DFT study on mechanism of the classical Biginelli reaction

The condensation of benzaldehyde, urea, and ethyl acetoacetate according to the procedure described by Biginelli was investigated at the B3LYP/6-31G（d）, B3LYP/6-31 ＋G（d,p）, and B3LYP/6-311＋G（3df,2p）//B3LYP/6-31＋G（d,p） levels to explore the reaction mechanism. According to the mechanism proposed by Kappe, structures of five intermediates were optimized and four transition states were found. The calculation results proved that the mechanism proposed by Kappe is right.     

Dichloroacetylaroylmethanes as two-carbon synthons in the Biginelli reaction

Acid-catalyzed cyclocondensation in a three component system of dichloromethylacetylbenzoylmethanes, urea, and aromatic aldehydes occurred regio-and stereoselectively to give polyfunctional derivatives of perhydropyrimidine. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1414–1417, September, 2006.     

A mechanistic investigation of Biginelli reaction under base catalysis

The mechanism of the three component base mediated Biginelli dihydropyrimidines synthesis was investigated using Accurate Mass TOF LC-MS-ESI and Tandem TOF LC-MS-ESI. We suggest hemiaminal as a possible intermediate leading to the formation of Biginelli product. Under our current experimental conditions we did not observe any bis-ureide as reported by ji et al.     

Versatility of the Biginelli reaction: Synthesis of new biphenyl dihydropyrimidin-2-thiones using different ketones as building blocks

A multi-component synthesis of biphenyl dihydropyrimidin-2-thiones from 1-phenylthiourea, aldehydes and ketones or di-ketones has been demonstrated. The reaction proceeded well for aldehydes with electron donor or acceptor substituents under mild conditions.     

Biginelli reaction for synthesis of novel trifluoromethyl derivatives of bis(tetrahydropyrimidinone)benzenes

A facile one-pot three-component condensation of terephthalic aldehyde with urea and fluorinated 1,3-dicarbonyl derivatives is developed using catalytic quantities of chlorotrimethylsilane at ambient temperature. As a consequence, efficient synthesis of novel trifluoromethyl derivatives of bis(tetrahydropyrimidinone)benzenes is observed within short time periods. The procedure is shown to be equally efficient when urea is replaced with thiourea or guanidine.     

Biorenewable and mercaptoacetylating building blocks in the Biginelli reaction: synthesis of thiosugar-annulated dihydropyrimidines

A novel version of the Biginelli reaction using an unprotected aldose as a biorenewable aldehyde component and 2-methyl-2-phenyl-1,3-oxathiolan-5-one as a mercaptoacetylating active methylene building block with urea/thiourea is reported. The reaction is nanoclay-catalysed, expeditious and effected under solvent-free microwave irradiation conditions in a one-pot procedure to yield diastereoselectively, thiosugar-annulated multifunctionalized dihydropyrimidines via intramolecular domino cyclocondensation reactions of an isolable intermediate.     

Features of two- and multicomponent heterocyclization reactions involving 3,4-disubstituted 5-aminopyrazoles and alkyl pyruvates

Three-component heterocyclizations of pyruvic acids and their esters with 5-aminopyrazoles and aromatic aldehydes, in addition to the sequential versions of these reactions, under different activating conditions were studied. Under conventional heating, pyrazolopyrimidine derivatives containing a hydroxyl group in the 6-position were formed in both two- and three-component treatments. Whereas the application of an inert atmosphere did not influence the outcome of these reactions, the use of ultrasonic irradiation led to the formation of 7-hydroxy-tetrahydropyrazolopyrimidines in multi-component reactions and 6-hydroxy-dihydropyrazolopyrimidines in the case of a step-by-step approach. The products of the latter treatment were further transformed into heteroaromatized 6-hydroxy-pyrazolopyrimidines by conventional heating.     

A facile synthesis of clay – graphene oxide nanocomposite catalysts for solvent free multicomponent Biginelli reaction

In the present study, clay – graphene oxide nanocomposite catalysts were successfully used for the first time in the multicomponent one pot organic synthesis. The facile development of the hybrid clay – graphene oxide nanocomposite has been achieved by a cost-effective method without the use of any surfactants. The partial reduction of graphene oxide, upon incorporation of clay layers and subsequent heat treatment, is evident from the X-ray diffraction patterns and FTIR spectra of the samples. X-ray photoelectron spectroscopy as well as ²⁷Al and ²⁹Si NMR spectral analyses provided useful information regarding the interaction between clay layers and graphene oxide through SiOC and AlOC bonding. The deconvoluted XPS spectrum of O (1s), Al (2p) and Si (2p) indicates the increased availability of acidic functionalities in the hybrid nanocomposite. FESEM and TEM photographs show the random distribution of the clay nanoflakes over the graphene oxide sheets and this may be the reason for the availability of more of the active sites for catalysis. Synthesis of 3,4-dihydropyrimidinones by the one pot Biginelli reaction was done over the present clay – graphene oxide heterogeneous catalysts with high product yield. Short time period of reaction and excellent reusability up to 8 repeated cycles under solvent free conditions are the key advantages of the present highly active hybrid nanocomposite clay – graphene oxide catalysts over most of the other reported catalysts used for Biginelli reaction.     

Hydrogen-bonding 2D metal-organic solids as highly robust and efficient heterogeneous green catalysts for Biginelli reaction

Two new Zn(II) and Cd(II) MOFs have been synthesized. These MOFs have been applied as heterogeneous catalysts for the green synthesis of a variety of dihydropyrimidinone derivatives through the Biginelli reaction and the desired products were obtained in high yields with short reaction time under mild solvent-free conditions. Moreover, the MOF catalysts may be readily recovered after the reaction and reused for many cycles.     

