In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted tetrahydrofurans via Lewis acid catalyzed [3 + 2] cycloadditions of donor-acceptor (D-A) cyclopropanes and aldehydes is described. The scope and limitations with respect to both reaction partners are provided. A detailed examination of the mechanism has been performed, including stereochemical analysis and electronic profiling of both reactants. Experimental evidence supports an unusual stereospecific intimate ion pair mechanism wherein the aldehyde functions as a nucleophile and malonate acts as the nucleofuge. The reaction proceeds with inversion at the cyclopropane donor site and allows absolute stereochemical information to be transferred to the products with high fidelity. The mechanism facilitates the stereospecific synthesis of a range of optically active tetrahydrofuran derivatives from enantioenriched D-A cyclopropanes.

A method for the room temperature copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids has been developed. This protocol is amenable to normal benchtop setup and reactions typically require only 1-4 hours. Proceeding under mild conditions, the method tolerates a range of functional groups, allowing access to a variety of trifluoromethylarenes.The development of methods for the construction of organofluorine compounds is of great importance due to the presence of fluorine in 20% of pharmaceuticals and 30% of agrochemicals that are currently on the market.1 In particular, the benzotrifluoride group is present in several top-selling pharmaceuticals, including Januvia® (Sitagliptin), Celebrex® (Celecoxib), Prozac® (Fluoxetine), and Avodart® (Dutasteride). While trifluoromethyl groups possess many desirable characteristics such as electron-withdrawing character, high lipophilicity, and excellent metabolic stability,2 their installation is often far from routine.Traditionally, benzotrifluorides are formed through treatment of benzotrichlorides with HF and/or metal fluorides such as SbF 5 (Swarts reaction),3 conditions that are typically unsuitable for functionalized late-stage intermediates. Transition metal-mediated crosscoupling offers the potential for mild conditions. Nevertheless, progress has been hampered by the inherent instability of the trifluoromethyl anion4 and reluctance of the metal center to undergo reductive elimination to afford trifluoromethylarenes.5 Despite these challenges, recent reports from Grushin,6a Sanford,6b,c Yu,7 and our own group8 have demonstrated the use of Pd catalysts for the trifluoromethylation of aromatic substrates. While these represent important achievements in trifluoromethylarene synthesis, significant limitations of these Pd-based methods remain (e.g., generality, user friendliness, cost). Thus we decided to also investigate copper-mediated processes.While there are few reports of palladium-mediated trifluoromethylation protocols, coppermediated processes have been studied extensively. Pioneering investigations by Burton shed light on the instability and complexity of .9 Matsui's use of trifluoroacetate salts10 and Chen's methyl fluorosulphonyldifluoroacetate11 have been shown to be attractive sources of trifluoromethyl anion for copper-mediated couplings with aryl iodides. Schlosser's trifluoromethylation of pyridine iodides proceeds at room temperature, but to sbuchwal@mit.edu. Supporting Information Available: Detailed reaction protocols as well as spectral data of all products is available free of charge via http://pubs.acs.org. .13 This concept was further expanded upon in an important paper by Amii that disclosed the first copper-catalyzed trifluoromethylation process of aryl iodides.14 As is the case with many copper-based cross-coupling reactions, these techniques are applicable to aryl iodides or activated aryl bromides, providing complementary reactivity to palladiumbased systems. While substantial progress has been made, the developmen...

Activating the inactive: A copper‐catalyzed allylic trifluoromethylation of unactivated terminal olefins proceeds under mild conditions to produce linear allylic trifluoromethylated products with high E/Z selectivity (see scheme). The reaction can be applied to a range of substrates bearing numerous functional groups. Furthermore, the reaction is scalable and amenable to a benchtop setup.

Aktivierung unnötig: Eine Kupfer‐katalysierte allylische Trifluormethylierung nichtaktivierter Olefine verläuft unter milden Reaktionsbedingungen und führt zu linearen allylischen trifluormethylierten Produkten mit hoher E/Z‐Selektivität (siehe Schema). Die Reaktion kann für eine Vielzahl an Substraten mit unterschiedlichsten funktionellen Gruppen verwendet werden.

Palladium(0)-catalyzed cycloadditions of malonate-derived vinylcyclopropane 1 and aldehydes to afford 2,5-cis disubstituted tetrahydrofuran derivatives are described. Pd loadings as low as 0.5 mol % were effective in catalyzing the transformation with high yields and diastereoselectivities. Electron-poor aldehydes work best, suggesting that a mechanism involving an initial aldol reaction may be operative.