Modified multicomponent Biginelli–Atwal reaction towards a straightforward construction of 5,6-dihydropyrimidin-4-ones

Abstract

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Organocatalyzed Multicomponent Synthesis of Isoxazolidin-5-ones

“… This process highlighted an unprecedented asymmetric and chemoselective aza-Michael reaction to NHR 1 of pyrazolidinones 6 (R 1 = EWG) to highly reactive transient alkylidene Meldrum’s acids 7 , , unusually catalyzed at room temperature by a dedicated tertiary Brønsted base, namely (DHQ) 2 PHAL . This MCR complements racemic domino hetero-Michael–cyclocondensation reactions involving alkylidene Meldrum’s acid 7 , which usually leads to six-membered rings and, in many cases, requires harsh conditions. − Nonetheless, we were not able to extrapolate this sequence to noncyclic hydrazine showing a specific reactivity in action. We are pleased to report herein a novel development of the organocatalytic multicomponent KaMC reaction between hydroxylamines 5 and Meldrum’s acid 3 , achieving a straightforward construction of isoxazolidin-5-one derivatives 1 .…”

Water-Tuned Tautomer-Selective Tandem Synthesis of the 5,6-Dihydropyrimidin-4(3H)-ones, Driven under the Umbrella of Sustainable Chemistry

“…The crucial DHPMs scaffold is 5,6-dihydropyrimidin-4­(3 H )-one, which presents backbones or toolkit to access dihydrouracil, that is well-known as an intermediate in the catabolism of uracil, which is one of the fundamental building blocks of life. In earlier published methods, a few examples of the 5,6-dihydropyrimidin-4-ones were observed as a mixture of prototropic tautomers with very unfavorable purity (see Scheme a) . In one variation of the Biginelli–Atwal reaction, poor selectivity has been achieved (see Scheme b) .…”

“…31−34 However, Atwal proposed a different approach to obtain DHPMs in 1987, which allowed the use of isouronium salts and enones under basic conditions. 35,36 Traditional methods leading to a DHPM scaffold via Atwal's modification of the Biginelli reaction have been performed in hazardous, toxic organic solvents and reagents such as acetonitrile, 37 ethanol/Et 3 N, 38 dimethylacetamide, 39 trifluoroacetic acid, 39 and N-methyl-2-pyrrolidone. 40 Previously, all of these methods have led to undesirable drawbacks, such as complicated two-step procedures, difficult isolation, the application of special apparatus (e.g., microwave irradiation), limited-scope procedure, etc.…”

“…In earlier published methods, a few examples of the 5,6-dihydropyrimidin-4-ones were observed as a mixture of prototropic tautomers with very unfavorable purity (see Scheme 1a). 37 In one variation of the Biginelli− Atwal reaction, poor selectivity has been achieved (see Scheme 1b). 42 Both protocols performed with solvents indicate that high tautomer purity (≥99%), in Atwal's modification of the Biginelli reaction, was a very problematic synthetic challenge and, so far, it has not been achieved.…”

CsF-Catalyzed Transannulation Reaction of Oxazolones: Diastereoselective Synthesis of Diversified trans-N-(6-Oxo-1,4,5,6-tetrahydropyrimidin-5-yl)benzamides with Arylidene Azlactones and Amidines

“…Despite the privilege structure of this framework in pharmacological and biological investigations, particularly in the designing of new drug candidates, only a few synthetic routes, such as aza-Wittig reaction, azide–alkyne cycloaddition, , multi-step amidation reaction, and the modified Biginelli–Atwal reaction , are available in the literature for the synthesis of 6-oxo-1,4,5,6-tetrahydropyrimidines. However, the majority of them suffer from partial diversity or complexity associated with the usage of a multistep method under harsh conditions.…”