Rapid formation of chemical complexity via a modified Biginelli reaction leading to dihydrofuran-2(3H)-one spiro-derivatives of triazolo[1,5-a]pyrimidine

The regio- and stereoselective, catalyst-free multicomponent synthesis of spiro-conjugated dihydrofuran-2(3H)-one/triazolo[1,5-a]pyrimidine derivatives in good to high yields via a Biginelli approach starting from ortho-substituted benzaldehydes, 3-amino-1,2,4-triazole and α-acetylbutyrolactone is reported. A plausible reaction mechanism for this transformation is discussed. The obtained heterocycles possess a drug-like conformationally restricted structure with defined stereochemistry and increased stability compared to other products obtained by this mode of the Biginelli reaction.     

Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles

A small library of 2-oxo-5-(hetero)arylpyrroles was prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The large synthetic possibilities of these 2-oxopyrroles were investigated. The 2-oxopyrroles offer a large number of possible derivatizations including reactions with electrophiles. The chloroformylation of 2-oxo-5-(hetero)arylpyrroles provides pyrrole carbaldehydes. Some pyrrole carbaldehydes were used to synthesize polycyclic compounds like pyrrolo[3,4-d]pyridazinones, a thienopyrrole, a pyrrolobenz[1,4]oxazepine, a pyrrolobenzo[1,4]thiazepine, and a pyrrolobenzo[1,4]diazepine. Hereby we showed through a short exploration that the oxopyrroles and analogues are interesting and versatile synthetic building blocks.     

Integration of high speed microwave chemistry and a statistical ‘design of experiment’ approach for the synthesis of the mitotic kinesin Eg5 inhibitor monastrol

The rapid preparation of the mitotic kinesin Eg5 inhibitor monastrol has been performed using multicomponent chemistry and combining microwave-assisted synthesis and a statistical design of experiments (DoEs) approach. By variation of the solvent, catalyst type and concentration, reaction time, and temperature a matrix of experiments for the DoE method was derived. As a result of 29 experiments with reaction times ranging from 10 to 30 min, an optimized procedure was derived that allowed the preparation of monastrol in 82%.     

A one-pot Biginelli synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones catalyzed by triphenylphosphine as Lewis base

We report herein the use of triphenylphosphine (TPP) as a new catalyst for the one-pot Biginelli reaction coupling of β-ketoesters, aldehydes and urea (or thiourea) to afford the corresponding dihydropyrimidinones/thiones.     

A Different Role of Meldrum's Acid in the Biginelli Reaction

A Biginelli‐type condensation using Meldrum's acid has been accomplished in refluxing AcOH to give 6‐substituted dihydropyrimidine‐2,4‐(1H,3H)‐diones. In contrast to other aldehydes, the three‐component reaction with salicylaldehyde led to an oxygen‐bridged pyridine. A reaction mechanism is proposed.     

Biginelli reaction starting directly from alcohols

An efficient of one-pot oxidative access to 3,4-dihydropyrimidin-2-(1H)-ones directly from aromatic alcohols under mild conditions is reported. The protocol involves 1-methylimidazolium hydrogen sulphate [Hmim]HSO₄ catalyzed oxidation of aromatic alcohols to aromatic aldehydes with NaNO₃ followed by their cyclocondensation with 1,3-dicarbonyl compounds and urea in the same reaction vessel at 80 °C within 2-4 h to afford 3,4-dihydropyrimidin-2-(1H)-ones in 55-97% overall yields. Thus, the present work utilizing alcohols instead of aldehyde in Biginelli reaction is a valid and green alternative to the classical synthesis of 3,4-dihydropyrimidin-2-(1H)-ones.     

MCM-41 anchored sulfonic acid (MCM-41-R-SO3H): A mild, reusable and highly efficient heterogeneous catalyst for the Biginelli reaction

An efficient three-component synthesis of 3A-dihydropyrimidinones using MCM-41 anchored sulfonic acid (MCM-41-R-SO3H) as a mild, heterogeneous catalyst for Biginelli reaction in CH3CN under reflux condition is described.     

First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction

For the first time hexaaquaaluminium(III) tetrafluoroborate has been used as a mild acid catalyst in organic synthesis. A simple method of its preparation based on the reaction of aluminium triisopropoxide and tetrafluoroboric acid in isopropanol afforded catalyst of high purity and activity. The three-component Biginelli condensation of acetoacetate esters, urea and aldehydes catalyzed by 10 mol % of [Al(H₂O)₆](BF₄)₃ in refluxing acetonitrile afforded 3,4-dihydropyrimidonones in good to high yields on multigram scales. The tolerance to acid sensitive reactants such as thienyl and furyl carbaldehydes, applicability to sterically hindered β-ketoesters and simple recyclability without losing catalytic activity make this catalyst as good replacement to literature methods. The mechanism of the reaction includes formation of the so called ‘ureido-crotonate’ rather than corresponding acylimino intermediate as found with Brønsted type catalysts.     

A green synthesis of dihydropyrimidinones by Biginelli reaction over Nafion-H catalyst

A Nafion-H catalyzed, single step and environmentally friendly process for synthesis of dihydropyrimidinones is described. This adopted protocol for Biginelli reaction has the advantages of reusability of the catalyst, high yields and ease of separation of pure products.     

An interrupted Ugi reaction enables the preparation of substituted indoxyls and aminoindoles

In a variation of the classical Ugi reaction, an acid-promoted reaction between imines and isocyanides forms both 3-aminoindoles and substituted indoxyls. A recently reported triflyl phosphoramide is shown to be critical to obtain high yields under mild conditions.