Enantioselectively functionalised phenytoin derivatives by auxiliary-directed N to C aryl migration in lithiated α-amino nitriles

Mas‐Roselló, Josep; Okoh, Mary; Clayden, Jonathan

doi:10.1039/c8cc06833j

Cited by 12 publications

(4 citation statements)

References 40 publications

(10 reference statements)

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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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“…[20][21][22][23][24] Given this conformational constraint, nitrile-stabilised carbanions 25 will attack an unactivated C-N bond, directed by the conformational preference of a urea function (Scheme 1a), yielding iminohydantoin and hydantoin products. [26][27][28] We now show that the use of such anions in a ringexpansion reaction of nitrogen heterocycles leads to a two-carbon insertion into an aromatic C-N bond, with tandem formation of a bridging (imino)hydantoin ring (Scheme 1b).…”

Section: Introductionmentioning

confidence: 89%

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

et al. 2021

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“…Arylation was followed by spontaneous cyclization of the Enolates of phenylglycine-derived substrates were too unreactive under these conditions, so a chiral cyclohexyl auxiliary was instead appended to the nitrogen of an amino nitrile-derived substrate, 57 (Scheme 16b). 54 This modified approach enabled the enantioselective synthesis of the previously elusive chiral (imino)phenytoin analogues 58 and 59.…”

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

confidence: 99%

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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Enantioselectively functionalised phenytoin derivatives by auxiliary-directed N to C aryl migration in lithiated α-amino nitriles

Cited by 12 publications

References 40 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

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

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

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Enantioselectively functionalised phenytoin derivatives by auxiliary-directed N to C aryl migration in lithiated α-amino nitriles

Cited by 12 publications

References 40 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

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

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

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