Sustainable and Environmentally Friendly Approach for the Synthesis of Azoxybenzenes from the Reductive Dimerization of Nitrosobenzenes and the Oxidation of Anilines.

This study demonstrates a comparative synthesis of azoxybenzenes through the reductive dimerization of nitrosobenzenes and the oxidation of anilines. Utilizing the cost-effective DIPEA catalyst at room temperature with water as a green solvent, the one-pot procedure involves in situ generation of nitrosobenzene derivatives from anilines in the presence of oxone, followed by DIPEA addition. Both methods yield azoxybenzenes with high selectivity, showcasing the versatility of DIPEA in facilitating the synthesis of azoxybenzenes with various substituents in ortho, meta, and para positions, encompassing electron-donating and electron-withdrawing groups. The use of DIPEA proves pivotal in achieving moderate to high yields, emphasizing its significance in this environmentally friendly synthesis.

Design, synthesis and biological evaluation of novel bischalcone derivatives as potential anticancer agents.

Building on our previous work that discovered chalcone as a promising pharmacophore for anticancer activity, we have various other chalcone derivatives and have synthesized a series of novel bischalcone to explore their anticancer activity. Among all tested compounds, compounds 6a, 6b, and 6c showed the highest antiproliferative activity against A-549 cancer cell lines with the average IC50 values of 4.18, 4.52, and 5.05 µM, respectively. Moreover, compound 6c showed high antiproliferative activity against the Caco-2 cell line; thus, it was 2- and 4-fold more active than the reference compounds, i.e., methotrexate and capecitabine. Compound 6a also induced cell-cycle arrest in the S phase, whereas compounds 6b and 6c were observed to stop at the G0/G1 phase. Thereafter, we evaluated that compound 6c also had the highest apoptosis/necrosis ratio than other compounds and the standard compound. The anticancer property of the 6c was also supported by molecular docking studies carried out on the EGFR and HER2 receptors. Overall, we expect that these compounds can be further developed for the potential treatment of lung cancer.

Syntheses and evaluation of multicaulin and miltirone-like compounds as antituberculosis agents.

Four multicaulin and miltirone-like phenanthrene derivatives were synthesised and evaluated as antituberculosis agents. The crucial step of the synthesis was Pschorr coupling of 4-(3-isopropyl-4-methoxyphenyl)-2-(2-aminophenyl)ethane (13) to give 2-isopropyl-3-methoxy-9,10-dihydrophenanthrene (9) and 4-isopropyl-3-methoxy-9,10-dihydrophenanthrene (9a). Compound 9 was converted to multicaulin and miltirone-like phenanthrene derivatives by further reactions. The best antituberculosis activity was exhibited by 2-isopropylphenanthrene-3-ol (11).

Cyclic Alkenenitriles: Copper-Catalyzed Deconjugative α-Alkylation.

An amido cuprate formed from CuCN and LDA allows a general deconjugative α-alkylation of cyclic alkenenitriles. Deprotonating cyclic alkenenitriles with LDA-CuCN avoids polymerization that otherwise plagues these alkylations and generates a reactive metalated nitrile for alkylations with a range of carbon and heteroatom electrophiles. The strategy provides an effective synthesis of quaternary 5-, 6-, and 7-membered cycloalk-1-enecarbonitriles substituted on the nitrile-bearing carbon.

Total syntheses of multicaulins via oxidative photocyclization of stilbenes.

The Wittig reaction of 3-isopropyl-4-methoxybenzaldehyde and 2,3-dimethylbenzylphosphonium bromide afforded the corresponding stilbene mixture 16. Oxidative photocyclization of stilbene 16 with iodine facilitated the first total synthesis of 7-isopropyl-6-methoxy-1,2-dimethylphenanthrene, multicaulin (1). The O-demethylation of 1 with BBr3 afforded the 7-isopropyl-1,2-dimethylphenanthren-6-ol, O-demethylmulticaulin (2).

Photooxygenation of azidoalkyl furans: catalyst-free triazole and new endoperoxide rearrangement.

Photooxygenation of azidoalkyl furans has revealed both a novel triazole formation method and a unique endoperoxide rearrangement. The key step of this method is a 3 + 2 cycloaddion of the azide to the endoperoxide intermediate. The reduction of the peroxide bond and two subsequent C-C bond cleavages provide a triazole having a newly formed carboxylic acid functionality. The reactions are clean and efficient with yields ranging from 60% to 90%.

Enantioselective synthesis of cyclic, quaternary oxonitriles.

Quaternary oxonitriles are stereoselectively generated from the union of five-, six-, and seven-membered 2-chloroalkenecarbonitriles with chiral alcohols via a Claisen rearrangement. The strategy rests on a new conjugate addition-elimination of allylic alkoxides to 2-chlorocycloalkenecarbonitriles to afford substituted 2-alkoxyalkenenitriles. Subsequent thermolysis unmasks a cyclic oxonitrile while selectively forming a new quaternary center with enantiomeric ratios typically greater than 9:1. The overall alkylation strategy addresses the challenge of enantioselectively generating hindered, quaternary centers while simultaneously installing ketone, nitrile, and olefin functionalities.

Synthesis and evaluation of ligands for D2-like receptors: the role of common pharmacophoric groups.

Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D(2)-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 4'-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D(2)-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors.

Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.

The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.

Cyclic alkenenitriles: chemoselective oxonitrile cyclizations.

Potassium tert-butoxide triggers the chemoselective cyclization between nitrile anions and remote, enolizable carbonyl groups, despite the acidity difference favoring enolate formation and addition to the nitrile group. Domino deprotonation, cyclization, and dehydration efficiently transform a diverse array of omega-oxonitriles into carbocyclic and heterocyclic five- and six-membered alkenenitriles in a single synthetic operation.