Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• industrialized total synthesis of a nontrivial natural product. The original experimental protocol was recently improved by replacing the inorganic base (KOH, NaOH) with the amidine base diazobicycloundecane (DBU) as well as ethanol with n-propanol [49]. The type-III Guareschi reaction is a three-component

• reaction reported in 1898 [50]. It involves the reaction of a β-dicarbonyl (ester or diketone) with a primary amine or ammonia and a cyanoacetic ester. The mechanism of this condensation closely resembles the three-component version of the Hantzsch pyridine synthesis and generates 6-hydroxypyridones. Also

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

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

• ; 4, Figure 1) [36][37]. The relevance of acridine in drug discovery galvanized Singh and co-workers [38] to develop a water-promoted three-component reaction involving aldehydes 5, cyclic 1,3-diketone 6 and ammonium acetate powered by microwave irradiation resulting in 4-arylacridinediones 7 in

• with N,O-acetyl intermediate E, this may lead to the formation of a very hindered intermediate C via SN2 inversion of B and thus favors the involvement of pathway A rather than pathway B. Simultaneously, Li and co-workers [46] reported a three-component reaction for the synthesis of benzo[f]azulen-1

• marketed drugs structured around indole implying its pharmacological significance such as oxypertine (27), ateviridine (28) [47] and spirooxindole-based potent cytotoxic agents 29, 30 and 31 [48]. In 2017, Lin and co-workers [49] designed a TFA-catalyzed three-component reaction for the regioselective

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• -bond adduct. The first light-promoted three-component reaction has been realized by a halogen-bond adduct, forming perfluoroalkylated pyrimidines 26 (Scheme 8). A variety of perfluorinated chains were assembled with methylene compounds and guanidines or amidines, giving the corresponding

• three-component reaction in the absence of light, which is of great significance for the later study of temperature-driven EDA complexes. In 2017, König and colleagues [42] discovered an EDA complex 75 formed by bromothiophene 72, aniline (73), and N,N-diisopropylethylamine (DIPEA) as organic base

• the subsequent reaction (Scheme 28). On account of a wide range of substrates and functional group compatibility, this protocol can be exploited to assemble various β-trifluoromethylated alkynes by three-component reaction without transition-metal catalysis. In 2018, Xu and colleagues [48] proposed

Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes

• Yajing Zhang,
• Qingshan Tian,
• Guozhu Zhang and
• Dayong Zhang

Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258

• 200032, P. R. China 10.3762/bjoc.16.258 Abstract A silver-catalyzed three-component reaction involving alkynes, Selectfluor®, and diethyl phosphite was employed for the one-pot formation of C(sp2)–F and C(sp2)–P bonds to provide an efficient access to β-fluorovinylphosphonates in a highly regio- and

• subsequent fluorine atom transfer. Keywords: β-fluorovinylphosphonates; fluorine atom transfer; P-centered radical; silver catalysis; three-component reaction; Introduction As one of the most important topics in organic chemistry, the introduction of fluorine and phosphorus atoms into double bonds is an

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• , aliphatic primary amines and ammonia, such as benzylamine and N-butylamine, were also examined as nitrogen donors; however, no desired product was detected. Then, we attempted to synthesize pharmaceutically active N-heterocyclic pyrrole derivatives with the aid of this three-component reaction. To our great

• aromatization to produce 5a. KI may play a key role in the last step, and we suspected that it can promote the removal of bromide. Although 5a can theoretically be synthesized through a three-component reaction of 1b, 2a, and an appropriate aldehyde, for example, acetaldehyde [50][51] owing to the insufficient

• . Direct synthesis of pyrrole-3-carboxamide derivatives. Plausible mechanism of the three-component reaction. Synthesis of polysubstituted pyrazolo[3,4-b]pyridine derivatives. Optimization of the conditions for the reaction between 1a, 2a, and 3a.a Supporting Information Supporting Information File 500

A novel and robust heterogeneous Cu catalyst using modified lignosulfonate as support for the synthesis of nitrogen-containing heterocycles

• Bingbing Lai,
• Meng Ye,
• Ping Liu,
• Minghao Li,
• Rongxian Bai and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2888–2902, doi:10.3762/bjoc.16.238

• activity in organic reactions. Tricyclic indole alkaloids bearing 3,4-fused seven-membered rings have attracted much attention because of their interesting molecular architectures and important biological activities [32][33]. Here the three-component reaction of 4-aminoindole (1a), 4-methylbenzaldehyde (2a

