Consecutive and Selective Double Methylene Insertion of Lithium Carbenoids to Isothiocyanates: A Direct Assembly of Four‐Membered Sulfur‐Containing Cycles

Abstract

A formal CH 2 À CH 2 homologation conducted with C1 carbenoids on a carbon electrophile for the obtainment of a four-membered cycle is reported. The logic proposes the consecutive delivery of two single nucleophilic CH 2 units to an isothiocyanate-as competent electrophilic partner-resulting in the assembling of a rare imino-thietane cluster. The single synthetic operation procedure documents genuine chemocontrol, as indicated by the tolerance to various reactive elements decorating the starting materials. Significantly, the double homologation protocol is accomplished directly on a carbon electrophile, thus not requiring the installation of heteroatomcentered manifolds (e.g. boron).

Fluoroiodomethane: A CH2F‐Moiety‐Delivering Agent Suitable for Nucleophilic‐, Electrophilic‐, and Radical‐Harnessed Operations

“…[48] In the course of studies aimed at designing unprecedented C2-homologation strategies, in 2021 Pace showed that LiCH 2 F could consecutively deliver two methylene groups to a starting isothiocyanate, thus assembling previously unknown imino-thietanes (Scheme 6). [49] Although LiCH 2 Br resulted the optimal carbenoid for the transformation, it is worth noting the leaving-group capability manifested by the fluorine atom of the (firstly installed) CH 2 F motif. [50] Mechanistically, upon the first homologative event conducting to a thioimidate, a three-membered thiirane ring is formed as the result of the expulsion of the fluoride ion; then, the same carbenoid opens the ring, yielding a new thioimidate susceptible of a second ring-closure en route to the thietane.…”

(1RS,3SR)-1-(4-Methylbenzyl)-7-phenyl-5-oxa-6-azaspiro[2.4]hept-6-en-4-one

“…In our previous works, we have used different isoxazole derivatives as starting materials for the synthesis of nitrogen heterocycles [15][16][17][18]. In search of new isoxazole substrates, we became interested in isoxazol-5-ones spiro-fused with a cyclopropane ring.…”

Recent Advancement in Synthesis of Isothiocyanates

“…Therefore, isothiocyanates are promising platforms in medicinal chemistry. [33][34][35][36][37][38][39][40] As isothiocyanate is an important functional group in both biochemistry and synthetic chemistry, numerous synthetic methods have been developed. [41,42] This review provides a comprehensive summary of recent progress in isothiocyanate synthesis, with a focus on substrate categorization.…”