经典合成反应标准操作—Suzuki反应
Pd(0)LnROTf[R-Pd(I)][TfO]LnPPh3 药明康德新药开发有限公司
LiBrR-Pd-BrnL2[Ph3PR] [TfO]+Pd(0)
4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例19
CO2MeOTfHOBOHPd(PPh3)4Na2CO3 eq., EtOH, tolueneCO2MeFF
To 1.5 g (4.8 mmol) of product in 12.5 mL of toluene at room temperature was added 0.28 g (0.24 mmol, 0.05 eq. ) of Pd (PPh3)4. After stirring for 5 min, 1.1 g (5.7 mmol, 1.2 eq. ) of 4-fluorophenylboronic acid in 5.5 mL of EtOH followed by 11.5 mL of 2 M aqueous Na2CO3 were added. After heating at 90 .deg.C for 12 h the reaction was judged complete, cooled and diluted with Et2O (100 mL) and water (50 mL). The resulting layers were separated and the aqueous layer extracted twice with Et2O (100 mL). The combined organic layers are dried over MgS04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the desired methyl 4-ethyl-4'-fluoro-1, 1'- biphenyl-2-carboxylate 4.7.2 芳基的Triflate与芳基硼酸偶联示例20
ClTfOOTfHOBOHPd(PPh3)4Na2CO3 eq., THFClCl
Synthesis of 9,9-bis(4'-chloro-biphenyl-4-yl)fluorene: 16 g of
9,9-bis[4-(trifluoromethylsulfonyl)phenyl]fluorene, 100 ml of tetrahydrofuran, 62 g of a 20percent sodium carbonate aqueous solution, 8.54 g of 4-chlorophenylboronic acid, and 0.6
1920
Patent; ELAN PHARMACEUTICALS, INC.; Publ.: WO2005/95326 A2 (2005/10/13) Patent; Tosoh Corporation; Publ.: EP1400578 A1 (2004/03/24)
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g of tetrakis(triphenylphosphine)palladium were placed in a 300 ml four-necked flask, and the mixture was heated at 70.deg.C. The resulting mixture was aged at the same temperature for 18 hours, and the reaction mixture was then cooled to room temperature and subjected to liquid separation. An organic phase was washed with a saturated ammonium chloride aqueous solution and saturated salt water, and the resulting organic phase was concentrated and recrystallized from tetrahydrofuran to obtain 11.4 g of a white powder.
4.8 芳基氯参与Suzuki偶联反应
Mitchell等报导了用dppb作钯的配体，能够有效地催化氯代芳杂类同芳基硼酸进行Suzuki反应，产率高达98%; 之后Wang Shen等用三环已基磷(PCy3)作钯的配体，发现此配体催化剂能够最有效地激活芳氯键，这可能是由于三环已基磷比三苯基磷有更多的电子，因而可以增加钯氧化插入芳氯键的能力，同时还发现在Pd(PCy3)Cl2催化下，邻对位吸电子取代芳基氯能更有效的进行反应。
4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一）21
OHBOHClOOPd(Cy3)2Cl2, CsF, NMP
OO
The following is a typical experimental procedure. A mixture of methyl trarts-3shlorociunamate
(entry
18,
Table
2)
(393.2
mg,
2
mmol),
dichlorobis(tricyclobezylphosphine) palladium(73.8 mg, 0.10 mol), phenylboronic acid (292.6 mg. 2.4 mmol), and cesium fluoride (607 mg, 4.0 mmol) in 1-methyl-2-pyrrolidinone (NMP, 5 mL) was degassed by purging with nitrogen. The mixture was then heated at 100 ℃ for 10 hours. The mixture was then partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with water, dried, and concentrated} The residue was then purified by column chromatography eluting with 50/50/5 toluene/hexane/ether to give the coupled product (466 mg.98%).
