Selective Reduction of Barbituric Acids Using SmI<sub>2</sub>/H<sub>2</sub>O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adducts

Szostak, Michal; Sautier, Brice; Spain, Malcolm; Behlendorf, Maike; Procter, David J.

doi:10.1002/anie.201306484

Cited by 64 publications

(44 citation statements)

References 94 publications

(26 reference statements)

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“…Unfortunately, the formation of ketyl‐type radicals is typically limited to aldehyde or ketone substrates, regardless of the reagent used for radical generation. Recently, we and others have begun to extend the rich chemistry of ketyl‐type radicals to the reductive cyclizations of carboxylic acid derivatives, including cyclic esters– and cyclic amide derivatives,– possessing more electron‐rich carbonyls. However, engaging carbonyl‐containing substrates in which the carbonyl is flanked by two heteroatom substituents in ketyl‐type radical chemistry, until now, has not proved possible, despite the promise of new reaction space for exploration.…”

Section: Methodsmentioning

confidence: 99%

Radical Anions from Urea‐type Carbonyls: Radical Cyclizations and Cyclization Cascades

2018

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Radical anions generated from urea carbonyls by reductive electron transfer are exploited in carbon-carbon bond formation. New radical cyclizations of urea radical anions deliver complex nitrogen heterocycles and, depending upon the proton source used in the reactions,achemoselective switch between reaction pathwaysc an deliver two heterobicyclic scaffolds.Acomputational study has been used to investigate the selectivity of the urea radical processes. Furthermore,r adical cyclization cascades involving urea radical anions deliver unusual spirocyclic aminal architectures.Carbon-carbon bond formation is integral to almost any synthetic endeavor and provides af ocal point for contemporary synthetic method development. [1] Radical reactions constitute one of the most important and attractive tools to achieve carbon-carbon bond formation. [2] In particular, radical cyclizations and cyclization cascades are prized for their ability to construct carbo and heterocyclic motifs, including those found in complex natural products,b iologically active molecules and materials. [3] Within radical chemistry,k etyl radicals,t ypically derived by single electron transfer (SET) reduction of aldehydes and ketones,h old high status as one of the most important and versatile classes of open shell intermediates for use in synthesis. [4] Cyclization reactions involving ketyl radicals inherently give oxygenated cyclic products,o ften possessing valuable three-dimensional shape,and have been achieved by deploying reagents based on Sm II , [5] Ti III , [6a-e] Ru II , [6f-i] Ir III , [6j] and electrochemistry, [6k] amongst others. [4] In particular, samarium(II) iodide (SmI 2 )i st he reagent most frequently used to generate ketyl radicals and the reactive intermediates formed in this way have found widespread application in myriad cyclization and cyclization cascade strategies [5] thus establishing both reagent and reaction as standard tools for synthesis. [7] Unfortunately,t he formation of ketyl-type radicals is typically limited to aldehyde or ketone substrates, regardless of the reagent used for radical generation. Recently,w ea nd others have begun to extend the rich chemistry of ketyl-type radicals to the reductive cyclizations of carboxylic acid derivatives, [8a] including cyclic esters [8b-d] and cyclic amide derivatives, [8e-k] possessing more electronrich carbonyls.H owever,e ngaging carbonyl-containing sub-[*] Dr.

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Section: Methodsmentioning

confidence: 99%

Radical Anions from Urea‐type Carbonyls: Radical Cyclizations and Cyclization Cascades

2018

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“…The ubiquitous amide moiety is even more resistant to ET reduction and the development of new radical cyclization methods based on the reduction of amide derivatives presents a significant challenge. Inspired by the pioneering work of the groups of Reissig, Skrydstrup, Py, and Huang on SmI 2 ‐mediated nitrogen heterocycle synthesis (Scheme a), herein, we describe radical heterocyclizations,– and the first radical heterocyclization cascades of amide‐type substrates. The SmI 2 /H 2 O‐mediated radical processes involve the coupling of amide carbonyls and alkenes, tethered through an sp 2 ‐hybridized nitrogen center, and provide expedient access to important polycyclic heterocycles possessing bridgehead nitrogen atoms (Figure and Scheme b).…”

Section: Figurementioning

confidence: 99%

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide‐Type Carbonyl Compounds

Huang

Procter

2017

Angew Chem Int Ed

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Radical heterocyclizations triggered by electron transfer to amide-type carbonyls, using SmI -H O, provide straightforward access to bicyclic heterocyclic scaffolds containing bridgehead nitrogen centers. Furthermore, the first radical heterocyclization cascade triggered by reduction of amide-type carbonyls delivers novel, complex tetracyclic architectures containing five contiguous stereocenters with excellent diastereocontrol.

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“…Reductive cyclizations of barbituric acid derivatives proceeding via aminoketyl radicals were reported by Szostak and Procter in 2013 ( Scheme 3 ) [ 35 ]. The reaction constituted the first example of selective reductive umpolung cyclizations exploiting ketyl-type radicals generated from barbituric acids, and provided an efficient entry to functionalized pyrimidine scaffolds.…”

Section: Synthesis Of Nitrogen Heterocycles Via Aminoketyl Radicalmentioning

confidence: 99%

Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide

Shi

Szostak

2017

Molecules

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Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N-heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI2, Kagan’s reagent) has been widely used to forge challenging C–C bonds through reductive coupling reactions. Historically, the use of SmI2 in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI2 for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E1/2 of up to −2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI2. In particular, radical cross-coupling reactions exploiting SmI2-induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI2-promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen-containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI2. In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI2 are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan’s reagent.

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Selective Reduction of Barbituric Acids Using SmI₂/H₂O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adducts

Cited by 64 publications

References 94 publications

Radical Anions from Urea‐type Carbonyls: Radical Cyclizations and Cyclization Cascades

Radical Anions from Urea‐type Carbonyls: Radical Cyclizations and Cyclization Cascades

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide‐Type Carbonyl Compounds

Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide

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Selective Reduction of Barbituric Acids Using SmI2/H2O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adducts

Cited by 64 publications

References 94 publications

Radical Anions from Urea‐type Carbonyls: Radical Cyclizations and Cyclization Cascades

Radical Anions from Urea‐type Carbonyls: Radical Cyclizations and Cyclization Cascades

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide‐Type Carbonyl Compounds

Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide

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Selective Reduction of Barbituric Acids Using SmI₂/H₂O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adducts