3.05e3.19 (m, 2H), 3.93e3.95 (m, 6H),5.99e6.02 (m, 0.5H), 6.41e6.76 (m, 1.5H), 6.85e6.81 (m, 1H), 7.30(d, 0.5H, J 5.1 Hz), 7.35 (d, 0.5H, J 4.8 Hz), 7.51e7.63 (m, 2H), 8.39(d, 0.5H, J 4.8 Hz), 8.47 (d, 0.5H, J 4.8 Hz), 8.65 (s, 0.5H), 8.71 (s,0.5H). 13C NMR (75 MHz, CDCl3, d): 15.3, 23.4, 27.9, 37.1, 37.5, 56.0,56.1, 65.9, 110.0, 110.1, 110.1, 120.8, 121.1, 122.2, 122.7, 122.7, 124.9,127.0,127.4,129.9,130.0,135.6,137.2,144.4,144.9,148.0,148.1,149.1,149.1, 152.0, 152.4, 153.4, 153.4, 197.4, 197.4. HRMS (ESI): m/z calcdfor C18H19NO3Br [MH]: 376.0548; found 376.0534. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide; In ethanol; at 35℃; for 4h; | At 35 C, to a solution of NaOH (0.39 g, 9.7 mmol) in EtOH(12 mL) were added in one portion a mixture of 6,7-dimethoxy-1-tetralone 1c (1.0 g, 4.85 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong>2 (0.9 g, 4.85 mmol). The reaction mixture was then stirredfor 4 h at the same temperature. The resulting precipitate was filtered off then rinsed twice with cold diethyl ether to afford thetitle compound 3c as a pale yellow solid. (Yield 1.80 g, 99%). 1H NMR(300 MHz, CDCl3, d): 2.89 (br s, 4H); 3.92 (s, 6H), 6.65 (s, 1H), 7.17 (d,1H, J 5.1 Hz), 7.60 (s, 2H), 8.51 (d, 1H, J 5.1 Hz), 8.75 (s, 1H). 13CNMR (75 MHz, CDCl3, d): 27.7, 28.6, 56.1, 56.2, 109.6, 110.0, 122.6,124.5, 126.1, 131.6, 139.5, 144.5, 148.0, 148.5, 152.3, 154.1, 185.7.HRMS (ESI): calcd for [MH] C18H17NO3Br m/z 374,0392; found374.0392. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With toluene-4-sulfonic acid; In toluene; for 4h;Dean-Stark; Reflux; | General procedure: To a solution of 5-fluoro-1-indanone 1j (750.7 mg,5.0 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> 2 (0.93 g,5.0 mmol) in toluene (50 mL) was added p-toluenesulfonic acid(1.42 g, 7.5 mmol). After heated at reflux using a Dean-Stark apparatusfor 4 h, the mixture was cooled to room temperature and thesolvent was removed in vacuum, then 5% sodium bicarbonateaqueous solution was added until reach pH 8. After extractionwith dichloromethane (4), the organic layer was dried overmagnesium sulfate and concentrated to dryness. The residue wastaken up with EtOAc and the solidwas filtered, rinsed with EtOAc toafford compound 3j as a grey solid (1.59 g, 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid; In toluene; for 4h;Dean-Stark; Reflux; | General procedure: To a solution of 5-fluoro-1-indanone 1j (750.7 mg,5.0 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> 2 (0.93 g,5.0 mmol) in toluene (50 mL) was added p-toluenesulfonic acid(1.42 g, 7.5 mmol). After heated at reflux using a Dean-Stark apparatusfor 4 h, the mixture was cooled to room temperature and thesolvent was removed in vacuum, then 5% sodium bicarbonateaqueous solution was added until reach pH 8. After extractionwith dichloromethane (4), the organic layer was dried overmagnesium sulfate and concentrated to dryness. The residue wastaken up with EtOAc and the solidwas filtered, rinsed with EtOAc toafford compound 3j as a grey solid (1.59 g, 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With toluene-4-sulfonic acid; In toluene; for 4h;Dean-Stark; Reflux; | General procedure: To a solution of 5-fluoro-1-indanone 1j (750.7 mg,5.0 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> 2 (0.93 g,5.0 mmol) in toluene (50 mL) was added p-toluenesulfonic acid(1.42 g, 7.5 mmol). After heated at reflux using a Dean-Stark apparatusfor 4 h, the mixture was cooled to room temperature and thesolvent was removed in vacuum, then 5% sodium bicarbonateaqueous solution was added until reach pH 8. After extractionwith dichloromethane (4), the organic layer was dried overmagnesium sulfate and concentrated to dryness. The residue wastaken up with EtOAc