2‐Methyltetrahydrofuran: A Green Solvent for Iron‐Catalyzed Cross‐Coupling Reactions

Abstract

Iron-catalyzed cross-coupling reactions allow sustainable formation of C-C bonds using cost-effective, earth-abundant base-metal catalysis for complex syntheses of pharmaceuticals, natural products, and fine chemicals. The major challenge to maintain full sustainability of the process is the identification of green and renewable solvents that can be harnessed to replace the conventional solvents for this highly attractive reaction. Herein, iron-catalyzed cross-coupling of aryl chlorides and tosylates with challenging organometallic reagents possessing β-hydrogens is found to proceed in good to excellent yields with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. The reaction operates with excellent functional group tolerance under very mild conditions. Furthermore, large-scale cross-coupling, cross-coupling of heteroaromatic substrates, and cross-coupling of challenging aryl tosylates and carbamates mediated by Fe-N-heterocyclic carbene catalytic systems in eco-friendly 2-MeTHF were also carried out. The developed method was applied to the key cross-coupling in the synthesis of a fibrinolysis inhibitor, further highlighting the potential of 2-MeTHF as a general solvent for sustainable iron-catalyzed cross-coupling reactions.

Solvent effects in palladium catalysed cross-coupling reactions

“…330 An attempt to use 2-MeTHF in the Buchwald-Hartwig reaction was less productive than the conventional (and less dipolar) toluene and 1,4-dioxane, 246 but is suitable in combination with N,N-dimethyl octanamide for the synthesis of Imatinib, as described in Section 3.1.5. At present the number of examples where 2-MeTHF is being applied in C-C and C-N coupling reactions is fairly low, 331,332,333 but the benefits of a water-immiscible alternative to THF should be valued more highly.…”

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

“…Recently,o ur group reported the use of urea ligands as green alternatives to reprotoxic NMP in the iron-catalyzed C(sp 2 )ÀC(sp 3 )c ross-coupling of aryl halides and tosylates. [40] It is worthwhile to note that while NMP is by far the most effective O-coordinating ligand to iron, this additive poses serious safety concerns, [41] highlighting the need for its replacement with environmentally benign additives.W ehave demonstrated the utility of Fe(acac) 3 /DMI (DMI = 1,3-dimethyl-2-imidazolidinone) in the coupling of 2-chloro-6methyl-4-(trifluoromethyl)piperidine and cyclopropylmagnesium bromide (as in Scheme 2, not shown), which proceeded in 80 %yield.…”

Iron‐Catalyzed C(sp2)−C(sp3) Cross‐Coupling of Chlorobenzamides with Alkyl Grignard Reagents: Development of Catalyst System, Synthetic Scope, and Application

“…First, the coupling could be conducted in a sustainable solvent, 2‐MeTHF, with no detectable decrease in the reaction efficiency (entries 1–2). This finding further establishes the potential of 2‐MeTHF as a highly suitable, renewable solvent for iron‐catalyzed cross‐coupling reactions . Next, we were pleased to find that urea ligands, DMPU and DMI (DMPU=1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinone, DMI=1,3‐dimethyl‐2‐imidazolidinone), afforded the coupling product with efficiency comparable to NMP (entries 3–4).…”