Goldberg偶联反应

铜或铜盐催化下进行芳酰胺化的反应。此反应最早由德国女化学家、Fritz Ullmann 的妻子 Irma Goldberg 发现。但此反应有一些缺点：（1）反应温度一般是140℃，甚至更高；（2）部分的反应需要一个摩尔或更多的铜参与反应；（3）一般需要在高极性而且毒性较大的溶剂中进行。近年来，利用合适的配体，把铜的使用量缩减到了催化量。该反应不需要使用昂贵的Pd金属，在经济性上是十分有优势的。【】

九十多年后， Ukita 报道了几种芳香溴和碘代物和芳酰胺在以DMF为溶剂，120℃下，碳酸钾为碱可以顺利反应.

此反应经过发展可以在1，2-二胺类化合物做配体，K3PO4, K2CO3 和 Cs2CO3 做碱的条件下，在较温和的条件下进行。

常用的铜盐有:

Cu

CuI

CuCl

CuSCN

Cu2O

CuCl2

CuSO4·5H2O

CuO

Cu(OAc)2

Cu(acac)2

常用的配体有：N,N’-二甲基乙二胺和N,N’-二甲基环己二胺。关于配体对反应的作用，Buchwald认为配体的存在有助于提高铜盐的溶解性，阻碍催化剂的分解，减少副产物的生成，从而有利于反应。

溶剂：通常碘代物参与的芳酰胺化反应在大多数非质子溶剂如甲苯、二氧六环、THF，甚至DMF中都可以顺利进行。极性大的酰胺、乙酰胺和乳酰胺用DMF做溶剂要好于甲苯做溶剂。大部分的报道认为极性溶剂对铜催化的偶联反应至关重要。尽管异丙醇与水等质子性溶剂可以使用，非质子性极性溶剂往往给出最佳效果。

碱：碱的选择也起到了一个非常重要的作用。芳基碘的芳酰胺化，K3PO4的效果最好。如果改用K2CO3，则反应会慢很多。一般情况下，芳基溴比芳基碘的反应慢很多。有些情况下，芳基溴的酰胺化用K3PO4做碱效果会很差，换成K2CO3做碱则会好很多。研究表明，酰胺脱质子的速度与芳酰胺化的速度成正比。如果酰胺脱质子过快，则会由于形成钝化的铜盐络合物阻碍芳酰胺化的进行。也就是说对于酸性强度高的酰胺或反应活性弱的卤代芳烃尽量用弱碱。

合成示例一:

RepresentativeProcedures: N- (2-Methylphenyl) acetamide

A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol,5.0 mol %), acetamide (90 mg, 1.5 mmol), and K3PO4 (430mg, 2.03mmol), evacuated, and backfilled with argon. N,N¢-Dimethylethylenediamine(11ul, 0.10 mmol, 10 mol %), 2-iodotoluene (128 ul,1.01mmol), and dimethylformamide (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflonvalve and the reaction mixture was stirred at 80℃ for23 h. The resulting pale brown suspension was allowed to reach room temperatureand filtered through a 0.5 ×1 cm pad ofsilica gel eluting with 10 mL of ethyl acetate. The filtrate was concentratedand the residue was purified by flash chromatography on silica gel (2 ×15 cm; hexanes-ethyl acetate 1:4; 15 mL ractions). Fractions8-16provided 143 mg (95% yield) of the product as pale yellow fine needles.

合成实例二:

An Schlenk tubewas charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), amide (60 mg, 0.25 mmol),and K3PO4 (100mg, 2.0eq), evacuated, and backfilled with N2. ethylenediamine(30 ul, 10mol %), iodotoluene (62 mg, 1.2eq), and 1,4-dioxane (2.0 mL) were added under N2. The tube was sealed with a Teflon valveand the reaction mixture was stirred at 120℃ for 48hrs. The resulting suspension wasallowed to reach room temperature and filtered through a 0.5 ×1 cm pad of silica gel eluting with 10 mL of ethylacetate. The filtrate was concentrated and the residue was purified by flashchromatography on silica gel (2 ×15 cm; hexanes-ethyl acetate1:4; 15 mL ractions). We can obtain 63 mg (80% yield) product as white solid.

本文非原创内容，版权归原作者所有，如涉及版权问题，请联系本号删除。