Search

Isoxazolidin-5-ones have been regarded as β-amino acid surrogates owing to their labile N-O bond. While many efforts have been devoted to the catalytic enantioselective synthesis of the core of this heterocycle, its further transformation has been less explored, especially in the context of catalysis. This review summarizes the author's research on the development of catalytic reactions using isoxazolidin-5-ones as substrates. Asymmetric catalysis has proven effective for C-C bond formation at the carbonyl α-carbon. Catalytic asymmetric allylation and direct Mannich-type reactions have been developed. Further, the resulting products have been readily converted into the corresponding quaternary β2,2-amino acids. Moreover, isoxazolidin-5-ones have been identified as alkyl nitrene precursors in the presence of a suitable metal catalyst. The generated metallonitrene undergoes either the electrophilic amination of the aromatic ring or aliphatic C-H insertion, affording a series of cyclic β-amino acids. A remarkable difference in chemoselectivity between rhodium and copper alkyl nitrenes has also been demonstrated, highlighting the unique nature of the underexplored reactive intermediates. The various linear and cyclic β-amino acids obtained through the study are likely to find great utility in a broad range of chemical sciences.

Reported is the electrophilic amination of functional organolithium intermediates with well-designed aminating reagents under mild reaction conditions using flow microreactors. The aminating reagents were optimized to achieve efficient C-N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild reaction conditions, within 1 minute, by using flow microreactors. The aminating reagent was also prepared by the flow method. Based on stopped-flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without the necessity of work-up. Integrated one-flow synthesis consisting of the generation of an aryllithium, the preparation of an aminating reagent, and their combined reaction was successfully achieved to give the desired amine within 5 minutes of total reaction time.

An exceptionally general electrophilic amination, which directly transforms commercially available nitroarenes into alkylated aromatic aminoboranes with zinc organyl compounds was developed. The reaction starts with a two-step partial reduction of the nitro group to a nitrenoid, which is used in situ as the electrophilic amination reagent. To facilitate isolation, the resulting air- and moisture-sensitive aminoboranes were reacted with a range of electrophiles. The method not only represents a direct transformation of nitro compounds into electrophilic amination reagents but also provides an elegant alternative to dehydrocoupling methods for the generation of aminoboranes.

A copper-catalyzed regioselective and stereospecific aminoboration of vinylsilanes with bis(pinacolato)diboron (pinB-Bpin) and hydroxylamines has been developed. In the presence of a CuCl/MeO-dppbz catalyst, the boryl group and amino group are incorporated at the β position and α position, respectively, and the corresponding β-boryl-α-aminosilanes are obtained with good diastereoselectivity. The boryl group is a good latent functional group, and subsequent manipulations provide a variety of β-functionalized α-aminosilanes of great potential in medicinal chemistry. Additionally, preliminary application to asymmetric catalysis is also described.

Catalytic asymmetric aminative dearomatization of 1-substituted 2-naphthols was successfully implemented with electrophilic azodicarboxylates under the catalysis of chiral Sc(III)/pybox complexes. This intermolecular reaction represents a hitherto unknown enantioselective C-N bond-forming process through direct dearomatization of phenolic compounds to generate chiral nitrogen-containing quaternary carbon stereocenters.

A direct approach to important α-amino phosphonic acids and its derivatives has been developed by using copper-catalyzed electrophilic amination of α-phosphonate zincates with O-acyl hydroxylamines. This amination provides the first example of CN bond formation which directly introduces acyclic and cyclic amines to the α-position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope.

CrocaginA (1) combines an attractive molecular structure with an unusual biosynthesis and bioactivity. An efficient synthesis of crocaginA is presented that hinges on an early formation of the heterotricyclic core, an electrophilic amination, and the stereoselective hydrogenation of a tetrasubstituted double bond. This synthesis confirms the absolute configuration of crocaginA and provides access to the natural product and derivatives thereof for further biological testing. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3261]

A [Cp*Rh(III)]-catalyzed electrophilic amination of arylboronic acids with diethyl azodicarboxylate (DEAD) was developed, and arylhydrazides were produced in excellent yields and selectivity. The analogous amination with the arylazocarboxylates afforded the corresponding N,N-diarylhydrazides. The electrophilic amination of arylboronic acids with azocarboxylates proceeds readily under mild conditions with excellent functional group tolerance. Up to 99% yields were obtained. Preliminary mechanistic studies revealed that prior formation of an arylrhodium(III) intermediate for the azo coupling reaction can be ruled out.

