Asymmetric Lithiation of Boron Trifluoride-Activated Aminoferrocenes: An Experimental and Computational Investigation

• Published in: Advanced synthesis & catalysis 2010-10, Vol.352 (11-12), p.1967-1982
• Main Authors: Metallinos, Costa, Zaifman, Josh, Dudding, Travis, Van Belle, Lori, Taban, Keivan
• Format: Article
• Language: English
• Subjects: 1,2‐diaminocyclohexanes; 2-diaminocyclohexanes; aminoferrocenes; asymmetric synthesis; Asymmetry; Boron; boron trifluoride; Catalysis; Computation; Diamines; Ligands; lithiation; Mathematical models; planar chiral; Recrystallization
• ISSN: 1615-4150; 1615-4169; 1615-4169
• DOI: 10.1002/adsc.201000306

Tertiary aminoferrocenes complexed to boron trifluoride (BF3) are shown to undergo asymmetric lithiation with alkyllithiums in the presence of bulky chiral 1,2‐diaminocyclohexane ligands. This reaction represents the first BF3‐activated asymmetric lithiation of a prochiral aromatic amine and the first such transformation to be mediated by a chiral diamine other than (−)‐sparteine. The process provides rapid access to a broad range of enantiomerically enriched 2‐substituted‐1‐aminoferrocenes, including derivatives with uncommon substitution patterns that are of interest in catalysis. The enantioselectivity of the process is high enough (87:13 to 91:9 er) to allow for isolation of single enantiomers of several products after simple recrystallization as either the free aminoferrocenes or their ammonium fluoroborate salts. Both antipodes of the planar chiral 2‐substituted‐1‐aminoferrocene products are accessible, as confirmed by single crystal X‐ray diffraction analysis of two compounds with opposite relative stereochemistry. Single‐point calculation of thirty‐two different transition states of the reaction at the M06‐2X/6‐311+g(2d,2p) level produced a computational model that correctly predicted both the sense and extent of chiral induction. Three factors appeared to play important roles in determining enantioinduction during lithiation of BF3‐complexed tertiary aminoferrocenes: (i) the maintenance of a highly organized eight‐membered ring transition state; (ii) the existence of a strong Li⋅⋅⋅F contact which placed the chiral diamine ligand in close proximity to the ferrocene substrate; (iii) the orientation of the sterically demanding N‐alkyl groups of the chiral diamine additives, either away or towards, the aminoferrocene and the alkyllithium. The model may serve as a predictive tool for the rational design of new ligands for this and related asymmetric lithiations.