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

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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