Enantioselective Synthesis of Planar-Chiral Ferrocene-Fused 4-Pyridones and Their Application in Construction of Pyridine-Based Organocatalyst Library

Abstract

A couple of planar-chiral ferrocene-fused 4-pyridone derivatives 2a and 2b were synthesized in enantiomerically pure form by scalable asymmetric transformations. Pyridones 2 are versatile precursors to various ferrocene-fused pyridine derivatives, which are useful nucleophilic asymmetric organocatalysts.

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

“…The diastereoselective lithiation of (−)-3 using t BuLi followed by a reaction with tosyl azide afforded the corresponding ferrocenyl azide, and the subsequent palladium-catalyzed reduction of the crude azide under a hydrogen atmosphere gave the ferrocenylamine, which was immediately tosylated without purification to provide N-tosylaminoferrocenyl acetal (−)-5 in high yield ranging from 58 to 84%. Acetal (−)-5, purified by silica gel column chromatography, was confirmed to be diastereomerically pure by the 1 H-and 13 C-NMR analyses. The acidcatalyzed hydrolysis of (−)-5 gave the corresponding aldehyde (S)-11 in >92% yield in an enantiomerically pure form.…”

“…In the previous report, we demonstrated that planar-chiral N-tosyl-4-pyridones (S)-2a and (S)-2b were versatile precursors to various pyridine derivatives. 13 The direct conversion of (S)-2b into a series of 4-dialkylaminopyridine derivatives (S)-1bw-bz was achieved by the reaction with an appropriate N-trimethylsilylamine in the presence of titanium(IV) chloride in good to excellent yields (see Schemes 2 and 9). This detosylative amination reaction was also found to be operative for the sterically demanding ferroco-pyridones such as (S)-2c and (S)-2d, and the results are summarized in Scheme 9.…”

“…9i The η 5 -C 5 Me 5 derivatives, (S)-1bw−bz, were prepared by our first-generation synthesis, and their catalytic applications in this reaction were already examined in the previous report. 13 The reported results are included in the table for comparison (entries 1−4). Among them, ferroco-PPY (S)-1bx, which is Fu's original, showed good catalytic activity in the addition reaction to give ester 20 in 90% yield with 92% ee (entry 2).…”

Synthesis and Applications of Ferrocene‐Fused Nitrogen Heterocycles

“…In 2015, Takahashi, Yoshida and co-workers reported an enantioselective synthesis of planar-chiral ferrocene-fused 4pyridones, which were subsequently converted into enantiomerically pure ferrocene-fused pyridine derivatives. [32] The developed sequence to planar-chiral 4-pyridone-fused ferrocenes is shown in Scheme 5. Initially, an adaptation of Kagan's method for preparing enaniomerically enriched 2-substituted ferrocenecarboxaldehydes [33] allowed the authors to access amino-substituted ferrocene derivatives, which were subjected to a conventional three-step tosylation/allylation/deprotection of the acetal function sequence delivering the corresponding Nallyl-N-tosylaminoferrocenecarbaldehyde derivatives.…”

Enantioselective Synthesis of Ferrocene‐ or Cymantrene‐Fused Planar‐Chiral Phospholes

“…These planar‐chiral N‐heterocycles have been demonstrated to be excellent asymmetric organocatalysts or chiral ligands. Recently, we have developed a novel and efficient method of preparing Fu's planar‐chiral 4‐(dialkylamino)pyridine derivatives in an enantioselective fashion . Two features of our synthetic strategy are: (i) introduction of proper substituents at the 1‐ and 2‐positions of a ferrocene platform with controlling its planar chirality utilizing a chiral ortho ‐directing group, and (ii) construction of a six‐membered N‐heterocycle by a ring‐closure reaction between the two substituents at the 1‐ and 2‐ferrocenyl positions (Figure , bottom).…”