Synthesis of Nitrile‐Bearing Quaternary Centers by an Equilibrium‐Driven Transnitrilation and Anion‐Relay Strategy

Alazet, Sébastien; West, Michael S.; Patel, Purvish; Rousseaux, Sophie

doi:10.1002/anie.201903215

Cited by 11 publications

(7 citation statements)

References 48 publications

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“…Stereoselective differentiation of malononitriles is challenging, probably due to their coordinating affinity to transition metals and the minuscule steric size of the nitrile group. Moreover, decyanative decomposition of malononitriles in the presence of transition-metal catalysts or organometallic reagents would be problematic . Although enantioselective enzymatic hydrolysis of dinitriles has been known for decades, only two examples of chemical catalytic desymmetrization of malononitriles were revealed to date, namely, rhodium-catalyzed [2+2+2] cycloaddition by the Tanaka group (Scheme e) and ruthenium-catalyzed hydration reaction by the Ikariya group .…”

mentioning

confidence: 99%

Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis

Lü

Zhang

et al. 2020

J. Am. Chem. Soc.

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Chiral nitriles are valuable molecules in modern organic synthesis and drug discovery. Selectively differentiating the two nitrile groups of widely available malononitrile derivatives is a straightforward yet underdeveloped route to construct enantioenriched nitriles. Here we report an enantioselective nickel-catalyzed desymmetrization of malononitriles for the generation of nitrile-containing all-carbon quaternary stereocenters. This protocol involves a nickel-catalyzed addition of aryl boronic acids to alkynes, followed by a selective nitrile insertion, providing unprecedented access to enantioenriched 5−7-membered α-cyanocycloenones with a fully substituted olefin from a broad range of substrates. The synthetic utility of these nitrile products is demonstrated by gram-scale synthesis and conversion to several useful functional groups.

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confidence: 99%

Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis

Lü

Zhang

et al. 2020

J. Am. Chem. Soc.

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“…27−34 Nitrile-bearing carbon quaternary stereocenters are found in many medicinal compounds such as verapamil, gallopamil, and E2050 (Figure 1). 1,35 The construction of these frameworks is greatly important because it has become clear that the presence of a carbon quaternary center prevents the oxidation of the αcarbon of nitriles and the subsequent release of toxic cyanide. 8,10,11 α-Cyano carbonyl compounds are very important in the construction of bioactive molecules.…”

Section: ■ Introductionmentioning

confidence: 99%

Biocatalytic Synthesis of Nitrile-Bearing All-Carbon Quaternary Stereocenters

Rezaei,

Shahedi,

Habibi

2024

J. Org. Chem.

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The synthesis of all-carbon quaternary stereocenters containing nitriles is a very important and challenging subject in organic chemistry. We used a biocatalytic approach under mild conditions to obtain new derivatives of these scaffolds by oxidation of catechols by Myceliophthora thermophila laccase (Novozym 51003) to afford o-quinones and 1,4-addition of a series of carbon nucleophiles containing tertiary alkyle nitriles to these intermediates. Using this approach, α-cyano carbonyls bearing a quaternary stereocenter were also prepared. Finally, the yields for the prepared compounds were 72− 94%.

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“…The π-electrophilicity of malononitriles has been used for transnitrilation (nitrile-transfer) reactions that deploy malononitriles as C-bound sources of CN. − Our group has recently reported the use of 2-methyl-2-phenylmalononitrile (MPMN) for an efficient Ni-catalyzed reductive cyanation of aryl (pseudo)halides . The successful application of MPMN as a π-electrophilic CN source prompted us to explore its reactivity with other amenable reaction partners.…”

Section: Introductionmentioning

confidence: 99%

Nickel-Catalyzed Reductive Alkyne Hydrocyanation Enabled by Malononitrile and a Formaldehyde Additive

Palermo,

Chiu,

Patel

et al. 2023

J. Am. Chem. Soc.

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The development of a nickel-catalyzed reductive alkyne hydrocyanation is described using 2-methyl-2-phenylmalononitrile (MPMN), a C-bound electrophilic transnitrilation reagent. Reproducibility issues led to the detection of oxidized hemiaminal impurities within N,N-dimethylacetamide. These impurities release formaldehyde in situ, which was ultimately identified as a critical reaction additive. A range of diaryl and aryl-alkyl alkynes underwent hydrocyanation. Mechanistic experiments revealed that formaldehyde and MPMN undergo a Ni-catalyzed reductive coupling of two π-components, leading to the controlled release of glycolonitrile as the active cyanating agent.

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Synthesis of Nitrile‐Bearing Quaternary Centers by an Equilibrium‐Driven Transnitrilation and Anion‐Relay Strategy

Cited by 11 publications

References 48 publications

Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis

Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis

Biocatalytic Synthesis of Nitrile-Bearing All-Carbon Quaternary Stereocenters

Nickel-Catalyzed Reductive Alkyne Hydrocyanation Enabled by Malononitrile and a Formaldehyde Additive

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