Base-Promoted Cascade Transformation of Tetrahydropyrimidinones into Novel Tricyclic bis-Diazepinones

In the presence of strong bases (NaH, DBU, KOH), ethyl 4-chloromethyl-6-methyl-2-oxo1,2,3,4-tetrahydropyrimidine-5-carboxylate and 4-mesyloxymethyl-6-methyl-5-tosyl-1,2,3,4tetrahydropyrimidin-2-one are transformed into novel tricyclic compounds, diethyl 9-methyl-5methylene-3,11-dioxo-2,3,4,5,6a,7,10,11-octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]triazocine-6,8(1H)-dicarboxylate and 9-methyl-5-methylene-6,8-ditosyl-1,2,4,5,6,6a,7,10octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]triazocine-3,11-dione, respectively.


Introduction
Biginelli compounds, 1, are readily available heterocycles 1 with a wide range of biological activity (Scheme 1). 2 In contrast, their seven-membered analogues 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.
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. 5,6Subsequent 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.

Results and Discussion
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).Preliminary elucidation of the structure using 1 H and 13 C NMR showed that compound 5 contained two ethoxycarbonyl groups, three NH groups of two urea fragments, a methyl group attached to a double bond, and an exocyclic methylene group and did not contain any chloromethyl groups.The number of carbon and hydrogen atoms equaled 18 and 24, respectively.
The specific features of the 1 H NMR spectra of 5 are the presence of a long range coupling constant 5 J 7-H(a),9-CH3 = 1.7 Hz, which is typical for diazepinones 2, 5,6 and the zero value of the vicinal constant J 1-H,13-H(b) .The significant difference in the chemical shifts of the geminal protons 7-Hb and 7-Ha (0.83 ppm in DMSO-d 6 and 1.26 ppm in pyridine-d 5 ) was also noticeable and may be explained by the presence of the two neighboring anisotropic ethoxycarbonyl groups.

Conclusion
In conclusion, we have found that, under anhydrous basic conditions, the fate of Biginelli compound 4 strongly depends on the nucleophilicity and the polarity of the reaction medium.