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

• as a catalyst in three-component processes was also demonstrated in three-component reactions involving alkynes, amines and α,β-unsaturated aldehydes to obtain 1,4-dihydropyridines 20 (Scheme 14) [31]. By using terminal alkynes, 2,6-unsubstituted products were achieved. Concerning the mechanism, it

• dihydropyrimidines 18. Regioselective synthesis of 1,4-dihydropyridines 20. Synthesis of tetrahydropyridines 21. Synthesis of furoquinoxalines 22. Synthesis of 2,4-substituted quinolines 23. Synthesis of cyclic ether-fused tetrahydroquinolines 24. Practical route for 1,2-dihydroisoquinolines 25. Synthesis of 2,3

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• efficient methodology for synthesizing chiral benzofuran-fused 1,4-dihydropyridines 13 in excellent yields (90–99%) and excellent enantioselectivities (92–99% ee) (Scheme 4). The authors also attempted to perform the reaction using 2-tosylacetonitrile instead of malononitrile. However, in this case, the

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• to various enzymatic systems or receptors implicated in AD pathology. In 2019, Malek et al. [43] designed and obtained a new family of 1,4-dihydropyridines (DHPs), as a series of MTDLs, which were prepared using a multicomponent reaction, particularly the Hantzsch reaction (Scheme 9). The synthesized

• ]. The most potential β-amiloyd aggregation inhibitors generated by Galante et al. [37]. Best pyrazine-based MTDLs synthesized by Madhav et al. [40]. Most active 1,4-dihydropyridines developed by Malek et al. [43]. Best CDH-based MTDLs as AChE inhibitors synthesized by Malek et al. [46]. SIRT2 activity

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

• ethyl acetoacetate with aldehyde and ammonia to give 1,4-dihydropyridine [53]. Such scaffolds are seen in several FDA-approved calcium channel blockers including nifedipine, nicardipine and nimodipine and three site-specific deuterated analogs of approved 1,4-dihydropyridines (DHPs) are presented

• scrambling. GBB reaction products, no deuterium scrambling was observed. aA 70% [D2]-isocyanide was used in 7a and 7b. Ar = 4-PhPh, Ar1 = 4-MePh. Modified Hantzsch pyridine synthesis to afford 1,4-dihydropyridines. No deuterium scrambling was observed. CYP3A4 mediated dehydrogenation of dihydropyridines

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• dihydropyridines, specifically 3,5-acyl-1,4 dihydropyridines 77, are well suited for undergoing ring opening-ring closing cyclocondensation with hydrazine in a pseudo-multicomponent reaction to give bis(pyrazolyl)methanes 78 (Scheme 28) [106]. Interestingly, the use of ester derivatives leads to the formation of

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• )-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine

• on alkyl isocyanides, electron-deficient alkynes and other reagents have been successfully developed for the synthesis of various carbocyclic and heterocyclic compounds [27][28][29][30][31][32][33][34][35]. The 5,6-unsubstituted 1,4-dihydropyridine is one of special kinds of 1,4-dihydropyridines. It

• can act as an activated enamino unit and electron-rich dienophile to take part in some synthetic reactions [36][37][38][39]. In recent years, 5,6-unsubstituted 1,4-dihydropyridines have been recognized as the reactive electron-rich dienophiles, which proceeded several Povarov reactions with various 1

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

• Xiu-Yu Chen,
• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• -dihydropyridines in acetonitrile at room temperature afforded functionalized isoquinolino[1,2-f][1,6]naphthyridines in good yields and with high diastereoselectivity. More importantly, the formal [2 + 2] cycloaddition reaction of dialkyl acetylenedicarboxylates and 5,6-unsubstituted 1,4-dihydropyridines in

• ][28][29][30]. The 5,6-unsubstituted 1,4-dihydropyridines can be easily prepared from the three-component reaction of an arylamine, cinnamaldehyde, and methyl acetoacetate [31][32][33][34]. The unsubstituted C=C double bond in 5,6-unsubstituted 1,4-dihydropyridines exhibits high reactivity and could

• act as activated alkene to take part in various cycloaddition reactions [35][36][37][38][39][40]. For example, Lavilla and co-workers developed a Sc(OTf)3-catalyzed three-component reaction of 5,6-unsubstituted 1,4-dihydropyridines, arylamines and ethyl glyoxylate for the preparation of various pyrido

