Versatile and Enantioselective Preparation of Planar-Chiral Metallocene-Fused 4-Dialkylaminopyridines and Their Application in Asymmetric Organocatalysis

Abstract

A series of ferrocene-fused planar-chiral N-tosyl-4-pyridones (S)-2b–d were prepared in enantiomerically pure forms. Starting with the chiral ferrocenyl acetals, 1-[(2S,4S)-4-methoxymethyl-1,3-dioxan-2-yl]-1′,2′,3′,4′,5′-R5-ferrocenes ((−)-3b, R = Me; (−)-3c, R = Ph; (−)-3d, R = Bn), N-tosylamino and formyl groups were introduced at the 1- and 2-positions of the ferrocene cores in (S)-11b–d with control of the planar chirality. After the reaction with ethynylmagnesium bromide, generated propargyl alcohol derivatives (S)-17 were treated with MnO2 and catalytic tetrabutylammonium iodide to give the planar-chiral pyridones by the iodide-catalyzed cyclization. This method is highly practical with a shorter and higher-yield sequence without using noble metal catalysts. Planar-chiral ferroco-pyridones (S)-2b–d were reacted with various Me3SiNR2 compounds to give a library of ferrocene-fused 4-dialkylaminopyridines ((S)-1, DAAPs) in high yields as single enantiomers by the detosylative amination. The cymantrene-fused DAAPs were also prepared in the same way. The library of chiral DAAPs was examined in the two asymmetric reactions as organocatalysts, and some newly prepared Fc-DAAPs showed better enantioselectivity than the known species.

Oxidative Cyclization of o-(1-Hydroxy-2-alkynyl)-N-tosylanilides for the Synthesis of 4-Quinolones

“…In accordance with this, the geometry at N1 is trigonal pyramidal, and the sum of the three angles at N1 involving C1, C9, and S1 is 343.5°. This is in clear contrast to the structurally characterized 4-pyridone derivatives, in which the pyridone rings are nearly planar. , …”

“…Recently, we have developed a method of preparing ferrocene-fused planar-chiral pyridone/pyridine derivatives in an enantioselective manner (Scheme ). The key reaction step of the synthetic sequence was the intramolecular hydroamination/cyclization of 1-propynoyl-2-( N -tosyl)­amidoferrocene derivatives B . Because B were found to be relatively susceptible, they were not isolated.…”

Ferrocene derivatives with planar chirality and their enantioseparation by liquid‐phase techniques

“…Ferrocene has been considered a privileged framework for the construction of chiral organocatalysts [ 97 ]. Very recently, planar chiral catalysts 10 – 12 (Figure S3 ), featuring ferrocene‐fused nitrogen heterocycles, were developed as systems where the ferrocene backbone provides planar chirality, whereas the heterocyclic moiety maintains its nucleophilic and basic character [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ]. Although chiral ferrocenyl catalysts were developed for a long time in asymmetric noncovalent organocatalysis [ 97 ], it is not until the last 2 years that our groups reported the first examples of halogen bond (XB)‐based chiral ferrocenyl catalysts [ 87 , 106 ].…”

“…Interestingly, both enantiomers of 39 could be enantioseparated by HPLC [ 28 ]. In two more recent publications by the group of Ogasawara and Yoshida, the asymmetric synthesis of 39 and analogues was realized but only the ( S Fc ) enantiomers could be prepared [ 43 , 99 ]. More extended benzoquinoline derivative 40 was also prepared for catalysis purposes and, again, only the ( S Fc ) enantiomer was prepared by asymmetric synthesis [ 149 ].…”

Synthesis and Applications of Ferrocene‐Fused Nitrogen Heterocycles

“…In 2020, the same group developed an alternative approach to ferrocene-fused 4-pyridone derivatives that, at least in part, overcomes those limitations. [34] The key step in this improved sequence is a tetrabutylammonium iodide (TBAI)-catalyzed cyclization of propynoyl-N-tosylaminoferrocenes, generated in situ by manganese dioxide oxidation of the corresponding propargylic alcohols, which in turn are easily available by treatment of the respective optically active aldehydes with ethynylmagnesium bromide (Scheme 7). This sequence afforded the corresponding ferrocene-fused 4-pyridone derivatives as single enantiomers in good overall yield even for substrates featuring sterically demanding (η 5 -C 5 Ph 5 )Fe and (η 5 -C 5 Bn 5 )Fe substructures.…”