Microwave‐Assisted Dimroth Rearrangement of Thiazines to Dihydropyrimidinethiones: Synthetic and Mechanistic Aspects

Abstract

The Dimroth rearrangement of a set of substituted 2-amino-6H-1,3-thiazines into 3,4-dihydropyrimidine-2-thiones was investigated. The rearrangements were carried out under microwave irradiation conditions in batch or continuous flow format, employing either toluene or 1-methyl-2-pyrrolidone as solvent. Thiazines bearing an ester group at the C5 position rearranged at a considerably higher temperature than derivatives without substituents at this position into the corresponding pyrimidinethiones. This strictly thermal rearrangement was studied in detail using differential scanning calorimetry and density functional theory computational methods. The reaction pathway involves a zwitterionic intermediate.

Multicomponent Synthesis of Dihydropyrimidines and Thiazines

“…A more detailed study on this so-called Dimroth rearrangement [33,34] will be reported elsewhere. [35] Interestingly, not only electron-withdrawing but also alkyl R 4 -substituents Scheme 6. Use of chiral inputs in the HWE/aza-DA 4CR.…”

Continuous‐flow syntheses of heterocycles

“…For example, in a scale-up run, a Fischer indole synthesis was performed resulting in the preparation of 25 g (96%) of 2,3,4,9-tetrahydro-1H-carbazole starting from phenylhydrazine and cylohexanone within 1 h at 200 C using an acetic acid/2-propanol (3:1) mixture as a solvent, thus preventing precipitation of the formed product (Scheme 8). Applying microwave heating to a glass flow cell-a standard 10-mL Pyrex vial filled with sand [20] or with glass beads [21]-the latter synthesis has been previously achieved using somewhat lower temperatures.…”

“…Using a microwave-heated glass flow cell filled with glass beads, Kappe and coworkers reported on the wellknown multicomponent Biginelli reaction, going from milligram to 25 g/h scale [21]. The standard 10-mL reaction vessel was charged with 2-mm-sized glass beads, thus creating microchannels, which affect the residence time of the reaction mixture in the microwave heating zone (Scheme 43).…”

The Scale-Up of Microwave-Assisted Organic Synthesis

“…In a related study, the group of Kappe reported on Biginelli reactions and Dimroth rearrangements comparing batch and CF techniques (Scheme 17) [77]. Similar to the above-mentioned setup, a corresponding CF coil for the CEM Voyager unit was charged with 2 mm-sized glass beads in order to create microchannels, which result in increased residence time of the reaction mixture in the microwave heating zone (Fig.…”

“…The described setup was initially evaluated with the well-known Biginelli reaction going from a milligram to a 25 g h -1 scale, and furthermore extended to the microwave-assisted rearrangement of thiazines (Scheme 17). The Biginelli reaction was carried out with equimolar ratios of the building blocks in a concentration of 1.3 M at an adjusted flow-rate of 2 mL min -1 , resulting in an [77] identical residence time compared with the batch attempt. In contrast, the Dimroth rearrangement was performed with a flow-rate leading to an almost doubled residence time of the substrate within the microwave heating zone compared to the batch experiments.…”