21
Tetrahedron Letter: Vol. 38, No. 32, pp. 5575-5578, 1997
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4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二）22
(HO)2BCOCH3H3CO2CCl(1.5 equiv)Pd(OAc)2 (1 mol%)P(t-Bu)2(2 mol%)H3CO2CCOCH3
1.0 equiv of aryl chloride, 1.5 equiv of boronic acid, 3.0 equiv of KF, cat. Pd(OAc)2 , cat. (two ligands per Pd center), THF (1 mL per mmol of aryl chloride), room temperature. Reaction times t have not been minimized. 4.9 镍催化体系用于Suzuki偶联反应
Syun Satio等研究发现,在零价镍催化下氯代芳烃和芳基硼酸在80℃可高产率地发生偶联反应，零价镍自NiCl2(dppf) （10 mol%）和n-BuLi(40 mol%)―一锅‖反应来制备，而氯代芳烃可带有各种吸电子或给电子基因. 此方法中镍催化剂成本低，同时选用廉价的氯代芳烃作为反应物，因而有很高的工业应用价值；也有人研究使用NiCl2(PPh3)2来催化烷基取代硼酸盐和溴代物的偶取反应，在室温下以80%的高产率合成了生物活性化合物。
4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例23
10 mol% of NiCl2(dppf) + 4 BuLiZK3PO4, dioxane at 80°CZB(OH)2+ClZ = 4-CN, 4-CHO, 2- or 4-CO2Me, 4-COCH3, 4-NHAc, 3- or 4-CH3, 3- or 4-OMe, 4-NH2
Representative procedure: A solution of BuLi in hexane (0.4 mmol) was added to a solution of NiCl2(dppf) (0.1 mmol) in dioxane (4 ml) at room temperature to give a red solution of nickel(0) complex. After being stirred for 10 min, phenylboronic acid (1.1 mmol), K3PO4 (3.0 mmol), a chloroarene (1.0 mmol and an additional dioxane (2 ml) were added to the flask. The reaction mixture was stirred at 84 ℃ for the period indicated in the Table 2 The product
2223
Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2413–2416. Tetrahedron Letter: Vol.37, No. l7, pp. 2993-2996, 1996
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was isolated by chromatography over silica gel.
4.10 其他方法
研究发现，对某些碘代物，一些无磷配体催化剂可以在较为温和的条件下高效的催化反应，如PdCl2、Pd(OAc)2、Pd/C等。同时，也可以避免反应中配体所形成的杂质对产品分离过程产生的困扰。
4.10.1 直接Pd/C用于 Suzuki偶联反应示例
Hiroa24 等以水作溶剂，室温下Pd./C 催化碘代苯酚与芳基硼酸的Suzuki 偶联反应取得了非常好的结果。 这个方法因为号称清洁生产，对大规模生产具有很大意义。
HO+XAr(OH)20.3 mol% Pd/C300 mol% K2CO3H2O, r.t., 12 h, 77%~99%HOAr
D. S. Ennis25 等用Pd /C 做催化剂大批量的进行Suzuki-coupling反应，以生产抗抑郁药物，SB-245570。
CO2HBrCO2HPd / CNONa2CO3, MeOH /H2Oreflux, 91%N6.2 kg4.4 kg6.3 kgOB(OH)2
4.10.2 直接Pd(OAc)2用于 Suzuki偶联反应示例26
OHBOH+IOCH3Pd(OAc)2K2CO3, acetoneH2oOCH3
4-Methoxy-2'-methylbiphenyl . o-Tolylboronic acid, 10.0 g (73.6 mmol), 16.8 g (71.8 mmol) of 4-iodoanisole, and 200 mL of acetone are combined in a 1-L, three-necked flask equipped
2425
Sakurai, H. J. Org. Chem. 2002, 67, 2721
D. S. Ennis，Org. Process Res. Dev. 1999, 3, 248 26
Felix E. Goodson, Organic syntheses, Coll. Vol. 10, p.501; Vol. 75,p.61
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with an efficient stirbar, two stoppers, and a reflux condenser attached to a gas-flow adapter with a stopcock. Potassium carbonate, 25.0 g (0.180 mol), is dissolved in 200 mL of water in a separate 250-mL Schlenk flask. In a third flask (25-mL Schlenk flask) 3.30 mg (0.02 mmol, 0.2%) of palladium acetate is dissolved in 10 mL of acetone . All three flasks are then thoroughly degassed by four freeze-pump-thaw cycles. Under an argon back flow, one of the stoppers on the three-necked flask is replaced with a rubber septum, and the carbonate and catalyst solutions are added via cannula to form a biphasic mixture. The top layer turns brown upon addition of the catalyst. The septum is replaced with the glass stopper and three additional freeze-pump-thaw cycles are applied. The flask is then backfilled with argon, and the reaction is brought to reflux under a positive argon pressure. After 2 hr at reflux the heat source is removed and the reaction is allowed to cool. By this time the brown color has faded and the reaction is a triphasic mixture with copious amounts of palladium black floating between the layers. The reaction is transferred to a 1-L separatory funnel and extracted into diethyl ether (3 × 100 mL). The organic layers are combined, washed with water (1 × 100 mL) saturated with sodium chloride , and dried over magnesium sulfate . Solvent is removed with a rotary evaporator to yield a yellow oil which is distilled (125-130°C, 0.10 mm) to give 12.8 g of 4-methoxy-2'-methylbiphenyl as a colorless oil (90.3% yield).
The End
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