Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols

Dutta, Subhabrata; Lee, Donghyeon; Ozols, Kristers; Daniliuc, Constantin G.; Shintani, Ryo; Glorius, Frank

doi:10.1021/jacs.3c12894

Cited by 29 publications

(7 citation statements)

References 75 publications

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“…The aniline ring could be doubly or triply substituted, leading to densely substituted polycyclic products 27-36. For the symmetrical substrates derived from 2,6-dimethylaniline, 3,5-dimethylaniline, and 2,4,6-trimethylaniline, good to excellent yields were obtained despite the steric hindrance (27)(28)(29). For the non-symmetrical substrates derived from 2,3-dimethylaniline, 2,5-dimethylaniline, and 3,4-dimethylaniline, poor to moderate regioselectivities were observed (30)(31)(32)(33)(34)(35).…”

Section: Substrate Scope Studymentioning

confidence: 99%

Complexity from simplicity: intramolecular meta-thermocycloadditions of benzene rings via Wheland intermediates

Liu,

Xu,

Liu

et al. 2024

Preprint

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Dearomative cycloadditions are powerful synthetic transformations utilizing aromatic compounds for cycloaddition reactions1-4. Diverse complex three-dimensional architectures could be built upon the flat land of aromatic compounds. In addition, such transformations are atom- and step-economical and, thus, have been widely applied to the preparations of complex biologically relevant compounds5-7. For the ubiquitous and most studied yet challenging benzene ring systems8, ortho- and para-cycloadditions are feasible both photochemically and thermally, while the meta-cycloadditions are still limited to the photochemical processes from the 1960s9,10. Herein, we have realized the meta-thermocycloadditions of benzene rings in an intramolecular fashion. The reaction was proposed to proceed via [4π+2π] cycloadditions of Wheland intermediates from the electrophilic dearomatization of benzene rings. A broad spectrum of readily available C(sp2)-rich aniline-tethered enynes were transformed into C(sp3)-rich 3D complex polycyclic architectures simply by stirring in TFA. Moreover, the reaction could be performed in gram-scales and the products could be diversely elaborated.

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Section: Substrate Scope Studymentioning

confidence: 99%

Complexity from simplicity: intramolecular meta-thermocycloadditions of benzene rings via Wheland intermediates

Liu,

Xu,

Liu

et al. 2024

Preprint

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“…Ring systems, especially small and strained ring systems with a double bond or with a bridged bond, hold high-profile importance in transformations that generate bioisosteric systems. Recent works from Brown and our group , demonstrated that a high energy-containing molecule, bicyclo[1.1.0]butane (Δ E = 66.3 kcal/mol), could be efficiently engaged in [2π+2σ]-photocycloadditions giving rise to highly sought-after, yet complex sp 3 -rich units. Given the influence of saturated isosteres as target molecules in rational drug design, the demand for expanding its chemical space promises to unravel new exit vectors, potency, pharmacological properties, and physiological assessments (Scheme B) .…”

Section: Introductionmentioning

confidence: 99%

Double Strain-Release [2π+2σ]-Photocycloaddition

Dutta,

Lu,

Erchinger

et al. 2024

J. Am. Chem. Soc.

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In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both πunits in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]photocycloaddition takes place via a triplet mechanism.

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“…In addition, Hoz and co-workers postulated the existence of a radical cation intermediate, arising from single-electron oxidation, in the bromination of bicyclo[1.1.0]butane analogs . Despite these discoveries, the synthetic potential of bicyclo[1.1.0]butyl radical cations has been severely underexplored, with nonselective nucleophilic addition being the only transformation demonstrated for these intermediates. − We therefore determined to assess the feasibility of employing single-electron oxidation via photoredox catalysis as a strategy to access alternative bicyclo[1.1.0]butane reactivity.…”

Section: Introductionmentioning

confidence: 99%

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions

Tyler,

Schäfer,

Shao

et al. 2024

J. Am. Chem. Soc.

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As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, we report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio-and diastereoselective [2π + 2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations and thus provides a platform from which further studies into the synthetic applications of these intermediates can be built upon.

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Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols

Cited by 29 publications

References 75 publications

Complexity from simplicity: intramolecular meta-thermocycloadditions of benzene rings via Wheland intermediates

Complexity from simplicity: intramolecular meta-thermocycloadditions of benzene rings via Wheland intermediates

Double Strain-Release [2π+2σ]-Photocycloaddition

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions

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