* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 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).
Reference：
[1] European Journal of Organic Chemistry, 2008, # 12, p. 2049 - 2055
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 47, p. 14103 - 14107[3] Angew. Chem., 2015, vol. 127, # 47, p. 14309 - 14313,5
[4] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6806 - 6813
[5] European Journal of Organic Chemistry, 2014, vol. 2014, # 27, p. 5901 - 5905
[6] Organic Letters, 2004, vol. 6, # 19, p. 3337 - 3340
[7] Molecules, 2015, vol. 20, # 5, p. 9229 - 9241
[8] Organic Process Research and Development, 2002, vol. 6, # 3, p. 323 - 328
[9] Organometallics, 2015, vol. 34, # 11, p. 2683 - 2694
[10] Inorganica Chimica Acta, 2016, vol. 440, p. 102 - 106
[11] Journal of Organic Chemistry, 2006, vol. 71, # 26, p. 9589 - 9594
[12] Organic Letters, 2014, vol. 16, # 7, p. 2022 - 2025
[13] Organic Letters, 2014, vol. 16, # 7, p. 2046 - 2049
[14] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4414 - 4422
[15] Organic Letters, 2014, vol. 16, # 12, p. 3328 - 3331
[16] Organic Letters, 2014, vol. 16, # 20, p. 5466 - 5469
[17] Angewandte Chemie - International Edition, 2015, vol. 54, # 15, p. 4508 - 4511[18] Angew. Chem., 2015, vol. 127, # 15, p. 4591 - 4594,4
[19] Journal of Organic Chemistry, 2015, vol. 80, # 8, p. 4116 - 4122
[20] Angewandte Chemie - International Edition, 2015, vol. 54, # 40, p. 11677 - 11680[21] Angew. Chem., 2015, vol. 127, # 40, p. 11843 - 11846,4
[22] Journal of the American Chemical Society, 2015, vol. 137, # 42, p. 13448 - 13451
2
[ 109-09-1 ]
[ 59016-93-2 ]
[ 127406-56-8 ]
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.
Reference：
[1] Inorganica Chimica Acta, 2014, vol. 423, # PART A, p. 11 - 15
[2] Inorganica Chimica Acta, 2014, vol. 423, # 1, p. 11 - 15
[3] Inorganica Chimica Acta, 2014, # PA, p. 11 - 15
3
[ 109-04-6 ]
[ 24856-58-4 ]
[ 127406-56-8 ]
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.
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.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 35, p. 6944 - 6952
[2] Chemical and Pharmaceutical Bulletin, 2003, vol. 51, # 6, p. 702 - 709
[3] Chemical Communications, 2017, vol. 53, # 57, p. 7990 - 7993
[4] ChemCatChem, 2018, vol. 10, # 3, p. 601 - 611
[5] Green Chemistry, 2018, vol. 20, # 14, p. 3246 - 3252
[6] Patent: CN105061515, 2017, B, . Location in patent: Paragraph 0047
6
[ 109-04-6 ]
[ 105114-53-2 ]
[ 127406-56-8 ]
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.
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.
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).
Reference：
[1] Patent: EP2003120, 2008, A1, . Location in patent: Page/Page column 33
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6806 - 6813
[3] Organic Process Research and Development, 2002, vol. 6, # 3, p. 323 - 328
[4] Patent: US6765097, 2004, B1, . Location in patent: Page column 14-15
[5] Patent: WO2010/149356, 2010, A1, . Location in patent: Page/Page column 14; 15
[6] Molecules, 2015, vol. 20, # 5, p. 9229 - 9241
[7] Patent: CN106543073, 2017, A, . Location in patent: Paragraph 0040; 0041
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran; toluene at 50℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
1 Example 1; Preparation of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal
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 30% 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. 30% 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: 100%; 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: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran at 70℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
14 Example 14; Preparation of 4-(2'-pyridyl)benzaldehyde
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 30% 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 30% 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 17%, equal to 9.09 g, 0.049 mol; yield in moles relative to the 2-bromopyridine added: 99%, turnover of catalyst (Pd): 1960).
