Switchable Nucleophilic Site Enables Expedient Synthesis of CF₃-Containing Thiazoles and Allenes from 1,3-Enynes

Abstract

Typically, trimethylsilyl isothiocyanate (TMSNCS) is used as a nucleophilic thiocyanate building block ( − S−C�N) that reacts with various electrophiles. However, it has been less explored as a source of isothiocyanates ( − N�C�S), which can usually be converted by thermal isomerization of allyl or propargyl thiocyanates. Achieving a method with precise site control is even more challenging. Here, we demonstrate an approach that uses metal catalysts to control switchable nucleophilic sites and provide a strategy to construct CF 3 -containing thiazoles and allenes via the multicomponent reaction of 1,3-enynes, TMSNCS, and electrophilic trifluoromethyl reagent. In the presence of inexpensive Fe(III) or Cu(II) catalysts, the current reaction is practical and convenient, compatible with various substrates bearing sensitive functional groups that can be readily transferred to more complex scaffolds. The biological evaluation showed that two of the developed CF 3 -containing thiazoles exhibited dramatic inhibitory activities for three human cancer cell lines beyond those of 5fluorouracil. Both compounds increased the level of reactive oxygen species in MCF-7 cells, which is believed to be an early step in tumor cell apoptosis.

Synthetic and mechanistic study on the conjugate isothiocyanation of enones with trimethylsilyl isothiocyanate

“…This selectivity is dependent on the enone substrate, but the NCS isomer could be easily purified by column chromatography. This reactivity represents one of the few examples where TMSNCS is reported as a reagent for the formation of isothiocyanates (–NCS), 40–44 while there are many examples of its use to form thiocyanates (–SCN). 45–47 First, we checked the electronic effects of the aromatic substituents and found that enones with electron-donating (Me, OMe) and electron-withdrawing (CN, F, CF 3 , NO 2 ) groups at the para position of the phenyl ring were well-tolerated, giving the desired isothiocyanato products ( 2b–2g ) in excellent yields (87–94%).…”

Self‐ or Acridinium‐Catalyzed Electrophotosynthesis of Thiocyanato Heterocycles from Activated Alkenes

“…They are also versatile synthons which could be converted with ease to other sulfur-containing molecules such as thiols, thioethers, carbamothioates, thiotetrazole, perfluoromethylsulfanes and phosphinothioates. [23] Over the past decades, a wide range of methodologies have been developed to construct organic thiocyanates using an N-SCN agent, [24] TMSSCN [25] or KSCN, [26][27][28][29][30][31][32][33][34] or through sulfur cyanation. [35] The inexpensive and benchtop-stable KSCN is a particularly versatile thiocyanating agent, which might undergo a nucleophilic, [26][27][28][29] electrophilic [30,31] or radical coupling [32][33][34] under the conditions of an oxidant, [26,30,32] visible-light irradiation [27,33] or electrolysis.…”

Electrochemically mediated synthesis of trifluoromethylallenes

“…The trifluoromethyl (CF 3 ) group functions as an excellent bioisostere of the methyl group in medicinal chemistry and can improve the metabolic stability, bioavailability, and cellular membrane permeability of molecules. 7 Thus, introducing trifluoromethyl groups into molecular skeletons is of great importance. Among many trifluoromethyl substituents, trifluoromethyl-containing allene skeletons are preferred because of their good plasticity.…”