Ruthenium-Catalyzed Ligand-Enabled Regiodivergent Difluoroallylation of Aryl C-H Bonds.

The gem-difluoroallyl group is a sought-after structural motif commonly found in pharmaceutical compounds. Despite its appeal, achieving a controlled synthesis of both α,α- and γ,γ-difluoroallylated compounds has proven to be a challenging task. This study presents a new approach to difluoroallylation, which utilizes a regiodivergent C-H bond reaction catalyzed by ruthenium catalysis. This method enables the meta and ortho C-H α,α- and ortho C-H γ,γ-difluoroallylation of arenes using 3-bromo-3,3-difluoropropenes.

Palladium-Catalyzed gem-Difluoroallylation Reaction between Aryltributyltin and Bromodifluoromethylated Alkenes.

A robust Stille gem-difluoroallylation of arylstannanes with 3-bromo-3,3-difluoropropenes has been established. The catalyst was found to exert critical effect on the reaction chemoselectivity. By using Pd(OH)2/C as the catalyst, a series of 3-(hetero)aryl/vinyl-3,3-difluoropropenes were obtained in high efficiency with α-substitution regioselectivity. The reaction has a broad substrate scope, and various substitution patterns were well tolerated in both substrates. Notably, the reaction can be easily extended to late-stage gem-difluoroallylation of many bioactive molecules with good chemoselectivity.

Synthesis of aryldifluoromethyl aryl ethers via nickel-catalyzed suzuki cross-coupling between aryloxydifluoromethyl bromides and boronic acids.

As a unique organofluorine fragment, gem-difluoromethylated motifs have received widespread attention. Here, a convenient and efficient synthesis of aryldifluoromethyl aryl ethers (ArCF2OAr') was established via Nickel-catalyzed aryloxydifluoromethylation with arylboronic acids. This approach features easily accessible starting materials, good tolerance of functionalities, and mild reaction conditions. Diverse late-stage difluoromethylation of many pharmaceuticals and natural products were readily realized. Notably, a new difluoromethylated PD-1/PD-L1 immune checkpoint inhibitor was conveniently synthesized and showed both improved metabolic stability and enhanced antitumor efficacy. Preliminary mechanistic studies suggested the involvement of a Ni(I/III) catalytic cycle.

Catalytic Asymmetric Allylic Substitution with Copper(I) Homoenolates Generated from Cyclopropanols.

By using copper(I) homoenolates as nucleophiles, which are generated through the ring-opening of 1-substituted cyclopropane-1-ols, a catalytic asymmetric allylic substitution with allyl phosphates is achieved in high to excellent yields with high enantioselectivity. Both 1-substituted cyclopropane-1-ols and allylic phosphates enjoy broad substrate scopes. Remarkably, various functional groups, such as ether, ester, tosylate, imide, alcohol, nitro, and carbamate are well tolerated. Moreover, the present method is nicely extended to the asymmetric construction of quaternary carbon centers. Some control experiments argue against a radical-based reaction mechanism and a catalytic cycle based on a two-electron process is proposed. Finally, the synthetic utilities of the product are showcased by means of the transformations of the terminal olefin group and the ketone group.

Copper(I)-Catalyzed Asymmetric Alkylation of Unsymmetrical Secondary Phosphines.

A copper(I)-catalyzed asymmetric alkylation of HPAr1Ar2 with alkyl halides is uncovered, which provides an array of P-stereogenic phosphines in generally high yield and enantioselectivity. The electrophilic alkyl halides enjoy a broad substrate scope, including allyl bromides, propargyl bromide, benzyl bromides, and alkyl iodides. Moreover, 11 unsymmetrical diarylphosphines (HPAr1Ar2) serve as competent pronucleophiles. The present methodology is also successfully applied to catalytic asymmetric double and triple alkylation, and the corresponding products were obtained in moderate diastereo- and excellent enantioselectivities. Some 31P NMR experiments indicate that bulky HPPhMes exhibits weak competitively coordinating ability to the Cu(I)-bisphosphine complex, and thus the presence of stoichiometric HPAr1Ar2 does not affect the enantioselectivity significantly. Therefore, the high enantioselectivity in this reaction is attributed to the high performance of the unique Cu(I)-(R,RP)-TANIAPHOS complex in asymmetric induction. Finally, one monophosphine and two bisphosphines prepared by the present reaction are employed as efficient chiral ligands to afford three structurally diversified Cu(I) complexes, which demonstrates the synthetic utility of the present methodology.

Copper(I)-Catalyzed Asymmetric Conjugate 1,6-, 1,8-, and 1,10-Borylation.

Catalytic asymmetric remote conjugate borylation is challenging as the control of regioselectivity is not trivial, the electrophilicity of remote sites is extenuated, and the remote asymmetric induction away from the carbonyl group is difficult. Herein, catalytic asymmetric conjugate 1,6-, 1,8- and 1,10-borylation was developed with excellent regioselectivity, which delivered α-chiral boronates in moderate to high yields with high enantioselectivity. The produced chiral boronate smoothly underwent oxidation, cross-coupling, and one-carbon homologation to give synthetically versatile chiral compounds in moderate yields with excellent stereoretention. Furthermore, a stereomechanistic analysis was conducted using DFT calculations, which provides insights into the origins of the regioselectivity. Finally, the present 1,6-borylation was successfully applied in an efficient one-pot asymmetric synthesis of (-)-7,8-dihydrokavain.

Copper(I)-catalyzed asymmetric 1,6-conjugate allylation.

Catalytic asymmetric conjugate allylation of unsaturated carbonyl compounds is usually difficult to achieve, as 1,2-addition proceeds dominantly and high asymmetric induction is a challenging task. Herein, we disclose a copper(I)-NHC complex catalyzed asymmetric 1,6-conjugate allylation of 2,2-dimethyl-6-alkenyl-4H-1,3-dioxin-4-ones. The phenolic hydroxyl group in NHC ligands is found to be pivotal to obtain the desired products. Both aryl group and alkyl group at δ-position are well tolerated with the corresponding products generated in moderate to high yields and high enantioselectivity. Moreover, both 2-substituted and 3-substituted allylboronates serve as acceptable allylation reagents. At last, the synthetic utility of the products is demonstrated in several transformations by means of the versatile terminal olefin and dioxinone groups.

Iridium-catalyzed direct asymmetric vinylogous allylic alkylation.

The catalytic asymmetric vinylogous allylic alkylation of α,ß-unsaturated lactones (including coumarins) was achieved with excellent regio- and enantioselectivity. Transformations of the product were carried out by means of the versatile terminal olefin and lactone moieties. The synthetic application of the present methodology was showcased by the asymmetric synthesis of an advanced synthetic Merck intermediate toward a new drug candidate.

Direct Asymmetric Vinylogous and Bisvinylogous Mannich-Type Reaction Catalyzed by a Copper(I) Complex.

A direct catalytic asymmetric vinylogous Mannich-type reaction has been disclosed in good yield, excellent regio-, diastereo- and enantioselectivity. The key to control the regioselectivity is the combination of a bulky N-acylpyrazole and a bulky bisphosphine ligand. The catalytic system was extended to a bisvinylogous Mannich-type reaction by changing the ligand. The synthetic utility of the vinylogous products was demonstrated by several transformations.