One-pot Reductive Cyclization Research Articles

An Aldehyde-Driven, Fe(0)-Mediated, One-Pot Reductive Cyclization: Direct Access to 5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones and Photophysical Study.

A short, proficient, and regioselective synthesis of biheterocyclic 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones has been revealed via an Fe(0)-powder-mediated, one-pot reductive cyclization protocol. Mechanistic investigation proved that water acts as a source of hydrogen for the reduction of the nitro group and the reaction rate was accelerated by an aldehyde. The designed transformation works under aerobic conditions, providing a series of bio-inspired molecular scaffolds. In addition, the photophysical study showed blue fluorescence emission with a good fluorescence quantum yield.

Design, synthesis and evaluation of 2-aryl quinoline derivatives against 12R-lipoxygenase (12R-LOX): Discovery of first inhibitor of 12R-LOX

The 12R-lipoxygenase (12R-LOX), a (non-heme) iron-containing metalloenzyme belonging to the lipoxygenase (LOX) family catalyzes the conversion of arachidonic acid (AA) to its key metabolites. Studies suggested that 12R-LOX plays a critical role in immune modulation for the maintenance of skin homeostasis and therefore can be considered as a potential drug target for psoriasis and other skin related inflammatory diseases. However, unlike 12-LOX (or 12S-LOX) the enzyme 12R-LOX did not receive much attention till date. In our effort, the 2-aryl quinoline derivatives were designed, synthesized and evaluated for the identification of potential inhibitors of 12R-hLOX. The merit of selection of 2-aryl quinolines was assessed by in silico docking studies of a representative compound (4a) using the homology model of 12R-LOX. Indeed, in addition to participating in H-bonding with THR628 and LEU635 the molecule formed a hydrophobic interaction with VAL631. The desired 2-aryl quinolines were synthesized either via the Claisen-Schmidt condensation followed by one-pot reduction-cyclization or via the AlCl3 induced heteroarylation or via the O-alkylation approach in good to high (82–95%) yield. When screened against human 12R-LOX (12R-hLOX) in vitro four compounds (e.g. 4a, 4d, 4e and 7b) showed encouraging (>45%) inhibition at 100 μM among which 7b and 4a emerged as the initial hits. Both the compounds showed selectivity towards 12R-hLOX over 12S-hLOX, 15-hLOX and 15-hLOXB and concentration dependent inhibition of 12R-hLOX with IC50 = 12.48 ± 2.06 and 28.25 ± 1.63 μM, respectively. The selectivity of 4a and 7b towards 12R-LOX over 12S-LOX was rationalized with the help of molecular dynamics simulations. The SAR (Structure-Activity Relationship) within the present series of compounds suggested the need of a o-hydroxyl group on the C-2 phenyl ring for the activity. The compound 4a and 7b (at 10 and 20 µM) reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes in a concentration dependent manner. Further, both compounds decreased the protein levels of Ki67 and the mRNA expression of IL-17A in the IMQ-induced psoriatic-like keratinocytes. Notably, 4a but not 7b inhibited the production of IL-6 and TNF-α in the keratinocyte cells. In the preliminary toxicity studies (i.e. teratogenicity, hepatotoxicity and heart rate assays) in zebrafish both the compounds showed low safety (<30 µM) margin. Overall, being the first identified inhibitors of 12R-LOX both 4a and 7b deserve further investigations.

Synthesis, Characterization, Crystal Structure, and Hirshfeld Surface Analysis of Ethyl 2-(4-bromophenyl)-1-cyclohexyl-1H-benzo[d]imidazole-5-carboxylate

The title compound, C22H23N2BrO2 was synthesized via one-pot reductive cyclization method and characterized by CNH analysis, FT-IR, UV-visible, mass, 1H and 13C NMR spectra, thermogravimetric analysis (TGA) and single crystal X-ray diffraction method. The compound crystallizes in monoclinic crystal system: sp. gr. P21/c, Z = 4. The crystal data reveals that the intermolecular interactions of the C–H···π and π···π type connect the molecules which was also visualized with the help of Hirshfeld surface analysis.

