Α-functionalized Ketones Research Articles

In(OTf)3-catalyzed oxygenative bifunctionalization of alkynes

An In(OTf)3-catalyzed oxygenative bifunctionalization reaction has been developed for the facile synthesis of various α-functionalized ketones. A wide range of aryl sulfoxides and electron-rich arylalkynes prove to be suitable substrates for this transformation. The potential of our method was then extended to the synthesis of 8-substituted quinolines from ynamides and quinoline-N-oxides.

Organocatalytic Desymmetric Conjugate Addition to Cyclobutanone: An Enantio- and Diastereoselective Synthesis of [6,5,4]-Fused Carbocycles.

The first organocatalytic, non-destructive desymmetrisation of 3-substituted cyclobutanone followed by intramolecular cyclisation is described. Owing to the slow activation of the pronucleophile by the weak Brønsted base, the α-functionalization of ketones with tertiary-amine-derived Brønsted base catalysis has been chemically challenging in asymmetric transformations. Herein, we demonstrate that the cinchona-derived squaramide catalyst works effectively for the intramolecular Michael addition of cyclobutanone to enones and affords the architecturally fascinating [6,5,4]-fused carbocyclic skeleton in good yields and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and 96 % ee). Furthermore, as a synthetic application, this method provides an alternative pathway to enantioenriched high-value products like γ-lactones and indan-2-ol derivatives.

Discovering the Site-Selective Umpolung of Ketones Triggered by Hypervalent Fluoro-Iodanes – Why Investigating Side Reactions Matters!

AbstractIn this account, we describe our journey leading to the discovery of a generally applicable umpolung method for the α-functionalization of ketones. Central to this reaction is the cyclic hypervalent fluoro-iodane, which is mostly known for various alkene functionalizations enabling, for example, the synthesis of fluoro-benzoxazepines, indoles, and ketones. During this work, we encountered α-functionalized ketones as minor side products. This observation prompted us to further investigate this reactivity, thus revealing a directed umpolung of pyridyl ketones by the fluoro-iodane. The key to the success was the unexpected non-covalent interaction between the nucleophile, substrate, and iodane.1 Introduction2 Cyclizations Triggered by the Fluorination of Styrenes3 Umpolung Reactions Facilitated by Hypervalent Iodanes4 Discovering and Evolving a Fluoro-Iodane-Triggered Regioselective α-Functionalization of Carbonyl Compounds5 First Investigations on the Nitrogen-Directed Umpolung6 Conclusion

Molecular Iodine-Catalyzed N-Benzylic Sulfonamides C-N Bond Cleavage for the Decarboxylative Substitution of β-Keto Acids

Abstract:A molecular iodine-catalyzed system for the decarboxylative substitution reactions of β-keto acids with N-benzylic sulfonamides via sp3 C-N bond cleavage has been disclosed. This procedure provides a series of α-functionalized ketones in good to excellent yields. Furthermore, the practicability of this method could be manifested efficiently in a gram-scale synthesis.

Visible-light-induced N-heterocyclic carbene mediated cascade transformation of N-alkenoxypyridinium salts

While N-alkenoxypyridinium salts are widely used for the synthesis of α-functionalized ketones via umpolung strategy, such approaches are usually limited to special nucleophiles at high temperatures. Herein, we developed an alternative photoinduced N-heterocyclic carbene (NHC)- mediated functionalization of N-alkenoxypyridinium salts with various nucleophiles, including tetramethylammonium azide, secondary amines, aryl and alkyl thiols, and even the challenging C(sp3)-nucleophiles, under mild conditions. A cascade radical-radical coupling/nucleophilic substitution sequence was proposed, wherein the NHC enabled the formation of a photoactive electron donor-acceptor complex for α-iodo ketone synthesis.

CuCl2 -Mediated Oxidative Intramolecular α-Arylation of Ketones with Phenolic Nucleophiles via Oxy-Allyl Cation Intermediates.

α-Functionalization of ketones in an umpolung fashion can be achieved by nucleophilic addition to the oxy-allyl cation intermediate. However, applicable carbon nucleophiles are limited to ones with high nucleophilicity. Additionally, introduction of a leaving group to the α-position of ketone substrates is required beforehand. Herein, we report the CuCl2 -mediated oxidative intramolecular α-arylation of ketones with less nucleophilic phenolic moieties as carbon nucleophiles via α-chlorination of ketones and the subsequent generation of the oxy-allyl cation intermediates, giving ketones with a quaternary carbon center at the α-position.

Organocatalyzed Kinetic Resolution of α-Functionalized Ketones: The Malonate Unit Leads the Way

Developing a catalytic kinetic resolution (KR) protocol affording enantioenriched α-functionalized ketones with broad substrate scope and high efficiency has been a longstanding challenge. Here, we...

