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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)或碘甲烷进行烷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，而且此方法由于用的碱是NMI, 碱性很弱，基本不会发生消旋。投反应时，加料顺序很重要，TCFH最后加入，如果先加入，胺可能会先和其进行反应生成胍类副产物。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。
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生成酰基咪唑鎓盐iii的过程和HATU酰胺化机理类似。
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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。
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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。
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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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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).TCFH–NMI: Direct Access to N-Acyl Imidazoliums for Challenging Amide Bond Formations，Org. Lett. 2018, 20, 14, 4218–4222.
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