and the solidwas filtered, rinsed with EtOAc toafford compound 3j as a grey solid (1.59 g, 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In ethanol; for 28h;Reflux; | To a solution of 3,4-dimethoxyacetophenone 1a (7.21 g,40.0 mmol) and <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong> 2 (7.44 g,40.0 mmol) in ethanol (160 mL), was added K2CO3 (12.72 g,120.0 mmol) in one portion and the resulting mixturewas stirred atreflux for 28 h. After cooling at room temperature, the mixture wasconcentrated to dryness, diluted with dichloromethane, washedtwice with water and brine. The organic layer was then dried overanhydrous MgSO4, filtered and concentrated under vacuum. Thecrude solidwas triturated with diethyl ether, and the resulting solidwas filtered and dried to afford the compound 3a as a yellow solid.(Yield 8.96 g, 64%). 1H NMR (300 MHz, CDCl3, d): 3.97 (s, 3H), 3.98(s, 3H), 6.94 (d, 1H, J 8.4 Hz), 7.54e7.61 (m, 3H), 7.67 (dd, 1H,J 8.4 Hz, J 2.1 Hz), 7.95 (d, 1H, J 15.6 Hz), 8.56 (d, 1H,J 5.1 Hz), 8.80 (s, 1H). 13C NMR (75 MHz, CDCl3, d): 56.1, 56.2,110.0,110.7, 121.5, 122.8, 123.6, 128.1, 130.4, 139.2, 142.5, 148.6, 149.4,153.0, 153.8, 187.7. HRMS (ESI): calcd for [MH] C16H15NO3Br m/z348,0235; found 348.0250. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With toluene-4-sulfonic acid; In toluene; for 4h;Dean-Stark; Reflux; | To a solution of <strong>[700-84-5]5-fluoro-1-indanone</strong> 1j (750.7 mg,5.0 mmol) and 3-bromo-4-pyridinecarboxaldehyde 2 (0.93 g,5.0 mmol) in toluene (50 mL) was added p-toluenesulfonic acid(1.42 g, 7.5 mmol). After heated at reflux using a Dean-Stark apparatusfor 4 h, the mixture was cooled to room temperature and thesolvent was removed in vacuum, then 5% sodium bicarbonateaqueous solution was added until reach pH 8. After extractionwith dichloromethane (4), the organic layer was dried overmagnesium sulfate and concentrated to dryness. The residue wastaken up with EtOAc and the solidwas filtered, rinsed with EtOAc toafford compound 3j as a grey solid (1.59 g, 53%). 1H NMR (300 MHz,CDCl3, d): 3.96 (s, 2H), 7.12e7.20 (m, 2H), 7.48 (d,1H, J 5.1 Hz), 7.79(t, 1H, J 2.1 Hz), 7.95 (dd, 1H, J 8.4, J 5.4 Hz), 8.60 (d, 1H,J 5.1 Hz), 8.82 (s, 1H). 13C NMR (75 MHz, CDCl3, d): 31.6, 113.0,113.3, 116.4, 116.7, 123.5, 127.3, 129.6, 134.1, 140.1, 142.7, 148.4, 152.2,152.3, 153.0, 165.7, 169.1, 191.4. HRMS (ESI): calcd for [MH]C15H10NOBrF m/z 317.9924; found 317.9923. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In a flask equipped with a reflux condenser and a water separator, 384 mg (2 mmol) of <strong>[70201-43-3]3-bromo-4-pyridinecarboxaldehyde</strong>, 60 ml of toluene, 2 ml (mmol) of ethylene glycol, and 384 mg (2 mmol, 0.2 eq) of p-toluenesulfonic acidwere added. acid. Heated to reflux, TLC monitoring,After the reaction was completed, the reaction was quenched with 100 ml of saturated sodium hydrogen carbonate solution.Extract three times with 30 mL of ethyl acetate and combine ethyl acetate.Concentration gave an acetal compound. In a three-necked flask equipped with a reflux condenser and a constant pressure dropping funnel, magnesium chips (58 mg, 2.4 mmol) and a catalyst amount of iodine particles were added, and the surface of the magnesium chips was heated to a magenta color, and then a small amount of tetrahydrofuran was added to cover the magnesium particles. .The above acetal compound was dissolved in 5 ml of tetrahydrofuran, and a small amount was added dropwise to a three-necked flask. The electric heating gun was slightly heated to initiate the reaction, and then slowly dropped.Remaining solution.After the dropwise addition, the reaction flask was kept at 40 C for 2 hours. Return to room temperature and let stand. In a 100 mL single-mouth