96.4%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran at 50℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
9 Example 9; Preparation of the Grignard Reagent of 4-bromobenzaldehyde dimethyl acetal
A chip of iodine (50 mg) and p-bromobenzaldehyde dimethyl acetal (6.8 g, 98%, 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, 98%, 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 30% 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 30% 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 20.6%, equal to 43.42 g, 0.237 mol; yield in moles relative to the 2-bromopyridine added: 96.4%, turnover of catalyst (Pd): 2028).
96%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran at 50℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
12 Example 12; Preparation of 4-(2'-pyridyl)benzaldehyde
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 30% 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 30% 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 16.66%, equal to 8.95 g, 0.0489 mol; yield in moles relative to the 2-bromopyridine added: 96%; turnover of the catalyst (Pd): 1920).
93%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran; toluene at 50℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
6 Example 6; Preparation of 4-(2'-pyridyl)benzaldehyde
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 93%, the turnover of the catalyst (Pd) 1744.
93%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran; toluene at 50℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
5 Example 5; Preparation of 4-(2'-pyridyl)benzaldehyde
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 93%, the turnover of the catalyst (Pd) 1744.
91%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran; toluene at 50℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
3 Example 3; Preparation of 4-(2'-pyridyl)benzaldehyde
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 91% the turnover of the catalyst (Pd) 1707.
89%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran at 50℃; for 6.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
13 Example 13; Preparation of 4-(2'-pyridyl)benzaldehyde
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 30% 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 30% 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 11.1%, equal to 8.16 g, 0.0446 mol; yield in moles relative to the 2-bromopyridine added 89%; turnover of catalyst (Pd): 1620; turnover of Zn: 890).
88%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran; toluene at 50℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
4 Example 4; Preparation of 4-(2'-pyridyl)benzaldehyde
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 88%, the turnover of the catalyst (Pd) 1650.
81.2%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran at 50℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
10 Example 10; Preparation of 4-(2'-pyridyl)benzaldehyde
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 81.2%, turnover of the catalyst (Pd) equal to 1700.
3.8%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran at 50℃; for 4h;
11 Comparative example 11; Preparation of 4-(2'-pyridyl)benzaldehyde
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 3.8% relative to the 2-bromopyridine added is obtained, turnover of the catalyst (Pd) 76.
1%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-bromo-pyridine In tetrahydrofuran; toluene at 50℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
2 Comparative Example 2; Preparation of 4-(2'-pyridyl)benzaldehyde
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 1%, the turnover of the catalyst (Pd) 18.
37.b 37b
37b 4-(Pyridin-2-yl)-benzaldehyde 6.93 g (29.9 mmol) of 4-bromobenzaldehyde dimethyl acetal in 40 ml of THF are added dropwise to a warm (from 40° C. to 50° C.) suspension of 0.8 g (31.6 mmol) of magnesium turnings and a small amount of iodine in 10 ml of THF. The reaction mixture is heated to 65° C. and stirred at that temperature for about 30 min. The mixture is allowed to cool to room temperature and the Grignard reagent is added dropwise to a solution of 4.46 g (28.2 mmol) of 2-bromopyridine (Fluka, Buchs, Switzerland) and 0.4 g (0.74 mmol) of DPPP (Fluka, Buchs, Switzerland) in 100 ml of THF (slightly exothermic reaction). After the dropwise addition is complete, the reaction mixture is boiled under reflux for 4 hours and is then allowed to cool; 100 ml of water are added. The mixture is concentrated to about 50 ml using a rotary evaporator, diluted with ethyl acetate and extracted with 0.1N hydrochloric acid (3*). The combined HCl extracts are stirred at room temperature for 20 min, rendered basic with concentrated ammonia solution and extracted with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 2:1). The product-containing fractions are concentrated, with the desired title compound crystallising out spontaneously. TLC: Rt =0.22 (hexane/ethyl acetate 2:1). HPLC20-100: tRet =6.08. 1H-NMR (CDCl3; 200 MHz): 8.73/d, J=5 (2H); 8.16 and 7.97/each d (2*2H); 7.80/d, J=4 (2H); 7.3/m (1H).
