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

由于具有a-支链结构的胺类化合物广泛存在于天然和人工生物活性化合物中，而且许多胺类化合物都以光学活性形式存在，因此发展它们的合成方法是非常必要的。亚胺类化合物的合成，即亚胺的亲核加成和还原反应，是一种很有用的方法，因为亚胺类化合物是一种亲电底物。然而，我们已经发现，(η^2-亚胺)Ti(O-i-Pr)_2与二价钛试剂Ti(O-i-Pr)_4/2I-PrMgCl形成的配合物可以与多种亲电试剂如醛、亚胺、腈、炔反应，其中，这些配合物，即起始的亚胺，可以起到亲核作用。基于这类配合物具有独特的缩合反应活性，我们开展了合成α支化胺的立体选择性新方法的研究，发现如下反应：(1)(η^2-亚胺)钛(O-i-Pr)_2配合物与丙基…反应更多的甘醇衍生物得到α-烯丙基胺，其中从手性亚胺开始的络合物的反应以高度非对映选择性的方式进行。在铜的催化下，生成的α-烯丙基胺可有效地环合成3-吡咯烷。(2)(η^2-亚胺)Ti(O-i-Pr)_2与3，3-二乙氧基丙炔反应生成2-芳基吡咯。以芳醛、伯胺、3，3-二乙氧基丙炔和Ti(O-i-Pr)_4/2I-PrMgCl试剂为原料，一锅法合成2-芳基吡咯。反应机理研究表明，该反应涉及到4-钛化的2-芳基吡咯中间体的形成。(3)具有烯和亚胺结构的分子与Ti(O-i-Pr)_4/2I-PrMgCI试剂反应，生成相应的(η^2-亚胺)Ti(O-i-Pr)_2络合物，并与烯烃发生插入反应，生成双环钛环戊烷，再与甲醛反应生成具有较高立体选择性的双环吡咯烷。(4)芳醛亚胺与0.6~0.7当量的Ti(O-i-Pr)_4/2I-PrMgCl试剂通过相应的(η^2-亚胺)Ti(O-i-Pr)_2络合物反应，得到具有较高dl-选择性的1，2-二芳基-1，2-二胺。(5)在Ti(O-i-Pr)_4存在下，用CaH_2/α_2复合试剂可以将亚胺和酮还原为相应的胺和醇。这是第一个直接利用CaH_2还原有机分子的例子。较少

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