A copper-catalyzed amino lactonization of unsaturated carboxylic acids has been achieved as well as the analogous intermolecular three-component amino oxygenation of olefins. The transformation features mild conditions and a remarkably broad substrate scope, offering a novel and efficient approach to construct a wide range of amino lactones as well as 1,2-amino alcohol derivatives. Mechanistic studies suggest that the reaction proceeds via a distinctive O-benzoylhydroxylamine-promoted electrophilic amination of alkenes.

Copper-catalyzed electrophilic amination of a triarylboroxin using an N-methoxyamine to give quick access to a variety of anilines was reported. The reaction was especially useful for syntheses of functionalized anilines when combined with our previously reported nucleophilic addition to N-methoxyamides.

Diorganocadmium reagents cannot react with ketoxime at room temperature. CuCN catalysis allows diarylcadmium reagents to react with ketoxime and to give corresponding arylamines in good to high yields at room temperature. According to the electronic effects of the substituent attached to the aromatic ring, functionalized diarylcadmium reagents show meta-para selectivity in their amination reactions. Also compared to diarylzinc reagents, diarylcadmium reagents react with O-substituted ketoxime under milder reaction conditions and they form corresponding arylamines in higher yields. CuCN cannot help dialkyl-, dicycloalky-, and dibenzylcadmium reagents to react with ketoxime. Our Aryl C-N bond formation method does not include cadmium excretion into the environment.

Zinc-catalyzed asymmetric α-amination of various cyclic β-ketocarbonyl compounds using azodicarboxylate (II) as the electrophilic nitrogen source is described.

A copper-catalyzed regio- and enantioselective hydroamination of alkenyl dan boronates (dan =1,8-diaminonaphthyl) with hydrosilanes and hydroxylamines proceeds to deliver the chiral α-aminoboronic acids in good yields with high enantiomeric ratios. The key to success is the introduction of an umpolung, electrophilic amination strategy. The copper catalysis can provide an unprecedented catalytic asymmetric approach to alkyl-substituted chiral α-aminoboronic acid derivatives of great potential in the fields of organic synthesis and medicinal chemistry.

Boron trifluoride monohydrate is an excellent Bronsted acid catalyst system for a wide range of reactions. It is a non-oxidizing acid catalyst prepared easily by bubbling BF 3 into water. We have found boron trifluoride monohydrate/sodium azide combination to be an efficient reagent system for aromatic electrophilic amination. The present method avoids the use of expensive superacids such as trifluoromethanesulfonic acid and provides a facile access to aromatic amines directly from aromatics.

A series of novel heterocyclic amines (III), (V), (VII), (IX), (XI), and (XIII) are obtained through one-pot C—H lithiation/transalumination and subsequent electrophilic amination.

Various sulfonamides are obtained using O-benzoyl hydroxylamines as a novel type of amine source and sodium sulfinates.

In many cases the E-isomer is used, however, the E/Z-geometry of the starting ketene is not relevant for the yields.

No longer a hindrance: copper-catalyzed electrophilic amination of aryl boronic esters is accomplished under mild reaction conditions using 2.5-5.0 mol % of a catalyst derived from copper tert-butoxide and Xantphos ligand. The reaction tolerates a wide range of functional groups and can be used to prepare some of the most hindered anilines made to date.

This review covers literature data on the amination of arenes and considers both multistep methods for the introduction of an amino group in the aromatic ring and the direct amination (amidation) of aromatic hydrocarbons. The main attention is drawn to the electrophilic amination (amidation) of aromatic hydrocarbons because of the lack of comprehensive reviews on recent advances in this area.

The catalytic activity of the novel title catalyst (I) is demonstrated in the highly enantioselective amination of benzofuranones with diester (III).

