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

• DHPs result from the juxtaposition of nimodipine, a well-known calcium channel blocker and melatonin, a reputed antioxidant agent. This approach lies in the known association between increased cytosolic calcium levels and the formation of Aβ peptides, which are implicated in AD pathology. Calcium also

• channel blockade was determined by the measure of Ca2+ influx induced by K+-depolarization in SH-SY5Y neuroblastoma cells, previously loaded with the fluorescent dye Fluo-4AM. On the other hand, the antioxidant activity of the DHPs was evaluated using the ORAC-FL method. The most potent compounds

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

• significantly enhanced metabolic stability, a key parameter for property-based design efforts. Keywords: deuterated aldehydes; deuterated formamides; deuterated isocyanides; DHPs; kinetic isotope effect; Leuckart–Wallach; microsomal stability; multicomponent reactions; Introduction Multicomponent reactions

• 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

• , surrogate studies were conducted in mouse liver microsomes to compare deuterated DHPs with their non-deuterated counterparts (Table 2). D-Nicardipine saw a marginal increase in stability when compared to its non-deuterated counterpart H-nicardipine (3.0 vs 2.8 min) with both molecules being rapidly

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• ], pyrazolo-fused benzophenazines [45], 4,5-dioxopyrrolidines [46], 1,2-dihydropyridine (1,2-DHPs) [47], pyrimido[4,5-b]quinoline-tetraones [48], tetrahydrobenzo[b]pyrans and indazolo[2,1-b]phthalazinetriones [49]. Herein, we report the synthesis of imidazo[1,2-a]pyridines via the GBB-3CR using HPW as

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• dihydropyrans (DHPs) and aldehydes in the presence of Zn(II) (Scheme 37) [102]. The method has good enantioselectivity and functional group tolerance and provides a practical and economical route towards a series of enantiopure α-substituted DHPs through CDC, through an in situ NaBH4 reduction two-step sequence

• , various dicarbonyl compounds could be coupled with 2,4-disubstituted 3,6-dihydro-2H-pyrans (DHPs). The DHP motif is a structural component of several bioactive natural products and synthetic drugs with antioxidant, antipsychotic, antibacterial, antifungal, antiviral, and anticancer activities [106][107

• cross-coupling of ethers with enamides. Ni(II)-catalyzed CDC of indoles with 1,4-dioxane. Chemo- and regioselective ortho- or para-alkylation of pyridines. Asymmetric CDC of 3,6-dihydro-2H-pyrans with aldehydes. CDC of heterocyclic aromatics with ethers. Indium-catalyzed alkylation of DHPs with 1,3

Green synthesis of C5–C6-unsubstituted 1,4-DHP scaffolds using an efficient Ni–chitosan nanocatalyst under ultrasonic conditions

• Soumyadip Basu,
• Sauvik Chatterjee,
• Suman Ray,
• Suvendu Maity,
• Prasanta Ghosh,
• Asim Bhaumik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 133–142, doi:10.3762/bjoc.18.14

• new C5–C6-unsubstituted 1,4-DHPs under ultrasonic irradiation. The important focus of the methodology was to develop an environmentally friendly protocol with a short reaction time and a simple reaction procedure. The other advantages of this protocol are a wide substrate scope, a very good product

• yield, the use of an eco-friendly solvent and a recyclable nanocatalyst, as well as reaction at room temperature. Keywords: 1,4-DHPs; green synthesis; magnetically recyclable catalyst; Ni–chitosan nanoparticles; ultrasonication; Introduction Homogeneous catalysts, despite having an outstanding

• (NPs) and therefore automatically increases the dispersibility of the catalyst throughout the medium, resulting in a higher catalytic activity [23]. 1,4-DHPs are considered one of the most useful molecular scaffolds in medicinal chemistry. The scaffold is the main constituent of several crucial drugs

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• and trans-2,6-DHP, respectively, was reported by a [4 + 2]-annulation strategy. The authors utilized crotylsilanes syn-170 and anti-170, respectively, with an aldehyde 171 in the presence of TMSOTf to deliver different DHPs 172 (Scheme 41) [76]. For syn-170, the reaction went via the favored boat-like