bottle, 356 mg (2 mmol) of 1,4-dicyanophthalene, 20 mL of tetrahydrofuran, and cooled to 0 C,The reagent of the above format was slowly added dropwise to the reaction system and allowed to stand at room temperature.After the reaction was monitored by thin layer chromatography, the reaction was quenched with 1M HCl.Extracted three times with 30 mL of ethyl acetate, combined ethyl acetate and concentrated.Over-flash column (ethyl acetate / petroleum ether 5%-20%)The target compound solid was 283 mg, yield 43%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 90.476 % de | With triethylamine In ethanol at 110℃; for 6h; Sealed tube; Green chemistry; diastereoselective reaction; | General procedure for the synthesis of pyrrolidine adducts 5 General procedure: A solution of amino ester 1 (1.2 mmol), 2-bromobenzaldehyde 3 (1 mmol) and maleimide 4 (1.1 mmol) in EtOH (3 mL) with Et3N (1.5 mmol) was heated at 110 °C for 6 h in a sealed vial. The concentrated reaction mixture was isolated by column chromatography on silica gel to afford adduct 5 in 85-90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.91% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 0 - 20℃; | 1.5 (5) Combine 3-bromoisonicotinaldehyde (E1-1, 300mg, 1.61mmol), (2-(methylamino)ethyl) tert-butyl carbamate (F1-1, 421mg, 2.42mmol), glacial acetic acid (552μM, 9.66mmol) was added to dichloroethane, and sodium triacetoxyborohydride (682.45mg, 3.22mmol) was added in batches at 0°C. The reaction solution was reacted overnight at room temperature. After TCL monitors that the reaction is complete, saturated sodium bicarbonate solution is added to adjust the pH to 7-8, dichloromethane is added for extraction, and the organic phase is collected. Column chromatography obtained target compound C1-1, light yellow oily liquid 260 mg, yield: 46.91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene for 3h; Reflux; | 165.1; 192-1 Step 1: 3-Bromo-4-pyridinecarbaldehyde (164-1, 22.0 g, 118 mmol), ethylene glycol (14.7 g, 236 mmol) and TsOH (6.1 g, 35 mmol) were added to toluene (150 mL), and heated to reflux to separate water and react for 3h. TLC showed that the raw material was completely reacted. The reaction solution was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 164-2 as a yellow oil, which was directly used in the next step. | |
26.7 g | With toluene-4-sulfonic acid In toluene at 110℃; for 3h; | 3-bromo-4-(1,3-dioxolan-2-yl)pyridine (I7-2) A solution of 3-bromoisonicotinaldehyde (22.0 g, 118 mmol), ethylene glycol (14.7 g, 236 mmol) and p-toluenesulfonic acid (6.10 g, 35.0 mmol) in toluene (150 mL) was heated to reflux for 3 h. TLC showed the reaction completed. The reaction mixture was cooled to room temperature, poured into ice-water, extracted with Ethyl acetate. Combined organic phase washed with water, brine, dried over Na2SO4, concentrated under reduced pressure to afford compound I7-2 (26.7 g) as yellow oil, which was used directly for subsequent step. LC-MS: m/z = 230.1/232.1[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium acetate; palladium diacetate; triphenylphosphine In 1,4-dioxane at 150℃; for 24h; Inert atmosphere; Sealed tube; | 21.1 Step 1: Synthesis of dimethyl isoquinoline-6,7-dicarboxylate (compound 3) A mixture of 3-bromopyridine-4-carbaldehyde (1, 0.093 g, 0.5 mmol), dimethyl itaconate (2, 0.079 g, 0.5 mmol), Pd(OAc)2(0.0056 g, 0.025 mmol), PPh3(0.013 g, 0.05 mmol) and NaOAc (0.123 g, 1.5 mmol) in dioxane (10mL) was placed in a 50 mL pressure vessel. After the system was flushed with argon, the reaction mixture was allowed to react at 150oC for 24 h, and then the reaction mixture was cooled to room temperature. The reaction mixture was filtered through celiteto eliminate inorganic salts and washed by ethyl acetate. Removal of the solvent left a crude mixture which was purified by flash chromatography on silica gel (ethyl acetate-hexane) to give dimethyl isoquinoline-6,7-dicarboxylate (3, 0.082 g, 67%). |
