Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

Schehr, Miriam; Hugenbusch, Daniel; Moje, Tobias; Näther, Christian; Herges, Rainer

doi:10.3762/bjoc.14.257

Cited by 17 publications

(16 citation statements)

References 27 publications

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“…The required halogenated diazocines 35 and 43 were synthesized using two different synthetic routes ( Scheme 2 vs. Scheme 3 ). The sulfur–diazocines 35 and 36 were synthesized according to the procedure reported by Schehr using an intramolecular Baeyer–Mills reaction [ 42 ]. For the metalation of the diazocines, we slightly modified the stannylation protocol described above.…”

Section: Resultsmentioning

confidence: 99%

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Heintze

Schmidt

Rodat

et al. 2020

IJMS

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In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.

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Section: Resultsmentioning

confidence: 99%

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Heintze

Schmidt

Rodat

et al. 2020

IJMS

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“…The yields are higher and more reproducible using the above reduction/reoxidation scheme. Previously applied reducing agents include Ba(OH) 2 /Zn [27], glucose/NaOH [20], Pb/NEt 3 /HCOOH [22–23], or the Baeyer–Mills reaction via Zn/NH 4 Cl [25]. We chose the Ba(OH) 2 /Zn method because it provided superior yields even at larger scales.…”

Section: Resultsmentioning

confidence: 99%

“…1) [19,24]. The reverse stability of the cis and trans isomers in azobenzenes and diazocines should allow reciprocal applications in mechanoresponsive materials and in photopharmacology [25]. Another advantage of diazocines over azobenzenes is their switchability in the visible range (400 nm cis → trans , 530 nm trans → cis ) preventing deterioration of the material or tissue damage by UV light [19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of functionalized diazocines for application as building blocks in photo- and mechanoresponsive materials

Moormann¹,

Langbehn²,

Herges³

2019

Beilstein J. Org. Chem.

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Seven symmetrically 3,3’-substituted diazocines were synthesized. Functional groups include alcohol, azide, amine and vinyl groups, which are suitable for polymer synthesis. Upon irradiation at 385 and 530 nm the diazocines perform a reversible, pincer-type movement switching the 3,3’-distance between 6.1 Å (cis, stable isomer) and 8.2 Å (trans, metastable isomer). Key reactions in the synthesis are an oxidative C–C coupling of 2-nitrotoluenes (75–82% yield) and a reductive ring closure to form the diazocines (56–60% yield). The cyclization of the dinitro compound to the azo compound was improved in yield and reproducibility, by over-reduction to the hydrazine and reoxidation to the azo unit. In contrast to 3,3’- and 4,4’-diaminodiazocine, which have been implemented in macromolecules for conformation switching, our compounds exhibit improved photophysical properties (photostationary states, separation of absorption bands in the cis and trans configuration). Hence they are promising candidates as molecular switches in photo and mechanoresponsive macromolecules and other smart materials.

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“…15 In previous approaches, the nitro groups were reduced to hydroxylamines with zinc and oxidized to the corresponding nitroso compounds with iron(III) to perform an intramolecular Baeyer-Mills reaction. 15,21 We found that a complete reduction of the nitro group to the aniline 7 and oxidation with mCPBA is increasing the yield of the intramolecular cyclization from 39% to 62% (over two steps) for the unsubstituted diazocine 8c compared to the pathway via the hydroxylamine. 3-Bromo 8a and 3-iodo 8b compounds were obtained in 56% yield using the oxidative method of Trauner 22 with mCPBA.…”

Section: Synthesismentioning

confidence: 92%

Substituted Nitrogen-Bridged Diazocines

Lentes¹,

Rudtke²,

Herges³

2021

Preprint

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Novel nitrogen bridged diazocines (triazocines) were synthesized that carry a formyl or an acetyl group at the CH2NR- bridge and bromo- or iodo substituents at the distant phenyl ring. The photophysical properties were investigated in acetonitrile and water. As compared to previous approaches the yields of the intramolecular azo cyclizations were increased (from ~40 to 60%) by an oxidative approach starting from the corresponding aniline precursors. The Z→E photoconversion yields in acetonitrile are 80-85% and the thermal half-lives of the metastable E configurations are 31-74 min. Particularly, the high photoconversion yields (~70%) of the water-soluble diazocines are noteworthy, which makes them promising candidates for applications in photopharmacology. The halogen substituents allow further functionalization via cross-coupling reactions.

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Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

Cited by 17 publications

References 27 publications

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Synthesis of functionalized diazocines for application as building blocks in photo- and mechanoresponsive materials

Substituted Nitrogen-Bridged Diazocines

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