Displacement Reactions at Bridgeheads of Bridged Polycarbocyclic Systems.

Applequist, Douglas E.; Roberts, John D.

doi:10.1021/cr60172a005

Cited by 35 publications

(22 citation statements)

References 42 publications

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“…Grunwald and Winstein (298) Grunwald and Winstein found that the logarithms of the solvolysis rates of many compounds give linear correlations in Y which can be expressed by equation 11. ko is the rate of solvolysis in the standard solvent, chosen as 80 per cent aqueous ethanol. log L = mY + log ko (11) The slope m measures the susceptibility of the substrate t o the ionizing power of the solvent relative t o tert-butyl chloride. A few representative values are given in The dielectric constant has long been considered to be one of the important attributes of overall solvent "ionizing power."…”

Section: (D) Effect Of Solvationmentioning

confidence: 99%

Solvolytic Displacement Reactions At Saturated Carbon Atoms

1956

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Section: (D) Effect Of Solvationmentioning

confidence: 99%

Solvolytic Displacement Reactions At Saturated Carbon Atoms

1956

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“…Interestingly, despite receiving little attention in recent times, 1-aminoNBs were central to delineating the basic principles of S N 1 and S N 2 reactivity, 11…”

Section: Introductionmentioning

confidence: 99%

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Staveness

Sodano

et al. 2019

Chem

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The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO 2 Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. HIGHLIGHTSStrain-driven homolysis initiates radical cyclization sequence toward norbornane core Robust functional-group tolerance provides readily modifiable building blocks Unique modes of diastereocontrol afford enantiopure 1aminonorbornanes 1-Aminonorbornanes are shown to offer improved metabolic stability over anilines Staveness et al., Chem 5,[215][216][217][218][219][220][221][222][223][224][225][226] January 10, SUMMARYThis report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp 3 -rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.

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“…Theb ridgehead amine can also serve as ap recursor to abridgehead cation (via the bridgehead diazonium species 5). This methodology was originally developed as ameans of delineating S N 1m echanisms, [64] and variations have been developed to generate 1-hydroxy,1 -halo,a nd 1-aryl norbornanes [45,65,66] from these unique cationic species;conditions to afford the former [44] were recapitulated herein, providing 1- hydroxynorbornane 6 in 74 %y ield. Perhaps the most significant manipulation was the conversion of C7-CO 2 Me 1-aminoNB 2o to the C7-methylene 1-aminoNB 2v (see Figure 6B).…”

Section: Angewandte Chemiementioning

confidence: 99%

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

et al. 2019

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This report details the development of a masked N‐centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1‐aminonorbornanes. This process employs the N‐centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C−C bonds en route to the norbornane core. Achieving bond‐forming reactivity as a function of the N‐centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl‐fused 1‐aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.

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Displacement Reactions at Bridgeheads of Bridged Polycarbocyclic Systems.

Cited by 35 publications

References 42 publications

Solvolytic Displacement Reactions At Saturated Carbon Atoms

Solvolytic Displacement Reactions At Saturated Carbon Atoms

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

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