Duff反应
活泼的芳香族化合物（如酚或苯胺）与六亚甲四胺反应生成亚胺中间体，继而水解成醛。反应具有简便而迅速的特点，但这一经典方法往往产率不高，限制了它的应用。利芳香族化合物在三氟乙酸存在下与六亚甲基四胺反应，可以得到高产率的芳醛。改良方法不仅适用于活泼的芳香族化合物，亦可应用于简单的芳烃甲酰化。
反应机理
乌洛托品质子化、断裂产生亚胺离子，亚胺离子对芳环发生亲电芳香取代，经互变异构，生成一个苄胺衍生物。接下来乌洛托品部分发生第二次质子化、断裂产生亚胺离子，然后进行分子内氧化还原反应，苄胺部分被氧化为亚苄基亚胺离子，它经过水解，即得到醛。
反应实例
A mixture of 12.2 g of 2,6-xylenol (100 mmol), 14.0 g of HMTA (aka urotropine, hexamine orhexamethylenetetramine) (100 mmol) and 150 mL of trifluoroacetic acid was heated at reflux (83-90 oC) for 12 hrs. The products were concentratedand combined with 600 mL of ice water; the resulting mixture was stirred 15min, made basic with Na2CO3 and extracted with ether.Evaporation of the ether solution left a yellow solid which was recryst. fromCHCl3-pentane to afford 14.3 gof 3,5-dimethyl-4-hydroxy-benzaldehyde mp 113 ℃
【J. Org. Chem. 1972, 37, 3972】
Di-t-butylsalicylaldehyde (3). Phenol 1 (125 g, 0.61 mol) and 2 (170 g, 1.21 mol) in HOAc (300 mL)were heated to 130 C with stirring and kept at 130 ℃ for 2 h. At 75 ℃, 33% H2SO4 (300 mL) was added and the mixture was heated to 105–110 ℃ for 1 h. Workup afforded 56–71 g of 3 (40–50%), mp 53–56 ℃.
【J Org Chem. 1994, 59, 1939】
5-tert-Butyl-2-methoxybenzaldehyde (5): Prepared from 4-tert-butylanisole (4.80 g, 29.2 mmol), hexamethylenetetramine (9.35 g, 66.7 mmol) and TFA (60 mL) to give crude 5 as a yellow oil after aqueous workup. Purification by column chromatography (silica gel, CH2Cl2/petroleum ether 1:1 to 3:1) gave 5 as as lightly yellow oil; yield: 3.90 g (70%).
【Synthesis 1998, 1029】
【Tetrahedron Letters, 1999, 40, 5399-5400】
【Bioorganic and Medicinal Chemistry, 2007, 15, 6782-6795】
【Tetrahedron, 2008, 64, 741-748】
相关文献
1 Duff JC J Chem Soc . 1932, 1987
2 Duff JC J Chem Soc. 1934, 1305
3 Ferguson LN Chem Rev. 1946, 38, 230
4 Ogata Y Tetrahedron 1968, 24, 5001
5 Wada F Bull Chem Soc Jpn. 1980, 53, 1473
6 Jacobsen EN J Org Chem. 1994, 59, 1939
7 Yaseen M J Heterocycl Chem. 2009, 46, 251
参考资料
一、Organic Syntheses Based On Name Reactions, 3RdEd, A. Hassner, Page 133.
二、化学空间：https://cn.chem-station.com/reactions/%E5%8F%96%E4%BB%A3%E5%8F%8D%E5%BA%94/2015/09/post-6320.html
三、Reactionflash：Duff Aldehyde Synthesis