67% | With sodium acetate; palladium diacetate; triphenylphosphine In 1,4-dioxane at 150℃; for 24h; Inert atmosphere; | 1.1 Step 1: Synthesis of dimethyl isoquinoline-6, 7-dicarboxylate (compound 3) A mixture of 3-bromopyridine-4-carbaldehyde (1, 0.093 g, 0.5 mmol), dimethyl itaconate (2, 0.079 g, 0.5 mmol), Pd(OAc)2 (0.0056 g, 0.025 mmol), PPh3 (0.013 g, 0.05 mmol) and NaOAc (0.123 g, 1.5 mmol) in dioxane (lOmL) was placed in a 50 mL pressure vessel. After the system was flushed with argon, the reaction mixture was allowed to react at 150 °C for 24 h, and then the reaction mixture was cooled to room temperature. The reaction mixture was filtered through celite to eliminate inorganic salts and washed by ethyl acetate. Removal of the solvent left a crude mixture which was purified by flash chromatography on silica gel (ethyl acetate-hexane) to give dimethyl isoquinoline-6, 7-dicarboxylate (3, 0.082 g, 67%). |
67% | With sodium acetate; palladium diacetate; triphenylphosphine In 1,4-dioxane at 150℃; for 24h; Inert atmosphere; | 20.1 Step 1: Synthesis of dimethyl isoquinoline-6,7-dicarboxylate (compound 3) A mixture of 3-bromopyridine-4-carbaldehyde (1, 0.093 g, 0.5 mmol), dimethyl itaconate (2, 0.079 g, 0.5 mmol), Pd(OAc)2 (0.0056 g, 0.025 mmol), PPh3 (0.013 g, 0.05 mmol) and NaOAc (0.123 g, 1.5 mmol) in dioxane (10mL) was placed in a 50 mL pressure vessel. After the system was flushed with argon, the reaction mixture was allowed to react at 150 oC for 24 h, and then the reaction mixture was cooled to room temperature. The reaction mixture was filtered through celite to eliminate inorganic salts and washed by ethyl acetate. Removal of the solvent left a crude mixture which was purified by flash chromatography on silica gel (ethyl acetate-hexane) to give dimethyl isoquinoline-6,7-dicarboxylate (3, 0.082 g, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With ammonium acetate In ethanol at 90℃; for 12h; | 2.2 Chemical synthesis General procedure: The steroidal pyridine derivatives 4a-4l were synthesized by a one-pot multicomponent reaction through the mixing of pregnenolone, malononitrile, various substituted benzaldehyde and ammonium acetate in anhydrous ethanol. The reaction conditions were determined as follows: pregnenolone (1mmol), substituted arylaldehydes (1.1mmol), malononitrile (1.5mmol) and ammonium acetate (4mmol) were resolved in anhydrous ethanol. The mixture was refluxed at 90°C for 12h and then monitored by TLC. The organic phase was washed with brine and saturated NaHCO3 solution, dried with anhydrous Na2SO4, filtered, evaporated, and finally the crude product was purified by column chromatography (petroleum ether/ethyl acetate 4:1, v/v) to give the desired compounds 4a-4l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane at 20℃; for 2h; Inert atmosphere; | 3.34.1 Step 1: To a solution of 3-bromoisonicotinaldehyde (2 g, 10.7 mmol) in DCM (30 mL) was added a solution of ethyl 2-(triphenylphosphoranylidene)acetate (3.7 g, 10.7 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 2 hrs under N2 atmosphere. The DCM was removed under reduced pressure. The residue was purified by silica gel column (PE/EA = 1/1) to give (E)-ethyl 3-(3-bromopyridin-4-yl)acrylate (2.3 g, yield: 85%) as a yellow oil. MS: m/z 258.