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mmol) is equipped with a rubber septum, a 20-mL pressure-equalizing dropping funnel fitted with a rubber septum, a Teflon-coated magnetic stirring bar, and a reflux condenser fitted with an argon inlet adapter. The system is flame-dried and flushed with argon. Anhydrous ether (200 mL) is introduced to cover the magnesium, a crystal of iodine is added, and the mixture is heated to reflux in an oil bath. The dropping funnel is filled with 1-bromo-3,4,5-trifluorobenzene (8.36 mL, 14.8 g, 70.0 mmol) and ca. 1 mL is added to the boiling reaction mixture. After reaction has commenced, the oil bath is removed, and the remainder of the aryl bromide is added slowly at a rate sufficient to maintain reflux (addition time ca. 1 hr). The resulting mixture is stirred for an additional 2 hr. During this period, a flame-dried, 500-mL, single-necked, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar, a rubber septum, and an argon inlet is charged with dry tetrahydrofuran (THF, 50 mL) and trimethyl borate (15.7 mL, 14.5 g, 140 mmol). The mixture is cooled to 0°C, and the ether solution of (3,4,5-trifluorophenyl)magnesium bromide prepared above is introduced in one portion via a double-ended needle. The reaction mixture is allowed to warm to room temperature, stirred for 1 hr, and then treated with 200 mL of saturated ammonium chloride solution. The organic layer is separated and the aqueous layer is extracted with three 100-mL portions of ethyl acetate. The combined organic layers are washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid is dissolved in a minimal amount of hot (65°C) ethyl acetate, allowed to cool to room temperature, and then 600 mL of hexane is added. The resulting solution is allowed to stand overnight and then filtered to afford pure (3,4,5-trifluorophenyl)boronic acid as white crystals. Further recrystallization of the mother liquor 3-4 times provides a total of 6.3 g (51%) of (3,4,5-trifluorophenyl)boronic acid.
2.1.2 通过有机锂试剂制备单取代芳基硼酸示例3
TMS1. nBuLi, THF -78C, 15min2. B(OMe)3I -78C-25C, 30min3. H+/HCloooTMS(HO)2B
3
Chem. Eur. J. 2003, 9, 4430-4441
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nBuLi (1.6_ in hexane, 1 mL, 1.6 mmol) at - 78℃ under nitrogen was added to a solution of 4-(trimethylsilylethynyl) iodobenzene (0.3 g, 1.13 mmol) in THF (5 mL). After stirring for 15 min at - 78℃, trimethylborate (0.2 mL, 1.6 mmol) was added in one portion. The mixture was warmed to 25 ℃, stirred for 30 min, and quenched with dilute HCl solution. The mixture was extracted with EtOAc (20 mL), washed with water, dried (MgSO4) and evaporated to obtain the crude 4-(trimethylsilylethynyl) phenylboronic acid that was used without further purification.
2.2 通过二硼烷频哪酯制备芳基硼酸酯
(RO)2B-B(OR)2XXPd(dppf)Cl2KOAcDMSO, 80℃XB(OR)2
对于分子中带有酯基、氰基、硝基、羰基等官能团的芳香卤代物来说, 无法通过有机金属试剂来制备相应的芳基硼酸。 1995年由Ishiyama4率先取得了突破: 通过二硼烷频哪酯和芳基卤发生偶联反应制备相应的芳基硼酸酯 (yield: 60-98%)。这个方法还有一个突出的优点就是还可以原位制备硼酸酯, 然后―一锅法‖和芳基卤反应用于芳基-芳基偶联反应。
在极性溶剂里此偶联反应的产率可以得到很大的提高：DMSO≥ DMF > dioxane >
toluene。
经过验证，KOAc是应用于这个反应最合适的碱，其他的如K3PO4或K2CO3这些碱性略强的碱会进一步使原料芳基卤发生自偶联反应的结果。 4
Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
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对于制备溴代物和碘代物相应的芳基硼酸酯，Pd(dppf)Cl2一般可以得到很好的结果，又由于其具有易于反应的后处理的优点，因此是公司目前最常用的一类催化剂。
对于氯代物，2001年Ishiyama经过研究发现在 Pd(dba)2/2.4PCy3(3-6mol %) 的催化下此类反应可以接近当量的进行5，下表是研究过程中对配体的遴选的情况：
Table 1. Effect of ligands in the reaction of bis(pinacolato)diboron (2, 1.1 mmol) with 4-chlorobenzaldehyde (1.0 mmol) in dioxane (6 ml) at 80°C for 16 in the presence of KOAc (1.5 mmol), Pd(dba)2 (3 mol%), and a phosphine ligand (3.3-7.2 mol%)
Entry 1 2 3 4 5 6 7 8 9 10 11 a
Ligand None PPh3 P(o-MeC6H4)3 P(p-MeOC6H4)3 dppfc 4 5 6 7 PCy3 P(t-Bu)3 Ligand (equiv.)a 2.4 2.4 2.4 1.1 1.1 2.4 1.1 1.1 2.4 2.4 Yield (%)b 1 19 36 44 18 78 68 10 71 94 58 Equivalents to palladium metal.
