Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• aldehyde, urea and a 1,3-dicarbonyl compound [26][27]. In these reactions, the use of catalytic Cu(OTf)2 proved to be an excellent triflate surrogate, also revealing a remarkable reuse activity. The first example of a Biginelli reaction carried out with Cu(OTf)2 catalysis was reported by Sudalai and co

• Biginelli reaction was carried out starting from salicylaldehyde providing hydroxyphenyl-substituted dihydropyrimidines 18 [30]. Subsequently, the regioselective oxidation of the dihydropyrimidine ring in the presence of CAN allowed the formation of new pyrimidinone derivatives 19. The efficacy of Cu(OTf)2

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• presented in Scheme 7 in good yield with no observed deuterium scrambling. The 19th century Biginelli reaction utilizes an arylaldehyde, urea, and acetoacetate component to give 3,4-dihydropyrimidin-2(1H)-ones [46]. Such molecules are widely used as calcium channel blockers and antihypertensive agents

• converted to a carboxylic acid via typical saponification conditions without loss of deuterium (See Supporting Information File 1 for conditions). Biginelli reaction products, no deuterium scrambling was observed. Six site-specific deuterated Biginelli products are revealed in good yield with no deuterium

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ) are the key methodology to access valuable heterocycles for medicinal chemistry projects. The classical Biginelli reaction (1893) is an acid-catalyzed, three-component reaction between an aldehyde, β-ketoester, and urea that produces 3,4-dihydropyrimidin-2(1H)-ones, also known as DHPMs (Scheme 1A

• original Biginelli reaction shown in Scheme 1A was significantly extended by variation of the 1,3-dicarbonyl-containing building blocks. Many groups have elegantly demonstrated the synthetic versatility of numerous enolizable carbonyl components, including β-keto esters, cyclic/acyclic β-diketones, β-keto

• acidic conditions since such conditions enhance the selectivity, so various catalysts, mainly acidic, were tested for the model Biginelli reaction and the results are shown in Table 1. One of the most effective promoters for this type of reaction is TMSCl [29][30][31] and we also tried to involve TMSCl

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• materials to inductively heat up glass reactors. For the Biginelli reaction solubility of the starting urea (22) as well as the products 24a and 24b were an issue being overcome by using a solvent mixture of PEG/DMF 1:1. Also the proline-catalyzed asymmetric Mannich reaction was achieved with cyclohexanone

Synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylates from deep eutectic mixtures

• Sangram Gore,
• Sundarababu Baskaran and
• Burkhard König

Beilstein J. Org. Chem. 2022, 18, 331–336, doi:10.3762/bjoc.18.37

• (Mtb) [19]. Owing to the biological significance of 5-unsubstituted dihydropyrimidinones, a variety of multistep protocols has been reported for the synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones [20][21]. Typically, dihydropyrimidinones are obtained via a Biginelli reaction leading to an

• ester group at C5 and an alkyl group at C6 position. A group of researchers from Merck reported the synthesis of 5-unsubstituted DHPMs via a Biginelli reaction followed by saponification of the ester and subsequent decarboxylation [22]. Later, Bussolari and McDonnell demonstrated the synthesis of 5

• -unsubstituted 3,4-dihydropyrimidinone-4-carboxylate derivatives by employing oxalacetic acid as a β-ketoester equivalent in the presence of TFA via a Biginelli reaction [23]. Lam and Fang reported the same synthesis under microwave conditions [24]. Very recently, Kambappa and co-workers reported a one-pot

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• anticancer activities (72, Figure 6) [66][67][68][69] prompted chemists to develop newer methodologies for the synthesis of pyrimidinones with atom economy and high yields. The Biginelli reaction is one of the frequently employed MCRs for the synthesis of dihydropyrimidinones. The classical Biginelli

• reaction suffers from drawbacks such as harsh reaction conditions, longer reaction time and low yields [70]. Several attempts have been made to improve the reaction conditions using various catalyst/reagents, ionic liquids etc. [71][72]. Contributing to this need, dos Anjos et al. [73] reported a base

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

• Kumar Godugu,
• Venkata Divya Sri Yadala,
• Mohammad Khaja Mohinuddin Pinjari,
• Trivikram Reddy Gundala,
• Lakshmi Reddy Sanapareddy and
• Chinna Gangi Reddy Nallagondu

