Steglich酯化反应

Steglich酯化反应

在DMAP催化下，以DCC为偶联试剂的酯化方法，称为Steglich酯化反应。1978年Steglich首先提出【Angew. Chem. Int. Ed.1978,17,522】，DMAP也因此被称为Steglich催化剂，该方法条件温和，可用于位阻大的或对酸敏感底物的酯化，适用于从叔丁醇制备叔丁酯。而传统的（酸催化酯化）会导致叔丁醇消除。该法也可用于硫代酸酯的合成。Boc保护的氨基酸酯化时用常规的Ficher酯化反应会脱Boc，此反应是一个非常好的替代方案。

由于DMAP分子中二甲氨基上氮原子携带的孤对电子与芳环发生共振而增加了吡啶环上氮原子的亲核性。所以DMAP 作为一个酰化转移试剂，比吡啶催化的酰化反应速度快103~105 倍。

Keck在研究用此方法合成大环内酯时，发现加入DMAP.HCl可以提高质子转移效率，提高酯化收率。【J. Org. Chem.1985, 50, 2394】

除了利用DCC作为偶联试剂，后续利用DIC, EDCI等碳二亚胺类缩合进行类似的酯化反应也统称为Steglich酯化反应。

反应机理

一般认为，在Steglich酯化反应中，4-二甲氨基吡啶（DMAP）作为酰基转移试剂发挥作用。已知醇的亲核性弱于DMAP，且由羧酸与二环己基碳二亚胺（DCC）生成的O-酰基异脲中间体与醇的反应速率较慢；但如本文所示，通过DMAP的参与可显著加速该步骤。首先羧酸先和DCC反应生成活性酯，接着和DMAP交换生成活性酰胺，醇进攻活性酰胺，生成酯。

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

反应实例

此方法合成天然产物hapalosin，产率比Yamguchi法（）产率高。【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

参考资料

1、《有机人名反应、试剂与规则》，黄培强等。

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

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