Copper‐Catalyzed Trifluoromethylation of Aliphatic N‐Arylhydrazones: A Concise Synthetic Entry to 2‐Trifluoromethylindoles from Simple Aldehydes

Abstract

Thec opper-catalyzed C(sp 2 ) À Ht rifluoromethylation of N,N-disubstituted hydrazones using the Tognir eagent is demonstrated to proceed efficiently for aliphatic aldehyde-derived substrates. Thes uccess of the reactions relied on the choice of the N,N-diphenylamino group as the terminal hydrazone amino group where N,N-dialkylamino groups were preferredf or (hetero)aromatic aldehyde-derived substrates.I na ddition,t he trifluoromethylated N-arylhydrazones are shownt ob eideal substrates for Fischer indole synthesis allowing as traightforward,t hree-step access to 2-trifluoromethylindole derivatives from simplea ldehydes.

Recent advances in the synthesis of fluorinated hydrazones

“…51,52 Between 2013 and 2016, Bouyssi and co-workers reported a mild procedure for triuoromethylation of (hetero)aromatic aldehyde or aldehyde N,N-dialkylhydrazones using the Togni hypervalent iodine reagent with copper catalysis (Scheme 19). [53][54][55][56] The reaction pathway was proposed to begin with the activation of Togni s reagent 61 by Cu I via single-electron transfer (SET) to form Cu II species 62, which could act as a tri-uoromethyl radical donor. Reaction with the hydrazine 64 would generate (2-iodobenzoyloxy)copper(II) chloride 63 and the triuoromethylated aminyl radical intermediate 65, which could be stabilized by the lone pair of the adjacent nitrogen atom.…”

Electrophilic trifluoromethylation of carbonyl compounds and their nitrogen derivatives under copper catalysis

“…26 However, the choice of the N,N-diphenylamino as the terminal hydrazone amino group appeared to be the key to efficient trifluoromethylation of aliphatic substrates (Scheme 8, part 2). 27 Trifluoromethylated aliphatic aldehyde N,N-diphenylhydrazones were obtained as E-isomers, and their synthetic utility was then illustrated as a means of accessing 2-trifluoromethylindole derivatives 24 through Fischer indole-type heteroannulations (Scheme 9).…”

Thiocyanation of N,N‐Dialkylhydrazonoyl Bromides: An Entry to Sulfur‐Containing 1,2,4‐Triazole Derivatives

“…Given the importance of the hydrazone functional group in synthetic organic chemistry, we became interested in exploring the thiocyanation of N , N ‐dialkylhydrazonoyl halides, expecting the reaction to yield the corresponding hydrazonoyl isothiocyanates as reactive intermediates with high synthetic potential . Herein, we demonstrate that thiocyanation of N , N ‐dialkylhydrazonoyl bromides leads to the direct formation of uncommon 5‐thioxo‐1,2,4‐triazolium inner salts ( IV ), and establish hydrazonoyl thiocyanates ( III ) as first‐formed intermediates in this transformation (Scheme B).…”