With 2-((3-sulfonatomesityl)-5-sulfonatoindenyl)dicyclohexylphosphinehydrate sodium salt; palladium diacetate; potassium carbonate In water at 100℃; for 24h;
92%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane at 80℃; for 10h;
85%
With [N,N'-bis-[2,6-(di-iso-propyl)phenyl]imidazol-2-ylidene·H][Pd(η<SUP>3</SUP>-cinnamyl)Cl<SUB>2</SUB>]; potassium carbonate In ethanol at 20℃; for 16h; Inert atmosphere; Sealed tube;
83%
With C36H43Br2ClN2Pd; potassium carbonate In ethanol at 40℃; for 20h; Inert atmosphere; Glovebox;
70%
With (3-phenylallyl)(chloro)-[1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II); potassium carbonate In ethanol at 40℃; for 4h; Green chemistry;
35%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere;
1 Step 1: 4-(pyridin-2-yl)benzaldehyde
To a stirred solution of (4-formylphenyl) boronic acid (610 g, 4.0 mmol) and methyl 2-chloropyridine (0.43 ml_, 4.4 mmol) in dry dioxane (9 ml_), a solution of cesium carbonate (2.62 g, 8.0 mmol) in water (1 mL) was added at RT. Nitrogen was flushed through this mixture, before the addition of Tetrakis (triphenylphosphine)palladium(O) (0.92 g, 0.8 mmol). The mixture was then stirred at 100 °C overnight. After completion of the reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under vacuum. To the resulting crude product water was added and the aqueous suspension was extracted with EtOAc (2 x 40 mL). The combined organic layer was washed with water (10 mL) and brine (2 ml_), dried over Na2S04 and concentrated under vacuum. The resulting residue was purified by flash chromatography (Eluent: 24% EtOAc in pet ether) to afford the title compound. Yield: 35% (250 mg, off white liquid). 1H NMR (400 MHz, CDCIs): d 10.1 1 (s, 1 H), 8.78-8.76 (m, 1 H), 8.15 (t, J = 8.0 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.85- 7.82 (m, 2H), 7.36-7.33 (m, 1 H). LCMS: (Method A) 184.3 (M+H), Rt.1.43 min, 75.9% (Max).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 70℃; for 24h; Inert atmosphere;
2.1 (1)Synthesis of ligand CHO-ppy:
1 mmol of 4-aldehyde phenylboronic acid,1 mmol of 2-chloropyridine, 7% equivalent of tetrakis(3-phenylphosphine)palladium(0)And 1 mmol of potassium carbonate was added to the three-neck flask,Then 50 mL of a mixed solvent of THF and H2O (V/V = 1:1) was added. Under the protection of nitrogen,The reaction system was reacted at 70 oC for 24 h. Cool to room temperatureThe reaction solution was extracted with dichloromethane.The aqueous phase is extracted 3 times with dichloromethane (10 mL × 3).Combine organic layers,Dry over anhydrous sodium sulfate overnightThe solvent was removed under reduced pressure followed by column chromatography to give CHO-ppy.