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• , Gutierrez and Molander reported the coupling 4-alkyl-1,4-dihydropyridines 31 with heterobicyclic alkenes 30 under photoredox/Ni dual catalysis (Scheme 6) [39]. In contrast to other photoredox-mediated transformations, the authors utilized the inexpensive organic photosensitizer 4-CzIPN (Scheme 6 and Scheme

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

• Giovanna Bosica,
• Kaylie Demanuele,
• José M. Padrón and
• Adrián Puerta

Beilstein J. Org. Chem. 2020, 16, 2862–2869, doi:10.3762/bjoc.16.235

• 10.3762/bjoc.16.235 Abstract A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1,2-dihydropyridine

• equivalents of the β-ketoester ethyl acetoacetate (2) with benzaldehyde (1a) and ammonia (Scheme 1) [11]. This procedure was later optimized over the years using different substrates by varying the β-ketoesters and aldehydes in order to prepare a larger array of 1,4-dihydropyridines (1,4-DHPs) [12]. In

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• pyridinium nitrogen and the electrophilic C4 atom. Rearrangement of the protonated intermediate J with elimination of SO2 usually affords the 1,4-dihydropyridines with a very low admixture of other isomers. The 1,2- or 1,6-dihydropyridines may become predominant products depending on a particular combination

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds

• Alexey M. Starosotnikov,
• Dmitry V. Shkaev,
• Maxim A. Bastrakov,
• Ivan V. Fedyanin,
• Svyatoslav A. Shevelev and
• Igor L. Dalinger

Beilstein J. Org. Chem. 2017, 13, 2854–2861, doi:10.3762/bjoc.13.277

• 10.3762/bjoc.13.277 Abstract 4-Aza-6-nitrobenzofuroxan (ANBF) reacts with 1,3-dicarbonyl compounds and other CH acids to give carbon-bonded 1,4-adducts – 1,4-dihydropyridines fused with furoxan ring. In the case of most acidic β-diketones, which exist mainly in the enol form in polar solvents, the

• the design of pharmacology-oriented heterocyclic systems. Keywords: CH acids; dearomatization; 1,4-dihydropyridines; furoxans; nitropyridines; Introduction The reactions of condensed furoxans with CH acidic compounds have been extensively studied. There are two main possibilities for these reactions

• , reactions of 4-aza-6-nitrobenzofuroxan with CH acids gave carbon-bonded 1,4-adducts – 1,4-dihydropyridines fused with furoxan ring. In the case of the most acidic 1,3-dicarbonyl compounds the reactions proceed in the absence of a base. The resulting compounds combine in one molecule the NO-donor furoxan

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• , 1,4-dihydropyridines as calcium channel blockers, such as nifedipine and nicardipine, are found as effective chemotherapeutic medicines and antihypertensive agents [17]. Hence to attend their biological usefulness diverse synthetic processes are reported to access these molecules [18]. Multicomponent

• significance Hantzsch 1,4-dihydropyridines (1,4-DHP) have garnered substantial attention in the scientific community [48]. They are found in various chemotherapeutic agents and are used for the treatment of cardiovascular diseases such as hypertension and angina pectoris [49]. They are an important class of

• oxidation. One of the early examples of such reaction was demonstrated by Han et al. in 2006 [84]. Here in pyridines 71 and pyrazoles 72 were synthesized in excellent yield by the oxidation of 4-substituted Hantzsch 1,4-dihydropyridines 69 and 1,3,5-trisubstituted pyrazolines 70 via molecular oxygen. The

Photoinduced 1,2,3,4-tetrahydropyridine ring conversions

• Baiba Turovska,
• Henning Lund,
• Viesturs Lūsis,
• Anna Lielpētere,
• Edvards Liepiņš,
• Sergejs Beljakovs,
• Inguna Goba and
• Jānis Stradiņš

Beilstein J. Org. Chem. 2015, 11, 2166–2170, doi:10.3762/bjoc.11.234

• functional group is placed near to electronegative groups, the oxidizing capability of hydroperoxides can be increased. This effect was particularly observed on heterocyclic systems. Results and Discussion Photosensitized aerobic oxidative aromatization [11][12][13][14] of Hantzsch 1,4-dihydropyridines has