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil for 1h; Cooling with ice; Stage #2: 3-bromo-pyridine-4-carbaldehyde In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h; | 4.1.1 Synthesis of ethyl (E)-3-(3-bromopyridin-4-yl) acrylate (2) To a stirred solution of NaH (520mg, 60%) in dry THF (35mL) was added triethyl phosphonoacetate (2.912g, 13mmol) in an ice bath for 1h. Then, to the mixture was added 3-bromopyridine-4-carboxaldehyde (1) at 0°C and stirred at room temperature for 3h. After evaporation, saturated salt water (25mL) was added to this mixture, and the mixture was extracted with ethyl acetate (3×25mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude reaction mixture, which was chromatographed over silica gel column (PE/EA, 20:1) to obtain intermediate 2. Yield: 70%, white solid. |
70% | Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran; mineral oil for 1h; Cooling with ice; Stage #2: 3-bromo-pyridine-4-carbaldehyde In tetrahydrofuran; mineral oil at 20℃; for 0.3h; | 1.1 (1) Synthesis of (E)-3-(3-bromopyridin-4-yl)acrylic acidEthyl ester Weigh sodium hydride (content 60%, 520mg) in a dry round bottom flask,Add 5mL anhydrous tetrahydrofuran,Add 20mL slowly under ice bathPhosphonotriethyl ester (2.912g, 13mmol) dissolved in anhydrous tetrahydrofuran,After the addition is complete, continue to stir and react for 1 hour in an ice bath.Continue to drip 25mL into the above reaction systemTetrahydrofuran diluted3-Bromo-pyridine 4-carbaldehyde (1.86g, 10mmol), after the addition was completed, the reaction was stirred at room temperature for about 3h. After the reaction, the solvent was distilled off, extracted with ethyl acetate and saturated brine, the organic layers were combined and concentrated to obtain a pale yellow oil, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a white solid (1.8g) , The yield is 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.75% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 80℃; for 2h; Inert atmosphere; | 32.1 Step 1: fert-Butyl (3-(4-formylpyridin-3-yl)prop-2-yn-1-yl)carbamate A mixture of 3-bromopyridine-4-carbaldehyde (15 g, 80.64 mmol), fe/f-butyl prop-2-yn-1- ylcarbamate (13.14 g, 84.67 mmol), Et3N (81.60 g, 806.43 mmol, 112.25 ml_), Cul (1.54 g, 8.06 mmol) and Pd(PPh3)2Cl2(5.66 g, 8.06 mmol) in CH3CN (120 ml_) was stirred at 80 °C for 2 hrs under N2. The reaction mixture was quenched by addition of water (300 ml_) and extracted with ethyl acetate (300 ml_ * 3). The combined organic phase was washed with brine (300 ml_), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (18 g, 69.15 mmol, 85.75% yield) as a brown oil.LCMS (ESI) m/z: [M+H]+= 261 .1 .1HNMR (400 MHz, CDCb) d = 10.48 (s, 1 H), 8.66 (s, 1 H), 8.78 - 8.68 (m, 1 H), 7.78 - 7.62 (m, 1 H), 4.88 (br s, 1 H), 4.32 - 4.18 (m, 2H), 1.46 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 4-iodobenzonitrile With TurboGrignard In tetrahydrofuran at -15℃; for 1h; Stage #2: 3-bromo-pyridine-4-carbaldehyde In tetrahydrofuran at -15 - 20℃; for 16h; | Step A: (R,S)-4-((3-Bromopyridin-4-yl)(hydroxy)methyl)benzonitrile. i-PrMgCl•LiCl (9.1 mL, 1.3 M in THF, 12 mmol) was added dropwise to a solution of 4-iodobenzonitrile (2.71 g, 11.8 mmol) and THF (25 mL) that had been cooled to -15 °C. The mixture was stirred at - 15 °C for 1 hour and then added dropwise to a -15 °C solution of 3-bromoisonicotinaldehyde (2.0 g, 11 mmol) and THF (5 mL). The mixture was stirred at room temperature for 16 hours before quenching with saturated NH4Cl (50 mL) and extracting with ethyl acetate (50 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate, 20:1 to 2:1, gradient elution) to give the title compound (1.8 g, 58%) as a brown solid. MS (ESI): mass calcd. for C13H9BrN2O 287.99 m/z found 290.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With titanium(IV) tetraethanolate In dichloromethane at 20℃; for 16h; Inert atmosphere; Sealed tube; | |