Example 4. Synthesis of 1,14-Di(methyl-d3) (3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d9]-8-hydroxy-4,1-dioxo-9-(phenylmethyl)-6-[[ 4-(2-pyridinyl)phenyl]methyl-d2]-2,5,6,14,13-pentaazatetradecanedioate (Compound 131). [Show Image] Compound 131 was prepared according to Scheme 1, above, following the General Method A described above- Deuterium gas (Cambridge Isotopes, 99.8 atom% D), MeOD (Aldrich, 99.5 atom% D), iPrOD (Aldrich, 98 atom% D) and deuterium chloride (Aldrich, 99 atom% D) were used in this synthesis. Deuferated aldehyde X was prepared according to Scheme 2b using LiAlD4 (Cambridge Isotopes, 98 atom% D). 1H-NMR (300 MHz, CDCl3): delta 2.71 (dd, 2H), 2.94 (d, 2H), 3.56 (d, 2H), 3.77 (d, 1H), 4.02-4.05 (m, 1H), 4.83 (s, 1H), 5.19-5.29 (m, 2H), 6.40-6.47 (m, 2H), 7.20-7.23 (m, 6H, partially obscured by CDCl3), 7.41 (d, 2H), 7.69-7.76 (m, 2H), 7.95 (d, 2H), 8.69 (d, 1H). HPLC (method: 20 mm C18-RP column - gradient method 2- 95% ACN + 0.1 % formic acid in 3.3 min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention time: 3.22 min; purity: 99.2%. MS (M+H+): 731.7.; Example 8. Synthesis of 1,14-Dimethyl (3S,8S,9S,12S)-3,12-bis[(1,1-dimethylethyl)-d2]-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[ 4-(2-pyridinyl)phenyl]methyl-d2]-2,5,6,10-13-pentaazatetradecanedioate (Compound 113). [Show Image] Compound 113 was prepared according to Scheme 1, above, following the General Method A described above. Deuterium gas (Cambridge Isotopes, 99.8 atom% D), MeOD (Aldrich, 99.5 atom% D), iPrOD (Aldrich, 98 atom% D) and deuterium chloride (Aldrich, 99 atom% D) were used in this synthesis. Deuterated aldehyde X was prepared according to Scheme 2b using LiAlD4 (Cambridge Isotopes, 98 atom% D). 1H-NMR (300 MHz, CDCl3): delta 2.69 (dd, 2H), 2.94 (d, 2H), 3.56-3.59 (m, 2H), 3.64 (s, 3H), 3.67 (s, 3H), 3.77 (d, 1H), 4.02-4.05 (m, 1H), 4.84 (s, 1H), 5.18-5.32 (m, 2H), 6.40-6.45 (m, 2H), 7.14-7.26 (m, 6H, partially obscured by CDCl3), 7.41 (d, 2H), 7.61-7.80 (m, 2H), 7.95 (d, 2H), 8.69 (d, 1H). HPLC (method: 20 mm C18-RP column - gradient method 2-95% ACN + 0.1% formic acid in 3.3 min with 1.7 min hold at 95% ACN; Wavelength: 254 nm): retention time: 3.25 min; purity: 99.4%. MS (M+H+): 725.4.
With silver nitrate; sodium hydroxide; In ethanol; for 24h;
4-(2-Pyridyl)benzaldehyde (1 g, 5.46 mmol) and silver nitrate (1.4 g, 8.23 mmol) were dissolved in 80% ethanol solution (50 mL), and 1 M NaOH (30 mL) solution was added for 24 h. After the completion of the reaction, ethanol was removed under reduced pressure, hydrochloric acid was added dropwise, and a white precipitate was collected to obtain the structure of the main ligand pyridine benzoic acid
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water for 8h; Reflux;
100%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 18h; Inert atmosphere; Reflux;
100%
Stage #1: 2-bromo-pyridine; 4-formylphenylboronic acid, With potassium carbonate In 1,4-dioxane; water for 0.5h; Inert atmosphere;
Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water Inert atmosphere; Reflux;
99.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 150℃; Sealed tube; Microwave irradiation;
92%
With [(t-Bu)3PH]BF4; palladium diacetate; sodium hydroxide In water; butan-1-ol at 20℃; for 0.25h; Inert atmosphere; Glovebox;
89%
With potassium carbonate In N,N-dimethyl acetamide; water at 100℃; for 2h;
81%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water for 9h; Inert atmosphere; Reflux;
80%
With palladium diacetate; triphenylphosphine; potassium hydroxide In tetrahydrofuran; methanol at 60℃; for 24h; Inert atmosphere; Schlenk technique;
3.2.2. General Procedure for the Preparation of Derivatives 13a-14a
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 % and PPh3 4 mol % 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 80% (13a) and 75% (14a).
