Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

Yang, X.-M.; Nath, Dinesh; Gau, Michael R.; Steward, Omar W.; Fleming, Fraser F.

doi:10.1002/anie.201704028

Cited by 10 publications

(2 citation statements)

References 32 publications

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“…A remarkable sulfone–metal exchange–alkylation of 44 demonstrates that all three oxidation states of sulfur-substituted acetonitriles are precursors of metalated nitriles (Scheme ). Commercially available 2-pyridylsulfonylacetonitrile ( 43 ) readily alkylates diverse electrophiles in the presence of K 2 CO 3 or DBU to provide substituted sulfonyl nitriles such as 44 . The 2-pyridyl moiety is critical in anchoring the organometallic proximal to the sulfone moiety ( 45 ) to override competitive directed ortho-metalation.…”

Section: Generation Of Metalated Nitrilesmentioning

confidence: 99%

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

Yang

Fleming

2017

Acc. Chem. Res.

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Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent negative charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Solution and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temperature, and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp or sp hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in Si displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and N-metalated nitriles allows selective cyclization to afford nitrile-containing cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential Si displacements with allylic electrophiles on sp centers over sp centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal dimethyl groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor S2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively preparing C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that prov...

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Section: Generation Of Metalated Nitrilesmentioning

confidence: 99%

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

Yang

Fleming

2017

Acc. Chem. Res.

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“…Applying known methods to directly reduce or open aliphatic sultones [32] failed in our hands. Inspired by Fleming and co-workers' sulfone-metal exchange strategy, [33] we investigated the addition of lithium magnesiates to sultone 14. While sulfur-metal exchange would not be expected for a sultone, owing to the presence of an alkoxide leaving group, treating sultone 14 with lithium triphenyl magnesiate (Ph 3 MgLi) [34] afforded ring-opened phenyl sulfone 15, now bearing a suitable electron-sink to aid CÀ S bond reduction.…”

Section: Methodsmentioning

confidence: 99%

Unified Synthesis of 2‐Isocyanoallopupukeanane and 9‐Isocyanopupukeanane through a “Contra‐biosynthetic” Rearrangement

Hardy,

Hayward Cooke,

Feng

et al. 2023

Angew Chem Int Ed

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Herein, we describe our synthetic efforts toward the pupukeanane natural products, in which we have completed the first enantiospecific route to 2‐isocyanoallopupukeanane in 10 steps (formal synthesis), enabled by a key Pd‐mediated cyclization cascade. This subsequently facilitated an unprecedented bio‐inspired “contra‐biosynthetic” rearrangement, providing divergent access to 9‐isocyanopupukeanane in 15 steps (formal synthesis). Computational studies provide insight into the nature of this rearrangement.

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Carbanions and Electrophilic Aliphatic Substitution

Birsa¹

2020

Organic Reaction Mechanisms Series

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Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

Cited by 10 publications

References 32 publications

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

Unified Synthesis of 2‐Isocyanoallopupukeanane and 9‐Isocyanopupukeanane through a “Contra‐biosynthetic” Rearrangement

Carbanions and Electrophilic Aliphatic Substitution

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