Biginelli synthesis

The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas. 

Substantial MW rate enhancements have been reported in the Biginelli synthesis of dihydropyrimidines [50, 51] under homogeneous conditions. The synthesis involves a one-pot cyclocondensation of a /i-ketoester with an aryl aldehyde and urea or thiourea in the presence of a catalytic amount of HC1 in ethanol solution. An example of this synthesis is shown in Scheme 4.17. 

Quite recently this reaction was revisited by Kappe [91] et al. who reinvestigated the Biginelli synthesis under the action of microwave irradiation under a variety of different conditions. At atmospheric pressure in ethanol solution there is no difference from conventional heating. Under pressure the yield is reduced and byproducts are formed. In an open system rate and yield enhancements are significant and this is rationalized by the rapid evaporation of the solvent which means that this is in fact a solvent-free reaction. This was confirmed by running the reaction without solvent under the action of microwaves and with thermal heating. (Scheme 8.65)... 

The Biginelli synthesis (Scheme 3) is an important route to dihydropyrimidilies, e.g. (25),46a with many variants of the original reactants now established. The mechanism has now been re-investigated using 1H- and 13C-NMR.46b The first step does not appear to involve aldol condensation or a carbenium-ion intermediate rather, condensation of benzaldehyde and urea gives an A-acyliminium ion intermediate (26), which then goes on to react with ethyl acetoacetate. 

In a variation of the above protocol, the Biginelli synthesis was easily adapted to fluorous-phase conditions.23,24 Here a fluorous urea derivative... 

The microwave-assisted Biginelli synthesis of dihydropyrimidine was investigated in open vessels as well as sealed reaction vessels. The reaction carried out at atmospheric pressure under microwave irradiation in a solution showed no rate increase compared to... 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

Lewis acid (Yb-(III)-reagent supported on Amberlyst 15) in combination with polymer-supported urea scavenging resins (Amberlyst 15 and Ambersep 900 OH) permits a rapid parallel Biginelli synthesis with a simple and efficient purification strategy [126]. 

The classical Biginelli synthesis of heterocycles from /3-diketones, urea, and aldehydes has been extended by the replacement of the dione with a cycloalkanone.343 The... 

The classical Biginelli synthesis is a one-pot condensation using P-dicarbonyl compounds with aldehydes (aromatic and aliphatic ones) and urea or thiourea in ethanol solution containing catalytic amounts of acid. Peng et al. for the first time reported a novel method for the synthesis of dihydropyrimidinones by three-component Biginelli condensations of aldehydes with 1,3-dicarbonyl compounds and urea using room temperature ionic liquids based on [bmim][BF ] or [bmim][PFJ as catalyst under solvent-free and neutral conditions (Fig. 12.15) [11]. 

From an Aldehyde, a 1,3-Dicarbonyl-Compound and a Urea The Biginelli Synthesis ... 

In a solid-phase split-pool Biginelli synthesis of DHPMs, a urea derivative 23 studded with polystyrene macrobeads was condensed with an aldehyde to obtain a stable acylimine 24 intermediate on the bead, which upon reaction with p-ketoesters furnished 25. Upon cleavage of the resin, 25 yielded N-l functionalized DHPM derivatives 26 (Scheme 10) (04OL3237). 

Racemic monastrol 518 (R = Me, R = Et, R = W-OHC6H4, R = H) was prepared in 60% yield by MW-promoted condensation of ethyl acetoacetate, 3-hydro-xybenzaldehyde, and thiourea in a solvent-free variation of the classical Biginelli synthesis using PPE (00T1859). The racemic mixture was resolved by enantioselec-tive HPLC and the absolute configuration of the (S)-( +) enantiomer was established by CD spectroscopy. 

An MS investigation of the three-component base-mediated Biginelli synthesis of dihydropyrimidines has found evidence for a hemiacetal intermediate (117), but no sign of a bis-ureide (118). ° A prolinamide gives up to 99% ee in Biginelli cyclocondensations of urea, aldehyde, and ethyl acetoacetate. ... 

Biginelli synthesis [103] was also carried out by Kappe et al. [104] to get about 48 different products. The reactions were carried out under microwave irradiation to get nearly 52% average yield of products (Scheme 11.47). 

In a three-component process, a P-ketoester, a (preferentially aromatic) aldehyde, and urea undergo cyclocondensation catalyzed by acids, Lewis acids or metal ions to give 3,4-dihydropyrimidin-2-ones (33), whose dehydrogenation [260] leads to pyrimidin-2-ones (34) (Biginelli synthesis) [261-264] ... 

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]. 

The Biginelli synthesis shows considerable flexibility. Thus, it has been extended to other N-C-N systems like thioureas [267] or guanidines [268] in the presence of a BINOL-derived phosphoric acid as chiral organocatalyst, formation of dihydropyrimidi-nones or -thiones can be conducted enantioselectively [269]. 

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