Stereoselective Synthesis of a-Branched Amines Based on Formation of Azatitanacyclic Compounds

由于具有α-支链结构的胺广泛分布于天然和人工生物活性化合物中，并且它们中的许多以它们的光学活性形式存在，因此期望开发它们的合成方法。以亚胺为亲电底物，通过亚胺的亲核加成和还原反应合成该类化合物，是合成该类化合物的有效方法之一。而由亚胺和二价钛试剂Ti（O-i-Pr）_4/2 i-PrMgCl反应生成的（η^2-亚胺）Ti（O-i-Pr）_2配合物，与醛、亚胺、腈、炔等亲电试剂反应，起始亚胺可以作为亲核试剂。基于这类配合物独特的极化活性，我们开展了以立体选择性合成α-支链胺为目的的研究，发现了如下反应：（1）（η^2-亚胺）Ti（O-i-Pr）_2配合物与丙烯酰胺反应，得到α-支链胺的立体选择性合成新方法 ...更多信息 以手性亚胺为起始原料，通过与乙醇衍生物反应，得到α-联烯胺，反应具有高度的非对映选择性。研究了Cu催化的α-联烯胺环化反应。（2）（η^2-亚胺）Ti（O-i-Pr）_2配合物与3，3-二乙氧基丙炔反应生成2-芳基吡咯。本文还研究了以芳醛、伯胺、3，3-二乙氧基丙炔和Ti（O-i-Pr）_4/2 i-PrMgCl为原料合成2-芳基吡咯的一锅法。反应机理的研究表明，反应中生成了4-钛酸酯化的2-芳基吡咯中间体。（3）具有烯和亚胺结构的分子与Ti（O-i-Pr）_4/2 i-PrMgCl试剂的反应通过形成相应的（η^2-亚胺）Ti（O-i-Pr）_2配合物及其与烯烃的插入反应得到双环钛环戊烷，后者与甲醛反应得到双环吡咯烷，产率高，立体选择性高。（4）芳醛亚胺与0.6-0.7当量的Ti（O-i-Pr）_4/2 i-PrMgCl试剂反应，通过相应的（η^2-亚胺）Ti（O-i-Pr）_2配合物，高选择性地生成1，2-二芳基-1，2-二胺。(5)It在Ti（O-i-Pr）_4存在下，CaH_2/ZnX_2可将亚胺和酮还原为相应的胺和醇。与酮亚胺的反应以优异的产率提供α-支链胺。这是第一个直接利用CaH_2还原有机分子的例子。少

Since amines with a-branched structure are widely distributed in natural and artificial biologically active compounds and many of them exist as their optically active form, development of their synthetic method is desired. Imine-based synthesis of them, that is nucleophilic addition and reduction reaction of imines, is one of the useful methods, where imines act as an electrophilic substrate. Whereas, we have found that (η^2-imine)Ti(O-i-Pr)_2 complexes which can be generated from imines and a divalent titanium reagent, Ti(O-i-Pr)_4/2i-PrMgCl, react with a variety of electrophiles such as aldehydes, imines, nitriles, alkynes, where the complexes, i.e., starting imines, can act as a nucleophile. Based on such type complexes having their unique umpoling reactivity, the investigation purposing development of new stereoselective method for synthesizing α-branched amines was carried out and we could found the following reactions : (1)The (η^2-imine)Ti(O-i-Pr)_2 complexes reacted with propar … More gyl alcohol derivatives to give α-allenylamines, where the reaction of complexes starting from chiral imines proceeded in a highly diastereoselective manner. The efficient Cu-catalyzed cyclization reaction of the resulting a-allenyl amines to 3-pyrrolines has also been developed. (2)The (η^2-imine)Ti(O-i-Pr)_2 complexes reacted smoothly with 3,3-diethoxypropyne to afford 2-arylpyrroles. One-pot procedure for preparing 2-arylpyrroles from arylaldehydes, primary amines, 3,3-diethoxypropyne and a Ti(O-i-Pr)_4/2i-PrMgCl reagent has also been developed. Mechanistic investigation by the reaction with a deuterated starting imine and/or quenching with D_2O revealed that the reaction involves formation of 4-titanated 2-arylpyrrole intermediates. (3)The reaction of molecules having ene and imine structures with a Ti(O-i-Pr)_4/2i-PrMgCI reagent proceeded via formation of the corresponding (η^2-imine)Ti(O-i-Pr)_2 complex and its insertion reaction with alkene to provide the bicyclic titanacyclopentanes, which reacted with formaldehyde to yield bicyclic pyrrolidines in good yields with a high stereoselectivity. (4)The reaction of arylaldehyde imines with 0.6-0.7 equivalent of a Ti(O-i-Pr)_4/2i-PrMgCl reagent proceeded through the corresponding (η^2-imine)Ti(O-i-Pr)_2 complexes to give 1,2-diaryl-1,2-diamines with a high dl-selectivity. (5)It was found that imines and ketones could be reduced to the corresponding amines and alcohols by a combination reagent CaH_2/ZnX_2 in the presence of Ti(O-i-Pr)_4. The reaction with ketimines provided α-branched amines in an excellent yield. This was the first example for direct use of CaH_2 to reduce organic molecules. Less