低价钛介入下脂肪族酰胺和脂肪族醛/酮的还原偶联反应研究

Amide would receive two electrons from low valent titanium quickly and irreversibly to form an amide dianion prior to any electron transfer to an aliphatic aldehyde/ketone carbonyl,so long as second reduction potential of amide is adjusted to less negative than a aldehyde/ketone carbonyl by means of electronic effect of the substituents attached to amide nitrogen,consequently, leading to a dianion coupling mechanism and this process would permit the selectivity controlling.The nucleophilic addition of amide dianion to aldehyde/ketone carbonyl resulted in titanium pinacolate,with its two oxygens both coordinating to a "same" active titanium particle surface,this template effect would ensure the subsequent deoxygenative elimination.Following this line of reasoning,the project is aiming at the development of McMurry coupling between various aliphatic amides and aliphatic aldehydes/ketones effected with an active titanium species which is prepared from "instant" reduction of TiCln(n=3,4) coordinating to both coupling partners.On the basis of extensive investigations of various reaction conditions,substrate generality,functlonal-group compatibility, and contrast experiments with designed substrates bearing appropriate structural probes, meanwhile, with the help of electronchemical investigations and spectroscopic methods,a possible mechanism for such intermolecular amide-aldehyde/ ketone coupling processes would be proposed,thus,the corresponding synthetic methodology have been developed.Extending this cross coupling reaction to intramolecular contexts,the approaches to cyclic enamines should be established, in turn, [m.n.0]-bicyclo-1-azaalkane ("izidine") structural motif embedded within numerous known alkaloids can also be constructed.

利用酰胺氮原子上取代基的电性效应,调节酰胺羰基的还原电位以及与低价钛试剂的配位作用,只要其第二还原电位小于脂肪族醛/酮的还原电位,酰胺羰基即可快速、不可逆地从低价钛试剂接受两个电子生成双负离子中间体,促使反应按照双负离子机理进行,实现反应的选择性控制;酰胺双负离子对醛/酮亲核加成形成钛频哪醇盐中间体,低价钛试剂的模板效应促使其氧原子在同一活性钛粒子表面配位,利于随后的脱氧消除。本项目通过原位还原与偶联组分配位的钛试剂,形成"瞬间的"低价钛物种促进脂肪族酰胺和脂肪族醛/酮的还原偶联,系统考察各种反应条件对该分子间McMurry偶联的影响、反应的底物普适性和官能团耐受性,设计各种对比实验,结合电化学实验和谱学方法,验证可能的反应机理,建立酰胺与醛/酮间交叉还原偶联的方法学;通过脂肪族酰胺和醛酮的分子内偶联,建立环烯胺的合成方法,并尝试用于[m.n.0]-双环-1-氮杂烷烃生物碱骨架的构建。

低价钛试剂广泛应用金属介入的有机合成中，人们对基于低价钛的pinacol偶联、McMurry反应进行了广泛深入的研究，已成为天然产物合成中不可或缺的碳-碳键构建工具。然而在低价钛介入下，两种不同羰基化合物间(尤其是酰胺羰基和醛/酮羰基)间交叉的还原偶联还比较少见，由于醛/酮羰基接受单电子转移的活性远高于酰胺羰基，在正常的McMurry条件下，醛/酮的自身偶联不可避免。本项目计划酰胺氮原子取代基的电子效应，调节酰胺羰基的还原电位以及与低价钛试剂的配位作用，使酰胺羰基的第二还原电位，在醛/酮羰基的存在下，低价钛试剂选择性地对酰胺羰基的快速、不可逆地转移两个电子，生成双负离子中间体，完成酰胺羰基和醛/酮羰基的交叉还原偶联反应，建立酰胺羰基烯化的合成方法学，并用于脂肪氮杂环的合成。在项目的实施过程中，主要研究工作均按原申请书计划进行。经过两年的艰辛工作，对低价钛介入下脂肪族醛/酮和酰胺之间的交叉还原偶联反应进行了较为系统的探索研究，发现脂肪族醛/酮羰基和脂肪族酰胺羰基间的直接交叉偶联存在很大的挑战，经过反复实验，未能实现酰胺羰基的直接烯化。我们尝试了硫缩醛和酰胺羰基的分子内还原偶联，未能得到相应的偶联烯化产物，发现了低价钛试剂作用下硫缩醛部分还原脱硫生成硫醚的反应；研究发现，在丁基锂作用下，硫缩醛经α-消除生成卡宾活性中间体，进而发生分子内C-H键的插入反应，生成5/6稠合的含氮杂环化合物，可用于swainsonine等吲哚里西啶生物碱骨架的构建。同时，我们考察了FeCl3催化下烯烃和酰胺羰基的交叉复分解反应，完成脂肪族酰胺的间接烯化，实现了预期的研究目标。