70% | With titanium(IV) tetraethanolate In dichloromethane at 45℃; for 16h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-bromo-pyridine-4-carbaldehyde With titanium(IV) tetraethanolate In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: S-tert-butylsulfinimide In tetrahydrofuran at 20℃; for 16h; | 1 Step 1: To a solution of 3-bromo-4-pyridinecarboxaldehyde (42.0 g, 225 mmol) in THF (250 ml) was added titanium (IV) ethoxide (93.6 ml , 451 mmol) in one portion at RT. The mixture was stirred at RT for 5 min before (±)-tert-butylsulfinamide (30.1 g, 248 mmol) was added in one portion. The resulting mixture was stirred at RT for 16 h. Water (50 ml) was added at 0 °C, and the product was extracted with EtOAc (3 x 30 ml). The combined organic layers were concentrated in vacuo. The product was purified by silica gel chromatography (1- 100% EtOAc/ petroleum ether to give (E)-N-((3-bromopyridin-4-yl)methylene)-2- methylpropane-2-sulfinamide (l-7b) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 8.91 (s, 1H), 8.86 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 7.83 (d, J= 5.2 Hz, 1H), 1.29 (s, 9H). | |
Stage #1: 3-bromo-pyridine-4-carbaldehyde With titanium(IV) tetraethanolate In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: S-tert-butylsulfinimide In tetrahydrofuran at 20℃; for 16h; | 1 Step 1: To a solution of 3-bromo-4-pyridinecarboxaldehyde (42.0 g, 225 mmol) in THF (250 ml) was added titanium (IV) ethoxide (93.6 ml , 451 mmol) in one portion at RT. The mixture was stirred at RT for 5 min before (±)-tert-butylsulfinamide (30.1 g, 248 mmol) was added in one portion. The resulting mixture was stirred at RT for 16 h. Water (50 ml) was added at 0 °C, and the product was extracted with EtOAc (3 x 30 ml). The combined organic layers were concentrated in vacuo. The product was purified by silica gel chromatography (1- 100% EtOAc/ petroleum ether to give (E)-N-((3-bromopyridin-4-yl)methylene)-2- methylpropane-2-sulfinamide (l-7b) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 8.91 (s, 1H), 8.86 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 7.83 (d, J= 5.2 Hz, 1H), 1.29 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With anhydrous Sodium acetate; acetic anhydride at 100℃; for 3h; | General procedure for the preparation of 2-bromophenylazlactones 9a-n1 General procedure: A mixture of aldehydes 8 (1.0 equiv), N-acetylglycine derivatives 13 (1.2-1.8 equiv) andNaOAc (1.1-1.5 equiv) was added an appropriate portion of Ac2O (4-10 equiv) at roomtemperature. The mixture was allowed to heat at 100 .C for 1-16 h. After the completion, thereaction was cooled to room temperature and the excess amount of cold ethanol was pouredinto the reaction to furnish the precipitated crude azlactone product. The crude product waspurified by recrystallization with CH2Cl2 and cold ethanol to give the final product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tripotassium phosphate tribasic; palladium diacetate; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In water monomer; toluene at 115℃; for 16h; | 1-methylbenzo[g]quinolin-1-ium-1 General procedure: 2-Bromo-3-pyridinecarboxaldehyde (0.744 g, 4 mmol) and potassium benzyltrifluoroborate (1.1883 g, 6mmol), 2-Dicyclohexylphosphonium-2,6- diisopropoxy-1,1-biphenyl (0.3173 g, 0.68 mmol), potassium phosphate (4.415 g, 20.8 mmol), palladium acetate (0.0718 g, 0.32 mmol), were added in mixed solvent of toluene: water = 5:1 (V/V), the mixture was heated in oil bath at 115°C to refluxed for 16 h. When the reaction solution was cooled to room temperature, the organic phase was extracted by EtOAc (3 × 40 mL). After evaporating EtOAc under reduced pressure, the yellow oily liquid a was obtained (0.342 g, 46%); a (0.300 g, 1.5 mmol) and polyphosphoric acid (10.000 g) were heated in oil bath at 140°C to