在鈀催化下，有機(jī)硼化合物與有機(jī)鹵素化合物進(jìn)行偶聯(lián)反應(yīng)，這就提供了一類常用和有效的合成碳-碳鍵化合物的方法，我們稱之為 Suzuki 偶聯(lián)反應(yīng)，或 Suzuki-Miyaura 偶聯(lián)反應(yīng)。
Suzuki 反應(yīng)的通式
Suzuki 反應(yīng)的機(jī)理
Suzuki 偶聯(lián)反應(yīng)的催化循環(huán)過程通常認(rèn)為先是Pd(0)與鹵代芳烴發(fā)生氧化-加成反應(yīng)生成Pd(II) 的絡(luò)合物 1，然后與活化的硼酸發(fā)生金屬轉(zhuǎn)移反應(yīng)生成Pd(II)）的絡(luò)合物 2，后進(jìn)行還原-消除而生成產(chǎn)物和Pd(0)。
1.通過金屬有機(jī)試劑制備單取代芳基硼酸
經(jīng)典合成單取代芳基硼酸(酯)的方法是用格氏試劑或鋰試劑和硼酸酯反應(yīng)來制備。
用這種經(jīng)典方法的缺點(diǎn)是單取代芳基硼酸酯有進(jìn)一步生成二取代硼酸，甚至三烷基硼的可能，因此反應(yīng)須在低溫下進(jìn)行。解決這個(gè)問題的一個(gè)有效的
辦法是使用硼酸三異丙酯和有機(jī)鋰試劑反應(yīng), 可以避免二烷(芳)基硼烷和三烷(芳)基硼烷的產(chǎn)生。反應(yīng)完后通 常加入稀鹽酸酸化直接高收率地得到芳基硼酸酯。
Grinard 試劑制備單取代芳基硼酸示例
A 500-mL, three-necked, round-bottomed flask containing magnesium turnings (1.94 g, 80 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.
有機(jī)鋰試劑制備單取代芳基硼酸示例
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.通過二硼烷頻哪酯制備芳基硼酸酯
對(duì)于分子中帶有酯基、氰基、硝基、羰基等官能團(tuán)的芳香鹵代物來說, 無法通過有 機(jī)金屬試劑來制備相應(yīng)的芳基硼酸。1995年由Ishiyama率先取得了突破: 通過二硼烷頻哪酯和芳基鹵發(fā)生偶聯(lián)反應(yīng)制備相應(yīng)的芳基硼酸酯 (yield: 60-98%)。這個(gè)方法還有一個(gè)突出的優(yōu)點(diǎn)就是還可以原位制備硼酸酯, 然后“一鍋法”和芳基鹵反應(yīng)用于芳基-芳基偶聯(lián)反應(yīng)。
在極性溶劑里此偶聯(lián)反應(yīng)的產(chǎn)率可以得到很大的提高：DMSO≥ DMF > dioxane > toluene。
經(jīng)過驗(yàn)證，KOAc是應(yīng)用于這個(gè)反應(yīng)合適的堿，其他的如K3PO4或K2CO3這些堿性略強(qiáng)的堿會(huì)進(jìn)一步使原料芳基鹵發(fā)生自偶聯(lián)反應(yīng)。
對(duì)于制備溴代物和碘代物相應(yīng)的芳基硼酸酯，Pd(dppf)Cl2一般可以得到很好的結(jié)果，又由其具有易于反應(yīng)的后處理的優(yōu)點(diǎn)，因此是公司目前常用的一類催化劑。
對(duì)于氯代物，2001年Ishiyama經(jīng)過研究發(fā)現(xiàn)在 Pd(dba)2/2.4PCy3(3-6mol %) 的催化下此類 反應(yīng)可以接近當(dāng)量的進(jìn)行5，下表是研究過程中對(duì)配體的遴選的情況：
如Table 2所示，對(duì)一些有代表性的芳基氯進(jìn)行硼酸酯化反應(yīng)。對(duì)于含有吸電子集團(tuán)的芳基氯，例如NO2、CN、CHO和CO2Me（Entry 1,3,5 and 6），反應(yīng)進(jìn)行的很快。而對(duì)于含有給電子集團(tuán)(Entry 8-13)或有位阻影響的集團(tuán)(Entry 2, 4)的芳基氯，反應(yīng)就明顯緩慢下來，需要更長的時(shí)間和更多的催化劑來完成。例外的是，2-氯吡啶(Entry 15)不能得到目標(biāo)產(chǎn)物。對(duì)這種氯原子緊鄰芳環(huán)雜原子的芳基氯進(jìn)行反應(yīng)的過程中，產(chǎn)生的硼酸或硼酸酯實(shí)在是太敏感了，很容易就轉(zhuǎn)變?yōu)殡s原子芳環(huán)，如吡啶。
對(duì)于一些富電子的芳基氯化物和碘化物，用Pd(dppf)Cl2進(jìn)行硼酸酯化的收率較低，而用 Pd(dba)2/2.4PCy3(3-6mol %)在dioxone中會(huì)得到較好的結(jié)果，如下表所示：
二硼烷頻哪酯制備芳基硼酸酯示例
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.
芳基硼酸轉(zhuǎn)化為芳基硼酸酯
A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 m) was refluxed in a Dean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethyl ether and filtered to provide the desired product of sufficient purity for subsequent use.
烯基硼酸酯的制備
烷基硼酸酯的制備