• ) and diethyl acetylenedicarboxylate (3a) was performed to construct the seven-membered indole ring system with the aid of the LS-FAS-Cu catalyst, and the results are summarized in Table 1. At the beginning, the three-component reaction was conducted without the presence of any catalyst, but no products

• -Cu-promoted conditions as well, and gave the product 4o in 65% yield. The successful attempts in the three-component reaction of 4-aminoindoles (1a), alkynes and aldehydes indicate that the heterogeneous catalyst LS-FAS-Cu is competent for catalyzing nitrogen-containing heterocyclic compounds without

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• associated with controlling their stereochemical outcome [33][34][35] severely restrict their applicability in medicinal chemistry [36]. The typical Passerini three-component reaction (P-3CR) of a carboxylic acid 1, an aldehyde 2, and an isocyanide 3 being conducted in a polar-aprotic solvent such as THF or

• structure of (S)-12e (slow enantiomer). Post-transformations of 2-oxo-aldehyde-derived Ugi adducts 8. Synthesis of 2-oxo-aldehyde-derived Ugi adducts. Asymmetric protocols for Passerini three-component reaction (P-3CR). Asymmetric protocols for Ugi four-component reaction (U-4CR) by Houk, Tan and co-workers

Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

• Moustafa Sherief Moustafa,
• Ramadan Ahmed Mekheimer,
• Saleh Mohammed Al-Mousawi,
• Mohamed Abd-Elmonem,
• Hesham El-Zorba,
• Afaf Mohamed Abdel Hameed,
• Tahany Mahmoud Mohamed and
• Kamal Usef Sadek

Beilstein J. Org. Chem. 2020, 16, 1706–1712, doi:10.3762/bjoc.16.142

• sample synthesized by a conventional method. Conclusion The synthesis of biologically relevant 6-aryl/heteroaryl-N2-(5H-tetrazole-5-yl)-5,6-dihydro-1,3,5-triazine-2,4-diamines was achieved under controlled microwave heating via a simple one-pot, three-component reaction of cyanamide 1, aldehydes 2, and 5

One-pot synthesis of 1,3,5-triazine-2,4-dithione derivatives via three-component reactions

• Gui-Feng Kang and
• Gang Zhang

Beilstein J. Org. Chem. 2020, 16, 1447–1455, doi:10.3762/bjoc.16.120

• , and trifluoromethyl they smoothly took part in the three-component reaction and provided the desired products 6ja–na in moderate yields. It is noteworthy that benzaldehydes containing a halogen atom such as fluorine, chlorine, bromine, and iodine in the para and meta-positions were also compatible

• three component reaction of benzaldehyde, thiourea, and orthoformates. Reactions were performed with benzaldehyde (1.0 mmol, 1.0 equiv), thiourea (2.5 mmol, 2.5 equiv), orthoformates (1.0 mmol, 1.0 equiv) in 1 mL DMF at 80 °C for 5 h; yields refer to isolated yields. Gram-scale synthesis of 6aa. Control

• -component reaction of aldehydes, thiourea and trimethyl orthoformate. Reactions were performed with aldehydes (1.0 mmol, 1.0 equiv), thiourea (2.5 mmol, 2.5 equiv), trimethyl orthoformate (1.0 mmol, 1.0 equiv) in 1 mL DMF at 80 °C for 5 h; yields refer to isolated yields. Orthoformate substrate scope of the

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• reactions to make it a green synthetic method with pot, atom and step economy (PASE) [55][56]. Results and Discussion Following the reported procedures for amino ester- and amino acid-based [3 + 2] cycloaddition reactions, pyrrolidine adducts 5 and 6 were synthesized by a three-component reaction of 1 or 2

• achieved by the combination of a three-component reaction with one-pot reactions. This synthetic sequence is a new addition of our [3 + 2] cycloaddition-initiated reactions for making diverse cyclic scaffolds. Experimental General procedure for the synthesis of pyrrolidine adducts 5 A solution of amino

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

Aerobic synthesis of N-sulfonylamidines mediated by N-heterocyclic carbene copper(I) catalysts

• Faïma Lazreg,
• Marie Vasseur,
• Alexandra M. Z. Slawin and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2020, 16, 482–491, doi:10.3762/bjoc.16.43

• cleavage of the bond between the N-4 and C-benzene in thiadiazine ring-type molecules [9]. To date, only few examples of copper-based catalysts have been reported to enable access to such compounds [10][11][12][13]. Chang and co-workers were pioneers in this area [10][11][12]. A three-component reaction

