Synlett

This account summarises our recent efforts (2020 to mid-2024) in designing and developing a handful of promising organic transformations for accessing several diversely functionalized biologically relevant organic scaffolds by following the green-chemistry principles with a particular focus on the application of low-energy visible light and electrochemistry. Mechanistic studies of each of these reactions established the involvement of a radical pathway.1 Introduction2 Green-Inspired Organic Transformations2.1 Visible-Light-Driven Organic Synthesis2.1.1 Synthesis of Functionalized Dihydrofuro[3,2-c]chromenones2.1.2 Synthesis of Functionalized 2-(Aryl/alkylamino)-3-(aryl/alkylselanyl)naphthalene-1,4-diones and 2-(Arylamino)-3-(arylthio)naphthalene-1,4-diones2.1.3 Synthesis of Functionalized 6-(Arylthio/arylseleno)benzo[a]phenazin-5-ols2.1.4 Synthesis of Functionalized 3-(Alkyl/benzylthio)-4-hydroxy-2H-chromen-2-ones2.1.5 Synthesis of Functionalized 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxamides and 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates2.1.6 Synthesis of Functionalized 2-Hydroxyphenylated α-Ketoamides2.2 Electrochemical Organic Synthesis2.2.1 Synthesis of 3-Selenylated/Sulfenylated Derivatives of 2-Amino-1,4-naphthoquinones2.2.2 Synthesis of Functionalized 6-(Arylthio/Arylseleno)benzo[a]phenazin-5-ols2.2.3 Synthesis of Functionalized Alkyl 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates3 Conclusions

Studies on the transformations of some functionalized cycloalkene derivatives through their ring olefin-bond aziridination/aziridine opening with fluoride are presented. The selected model compounds submitted to fluorinative functionalization were an amino ester and diesters with a cyclohexene skeleton as well as a cyclopentene-fused β-lactam. Functionalization proceeded across a substrate-directed diastereoselective olefin-bond aziridination, followed by fluoride-mediated aziridine opening or intramolecular lactonization giving some fluorinated amino ester or amino lactone derivatives.

SynlettDOI: 10.1055/s-0043-1774966Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, GermanyArticle in Thieme eJournals:Table of contents  |  Full text

Cross-coupling reactions have been developed between C2-substituted 1-bromocyclobut-1-enes and Grignard reagents using two effective catalysts, e.g., Fe(acac)3 and Ni(acac)2. The iron catalyst works in THF but requires NMP as the co-solvent, with the advantage of achieving cross-coupling reactions with alkyl Grignard reagents. The nickel catalyst was able to promote the reactions in THF without any additive and showed high reactivity with electron-rich aryl Grignard reagents. These catalysts gave various types of substituted cyclobutenes in good yields.

In this research, we synthesized a novel mitochondrial-targeted antitumor lead compound named phenolthiazide-4C-Pvi (PCP) by modifying a phenothiazine with 3-(2-pyridin-4-ylvinyl)-1H-indole (Pvi) as a mitochondrial-targeted fluorescent cargo. Our preliminary findings indicated that PCP exhibits remarkable cell imaging and mitochondrial localization ability, and can induce apoptosis by influencing the membrane potential and reactive oxygen species levels in mitochondria. Compared with phenothiazines, PCP has an excellent ability to target the mitochondria of cancer cells, and its selectivity and toxicity to tumor cells are stronger than those toward normal cells. These results demonstrated that PCP possesses strong antitumor effects with excellent selectivity, making it a promising candidate as a mitochondrial-targeted antitumor drug.

Methyl 2-[bis(benzylthio)phosphoryl]acetate has proven to be an efficient Horner–Wadsworth–Emmons (HWE)-type reagent for the diastereodivergent synthesis of (E)- and (Z)-α,β-unsaturated esters. Under the conditions of excess NaHMDS relative to the HWE-type reagent, the HWE-type reactions of methyl 2-[bis(benzylthio)phosphoryl]acetate with various aldehydes afforded the corresponding α,β-unsaturated esters in an E-selective manner in up to 100:0 E/Z ratio. However, when an excess of the HWE-type reagent was used relative to NaHMDS, the stereoselectivity of the HWE-type reactions was dramatically changed from E to Z, yielding an E/Z ratio of up to 2:98.

We report a useful flow protocol for the preparation of alkenyl thioethers from alkenyl bromides and thiols in basic media with visible-light irradiation. The reactions exhibit a wide functional-group tolerance, proceed under mild conditions, are stereoselective, and do not require the use of catalysts. The transformations can be successfully scaled up to 5 mmol scale without compromising the yield. The key to the success of these reactions is the photochemical excitation of halogen-bonding complexes to form alkenyl and sulfur-centered radicals, a protocol recently developed in our laboratories.

π-Stacking is common in materials, but different π–π stacking modes remarkably affect the properties and performances of materials. In particular, weak interactions, π-stacking and hydrogen bonding often have a significant impact on the stability and sensitivity of high-energetic compounds. A fused [5,7,5]-tricyclic energetic compound with a conjugated structure has been designed and synthesized. 4H-[1,2,5]Oxadiazolo[3,4-e][1,2,4]triazolo[3,4-g][1,2,4]triazepin-8-amine is obtained in 48% yield from 3-amino-4-carboxy-1,2,5-oxadiazole through an efficient two-step reaction. Owing to its layered planar structure and weak π interactions between layers, 4H-[1,2,5]oxadiazolo[3,4-e][1,2,4]triazolo[3,4-g][1,2,4]triazepin-8-amine exhibits high thermal stability (T
d = 318 °C), low sensitivity (IS = 40 J, FS = 360 N), and relatively excellent detonation performance (D = 7059 ms–1, P = 20.2 GPa). This detonation performance is superior to that of the conventional explosive TNT. The developed procedure provides a new method for the synthesis of fused ring compounds.

A metal-free synthesis of 2-benzylideneindolin-3-ones through a formal [4+1] annulation from o-azidobenzaldehydes and terminal alkynes has been developed. The method features operational simplicity, mild reaction conditions, and ready availability of starting materials. A broad range of 2-benzylideneindolin-3-ones were prepared in moderate to excellent yields. Mechanistic studies indicated that the reaction might proceed through a nucleophilic addition/rearrangement/azide–alkene cycloaddition pathway to produce 2-benzylideneindolin-3-ones.

We propose a synthetic process for the preparation of a benzoxazole building block for a programmed death-ligand 1 inhibitor that is a candidate currently under clinical investigation for cancer treatment. Our research focused on searching for mild, scalable, and ecofriendly conditions for the synthesis of benzoxazoles. To reduce the use of toxic reagents or solvents and to minimize the production of organic wastes, the cyclization reaction was performed in an aqueous micellar medium. This in-water benzoxazole synthesis gave comparable yields to previously reported processes, and was applied to a broad range of benzoxazoles with various substitution patterns, showcasing its effectiveness in ecofriendly benzoxazole cyclization reactions.