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CAS No. : | 127406-56-8 | MDL No. : | MFCD01863537 |
Formula : | C12H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NMLYGLCBSFKJFI-UHFFFAOYSA-N |
M.W : | 183.21 | Pubchem ID : | 1515240 |
Synonyms : |
|
Chemical Name : | 4-(Pyridin-2-yl)benzaldehyde |
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 55.06 |
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) : | -5.93 cm/s |
Log Po/w (iLOGP) : | 1.8 |
Log Po/w (XLOGP3) : | 2.09 |
Log Po/w (WLOGP) : | 2.56 |
Log Po/w (MLOGP) : | 1.41 |
Log Po/w (SILICOS-IT) : | 3.17 |
Consensus Log Po/w : | 2.21 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.79 |
Solubility : | 0.294 mg/ml ; 0.0016 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.35 |
Solubility : | 0.82 mg/ml ; 0.00448 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.49 |
Solubility : | 0.00593 mg/ml ; 0.0000324 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
80% | With palladium diacetate; triphenylphosphine; potassium hydroxide In tetrahydrofuran; methanol at 60℃; for 24 h; Inert atmosphere; Schlenk technique | General procedure: The brominated derivative (2-bromopyridine for 13a and 1-bromo-4-nitrobenzene for 14a) 1.1 equiv.of 4-formylphenyl boronic acid, Pd(OAc)2 2 mol percent and PPh3 4 mol percent were added to a Schlenk flask.Then, under an inert atmosphere methanol/THF 1:1 (2mL/mmol) and 2 equiv. of KOH were added. Thesystem was stirred for 24 h at 60 °C [21]. Compounds were purified by column chromatography(cyclohexane/EtOAc, 9:1) in yields of 80percent (13a) and 75percent (14a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
88% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
88% | With C46H49BrClFeN3Pd; copper diacetate; caesium carbonate In 1,4-dioxane at 110℃; for 24 h; | General procedure: A 10 mL round-bottom flask was charged with the prescribedamount of catalyst Pd/Cu, aryl chlorides (0.5 mmol), phenylboronicacids containing hydroxymethyl (0.75 mmol), Cs2CO3 (1.0 mmol)and dioxane (5 mL) in air. The reaction mixture was then placedin an oil bath and heated at 110 C for 24 h. After removal of thesolvent, the resulting residue was purified by flash chromatographyon silica gel using CH2Cl2 as eluent. The products 4a–k, and4m are known compounds [6,9] except for 4l and 4n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; |
While regulating the temperature at from 30 to 35° C., iodine (0.2 g) and then, over a period of approximately one hour, a solution of 4-bromobenzaldehyde dimethyl acetal (93 g, 0.394 mol) in tetrahydrofuran (80 g) are added to a suspension of magnesium (9.6 g, 0.394 mol) in tetrahydrofuran (68 g) maintained at 30° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 35° C. with agitation for one hour. Toluene (88 g) is added to the reaction mixture. [00039] Coupling Reaction: Preparation of 4-(2'-pyridyl)benzaldehyde [00040] Anhydrous zinc chloride (13.6 g 0.1 mol) and then 2-bromopyridine (52.8 g, 0.334 mol) are added, with agitation under an inert atmosphere, to a solution constituted by toluene (156 g) and tetrahydrofuran (132 g). Palladium tetrakistriphenylphosphine (0.204 g, 0.178 mmol) and then, over a period of two hours, the Grignard solution are added to the suspension maintained at 50° C. with agitation and under an inert atmosphere. The reaction mixture is maintained at 50° C. for approximately 30 minutes and then cooled to 25° C. [00041] A solution constituted by water (300 g) and 30percent hydrochloric acid (70 g) is added to the reaction mixture over a period of approximately 30 minutes. The mixture is maintained under agitation at 25° C.-30° C. for one hour and then the phases are separated. 30percent ammonia is added to the aqueous phase up to a pH of 8, and then toluene (90 g) is added. The phases are separated, the organic phase is evaporated under vacuum to yield a residue constituted by 4-(2'-pyridyl)benzaldehyde (61.1 g, 0.334 mol; yield in moles relative to the 2-bromopyridine added: 100percent; turnover of the catalyst (Pd) 1876). [00042] IR: 1695.7 cm-1 (aldehyde CO stretching); M.P.: 52°-53° C.; 1H-NMR (300 MHz, CDCl3): ppm 10.2 (1H, s); 8.8 (1H,dt, J=4.8 Hz, J=1.4 Hz); 8.25 (2H, part B of an AB system, J=7.0 Hz); 8.15 (2H, part A of an AB system, J=7.0 Hz); 7.8 (2H, AB system, J=8.6 Hz, J=1.4 Hz); 7.35 (1H,m). [00043] The product as identified by comparison with an authentic sample prepared in accordance with Example 37b described in patent WO97/40029. |
99% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 70℃; for 3.5 h; |
2-bromopyridine (7.90 g, 0.050 mol) and palladium tetrakistriphenylphosphine (0.029 g, 0.025 mmol) and then, at a temperature of 70° C. and over a total of 3 hours, a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (53 g of solution, containing 0.062 mol), prepared analogously to Example 9, are added to a mixture of ZnCl2 (0.72 g, 0.0053 mol) in tetrahydrofuran (12.4 g) maintained under agitation under an inert atmosphere. The reaction mixture is maintained at 70° C. for 30 minutes and then cooled to 25° C. [00082] A solution constituted by water (28 g) and 30percent hydrochloric acid (10 g) is added to the reaction mixture and the mixture is maintained under agitation for 2 hours at 25° C. Toluene (30 g) and 30percent ammonia (9.7 g), are added and the phases are separated to give a solution of 4-(2'-pyridyl)benzaldehyde (53.5 g, HPLC strength 17percent, equal to 9.09 g, 0.049 mol; yield in moles relative to the 2-bromopyridine added: 99percent, turnover of catalyst (Pd): 1960). |
96.4% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 50℃; for 3.5 h; |
A chip of iodine (50 mg) and p-bromobenzaldehyde dimethyl acetal (6.8 g, 98percent, 0.029 mol) are added to a suspension of magnesium filings (7.0 g, 0.287 mol) in tetrahydrofuran (109 g) maintained at 30° C. with agitation under an inert atmosphere: after a few minutes, the reaction is triggered and the internal temperature reaches 35° C. At the end of the exothermic reaction, a solution of p-bromobenzaldehyde dimethyl acetal (62.4 g, 98percent, 0.262 mol) in tetrahydrofuran (64.3 g) is added over a period of 1.5 hours while regulating the temperature at from 30 to 35° C. The reaction mixture is maintained under agitation at 30° C. for one hour. [00066] Coupling Reaction: Preparation of 4-(2'-pyridyl)benzaldehyde [00067] 2-bromopyridine (38.92 g, 0.246 mol) and palladium tetrakistriphenylphosphine (0.135 g, 0.117 mmol) are added to a mixture of ZnCl2 (3.08 g, 0.0226 mol) in tetrahydrofuran (59.6 g) maintained at 50° C. with agitation under an inert atmosphere. The Grignard solution (249.5 g of solution, equal to 0.291 mol) is added dropwise over a total of 3 hours to the resulting suspension, which is still maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 18° C. [00068] A solution constituted by water (126 g) and 30percent hydrochloric acid (40 g) is added to the reaction mixture, keeping the temperature of the mixture below 35° C. After 30 minutes' agitation at 25° C., toluene (44 g) is added and the phases are separated. Toluene (87 g) and 30percent ammonia (42 g) are added to the aqueous phase, and the phases are separated to yield, as the organic phase, a solution of 4-(2'-pyridyl)benzaldehyde (210.8 g, HPLC strength 20.6percent, equal to 43.42 g, 0.237 mol; yield in moles relative to the 2-bromopyridine added: 96.4percent, turnover of catalyst (Pd): 2028). |
96% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 3.5 h; |
2-bromopyridine (8.07 g, 0.051 mol) and palladium tetrakistriphenylphosphine (0.032 g, 0.028 mmol) and then, over a total of 3 hours, a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (50 g of solution, equal to 0.058 mol), prepared analogously to Example 9, are added to a mixture of ZnCl2 (7.12 g, 0.052 mol) in tetrahydrofuran (24.2 g) maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 25° C. [00076] A solution constituted by water (30 g) and 30percent hydrochloric acid (9 g) is added to the reaction mixture and the mixture is maintained under agitation for 2 hours at 25° C. A portion of the solvent (30 g) is evaporated under vacuum and replaced by an equal amount of toluene and then the phases are separated. Toluene (30 g) and 30percent ammonia (14 g) are added to the aqueous phase. The phases are separated to give a solution of 4-(2'-pyridyl)benzaldehyde (53.74 g, HPLC strength 16.66percent, equal to 8.95 g, 0.0489 mol; yield in moles relative to the 2-bromopyridine added: 96percent; turnover of the catalyst (Pd): 1920). |
93% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; |
