Open-chain ureide

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

In the currently accepted mechanistic pathway outlined in Scheme 7, the key step in the Biginelli sequence involves the acid-catalyzed formation of an Wacyliminium ion intermediate of type 719 from the aldehyde and urea precursors <1997JOC7201, 2000ACR879, 20040R1>. Interception of the iminium ion 719 by the CH-acidic carbonyl component 715, presumably through its enol tautomer, produces an open-chain ureide 720, which subsequently cyclizes to hexahydropyrimidine 721. Acid-catalyzed elimination of water from 721 ultimately leads to the... 

The first step in the mechanism of the Biginelli reaction is the acid-catalyzed condensation of the urea with the aldehyde affording an aminal, which dehydrates to an A/-acyliminium ion intermediate. Subsequently, the end form of the 3-keto ester attacks the A/-acyliminium ion to generate an open chain ureide, which readily cyclizes to a hexahydropyrimidine derivative. 

Hexobarbital is prepared by reacting together methyl urea and methyl-a-methyl-a-cyclo-hexen-1-yl-a-cyano acetate when an open-chain ureide is formed as an intermediate with the elimination of a molecule of methanol. This upon hydrolysis affords spontaneous closure of the ring thereby resulting into the formation of hexobarbital. 

In the mechanism of the Biginelli synthesis [265], the rate-determining step is the acid-catalyzed formation of an acylimine 35 from aldehyde and urea. By N-protonation (or metal-N-coordination), the imine 35 is activated (as an iminium ion) and intercepted by the P-ketoester (as enol or metal enolate) to give rise to an open-chain ureide 36, which subsequently cyclizes (via the cyclic ureide 37 and its dehydration) to afford the dihydropyrimidinone 33. Biginelli compounds of type 33 have been synthesized independently in multistep sequences [266]. 

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