A copper-catalyzed electrophilic amination of aryl and heteroaryl aluminums with N,N-dialkyl-O-benzoyl hydroxylamines that affords the corresponding anilines in good yields has been developed. The catalytic reaction proceeds very smoothly under mild conditions and exhibits good substrate scope. Moreover, the developed catalytic system is also well suited for heteroaryl aluminum nucleophiles, providing facile access to heteroaryl amines.

A novel Cu-catalyzed electrophilic ring-opening amination of cyclopropanols with N,N-dialkyl-O-benzoylhydroxylamines is studied to give β-aminoketones in good to excellent yields.

Three new saccharin-based hypervalent iodine compounds and a dinuclear analogue are prepared.

The first enantioselective three-component electrophilic amination of α-substituted enecarbamates using chiral phosphoric acid as catalyst leading to α-hydrazinoimines is developed.

The formation of an NCF3 bond or an NCF2R bond still remains scarce. An efficient direct electrophilic amination of fluoroalkyl groups was developed. Difluoroenoxysilanes reacted easily on azodicarboxylate derivatives. These results led to a novel family of NCF3 and NCF2 hydrazine derivatives.

A highly enantioselective, chiral, Lewis acid calcium–bis(phosphate) complex, Ca[3a]n, which catalyzes the electrophilic amination of enamides with azodicarboxylate derivatives 2 to provide versatile chiral 1,2-hydrazinoimines 4 is disclosed. The reaction gives an easy entry to optically active syn-1,2-disubstituted 1,2-diamines 6 in high yields with excellent enantioselectivities, after a one-pot reduction of the intermediate 1,2-hydrazinoimines 4. The geometry and nature of the N-substituent of the enamide affect dramatically both the reactivity and the enantioselectivity. Although the calcium bis(phosphate) complex was a uniquely effective catalyst, the exact nature of the active catalytic species remains unclear. NMR spectroscopy and MS analysis of the various calcium complexes Ca[3]n reveals that the catalysts exist in various oligomer forms. The present mechanistic study, which includes nonlinear effects and kinetic measurements, constitutes a first step in understanding these calcium–bis(phosphate) complex catalysts. DFT calculations were carried out to explore the mechanism and the origin of the enantioselectivity with the Ca[3]n catalysts the calcium–bis(phosphate) complex was a uniquely effective catalyst, the exact nature of the active catalytic species remains unclear. NMR spectroscopy and MS analysis of the various calcium complexes Ca[3]n reveals that the catalysts exist in various oligomer forms. The present mechanistic study, which includes nonlinear effects and kinetic measurements, constitutes a first step in understanding these calcium–bis(phosphate) complex catalysts. DFT calculations were carried out to explore the mechanism and the origin of the enantioselectivity with the Ca[3]n catalysts.

Catalytic asymmetric aminative dearomatization of 1-substituted 2-naphthols is successfully implemented with electrophilic azodicarboxylates under the catalysis of chiral ScIII/pybox complexes.

The catalytic asymmetric electrophilic amination has been established as a fruitful methodology for the construction of nitrogen-bearing tetrasubstituted carbon stereocenters, with its roots nourished by the latest achievements in chiral catalysis and synthetic strategies. This review summarizes the recent progresses, briefly discusses the reaction mechanism and challenges in this context, and outlines synthetic opportunities for future development. 1 Introduction 2 Transformations Based on Azodicarboxylates 2.1 α-Substituted Prochiral Aldehydes and Ketones 2.2 Ketenes 2.3 Doubly Activated Dicarbonyl Compounds 2.4 Heteroatom-Containing Activated Methines 2.5 Heterocyclic Nucleophiles 3 Amination Reactions Using other Amination Reagents 4 Conclusion

Copper-catalyzed coupling reactions have been recognized as one of the most useful strategies for the formation of C–N bonds. This perspective gives an overview of the recent developments in copper-catalyzed electrophilic amination for the construction of various amines and their derivatives, including the electrophilic amination of various organometallic reagents and direct C–H bonds as well as the annulative electrophilic amination of o-alkynylphenols and o-alkynylanilines.

[reaction: see text] A new electrophilic amination reaction of functionalized arylazo tosylates with alkylzinc halides or dialkylzinc reagents in THF leads to the corresponding hydrazines. A facile cleavage of the N-N bond is achieved using Raney nickel in refluxing ethanol, leading to substituted secondary aryl-alkylamines in 45-79% yield.

