Steglich酯化反應

Steglich酯化反應

在DMAP催化下，以DCC為偶聯試劑的酯化方法，稱為Steglich酯化反應。1978年Steglich首先提出【Angew. Chem. Int. Ed.1978,17,522】，DMAP也因此被稱為Steglich催化劑，該方法條件溫和，可用于位阻大的或對酸敏感底物的酯化，適用于從叔丁醇制備叔丁酯。而傳統的（酸催化酯化）會導致叔丁醇消除。該法也可用于硫代酸酯的合成。Boc保護的氨基酸酯化時用常規的Ficher酯化反應會脫Boc，此反應是一個非常好的替代方案。

由于DMAP分子中二甲氨基上氮原子攜帶的孤對電子與芳環發生共振而增加了吡啶環上氮原子的親核性。所以DMAP 作為一個酰化轉移試劑，比吡啶催化的酰化反應速度快103~105 倍。

Keck在研究用此方法合成大環內酯時，發現加入DMAP.HCl可以提高質子轉移效率，提高酯化收率。【J. Org. Chem.1985, 50, 2394】

除了利用DCC作為偶聯試劑，后續利用DIC, EDCI等碳二亞胺類縮合進行類似的酯化反應也統稱為Steglich酯化反應。

反應機理

一般認為，在Steglich酯化反應中，4-二甲氨基吡啶（DMAP）作為酰基轉移試劑發揮作用。已知醇的親核性弱于DMAP，且由羧酸與二環己基碳二亞胺（DCC）生成的O-酰基異脲中間體與醇的反應速率較慢；但如本文所示，通過DMAP的參與可顯著加速該步驟。首先羧酸先和DCC反應生成活性酯，接著和DMAP交換生成活性酰胺，醇進攻活性酰胺，生成酯。

https://cheminfographic.wordpress.com/2018/04/15/94-steglich-esterification-1978/

反應實例

此方法合成天然產物hapalosin，產率比Yamguchi法（）產率高。【J. Comb. Chem.2007, 9, 386】

A 500-mL, one-neckedflask equipped with a calcium chloride drying tube was charged with 28.83 g(0.20 mol) of monoethyl fumarate, 200 mL of dry dichloromethane, 44.47 g (0.60mol) of tert-butyl alcohol, and 2.00 g (0.16 mol) of 4-dimethylaminopyridine.The solution was stirred and cooled in an ice bath to 0°C while 45.59 g (0.22mol) of dicyclohexylcarbodiimide was added over a 5-min period. After a further5 min at 0°C the ice bath was removed and the dark-brown reaction mixture wasstirred for 3 h at room temperature. The dicyclohexylureathat has precipitated was removed by filtration through a fritted Büchnerfunnel (G3), and the filtrate was washed with two 50-mL portions of 0.5 Nhydrochloric acid and two 50 mL portions of saturated sodium bicarbonatesolution. During this procedure some additional dicyclohexylurea wasprecipitated, which was removed by filtration of both layers to facilitatetheir separation. The organic solution was dried over anhydrous sodium sulfateand concentrated with a rotary evaporator. The concentrate was distilled underreduced pressure, affording after a small forerun, 30.5–32.5 (76–81%) oftert-butyl ethyl fumarate, bp 105–107°C (12 mm)。

【Organic Syntheses, Coll. Vol. 7, p.93 (1990); Vol. 63, p.183 (1985)】

J. Org. Chem.

【A. Chem. Asian J. 2020;15:2467-2469】

J. Org. Chem.

Angewandte Chemie, International Edition

J. Org. Chem.

ChemCatChem

參考資料

1、《有機人名反應、試劑與規則》，黃培強等。

2、https://cheminfographic.wordpress.com/2018/04/15/94-steglich-esterification-1978/

3、Comprehensive Organic Name Reactions and Reagents, by Zerong Wang，P2651-2655.