Piperidine and pyridine are the two most common nitrogen heterocyclic compounds. Therefore, cost-effective methods for the synthesis of piperidines and pyridines are of crucial importance and of general research interest to chemists and related researchers. Amine refers to the product of one or more hydrogen atoms in the ammonia molecule being replaced by a hydrocarbon group; amines are widely found in the biological world and have extremely important physiological and biological activities. For example, proteins, nucleic acids, antibiotics and alkaloids are all derivatives of amines, and most drugs used clinically are also amines or derivatives of amines. Dihydropyridine (DHP) is a highly researched compound in the field of chemical and biomedical research. 1,2- and 1,4-dihydropyridines are the most common DHP isomers. However, since the available synthetic methods are very limited, especially the methods with good enantioselectivity are less reported, the research to develop new synthetic methods for 1,2-dihydropyridine (1,2-DHP) is of great importance.
Previous studies have shown that 1,2-dihydropyridines can be prepared by nucleophilic addition of pyridinium salts. However, the preparation of multi-substituted pyridines by this method is limited due to the regioselectivity of nucleophiles, and the synthesis of 1,2-dihydropyridines with different substitution positions still faces certain challenges. Therefore, the method of directly constructing 6-membered nitrogen-containing heterocycles from carbon chain backbones has become the most important strategy for functionalizing DHPs. Distinguished from the source of cyclization, the synthesis of DHP can be divided into chain condensation or fragment condensation. Although chain condensation can give functionalized substituted DHPs, the construction of condensed chain precursors is difficult and challenging due to the multi-step synthesis required. The fragment condensation approach has the distinct advantage of being able to obtain different substitution patterns from more readily available "subunits". Although these reactions can give great structural diversity, excellent stereoselectivity remains challenging.
Recently, asymmetric 1,2-dihydropyridines were efficiently synthesized by chiral gold-catalyzed amine tandem addition diyne-alkene cyclization.
This gold-catalyzed amination reaction tolerates a wide variety of diacetylene-enyl substrates and affords 1,2-DHP in high yield. Substituents on diynylene substrates have a strong effect on regioselectivity. Based on the good enantioselectivity (d.r. > 20:1), the researchers focused on asymmetric synthesis. With (rac)-1u (racemate), excellent enantioselectivity was observed, giving the product with d.r. values >20:1. Chiral (S)-1u (98% e.e.) was prepared from chiral allylamine by reaction with benzyl carbamate followed by hydrogenation to give chiral piperidine (98% e.e.).
Gold-catalyzed asymmetric amide tandem addition was achieved by R-DTBM-SEGPHOS(AuCl)2, and various functional group-modified bis-alkyne-enyl substrates were suitable for this conversion reaction, which can give 1,2-DHP with excellent enantioselectivity.
The reaction with aliphatic alkynes has good stereoselectivity in the initial addition reaction. The modified styrenes performed well, with excellent enantioselectivity. The absolute stereochemistry of the final product was confirmed by X-ray diffraction to be the R configuration. Notably, the application of chiral bisamides and R- and S-chiral gold catalysts gave good enantioselectivity, confirming that this stereoselectivity is related to catalyst control (rather than substrate control).
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Reference
- Gold-Catalyzed Amine Cascade Addition to Diyne-Ene: Enantioselective Synthesis of 1,2-Dihydropyridines
Angew. Chem. Int. Ed., 2023
