Spirocyclic Dihydropyridines by Electrophile-Induced Dearomatizing Cyclization of N-Alkenyl Pyridinecarboxamides

Senczyszyn, Jemma; Brice, Heloise; Clayden, Jonathan

doi:10.1021/ol400571j

Cited by 27 publications

(10 citation statements)

References 42 publications

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“…45 Recently, Clayden et al reported another electrophile-induced dearomatizing cyclization of N-alkenyl pyridinecarboxamides (Scheme 30, eqn (3)). 46 A range of spirocyclic dihydropyridines were obtained from a series of N-alkenylisonicotinamides incorporating variously substituted alkenes in the presence of triflic anhydride or chloroformates. The resulting products could be further elaborated to spirocyclic heterocycles with drug-like features.…”

Section: Dearomatization Of Pyridinesmentioning

confidence: 99%

Recent advances in dearomatization of heteroaromatic compounds

2014

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Dearomatization reactions provide the most efficient method for the synthesis of spiro- or fused-ring systems from readily available compounds. This review summarizes the recent developments in dearomatization reactions of indoles, pyridines, quinolines, isoquinolines, and some other heteroaromatic compounds. The applications of these methods in total synthesis of natural products are also briefly introduced.

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Section: Dearomatization Of Pyridinesmentioning

confidence: 99%

Recent advances in dearomatization of heteroaromatic compounds

2014

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“…A variety of arenesulfonyl chlorides and differently substituted benzoylacetamides were tolerated, affording the corresponding dearomatized products moderate to good yields. Triflic anhydride was employed by Clayden in 2013 to promote an intramolecular spirocyclization of N-alkenyl isonicotinamides [49]. If the unactivated substrate was completely inert, upon salification of the pyridinic nitrogen into a triflate salt, the enamide moiety became nucleophilic enough to promote dearomatization, generating a 1,4-dihydropyridine displaying a spirobicyclic structure (Scheme 15).…”

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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“…63 Precise control of temperature has been shown to significantly affect hydrogenation chemoselectivity, e.g. 64 Selective control over olefin, furan and nitrile moiety hydrogenation has also been reported (Scheme 19). 69 Catalyst switching also effects chemoselectivity with hydrogenation of 19 using 10% Pd/C resulting in specific olefin reduction to afford 59.…”

Section: Chemoselective Olefin and Alkyne Hydrogenationmentioning

confidence: 99%

“…The significant portion of currently reported olefin reduction flow protocols employ 10% Pd/C, with sterically hindered or highly substituted bonds requiring elevated temperature or pressures (Scheme 13). 4,44,61,[63][64][65][66] As previously mentioned flow reduction of olefins has been reviewed by Irfan et al 2 and consequently discussion herein is limited to hydrogenation of olefin moieties using organometallic flow protocols, chemoselective and asymmetric olefin hydrogenations.…”

Section: Olefin Hydrogenationsmentioning

confidence: 99%

The expanding utility of continuous flow hydrogenation

et al. 2015

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There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations. Moreover flow reactors enhance laboratory safety with pyrophoric catalysts contained in sealed cartridges and hydrogen generated in situ from water. This mini-review focuses on recent applications of flow chemistry to mediate nitro, imine, nitrile, amide, azide, and azo reductions. Methodologies to effect de-aromatisation, hydrodehalogenation, in addition to olefin, alkyne, carbonyl, and benzyl reductions are also examined. Further, protocols to effect chemoselective reductions and enantioselective reductions are highlighted. Together these applications demonstrate the numerous advantages of performing hydrogenation under flow conditions which include enhanced reaction throughput, yields, simplified workup, and the potential applicability to multistep and cascade synthetic protocols.

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Spirocyclic Dihydropyridines by Electrophile-Induced Dearomatizing Cyclization of N-Alkenyl Pyridinecarboxamides

Cited by 27 publications

References 42 publications

Recent advances in dearomatization of heteroaromatic compounds

Recent advances in dearomatization of heteroaromatic compounds

Nucleophilic Dearomatization of Activated Pyridines

The expanding utility of continuous flow hydrogenation

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