79.5%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; toluene at 76℃; for 20h; Inert atmosphere;
75%
Stage #1: 2-bromo-pyridine; 4-formylphenylboronic acid, With sodium carbonate In tetrahydrofuran; water at 20℃; for 1h; Inert atmosphere;
Stage #2: With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran; water at 99.84℃; for 24h; Inert atmosphere;
60%
With potassium phosphate monohydrate; palladium diacetate In water; isopropyl alcohol at 80℃; for 2h;
44%
With sodium carbonate In tetrahydrofuran; toluene at 80℃; for 48h;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 95℃; for 18h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; toluene for 12h; Inert atmosphere; Schlenk technique; Reflux;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 12h; Reflux;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 12℃; Inert atmosphere; Resolution of racemate;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 16h; Inert atmosphere; Schlenk technique; Reflux;
With palladium diacetate; potassium carbonate; triphenylphosphine In water; N,N-dimethyl-formamide at 130℃; for 12h;
With palladium diacetate; potassium carbonate In ethanol; water at 80℃; for 20h; Inert atmosphere; Schlenk technique;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 12h; Inert atmosphere; Reflux;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 12h; Inert atmosphere; Schlenk technique; Reflux;
Compound 8; <strong>[5331-43-1]Benzyl carbazate</strong> (17.3195 g, 104.2 mmol) and 4-(2-pyridyl)benzaldehyde (20.047 g, 109.4 mmol) were dissolved in isopropanol (315 mL) and stirred at 8O0C for 16 h. The product, i.e., Compound 8, was precipitated out of solution by addition of ice, filtered and dried under vacuum at 40C to give a solid (34.529 g, 104.2 mmol, 100%). Mass spectrum: (M+H)+ = 332.1.
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 40C 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 %).
85.5%
In ethanol; at 70℃; for 6h;Industrial scale;
(1) In a 250 L reactor, 125 kg of ethanol, 25 kg of 4-(2-pyridyl)-benzaldehyde (molar amount: 183.21, mole number: 136 mol), and tert-butyl carbazate(23.4 kg) (molar amount: 132.16, mole number: 176.8 mol) were added. The nitrogen gas was refluxed at 70 C, and the reaction was monitored by HPLC, and the reaction was completed in 6 hours.2) The system was cooled to 0-5 C, stirred for 1 h, and centrifuged. The centrifuged solid was rinsed once with cold methanol, and the solid was centrifuged to obtain a white solid of 34.55 kg, yield 85.5%, HPLC purity >99%.
In ethanol; at 80℃; for 5h;Conversion of starting material;
A solution of 2 g (1.05 mmol) of 4-(2'-pyridyl)-benzaldehyde and 1.37 g (1 mmol) of tert-butyl carbazate in 30 ml of ethanol is agitated at 80 C. for 5 hours (after 4 hours a further 0.05 equivalent of tert-butyl carbazate is added). The reaction mixture is cooled and diluted with water; the product separates from the mixture in the form of crystals. [00132] TLC: Rf=0.51 (methylene chloride:methanol=15:1) 1H-NMR (200 MHz, CDCl3): ppm 8.68 (1H, m); 8.21 (1H, s); 7.98 (2H, portion A of an AB system, J=9 Hz); 7.85 (1H, s); 7.8-7.6 (4H, m); 7.22 (1H, m); 1.53 (9H, s).
acetic acid; In toluene; at 80℃; for 2h;Industry scale; Inert atmosphere;Product distribution / selectivity;
In a stainless steel reactor, under inert atmosphere, charge the organic phase of the previous step containing about 340 kg of 4-(2'- pyridyl)benzaldheyde and add acetic acid (7.8 It). Warm the solution at 800C and add under stirring tert-butylcarbazate (258 kg). After two hours at 800C cool the mixture at 15C and then filter the product, wash with cold toluene and dry at reduced pressure at a temperature of 45C obtaining about 540 kg of hydrazone.
In ethanol; for 5h;Reflux;
The reactants of the weight ratio of ethanol of 4- (2-pyridyl) benzaldehyde to A, 4- (2-pyridyl) benzaldehyde and t-butyl hydrazinecarboxylate were fed into the reactor , Stir. Heating and refluxing for 5 hours; cooling the crystals, filtering, washing, and filtering to give tert-butyl 2-2- [4- (2'-pyridyl) benzylidene] -hydrazinecarboxylate, , The yield is I.
