Abstract
In a recent report on the synthetic approach to the novel substance class of 1-alkylidene/arylidene-1,2,4-triazolinium salts, a reaction mechanism suggesting a regioselective outcome was proposed. This hypothesis was tested via a combined NMR and density functional theory (DFT) approach. To this end, three experiments with 13C-labeled carbonyl reactants were monitored in situ by solution-state NMR. In one experiment, an intermediate as described in the former mechanistic proposal was observed. However, incorporation of 13C isotope labels into multiple sites of the heterocycle could not be reconciled with the “regioselective mechanism”. It was found that an unproductive reaction pathway can lead to 13C scrambling, along with metathetical carbonyl exchange. According to DFT calculations, the concurring reaction pathways are connected via a thermodynamically controlled cyclic 1,3-oxazetidine intermediate. The obtained insights were applied in a synthetic study including aliphatic ketones and para-substituted benzaldehydes. The mechanistic peculiarities set the potential synthetic scope of the novel reaction type.
Highlights
Thiosemicarbazide (I) and the closely related thiosemicarbazones (II) and isothiosemicarbazones (III) have been synthetically exploited over decades (Scheme 1A)
After early applications in the qualitative analysis of aldehydes and ketones,[1] the applicative focus later shifted toward their use as ligands in coordination chemistry.[2−4] Compounds I−III were soon identified as versatile starting materials in organic synthesis offering four distinct nucleophilic centers and allowing cascade reactions to give various heterocyclic compounds.[5−8] Even after more than 100 years of research,[9] unprecedented reaction outcomes of these starting materials have still been recently reported.[10]
We further investigated the reactivity of benzaldehydes with different electron-donating and -withdrawing para-substituents (−H, −Me, −OMe, −Cl, and −NO2)
Summary
Thiosemicarbazide (I) and the closely related thiosemicarbazones (II) and isothiosemicarbazones (III) have been synthetically exploited over decades (Scheme 1A). Depending on the substitution patterns of the starting materials, a nucleophilic attack of the carbonyl oxygen onto the iminic carbon in intermediate i can alternatively result in the formation of a cyclic 1,3-oxazetidine intermediate (v) This can lead to the activation of pathway B (Scheme 2, highlighted in blue) upon its dissociation to intermediate i′. As expected from the mechanistic study, the reaction using aliphatic ketones and starting materials with different substitution patterns led to complex product mixtures according to 13C NMR spectra of the collected raw products This is a consequence of the low energetic barrier of the 1,3oxazetidine intermediate activating both scrambling and the carbonyl exchange reaction. Attempts to induce a similar alkyl shift in 7b through incubation of the NMR tube at 95 °C were not successful
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