经典合成反应标准操作—Suzuki反应 药明康德新药开发有限公司
FConditionsCNClNCNNHFClBrNNHROBROHOBOHCNOBOCNOBOCN0 B 0 %
4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应
2-醛基苯硼酸和2-碘甲苯在Na2CO3水溶液和DME中80℃反应, 目标化合物的收率只有39%. 提高收率的一个方法是: 使用相应的芳基硼酸酯代替芳基硼酸, 以无水K3PO4为碱, 用DMF作溶剂, 收率可以提高到89%6.
OBOCHO+ArXPd(PPh3)4K3PO4DMF, 80℃ArCHO
如果芳基硼酸或芳卤本身带有其它对水敏感的集团，如易水解的酯基（尤其是甲酯，乙酯活性还低些）、氰基等等，这时也可以应用这种方法，实验证明在无水的情况下，即使碱不溶解，很多的底物也可以进行Suzuki偶联反应。相应的芳基硼酸酯的制备方法可参考前述有关章节。
如果底物既带着酯基又只能在有水存在下才能反应的，怎么办？ 方法之一：加入痕量的水, 如果底物本身含有甲酯就不能在toluene/EtOH/H2O里反应了，因为会发生酯交换反应，但只要把其中的EtOH换成MeOH即可解决这个问题。方法之二：先得到羧酸产物然后再酯化。例如 4.3.3所示操作:
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经典合成反应标准操作—Suzuki反应 药明康德新药开发有限公司
4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联
OONHBr+OBO(PH3P)4Pd IIIK2CO3 IVH2O Vdioxane VIrefluxOONHIIIVII
To a solution of 3.862 g of I and 3.401 g of II in 80 mL of dioxane and 20 mL of water was added 2.245 g of K2CO3 followed by 0.328 g of (Ph3P)4Pd under N2 with stirring. The mixture was refluxed for several hours until the material was disaappeared. The reaction mixture was cooled to room temperature. The dioxane was removed by rotary evaporation. The residue was poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. The product was isolated by flash chromatography on silica gel using 10:90 EtOAc-hexanes as eluant. The product was a clear, colorless oil.
4.3.2 带着酯基底物的Suzuki偶联反应示例（一）13
OHBrMeO2CFBOHPd(dppf)Cl2Na2CO3, DCM, refluxMeO2CF
A mixture of methyl 4-bromobenzoate (21.5 g, 100 mmol), 4-fluorophenylboronic acid (14.7 g, 105 mmol), Pd(dppf)Cl2, CH2Cl2(1.48 g, 2.0 mmol), and 2M Na2CO3(100 ML) in toluene (200 ML) and was heated to reflux, stirred for 10 hours, diluted with ethyl acetate (200 ML), washed with water (100 ML) and brine (50 ML), dried (MgSO4), filtered, and concentrated.The concentrate was recrystallized from ethyl acetate/hexanes to provide the desired product. The mother liquor was concentrated and purified by flash column chromatography on silica gel with 10percent ethyl acetate/hexanes to provide additional product.
13
Patent; Augeri, David J.; Publ.: US2002/55631 A1 (2002/05/09)
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经典合成反应标准操作—Suzuki反应 药明康德新药开发有限公司
4.3.3 带着酯基底物的Suzuki偶联反应示例（二）14
COOEtB(OH)2COOMe1.Suzuki-couplingClNCOOMe2.EtOH, HCl, refluxHNNCOOEtHN
Into 500 ml anhydrous toluene in a 1 liter round bottom flask equipped with stirring bar was bubbled in a stream of argon via a needle for 30 min. Pd(PPh3)4 (0.878g, 0.75 mmol) and 3-chloro-pyridine-2,5-dicarboxylic acid dimethyl ester (3.44g, 15.0 mmol) were added into this solvent and the resulting mixture was stirred at r.t. under argon for 1 hour. A solution of indole-4-boronic acid (1.86g, 11.5 mmol) in 50 ml EtOH and a solution of 2M aqueous Na2CO3 (11.5 ml) was added into the reaction mixture at r.t. under argon. The mixture was heated under argon with vigorous stirring at 105?C for 8 hours. The reaction mixture was cooled and brine (200 ml) was added. The organic layer was separated and aqueous layer extracted with additional CH2Cl2 (2x100 ml). The combined organic layer was dried over Na2SO4 and evaporation of the solvent left a yellowish solid. Purification of the crude material through a short plug of silica gel (hexane:ethyl acetate, 1:2) afforded a yellow solid. The TLC of this material showed it to be a mixture of three different compounds due to ester exchange. This solid was dissolved in 500 ml EtOH and the solution was stirred overnight at r.t. in the presence of catalytic HCl in diethyl ether. A single compound (3.54g) was obtained (mp. 212.3-213.0°C) in 91.0% yield.
