Achiral imines additions

Scheme 17 Asymmetric synthesis of 2,3-diaminoacids by the addition of a chiral imi-noester enolate to achiral imines...

Catalytic Asymmetric Nucleophilic Addition to Achiral Imines (15... 

Catalytic Asymmetric Nucleophilic Addition to Achiral Imines 37 Table 1.18 Addition of a lboronic adds to N tosyl imines. 

The ionic liquid [bmim][BF ] is known to catalyze the aza-Diels-Alder reaction in the synthesis of pyrano- and furanoquinolines [190]. This reaction was also catalyzed by the enantiopure bis-imidazolinium salt 67 in 67% yield with an endo. exo ratio of 60 40 (Scheme 69) [191]. The product was obtained as a race-mate. In addition the aza-Diels-Alder reaction with imines and Danishefsky s diene was catalyzed by the salt 67 giving racemic product. The salt and its analogues could be easily prepared via the oxidation of the corresponding aminals [192]. Investigation of the influence of the counter anion in achiral C2-substituted imidazolinium salts, which can be also described as 4,5-dihydroimidazolium or saturated imidazolium salts, in the aza-Diels-Alder reaction showed, that the catalytic activity increased, the more lipophilic the counter anion and therefore the more hydrophobic the salt was [193]. 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

A library of chiral zinc complexes formed in situ by the combination of achiral and racemic diimines with 3,30-di(3,5-ditrifluoromethylphenyl)-BINOL and diethylzinc have been evaluated in the asymmetric addition of diethylzinc to V-acylimines.126 High enantioselectivities of up to 97% ee and yields of up to 96% have been achieved for a wide range of aromatic imines in dichloromethane at -30 °C. 

Hence, the initial reactions were conducted using BINOL-phosphate 5 in combination with various achiral Brpnsted acids, including pro-tonated pyridine derivatives, alcohols and acids. Best enantioselectiv-ities were observed with the addition of carbonic acids, phenol and hexafluoro isopropanol which provided the isoquinuclidines 28 with up to 88% ee. Further explorations concentrated on varying the reaction parameters including different protected imines, catalyst load-... 

It is interesting to note that catalyst derived from imines of 2,4,6-trunethylbenzaldehyde were found to result in the most enantioselective catalysts with resolved, achiral, and meso ligands in the asymmetric addition (Figme 15 and Table 4). This suggests that the placement and orientation of the 2,4,6-trimethylphenyl groups plays a crucial role in the stereoinduction. 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

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