Α-amino Carbonyl Research Articles

Copper-Catalyzed Oxidative α-Double Bond Construction in α-Amino Carbonyl Compounds via Homocoupling with Arylamine Release.

Herein, we present a copper-catalyzed method for oxidative α-double bond formation in α-amino ketone compounds using DTBP as the oxidant. This process, involving homocoupling of α-amino radicals and arylamine release, efficiently produces a series of enaminone skeletons. The strategy has a broad substrate scope and functional group tolerance. In particular, arylamines bearing electron-rich substituents exhibit a pronounced reactivity. This approach facilitates the synthesis of diverse enaminones, enabling the efficient construction of nitrogen-containing heterocycles.

Versatile, Modular, and General Strategy for the Synthesis of α-Amino Carbonyls.

Modulating the basicity of alkylamines is a crucial factor in drug design. Consequently, alkylamines with a proximal amide, ester, or ketone have become privileged features in many pharmaceutical candidates. The impact of α-amino carbonyls has made the development of new methods for their preparation a continuous challenge in synthesis. Here, we describe a practical strategy that provides a modular and programmable synthesis of a wide range of α-amino carbonyls. The generality of this process is made possible by an extremely mild method to generate carbamoyl radicals, proceeding via a Lewis acid-visible-light-mediated Norrish type-I fragmentation of a tailored carboxamide reagent and intercepted through addition to in situ generated unbiased imines. Aside from the reaction's broad scope in each component, its capacity to draw on plentiful and diversely populated amine and carbonyl feedstocks is showcased through a two-dimensional array synthesis that is used to construct a library of novel, assay-ready, α-amino amides.

Formal One Carbon Deletion of Indoline Hemiaminals under Tautomeric Control to Access 2-Aminobenzyl Compounds.

Unprecedented tert-BuOK-mediated one carbon deletion of indoline hemiaminals has been achieved. This novel protocol provides an efficient synthetic tool for the construction of 2-aminobenzyl compounds with high chemoselectivity. In addition, functionalized 2-aminobenzyl compounds are difficult to make, for which few limited means of access currently exist. The key to success is the use of in situ generated Heyns rearrangement products (α-amino carbonyl compounds) as precursors for formal one carbon deletion.

Photochemical α-amination of carbonyl groups with iodinanes.

We report on a photochemical reaction of silyl enol ethers with iminoiodinanes. This aza Rubottom reaction provides a direct access towards α-amino carbonyl compounds under catalyst free reaction conditions with light as the sole source of energy. Control experiments suggest the participation of triplet nitrene intermediates.

Nickel-catalyzed oxidative thiolation of α-amino carbonyl compounds with thiols.

An efficient oxidative thiolation of α-amino carbonyl compounds with thiols by the catalysis of an Earth-abundant nickel salt is disclosed for the first time. A variety of alkyl thiols and (hetero)aryl thiols underwent the reaction well with α-amino ketones and an α-amino ester to produce the desired α,α-aminothiocarbonyl compounds in good to excellent yields under ligand- and base-free conditions.

Free Amino Group Transfer via α-Amination of Native Carbonyls.

We report herein a straightforward transfer of a free amino group (NH2 ) from a commercially available nitrogen source to unfunctionalized, native carbonyls (amides and ketones) resulting in direct α-amination. Primary α-amino carbonyls are readily produced under mild conditions, further enabling diverse in situ functionalization reactions-including peptide coupling and Pictet-Spengler cyclization-that capitalize on the presence of the unprotected primary amine.

Synthesis of α-amino carbonyl compounds: a brief review

α-Amino carbonyl compounds are an important class of nitrogen-containing substances. This review highlights their synthesis using various strategies and considers mechanisms of the processes. The strategies are classified into subcategories based on the type of starting materials, chemical reactions and synthetic methods in use. In the literature survey, different types of reactions are discussed like oxidation, reduction, addition, coupling, C–H amination, oxidative cleavage and rearrangement, amidation, multicomponent cascade reaction, <i>etc</i>., for the synthesis of these compounds.<br> The bibliography includes 100 references

α-Amination of Carbonyl Compounds by Using Hypervalent Iodine-Based Aminating Reagents Containing a Transferable (Diarylmethylene)amino Group.