4.4 杂环芳基硼酸参与Suzuki偶联反应
杂环芳基硼酸参与Suzuki偶联反应同样可以得到好的结果15.
MeOOCNBr+O2NB(OH)2Pd(PPh3)4aq. Na2CO3benzeneNMeOOCNO2
1415
http://www.rhodium.ws/chemistry/lysergic.hendrickson.html
a) Thompson, W. J.; Gaudino, J . J . Org. Chem. 1984, 49, 5237. b) Thompson, W. J.; Jones, J. H.; Lyle, P. A,; Thies,
J. E. J . Org. Chem. 1988, 53, 2052.
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经典合成反应标准操作—Suzuki反应 药明康德新药开发有限公司
3-吡啶基二乙基硼烷是一个对空气和水份稳定的化合物, 可以用来作杂环的芳化反应16.
MeOCNBr+NBEt2Pd(PPh3)4aq. NaOH,/ Bu4NClTHFMeOCNN
一般说来2-噻吩硼酸，3-吡啶硼酸做Suzuki结果都不是太理想。
4.5烷基硼酸参与Suzuki偶联反应
对于芳基卤和甲基硼酸(酯)参与的Suzuki反应, 收率一般都很低。一个改进的方法是用剧毒的TlOH或Tl2CO3作碱, Suzuki反应的收率有提高17。近来有报道用甲基三氟硼酸钾代替甲基硼酸, 取得了较好的结果。这种方法突出的优点是试剂易于制备, 对空气稳定, 并且用于Suzuki偶联反应一般可以得到较好的结果18。
ArOTfMeBF3K+orArXCs2CO3THF / H2O= 1: 1Pd(dppf)Cl2ArMe
Entry ArBr or ArOTf Product Yield Entry ArBr or ArOTf Product Yield 1 TfOO O 85% 8 BrCNCN60% 92% 2 BrO O 80% 9 BrO O 57% CO2MeCO2Me3 BrO O61% 10 Br 16
Ishikura, M.; Kamada, M.; Terashima, M. Synthesis 1984, 936.
17
Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405-1408 18
Molander, G. A.; Yun C. S.; Ribagorda, M.; Biolatto B.. J . Org. Chem. 2003, 68, 5534-5539.
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经典合成反应标准操作—Suzuki反应 药明康德新药开发有限公司
Br4 TfONO2 NO2 85% 11 F3CF3CNO285% O2NNO25 BrNO2 NO2 77% 12 Br 83% O2N6 BrNHAc NHAc 67% 13 ClN32% N 7 BrCN CN 68%
4.6烯基硼酸参与Suzuki偶联反应
OOBrB(CH2)8CNPdCl2(dppf) (3 mol%)K2CO3 (2 equiv)DMF, THF, 50oC81%Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc.1989, 111, 314–321.
(CH2)8CN
4.7 Triflate参与Suzuki偶联反应
因为三氟甲基磺酸酯可以由相应的酚或者酮方便地制备, 这个试剂参与Suzuki偶联反应吸引了越来越多的科学研究者的兴趣。
ArB(OH)2OTfBocHNCO2MePd(PPh3)4K2CO3toluene90℃BocHNCO2Me75-94%Ar
三氟甲基磺酸酯和芳基硼酸的偶联反应有时候会因为在反应初期, 催化剂配体PPh3容易和triflate反应, 从而导致催化剂分解破坏为钯黑。如果在反应体系中加入和催化剂等当量的LiBr 或KBr就足以阻止这种分解反应。
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