【原】縮合酰胺化總是消旋, 你有必要了解一下這個試劑！

有機合成公眾號 2024-12-09 發(fā)布于上海

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?；溥蜴f鹽是一種活性非常高的酰胺化試劑，但是合成起來非常麻煩，酰基咪唑利用Meerwein鹽（Me3OBF4), methyl triflate (MeOTf)或碘甲烷進(jìn)行烷基化以及活性酯或酰氯和N-甲基咪唑交換都不能取得很好的效果。2018年，百時美施貴寶公司的Gregory L. Beutner和Ian S. Young等人報道了利用TCFH(N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate)和NMI (N-methylimidazole)原位生成?；溥蜴f鹽并直接用于酰胺化的方法【Org. Lett. 2018, 20, 4218–4222】。此方法以乙腈為溶劑，室溫下就可以反應(yīng)。對于一些大位阻的羧酸和親核性很弱的胺都可高產(chǎn)率的進(jìn)行酰胺化，而且此方法由于用的堿是NMI, 堿性很弱，基本不會發(fā)生消旋。

投反應(yīng)時，加料順序很重要，TCFH最后加入，如果先加入，胺可能會先和其進(jìn)行反應(yīng)生成胍類副產(chǎn)物。

反應(yīng)機理

在NMI存在下，TCFH會迅速轉(zhuǎn)化為中間體ii，ii和羧酸反應(yīng)生成?；溥蜴f鹽iii，由于酰基咪唑鎓鹽iii活性極高，會迅速和胺反應(yīng)得到酰胺。按照此反應(yīng)歷程，至少需要兩個當(dāng)量的NMI，反應(yīng)才能順利進(jìn)行。

生成酰基咪唑鎓鹽iii的過程和HATU酰胺化機理類似。

對于一些反應(yīng)活性很低的胺作為底物進(jìn)行反應(yīng)，發(fā)現(xiàn)在室溫下進(jìn)行也可以得到很高的產(chǎn)率。

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).

但是對于α-位有手性中心的羧酸，NMI的量太多會發(fā)生消旋。

因此得到優(yōu)化的反應(yīng)條件：TCFH(1.1 eq），NMI(2.1eq），乙腈，23℃。

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).

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