EXAMPLE 7 Production of N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine In a 100 ml four neck flask were placed tert-butyl carbazate (1.87 g, 14.1 mmol) and methanol (5 ml), and a solution of 4-(pyridin-2-yl)benzaldehyde (2.16 g, 11.8 mmol) obtained in Example 2 in methanol(5 ml) was added dropwise at 25 C. over 20 minutes with stirring. The reaction mixture was stirred at 50 C. for 2 hours and analyzed by HPLC. As a result, N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine was confirmed to have been produced quantitatively. The reaction mixture was concentrated under reduced pressure, and the crystalline residue was washed with a small amount of cold methanol to give N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine (yield 2.3 g). Various spectrum data of the obtained N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine were the same as those obtained in Example 6.
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-chloropyridine With 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 70℃; for 3.5h;
21 Example 21; Preparation of 4-(2'-pyridyl)benzaldehyde
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: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-chloropyridine In tetrahydrofuran at 70℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
20 Example 20; Preparation of 4-(2'-pyridyl)benzaldehyde
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 99.4% is obtained, turnover of catalyst (Pd) equal to 2075.
97%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-chloropyridine In tetrahydrofuran at 50℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
18 Example 18; Preparation of 4-(2'-pyridyl)benzaldehyde
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 30% 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 30% 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 22.2%, equal to 43.75 g, 0.239 mol; yield in moles relative to the 2-chloropyridine added: 97%, turnover of the catalyst (Pd): 1940).
97.8%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-chloropyridine In tetrahydrofuran at 50℃; for 3.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
19 Preparation of 4-(2'-pyridyl)benzaldehyde
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 97.8%, turnover of the catalyst (Pd) equal to 1974.
95%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-chloropyridine With 1,3-bis-(diphenylphosphino)propane In tetrahydrofuran at 30℃; for 4h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
23 Example 23; Preparation of 4-(2'-pyridyl)benzaldehyde
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 30% 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 30% 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 22.7%, equal to 11.0 g, 0.060 mol; yield in moles relative to the 2-chloropyridine added: 95%, turnover of the catalyst (Pd): 1941).
84%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2h;
Stage #2: 2-chloropyridine In tetrahydrofuran; toluene at 50 - 85℃; for 2.5h;
Stage #3: With hydrogenchloride; ammonia; water more than 3 stages;
17 Example 17; Preparation of 4-(2'-pyridyl)benzaldehyde
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 30% 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. 30% 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 %, turnover of the catalyst (Pd) 160).
26%
Stage #1: 1,1-dimethoxy-1-(4-bromophenyl)methane With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5h;
Stage #2: 2-chloropyridine With 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 70℃; for 3.5h;
22 Comparative Example 22; Preparation of 4-(2'-pyridyl)benzaldehyde
Example 21 was repeated in the absence of zinc chloride. A yield in moles of 4-(2'-pyridyl)benzaldehyde of 26% was obtained relative to the 2-chloropyridine added, palladium turnover of 520.
With triethylamine; In dichloromethane; at 20℃; for 1h;
General procedure: To a mixture of aldehyde (1 mmol) and amine/amine hydrochloride (1 mmol) in anhydrous CH2Cl2 (10 mL) was added triethylamine (2.5 mmol) at rt, and the resulting solution was stirred vigorously for 1 h. To this was then added (Boc)2O (1.2 mmol) followed by sodium triacetoxyborohydride (2 mmol). The reaction was stirred for an additional 4 h at rt, quenched with saturated NaHCO3 solution, and extracted with CH2Cl2. The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (95:05?50:50, hexanes/EtOAc) to afford the N-Boc secondary amine. Most of the title compounds were present as a mixture of rotational isomers in their 1H and 13C NMR spectra.
