Iron-catalyzed zincation of terminal alkynyl vinyls
Organozinc reagents are among the most commonly used metal reagents in modern synthetic chemistry. Carbon-zincification of alkynes is an important method for the synthesis of organozinc reagents, but problems such as the inability to tolerate the hydrogen of the terminal alkynes and the difficulty of converting the introduced carbon groups are common, which severely limit the application of this reaction. Catalytic vinyl zincation of alkynes, which can introduce easily transformable alkenyl and zinc at both ends of the alkynes simultaneously, has important application potential in synthesis. However, multiple challenges need to be overcome to achieve the vinyl zincation reaction of terminal alkynes (Fig. 1B): (1) the acidic hydrogen of the terminal alkynes is capable of quenching the catalyst or undergoing a displacement reaction with the zinc reagent; (2) the terminal alkynes are susceptible to dimerization under the action of transition metal catalysts to generate alkenyl compounds; (3) the alkenyl zinc product may further undergo alkenyl zincation with the alkynes to generate alkenyl zwitterionic products; and (4) zinc reagents under the catalyzed by transition metals may generate free radicals, resulting in difficult control of the stereoselectivity of the reaction.
Recently, Shoufei Zhu’s group at the School of Chemistry, Nankai University, developed a 1,10-phenanthroline-imine ligand-modified iron catalyst, which realized for the first time the challenging vinyl zincation reaction of terminal alkynes (Fig. 1C), and provided a new and highly efficient method for the synthesis of organo-zinc reagents and polysubstituted conjugated olefins. With very good functional group tolerance and substrate universality, this reaction was successfully used for the facile synthesis of important bioactive molecules such as vitamin A, which significantly improved the synthesis efficiency. The research results were recently published in J. Am. Chem. Soc. and selected as JACS Spotlights by the editors, and Dr. Qiang Huang was the first author of this paper.
1. Catalytic zincation of terminal alkynyl vinyls
It was found that iron complexes of o-phenanthroline-imine exhibited high catalytic activity in model reactions, especially catalysts C1-C3 with a large site resistance 2,4,6-triisopropylphenyl at the 9-position of the o-phenanthroline skeleton and catalyst C6 with 2,4,6-trimethylphenyl could afford vinyl zincylation product 2 in nearly quantitative yields and with a single regioselective and stereoselective character (Fig. 2). Other tridentate ligands, bidentate nitrogen ligands, monophosphine ligands and bisphosphine ligands do not give good results. The activity and selectivity of the reaction were significantly reduced by replacing the center metal iron in the C3 catalyst with other metals.
2. Reaction optimization
Under optimal conditions, the researchers examined the substrate range. The reaction has good functional group tolerance with methoxy, amine, silyl, sulfhydryl, ester, acyl, amide, cyano, sulfone, acetal, trifluoromethyl, and halogen. Alkynyl substrates with functional groups with active protons (-NHMe, -OH) also react smoothly. Thick ring substituted acetylenes (2-naphthylacetylene) and aromatic heterocyclic substituted acetylenes (furan, thiophene, pyridine, indole substituted acetylenes) give equally good results. In addition to vinyl zincs, other alkenyl zincs can be used in this reaction, with β-alkyl, α-alkyl, bis-alkyl, and aryl-substituted vinyl zinc reagents being less reactive in that order.
3. Iron-catalyzed alkenyl zincation of aryl-terminated alkynes
In addition to aryl-substituted terminal alkynes, conjugated alkynes, aliphatic terminal alkynes, and energetic grouped alkynes are also able to undergo vinyl zincation smoothly under the promotion of iron catalysts, and the corresponding products are given in high yields and with high regioselectivities and stereoselectivities.
4. Iron-catalyzed vinyl zincation of other terminal alkynes
The reaction shows good functional group tolerance and can be used in the late modification of multifunctionalized drug molecules. Rivaroxaban, dronedarone, febuxostat, duloxetine, estrone and onyx derivatives were able to give the corresponding vinyl zincated products 2ga-2gf in good to high yields and excellent selectivity.
5. Post-modification of drug molecules
The method has good potential for application in synthesis. The C-Zn bond in the product can undergo a series of transformations, including alkylation, arylation, allylation, alkynylation and addition reactions, to efficiently generate a variety of multisubstituted conjugated olefins (. This reaction has also been successfully applied to the highly efficient and selective synthesis of a variety of biologically active molecules, including vitamin A and its derivatives, with a significant improvement in synthetic efficiency compared to the literature methods.
6. Application of iron-catalyzed vinyl zincation reaction
The researchers conducted a systematic study of the mechanism: the structures of the organozinc products were characterized; the hydrogen of the terminal alkynes was found to be easily exchanged with the zinc reagent, and the iron catalyst could inhibit this background reaction; deuterium band labeling experiments showed that there was no H-D exchange between the substrate and the product; and the vinyl zinc could reduce Fe(II) precursors to Fe(I) activated catalysts. dft calculations showed that the activated iron species were in the open-shell layer tetrad (S = 3/2) mode to catalyze the reaction; the activation energy of β-addition (10.9 kcal/mol) is 10.0 kcal/mol higher than that of α-addition (0.9 kcal/mol), and the activation energy of the secondary insertion (10.6 kcal/mol) is also much higher than that of the primary insertion (0.9 kcal/mol); the analysis of the transition state structure and the frontline orbital analysis reveals that the dz2 orbital of Fe in TS1 has p-π conjugation with the π orbital of o-phenanthroline, resulting in a more dispersed charge and therefore a lower energy. Overall, the crowded reaction cavity constructed by the ligand and the smaller atomic radius of the Fe atom enable the Fe catalyst to accurately recognize the difference between the two substituent groups at the ends of the alkynes, giving high regioselectivity; and the open-shell layer structure of the Fe catalyst significantly lowers the transition state energy barrier of the reaction, reducing the competing reactions such as substitution of end-alkynyl acidic hydrogens with the zinc reagent, polymerization of alkynes, and further zinc zinc allylic product zeolites, and thus realizing high The chemical selectivity is thus high.
7. Mechanical studies
In conclusion, Shoufei Zhu’s group developed a tridentate nitrogen ligand and iron complex catalyst based on 1,10-phenanthroline-imine skeleton to realize the vinyl zincation of terminal alkynes for the first time. The reaction has excellent functional group tolerance and substrate universality, as well as good chemoselectivity, regioselectivity and stereoselectivity. The conjugated alkenyl zinc products can undergo various transformations and have been successfully used in the synthesis of a variety of natural products and pharmaceutical intermediates, which significantly enhanced the synthesis efficiency. Mechanistic studies have shown that the rigid structure of the 1,10-phenanthroline-imine ligand, the smaller ionic radius of the iron ions, and the open-shell layer structure of the iron catalyst are crucial for the reaction to achieve excellent results. This study expands the types of iron-catalyzed reactions, deepens the understanding of the mechanism of iron-catalyzed reactions, and enriches the synthetic methods and types of organozincs, which is of great significance for the development of both iron-catalyzed reactions and metal-organic reagents.
