Aldrichimica Acta Vol. 45, No. 3 - Sigma-Aldrich

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Transition-Metal-Mediated Fluorination, Difluoromethylation, and Trifluoromethylation Dr. Zhuang Jin Prof. Gerald B. Hammond Dr. Bo Xu Keywords. transition metal; catalysis; fluorination; difluoromethylation; trifluoromethylation. Abstract. Introducing fluorine into organic molecules is a proven successful strategy in designing pharmaceuticals with improved therapeutic effects, but has remained a long-standing challenge for synthetic organic chemists. Fortunately, newly developed transitionmetal-catalyzed or mediated fluorination, difluoromethylation, and trifluoromethylation reactions are addressing this challenge and facilitating the synthesis of fluorinated compounds. In this review, we have classified and organized the recent developments in fluorination, difluoromethylation, and trifluoromethylation reactions based on the metal catalyst and the underlying mechanism of the C–F, C–CF 2, and C–CF 3 bond formation. We also comment on the limitations of these methods. Outline 1. Introduction 2. Transition-Metal-Promoted Fluorination 2.1. Pd-Mediated Fluorination 2.1.1. Fluorinations via Reductive Elimination from R–Pd–F 2.1.1.1. Reductive Elimination from R–Pd(II)–F 2.1.1.2. Reductive Elimination from R–Pd(IV)–F 2.1.2. Pd-Catalyzed Fluorination of Allyl Halides and Allyl Esters 2.1.3. Pd-Catalyzed Fluorination via Oxidative Addition to C–C Unsaturated Bonds 2.2. Gold-Catalyzed Fluorination 2.2.1. Using a Nucleophilic Fluorine Source 2.2.2. Using an Electrophilic Fluorine Source 2.3. Silver-Mediated Fluorination 2.4. Fluorination Mediated by Other Transition Metals 3. Transition-Metal-Promoted Trifluoromethylation 3.1. Copper-Mediated Trifluoromethylation 3.1.1. Trifluoromethylation of Electrophiles (Mainly ArI) 3.1.1.1. Trifluoromethylation via a CF 3Cu Intermediate Generated in Situ 3.1.1.2. Trifluoromethylation via a Preformed CF 3Cu Complex Zhuang Jin, Gerald B. Hammond,* and Bo Xu* Department of Chemistry University of Louisville Louisville, Kentucky 40292, USA Email: gb.hammond@louisville.edu VOL. 45, NO. 3 • 2012 3.1.2. Trifluoromethylation of Nucleophiles through Oxidative Coupling 3.1.3. Other Copper-Mediated Trifluoromethylations 3.2. Palladium-Mediated Trifluoromethylation 3.2.1. Pd-Catalyzed Trifluoromethylation of Aryl and Alkenyl Halides via a Pd(0)–Pd(II) Cycle 3.2.2. Pd-Catalyzed Trifluoromethylation via a Pd(II)–Pd(IV) Cycle 3.3. Trifluoromethylation Mediated by Other Metals 3.4. Trifluoromethylation Involving Free Radicals 4. Transition-Metal-Promoted Difluoromethylation 4.1. Difluoromethylation through an RCF 2Cu Intermediate 4.2. Difluoromethylation via Radical Species 5. Summary and Outlook 6. Acknowledgements 7. References 1. Introduction Extensive research has established that introducing fluorine into a target molecule can effectively modify its physicochemical properties. 1 As a result, up to 20% of pharmaceuticals 2 and approximately 30% of agrochemicals 2b contain fluorine and/or the trifluoromethyl group. Additionally, fluorine-18 ( 18 F) is regarded as one of the most clinically important radioisotopes for Positron Emission Tomography (PET). 3 Nevertheless, over a century after its discovery, the introduction of fluorine into organic molecules continues to be a long-standing challenge for synthetic organic chemists. In general, fluorinated compounds can be prepared through the use of molecular-building-block methods or of fluorination reagents. 1g The former utilizes commercial fluorine-containing building blocks 1f (functionalized compounds containing F, CF 2, CF 3, and/or OCF 3; e.g., 4-fluorobenzaldehyde). The latter method utilizes fluorinating reagents, most of which are commercially available (Figure 1). Their mode of action is to introduce F or CF 3 into target molecules through functional group transformations. If suitable fluorination methods are available, medicinal chemists usually prefer these because they can introduce fluorine where and when they want it. Fluorination of an aromatic system has been effected most commonly through the Balz–Schiemann reaction (transformation of anilines into 67
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