Synthesis of Functionalized Pyrrolines via Microwave-Promoted Iminyl Radical Cyclizations

Singh, Jatinder; Nickel, Garrison A.; Cai, Yu; Jones, Dakota D.; Nelson, Tanner J.; Small, Jeshurun E.; Castle, Steven L.

doi:10.1021/acs.orglett.1c01148

Cited by 11 publications

(12 citation statements)

References 56 publications

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“…The bond dissociation energy for O-phenyl oximes ( 27) is around 35 kcal mol −1 , which suggests that heat, such as microwave irradiation, can promote the homolysis of these bonds and result in an iminyl radical (17) and an oxygen-centred radical (28) 42 . Recent progress in this area includes the development of oximes capable of undergoing fragmentation at lower temperatures 10 , and the modification of previous cyclization conditions to allow multicomponent coupling to synthesize functionalized pyrrolines 43 and dihydropyrrole-functionalized phenanthridines 44 .…”

Section: Mechanisms Of N-o Bond Fragmentationmentioning

confidence: 99%

“…Oximes that contained extended alkyl chains (39) were investigated, and 1,5-HAT occurred upon the formation of the iminyl radical (40). The resulting radical (41) can be carbonylated (42), oxidized (43) and trapped by the imine to cyclize and form a six-membered lactam (44) through a radical cascade (Fig. 3e) 49 .…”

Section: Transition-metal-mediated N-o Bond Fragmentationmentioning

confidence: 99%

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Reactivity of oximes for diverse methodologies and synthetic applications

et al. 2022

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Oximes are valuable synthetic building blocks with reactivity modes that enable their use in diverse methodologies, from cycloadditions to bioconjugation. Their reactivity towards photocatalysis and transition metals makes them ideal starting materials for N-containing heterocycles, amino alcohols and amines. Developments in oxime reactivity since 2016 have enabled transformations such as the addition of iminyl radicals to alkenes to generate functionalized imines, and [2 + 2]-cycloadditions to access azetidines. The unique properties imparted by the oxime N-O bond have also been used to integrate dynamic chemistries into materials. In this Review, we discuss the innovative use of this powerful functional group, with a focus on N-O bond fragmentation and cycloadditions, along with applications including dynamic materials, energetic materials and biocatalytic oxime reductions. We conclude by highlighting methodologies based on oxime starting materials, along with the challenges of using oximes for diverse applications, and offer insight into future directions in these areas.

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Section: Mechanisms Of N-o Bond Fragmentationmentioning

confidence: 99%

Section: Transition-metal-mediated N-o Bond Fragmentationmentioning

confidence: 99%

Reactivity of oximes for diverse methodologies and synthetic applications

et al. 2022

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“…Flash chromatography (SiO 2 , 0.9 × 13.5 cm, 2–30% EtOAc in hexane gradient elution) afforded 3e (13.0 mg, 0.0456 mmol, 81%) as a yellow–orange oil. Spectral data were identical to the previously reported data …”

Section: Methodsmentioning

confidence: 99%

“…Microwave-promoted reactions were carried out by irradiating sealed reaction mixtures inside a CEM Discover SP microwave reactor that was set at 200 W. Reactions employing conventional heating were performed in an oil bath. The preparation of compounds 1 , 4 , 5 , 6a – i , 7a – i , 17 , 18 , 19 , and 20 has been described in our previous report …”

Section: Methodsmentioning

confidence: 99%

“…We reasoned that replacing the toluene solvent with poor hydrogen atom donors such as PhCF 3 , CH 3 CN, or CH 3 OH would allow the trapping of the cyclic radical intermediate with a wide range of agents, including some that would not be compatible with the redox cycles inherent to most modern iminyl radical cyclizations (Scheme c). We recently published a preliminary report demonstrating the viability of microwave-promoted catalyst-free 5- exo -trig iminyl radical cyclizations for the construction of various functionalized pyrrolines . Herein, we provide a comprehensive description of these studies.…”

Section: Introductionmentioning

confidence: 99%

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Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines

et al. 2022

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A detailed study of iminyl radical cyclizations of O-aryloximes tethered to alkenes is reported. The reactions can be triggered by either microwave irradiation or conventional heating in an oil bath. A variety of radical traps can be employed, enabling C–C, C–N, C–O, C–S, or C–X bond formation and producing a diverse array of functionalized pyrrolines. Substrates containing an allylic sulfide furnish terminal alkenes by a tandem cyclization–thiyl radical β-elimination pathway. Cyclizations of hydroxylated substrates exhibit moderate diastereoselectivity that in some cases can partially be attributed to intramolecular hydrogen bonding. Computational studies suggested a possible role for thermodynamics in controlling the stereochemistry of cyclizations. The reaction temperature can be lowered from 120 to 100 °C by employing O-(p-tert-butylphenyl)oximes instead of O-phenyloximes as substrates, and these second-generation iminyl radical precursors can be used in a one-pot oxime ether formation–cyclization that is promoted by conventional heating. The functionalized pyrrolines obtained from these reactions can be conveniently transformed in several different ways.

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Cyclization Reactions of Nitrogen‐Centered Radicals

McCombie¹,

Quiclet‐Sire²,

Zard³

2021

Organic Reactions

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The cyclization of nitrogen‐centered radicals constitutes a powerful approach for the synthesis of a broad variety of nitrogen heterocycles. As with carbon‐centered radicals, the most common ring‐closure mode is the 5‐ exo cyclization onto an internal unsaturation, and the stereoselectivity is similar. Numerous methods for the generation of almost every type of nitrogen‐centered radical have been described. They involve the direct or indirect rupture of N–Y bonds, with Y = halogen (except fluorine), oxygen, nitrogen, sulfur, and hydrogen. Indirect methods, such as the addition of carbon radicals to imines, azides, and nitriles, have also been devised. The extended choice of methods and precursors, and the general mildness of the experimental conditions and tolerance for numerous functional groups, represent valuable synthetic advantages. Furthermore, the cyclization step can be part of a radical cascade leading to multiple bond formations and the rapid construction of complex molecular frameworks. This chapter describes the types, structures, and reactivity of nitrogen‐centered radicals, and details the mechanistic basis of the methods used to generate them. The methods include stannane‐based processes, oxidations and reductions by single‐electron transfer, thermolysis, electrolysis, photolysis, and photoredox catalysis. The factors that influence the stereoselectivity of the ring‐closures are discussed briefly. Applications to the total synthesis of natural products, as well as functional‐group compatibilities, reaction variants, and comparison to other methods for the synthesis of nitrogen heterocycles by ionic, organometallic, and uncatalyzed ring‐closures onto alkenes are also presented. The tabular surveys are organized according to the type of nitrogen‐centered radical involved in the cyclization step: aminyls, amidyls, carbamyls, iminyls, amidinyls, and other types of nitrogen‐centered radicals.

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Synthesis of Functionalized Pyrrolines via Microwave-Promoted Iminyl Radical Cyclizations

Cited by 11 publications

References 56 publications

Reactivity of oximes for diverse methodologies and synthetic applications

Reactivity of oximes for diverse methodologies and synthetic applications

Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines

Cyclization Reactions of Nitrogen‐Centered Radicals

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