The catalytic enantioselective electrophilic α-amination promoted chiral palladium complexes is described. Treatment of β-ketoesters with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the corresponding α-amino β-ketoesters with excellent enantiomeric excesses (91–99% ee). Palladium complexes were immobilized in [bmim]PF6, and their applications to catalytic α-amination of β-ketoesters were successfully demonstrated.

The SN2 reaction has been well recognized not to occur at sp2 carbons, while such an SN2-type substitution reaction was found to proceed readily at the sp2 nitrogen of oximes. Ab initio MP2 calculations show that the activation energy of the nucleophilic substitution at sp2 nitrogen is almost same as that of the Beckmann rearrangement. By the intramolecular SN2-type reaction at the oxime nitrogen, various aza-arenes and cyclic imines, such as quinolines, aza-spiro compounds, and dihydropyrroles, can be synthesized. Intermolecular substitution of oximes with organometallic reagents also proceeds, and electrophilic amination of Grignard reagents is accomplished by the use of 4,4,5,5-tetramethyl-1,3-dioxolan-2-one O-(phenylsulfonyl)oxime. Anion radicals generated by one-electron reduction of oxime derivatives act as iminyl radical equivalents. That is, the intramolecular C–N bond formation of γ,δ-unsaturated or β-aryl oximes is induced by a single electron transfer to give various pyrroles, quinolines, and carbolines, in which phenols, hydroquinones, or copper reagents can be used as electron donors. A photo-induced radical process is also applied to the transformation of γ,δ-unsaturated oximes to dihydropyrroles. Oxidative addition of oximes to palladium(0) complexes generates alkylideneaminopalladium(II) species, which are utilized as key intermediates in carbon–nitrogen bond formation. Various aza-heterocycles, including pyrroles, pyridines, isoquinolines, spiroimines, and aza-azulenes, are synthesized from O-(pentafluorobenzoyl)oximes having olefinic moieties via the intramolecular Heck-type reaction (amino-Heck reaction) by treatment with a catalytic amount of a Pd0 complex. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Published data on direct electrophilic amination of aromatic compounds are summarized and analyzed on the basis of nitrenium ion properties.

Electrophilic amination of primary aliphatic and aromatic amines is reported using a diethylketomalonate-derived oxaziridine to afford the corresponding N-Boc hydrazines in good to excellent yields. The method allows a one-pot synthesis of pyrazoles from primary amines. [Reaction: see text]

A general two-step preparation of enantiopure N(alpha),N(beta)-orthogonally diprotected alpha-hydrazino acids 1 is developed on a multigram scale. The key reaction is the efficient electrophilic amination of N-benzyl amino acids 6 with N-Boc-oxaziridine 7 and accommodates various functional groups encountered in side chains of amino acids. The cyclic 2,3,4,5-tetrahydro-3-pyridazine carboxylic acid (piperazic acid) derivatives 2 and 3 or the cyclic 3,4-dihydro-3-pyrazolecarboxylate 4 are conveniently prepared from glutamic acid or aspartic acid via orthogonally diprotected alpha-hydrazino acids 1m and 1n.

A total synthesis of the von Willebrand factor receptor antagonist sulfobacin A is described. Key steps for this short route to sulfobacin A include ruthenium-catalyzed asymmetric hydrogenation and diastereoselective electrophilic amination for the construction of the three stereogenic centers.

Electrophilic amination of Grignard reagents has been accomplished by using O-sulfonyloximes as amination reagents. Benzophenone O-sulfonyloxime derivatives react with Grignard reagents on sp2 nitrogen, yielding primary amines by successive hydrolysis of the resulting N-alkylimines. Various cyclic imines are synthesized by Pd-catalyzed reaction from olefinic oxime derivatives. That is, treatment of O-pentafluorobenzoyloximes of olefinic ketones with a catalytic amount of Pd(PPh3)4 and triethylamine affords nitrogen-containing heterocycles, such as pyrroles, pyridines, isoquinolines, spiro-imines, and aza-azulenes. This reaction proceeds via the initial formation of alkylideneaminopalladium(II) species generated by oxidative addition of the oximes to the Pd(0) complex, and the following intramolecular amination on the olefinic moiety. Cyclic imines are prepared from γ,δ-unsaturated O-acetyloximes by treatment with acetic acid and 1,4-cyclohexadiene in the presence of a catalytic amount of 1,5-naphthalene-diol. γ,δ-Unsaturated ketone O-methoxycarbonyloximes are transformed to 2-bromomethyl-3,4 dihydro-2H-pyrroles by the action of a catalytic amount of Cu(I) bromide dimethyl sulfide complex and lithium bromide.