Synthetic Strategy toward the Pentacyclic Core of Melodinus Alkaloids.

The three-component Povarov reaction is efficiently utilized for construction of the pentacyclic framework of complex Melodinus alkaloids, which is amenable to expansion to other complex natural products. The key steps were Povarov reaction, one-pot reductive cyclization, and ring-closing metathesis (RCM) reaction.

Total synthesis of the reported structure of 13a-hydroxytylophorine

The first total synthesis of the reported structure of 13a-hydroxytylophorine was accomplished. The key step was an unprecedented NaBH4-promoted one-pot reductive cyclization cascade that efficiently yielded a hydroxyl azonane intermediate. The indolizidine framework was obtained by means of oxidation and a subsequent unexpected protecting-group migration. This total synthesis revealed that the reported structure of the naturally isolated compound is incorrect.

Palladium-Catalyzed Copper-Free Sonogashira Coupling of 2-Bromoarylcarbonyls: Synthesis of Isobenzofurans via One-Pot Reductive Cyclization

Palladium-catalyzed copper-free Sonogashira coupling of 2-bromocarbonyls is presented. This method afforded the 2-alkynylaryl carbonyls, useful synthons for the accomplishment of many carbocyclic and heterocyclic motifs. Significantly, the strategy was extended to the one-pot synthesis of isobenzofurans via reduction followed by intramolecular 5-exo-dig cyclization.

Synthesis and glycosidase inhibition evaluation of (3S,4S)-3-((R)-1,2-dihydroxyethyl)pyrrolidine-3,4-diol

A new azasugar (3S,4S)-3-((R)-1,2-dihydroxyethyl)pyrrolidine-3,4-diol (1) was obtained from commercially available d-glucose using one-pot reductive cyclization as a key step. The target product, i.e., the iminosugar isomer, was obtained in 10 steps and 24.3% overall yield. Only three column chromatography purifications were needed in this synthesis. The biological activity of the target molecule as glycosidase inhibitor was studied, but the inhibitory activity against four glycosidases was not good (IC50 > 100 μM).

ChemInform Abstract: Synthesis of New 2,4‐Disubstituted 2,3‐Dihydrobenzo[g]indol‐5‐ones by an SRN1 Strategy.

An original and short synthesis of substituted 2,3-dihydrobenzo[ g ]indol-5-ones by S RN 1-mediated synthesis of 2-nitroalkyl-substituted­ naphthalene-1,4-diones followed by a one-pot reduction–cyclization reaction is reported.

Synthesis of New 2,4-Disubstituted 2,3-Dihydrobenzo[g]indol-5-ones by an SRN1 Strategy

An original and short synthesis of substituted 2,3-dihydrobenzo[<i>g</i>]indol-5-ones by S_RN1-mediated synthesis of 2-nitroalkyl-substituted­ naphthalene-1,4-diones followed by a one-pot reduction–cyclization reaction is reported.

An efficient and one-pot reductive cyclization for synthesis of 2-substituted benzimidazoles from o-nitroaniline under microwave conditions

A versatile and high yielding procedure for the direct generation of 2-substituted benzimidazoles from o-nitroaniline and aryl aldehydes in the presence of sodium dithionite as reducing agent under microwave irradiation is described. The obtained products were confirmed by physical and spectroscopic data such as IR, 1H NMR and 13C NMR. This procedure has a lot of advantages including; excellent yields of products, short reaction times, mild reaction conditions, easy work-up and other noteworthy advantages which make this method a valid contribution to the existing methodologies.

A Concise Synthesis of 6H-Indolo[2,3-b]quinolines: Formal Synthesis of Neocryptolepine

A new two-step approach for the synthesis of 6H-indolo[2,3-b]quinolines is described using indole C3 alkylation and a one-pot reduction–cyclization–aromatization sequence. The synthesis of the parent 6H-indolo[2,3-b]quinoline system constitutes a formal synthesis of the alkaloid neocryptolepine (cryptotackieine).