With borane pyridine; acetic acid; In methanol; at 0 - 20℃; for 2h;
To a mixture of N-tert-butoxycarbonylhydrazine (18; 249 mg, 1.88 mmol) and 4-(pyridin-2-yl)benzaldehyde (16; 344 mg, 1.88 mmol) in MeOH (5 mL) was added AcOH (0.5 mL) and alpha-PicBH3 (201mg, 1.88 mmol) at 0 C. The reaction mixture was allowed to warm to r.t. and stirred for 2 h at the same temperature. The mixture was mL) at 0 C. The mixture was warmed to r.t. and stirred for 30 min at the same temperature. After cooling to 0 C, 25% aq Na2CO3 (20mL) was added to the mixture and extracted with EtOAc (3 × 20mL). The combined extracts were washed with brine (10 mL), dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc, 5:1-1:1) to give 17; yield: 437 mg (78%); colorless oil. IR (neat): 3410, 1683 cm-1.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver(I) triflimide In 1,2-dichloro-ethane at 40℃; for 12h; Autoclave;
91%
With [(1,2,3,4,5-pentamethylcyclopentadienyl)*Co(CH3CN)3](SbF6)2 In 1,2-dichloro-ethane at 80℃; for 12h;
87%
With silver hexafluoroantimonate; di-μ-chloro-bis[chloro(η5-pentamethylcyclopentadienyl)cobalt] In 1,2-dichloro-ethane at 80℃; for 24h;
75%
With bromopentacarbonylmanganese(I) at 50℃; for 4h; Ionic liquid;
4. General procedure for the Mn-Catalyzed amidations
General procedure: Starting material 1 (0.2 mmol), dioxazolones 2 (0.21 mmol), MnBr(CO)5 (2.5 mol %) and [Hmim]OAc (1 mL) were added to an oven-dried 25 mL-vial equipped with a stir bar, The reaction mixture was stirred in a pre-heated oil bath at 50 oC for 4 h in an oil bath with vigorous stirring. Upon completion, the mixture was diluted with H2O. The layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL 3). The combined organic layers were dried over MgSO4. The solvents were removed under reduced pressure, and the crude reaction mixture was purified by chromatography on silica gel (n-hexanes/EtOAc) as an eluent to give the desired product 3. Reuse of MnBr(CO)5/[Hmim]OAc catalytic system. The reaction was set up the same as above. After the reaction was complete, diethyl ether (20 mL) was added to extract the product 3 from the reaction mixture, the ionic liquid containing the Mn catalyst was separated and could be used for next reaction without further treatment. After removal of excess ether solvent, the product 3 was purified by chromatography on silica gel (n-hexanes/EtOAc) as an eluent.
2-((4-(pyridin-2-yl)benzylidene)amino)-5,6-dihydro-4Hcyclopenta[b]thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With sulfuric acid In ethanol
2.2.4. General Synthetic Procedure for Compounds (7a-f).
General procedure: Few drops of sulfuric acid were added to a mixture of theappropriate lead compound 2d-f (5.6 mmol) and 1 equivalentof 4-(trifluoromethyl)benzaldehyde or 4-(2-pyridyl)benzaldehyde in absolute ethanol. Precipitation occurredonce sulfuric acid was added. The precipitate was filtered,washed with absolute ethanol, and dried.
2-((4-(pyridin-2-yl)benzylidene)amino)-5,6,7,8-tetrahydro-4H-cyclohepta [b]thiophene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sulfuric acid In ethanol
2.2.4. General Synthetic Procedure for Compounds (7a-f).
General procedure: Few drops of sulfuric acid were added to a mixture of theappropriate lead compound 2d-f (5.6 mmol) and 1 equivalentof 4-(trifluoromethyl)benzaldehyde or 4-(2-pyridyl)benzaldehyde in absolute ethanol. Precipitation occurredonce sulfuric acid was added. The precipitate was filtered,washed with absolute ethanol, and dried.
(2R,3R,4S,5R)-2-(6-amino-2-(2-((E)-4-(pyridin-2-yl)benzylidene)hydrazineyl)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
In methanol at 80℃; for 0.5h;
General procedure for the synthesis of compounds (12-43).
General procedure: First, 0.5 g of 2-hydrazinoadenosine (11) and different aralkyl or alkylaldehyde compounds (1.1 equivalent) were combined in methanol(30 ml) and heated by microwave at 80 °C for 30 min. The crudeproducts (12-13, 17, 19, 21-32, and 35-39) were precipitated frommethanol, and the other products (14-16, 18, 20, 33-34, and 40-43) were purified from the reaction mixture using silica gel column chromatography. All the crude products were further purified by MPLC on reverse phase C18 material to yield the products(12-43).
