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

• . Optimization of deuterated Leuckart–Wallach reactiona. Microsomal stability package of deuterated and non-deuterated dihydropyridines. Supporting Information Supporting Information File 86: Experimental and analytical data and copies of NMR spectra. Acknowledgements We thank the UA mass spectrometry and NMR

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

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• corresponding GBB products 64. The authors proposed that adducts 64 were transformed into the intermediates 65 under atmospheric conditions which in turn underwent intramolecular Pictet–Spengler reaction through the addition of C-2 to the imine, to produce dihydropyridines 66. Further oxidation converted 66

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

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

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

Correction: 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. 2021, 17, 2026–2027, doi:10.3762/bjoc.17.130

• 10.3762/bjoc.17.130 Keywords: antiproliferative activity; 1,2-dihydropyridines; green Hantzsch synthesis; heterogeneous catalysis; one-pot multicomponent reaction; The authors noticed that the E-factor (E) was calculated using a wrong Equation 2 in the original publication: The correct Equation 2 should

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

• preliminary study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth in the low micromolar range. Keywords: antiproliferative activity; 1,2-dihydropyridines; green Hantzsch synthesis; heterogeneous catalysis; one-pot multicomponent

• contributions. As a result, such research has grown exponentially in the past decade [5][6]. The work conducted by the German chemist Arthur Hantzsch exploded in the synthetic interest in dihydropyridines and pyridines when the pharmacological usefulness of these compounds in medicine was discovered [7]. The

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

• different redox-active functional groups (Figure 2) [48]. Among them, dihydropyridines (DHPs), silicates, and tetrafluoroborate salts were recently exploited in organophotocatalytic reactions. These functionalities can act as donors in reductive quenching manifolds and release the desired C(sp3) radicals

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

• + and its derivatives Chemical reduction of N-substituted pyridinium salts may result in three isomeric products: 1,2-, 1,4-, and 1,6-dihydropyridines (DHP) as illustrated in Figure 5 for the corresponding dihydro-1-β-D-ribofuranosyl-3-pyridinecarboxamides. The reduction of pyridinium salts to

• dihydropyridines has been well studied and extensively reviewed [61][62][63][64]. It was demonstrated that the outcome of the reduction reaction is dependent on many factors, such as the electron withdrawing/releasing properties and locations of the substituents on the pyridinium core. They also depend on the

• 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

• hypertension. Dihydropyridine derivatives are relatively vascular selective in their mechanism of action in lowering blood pressure [31][32]. Dimeric dihydropyridines are used as the precursors for HIV-1 protease inhibitors [33][34]. The furoxan system is used in the design of new NO donors [35][36][37][38][39

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

• electron-withdrawing substrates were favored in this case. A slight modification (5 mol % phd, 1 mol % ZnI2 and 1 mol % PPTS) of the existing procedure afforded indoles 62 from indolines 61. Bioinspired flavin mimics were also used as catalysts for oxidative dehydrogenation of dihydropyridines 63 and

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

• showed that benzimidazoles, Biginelli adducts, dihydropyridines, furans, pyrans, pyridinones, and thiophenes had a high representation of intrinsic greenness; whereas, a high proportion of MCRs producing chromene-4-ones, coumarins, indoles, and pyrazoles had low probabilities of achieving intrinsic

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• selectivity reverses or the performance of the reaction and selectivity drastically alter. In solution, the reaction of N-acyl-1,2-dihydropyridines 85 with nitrosobenzene (47) yielded cycloadducts 88. On the other hand, the reactions with acylnitroso dienophiles 86 afforded the reversed regioisomeric

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

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

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

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

• Dihydropyridines and piperidines Pyrimidines and quinazolines Pyrazines and piperazines Pyridazines and perhydropyridazines Triazines and polyazacyclic systems Synthetic chemistry can rightfully be considered a prerequisite of our modern society [1]. This discipline supplies many valuable resources to our world

• derivatives are treated with α,β-unsaturated carbonyl compounds in the presence of ammonia to initially form dihydropyridines 1.38, which can ultimately be converted into the corresponding aromatic pyridine upon oxidation with a variety of oxidants such as MnO2, HNO2, HNO3 or cerium ammonium nitrate (CAN

• ester hydrolysis). 2. Dihydropyridines and piperidines The prevalence of dihydropyridines and their fully reduced counterparts the piperidines is high in many drug substances due to their high transport tolerance in many active processes and their structural spacing especially in a 1,4-disposition. The

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

• flow processing, using either microwave dielectric heating or conductive heating, which in this case gave comparable results. Synthesis of dihydropyridines in a continuous flow reactor Introduction to Hantzsch dihydropyridines The Hantzsch dihydropyridine (DHP) synthesis, first discovered in 1881 [61

• process reported by Leadbeater on 0.5 mol scale under open vessel conditions, which delivered an outstanding yield of 15a (96%) [10], so further experiments to improve the continuous flow processing of Hantzsch dihydropyridines were considered. In an effort to improve the flow process further, a 3

• used for the one-step preparation of pyridines and dihydropyridines using the Bohlmann–Rahtz reaction or Hantzsch multicomponent reaction, respectively. Bohlmann–Rahtz pyridine synthesis under continuous flow processing in the presence of a Brønsted acid catalyst allows Michael addition and

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

• been proven to be a powerful method for the construction of various dihydropyridines [1][2][3][4], which are not only valuable intermediates in organic synthesis [5][6][7][8][9][10][11][12], but also interesting compounds in medicinal [13] and bioorganic chemistry [14][15][16]. The tetrahydropyridine

• , 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