Highly chemoselective difluoromethylative homologation of iso(thio)cyanates: expeditious access to unprecedented α,α-difluoro(thio)amides

Abstract

The new motif – α,α-difluoromethyl thioamide – has been assembled starting from isothiocyanate (as thioamide precursor) and a formal difluoromethyl-carbanion generated from commercially available TMSCHF2.

Consecutive C1‐Homologation / Displacement Strategy for Converting Thiosulfonates into O,S‐Oxothioacetals

“…The O1À C1 bond (1.421 Å) is significantly shorter than the S1À C1 bond (1.819 Å), whereas the distance between the heteroatoms (O1À S1) is 2.736 Å and the dihedral angle S1À C1 O1À C1 is 114.68°. The presence of potentially exchangeable halogen on the core of the phenol did not minimally affect the transformation, as evidenced in the cases of bromo (4) or chloro (5)(6)(7)(8) derivatives. The employment of nitrogen-substituted phenol at FULL PAPER asc.wiley-vch.de different oxidation state is fully compatible with the methodology, as indicated by the somehow reluctant (to organolithium carbenoids) [17] nitro compound 9.…”

“…The selective deprotonation of the oxothioacetal methylene of 30 with n-BuLi furnished an intermediate oxo-thio geminal lithium anion which was intercepted with a Weinreb amide en route to a mixed oxo-thio ketone 33, thus complementing our previous achievements on the synthesis of α-substituted ketones (path b). [6,21] Finally, we were pleased in using a bisdisulfide-containing diphenol as the displacing alcohol for the tandem protocol: upon completing the carbenoid homologation, the nucleophilic substitution could be executed on only one of the phenolic groups with full retention of the labile SÀ S bond (34 -path c).…”

“…Among the plethora of reagents developed to this end (e. g. diazomethane, ylides), [3] carbenoid reagents constitute important players for the release of the methylene under tuneable nucleophilic or electrophilic regime governed (mainly) by the nature of the metal. [4] Two main -intimately connected (Scheme 1b) -mechanistic pathways can be devised for the reaction of a metal carbenoid (e. g. LiCH 2 X -usually nucleophilic) with an electrophilic manifold (RÀ Y): [5] i) the interrupted homologation in which upon forming the new R-CH 2 X bond, the X defining element remains constitutively in the final scaffold; [6] ii) the pure homologation leading through an internal displacement of the X element -carried out with an internal nucleophilic species (e. g. Nu int ) -to the homologue, as illustrated by the (aza)-carbonyl homologation to aziridines and epoxides [7] or by the elegant Matteson-type boronic esters homologation. [8] Motivated by the interest towards such chemistry, we designed selective processes characterized by the triggering of molecular rearrangements once the initial homologation was accomplished, e. g. fully α-substituted aldehydes from vinyl ketones [9] or, aziridines via telescoped homologations of TFAICs.…”

Modular and Chemoselective Strategy for Accessing (Distinct) α,α‐Dihaloketones from Weinreb Amides and Dihalomethyllithiums

“…Aromatic Weinreb amides smoothly underwent the dichloromethylation procedure in the presence of a plethora of decorating elements on the nuclei. Halogens-containing motifs (17)(18)21) were tolerated, as well as, the more challenging nitrile (19) and nitro (20) groups. The presence of motifs of different electronic behaviour was not detrimental as deducted in the cases of methoxy (22), t-Bu (23), 1-adamantyl (24) and phenyl (25).…”

“…In 2019, our group developed an effective tactic for assembling tertiary difluoromethyl ketones via the direct attack of a nucleophilic difluoromethylated synthon to a Weinreb amide as the competent acylating agent [19] . Cognizant of the extreme liability of fluorinated carbanions, we found highly beneficial using TMSCHF 2 as the pro‐nucleophile, which upon activation with an alkoxide, [20] furnished the reactive nucleophilic CHF 2 element (Scheme 1 – path f ).…”