Example 1 was repeated using anhydrous zinc bromide (22.5 g, 0.10 mol) instead of zinc chloride. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 93percent, the turnover of the catalyst (Pd) 1744. |
93% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; |
Example 1 was repeated using a different amount of zinc chloride (2.28 g, 0.0167 mol). The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 93percent, the turnover of the catalyst (Pd) 1744. |
91% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; |
Example 1 was repeated using palladium acetate (0.040 g, 0.178 mmol) and triphenylphosphine (0.186 g, 0.712 mmol) instead of palladium tetrakistriphenylphosphine. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 91percent the turnover of the catalyst (Pd) 1707. |
89% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 50℃; for 6.5 h; |
A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (63 g of solution, containing 0.074 mol), prepared analogously to Example 9, is added dropwise over a total of 6 hours to a solution of 2-bromopyridine (7.95 g, 0.050 mol), ZnCl2 (0.0071 g, 0.052 mmol) and palladium tetrakistriphenylphosphine (0.032 g, 0.028 mmol) in tetrahydrofuran (23.6 g) maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 25° C. [00079] A solution constituted by water (28 g) and 30percent hydrochloric acid (9 g) is added to the reaction mixture and the mixture is maintained under agitation for 2 hours at 25° C. 30 g of solvent are evaporated under vacuum and replaced by an equal amount of toluene and then the phases are separated. Toluene (30 g) and 30percent ammonia (12 g) are added to the aqueous phase. After filtering over a panel of Celite the solid at the interphase and washing the panel with toluene, the phases are separated to give a solution of 4-(2'-pyridyl)benzaldehyde (73.53 g, HPLC strength 11.1percent, equal to 8.16 g, 0.0446 mol; yield in moles relative to the 2-bromopyridine added 89percent; turnover of catalyst (Pd): 1620; turnover of Zn: 890). |
88% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; |
Example 1 was repeated using palladium acetate (0.04 g, 0.178 mmol) and triphenylphosphine (0.186 g, 0.712 mmol) instead of palladium tetrakistriphenylphosphine and a different amount of anhydrous zinc chloride (18.2 g, 0.133 mol). The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 88percent, the turnover of the catalyst (Pd) 1650. |
81.2% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 50℃; for 3.5 h; |
Example 9 is repeated using a different amount of ZnCl2 (0.1 g, 0.73 mmol), to give a molar yield of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added of 81.2percent, turnover of the catalyst (Pd) equal to 1700. |
3.8% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 50℃; for 4 h; |
A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (51.4 g of solution, equal to 0.060 mol), prepared analogously to Example 9, is added dropwise over a total of 3 hours to a solution of 2-bromopyridine (8.04 g, 0.0509 mol) and palladium tetrakistriphenylphosphine (0.29 g, 0.25 mmol) in tetrahydrofuran (24 g) maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for one hour and then cooled to 25° C. [00073] A yield of 4-(2-pyridyl)benzaldehyde solution of 3.8percent relative to the 2-bromopyridine added is obtained, turnover of the catalyst (Pd) 76. |
1% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; |
Example 1 was repeated without the addition of the catalytic amount of zinc chloride. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 1percent, the turnover of the catalyst (Pd) 18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: With 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 70℃; for 3.5 h; |
A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (49.2 g of solution, corresponding to 0.057 mol), prepared analogously to Example 9, is added dropwise over a total of 3 hours to a mixture of 2-chloropyridine (5.82 g, 0.051 mol), ZnCl2 (0.48 g, 0.00352 mol), palladium acetate (0.00582 g, 0.026 mmol), 1,4-bis(diphenylphosphine)butane (0.0115 g, 0.027 mmol) in tetrahydrofuran (26.2 g) maintained at 70° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 70° C. for 30 minutes and then cooled to 25° C. [00109] A quantitative yield of 4-(2'-pyridyl)benzaldehyde is obtained relative to the chloropyridine added, turnover of the catalyst (Pd) of 1969. |