Hypervalent iodine-based aminating reagents containing a transferable (diarylmethylene)amino group can be used for the α-amination of simple carbonyl compounds such as esters, amides, and ketones in the presence of a lithium base. The (diarylmethylene)amino groups of the products can be readily modified, thus providing access to primary amines and diarylmethylamines. The developed method features transition-metal-free conditions and a simple one-pot procedure without the need to prepare enolate equivalents separately, thus offering a general and practical approach to the synthesis of a wide variety of α-amino carbonyl compounds. Experimental mechanistic investigations indicate that this amination proceeds through a unique radical coupling of an α-carbonyl radical with an iminyl radical; they are generated through a single-electron transfer between a lithium enolate and the hypervalent iodine reagent.

Making and Breaking of C-N Bonds: Applications in the Synthesis of Unsymmetric Tertiary Amines and α-Amino Carbonyl Derivatives.

An operationally simple process has been developed for the synthesis of unsymmetrical amines and α-amino carbonyl derivatives in the absence of a catalyst, ligand, oxidant, or any additives. Contrary to known reductive amination methods, this protocol is amenable to substrates containing other reducible groups. This process effectively results in consecutive cleavage and formation of C-N bonds. DFT studies and Hammett analysis provide useful insight into the mechanism. The role of noncovalent interactions as a stabilizing factor have been examined in the protocol. A wide range of alkyl-bromides have been coupled efficiently with a variety of dimethyl anilines to get unsymmetric tertiary amines with yields up to 90%. This methodology was further extended to the synthesis of α-amino carbonyl derivatives with yields up to 93%.

Chain Walking as a Strategy for Iridium-Catalyzed Migratory Amidation of Alkenyl Alcohols to Access α-Amino Ketones.

Catalytic carbon-nitrogen bond formation in hydrocarbons is an appealing synthetic tool to access valuable nitrogen-containing compounds. Although a number of synthetic approaches have been developed to construct a bifunctional α-amino carbonyl scaffold in this realm, installation of an amino functionality at the remote and unfunctionalized aliphatic sites remains underdeveloped. Here we present a tandem iridium catalysis that enables the redox-relay amidation of alkenyl alcohols via chain walking and metal-nitrenoid transfer, which eventually offers a new route to various α-amino ketones with excellent regioselectivity. The virtue of this transformation is that an unrefined isomeric mixture of alkenyl alcohols can be utilized as the readily available starting materials to lead to the regioconvergent amidation. Mechanistic investigations revealed that the reaction proceeds via a tandem process involving two key components of redox-relay chain walking and intermolecular nitrenoid transfer with the assistance of hydrogen bonding, thus representing the competence of Ir catalysis for the olefin migratory C-N coupling with high efficiency and exquisite selectivity.

Synergistic Dual Catalyzed Aza-[4+2] Cycloaddition of α-Amino Carbonyl Compounds and 1,3-Dienes

Synergistic Dual Catalyzed Aza-[4+2] Cycloaddition of α-Amino Carbonyl Compounds and 1,3-Dienes

Highly Efficient Copper-Catalyzed Dehydrogenative Cross-Coupling of Azoles with α-Amino Carbonyl Compounds

AbstractA novel and highly efficient dehydrogenative cross-coupling­ reaction between α-amino carbonyl compounds and azoles by copper catalysis using di-tert-butyl peroxide (DTBP) as an oxidant is described­. A diverse range of azoles undergo the dehydrogenative imidoylation smoothly with various α-amino carbonyl compounds for the exclusive formation of the corresponding N-imidoyl azoles in high yields under air. The synthetic method has the advantages of good functional-group tolerance, wide substrate scope, excellent yields, and simple operation­, thus providing a convenient and practical protocol for the synthesis of functionalized azoles.

Nature inspired singlet oxygen generation to access α-amino carbonyl compoundsvia1,2-acyl migration

We have discovered chlorophyll catalyzed 1,2-acyl migration reactions to achieve α-amino carbonyl compounds directly from the enaminones.

Visible-Light-Induced Dehydrogenative Imidoylation of Imidazo[1,2-a]pyridines with α-Amino Acid Derivatives and α-Amino Ketones.

