{"id":25824,"date":"2026-06-15T08:16:59","date_gmt":"2026-06-15T12:16:59","guid":{"rendered":"https:\/\/hepatochem.com\/biginelli-dihydropyrimidines-as-tunable-alkyl-radical-precursors\/"},"modified":"2026-07-10T12:28:10","modified_gmt":"2026-07-10T16:28:10","slug":"biginelli-dihydropyrimidines-as-tunable-alkyl-radical-precursors","status":"publish","type":"post","link":"https:\/\/hepatochem.com\/euro\/biginelli-dihydropyrimidines-as-tunable-alkyl-radical-precursors\/","title":{"rendered":"Biginelli Dihydropyrimidines as Tunable Alkyl Radical Precursors"},"content":{"rendered":"

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A new class of radical precursors from the Janssen-M\u00fcller group at G\u00f6ttingen combines the synthetic accessibility of the century-old Biginelli reaction with redox properties that outperform the standard Hantzsch ester, allowing reactions that classical dihydropyridines cannot.<\/em><\/p>\n

Hantzsch esters are one of the most useful reagents in modern photoredox chemistry. Easily made from aldehydes, bench-stable, and oxidizable under mild photochemical conditions, it has enabled a wide range of radical-mediated transformations including Giese additions, nickel-catalyzed cross-couplings, and reductive functionalization reactions. But it has a fixed redox profile, and the oxidation potentials available from the standard Hantzsch series \u2014 typically 1.0\u20131.2 V \u2014 set a ceiling on what the reagent can do.<\/p>\n

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A new paper in Chemical Science<\/em> from Shahilan Ratnam, Shreya Unone, Nabeel Alia, Enyu Denny Hafeneger, and Daniel Janssen-M\u00fcller at Georg-August-Universit\u00e4t G\u00f6ttingen introduces a new family of heterocyclic radical precursors that addresses this ceiling directly. Their work, “Biginelli dihydropyrimidines: a tunable class of alkyl radical precursors,”<\/a> shows that dihydropyrimidines (DHPyms) synthesized via the Biginelli reaction are not only competent radical precursors but are meaningfully more reducing than Hantzsch DHPs \u2014 and that their redox properties can be dialed in by changing substituents.<\/p>\n

The Biginelli reaction as a modular entry point<\/h2>\n

The Biginelli reaction condenses an aldehyde, a \u03b2-ketoester, and a urea or guanidine derivative into a dihydropyrimidine in one step. The reaction has been known since 1891 and is operationally simple: stir at 75\u00b0C in DMSO or MeCN with sodium bicarbonate as base, and isolate the product by column chromatography. What the Janssen-M\u00fcller group recognized is that the nitrogen substituent at C2 of the pyrimidine ring \u2014 the component contributed by the urea or guanidine \u2014 has a direct and predictable effect on the oxidation potential of the resulting heterocycle.<\/p>\n

Systematic variation of this substituent across five DHPym compounds revealed oxidation potentials spanning 0.68 to 1.05 V by cyclic voltammetry, with the dimethylamino-substituted compound (DHPym 1a) the most reducing. The excited state oxidation potential of 1a, calculated via the Rehm-Weller equation from absorption and emission data, is \u22122.71 V \u2014 substantially more negative than the corresponding value for the standard Hantzsch DHP. This means DHPym 1a is a significantly stronger photoreductant.<\/p>\n

What the enhanced reducing power enables<\/h2>\n

The practical consequences show up immediately in competition experiments and substrate scope. In a head-to-head photocatalyst-free Giese addition using Ni(bpy)\u2083(BF\u2084)\u2082 as an electron mediator at 405 nm, DHPym 1a outperforms the Hantzsch ester. The enhanced conversion rate is consistent with the more negative excited-state potential driving faster single-electron transfer.<\/p>\n

In Ni\/photoredox dual catalysis cross-coupling at 450 nm with 4CzIPN, the DHPym substrate scope is broad:<\/p>\n