Convenient One-Pot Four-Component Synthesis of 6,8-Disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones via a Triple Mannich Reaction
Ahmed F. M. EL-Mahdy A B C , Hassan A. H. El-Sherief A C and Zainab A. Hozien A
+ Author Affiliations
- Author Affiliations
A Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt.
B Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
C Corresponding authors. Email: ahmedelmahdy@mail.nsysu.edu.tw; hassan.elsherief@science.au.edu.eg
Australian Journal of Chemistry 72(7) 542-554 https://doi.org/10.1071/CH19088
Submitted: 22 February 2019 Accepted: 15 April 2019 Published: 21 May 2019
Abstract
An efficient and simple one-pot four-component protocol has been developed and performed for the synthesis of 6,8-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones, involving a triple Mannich reaction of 6-amino-2-(ethylthio)pyrimidin-4(3H)-one, formaldehyde, primary amines, and alcohols. Secondary amines were also utilised instead of alcohols as Mannich nucleophiles, and a variety of functional groups and electronically varied reaction partners were tolerated. This one-pot reaction facilitated the generation of a library of pyrimido[4,5-d]pyrimidin-4(3H)-ones in very good to excellent yields. The regioselectivity of this reaction was investigated using atomic charge calculations, and spectroscopic data confirmed that the triple Mannich products were 6,8-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones rather than the isomeric 3,6-disubstituted-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4(3H)-ones. The structures of all compounds synthesised using the triple Mannich reaction were confirmed via spectroscopic and elemental analyses. The reaction mechanism was studied and confirmed by isolation of the intermediate.
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