• ]. Based on these earlier results, the reactivity of these catalysts was investigated in the context of achieving formation of the challenging sulfonamide derivatives. Herein, we report the high efficiency of cationic copper(I) complexes for the formation of N-sulfonylamidines via a three-component

• reaction performed in air, using solvent-free conditions and in the absence of any additive. Results and Discussion [Cu(ICy)2]BF4 (1), [Cu(IPr)(ICy)]BF4 (2) and [Cu(IPr)(Pt-Bu3)]BF4 (3) were initially selected as optimum candidates [22]. This class of catalysts was expanded through the synthesis of the

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• , which had been obtained earlier [5] by the three-component reaction of starting materials 1c, 2a–f, and 3a (HOAc, 65 °C, 48 h). This instability complicated the isolation and characterization of the heterocycles 4p–u. The condensation of compounds 1c, 2a–f, and 3a in dry DMF under otherwise identical

• 35%). The same carboxylic acid 7 was obtained by counter synthesis through a three-component reaction involving 5-aminopyrazole-4-carbonitrile (1a), 4-methoxybenzaldehyde (2b), and pyruvic acid (3a) under heating at reflux in acetic acid for 240 min (yield 28%) or through two-component

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

• Thomas J. Cogswell,
• Craig S. Donald and
• Rodolfo Marquez

Beilstein J. Org. Chem. 2020, 16, 135–139, doi:10.3762/bjoc.16.15

• and co-workers, who developed a one-pot, three-component reaction to produce protected homoallylic amines 4 (Scheme 1) [19]. It was reasoned that adaptation of the Veenstra protocol would allow us to introduce a second alkene unit during the same process, thus generating a ring-closing metathesis

One-pot synthesis of substituted pyrrolo[3,4-b]pyridine-4,5-diones based on the reaction of N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamide with amines

• Valeriya G. Melekhina,
• Andrey N. Komogortsev,
• Boris V. Lichitsky,
• Vitaly S. Mityanov,
• Artem N. Fakhrutdinov,
• Arkady A. Dudinov,
• Vasily A. Migulin,
• Yulia V. Nelyubina,
• Elizaveta K. Melnikova and
• Michail M. Krayushkin

Beilstein J. Org. Chem. 2019, 15, 2840–2846, doi:10.3762/bjoc.15.277

• amines 3 did not only furnish the desired scaffolds in satisfactory yields but also allowed to use a variety of readily available substituted substrates (Scheme 1). Results and Discussion The published synthesis of acetamides 2 includes a one-pot three-component reaction of 4-hydroxy-6-methyl-2H-pyran-2

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• equivalents) was added to a solution of PPh3 and an active methylene compound 2a–c,e,f, a 1:1:1 three-component reaction occurred smoothly within 0.5–6 hours and yielded the phosphonium-1,5-betaines 3a–o in mostly high yields (Scheme 3 and Figure 1). Meldrum’s acid (2a), N,N’-dimethylbarbituric acid (2b), 1,3

• in transamidation reactions with nucleophilic amines [18][22]. Therefore, it was interesting to know the performance of propiolic acid chlorides in the same betaine syntheses. We found that acid chlorides 4 indeed underwent the three-component reaction with N,N’-dimethylbarbituric acid and furnished

• ]. Conclusion We have observed that the reaction of N-triflyl-N-phenylpropiolamides with triphenylphosphane results in undefined polymerization and formation of N-phenyltriflamide. In the presence of several active methylene compounds, however, a clean three-component reaction leads to a novel type of

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• , Ukraine Bar-Ilan University Ramat Gan, 5290002, Israel 10.3762/bjoc.15.231 Abstract The three-component reaction of 5-aminotetrazole with aliphatic aldehydes (formaldehyde, acetaldehyde) and acetoacetic ester derivatives in water under microwave irradiation leads to the selective formation of 4,7

• ] comprises the three-component reaction of amine 1 with the synthetic precursors of the unsaturated ketone 2 (Scheme 1, reaction 2), i.e., carbonyl compound 4 and a methylene-active compound 5. These approaches are general and useful for the preparation of variety of dihydroazolopyrimidines which is easily

• 1,3-dicarbonyl compound was observed in the three-component reaction. Reacting it with amine 1 and aldehyde 7a under conditions similar to those for acetoacetic esters (8a–d) led to formation of a mixture of compounds 11 and 12 (Scheme 3). Heteroaromatic tetrazolopyrimidine 11 was obtained as a single

Synthesis of benzo[d]imidazo[2,1-b]benzoselenoazoles: Cs₂CO₃-mediated cyclization of 1-(2-bromoaryl)benzimidazoles with selenium