• deprotonated efficiently in the presence of superoxide including Hantzsch 1,4-dihydropyridines [31][32]. Cation radicals have increased acidity comparing to the parent molecules from which they are derived by oxidation [33][34][35]. Consequently, their deprotonation proceeds more efficiently. Photooxygenation

One-pot four-component reaction for convenient synthesis of functionalized 1-benzamidospiro[indoline-3,4'-pyridines]

• Chao Wang,
• Yan-Hong Jiang and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2014, 10, 2671–2676, doi:10.3762/bjoc.10.281

• (600 and 150 MHz for 1H and 13C NMR spectra, respectively). HPLC/MS were measured at Bruker MicroTOF spectrometer. Single-crystal structure was determined on Bruker Smart-2 CCD diffractometer. General procedure for the synthesis of 1,4-dihydropyridines 1a–m via four-component reactions: In a round

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

Tandem dinucleophilic cyclization of cyclohexane-1,3-diones with pyridinium salts

• Mostafa Kiamehr,
• Firouz Matloubi Moghaddam,
• Satenik Mkrtchyan,
• Volodymyr Semeniuchenko,
• Linda Supe,
• Alexander Villinger,
• Peter Langer and
• Viktor O. Iaroshenko

Beilstein J. Org. Chem. 2013, 9, 1119–1126, doi:10.3762/bjoc.9.124

• , which are subsequently cyclized by the addition of acid). In some cases the cyclization step failed, e.g., the reaction of 1,3-bis(silyl enol ethers) with pyridine in the presence of methyl chloroformate resulted in the formation of 1,4-dihydropyridines, which however, could not be cyclized by the

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• 10.3762/bjoc.8.250 Abstract We have developed a general synthesis of polysubstituted 1,4-dihydropyridines and pyridines based on a highly regioselective lithiation/6-endo-dig intramolecular carbolithiation from readily available N-allyl-ynamides. This reaction, which has been successfully applied to the

• carbolithiation of ynamides, which may provide an interesting entry to highly functionalized 1,4-dihydropyridines [27][28][29] and pyridines [30][31][32][33], most useful building blocks in organic synthesis and medicinal chemistry as well. Our strategy is summarized in Scheme 1 and is based on the following

• , therefore demonstrating the compatibility of the ynamide group with the deprotonation step (Scheme 2a), although longer reaction times before the addition of methyl iodide resulted in much lower yields and extensive degradation: The intramolecular carbolithiation of N-allyl-ynamides to 1,4-dihydropyridines

Enaminones in a multicomponent synthesis of 4-aryldihydropyridines for potential applications in photoinduced intramolecular electron-transfer systems

• Nouria A. Al-Awadi,
• Maher R. Ibrahim,
• Mohamed H. Elnagdi,
• Elizabeth John and
• Yehia A. Ibrahim

Beilstein J. Org. Chem. 2012, 8, 441–447, doi:10.3762/bjoc.8.50

• resulted in easy access to 1,4-dihydropyridines with different substituents at the 1-, 3-, 4- and 5-positions. Microwaves improved the reaction yield, reducing also considerably the reaction time and the amount of solvent used. Chiral primary amines gave chiral 1-substituted-1,4-dihydropyridines. The 4-(1

• -naphthyl) and 4-(phenanthren-9-yl)dihydropyridine derivatives exhibited an interesting photoluminescence behavior, which suggests their potential application as suitable photoinduced intramolecular electron-transfer systems. Keywords: enaminones; 1,4-dihydropyridines; microwaves; multi-component reactions

Reductive amination with zinc powder in aqueous media

• Giovanni B. Giovenzana,
• Daniela Imperio,
• Andrea Penoni and
• Giovanni Palmisano

Beilstein J. Org. Chem. 2011, 7, 1095–1099, doi:10.3762/bjoc.7.125

• ], Zn(BH4)2/ZnCl2 [10], NaBH4/Mg(ClO4)2 [11], electrochemistry [12], 1,4-dihydropyridines [13][14], Ti(OiPr)4-PMHS [15], NaBH4-CoCl2 [16], iPrOH/RuCl(PPh3)2 [17], BH3·Me2S [18], PhSiH3-Bu2SnCl2 [19], and Zn/HCOONH4 [20]. Although the choice of reagents for reductive amination is quite large, a closer