Comparison of several hydroxylamine-based electrophilic ammonia equivalents in the N-amination of 2-oxazolidinones revealed that O-(p-nitrobenzoyl)hydroxylamine (NbzONH(2)) and sodium hydride in dioxane is a superior reagent combination for this purpose. Practical preparations of a variety of chiral N-acylhydrazones by this method gave yields ranging from 45 to 95%. Methods for exchange or removal of the aldehyde component have been developed, making this a general route to chiral N-acylhydrazones of interest for asymmetric synthesis applications.

A highly efficient catalytic asymmetric dearomatization of naphthols by means of an electrophilic amination reaction catalyzed by chiral phosphoric acid is presented. This protocol provides a facile access to functionalized β-naphthalenone compounds with a chiral quaternary carbon center in excellent yields and enantioselectivity (up to 99 % yield, up to 96 % ee).

Electrophilic nitrogen sources are an increasingly popular class of reagents for the formation of C–N bonds. Recently, a significant number of useful methodologies have been reported, in particular, examples using transition-metal catalysis. This review summarizes the latest developments in this field, with a focus on very recent advances. 1 Introduction 2 Reactions with Stoichiometric Organometallic Reagents 2.1 Organoboron Nucleophiles 2.2 Zirconium Derivatives 2.3 Silicon Derivatives 2.4 Grignard Reagents 2.5 Organozinc Reagents 3 Catalytic Organometallic Species 3.1 C–H Activation Reactions 3.2 Heterocycle Synthesis via Addition/Amination Sequences 3.3 Narasaka–Heck (or Amino-Heck) Reactions 4 Enolates as Nucleophiles 5 Conclusion

We have developed sequential Zr/Cu catalysis involving regioselective hydroboration and electrophilic amination for the formal anti-Markovnikov hydroamination of terminal aryl alkynes. The reaction...

A broader substrate scope for direct heteroarene amination is achieved by C—H zincation and subsequent Cu-catalyzed electrophilic amination.

The synthesis of fused N-heterocycles starting from readily available 2-nitrobiaryls and phenylmagnesium bromide is disclosed.

Adding value: The catalytic hydroamination of alkenes with amines holds promise to rapidly deliver value-added chiral amines from simple and accessible starting materials. The use of mild, Cu-catalyzed electrophilic amination strategies for the regioselective preparation of both linear and chiral branched amines is highlighted.

The use of the siloxane transfer agent enables the direct electrophilic amination of organolithium substrates under mild and simple conditions without the use of stoichiometric amounts of toxic heavy metals.

Condensed system (II) is obtained from aroylindoles (I) via Schmidt reaction and subsequent electrophilic amination of arenes using the sodium azide/PPA reagent system.

Heteroaromatic amines are key structural motifs that are widely found in biologically important molecules and medicines; therefore, efficient methods for the synthesis of these important heteroaryl amines are highly valuable. Direct amination of heteroarenes and arenes has been achieved in a one-pot C–H zincation/copper-catalyzed electrophilic amination procedure. This amination method provides an efficient and rapid approach to access a diverse range of heteroaromatic and aromatic amines including those previously inaccessible using C–H amination methods. The mild reaction conditions and good functional-group compatibility demonstrate its great potential for the synthesis of important and complex amines.

The nickel-catalyzed electrophilic amination of organozinc halides with O-benzoyl N,N-dialkyl hydroxylamines allows for the preparation of a variety of aryl and alkyl tertiary amines in good yield. The reaction is noteworthy for the mild reaction conditions employed (room temperature) and the ease of product purification (acid/base extractive work up).