Identification of volatiles from six marine Celeribacter strains

• Anuj Kumar Chhalodia,
• Jan Rinkel,
• Dorota Konvalinkova,
• Jörn Petersen and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 420–430, doi:10.3762/bjoc.17.38

• interaction. Isotopic labeling experiments demonstrated that also in laboratory cultures roseobacter group bacteria efficiently degrade DMSP into sulfur volatiles [22][23], but also from other sulfur sources including 2,3-dihydroxypropane-1-sulfonic acid (DHPS, Scheme 1C) labeling was efficiently incorporated

• into sulfur volatiles [24][25]. Notably, DHPS is produced in large quantities by the marine diatom Thalassiosira pseudonana [26], and diatoms from this genus live in symbiotic relationship with bacteria of the roseobacter group [27]. Another interesting aspect of sulfur metabolism in marine bacteria

• by DddW, DddP, DddQ, DddL, DddY or DddK, and C) structures of DHPS and sulfur-containing secondary metabolites. Synthesis of sulfur-containing compounds detected in the Celeribacter headspace extracts. A) Synthesis of 2-(methyldisulfanyl)benzothiazole (41) and B) synthesis of ethyl (Z)- and (E)-3

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

• shown to have the potential of being reused for up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The

• 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

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• radical precursors in this system, allowing for both alkyl [44] and acyl [45] RCA reactions. In the case of acyl DHPs, they propose that direct excitation of the DHP leads to radical generation rather than the iminium intermediate (Scheme 9c). The same system was used for the radical cascade reaction

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

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

• ash-supported Sc(OTf)3 for Friedal–Crafts acylation reaction, also the group of Fukuzawa has exploited Sc(OTf)3 in the synthesis of N-substituted 1,4-DHPs [26][82]. Enhancement in reactivity and selectivity of many reactions, ability to polarize bonds upon coordination and thus altering their

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

• reaction was facilitated at room temperature by N-hydroxyphthalimide (NHPI) and cobalt acetate (Co(OAc)2) as catalysts in acetonitrile (Scheme 20). The reaction followed a free radical mechanism as exemplified by the oxidative dehydrogenation of DHPs. The initial step involved the formation of the

• -mediated oxidative dehydrogenation. NBS-mediated oxidative dehydrogenation of tetrahydro-β-carbolines. One-pot synthesis of various methyl(hetero)arenes from o-aminobenzamide in presence of di-tert-butyl peroxide (DTBP). Oxidative dehydrogenation of 1, 4-DHPs. Synthesis of quinazolines in the presence of

• , phd = 1,10-phenanthroline-5,6-dione. Oxidative dehydrogenation with Flavin mimics. o-Quinone based bioinspired catalysts for the synthesis of dihydroisoquinolines. Cobalt-catalyzed aerobic dehydrogenation of Hantzch 1,4-DHPs and pyrazolines. Mechanism of cobalt-catalyzed aerobic dehydrogenation of

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

• The classical Hantzsch reaction provides 1,4-dihydropyrimidines (1,4-DHPs) from 1,3-dicarbonyl compounds, aldehydes and ammonia (Scheme 32) [19]. The reaction has attracted a considerable attention because of the therapeutic usefulness of drugs featuring the 1,4-DHP scaffold, i.e., nifedipine and

• olanzapine [105]. The preparation of unsymmetrical 1,4-DHPs by the Hantzsch reaction involving two different β-ketoesters has been reported [106]. The literature survey revealed that the Hantzsch reaction served as a tool for the preparation of C-nucleosides with the C-4-substituted 1,4-DHP moiety as a

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 reactions were slightly lower than their batch mode counterparts, (96% batch yield vs 85% yield under flow processing for the synthesis of 15c) the continuous processing of Hantzsch DHPs had been realized. Reviewing all of our methods for the microwave-assisted preparation of DHP derivatives, the

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

• studies of DHPs containing the enaminocarboxylate chromophore with suitable substituents in the 4-position [7][8]. The DHP products reported in the present synthesis allow an easy method for a wide range of DHP derivatives having this expected characteristic of a photoinduced intramolecular electron

• -transfer system. Results and Discussion In the present work we have investigated the synthesis of DHPs 2 from 1, aromatic aldehydes, and ammonia or primary amines, in a three-component one-pot reaction. First, we investigated different conditions to achieve this goal (Scheme 2, Table 1). Thus, the reaction