A novel four-component reaction for the synthesis of functionalised dihydropyrimidinesElectronic supplementary information (ESI) available: 1H and 13C NMR data for 9 and 10. See http://www.rsc.org/suppdata/cc/b3/b308243a

Abstract

In a multi-component reaction (MCR) of a phosphonate, nitriles, aldehydes and isocyanates, N3-functionalised dihydropyrimidines can be synthesised efficiently via a Horner-Emmons/aza Diels-Alder pathway.

Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity

“…[47] In another one-pot procedure, Kiselyov treated 54 with the dianion of methyl imidazolyl acetates 61 to yield imidazo[1,2-a]pyridines 62 (12 examples, 54-75 % yield; R 1 = H, R 2 = R 3 = Ar). [48] Our research group has also contributed to these 1azadiene-based MCRs by treating 54 with isocyanates to selectively afford functionalized 3,4-dihydropyrimidine-2ones 63 (29 examples, 15-90 % yield) [49,50] and triazinane diones 64 (17 examples, 25-91 % yield) [51,52] depending on the nature of the isocyanate (Scheme 6). The use of isocyanates with strongly electron-withdrawing groups (R 4 = Ts, p-NO 2 Ph, CO 2 Me, Bz) resulted in the exclusive formation of the dihydropyrimidones 63, thus establishing a useful and versatile alternative to the well-known Biginelli 3CR.…”

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

“…The Yi [192] example follows the traditional coupling using a nitrile instead of a urea precursor, which ultimately leads to a heterocyclic ring that contains only one nitrogen atom instead of two. Scheme 12 shows a novel [2 + 2 + 1 + 1] four-component strategy by Orru [193–194]. Since the Biginelli adduct is an even-membered ring with alternating nucleophilic and electrophilic centres, all but two of the cited examples do not involve redox chemistry and are simply characterized as condensation or coupling reactions.…”

Acyclic and Cyclic Ureas (Update 2013)

“…In this approach, reaction of a phosphonate, a nitrile, an aldehyde, and an isocyanate affords the corresponding 3,4-dihydropyrimidin-2(1H)-one (Scheme 66). [185,186] The synthesis allows wide structural variation of the nitrile and the aldehyde; variation of the phosphonate, however, is more limited. Furthermore, the reaction works best when isocyanates with electron-withdrawing substituents are used, although isocyanates with less electron-withdrawing substituents are tolerated when the reaction is performed under microwave conditions.…”

“…[187] A one-pot condensation of urea, aromatic aldehydes, and ammonium acetate in the presence of catalytic amounts of sodium hydrogen sulfate/silica gel in the absence of solvent and under microwave irradiation has been claimed to yield 6-aryl-1,2,4,5-tetrazinan-3-ones. [188] Scheme 66 Formation of N3-Substituted 3,4-Dihydropyrimidin-2(1H)-ones from a Phosphonate, a Nitrile, an Aldehyde, and an Isocyanate [185,186] …”