Goldberg偶聯(lián)反應(yīng)

銅或銅鹽催化下進(jìn)行芳酰胺化的反應(yīng)。此反應(yīng)最早由德國(guó)女化學(xué)家、Fritz Ullmann 的妻子 Irma Goldberg 發(fā)現(xiàn)。但此反應(yīng)有一些缺點(diǎn)：（1）反應(yīng)溫度一般是140℃，甚至更高；（2）部分的反應(yīng)需要一個(gè)摩爾或更多的銅參與反應(yīng)；（3）一般需要在高極性而且毒性較大的溶劑中進(jìn)行。近年來(lái)，利用合適的配體，把銅的使用量縮減到了催化量。該反應(yīng)不需要使用昂貴的Pd金屬，在經(jīng)濟(jì)性上是十分有優(yōu)勢(shì)的?！尽?/p>

九十多年后， Ukita 報(bào)道了幾種芳香溴和碘代物和芳酰胺在以DMF為溶劑，120℃下，碳酸鉀為堿可以順利反應(yīng).

此反應(yīng)經(jīng)過(guò)發(fā)展可以在1，2-二胺類化合物做配體，K3PO4, K2CO3 和 Cs2CO3 做堿的條件下，在較溫和的條件下進(jìn)行。

常用的銅鹽有:

Cu

CuI

CuCl

CuSCN

Cu2O

CuCl2

CuSO4·5H2O

CuO

Cu(OAc)2

Cu(acac)2

常用的配體有：N,N’-二甲基乙二胺和N,N’-二甲基環(huán)己二胺。關(guān)于配體對(duì)反應(yīng)的作用，Buchwald認(rèn)為配體的存在有助于提高銅鹽的溶解性，阻礙催化劑的分解，減少副產(chǎn)物的生成，從而有利于反應(yīng)。

溶劑：通常碘代物參與的芳酰胺化反應(yīng)在大多數(shù)非質(zhì)子溶劑如甲苯、二氧六環(huán)、THF，甚至DMF中都可以順利進(jìn)行。極性大的酰胺、乙酰胺和乳酰胺用DMF做溶劑要好于甲苯做溶劑。大部分的報(bào)道認(rèn)為極性溶劑對(duì)銅催化的偶聯(lián)反應(yīng)至關(guān)重要。盡管異丙醇與水等質(zhì)子性溶劑可以使用，非質(zhì)子性極性溶劑往往給出最佳效果。

堿：堿的選擇也起到了一個(gè)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，則反應(yīng)會(huì)慢很多。一般情況下，芳基溴比芳基碘的反應(yīng)慢很多。有些情況下，芳基溴的酰胺化用K3PO4做堿效果會(huì)很差，換成K2CO3做堿則會(huì)好很多。研究表明，酰胺脫質(zhì)子的速度與芳酰胺化的速度成正比。如果酰胺脫質(zhì)子過(guò)快，則會(huì)由于形成鈍化的銅鹽絡(luò)合物阻礙芳酰胺化的進(jìn)行。也就是說(shuō)對(duì)于酸性強(qiáng)度高的酰胺或反應(yīng)活性弱的鹵代芳烴盡量用弱堿。

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.

合成實(shí)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.

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