An efficient synthesis of indoloquinoline alkaloid—neocryptolepine (cryptotackieine)

A short and convenient method for the synthesis of neocryptolepine (cryptotackieine) is described using Wittig reaction and one-pot reduction–cyclization–dehydration approach as the key steps.

Novel synthesis of indolylquinoline derivatives via the C-alkylation of Baylis–Hillman adducts

A new and simple method for the C-alkylation of indoles by various Baylis–Hillman adducts and the one-pot reductive cyclization of C-alkylated indole derivatives generated from 2-nitro-Baylis–Hillman adduct to form indolylquinoline derivatives is described.

ChemInform Abstract: An InCl3‐Catalyzed Facile One‐Pot Synthesis of Novel Dispiro[cyclopent‐3′‐ene]bisoxindoles.

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An InCl 3 catalyzed facile one-pot synthesis of novel dispiro[cyclopent-3′-ene]bisoxindoles

An InCl 3 catalyzed efficient synthesis of novel dispiro[cyclopent-3′-ene]bisoxindoles is accomplished via a one-pot reductive cyclization of isatylidene malononitriles using the Hantzsch ester.

Efficient Synthesis of New 8‐Aryl Tricyclic Pyridinones.

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Efficient Synthesis of New 8-Aryl Tricyclic Pyridinones

New tricyclic pyridinones were synthesized from 6-bromo-2-chloromethyl-3-nitroimidazo[1,2-a]pyridine in four steps involving a Suzuki-Miyaura cross-coupling reaction and a direct olefination with diethyl ketomalonate as key steps. Subsequent one-pot reduction-cyclization provided new ethyl 8-aryl-2-oxo-1,2-di-hydrodipyrido[1,2-a:3',2'-d]imidazole-3-carboxylates.

Design, synthesis, and evaluation of a novel sequence-selective epoxide-containing DNA cross-linking agent based on the pyrrolo[2, 1-c][1,4]benzodiazepine system.

Synthetic routes have been investigated to prepare a novel C8-epoxide-functionalized pyrrolo[2,1-c][1,4]benzodiazepine 6 as a potential sequence-selective DNA cross-linking agent (Wilson et al. Tetrahedron Lett. 1995, 36, 6333-6336). A successful synthesis was accomplished via a 10-step route involving a pro-N10-Fmoc cleavage method that should have general applicability to other pyrrolobenzodiazepine (PBD) molecules containing acid- or nucleophile-sensitive groups. During the course of this work, a one-pot reductive cyclization procedure for the synthesis of PBD N10-C11 imines from nitro dimethyl acetals was also discovered, although this method results in C11a racemization which can reduce DNA binding affinity and cytotoxicity. The target epoxide 6 was shown by thermal denaturation studies to have a significantly higher DNA-binding affinity than the parent DC-81 (3) or the C8-propenoxy-PBD (15), which is structurally similar but lacks the epoxide moiety. The time course of effects upon thermal denaturation indicated a rapid initial binding phase followed by a slower phase consistent with the stepwise cross-linking of DNA observed for a difunctional agent. This was confirmed by an electrophoretic assay which demonstrated efficient induction of interstrand cross-links in plasmid DNA at concentrations >1 microM. Higher levels of interstrand cross-linking were observed at 24 h compared to 6 h incubation. A Taq polymerase stop assay indicated a preference for binding to guanine-rich sequences as predicted for bis-alkylation in the minor groove of DNA by epoxide and imine moieties. The pattern of stop sites could be partly rationalized by molecular modeling studies which suggested low-energy models to account for the observed binding behavior. The epoxide PBD 6 was shown to have significant cytotoxicity (45-60 nM) in the A2780, CH1, and CH1cis(R) human ovarian carcinoma cell lines and an IC(50) of 0.2 microM in A2780cis(R). The significant activity of 6 in the cisplatin-resistant CH1cis(R) cell line (IC(50) = 47 nM) gave a resistance factor of 0.8 compared to the parent cell line, demonstrating no cross-resistance with the major groove cross-linking agent cisplatin.