refluxed for 1.5 h. H2O (20 mL) was added in the cool reaction solution. And the organic phase was extracted by DCM (3 × 60 mL), after evaporating solvent under reduced pressure, the brown solid b was obtained (0.12 g, 40%); To a solution of CH3CN (12 mL) was added compound b (36 mg, 2 mmol), then methyl iodide (1 mL) was added, the mixture was heated in oil bath to reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in H2O (10 mL), added excess NH4PF6 and the filter cake was filtered, purified by silica gel column chromatograph (EtOAc: PE =1:8) to give yellow solid, the solid was washed by H2O for three times in order to wash off excess NH4PF6, dried in vacuum at 60 °C, the solid was dissolved in acetone (10 mL), and excess Bu4N+Br- was added, the filter cake was centrifuged, washed by acetone for three times and dried in vacuum at 60 to give orange solid 1 (43 mg, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tripotassium phosphate tribasic; palladium diacetate; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In water monomer; toluene at 115℃; for 16h; | 1-methylbenzo[g]quinolin-1-ium-1 General procedure: 2-Bromo-3-pyridinecarboxaldehyde (0.744 g, 4 mmol) and potassium benzyltrifluoroborate (1.1883 g, 6mmol), 2-Dicyclohexylphosphonium-2,6- diisopropoxy-1,1-biphenyl (0.3173 g, 0.68 mmol), potassium phosphate (4.415 g, 20.8 mmol), palladium acetate (0.0718 g, 0.32 mmol), were added in mixed solvent of toluene: water = 5:1 (V/V), the mixture was heated in oil bath at 115°C to refluxed for 16 h. When the reaction solution was cooled to room temperature, the organic phase was extracted by EtOAc (3 × 40 mL). After evaporating EtOAc under reduced pressure, the yellow oily liquid a was obtained (0.342 g, 46%); a (0.300 g, 1.5 mmol) and polyphosphoric acid (10.000 g) were heated in oil bath at 140°C to refluxed for 1.5 h. H2O (20 mL) was added in the cool reaction solution. And the organic phase was extracted by DCM (3 × 60 mL), after evaporating solvent under reduced pressure, the brown solid b was obtained (0.12 g, 40%); To a solution of CH3CN (12 mL) was added compound b (36 mg, 2 mmol), then methyl iodide (1 mL) was added, the mixture was heated in oil bath to reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in H2O (10 mL), added excess NH4PF6 and the filter cake was filtered, purified by silica gel column chromatograph (EtOAc: PE =1:8) to give yellow solid, the solid was washed by H2O for three times in order to wash off excess NH4PF6, dried in vacuum at 60 °C, the solid was dissolved in acetone (10 mL), and excess Bu4N+Br- was added, the filter cake was centrifuged, washed by acetone for three times and dried in vacuum at 60 to give orange solid 1 (43 mg, 90%). |
Tags: 70201-43-3 synthesis path| 70201-43-3 SDS| 70201-43-3 COA| 70201-43-3 purity| 70201-43-3 application| 70201-43-3 NMR| 70201-43-3 COA| 70201-43-3 structure
[ 886364-94-9 ]
5-Bromo-4-methylpicolinaldehyde
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[ 850892-12-5 ]
5-Bromo-4-methylpyridin-3-amine
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[ 1227573-02-5 ]
3-Bromo-5-fluoroisonicotinaldehyde
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[ 886364-94-9 ]
5-Bromo-4-methylpicolinaldehyde
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[ 1227573-02-5 ]
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[ 118289-17-1 ]
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[ 886364-94-9 ]
5-Bromo-4-methylpicolinaldehyde
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[ 850892-12-5 ]
5-Bromo-4-methylpyridin-3-amine
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[ 1227573-02-5 ]
3-Bromo-5-fluoroisonicotinaldehyde
Similarity: 0.81
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