Beilstein J. Org. Chem. 2020, 16, 1881–1900, doi:10.3762/bjoc.16.156

• Biginelli reaction is a renowned and tunable MCR to synthesize the pharmacologically active 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs, Biginelli products) [31]. These compounds occupy an important position in the fields of natural products and synthetic organic chemistry owing to their potential

• pharmacological properties [32][33][34][35][36][37]. A wide variety of Brønsted acids and Lewis acids are employed as efficient catalysts for the Biginelli reaction [38][39][40][41][42][43][44][45][46][47]. In addition, some transition metal-based catalysts and a few nonacidic inorganic salts are also utilized as

• catalysts for the above reaction [48][49][50][51][52][53][54][55][56][57][58]. Only few basic catalysts, such as t-BuOK, Ph3P, and ʟ-proline are reported for the Biginelli reaction [59][60][61]. 2-Amino-4-aryl-3,5-dicarbonitrile-6-sulfanylpyridines have gained considerable attention due to their wide

Stereoselective Biginelli-like reaction catalyzed by a chiral phosphoric acid bearing two hydroxy groups

• Xiaoyun Hu,
• Jianxin Guo,
• Cui Wang,
• Rui Zhang and
• Victor Borovkov

Beilstein J. Org. Chem. 2020, 16, 1875–1880, doi:10.3762/bjoc.16.155

• DHPMs becomes an urgent and paramount task. In connection with this, multicomponent Biginelli and Biginelli-like reactions of aldehydes, urea/thiourea, and enolizable carbonyls revealed as very efficient tools to prepare DHPMs [3]. Although the Biginelli reaction was firstly discovered over a century

• described the efficient asymmetric Biginelli reaction with a chiral ytterbium catalyst to provide excellent enantioselectivities up to >99% ee [12]. Later, Gong reported the first organocatalytic Biginelli reaction using 1,1'-bi-2-naphthol (BINOL) derived chiral phosphoric acids as catalysts, furnishing the

• compound making its application highly attractive from the viewpoint of sustainability and green chemistry. Recently, our group reported an asymmetric Biginelli reaction catalyzed by a new chiral phosphoric acid derived from natural tartaric acid, that yielded a high enantioselectivity (up to 99% ee) [17

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• steroids. To our knowledge, there are no reports of fused heterocyclic or carbocyclic rings on the ring C of the steroid. In this section, we discuss different reports on the synthesis of steroid-fused heterocycle using MCRs. Wang et al. [39] developed a synthetic route based on the Biginelli reaction for

• , etc. The urea component has the main structural restrictions, since monosubstituted alkyl ureas work well but thioureas have provided much lower yields. Wang et al. produced a library of steroidal [17,16-d]pyrimidine derivatives such as 40 employing a particular extension of the Biginelli reaction

• the preparation of steroidal derivatives with a pyrimidine moiety fused to ring D. This heterocycle moiety appears in different biologically active steroids fused to ring D, and previous non-MCR methods had been reported for the creation of libraries of such hybrid compounds [40]. The Biginelli

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• through the enolate mechanism and complete noncovalent catalysis still needs further investigation. Biginelli reaction The catalysts 69f–j (Figure 8) were successfully applied to the enantioselective multicomponent Biginelli reaction of benzaldehyde, ethyl acetoacetate and urea [68]. The results show that

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• intermediate β-enaminone which further reacted with α-iodoketone following by a cyclo-condensation which resulted in the substituted pyrroles shown in Scheme 31. The Biginelli reaction is a well-known 3-component reaction for the synthesis of dihydropyrimidinones [124][125]. During the last few decades many

• reaction medium, solvent-free synthesis, microwave synthesis, use of different Lewis acids FeCl3, NiCl2, BiCl3, InBr3, use of Brønsted acids PTSA, etc. are also reported [129][130]. Recently, Mal and co-workers reported a mechanochemical Biginelli reaction by a subcomponent synthesis approach [131][132

• [120]. Mechanochemical Hantzsch pyrrole synthesis [121]. Mechanochemical Biginelli reaction by subcomponent synthesis approach [133]. Mechanochemical asymmetric multicomponent reaction[134]. Mechanochemical Paal–Knorr pyrrole synthesis [142]. Mechanochemical synthesis of benzothiazole using ZnO nano

Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

• Andreas C. Boukis,
• Baptiste Monney and
• Michael A. R. Meier

Beilstein J. Org. Chem. 2017, 13, 54–62, doi:10.3762/bjoc.13.7

• Andreas C. Boukis Baptiste Monney Michael A. R. Meier Karlsruhe Institute of Technology (KIT), Institute of Organic Chemistry, Materialwissenschaftliches Zentrum MZE, Building 30.48, Straße am Forum 7, 76131 Karlsruhe, Germany 10.3762/bjoc.13.7 Abstract The Biginelli reaction was combined with

• reactions, a large number of structurally diverse compounds could be synthesized. In addition, a one-pot Biginelli–Passerini tandem reaction was demonstrated. All products were carefully characterized via 1D and 2D NMR as well as IR and HRMS. Keywords: Biginelli reaction; molecular diversity

• , hence both reactions will be described in detail. The Biginelli reaction The Biginelli reaction is a three-component reaction between an aldehyde (in many cases aromatic aldehydes give much better results than aliphatic ones), a β-keto ester (α-acidic compound) and urea or thiourea (some mono N

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

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• strategies. Biginelli adduct The Biginelli reaction [163][164][165] is by far the most studied multicomponent reaction since its discovery in 1891 with nearly 2000 citations in the literature. The 3,4-dihydro-1H-pyrimidin-2-one adduct has been made essentially by one [3 + 2 + 1] strategy via condensation of

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• carbonyl compounds such as β-diketones, β-keto thioesters, acetoacetamides and nitroacetone have been shown to participate in the classical Biginelli reaction [25], β-ketophosphonates 6 were found to be unreactive in similar conditions [26]. However, Yuan et al. developed a modified Biginelli condensation

• peptidomimetics possessing phosphonate groups by MCR-based strategies would significantly extend the synthetic potential of MCRs towards heterocyclic phosphonates. The Biginelli condensation. The Biginelli reaction of β-ketophosphonates catalyzed by ytterbium triflate. Trimethylchlorosilane-mediated Biginelli

• reaction of diethyl (3,3,3-trifluoropropyl-2-oxo)phosphonate. Biginelli reaction of dialkyl (3,3,3-trifluoropropyl-2-oxo)phosphonate with trialkyl orthoformates and urea. p-Toluenesulfonic acid-promoted Biginelli reaction of β-ketophosphonates, aryl aldehydes and urea. General Kabachnik–Fields reaction for

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• both electron-poor and electron-rich aldehydes. The four-component variant of the reaction employing 2-thiouracil led to compound 72 with a slightly lower yield than those obtained from pseudo-four component cascade leading to compounds 71. 5. The Biginelli reaction The Biginelli reaction (Scheme 26

• asymmetric Biginelli reaction have been reviewed [97]. The reaction has been employed in the synthesis of C-nucleosides with 3,4-dihydropyrimidin-2(1H)-one or 3,4-dihydropyrimidin-2(1H)-thione as the nucleobase mimic. Up to date, depending on the role of the carbohydrate component in the reaction, C

• the previously reported Biginelli reaction [103], compounds 85 were obtained in high yields under the TCT-catalysis conditions. A pyranose-derived nucleoside analog was also prepared by this method. Using compound 87 as an example (Scheme 34), the Dondoni group demonstrated that the C-nucleosides with

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

• Mrinal K. Bera,
• Moisés Domínguez,
• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 394–404, doi:10.3762/bjoc.10.37

• powerful tools for the assembly of small-molecule libraries [1][2]. MCRs leading to functionalized N-heterocycles [3][4][5][6][7] have long been known before the general concept of MCRs was introduced, e.g. the Hantzsch dihydropyridine synthesis [8] or the Biginelli reaction [9] leading to

Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

• Jie-Ping Wan,
• Yunfang Lin,
• Kaikai Hu and
• Yunyun Liu

Beilstein J. Org. Chem. 2014, 10, 287–292, doi:10.3762/bjoc.10.25

• attractiveness in biological and medicinal researches, DHPMs have also been demonstrated as quite flexible precursors for the synthesis of many other derived heterocyclic scaffolds [13]. For a rather long period, the Biginelli reaction involving the condensation of aldehydes, β-ketoesters and ureas (thioureas

• ) [14] has been dominantly employed for DHPMs synthesis in both racemic [15][16][17][18] and asymmetric versions [19][20][21][22][23]. Despite of many recognized advantages of the Biginelli reaction, the product diversity suffered from limitations because β-ketoesters or 1,3-diketones are intrinsically

• required as donors of the C5–C6 fragment in this reaction, which predetermined the presence of a C6 substitution in the produced DHPMs. On the other hand, DHPMs without a substituent at the C6 site were hardly accessible by the classical Biginelli reaction, probably because of either the rare availability