GC yields based on 4-chlorobenzaldehyde.
bc
1,1’-Bis(diphenylphosphino)ferrocene.
如Table 2所示，对一些有代表性的芳基氯进行硼酸酯化反应。对于含有吸电子集团
的芳基氯，例如NO2、CN、CHO和CO2Me（Entry 1,3,5 and 6），反应进行的很快。而对于含有给电子集团(Entry 8-13)或有位阻影响的集团(Entry 2, 4)的芳基氯，反应就明显缓慢下来，需要更长的时间和更多的催化剂来完成。例外的是，2-氯吡啶(Entry 15)不能得
5
Tatsuo Ishiyama, Tetrahedron 57 (2001) 9813-9816
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到目标产物。对这种氯原子紧邻芳环杂原子的芳基氯进行反应的过程中，产生的硼酸或硼酸酯实在是太敏感了，很容易就转变为杂原子芳环，如吡啶。
Table 2. Synthesis of pinacol arylboronates
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 aChloroarene 4-O2NC6H4Cl 2-O2NC6H4Cl 4-NCC6H4Cl 2-NCC6H4Cl 4-OHCC6H4Cl 4-MeO2CC6H4Cl C6H5Cl 4-MeC6H4Cl 2-MeC6H4Cl 4-MeOC6H4Cl 3-MeOC6H4Cl 2-MeOC6H4Cl 4-Me2NC6H4Cl 2-Chloronaphthalene 2-Chloropyridine 3-Chloropyridine ClOClHNMol%a 3 3 3 3 3 3 6 6 3 6 6 3 6 3 3 3 3 3 Time (h) 4 48 4 48 6 6 48 48 48 48 48 48 48 48 48 48 48 48 Yield (%)b 88 72 98 72 94 87 91 92 86 78 92 70 73 77 0 82 73 72 b
Mol% of catalyst. GC yields based on chloroarenes.
对于一些富电子的芳基氯化物和碘化物，用Pd(dppf)Cl2进行硼酸酯化的收率较低，而用
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Pd(dba)2/2.4PCy3(3-6mol %)在dioxone中会得到较好的结果，如下表所示：
EDGX2KOAc80oCOEDGBO
EDG MeO Me2N
X= I Br Br OTf OTf I Br Br Catalyst/solvent PdCl2(dppf)/DMSO PdCl2(dppf)/DMSO Pd (dba) 2-PCy3/dioxane PdCl2(dppf)-dppf/dioxane Pd (dba) 2-PCy3/dioxane PdCl2(dppf)/DMSO PdCl2(dppf)/DMSO Pd (dba) 2-PCy3/dioxane Time/h 2 24 7 13 2 6 24 6 Yield% 82 69 81 93 83 90 23 81 2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一）
OOBBOOBrPd(dppf)Cl2OBOKOAcDMSO, 80℃, 98 %
A flask charged with palladium catalyst (0.03 mmol), KOAc (294 mg, 3.0 mmol), and diboron (279 mg, 1.1 mmol) was flushed with nitrogen. DMSO (6 mL) and haloarene (1.0 mmol) were then added. After being stirred at 80 ℃ for an appropriate period, the product was extracted with benzene, washed with water, and dried over anhydrous magnesium sulfate. Kugelrohr distillation in vacuo gave the arylboronates.
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