An Expedient and Divergent Tandem One-Pot Synthesis of Pyrimidin-2,4-diones Using the Blaise Reaction Intermediate

Abstract

A novel divergent tandem one-pot method for the synthesis of 3,5,6-trisubstituted 1H-pyrimidin-2,4-dione derivatives is developed. In the presence of 10 mol % of Cu(OAc)2, the α-substituted Blaise reaction intermediates (R(2) ≠ H) reacted with isocyanates chemoselectively to afford pyrimidin-2,4-diones, whereas the α-unsubstituted Blaise reaction intermediate (R(2) = H) showed a propensity to be a C-nucleophile toward electrophiles, permitting the installation of different functionalities at the 5-position through sequential tandem reactions.

Advances in tandem reactions with organozinc reagents

“…73 Tandem Blaise/Cu-catalysis Lee and co-workers also combined the Blaise reaction intermediate with copper-catalyzed reactions for the one-pot syntheses of pyrimidine-4-ones 92 and pyrimidin-2,4-diones 94 (Scheme 28). 75,76 The intermediate 91 bearing an a-substituent (R 2 a H) reacted with nitriles in the presence of 10 mol% Cu(OAc) 2 catalyst to afford pyrimidine-4-ones 92 in up to 80% yield. With an a-unsubstituted intermediate 59 (R 1 = Ph, R 2 = H), the 5-benzoylated pyrimidin-4-one (R 1 = R 3 = Ph) was isolated.…”

Synthesis of α-enamino esters via Cu(ii)-promoted dehydrogenation of α-amino acid esters: application to the synthesis of polysubstituted pyrroles

“…1 Therefore, they have been widely used as nucleophiles and electrophiles in organic synthesis. 7 In organic synthetic chemistry, β-enamino esters are usually used as valuable reagents in the synthesis of various heterocycles, such as pyrroles, 8 indoles, 9 pyridines, 10 quinolines, 11 pyrimidineones, 12 pyrazoles, 13 amino-furanones 14 and so on. For the synthesis of β-enamino esters, based on the classical condensation reaction between keto-esters and amines, 3 there have been general and efficient methods developed by Wang 4 and Menéndez 5 as well as several novel and efficient routes reported by Pellicciari, 6 Muthusubramanian 1a and Burgess.…”

“…For the synthesis of β-enamino esters, based on the classical condensation reaction between keto-esters and amines, 3 there have been general and efficient methods developed by Wang 4 and Menéndez 5 as well as several novel and efficient routes reported by Pellicciari, 6 Muthusubramanian 1a and Burgess. 7 In organic synthetic chemistry, β-enamino esters are usually used as valuable reagents in the synthesis of various heterocycles, such as pyrroles, 8 indoles, 9 pyridines, 10 quinolines, 11 pyrimidineones, 12 pyrazoles, 13 amino-furanones 14 and so on. Meanwhile, they also act as key intermediates in the total synthesis of natural products.…”

Tandem One-Pot Synthesis of Polysubstituted NH-Pyrroles Involving the Palladium-Catalyzed Intramolecular Oxidative Amination of the Zinc Bromide Complex of β-Enamino Esters

“…During our continuing studies on the tandem use of the Blaise reaction, we have found that the Blaise reaction intermediate A , formed by reaction of nitriles 1 with Reformatsky reagents, could react chemo- and regioselectively with 1-alkynes to afford the corresponding α-vinylated β-enamino esters. Mechanistic studies suggested that a zinc bromide complex of α-vinylated β-enamino ester B was formed as a second intermediate .…”