With sodium hydrogencarbonate; sodium sulfate; In dichloromethane; for 48h;Inert atmosphere; Reflux;
Synthesis of nitrone ligand was referred to previous reports [29,30]. A solution of isopropyl hydroxylaminehydrochloride (2 mmol, 250 mg), 4-(pyridin-2-yl)-benzaldehyde (2 mmol, 366 mg), Na2SO4 (6 mmol, 852 mg),and NaHCO3 (6 mmol, 504 mg) in dichloromethane (DCM)(15 mL) was refluxed under nitrogen atmosphere for 48 h.The residue was filtered through Celite, and the solvent wasthen removed on rotary evaporator. The crude product waspurified by column chromatography (hexane/ethyl acetate(5:1)), to give a pale yellow solid (yield=446 mg, 93%).
With Pd/C; hydrogen In methanol at 21 - 24℃; for 12h;
Tris[[(4-(pyridin-2-yl)benzyl)amino]ethyl]amine (2a):
4-(dimethylamino)benzaldehyde (1.00 g, 5.46 mmol) was added to a stirring solution of tris(2-aminoethyl)amine(266 mg, 1.82 mmol) in 60 mL of methanol. 10% Palladium on activated carbon (500 mg) was then added to the solution. The reaction solution was stirred under one atmosphere of H2 for 12 h at room temperature and then filtered through a Büchner funnel. The solid was washed with 15 mL of methanol and the filtrate was dried under reduced pressure at 50 oC, producing a waxy solid in 79 % yield. 1H NMR (CDCl3, 500 MHz) δ = 1.75 (br, 3H, NH), 2.62 (t, 6H, CH2CH2N), 2.72 (t, 6H, NCH2CH2), 3.81 (s, 6H, 2-Py-o-Ph-CH2N), 7.17 (t, 3H, Py), 7.35 (d, 6H, Ph), 7.62 (m, 6H, Py), 7.88 (d, 6H, Ph), 8.65 (d, 3, Py). 13C{1H} NMR (CDCl3, 126 MHz) δ = 47.4, 53.9, 54.4, 120.6, 122.1, 127.1, 128.6, 136.8, 138.1, 141.6, 149.8, 157.4. ESI-MS (M+) Calculated for C42H45N7: 647.37, Found: 648.59 [M+H]+. We had less starting material aldehyde for 2a in comparison to 1a, 3a, and 4a. The simple work-up afforded by running the hydrogenation reaction using Pd/C and H2 was our main consideration as to why we did not follow the procedures for 1a, 3a, and 4a with NaBH4.
In lithium hydroxide monohydrate at 130℃; for 23h;
70%
In lithium hydroxide monohydrate at 130℃; for 23h;
27 Dichloro(4-(2-pyridyl)benzaldehyde)gold(III)
In a 30 ml pressure vessel, 4-(2-pyridyl)benzaldehyde (0.103 g, 0.560 mmol) and HAuCL AH2O (0.206 g, 0.523 mmol) were dissolved in distilled water (10 mL). The reaction mixture was stirred for 23 h at 130 °C. The precipitate was then vacuum filtered and washed with water to afford an off-white solid (0.165 g, 70 % yield), which could then be used without further purification. ’H NMR (400 MHz, DMSO-t/6) 6 10.01 (s, 1H), 9.59 - 9.53 (m, 1H), 8.54 (d, J= 7.9 Hz, 1H), 8.46 (t, J= 7.7 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J= 7.9 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.87 (t, J= 6.6 Hz, 1H).
70%
In lithium hydroxide monohydrate at 130℃; for 23h;
27 Dichloro(4-(2-pyridyl)benzaldehyde)gold(III)
In a 30 ml pressure vessel, 4-(2-pyridyl)benzaldehyde (0.103 g, 0.560 mmol) and HAuCL AH2O (0.206 g, 0.523 mmol) were dissolved in distilled water (10 mL). The reaction mixture was stirred for 23 h at 130 °C. The precipitate was then vacuum filtered and washed with water to afford an off-white solid (0.165 g, 70 % yield), which could then be used without further purification. ’H NMR (400 MHz, DMSO-t/6) 6 10.01 (s, 1H), 9.59 - 9.53 (m, 1H), 8.54 (d, J= 7.9 Hz, 1H), 8.46 (t, J= 7.7 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J= 7.9 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.87 (t, J= 6.6 Hz, 1H).
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