Iron-Catalyzed Cross-Coupling of Unactivated Secondary Alkyl Thio Ethers and Sulfones with Aryl Grignard Reagents

Abstract

The first systematic investigation of unactivated aliphatic sulfur compounds as electrophiles in transition metal-catalyzed cross-coupling are described. Initial studies focused on discerning the structural and electronic features of the organosulfur substrate which enable the challenging oxidative addition to the C(sp3)–S bond. Through extensive optimization efforts, an Fe(acac)3-catalyzed cross-coupling of unactivated alkyl aryl thio ethers with aryl Grignard reagents was realized, in which a nitrogen “directing group” on the S-aryl moiety of the thio ether served a critical role in facilitating the oxidative addition step. In addition, alkyl phenyl sulfones were found to be effective electrophiles in the Fe(acac)3-catalyzed cross-coupling with aryl Grignard reagents. For the latter class of electrophile, a thorough assessment of the various reaction parameters revealed a dramatic enhancement in reaction efficiency with an excess of TMEDA (8.0 equiv). The optimized reaction protocol was used to evaluate the scope of the method with respect to both the organomagnesium nucleophile and sulfone electrophile.

Iron Catalysis in Organic Synthesis

“…The reaction proceeds in the presence of 8 equiv of TMEDA in cyclopentyl methyl ether (CPME) at room temperature providing the coupling products mostly in good yields (Scheme 186, eq a). 385 Moreover, unactivated alkyl aryl thioethers have also been applied as electrophiles for this transformation. The best results were obtained with a thioether bearing a 2-pyridyl directing group (eq b).…”

Photochemical Strain-Release Driven Cyclobutylation of C(sp3)-Centered Radicals

“…[19] Them echanistic details on our photoredox decarboxylative conjugate addition are outlined in Scheme 3A.I nitial single-electron transfer (SET) between the photoexcited Ir III catalyst and the in situ formed cesium carboxylate I generates a-carboxyl radical II that undergoes CO 2 -extrusion to form the carbon-centered radical III.Upon Giese radical addition of the highly nucleophilic species III to BCB 2a,strain-release driven rupture of the central s-bond generates the a-sulfonyl At raceless cyclobutylation could easily be achieved through phenyl sulfone cleavage under mild reductive conditions (Mg, MeOH) in excellent yield (35).…”

Oxidative Catalysis Using the Stoichiometric Oxidant as a Reagent: An Efficient Strategy for Single‐Electron‐Transfer‐Induced Tandem Anion–Radical Reactions

“…SET-mediated reactions can be classified according to the overall change of the oxidation state as redox-neutral, oxidative, or reductive. Redox-neutral processes are often transition-metal-catalyzed cross-coupling reactions involving alkyl halides or sulfur electrophiles, [1,2] transition-metal-catalyzed atom-transfer radical reactions, [1, 3] the more recently rediscovered homolytic aromatic substitutions, [1,4] tetrathiafulvalene-promoted radical reactions [5a] and cycloaddition reactions, [1] in which the catalytic SET oxidant or reductant is regenerated at the end of the catalytic cycle by the reverse electron transfer. The majority of the known SETinduced reactions are, however, overall reductive [1,5] or oxidative, [1, 6] which means that at least two equal SET steps occur sequentially in the process.…”

“…It is known that ferrocenium hexafluorophosphate (1 + ) does not oxidize TEMPO (2) and thus the equilibrium is on the left (Scheme 1). [11] Therefore the opposite process should proceed spontaneously and allow the catalytic SET oxidation.…”

“…The subsequent cyclization step does not proceed at the oxidation state of the enolate 24, but SET oxidation allows the switch to the much more reactive radical 25. The catalytic SET oxidation cycle for this step begins with oxidation of ferrocene (1) by the stable oxopiperidinium salt 2 + leading to the active ferrocenium oxidant 1 + and TEMPO (2). The resulting radical 25 undergoes 5-exo (or 6-endo) cyclizations to give radical 26 which couples with co-generated 2 to furnish the oxygenated products 5, 6, or 11.…”