Hofmann 降解反应是将伯酰胺通过氧化降解形成少一个碳原子的伯胺的过程。其反应的机理如下：
早期的Hofmann降解通常采用NaOH水溶液和液溴来实现，其反应的条件比较苛刻，后来人们对反应的条件进行了不断地改进，能够采用不同氧化剂和碱温和地实现。目前，通常采用的条件：
1，Br-NaOH体系Hofmann降解
2，NaClO做氧化剂的Hofmann降解
3，NBS与DBU体系的Hofmann降解
上面的几种体系大家在反应中经常用到，通常会很顺利地得到产品。但是在最近所负责的项目中，采用上述条件遇到了一些问题，均没有直接拿到目标产物，主要由其化合物结构所造成的。底物酰胺连在季碳原子上而季碳原子上又连有芳环或芳杂环结构，因此这种酰胺具有较大的空间位阻，决定了其性质的特殊性。
如Scheme 1所示：胺是我们想要得到的目标产物，我们尝试了三种不同的常用条件：
1，Br2-NaOH 体系Hofmann降解：
A solution of NaOH (5 eq) in water was cooled to 0oC, and treated withbromine (1 eq). After 10 min, the material (1 eq) in acetone was added and themixture was heated to 70-75 oC and stirred for another 45min, the mixture wasdiluted with ethyl acetate, washed with water, brine. TLC showed the reactiongot messy, and no desired product was detected by LC_MS。
2，NaClO做氧化剂的Hofmann降解:
To a solution of NaClO (5 eq) was added the material (1 eq), and thesolution was stirred for 2h at room temperature. TLC showed no reaction, andthe temperature was warmed up to 60-70 oC, stirring for 30min, TLC showed thereaction got messy.
3，NBS 与DBU体系的Hofmann降解:
To a solution of material (1 eq) wasadded the NBS (1 eq), and DBU (1.1 eq) in the methanol. The mixture was stirredfor 20 min at 80 oC, at which point more NBS (1 eq) was added to the mixture,stirred for another 10 min. TLC showed got messy, and no desired product wasdetected by LC_MS.
上面的三种方法我们都没有得到目标产物，于是我们参考相关文献，使用PhI(OCOCF3)2 做氧化剂进行反应，同样目标产物并没有得到，但是得到了比较干净的新化合物，进过鉴定分析，新的化合物为异氰酸酯中间产物，如下图所示：
此结构的异氰酸酯能够稳定地存在，我们采用不同的酸碱条件均可以把中间态异氰酸酯很好地转化为目标产物胺。具体方法如下：
To a solution of 1 (1eq) was added the PhI(OCOCF3)2 (1.2 eq ) in MeCN at room temperature. The mixture was stirred at ambient temperature for 4hs, the solvent was removed and water added, extracted with ethyl acetate, evaporation, after giving the product 2.
A mixture of potassium hydroxide (3 eq) and the product 2 (1 eq) in tetrahydrofuran: water (1:1) was stirred at room temperature for 12hs. The amine was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the desired product.
The solution of the product 2 and HCl aqueous in tetrahydrofuran was stirred at ambient temperature for 30min, then extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the desired product.
讨论部分：
讨论部分：
1.上面提到的三种方法对于我们做伯，仲碳原子相连酰胺的Hofmann降解反应，通常大都能够得到很好的结果。
2.采用PhI(OCOCF3)2作为氧化剂，同样也适用于伯，仲碳原子相连酰胺Hofmann降解反应，相比之下其条件更加温和，收率也更高。
3.PhI(OCOCF3)2作为氧化剂，在制备季碳原子相连的胺的时候，由于空间位阻大，对有些反应很难进行，或者不能一步得到相应的胺，而是得到能够稳定存在的中间态异氰酸酯。
4.对于得到的能够稳定存在的中间态异氰酸酯，可以通过酸碱条件处理得到相应的胺。
