Co-catalyzed coupling of alkyl zinc reagents with (hetero)aryl halides
The construction of carbon-carbon bonds is a constant theme in organic synthetic chemistry, in which the transition metal-catalyzed coupling reactions of alkyl carbons have received much attention. The fact that organozinc reagents can tolerate a wide range of functional groups, such as aldehydes, ketones, esters, and cyano groups, as well as their low toxicity and ease of preparation, has made transition-metal-catalyzed Neigishi reactions an important method for the construction of carbon-carbon bonds, and they have been widely used in both academia and industry. Pd catalysts are mostly used in literature reports, and recent studies have shown that Fe, Co or Ni catalysts have great advantages over Pd catalysts for the coupling of alkyl zinc reagents. Recently, Paul Knochel’s group reported that the use of cheap and readily available CoCl₂ (10 mol%) (cas: 7646-79-9, anhydrous, <$400/25 g, sigma aldrich) coupled with the simple ligand 2,2′-bipyridine (20 mol%) (cas: 366-18-7, <$500/100 g) was sufficient to effectively catalyze the reaction. The coupling of straight-chain alkyl and cycloalkyl zinc reagents with (hetero)aryl halides can be efficiently catalyzed by the simple ligand 2,2′-bipyridine (20 mol%) (cas: 366-18-7, <500 metric tons/100 grams), and the reaction can be carried out gently at temperatures ranging from 0ºC to room temperature.
Under these conditions, azaheteroaryl halides (e.g., pyridine and pyrimidine compounds) can be efficiently coupled with a variety of straight-chain alkyl zinc reagents, and functional groups such as double bonds (3c, 3h, 3i, 3r), triple bonds (3d, 3k), cyano (3e), ester groups (3g), acetals (3l), and heteroaromatic rings (3f, 3j) are not affected in zinc reagents, and the reaction is favored by the presence of electron-withdrawing groups in the heteroaryl halides The reaction is favored by the presence of electron-withdrawing groups in the heteroaryl halides, and the more reactive halogen position is preferred (3p).
The heteroaryl halogenates also contain electron-withdrawing groups, and the coupling of cyclopropyl zinc reagents also gave good yields (3y, 3z).
After trying more cycloalkyl zinc reagents, it was found that the reaction not only had good coupling yields, but also very good diastereoselectivity, and usually yielded thermodynamically more stable products. Previous studies have shown that the Zn-C bond is more susceptible to isomerization, and it is assumed that the rapid transmetallation of the thermodynamically more stable alkyl zinc reagent in this reaction contributes to the high stereoselectivity of the product.
The stereoselectivity is also maintained at a high level for complex ring systems.
The reaction can also be extended to alkynyl halides with good yields and selectivity.
In previous work, the use of the radical trapping agent TEMPO significantly inhibited a variety of Co-catalyzed reactions. However, the addition of 2 equivalents of TEMPO did not affect the reaction yields under these conditions, suggesting that this condition has a different reaction mechanism than in the past.