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• Biginelli reaction and for the preparation of N3-substituted dihydropyrimidinone 10 by Dimroth rearrangement of 1,3-thiazine 9 [46]. In these studies, the 10 mL flow cell was loaded with glass beads and irradiated at 120 or 200 °C, respectively, to give the target heterocycle in yields that compared very

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• is assessed by studying four reactions, all involving formation of products bearing α,β-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen–Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by

• product conversions of 66−98% depending on how electron rich or deficient the aromatic ring of the aldehyde was (Table 3). The Biginelli reaction As our final reaction for study, we turned to the Biginelli reaction (Scheme 4) [43][44][45][46][47][48]. This acid-catalyzed cyclocondensation of urea, β

• -ketoesters and aromatic aldehydes to yield dihydropyrimidines has received significant attention, these products having pharmacological activity including calcium channel modulation, mitotic kinesin Eg5 inhibition, and antiviral and antibacterial activity [49][50]. The Biginelli reaction has been performed

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

• Marcus Frings,
• Isabelle Thomé and
• Carsten Bolm

Beilstein J. Org. Chem. 2012, 8, 1443–1451, doi:10.3762/bjoc.8.164

• backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic routes provide the newly designed thiourea-sulfoximine

• catalysts in high overall yields without affecting the stereohomogeneity of the sulfur-containing core fragment. Keywords: anhydride opening; catalytic asymmetric Biginelli reaction; organocatalysis; sulfoximines; thioureas; Introduction Since their discovery in the middle of the last century

• , enantioenriched dihydropyrimidines could only be obtained by special resolution methods which were not generally applicable. The search for a truly catalytic asymmetric Biginelli reaction with high enantiocontrol has proven very challenging for a long time and useful protocols have just recently been developed

Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

• Bruno Piqani and
• Wei Zhang

Beilstein J. Org. Chem. 2011, 7, 1294–1298, doi:10.3762/bjoc.7.150

• achieved by conducting a multicomponent reaction for improved atom economy, under microwave heating for fast reaction, and with fluorous solid-phase extractions (F-SPE) for ease of purification. Keywords: Biginelli reaction; dihydropyrimidine; diversity-oriented synthesis; fluorous; Suzuki coupling

• leads for AIDS therapies [2]. The Biginelli reaction of a β-keto ester, an aldehyde, and urea is considered as one of the most efficient ways to synthesize dihydropyrimidinones [3]. This acid-catalyzed reaction can be conducted under conventional or microwave heating [4][5]. Reported in this paper is a

• synthesis of heterocyclic scaffolds. The intermediates obtained from the Biginelli reaction were used for post-condensation modifications to afford biaryl-substituted dihydropyrimidinone, dihydropyrimidine, and thiazolopyrimidine compounds. A set of reaction and separation techniques such as multicomponent

Zeolite catalyzed solvent- free one-pot synthesis of dihydropyrimidin- 2(1H)-ones – A practical synthesis of monastrol

• Mukund G. Kulkarni,
• Sanjay W. Chavhan,
• Mahadev P. Shinde,
• Dnyaneshwar D. Gaikwad,
• Ajit S. Borhade,
• Attrimuni P. Dhondge,
• Yunnus B. Shaikh,
• Vijay B. Ningdale,
• Mayur P. Desai and
• Deekshaputra R. Birhade

Beilstein J. Org. Chem. 2009, 5, No. 4, doi:10.3762/bjoc.5.4

• monastrol, a potent inhibitor of kinesin Eg5. Keywords: Biginelli reaction; DHPMs; neat; MCR; zeolite; Introduction The Biginelli reaction is a well-known multicomponent reaction involving a one-pot cyclocondensation of an aldehyde, β-ketoester and urea/thiourea [1][2][3]. Multicomponent reactions (MCRs

• diverse important biological activities like antiviral, antitumor, antibacterial and antiinflammatory properties [11][12][13]. The first report of the Biginelli reaction dates back to 1893. This involved a very simple and straightforward procedure for the synthesis of DHPMs. A one-pot cyclocondensation of

• aliphatic aldehydes and thiourea were used low yields of DHPMs were realized. Results and Discussion We herein report a one-pot synthesis of DHPMs using a catalytic amount of zeolite under solvent-free conditions. In our quest to bring about the Biginelli reaction, we attempted the reaction using zeolite