A nitrogen-containing heterocycle is a heterocycle containing at least one nitrogen atom. Nitrogen heterocycles can be aromatic, saturated or unsaturated. They are also grouped according to ring size, as ring size is related to their properties, reactivity, and stability. Common nitrogen-containing heterocycles include pyrazine, pyridine, pyrimidine, etc.
Recently, it has been reported that the domino coupling reaction can stereoselectively generate 5-7 membered nitrogen-containing heterocyclic rings and 5-6 membered carbocyclic rings, providing new efficient synthetic method of multi-substituent pyrrolidine, piperidine, and tetrahydroazepine rings. Among them, multi-substituted pyrrolidine and piperidine are common structural skeletons in small molecule drug molecules.
The researchers found that Josiphos L1 or L2 coordinated palladium catalysts can catalyze the domino cyclization-alkynylation reaction of non-conjugated iododiene 1a to generate pyrrolidine products, avoiding related side reactions as much as possible. Using the optimized Josiphos L2 palladium catalyst, the researchers obtained a variety of polysubstituted pyrrolidine products, including electron-rich aromatic rings, electro-deficiency aromatic rings, thiopheneacetylene, pyridine, quinoline pyrimidine and other nitrogen-containing heterocyclic terminal alkynes.
The domino coupling reaction of non-conjugated iododiene to generate tetrahydropyridine product also has good substrate universality. Tetrahydropyridine products can have ethyl, benzyl and ethyl ester groups, as well as phenyl and cyclohexyl groups. Alkyl-terminal alkynes can also react, and the corresponding domino-alkynylated products are obtained in high yields and high enantioselectivities. This reaction is also compatible with aldehyde and hydroxyl active functional groups. The palladium catalyst with Josiphos L4 as a ligand can also use 2-iodo-1,7-diene and (Z)-1-iodo-1,7-diene as substrates to obtain piperidine and tetrahydroxaline products , and the substituent phenylacetylene, heterocyclic alkynes with different electrical properties have achieved good results.
Finally, the researchers used malonate iododiene to construct the full carbocycle, and under the action of Josiphos L3 palladium catalyst, the target full carbocycle product was obtained with high yield and high enantioselectivity.
The study of the reaction mechanism shows that the silver phenylacetylene species generated in situ from phenylacetylene is involved in the transmetallation, and the transmetallation needs the help of potassium carbonate. At the same time, the alcohol solvent and the tetrabutylamine salt help the dissociation of the alkene-based palladium iodide to generate cationic palladium species B. In the catalytic cycle, first, substrate 1a undergoes oxidative addition to produce species A, and under the action of alcohol solvent and tetrabutylamine salt, cationic palladium species B is generated, and its 5-exo-trig migrates and inserts into intermediate C after cyclization, transmetallation with in situ generated silver phenylacetylene to obtain intermediate D and further reductive elimination to generate the target compound 2a.
Finally, the researchers derivatized the pyrrolidine compounds generated by the reaction to realize oxidation, isomerization, and epoxidation and cyclization reactions. Some of the ring-joined compounds and bridged ring compounds obtained after derivatization of products are the core structural skeletons of small molecule drugs or lead compounds with important biological activities.
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Reference
- Catalytic Enantioselective Domino Alkenylation-Alkynylation of Alkenes: Stereoselective Syntheses of 5-7 Membered Azacycles and Carbocycles
Sci. China Chem., 2023
