Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C–N bonds

Millward, Makenzie J.; Ellis, Emily A.; Ward, John W.; Clayden, Jonathan

doi:10.1039/d0sc06188c

Cited by 8 publications

(7 citation statements)

References 71 publications

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“…Generally, Smiles and Truce-Smiles rearrangements proceed through the formation of a spiro intermediate, which subsequently undergoes a ring-opening to yield the product [6,17]. Mechanisms featuring a spiro transition state rather than a spiro intermediate have been proposed [7], with several examples being identified by Clayden et al for the Smiles and Truce-Smiles rearrangements [56][57][58][59][60][61][62]. Concerted reaction pathways have also been identified for other Smiles-type rearrangements [63][64][65].…”

Section: Resultsmentioning

confidence: 99%

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu

et al. 2021

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Rearrangements of o-tolyl aryl ethers, amines, and sulfides with the Grubbs–Stoltz reagent (Et3SiH + KOtBu) were recently announced, in which the ethers were converted to o-hydroxydiarylmethanes, while the (o-tol)(Ar)NH amines were transformed into dihydroacridines. Radical mechanisms were proposed, based on prior evidence for triethylsilyl radicals in this reagent system. A detailed computational investigation of the rearrangements of the aryl tolyl ethers now instead supports an anionic Truce–Smiles rearrangement, where the initial benzyl anion can be formed by either of two pathways: (i) direct deprotonation of the tolyl methyl group under basic conditions or (ii) electron transfer to an initially formed benzyl radical. By contrast, the rearrangements of o-tolyl aryl amines depend on the nature of the amine. Secondary amines undergo deprotonation of the N-H followed by a radical rearrangement, to form dihydroacridines, while tertiary amines form both dihydroacridines and diarylmethanes through radical and/or anionic pathways. Overall, this study highlights the competition between the reactive intermediates formed by the Et3SiH/KOtBu system.

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Section: Resultsmentioning

confidence: 99%

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu

et al. 2021

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“…Related nitrile-stabilized carbanions 47 – allowed ring expansion of heterocycles 47 to iminohydantoin-bridged eight- to ten-membered N-heterocycles 49 ( Scheme 14 ). 51 When X was (or was part of) a pronucleophile (e.g., CO or NBoc as in 49b ), a second transannular exo -cyclization onto the C=N bridge formed even more complex caged structures. 51 …”

Section: N → C Aryl Migration In Ureas: Synthesis Of α-Tertiary Aminesmentioning

confidence: 99%

“… 51 When X was (or was part of) a pronucleophile (e.g., CO or NBoc as in 49b ), a second transannular exo -cyclization onto the C=N bridge formed even more complex caged structures. 51 …”

Section: N → C Aryl Migration In Ureas: Synthesis Of α-Tertiary Aminesmentioning

confidence: 99%

“…Related nitrilestabilized carbanions 47 − allowed ring expansion of heterocycles 47 to iminohydantoin-bridged eight-to ten-membered N-heterocycles 49 (Scheme 14). 51 When X was (or was part of) a pronucleophile (e.g., CO or NBoc as in 49b), a second transannular exo-cyclization onto the CN bridge formed even more complex caged structures. 51 The synthesis of α-aryl hydantoins by enolate arylation was streamlined into a one-pot sequential α-amination and αarylation of silyl ketene acetals (Scheme 15).…”

Section: Enolates and Metalated Nitriles: Synthesis Of Hydantoins And...mentioning

confidence: 99%

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C(sp³)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (S_NAr)

2022

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Conspectus The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N ′-aryl group to the α-carbanion of an adjacent N -benzyl group. Despite this reaction formally constituting an S N Ar substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical S N Ar reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N ′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N ′-aryl group, hugely accelerating ipso -substitution. This discovery led us to uncover a whole series of conformationally accelerated intramolecular N → C aryl transfers using different anilide-based functional groups, including a diverse range of urea, carbamate, and thiocarbamate-substituted anions. Products included enantioenriched α-tertiary amines (including α-arylated N-heterocycles) and alcohols, as well as rare α-tertiary thiols. Synthetically challenging diarylated centers with differentiated aryl groups featured heavily in all product sets. The absolute enantiospecificity (retention versus inversion) of the reaction was dependent on the heteroatom α to the lithiation site: the origin of this stereodivergence was probed both experimentally and computationally. Asymmetric variants of the rearrangement were realized by enantioselective deprotonation, and connective strategies were developed in which an intermolecular C–C bond-forming event preceded the anionic rearrangement. Substrates where the N ′-nucleofuge (at the aryl ipso position) was tethered to the migrating arene allowed us to use the rearrangement as a ring expansion method to generate 8- to 12-membered medium-ring ...

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“…[28] A related reaction by the same group built on this idea of ring expansion via aryl migration, showing that metalated nitriles tethered to a urea linkage can undergo a Smiles rearrangement, giving a medium sized ring (see Scheme 3). [29] After deprotonation via a strong base, the α-nitrile carbanion 13 can undergo ipso-substitution on to the neighboring aromatic ring, giving a ring expansion. The urea anion 14 can then undergo nucleophilic attack of the nitrile, giving the unusual hydantoin-bridged medium ring scaffold 15.…”

Section: Polar Smiles Rearrangementsmentioning

confidence: 99%

Recent Advances in the Smiles Rearrangement: New Opportunities for Arylation

Whalley¹,

Greaney²

2021

Synthesis

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The Smiles rearrangement has undergone a renaissance in recent years providing new avenues for non-canonical arylation techniques in both the radical and polar regimes. This Short Review will discuss recent applications of the reaction (from 2017 onwards), including its relevance to areas such as heterocycle synthesis, functionalisation of alkenes and alkynes as well as glimpses at new directions for the field.

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Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C–N bonds

Abstract: Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by ring expanding intramolecular SNAr on a series of electronically unactivated heterocyclic precursors.

Cited by 8 publications

References 71 publications

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu

C(sp³)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (S_NAr)

Recent Advances in the Smiles Rearrangement: New Opportunities for Arylation

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Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C–N bonds

Abstract: Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by ring expanding intramolecular SNAr on a series of electronically unactivated heterocyclic precursors.

Cited by 8 publications

References 71 publications

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu

C(sp3)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (SNAr)

Recent Advances in the Smiles Rearrangement: New Opportunities for Arylation

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C(sp³)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (S_NAr)