A new and efficient visible-light-promoted dehydrogenative cross-coupling reaction of imidazo[1,2-a]pyridines with α-amino carbonyl compounds toward imidoyl imidazo[1,2-a]pyridines is developed. A diverse range of imidazo[1,2-a]pyridines undergoes the dehydrogenative imidoylation smoothly with α-amino carbonyl compounds to access the corresponding products in satisfactory yields. We have also proposed the possible reaction mechanism based on preliminary mechanistic studies. The synthetic method has the advantages of wide substrate scope, good functional tolerance, and mild reaction conditions, which make this transformation more practical and sustainable.

On the Mechanism of Cross-Dehydrogenative Couplings between N-aryl Glycinates and Indoles: A Computational Study.

Despite the widespread use of cross-dehydrogenative couplings in modern organic synthesis, mechanistic studies are still rare in the literature and those applied to α-amino carbonyl compounds remain virtually unexplored. Herein, the mechanism of Co-catalyzed cross-dehydrogenative couplings of N-aryl glycinates with indoles is described. Density functional theory studies supported the formation of an imine-type intermediate as the more plausible transient electrophilic species. Likewise, key information regarding the role of the N-aryl group and free NH motif within the reaction outcome has been gained, which may set the stage for further developments in this field of expertise.

Copper-catalyzed enantioselective direct α-C-H amination of β-dicarbonyl derivatives with aryl hydroxylamines and mechanistic insights

We report a novel and efficient Cu-catalyzed direct asymmetric amination of tertiary β-carbonyl compounds using aryl hydroxylamine as electrophilic nitrogen donor. The process facilitates the convenient and direct synthesis of chiral α-amino carbonyl derivatives, without the need for any post-reaction manipulation. This method reveals an effective strategy for the synthesis of enantioenriched α-CH aminated derivatives which is hitherto challenging. The choice of the robust chiral indabox ligand was ascertained to be very crucial for the desired enantioselectivity in the contemporary transformation. The reaction mechanism is fully supported by ab initio electronic structure calculations. The reaction is facile, efficient and performs well at room temperature with an enantiomeric excess (ee) up to 93 %.

Thiocyanation of α-amino carbonyl compounds for the synthesis of aromatic thiocyanates

A procedure for K2S2O8-mediated thiocyanation of α-amino carbonyl compounds has been developed for the synthesis of aromatic thiocyanates. A series of α-amino carbonyl compounds have been investigated, and the desired products are obtained in 74%–93% yields. This strategy has the advantages of simple reaction conditions without use of a transition-metal catalyst, high regioselectivity, and high efficiency. Moreover, we found that arylamine thiocyanates can also be obtained from α-amino carbonyl compounds and potassium thiocyanate in the presence of CoCl2·6H2O, I2, and dimethyl sulfoxide through the cleavage of the C–N bond. To explore the reaction mechanism, we designed several control experiments and proposed a possible mechanism using the experimental results and related literature reports.

Visible-Light-Mediated Amination of π-Nucleophiles with N-Aminopyridinium Salts.

N-Aminopyridinium salts generate nitrogen-centered radicals by means of photoredox catalysis. Herein, we report that they can be trapped by enol equivalents to give α-amino carbonyl compounds in excellent yields. The broad synthetic utility of this method is demonstrated by functionalization of ketones, aldehydes, esters enol equivalents, vinyl ethers, and 1,3-diketones without the need for prior conversion to enol derivatives. The developed method is easily scalable, offers broad substrate scope, high chemoselectivity.

Iron(III)-catalyzed synthesis of selenoesters from α-amino carbonyl derivatives at room temperature

An Fe(III)-catalyzed efficient method has been developed for the synthesis of selenoester derivatives in high yields through the coupling of α-amino carbonyl/glycine derivatives and diselenides under ambient air. A library of benzoselenoate derivatives having a variety of substituents has been synthesized. A plausible reaction pathway has been predicted. Experimental results suggest that the reaction proceeds through a radical pathway. Operational simplicity, compatibility with various α-amino carbonyls and diselenides, high yields, fast reaction and mild reaction conditions are the notable advantages of this procedure. We have also shown the practical application of the synthesized selenoesters which is useful to generate peptide bonds in biological sciences.

TBHP promoted demethylation of α-amino carbonyl compounds: a concise approach to substituted γ-lactams

A novel tert-butyl hydroperoxide (TBHP) promoted CH2-extrusion reaction of α-amino carbonyl compounds has been developed, which is driven by a demethylenation process to give various ring contraction products γ-lactams under radical conditions.