Experimental and Theoretical Study of an Intramolecular CF₃‐Group Shift in the Reactions of α‐Bromoenones with 1,2‐Diamines

Abstract

The reactions of trifluoromethylated 2-bromoenones and N,N'-dialkyl-1,2-diamines have been studied. Depending on the structures of the starting compounds, the formation of 2-trifluoroacetylpiperazine or 3-trifluoromethylpiperazine-2-ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting α-bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated.

Multichannel Reaction of α‐Bromo­enones with 1,2‐Diamines: Synthesis of 1,4‐Diazabicyclo[4.1.0]hept‐4‐enes by Reaction with N‐Unsubstituted 1,2‐Diamines

“…The latter then undergoes a 1,2‐shift of the CF 3 group to finally give piperazinones 3 6. In the case of N , N′ ‐dicyclopropyl ethylenediamine, an alternative sequence is preferable, as confirmed by calculations 6b. Instead of intermolecular nucleophilic substitution to form intermediate B with a second molecule of diamine, cyclization takes place through intramolecular nucleophilic substitution of bromine (Scheme ).…”

The Wonderful Chemistry of Trifluoromethyl α‐Haloalkenyl Ketones

“…In order to develop methods for the preparation of six‐membered aza‐heterocycles, non‐fluorinated enones 1 were treated with symmetric dimethylethylenediamine (DMEDA). We showed that in this case complex reaction mixtures were formed, usually containing fragmentation and unidentified products (Scheme ) …”

“…However, the expected trifluoroacetylpiperazines 12 were obtained only with the dicyclopropyl derivative of ethylenediamine. To our great surprise, in all other cases in which bromoenones reacted with N , N′ ‐dialkylethylenediamines the isomeric piperazinones 11 were isolated in good to excellent yields , . It should be emphasized that the piperazinones obtained are a very rare type of heterocycles and that, to the best of our knowledge, no other methods for their assembly are yet known.…”

“…In fact, because of the high acidity due to the presence of the adjacent CF 3 group, the proton of the OH group in piperazinol 13 transfers to the β‐olefinic carbon and promotes a subsequent nucleophilic 1,2‐shift of the CF 3 moiety. Now it is also quite clear that the solvent plays the essential role in the different behavior of diamines bearing cyclopropyl and other alkyl groups , . The results of the calculations are in excellent agreement with experimental data.…”

Regioselectivity Issues in the Addition of Grignard Reagents to Trifluoromethylated α‐Bromoenones

“…The conjugate nucleophilic addition to functionalized enones is a straightforward method for the carbon–carbon or carbon–heteroatom bond formation. In this context, we recently demonstrated that trifluoromethylated α‐bromoenones are excellent Michael acceptors and valuable starting materials in the reaction with nitrogen‐bearing mono‐ or binucleophiles for assembly of a diversity of trifluoromethylated linear as well as carbo‐ and heterocyclic derivatives . These enones are ambivalent bielectrophiles bearing electrophilic centers at the carbonyl function and at the olefinic β‐carbon; therefore, they can react with nucleophiles either in 1,2‐ or 1,4‐addition mode.…”