极高效酰胺化试剂----TCFH−NMI

chem 34981 0

极高效酰胺化试剂----TCFH−NMI  第1张

酰基咪唑鎓盐是一种活性非常高的酰胺化试剂,但是合成起来非常麻烦,酰基咪唑利用 Meerwein盐 (Me3OBF4), methyl triflate (MeOTf)或碘甲烷进行酰基化以及活性酯或酰氯和N-甲基咪唑交换都不能取得很好的效果。2018年,百时美施贵宝公司的Gregory L. Beutner和Ian S. Young等人报道了利用TCFH(N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate)和NMI (N-methylimidazole)原位生成 酰基咪唑鎓盐并直接用于酰胺化的方法【 Org. Lett. 2018, 20, 4218–4222】。此方法以乙腈为溶剂,室温下就可以反应。对于一些大位阻的羧酸和亲核性很弱的胺都可高产率的进行酰胺化,而且此方法基本不会发生消旋。

反应机理

在NMI存在下,TCFH会迅速转化为中间体 ii, ii和羧酸反应生成酰基咪唑鎓盐 iii,由于酰基咪唑鎓盐 iii活性极高,会迅速和胺反应得到酰胺。按照此反应历程,至少需要两个当量的NMI,反应才能顺利进行。

极高效酰胺化试剂----TCFH−NMI  第2张

生成酰基咪唑鎓盐 iii的过程和HATU酰胺化机理类似。

对于一些反应活性很低的胺作为底物进行反应,发现在室温下进行也可以得到很高的产率。

极高效酰胺化试剂----TCFH−NMI  第3张

General Procedure 1. N-(4-cyanophenyl)-2-methyl-2-phenylpropanamide (3a): The 2-methyl-2- phenylpropanoic acid 1 (0.250 g, 1.52 mmol, 1.0 equiv), 0.234 g 4-aminobenzonitrile (2a) (1.98 mmol, 1.3 equiv) and 0.42 mL N-methylimidazole (5.33 mmol, 3.5 equiv) were combined and dissolved in 4 mL MeCN for addition of 0.517 g TCFH (1.83 mmol, 1.2 equiv) in a single portion. The reaction was stirred until complete by HPLC (21h). The reaction was then diluted with 6 mL of isopropyl acetate and 4 mL of water. The layers were separated, the aqueous layer was extracted with 4 mL of isopropyl acetate and the combined organics were washed with 4 mL of water, dried with MgSO4, filtered and concentrated before purification by silica gel chromatography with heptane/isopropyl acetate to give 374 mg of 3a as a white solid (93% yield).2 In some cases, direct isolation of the desired amide could be achieved through addition of 4-6 mL water, filtration and washing with 5 mL of 2:1 water/MeCN before drying under nitrogen without a significant change in yield. Reported yields represent those obtained by chromatography for consistency. TLC Rf = 0.38 (7:3 heptane/isopropyl acetate, UV 254 nm).

但是对于α-位有手性中心的羧酸,NMI的量太多会发生消旋。

极高效酰胺化试剂----TCFH−NMI  第4张

因此得到优化的反应条件:TCFH(1.1 eq),NMI(2.1eq),乙腈,23℃。

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极高效酰胺化试剂----TCFH−NMI  第6张

General Procedure 2. (S)-N-(4-cyanophenyl)-2-phenylpropanamide (6a): The (S)-2-phenylpropionic acid (S)-5 (0.45 mL, 3.23 mmol, 1.0 equiv), 0.47 g 4-aminobenzonitrile 2a (3.87 mmol, 1.2 equiv), 0.54 mL N-methylimidazole (6.78 mmol, 2.1 equiv) were combined and dissolved in 10 mL MeCN for addition of the 1.0 g of TCFH (3.55 mmol, 1.1 equiv) in a single portion. The reaction was stirred until complete by HPLC (30 min). The reaction was then diluted with 20 mL isopropyl acetate and 20 mL of water. The layers were separated, dried over Na2SO4, filtered and concentrated before purification by silica gel chromatography with heptane/ethyl acetate to give 749 mg of 6a as a white solid (93% yield).3 Direct isolation of the desired amide could be achieved through addition of 4-6 mL water, filtration and washing with 5 mL of 2:1 water/MeCN before drying under nitrogen without a significant change in yield. Reported yields represent those obtained by chromatography for consistency and to avoid enrichment through crystallization. TLC Rf = 0.29 (7:3 heptane/EtOAc, UV 254 nm).

参考资料:

TCFH–NMI: Direct Access to N-Acyl Imidazoliums for Challenging Amide Bond Formations, 

Org. Lett. 2018, 20, 14, 4218–4222.

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