Resistant anionic effects of zinc reagents dominate cobalt-catalyzed radical graft coupling processes

Resistant anionic effects of zinc reagents dominate cobalt-catalyzed radical graft coupling processes
Sulfonyl groups, as one of the extremely important pharmacophores, are widely present in various drug molecules. Therefore, synthetic chemists have developed various synthetic strategies around how to introduce sulfonyl fragments efficiently and highly selectively. Among them, the strategy to synthesize sulfone compounds by using sulfonyl chloride, which is widely available, as a sulfonyl source and realizing the precise C-S/C-C bonding reaction of olefins under transition metal catalysis still faces the following challenges: i) the existence of a competitive coupling reaction between organometallic reagents and sulfonyl chloride; ii) the atom transfer radical addition reaction of olefins ( ATRA) inhibits the subsequent carbon-carbon bonding process; and iii) difficulty in avoiding the β-H elimination process of the intermediate Csp3-[M]. In order to solve the above challenges, the team of Prof. Jie Li at Soochow University has realized the controlled conversion of zinc reagents in the overmetallic cobalt-catalyzed coupling reaction by precisely regulating the reactivity of organozinc reagents with the strategy of resisting the anionic effect, effectively inhibiting the occurrence of the above competing processes, and efficiently realizing the carbon-sulfonation of olefins in simple and mild conditions to construct a variety of sulfone compounds
Sulfonylation of olefins by anionic ligand modulation strategy

Firstly, the authors chose 4-methoxystyrene 3a as the olefin and reacted it with zinc phenylpivalate reagent 1a and p-toluenesulfonyl chloride 2a, and screened the relevant reaction conditions. When CoI2 (10 mol%) was used as catalyst and reacted in acetonitrile at 23 °C for 12 h, the phenylsulfonylation product 5 of the olefin could be obtained in 86% isolated yield.However, when the phenyl zinc pivalate reagent was replaced by the conventional halogen-coordinated phenyl zinc reagent, there was a significant decrease in the yields of all the target products 5, however, a direct arylation of sulfonyl chloride, 4, was obtained as the main product. It is noteworthy that the two cobalt-catalyzed reaction pathways can be effectively modulated by varying the ratio of halogen (Br) to pivalate ion (OPiv) in the zinc reagent Ph-Zn(Br)n%(OPiv)(100-n)%: for example, as the ratio of bromide ions increases gradually, the two-component coupling reaction becomes the main reaction; as the ratio of bromide ions increases gradually, the two-component coupling reaction becomes the main reaction; and as the ratio of pivalate ions increases, the two-component coupling reaction becomes the main reaction. For example, the two-component coupling reaction became the main reaction with the gradual increase of the proportion of bromide ions, and the three-component radical graft coupling reaction became the main reaction with the increase of the proportion of valeric acid ions, which effectively suppressed the direct sulfonation process of the zinc reagent. This demonstrates the important influence of the counterbalancing anion effect on the activity of aryl zinc reagents and the regulation of cobalt-catalyzed reaction pathways.

In order to deeply understand the cobalt-catalyzed olefin radical graft coupling process, Prof. Lan Yu’s team carried out systematic theoretical calculations for the reaction system. The DFT calculations matched with the synchrotron radiation experimental results, which again verified that the reaction process was initiated by the monovalent cobalt reactive species, which involves a one-electron transfer process to generate the sulfonyl radical, and alkyl radicals were obtained by free radical addition to olefins. that the divalent cobalt species oxidized by single electron oxidation with zinc reagents undergoing transmetallation with alkyl radicals undergoes a more favorable radical substitution process than the radical addition/reduction elimination process. Therefore, a cobalt-catalyzed radical graft coupling process of olefins via Co(I/II/I) cycle was proposed (Figure 4).
Subsequently, the authors expanded the range of applicability of the reaction substrates (Fig. 5). The experimental results showed that all types of electrically different substituents substituted aryl olefins were well compatible, and the target arylated sulfonylation products were obtained in moderate to excellent yields. In addition, the authors examined the suitability of sulfonyl chlorides and showed that both alkyl sulfonyl chlorides and (hetero)aryl sulfonyl chlorides gave the target products in high yields. Notably, alkyl-substituted 1,3-butadiene substrates at position 2 or 3 were able to give 1,4-arylated sulfonylated products in high reactive sites, stereoselectivity and high reaction yields. Examination of the general applicability of zinc pivalate reagents revealed that aryl or heteroaryl zinc pivalate reagents with various functional group substitutions were able to promote the reaction well, showing excellent reactivity and broad-spectrum applicability. In addition, alkyl or benzyl zinc pivalate reagents were also able to carry out the carbenesulfonation of olefins without difficulty, but the target products were obtained in relatively low isolated yields due to the inherent challenges of Csp3-Csp3 coupling. The catalytic system can be scaled up to the gram scale without difficulty and with only a slight decrease in reaction yield. Finally, in order to illustrate the usefulness of the synthetic method, the authors carried out the subsequent derivatization of the

carbonsulfonylated products by selective double hydroxylation and oxidation, which can provide an effective synthetic method for the rapid construction of complex skeletons; at the same time, the synthetic method can be applied to the “integrated” late-structural modification of complex molecules, such as a variety of drug molecules and complex natural products, to develop the “integrated” and “integrated” structure of complex molecules. At the same time, the method can also be applied to the “integrated” post-structural modification of complex molecules, such as many drug molecules and complex natural products, which demonstrates that the synthesis method has