• Mio Matsumura,
• Yuki Kitamura,
• Arisa Yamauchi,
• Yoshitaka Kanazawa,
• Yuki Murata,
• Tadashi Hyodo,
• Kentaro Yamaguchi and
• Shuji Yasuike

Beilstein J. Org. Chem. 2019, 15, 2029–2035, doi:10.3762/bjoc.15.199

• -bromophenyl)imidazole (1i) with Se powder gave the corresponding tricyclic product 10 in low yield. Since the reaction conditions for the synthesis of the starting material 1 and the cyclization of 1 with Se powder are similar, we carried out a three-component reaction of benzimidazole, 1-bromo-2

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• the use of toxic reagents and solvents, harsh reaction conditions and long reaction times. The use of a heterogeneous catalyst and water made this method a green and sustainable approach for organic transformations. This transformation involved the well known three-component reaction of 3 with 1 and 2

• might be due to the formation of Cu(II)-mediated propargylamine 68 from the alkyne and Schiff base-copper complex that was cyclized and aromatized to form the target compound 67 (Scheme 24). Kumar et al. have described a Cu(OTf)2-catalyzed three-component reaction for the synthesis of imidazo[1,2-a

• ]pyridines under microwave irradiation [115]. 1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) was used as ionic liquid for this three-component reaction of pyridine-2(1H)-one 70, acetophenone 71 and o-tosylhydroxylamine (72, Scheme 25). The reason behind the use of an ionic liquid as reaction

A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

• András György Németh,
• György Miklós Keserű and
• Péter Ábrányi-Balogh

Beilstein J. Org. Chem. 2019, 15, 1523–1533, doi:10.3762/bjoc.15.155

• ][87] and reactions involving sulfur [88], herein, we describe a novel synthesis of O-thiocarbamates and dithiocarbamates via a three-component reaction of elemental sulfur, isocyanides and alcohols or thiols (Scheme 1). Moreover, during the investigation of the reaction mechanism, we have identified

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• different reaction pathways were applied based on known synthetic procedures (Scheme 2): the three-component reaction between pyruvic acid (1), aromatic aldehydes 2a,b and 5-amino-3-methylpyrazole (3) (HOAc, Δ, 30 min) [45] and a two-component condensation of the preliminary synthetized 4-(4-methoxyphenyl

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

• transformations used in steroid modification, in the last years various MCRs have emerged as suitable procedures for the diversification of this family of biomolecules. A remarkable example is the report of Iglesias-Arteaga and co-workers [34] on the application of the Pd(II)-catalyzed three-component reaction

• ]. Synthesis of ecdysteroid derivatives by Ugi-4CR using a steroidal isocyanide [30]. Stereoselective multicomponent synthesis of a steroid–tetrahydropyridine hybrid using a chiral bifunctional substrate and a cholestanic isocyanide. DBA: 3,5-dinitrobenzoic acid [31]. Pd(II)-catalyzed three-component reaction

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• equivalents of 2-formylbenzoic acid (33) in an Ugi three-component reaction with methanol as solvent at room temperature to afford tetrahydrodiisoindoloquinoxalinecarboxamides 43 (Scheme 12). More recently, Shafiee et al. [90] utilized propargylamine as the cycle-nitrogen delivering component and then

• three-component reaction between aryl iodides, incorporating a Michael acceptor 105, amines and amides 2 and carbon monoxide (23) (Scheme 30) [108]. It is remarkable that not only aromatic but also aliphatic amines and even amides and sulfonamides can be used as the nitrogen-containing substrate. With

• -methyleneoxindole derivatives (Scheme 31) [109]. In this three-component reaction, 2-ethynylanilines 109 reacted with carbon monoxide (23) and perfluoroalkyl iodides 110, in the presence of Pd(II) and phenylboronic acid (111), by means of an intramolecular amino-carbonylation reaction. Although phenylboronic acid

A three-component, Zn(OTf)₂-mediated entry into trisubstituted 2-aminoimidazoles

• Alexei Lukin,
• Anna Bakholdina,
• Anna Kryukova,
• Alexander Sapegin and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2019, 15, 1061–1064, doi:10.3762/bjoc.15.103

• .15.103 Abstract A three-component reaction involving in situ generation of propargylureas and subsequent Zn(OTf)2-mediated cyclocondensation with a primary amine yielded trisubstituted 2-aminoimidazoles. These findings are in contrast to the previously reported base-promoted unimolecular cyclization of