Preparative-Scale Synthesis of Vedejs Chiral DMAP Catalysts

Abstract

A scalable synthesis of chiral Vedejs-type DMAP catalysts is reported. The key step of the synthesis is amination of the enantiomerically pure 4-chloropyridine derivative using well-defined ZnCl 2 (amine) 2 complexes. A series of Zn(II)−amine complexes have been synthesized to explore the scope of the ZnCl 2 -mediated amination of 4-halopyridines. Mechanistic studies support a Zn(II)-facilitated nucleophilic aromatic substitution as a plausible mechanism for the chlorine-to-amine exchange.

Diffusion Control in Single-Site Zinc Reticular Amination Catalysts

“…In the pharmaceutical industry, efficient methods for the production of substituted pyridines by C–Cl amination are urgently needed. , Contemporary synthetic methods as Buchwald–Hartwig or Ullmann-type C–N couplings often require costly, air-sensitive homogeneous catalysts and stoichiometric amounts of base . In this sense, the use of a zinc­(II) Lewis acid (which is cheaper, less toxic, and naturally more abundant than precious metal catalysts) has been reported to activate 4-chloropyridine during nucleophilic aromatic substitutions with amines. , However, these promising results also anticipate the limitations intrinsic to homogeneous catalysis, as the recovery and recycle of the catalyst or the eventual contamination of the product. In order to improve the sustainability and innovate the catalysis of organic transformations, different approaches such as the use of ionic liquids, nanocages, coordination networks, or metal–organic frameworks (MOFs) are bridging the gap between traditional homogeneous and heterogeneous catalysts. − The incorporation of Zn­(II) as a single site (well-positioned and separated) in open frameworks as zeolites, coordination polymers, or MOFs would permit translating this reactivity to the heterogeneous phase for simple separation of the product, thus avoiding its contamination. − …”

“…43 The (reversible) complex formation between the Zn(II) Lewis acid and pyridine Lewis base through the binding of Zn to the pyridine nitrogen has been also proposed for the homogeneous case. 4,5 Finally, the formation of the product after the S N Ar reaction is exothermic by −212.3 kJ mol −1 (Figure 5c). Our simulations suggest that differences in activity are associated with the acid−base properties of the reagents with respect to the linker.…”

“…These sites are available for interaction with the nitrogen lone pair of 4-chloropyridine (see Figure S8), as recently described for homogeneous Zn­(II) complexes . The (reversible) complex formation between the Zn­(II) Lewis acid and pyridine Lewis base through the binding of Zn to the pyridine nitrogen has been also proposed for the homogeneous case. , Finally, the formation of the product after the S N Ar reaction is exothermic by −212.3 kJ mol –1 (Figure c).…”

“…3 In this sense, the use of zinc (II) Lewis acid (which is cheaper, less toxic and naturally more abundant than precious metal catalysts) has been reported to activate 4-chloropyridine during nucleophilic aromatic substitutions with amines. 4,5 However, these promising results also anticipate the limitations intrinsic to homogeneous catalysis, as the recovery and recycle of the catalyst or the eventual contamination of the product. In order to improve the sustainability and innovate in the catalysis of organic transformations, different approaches such as the use of ionic liquids, nanocages, coordination networks or metal-organic frameworks (MOFs) are bridging the gap between traditional homogeneous and heterogeneous catalysts.…”

Acylative Dynamic Kinetic Resolution of Secondary Alcohols: Tandem Catalysis by HyperBTM and Bäckvall’s Ruthenium Complex

“…For practical reasons, we focused on catalysts that would be efficient at room temperature, despite the abundance of reports that favor lower temperature conditions for optimal KR . Among the 12 catalysts screened (see Table S1 of the Supporting Information for a complete list), the highest selectivity ( s = 23) of KR was observed using chiral DMAP 8 developed by Fu et al The second best selectivity ( s = 20) was achieved by HyperBTM catalyst 3 , whereas chiral DMAP catalysts 6 and 7 afforded moderate efficiency in the KR ( s = 4). In contrast, Fu et al’s catalyst 8 turned out to be the least reactive (<2% conversion after 24 h) as compared to the other catalysts (25% conversion within 4 h).…”