α-Cyanation of Tertiary Amines

Groutas, William C.; Essawi, M. Y. H.; Portoghese, Phillip

doi:10.1080/00397918008069324

Cited by 30 publications

(6 citation statements)

References 15 publications

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“…Such compounds (67, Scheme 10) are at the same oxidation state as MPTP. Consequently, ring R-carbon oxidation of 67 will generate iminium products 68, which, as the corresponding enamine free bases 69, will undergo spontaneous elimination (224) to form the unstable dihydropyridinium products 70. In the brain, which lacks aldehyde oxidase activity, these intermediates may spontaneously oxidize to the pyridinium products 71.…”

Section: Piperidinols and Related Compoundsmentioning

confidence: 99%

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Castagnoli

Rimoldi

Bloomquist

et al. 1997

Chem. Res. Toxicol.

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A major theme explored in this review is the MAO-and cytochrome P450-catalyzed alpha-carbon oxidations of selected cyclic tertiary amines to give iminium metabolites that undergo further chemical modifications to form known or potentially toxic products. The most dramatic illustration of this type of bioactivation process is the conversion of the parkinsonian-inducing neurotoxin MPTP (23) by brain MAO-B to the iminium (dihydropyridinium) metabolite 24 which is oxidized further to the pyridinium species MPP+ (25). The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events (transport into the nerve terminals by the dopamine transporter, localization in the inner mitochondrial membrane by electromotive forces, and inhibition of complex I of the mitochondrial electron transport chain) that, fortunately, are unlikely to be encountered with many substances. A second example of a well-documented metabolic bioactivation sequence involves the highly toxic pyrrolizidine alkaloids (102). These compounds undergo cytochrome P450-catalyzed alpha-carbon oxidation which converts the 3-pyrrolinyl moiety present in the parent alkaloids into a pyrrolyl-containing metabolite (105). The presence of labile functional groups results in the spontaneous conversion of 105 to reactive electrophilic products (106 and 108) that undergo Michael addition reactions with nucleophiles on biomacromolecules leading to a variety of toxic outcomes. Less clearly defined are the potential contributions to neurodegenerative processes that may be mediated by low-level, long term exposure to less potent toxins. Examples of potential proneurotoxins are the endogenously formed tetrahydroisoquinolines (such as40-50) and tetrahydro-beta-carbolines (such as 54) that may be biotransformed to neurotoxic isoquinolinium (such as 51) and beta-carbolinium (such as 52) species in the brain. A similar argument can be made for 4-piperidinols (compounds that are at the same oxidation state as the tetrahydropyridines) which may be metabolized via iminium intermediates to amino enols that spontaneously convert to dihydropyridinium species and hence to pyridinium metabolites (67-->68-->69-->70-->71, Scheme 10). This type of reaction sequence has been well documented with the parkinsonian-inducing neuroleptic agent haloperidol (72) which is metabolized in humans, baboons, and rodents to the pyridinium species HPP+ (75), a potent inhibitor of mitochondrial respiration. Finally, an appreciation of the alpha-carbon oxidations of fully reduced azacycles such as (S)-nicotine (61) and phencyclidine (82) to chemically reactive metabolites that form covalent adducts with proteins, including the enzymes that are responsible for their formation, may prove of toxicological importance when attempting to account for the effects of chronic abuse of these potent drugs.1

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Section: Piperidinols and Related Compoundsmentioning

confidence: 99%

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Castagnoli

Rimoldi

Bloomquist

et al. 1997

Chem. Res. Toxicol.

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“…In the case of secondary amines, this can be achieved either by the use of phenylseleninic acid [7] or via N-chlorination, dehydrochlorination and then trapping of the in-situ generated imine with cyanide. [8] However, tertiary amines can only be converted into a-amino nitriles by the oxidation with wastegenerating oxidants such as chlorine dioxide, [9] mchloroperbenzoic acid, [10] hydrogen peroxide [11] or mercuric acetate, [12] followed by the reaction of the iminium intermediate with cyanide ion. Oxidation with hypervalent iodine compounds, [13] metal-based catalysts such as iron salts, [14] V 2 O 5 [15] have also been reported.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneously Catalyzed Oxidative Cyanation of Tertiary Amines with Sodium Cyanide/Hydrogen Peroxide using Polymer‐Supported Iron(II) Phthalocyanines as Catalyst

2010

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The first report on heterogeneously catalyzed oxidative cyanation of various tertiary amines to the corresponding a-amino nitriles with high yields and selectivity by using hydrogen peroxide oxidant in presence of sodium cyanide and Fe(II) phthalocyanine supported on a polymer as catalyst is described. The present method has the added benefits of facile recovery of the catalyst from the reaction mixture and its subsequent use without further activation. Consistent catalytic activity with no metal leaching was observed during this course.

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“…The classic method known as Strecker reaction [6] involving the one pot condensation of a carbonyl compound, an amine and cyanide in presence of homogeneous [7][8][9] or heterogeneous [10][11][12][13] catalysts is well documented albeit provide poor product yields. Alternatively, the oxidation of tertiary amines with stoichiometric oxidants such as chlorine dioxide [14], m-chloroperbenzoic acid [14,15], hydrogen peroxide [16,17] or mercuric acetate [18], followed by the reaction of the iminium intermediate by cyanide ion represents a simple approach for their synthesis. However, the use of stoichiometric oxidants and production of huge amounts of hazardous waste is undesirable from environmental viewpoints.…”

mentioning

confidence: 99%

Acetone Cyanohydrin: A Convenient Alternative of Toxic Sodium Cyanide/Acetic Acid for Oxidative Cyanation of Tertiary Amines

2011

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Acetone cyanohydrin was found to be a facile, convenient and comparatively safer alternative to toxic sodium cyanide/acetic acid system for generating in situ HCN for the oxidative cyanation of tertiary amines to a-aminonitriles in high yields with hydrogen peroxide using RuCl 3 as catalyst. In addition organic nature of acetone cyanohydrin makes it more suitable for an organic transformation since it is readily soluble in reaction medium and can be added in a controlled manner.

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α-Cyanation of Tertiary Amines

Cited by 30 publications

References 15 publications

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Heterogeneously Catalyzed Oxidative Cyanation of Tertiary Amines with Sodium Cyanide/Hydrogen Peroxide using Polymer‐Supported Iron(II) Phthalocyanines as Catalyst

Acetone Cyanohydrin: A Convenient Alternative of Toxic Sodium Cyanide/Acetic Acid for Oxidative Cyanation of Tertiary Amines

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