Dihydropyrimidines

Dihydropyrimidines are heterocyclic compounds derived from pyrimidine by partial saturation of the ring, resulting in a nonaromatic six-member ring containing two nitrogen atoms. The class includes several regioisomers depending on which double bond in the pyrimidine ring is reduced, with the common 2,3-dihydropyrimidines and 4,5-dihydropyrimidines being the most encountered. The ring can bear a range of substituents at the carbon and nitrogen atoms, affecting basicity, polarity, and reactivity. Dihydropyrimidines often exist as DHPMs (dihydropyrimidinones) when a carbonyl group is present at the 2-position; they may also be obtained as neutral or zwitterionic forms depending on substitution.

Synthesis methods include selective hydrogenation of pyrimidines or cyclocondensation reactions that assemble the dihydropyrimidine ring in one step. The most prevalent medicinal-chemistry route is the Biginelli reaction, a three-component condensation of an aldehyde, a β-dicarbonyl compound, and urea or thiourea, which furnishes dihydropyrimidinones that can be further modified.

Applications center on the use of dihydropyrimidines as versatile building blocks in medicinal and synthetic chemistry. DHPMs are prominent scaffolds in the development of bioactive molecules, including enzyme inhibitors and antiviral agents, and are studied for conformational flexibility and hydrogen-bonding patterns. They also serve as intermediates in the synthesis of more complex heterocycles.

Challenges and notes include the fact that, as nonaromatic rings, dihydropyrimidines can be less chemically stable than their pyrimidine precursors and may exhibit tautomerism and variable acidity, depending on substitution. Their chemistry is active in both academia and industry, with ongoing exploration of new catalysts and reaction conditions to improve selectivity and yield.