Amplification of Trichloroisocyanuric Acid (TCCA) Reactivity for Chlorination of Arenes and Heteroarenes via Catalytic Organic Dye Activation

Rogers, D.; Bensalah, Adam T.; Espinosa, Alvaro Tomas; Hoerr, John L.; Refai, Fares H.; Pitzel, Amy K.; Alvarado, Juan José; Lamar, Angus A.

doi:10.1021/acs.orglett.9b01414

Cited by 34 publications

(25 citation statements)

References 66 publications

(36 reference statements)

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“…A large number of electrophilic chlorinating reagents for the direct chlorination of aromatic rings have been reported [17]. Recently, Xue et al described the electrophilic chlorination of arenes and heterocycles by 1-chloro-1,2-benziodoxol-3-one ( 12 ) [18–19].…”

Section: Resultsmentioning

confidence: 99%

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

Willis¹,

Bayle²,

Papageorgiou³

et al. 2019

Beilstein J. Org. Chem.

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Background: The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 (1) is an orally active inhibitor of Notum. We are investigating the role of Notum in modulating Wnt signalling in the central nervous system and wished to establish if 1 would serve as a peripherally restricted control. An accessible and improved synthetic route would allow 1 to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs. Results: An improved, scalable synthesis of 1 is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki–Miyaura cross-coupling reaction with MIDA-boronate 11 (5 → 6), and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 → 7) as a mild and selective electrophilic chlorination agent. This 7-step route from 16 has been reliably performed on large scale to produce multigram quantities of 1 in good efficiency and high purity. Pharmacokinetic studies in mouse showed CNS penetration of 1 is very low with a brain/plasma concentration ratio of just 0.01. A small library of amides 17 were prepared from acid 1 to explore if 1 could be modified to deliver a CNS penetrant tool by capping off the acid as an amide. Although significant Notum inhibition activity could be achieved, none of these amides demonstrated the required combination of metabolic stability along with cell permeability without evidence of P-gp mediated efflux. Conclusion: Mouse pharmacokinetic studies demonstrate that 1 is unsuitable for use in models of disease where brain penetration is an essential requirement of the compound but would be an ideal peripherally restricted control. These data will contribute to the understanding of drug levels of 1 to overlay with appropriate in vivo efficacy endpoints, i.e., the PK-PD relationship. The identification of a suitable analogue of 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models.

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Section: Resultsmentioning

confidence: 99%

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

Willis¹,

Bayle²,

Papageorgiou³

et al. 2019

Beilstein J. Org. Chem.

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“…The reaction mixture was then stirred for 10 min. Next, 0.5 equiv of NaBH 4 was then added slowly, and the reaction mixture was heated to 60 °C for 4 h using an oil bath . After completion, the reaction mixture was washed with 30 mL of distilled water (3 × 10 mL) and extracted with ethyl acetate.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…4-Methylbenzaldehyde (Table 3, entry 4g): 25 Yellow liquid (11.8 mg, 49%); isolated from column chromatography (5% EtOAc/nhexane); 1 Bis(4-(tert-butyl)benzyl)amine (Scheme 3, 6a). 29 To an ovendried screw cap reaction vial charged with a spin vane magnetic stirbar was added 168 μL of C 70 solution (1 mg/2 mL in toluene) (0.05 mol %) and dried over rotary evaporator. To this were added primary benzylic amine (21.9 μL, 0.2 mmol) and acetonitrile (4 mL).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Next, 0.5 equiv of NaBH 4 was then added slowly, and the reaction mixture was heated to 60 °C for 4 h using an oil bath. 29 After completion, the reaction mixture was washed with 30 mL of distilled water (3 × 10 mL) and extracted with ethyl acetate. The organic layer was then subjected to column chromatography using hexane/ethyl acetate (85:15) as an eluent to get the pure form of the desired product: white solid (50.0 mg, 81%); mp = 142−144 °C, 1 Reactive Oxygen Species Quenching Experiments.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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C₇₀ Fullerene Catalyzed Photoinduced Aerobic Oxidation of Benzylamines to Imines and Aldehydes

Kumar

Gupta

et al. 2021

J. Org. Chem.

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C 70 fullerene catalyzed photoinduced oxidation of benzylic amines at ambient conditions has been explored here. The developed strategy's main feature includes the additive/oxidantfree conversion of benzylic amine to corresponding imine and aldehydes. The reaction manifests broad substrate scope with excellent function group leniency and is applicable up to the gram scale. Further, symmetrical secondary amines can also be synthesized from benzylic amine in a one-pot two-step process. Various experiments and density functional theory studies revealed that the current reaction involves the generation of reactive oxygen species, single electron transfer reaction, and benzyl radical formation as key steps under photocatalytic conditions.

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“…Hammond and co-workers proposed a novel strategy for chlorination of arenes and heteroarenes using brilliant green (BG) in 2019 [ 54 ]. The chlorination was conducted via treatment of trichloroisocyanuric acid (TCCA) as a chlorine source in the presence of brilliant green (BG) under irradiation of white LEDs in acetonitrile ( Scheme 51 ).…”

Section: Photo-catalyzed Halogenations Of Aromatic C-h Bondsmentioning

confidence: 99%

Visible-Light-Induced Catalytic Selective Halogenation with Photocatalyst

2021

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Halide moieties are essential structures of compounds in organic chemistry due to their popularity and wide applications in many fields such as natural compounds, agrochemicals, and pharmaceuticals. Thus, many methods have been developed to introduce halides into various organic molecules. Recently, visible-light-driven reactions have emerged as useful methods of organic synthesis. Particularly, halogenation strategies using visible light have significantly improved the reaction efficiency and reduced toxicity, as well as promoted reactions under mild conditions. In this review, we have summarized recent studies in visible-light-mediated halogenation (chlorination, bromination, and iodination) with photocatalysts.

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Amplification of Trichloroisocyanuric Acid (TCCA) Reactivity for Chlorination of Arenes and Heteroarenes via Catalytic Organic Dye Activation

Cited by 34 publications

References 66 publications

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

C₇₀ Fullerene Catalyzed Photoinduced Aerobic Oxidation of Benzylamines to Imines and Aldehydes

Visible-Light-Induced Catalytic Selective Halogenation with Photocatalyst

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Amplification of Trichloroisocyanuric Acid (TCCA) Reactivity for Chlorination of Arenes and Heteroarenes via Catalytic Organic Dye Activation

Cited by 34 publications

References 66 publications

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

C70 Fullerene Catalyzed Photoinduced Aerobic Oxidation of Benzylamines to Imines and Aldehydes

Visible-Light-Induced Catalytic Selective Halogenation with Photocatalyst

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C₇₀ Fullerene Catalyzed Photoinduced Aerobic Oxidation of Benzylamines to Imines and Aldehydes