Matthias F. Grünberg

Sandmeyer Trifluoromethylation of Arenediazonium Tetrafluoroborates

The development of methods for the introduction of trifluoromethyl groups into functionalized molecules is of great importance due to their presence in many top-selling pharmaceuticals, agrochemicals, and functional materials. Trifluoromethyl groups are known to impart desirable properties, such as higher metabolic stability, increased lipophilicity, and stronger dipole moments to druglike molecules. Celecoxib, dutasteride, fluoxetine, and sitagliptin are some examples of top-selling pharmaceuticals featuring trifluoromethyl groups, and beflubutamid, diflufenican, and norfluazon examples of agrochemicals. However, traditional methods to access benzotrifluorides, for example, the Swarts reaction, typically require harsh conditions and have a low substrate scope, so that they are confined to the beginning of a synthetic sequence (Scheme 1a). Building on pioneering work on Cu– and Pd–perfluoroalkyl complexes by McLoughlin, Yagupolskii, Burton, Chambers, Grushin, and others, substantial progress has recently been made in the development of trifluoromethylation reactions that allow the selective introduction of CF3 groups into functionalized, late-stage synthetic intermediates. A wealth of new reactions has been disclosed, which can be roughly divided into five categories (Scheme 1b–f). The first are couplings of aryl halides with nucleophilic CF3 reagents (reaction type b), usually copper–CF3 complexes in stoichiometric amounts. These complexes may also be generated in situ from copper salts and Ruppert s reagent (CF3SiMe3), [7] fluoroform, potassium (trifluoromethyl)trimethoxyborate, trifluoroacetate salts, methyl trifluoroacetate, or fluorosulfonyldifluoroacetic acid. Grushin, Sanford, and Buchwald also disclosed trifluoromethylations of aryl halides based on palladium complexes. Palladium complexes also promote C H functionalizations of arenes with trifluoromethylating reagents (reaction type c). Examples are the ortho-trifluoromethylation of donor-substituted arenes with Umemoto s reagent described by Yu et al. and the Pd-catalyzed coupling of arenes with perfluoroalkyl iodides reported by Sanford et al. C H trifluoromethylations of heteroarenes have recently been reported also with nucleophilic trifluoromethylation reagents under oxidative conditions. Examples of couplings of aryl nucleophiles with electrophilic CF3 sources (reaction type d) include the coupling of arylboronic acids with Togni s and Umemoto s reagent disclosed by Shen and Liu, respectively. Sanford et al. employed a copper/ruthenium photocatalyst system to promote a radical trifluoromethylation of boronic acids. The copper-catalyzed syntheses of benzotrifluorides from boronic acids and CF3SiMe3 or K [CF3B(OMe)3] developed by Qing et al. and ourselves exemplify oxidative couplings of aryl nucleophiles with nucleophilic CF3 reagents (reaction type e). The radical trifluoromethylation of arenes (reaction type f) was pioneered by Langlois. Baran and MacMillan recently reported modern variants of this reaction concept based on peroxide or ruthenium initiators. From a practical standpoint, nucleophilic reagents are appealing for the introduction of trifluoromethyl groups for the following reasons. CF3SiMe3 and K [CF3B(OMe)3] are available in large quantities for a reasonable price, and are easy to store and handle. They are accessible not only from halofluorocarbons, but also from fluoroform, a by-product in the production of Teflon. One of the most widely used methods for the introduction of halides and related nucleophiles is the Sandmeyer reaction. Aromatic amines, which are available in great structural diversity, are diazotized using, for example, NaNO2 or organic nitrites. Upon treatment with the appropriate copper(I) halides, nitrogen gas is released, and a halide group is installed regiospecifically in the position Scheme 1. Strategies for the introduction of trifluoromethyl groups.

[Pd(μ-Br)(PtBu3)]2 as a Highly Active Isomerization Catalyst: Synthesis of Enol Esters from Allylic Esters

The dimeric Pd(I)-complex [Pd(μ-Br)(P(t)Bu3)]2 was found to be highly active for catalyzing double-bond migration in various substrates such as unsaturated ethers, alcohols, amides, and arenes, under mild conditions. It efficiently mediates the conversion of allylic esters into enol esters, rather than inserting into the allylic C-O bond. The broad applicability of this reaction was demonstrated with the synthesis of 22 functionalized enol esters.

Synthesis of Arylacetates from Benzylic Alcohols and Oxalate Esters through Decarboxylative Coupling

Follow that dream: By combining a reversible transesterification between benzylic alcohols and dialkyl oxalates with catalytic decarboxylation of the resulting esters, a regiospecific C-C-bond-forming reaction to give α-arylacetates was achieved. In the overall process, CO2 and a volatile alcohol are the only byproducts. Various α-arylacetates were thus synthesized in high yields from easily accessible starting materials in the presence of catalytic amounts of Pd(OAc)2, dppp, and DABCO (see scheme).

Bimetallic Cu/Pd Catalysts with Bridging Aminopyrimidinyl Phosphines for Decarboxylative Cross-Coupling Reactions at Moderate Temperature

A bimetallic catalyst system is presented that enables the decarboxylative cross‐coupling of triflates with carboxylate salts at only 100 °C, which is 70 °C lower than with previous Cu/Pd‐based systems. The new protocol allows the coupling of a broad range of aryl triflates with various substituted 2‐nitrobenzoates in good to excellent yields. The key feature of the catalyst system is a bidentate P,N‐ligand designed to bridge the Pd and Cu centres and thereby facilitating the rate‐determining transmetalation step. Mass spectrometry (ESI‐MS) studies support the ability of the aminopyrimidinyl phosphine to simultaneously coordinate copper and palladium.