Sulfonium-based precise alkyl transposition reactions.

S-adenosyl-L-methionine (SAM), a sulfonium-based cofactor, plays an important role in numerous biological processes as methyl donor. Inspired by the function of sulfonium motif in this nature's synthetic toolkit, we here present an aryne-activation strategy that the sulfonium intermediates in situ generated from thioethers display unique reactivity toward alkyl group transposition. Experimental and theoretical studies indicate that the reaction occurs in an intermolecular fashion where the TfO--incorporated [K(18-crown-6)] complex acts as a key promoter for this thermodynamically favored process. Next, a series of robust, easy-to-prepare sulfonium salts are designed and developed as electrophilic alkylation reagents accordingly. Both systems feature for broad scope, excellent selectivity, and simple operation. Moreover, we highlight the synthetic value through molecular editing and late-stage modification of complex scaffolds or even active pharmaceutical ingredients.

Transition-metal-free formal cross-coupling of aryl methyl sulfoxides and alcohols via nucleophilic activation of C-S bond.

Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. Herein we report a transition-metal-free cross-coupling strategy utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers. Two drug molecules were successfully prepared using this protocol as a key step, emphasizing its potential utility in medicinal chemistry. A DFT computational study suggests that the reaction proceeds via initial addition of the alkoxide to the sulfoxide. This adduct facilitates further intramolecular addition of the alkoxide to the aromatic ring wherein charge on the aromatic system is stabilized by the nearby potassium cation. Rate-determining fragmentation then delivers methyl sulfenate and the aryl or heteroaryl ether. This study establishes the feasibility of nucleophilic addition to an appended sulfoxide as a means to form a bond to aryl(heteroaryl) systems and this modality is expected to find use with many other electrophiles and nucleophiles leading to new cross-coupling processes.

An aryne triggered ring-opening fluorination of cyclic thioethers with potassium fluoride.

Herein, we report an aryne triggered ring-opening fluorination protocol of a great variety of saturated sulfur heterocycles. A key factor for the success is the identification of a suitable mediator. Compared to previous methods, this transition-metal free protocol employs low-cost potassium fluoride as the fluorine source. The operational simplicity and mild reaction conditions allow for the rapid synthesis of a wide range of aliphatic fluoride compounds in good yields.

Diverse ring opening of thietanes and other cyclic sulfides: an electrophilic aryne activation approach.

Organosulfides are a common class of structure units in bioactive molecules and functional materials motivating continuous developments of efficient synthetic methods. Herein, we report an electrophilic aryne-activated ring opening protocol of one or two heteroatom containing saturated sulfur heterocycles. This three-component transformation proceeds under mild reaction conditions and displays exceptional generality of nucleophiles (C, O, S, N, and F centered nucleophiles), giving structurally diverse thioethers in good yields.