Unprecedented base-promoted cascade transformation of a pyrimidinone derivative into a novel tricyclic bis-diazepinone
✍ Scribed by Anatoly D. Shutalev; Anastasia A. Fesenko; Dmitry A. Cheshkov; Dmitry V. Goliguzov
- Book ID
- 104095378
- Publisher
- Elsevier Science
- Year
- 2008
- Tongue
- French
- Weight
- 248 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0040-4039
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✦ Synopsis
Biginelli compounds, 1, are readily available heterocycles 1 with a wide range of biological activity (Scheme 1). 2 In contrast, their seven-membered analogs 2 are poorly accessible. Although several of these compounds have demonstrated promising antihypertensive action, 3 further studies of biological activity of compounds 2 are hindered by the lack of efficient methods for their preparation.
The only reported approach to diazepinones 2 consists of the treatment of 1 (R = Me, Et; R 1 = CH 2 Cl; R 2 = Me, Ph) with nucleophilic agents such as NaBH 4 , NaCN, sodium malonate, Grignard reagents, sodium succinimide, MeONa, and EtONa (Scheme 1). [3][4][5][6][7] The formation of diazepinones 2 was postulated to proceed via proton abstraction from N(1)H followed by intramolecular nucleophilic substitution at CH 2 Cl to give a bicyclic intermediate 3 containing a cyclopropane ring. 5,6 Subsequent ring expansion in 3 led to diazepinones 2. Summarizing their observations, the authors 5,6 concluded that the basic properties of the nucleophilic agent were important for the success of the reaction.
In our attempt to reveal the mechanistic details of this transformation, we studied the reaction of 1 with strong, non-nucleophilic bases without addition of nucleophilic agents using readily available pyrimidinone 4 5,6 as a model compound.
When treated with NaH (1.1 equiv) in anhydrous MeCN at room temperature, compound 4 rapidly reacted to form, as evidenced by TLC, a single product 5 which was isolated after evaporation and aqueous work-up in 78% yield (Scheme 2). 8 Preliminary elucidation of the structure using 1 H and 13 C NMR 9 showed that com-