99.4% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 70℃; for 3.5 h; |
Example 18 is repeated using a different amount of THF (114 g) in the coupling reaction and adding the Grignard reagent at 70° C. (instead of at 50° C.): a molar yield relative to the 2-chloropyridine added of 99.4percent is obtained, turnover of catalyst (Pd) equal to 2075. |
97% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 50℃; for 3.5 h; |
2-chloropyridine (27.95 g, 0.246 mol), palladium acetate (0.0276 g, 0.123 mmol) and 1,3-bis(diphenylphosphine)propane (0.0509 g, 0.123 mmol) are added to a mixture of ZnCl2 (1.8 g, 0.013 mol) in tetrahydrofuran (53.3 g) maintained at 50° C. with agitation under an inert atmosphere. A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (239.6 2 of solution, containing 0.279 mol), prepared analogously to Example 9, is added dropwise over a total of 3 hours to the resulting suspension, still at 50° C. and under agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 18° C. [00102] A solution constituted by water (126 g) and 30percent hydrochloric acid (40 g) is added to the reaction mixture, keeping the temperature of the mixture below 35° C. After agitation for 1 hour at 25° C., toluene (44 g) is added and the phases are separated. Toluene (87 g) and 30percent ammonia (42 g) are added to the aqueous phase and the phases are separated to give, as the organic phase, a solution of 4-(2'-pyridyl)benzaldehyde (197.1 g, HPLC strength 22.2percent, equal to 43.75 g, 0.239 mol; yield in moles relative to the 2-chloropyridine added: 97percent, turnover of the catalyst (Pd): 1940). |
97.8% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: at 50℃; for 3.5 h; |
Example 18 is repeated using a different amount of ZnCl2 (1.0 g, 0.0073 mol), to give a molar yield relative to the 2-chloropyridine added of 97.8percent, turnover of the catalyst (Pd) equal to 1974. |
95% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: With 1,3-bis-(diphenylphosphino)propane In tetrahydrofuran at 30℃; for 4 h; |
2-chloropyridine (7.17 g, 0.063 mol), palladium acetate (0.0070 g, 0.031 mmol) and 1,3-bis(diphenylphosphine)propane (0.013 g, 0.033 mmol) are added to a mixture of ZnCl2 (0.42 g, 3.08 mmol) in tetrahydrofuran (13.7 g) maintained at 30° C. with agitation under an inert atmosphere. A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (80.5 g of solution, containing 0.070 mol), prepared analogously to Example 9, is added dropwise over a total of 3.5 hours to the resulting suspension, still at 30° C. and under agitation under an inert atmosphere. The reaction mixture is maintained at 30° C. for 30 minutes and then cooled to 18° C. [00114] A solution constituted by water (32 g) and 30percent hydrochloric acid (10.3 g) is added to the reaction mixture, keeping the temperature of the mixture below 35° C. After 1 hour's agitation at 25° C., toluene (11 g) is added and the phases are separated. Toluene (22 g) and 30percent ammonia (11 g) are added to the aqueous phase and the phases are separated to give, as the organic phase, a solution of 4-(2'-pyridyl)benzaldehyde (48.6 g, HPLC strength 22.7percent, equal to 11.0 g, 0.060 mol; yield in moles relative to the 2-chloropyridine added: 95percent, turnover of the catalyst (Pd): 1941). |
84% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50 - 85℃; for 2.5 h; |
Anhydrous zinc chloride (13.6 g, 0.10 mol) and then 2-chloropyridine (39.9 g, 0.29 mol) are added, with agitation under an inert atmosphere, to a solution constituted by toluene (156 g) and tetrahydrofuran (12 g). [00098] Palladium tetrakistriphenylphosphine (1.77 g, 0.00153 mol) and then, over a period of 2 hours at 85° C., a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (338.6 g of solution, equal to 0.394 mol), prepared analogously to Example 1, are added to the suspension maintained at 50° C. with agitation and under an inert atmosphere. The reaction mixture is maintained at 85° C. for approximately 30 minutes and then cooled to 25° C. A solution constituted by water (300 g) and 30percent hydrochloric acid (70 g) is added to the reaction mixture over a period of approximately 30 minutes. The mixture is maintained under agitation at 25° C.-30° C. for one hour and the phases are separated. 30percent ammonia (32 g) is added to the underlying aqueous phase up to a pH of 8, followed by toluene (90 g). [00099] The phases are separated and the organic phase is evaporated under vacuum to give a residue constituted by 4-(2'-pyridyl)benzaldehyde (44.6 g, 0.243 mol, yield in moles relative to the 2-chloropyridine added: 84 percent, turnover of the catalyst (Pd) 160). |
26% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h; Stage #2: With 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 70℃; for 3.5 h; |
Example 21 was repeated in the absence of zinc chloride. A yield in moles of 4-(2'-pyridyl)benzaldehyde of 26percent was obtained relative to the 2-chloropyridine added, palladium turnover of 520. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h; Stage #3: Acidic aqueous solution |
Example 7 was repeated without the addition of the catalytic amount of zinc chloride. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 2percent, turnover of the catalyst (Pd) 37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Acidic aqueous solution | A mixture constituted by 4-bromobenzaldehyde (100 g, 0.54 mol), toluene (300 ml), monohydrated p-toluenesulphonic acid (2.79 g, 0.0162 mol) and 2.2-dimethyl-1,3-propanediol (84 g, 0.81 mol) is maintained under agitation at 125° C. for 4 hours while the water is removed by azeotropic distillation using a Florentine flask. [00056] A 30percent solution of sodium methoxide in methanol (5.8 g, 0.0324 mol) is added to the reaction mixture cooled to 30° C. The whole is cooled to 25° C. and washed with water (2.x.100 ml). The phases are separated and the organic phase is reduced to a residue. Heptane (137 ml) is added to the dry residue and the whole is heated at 40° C. until dissolution is complete. The whole is cooled to 10° C. to give a suspension. After filtration and evaporation of the solvent under vacuum, a residue is obtained which is constituted by 2-(4'-bromophenyl)-5,5-dimethyl-1,3-dioxane (91 g, 0.335 mol, 62percent). [00057] 1H-NMR (300 MHz, CDCl3), ppm 0.8 (3H, s); 1.3 (3H, s); 3.65 (2H, part A of an AB system, J=10.6 Hz); 3.8 (2H, part B of an AB system, J=10.6 Hz); 5.4 (1H, s); 7.4 (2H, part A of an AB system, J=8.4 Hz); 7.5 (2H, part B of an AB system, J=8.4 Hz). [00058] Preparation of the Grignard Reagent of 2-(4'-bromophenyl)-5,5dimethyl-1,3-dioxane [00059] While regulating the temperature at from 30 to 35° C., iodine (0.05 g) and then, over a period of approximately one hour, a solution of 2-(4'-bromophenyl)-5.5-dimethyl-1,3-dioxane (26.7 g, 0.098 mol) in tetrahydrofuran (20 g) are added to a suspension of magnesium (2.4 g, 0.0985 mol) in tetrahydrofuran (17 g) maintained at 30° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 35° C. with agitation for one hour. Toluene (22 g) is added to the reaction mixture.Coupling Reaction: Preparation of 4-(2'-pyridyl)benzaldehyde [00060] Anhydrous zinc chloride (3.4 g, 0.025 mol) and then 2-bromopyridine (13.2 g, 0.0835 mol) are added, with agitation under an inert atmosphere, to a solution constituted by toluene (39 g) and tetrahydrofuran (33 g). [00061] Palladium tetrakistriphenylphosphine (0.051 g, 0.0442 mmol) and then, over a period of approximately 2 hours, the Grignard solution are added to the suspension maintained at 50° C. with agitation and under an inert atmosphere. The reaction mixture is maintained at 50° C. for approximately 30 minutes and then cooled to 25° C. 2-[4'-(2-pyridyl)phenyl]-5,5-dimethyl-1,3-dioxane is obtained with a yield of 84percent in moles relative to the 2-bromopyridine added. Acid hydrolysis results in the formation of 4-(2'-pyridyl)benzaldehyde with an almost quantitative yield, turnover of the catalyst (Pd) 1889. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.1% | for 4 h; Heating / reflux | Synthesis of tert-butyl 2-(4-(pyridin-2-yl)benzylidene)hydrazinecarboxylate (XII, Y1a = H).; A mixture of 4-(pyridin-2-yl)benzaldehyde X (17.7 g, 96.6 mmol) and tert-butyl carbazate (12.2 g, 92.3 mmol) in ethanol (125 mL) was kept at reflux under nitrogen for 4 hours (hrs). The reaction mixture was cooled to 40°C and ice (60 g) was added, The resulting mixture was stirred for 20 minutes (min). The precipitate was collected by filtration, washed with water and dried in a vacuum oven (60 °C) to give the product XII, wherein Y1a = H (25.0 g, 91.1 percent). |
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