Unexpected Direct Synthesis of <i>N</i>‐Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

Choi, Hans; Shirley, Harry J.; Hume, Paul A.; Brimble, Margaret A.; Furkert, Daniel P.

doi:10.1002/anie.201702727

Cited by 30 publications

(17 citation statements)

References 83 publications

(9 reference statements)

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“…The reaction most likely proceeds through the in situ formation of an N-vinyl azide 97, which undergoes facile azide-enolate [3+2] cycloaddition, followed by rearrangement and nitrogen extrusion (Scheme 15, C). This work was published in 2017 56 and remains an ongoing area of research within our group, using differentially substituted iodoazides and their reaction with aldehydes and esters to construct unique N-vinyl amide building blocks.…”

Section: Scheme 13mentioning

confidence: 99%

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Freeman

Furkert

et al. 2020

Synlett

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Cyclic imine marine toxins have attracted considerable attention from the synthetic community in the past two decades due to their unique chemical structures and clinically relevant biological activities. This review presents recent efforts of our group in the development of various strategies to efficiently construct the common spirocyclic imine fragments of the cyclic imine toxins. In particular, the use of α,β-unsaturated N-acyl iminium ion dienophiles in Diels–Alder reactions are highlighted, whereby direct access to spirocyclic imine motifs was obtained and important mechanistic details were discovered. Alternative approaches to spirocyclic imine systems involving hydroamination of amino alkynes are also summarized. One such approach led to serendipitous access to N-vinyl amide products, while our most recently reported approach involving an intermolecular Diels–Alder/cross-coupling sequence using novel 2-bromo-1,3-butadienes to access 5,6-spirocyclic imines is also discussed. Additionally, the development of a novel method to construct another challenging motif present in the portimines is also introduced.1 Introduction2 Strategies towards the Spirocyclic Imine Fragment of Cyclic Imine Toxins2.1 Diels–Alder Cycloadditions of α,β-Unsaturated N-Acyl Iminium Dienophiles2.2 Early Studies Using in situ-Generated Iminium Ion Dienophiles2.3 Use of More Stable Iminium Ion Dienophiles for Diels–Alder Reactions2.4 Other Notable Strategies towards Spirocyclic Imines2.5 Recent Efforts towards the 5,6-Spirocyclic Imine Marine Toxin Portimine A2.6 Construction of Another Challenging Motif of Portimine A3 Conclusion and Future Perspectives

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Section: Scheme 13mentioning

confidence: 99%

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Freeman

Furkert

et al. 2020

Synlett

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“…Recently, our group identified a novel N-vinyl amide synthesis via (3+2) vinyl azide-enolate cycloaddition of aldehyde and ester enolates. [57] At the outset of this study, we examined the analogous reaction of an amide substrate 1a, with -aryl vinyl azide 2a. Unexpectedly, the reaction proceeded cleanly to deliver α-iminyl amide 3a, in 80% yield.…”

Section: Figure 1 -Amination Of Carbonyl Compoundsmentioning

confidence: 99%

“…Mechanistically, the α-amination of amides and lactams appeared likely to proceed via an enolate-azide (3+2) cycloaddition to give triazolone type intermediates such as 9 as identified in our previous study (Scheme 1A). [57] On initial inspection, it seemed plausible that formal haloamides. [58][59][60] To confirm the utility of the current method for -…”

Section: Table 2 Exploration Of Amide Azide Substrate Scopementioning

confidence: 99%

Direct alpha-Amination of Amides and Lactams Enabled by the (3+2) Vinyl Azide-Enolate Cycloaddition Manifold

Bell-Tyrer

Hume

Grant

et al. 2022

Preprint

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Direct alpha-amination of carbonyl compounds remains an important yet synthetically challenging transformation. Here we report a solution for direct alpha-amination of amides and lactams, identified through fundamental exploration of (3+2) vinyl azide-enolate cycloaddition chemistry. Initial cycloadducts undergo rearrangement via 1,2-N-migration to afford imine intermediates that are readily converted to the target alpha-amino amides or lactams. The sequence requires no pre-functionalisation, can be performed on a range of substrates, including compound classes unsuccessful using reported methods, and delivers primary or secondary alpha-amines. This work highlights the diversity and synthetic potential of the rapidly expanding (3+2) azide-enolate cycloaddition manifold.

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“…These processes were shown to be viable for a wide range of activated carbonyls, including ketones and aldehydes, at room temperature ( Very recently, a novel method has been reported for the direct synthesis of N-vinyl amides 227, and α,β-unsaturated Nvinyl amides 228, from α-branched aldehydes 225 and esters 226 respectively (Scheme 54). 108 A mechanism was proposed involving in situ generation of azidoethene (from 1-azido-2iodoethane 224 under basic conditions); azide-enolate [3+2] annulation (as in Scheme 52) affords an intermediate triazole.…”

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confidence: 99%

α-Substituted vinyl azides: an emerging functionalized alkene

et al. 2017

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Vinyl azides are highly versatile synthons that provide access to numerous N-heterocycles and other functional groups. α-Substituted vinyl azides (azido vinylidenes) are a special class that display unique reactivity, able to react not only as azides, but also as radical acceptors, enamine-type nucleophiles, and even electrophiles, thus delivering a wide range of nitrogen-containing compounds and their derivatives. An impressive variety of intermediates - such as iminodiazonium ions, nitrilium ions, iminyl radicals, and metal enaminyl radicals - can be generated from vinyl azides and exploited in cycloadditions, C-H functionalizations, hydrolysis processes, and cascade reactions under transition metal/photoredox catalysis. In addition to presenting synthetic protocols to access vinyl azides, this Review offers a comprehensive coverage of the development of their multifaceted reactivity, and highlights their potential as versatile precursors for synthetic applications.

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Unexpected Direct Synthesis of N‐Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

Cited by 30 publications

References 83 publications

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Direct alpha-Amination of Amides and Lactams Enabled by the (3+2) Vinyl Azide-Enolate Cycloaddition Manifold

α-Substituted vinyl azides: an emerging functionalized alkene

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