Transition-Metal-Catalyzed Fluorination and Fluoroalkylation Reactions

Introduction

With the increasing demand for fluorinated organic compounds in academia and industry, the continuous development of new synthesis methods of fluorinated organic compounds has become an indispensable subject. In the past few decades, the synthesis of organofluorine compounds made significant progress. In recent years, the transition-metal-catalyzed fluorination/fluoroalkylation reactions to obtain organofluorine compounds has developed rapidly and has become an important and hot topic in fluorine chemistry. Because the application of this method reduces the need for pre-functionalized substrates, reduces the consumption of reaction time and cost, and makes it possible to produce enantioenriched target compounds ^[1]. At present, palladium and copper are the most commonly employed transition metal. Meanwhile, other transition metals, such as Fe, Ni, Rh, Ag, Co, etc., have received considerable attention and are widely applied. Herein, Alfa Chemistry tries to provide a brief introduction of this topic.

Transition-Metal-Catalyzed Fluorination Reactions

• Palladium catalysis: It is well known that Pd catalyst is an ideal catalyst for C-H activation. At present, a number of Pd-catalyzed methods have been developed to synthesize organic fluorides. In this regard, they can be used for allylic fluorination reactions, alkyl fluorination of acidic carbonyl compounds and other compounds, fluorination of arenes, aryl bromides, aryl alcohols, aryl triflates, and aryl boronic acid derivatives, aryl C–H fluorination with various directing groups.

Fig.1. Pd-catalyzed allylic fluorination reactions.

• Copper catalysis: Copper generally exists in four oxidation states, Cu(0), Cu(I), Cu(II), and Cu(III) and various fluorination reactions could be developed by different catalytic mechanism. Copper catalyst can be used to catalyze fluorination reactions of inert C–H bonds, alkyl bromides and alkyl triflates, allylic fluorination reactions, α-fluorination reactions of acidic carbonyl compounds, C_sp²-H bond formation reactions and other fluorination reactions.

Fig.2. Cu-catalyzed allylic fluorination reactions.

• Other metals catalysis: Other transition metals catalysts, including Ag, Co, Ni, Fe, Ag, Ir, Mn, etc., have received more and more attention in fluorination reactions. They can be used to catalyze aliphatic and benzylic C–H fluorination reactions and decarboxylative fluorination reactions, allylic fluorination reactions, fluorination reactions of acidic carbonyl compounds and Ar–F bond-forming reaction, and other fluorination reactions.

Fig.3. Ag-catalyzed decarboxylative fluorination of aliphatic carboxylic acids.

Transition-Metal-Catalyzed Fluoroalkylation Reactions

Compared with the fluorination reactions, the application of transition metal in catalyzing fluoroalkylation reactions is slightly less. However, it still has made great progress under the joint efforts of organic fluorine scientists and metalorganic chemists.

• Palladium catalysis: Palladium catalysis is widely used in trifluoromethylation reactions. More specifically, it is frequently used in C(sp²)–CF₃ bond formation of trifluoromethylation of aryl and vinyl compounds. In addition, it can be used in difluoromethylation of styrene derivatives, difluoroalkylation of aldehyde hydrazones, difluoromethylation of aryl phenol, boronate, ketones, nitriles, esters, etc.

Fig.4. Palladium-catalyzed trifluoromethylation of aryl compounds.

• Copper catalysis: In this regard, copper catalysts can be used to catalyze trifluoromethylation reactions, including C(sp³)–CF₃ bond formation reactions, C(sp²)–CF₃ bond formation reactions (trifluoromethylation reactions of aryl- and alkenyl-boronic acids, trifluoromethylation of alkenes, trifluoromethylation of arenes and heteroarenes), C(sp)–CF₃ bond formation reactions. They can also be used to catalyze difluoromethylation reactions, including difluoromethylation of α,β-unsaturated carboxylic acids, difluoromethylation of hydrazones, difluoromethylation of aryl phenol, boronate, ketones, nitriles, esters, etc., difluoroacetylation of quinoxalinones, etc. In addition, they can be used to catalyze trifluoromethylthiolation reactions, including trifluoromethylthiolation of enamines, indoles and β-ketoesters, trifluoromethylthiolation of boronic acids and alkynes, trifluoromethylthiolation of primary and secondary α-bromoketones, trifluoromethylthiolation of enamines, indoles, β-keto esters, pyrroles, and anilines, stereoselective trifluoromethylation of secondary propargyl sulfonates, etc.

Fig.5. Cu-catalyzed trifluoromethylation of aryl- and alkenylboronic acids.

• Other metals catalysis: In addition to palladium and copper, various transition metals are used as catalysts in trifluoromethylation reactions. For examples, Ru, Ir and their complexes are widely used as photocatalysts in C(sp³) -CF₃ bond formation of trifluoromethylation reaction. Fe, Ir, Ru, and Ag catalysts are widely used in vinyl C-CF₃ bond formation reactions. Ru, Ir, Ag, Mo, V, Ni catalysts can direct catalyze C–H bond trifluoromethylation of arenes and heteroarenes. Moreover, these catalysts are also used in the reactions of difluoromethylation, trifluoromethylation and trifluoromethoxylation of organic molecules.

As a leading global supplier of organofluorine compounds, Alfa Chemistry has accumulated extensive knowledge and experience in fluorination and fluoroalkylation reactions. Our fluorination and fluoroalkylation reaction development services can address most of your needs in this area. In addition, we offer a wide range of reagents and products for fluorination and fluoroalkylation reactions. Please contact us if required.

Reference

1. Li X., et al. Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups[J]. Beilstein Journal of Organic Chemistry, 2019, 15(1): 2213-2270.