Electrophile-Induced Dearomatizing Spirocyclization of <i>N</i>-Arylisonicotinamides: A Route to Spirocyclic Piperidines

Arnott, Gareth E.; Brice, Heloise; Clayden, Jonathan; Blaney, Emma L.

doi:10.1021/ol801092s

Cited by 51 publications

(12 citation statements)

References 49 publications

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“…Following N-protecting group removal by oxidation/dissolving metal reduction resulted in the final benzo-fused spiroheterocycles (Scheme 2 b). [58] In a contribution from the Ley group, the preparation of butane-2,3-diacetal tartrates using flow chemistry has been described. During the final step to produce synthetically useful quantities of the meso tartrate, the authors have used the H-Cube reactor in combination with a Rh/Al 2 O 3 catalyst.…”

Section: Hydrogenation Reactions Under Flow Conditions 41 Carbon-camentioning

confidence: 99%

Heterogeneous Catalytic Hydrogenation Reactions in Continuous‐Flow Reactors

2011

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Microreactor technology and continuous flow processing in general are key features in making organic synthesis both more economical and environmentally friendly. Heterogeneous catalytic hydrogenation reactions under continuous flow conditions offer significant benefits compared to batch processes which are related to the unique gas-liquid-solid triphasic reaction conditions present in these transformations. In this review article recent developments in continuous flow heterogeneous catalytic hydrogenation reactions using molecular hydrogen are summarized. Available flow hydrogenation techniques, reactors, commonly used catalysts and examples of synthetic applications with an emphasis on laboratory-scale flow hydrogenation reactions are presented.

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Section: Hydrogenation Reactions Under Flow Conditions 41 Carbon-camentioning

confidence: 99%

Heterogeneous Catalytic Hydrogenation Reactions in Continuous‐Flow Reactors

2011

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“…Such dearomatizing spirocyclizations were first explored by the Clayden group in 2008, when N-aryl isonicotinamides, activated by triflic anhydride, underwent dearomatization, with the aryl group reacting in a Friedel-Crafts fashion to the C-4 position of the activated pyridinium [50,51]. More recently, Parameswarappa and Pigge developed a variation of this methodology, based on 4-aminomethyl-or 4-aminoethylpyridines, in which the nucleophile, tethered to the C-4 position of the pyridine ring, is generated by a Lewis-acid promoted enolization of a 1,3-dicarbonyl moiety [52][53][54].…”

Section: N-sulfonylpyridinium Saltsmentioning

confidence: 99%

Nucleophilic Dearomatization of Activated Pyridines

2018

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Amongst nitrogen heterocycles of different ring sizes and oxidation statuses, dihydropyridines (DHP) occupy a prominent role due to their synthetic versatility and occurrence in medicinally relevant compounds. One of the most straightforward synthetic approaches to polysubstituted DHP derivatives is provided by nucleophilic dearomatization of readily assembled pyridines. In this article, we collect and summarize nucleophilic dearomatization reactions of - pyridines reported in the literature between 2010 and mid-2018, complementing and updating previous reviews published in the early 2010s dedicated to various aspects of pyridine chemistry. Since functionalization of the pyridine nitrogen, rendering a (transient) pyridinium ion, is usually required to render the pyridine nucleus sufficiently electrophilic to suffer the attack of a nucleophile, the material is organized according to the type of N-functionalization. A variety of nucleophilic species (organometallic reagents, enolates, heteroaromatics, umpoled aldehydes) can be productively engaged in pyridine dearomatization reactions, including catalytic asymmetric implementations, providing useful and efficient synthetic platforms to (enantioenriched) DHPs. Conversely, pyridine nitrogen functionalization can also lead to pyridinium ylides. These dipolar species can undergo a variety of dipolar cycloaddition reactions with electron-poor dipolarophiles, affording polycyclic frameworks and embedding a DHP moiety in their structures.

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“…Thus enolates of glycine esters 1 carrying isonicotinoyl or nicotinoyl N-substituents cyclise readily to yield bicyclic amino acid derivatives 2 (Scheme 1 for example) [39]. Even greater reactivity towards intramolecular nucleophilic attack is exhibited by isonicotinamides when activated by N-sulfonation [40–41]. For example, the N -furylmethyl isonicotinamide 3 cyclises to the doubly dearomatised bis-spirocycle 4 on treatment with triflic anhydride in the presence of an alcohol [41] (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

Brice¹,

Clayden²,

Hamilton³

2010

Beilstein J. Org. Chem.

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SummaryThe silyl enol ether derivatives of ketones or esters tethered by a hydrocarbon or ether linkage to the 3-position of a pyridine ring undergo dearomatising nucleophilic attack on the ring once it is activated (as an acylpyridinium species) by the addition of methyl chloroformate. The bicyclic dihydropyridine products are in some cases unstable, but may be isolated after hydrogenation as fused bicyclic piperidines.

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Electrophile-Induced Dearomatizing Spirocyclization of N-Arylisonicotinamides: A Route to Spirocyclic Piperidines

Cited by 51 publications

References 49 publications

Heterogeneous Catalytic Hydrogenation Reactions in Continuous‐Flow Reactors

Heterogeneous Catalytic Hydrogenation Reactions in Continuous‐Flow Reactors

Nucleophilic Dearomatization of Activated Pyridines

Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

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