Azido-Enolonium Species in C-C and C-N Bond-Forming Coupling Reactions.

Vinyl azides react with boron trifluoride activated Koser's hypervalent iodine reagent to afford azido-enolonium species. These previously unknown azido-enolonium species react efficiently with aromatic compounds, allyltrimethylsilane, and azoles under mild conditions, with no need for a transition-metal catalyst, forming C-C and C-N bonds to give a variety of α-functionalized ketones. The intermediacy of the proposed azido-enolonium species is supported by spectroscopic studies.

Synthesis of α-functionalized ketones by visible-light promoted oxygenation of alkenes.

This article gives a short review on the visible-light promoted synthesis of α-functionalized ketones from alkenes. Various α-functionalized ketones, including α-halo, sulfinyl/sulfonyl, aryl, azido and thiocyanato ketones can be synthesized from the reaction of alkenes with different radical species generated by visible-light catalysis. These transformations typically use dioxygen as the terminal oxidant and do not require a transition metal to activate the double bond, which is quite different from the transition-metal catalysed reactions (Wacker oxidation or hydroformylation).

A New Valuable Synthesis of Polyfunctionalized Furans Starting from β-Nitroenones and Active Methylene Compounds.

Highly functionalized furans are the key scaffolds of many pharmaceuticals and bioactive natural products. Herein, we disclose a new fruitful synthesis of polyfunctionalized furans starting from β-nitroenones and α-functionalized ketones. The protocol involves two steps promoted by solid supported species, and it provides the title targets from satisfactory to very good overall yields and in an excellent diastereomeric ratios.

Weinreb Amides as Privileged Acylating Agents for Accessing α-Substituted Ketones

The acylation of α-substituted carbanion-type reagents (MCR1R2X; X = halogen, OR, SR, NR3R4, SeR, etc.) with Weinreb amides constitutes a highly versatile and flexible approach for accessing α-functionalized ketones. In this short review we will present a series of transformations—from our own and the work of others—documenting the general applicability of the methodology. Chemoselectivity is uniformly manifested including for critical substrates featuring additional electrophilic functionalities or sterically demanding elements. Importantly, the stereochemical information contained in the Weinreb amides can be fully transferred to the targeted ketones without affecting the optical purity. The protocol is also applicable to chiral carbanions generated through sparteine-mediated asymmetric deprotonation: the careful design of the experimental procedure allows recycling of the sparteine and the Weinreb ‘amine’ (N,O-dimethylhydroxylamine), thus improving the sustainability perspective of the processes.1 Introduction1.1 The Problem of the Synthesis of α-Substituted Ketones1.2 Weinreb Amides: General Features and Preparation2 Synthesis of α-Substituted Ketones2.1 α-Haloketones2.2 Synthesis of α-Cyanoketones2.3 Synthesis of α-Oxyketones2.4 Synthesis of β-Oxo Thioethers (α-Thioketones)2.5 Synthesis of Chiral α-Oxy and α-Nitrogen Ketones via the Sparteine-Mediated Generation of Optically Active Organolithiums2.6 Synthesis of α-Selenomethyl Ketones2.7 Reactivity of α-Phosphorus Carbanions with Weinreb Amides2.8 Modification of the Weinreb Amide Core: The CLAmP Reagent3 Competing Attack of Nucleophiles at More Reactive Electrophilic Sites than Weinreb Amides4 Conclusions

Iodine-DMSO-promoted divergent reactivities of arylacetylenes.

An unprecedented set of efficient, economical, atom-economic and exceedingly selective I2-DMSO-promoted methods is described for the generation of different structures. The reaction represents the first of its kind, involving the use of different iodine concentrations, temperatures, acids and salt to adjust the selectivity for the synthesis of different alkenes, α-functionalized ketones and α-ketomethylthioesters.

Formation, Alkylation, and Hydrolysis of Chiral Nonracemic N-Amino Cyclic Carbamate Hydrazones: An Approach to the Enantioselective α-Alkylation of Ketones.

The α-alkylation of ketones is a fundamental synthetic transformation. The development of asymmetric variants of this reaction is important given that numerous natural products, drugs, and related compounds exist as α-functionalized ketones or derivatives thereof. We previously reported our preliminary studies on the development of a new enantioselective ketone α-alkylation procedure using N-amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based methods, ACC alkylation offers a number of advantages and is both highly enantioselective and high yielding. Herein, we provide a full account of our studies on the enantioselective ACC ketone α-alkylation method.

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species.

α-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond-forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

Asymmetric synthesis of benzofuryl β-amino alcohols by the transfer hydrogenation of α-functionalized ketones

The asymmetric transfer hydrogenation of representative benzofuryl α-sulfonyloxy ketones and N-protected α-amino ketones with an azeotropic mixture of formic acid/triethylamine, catalyzed by RhCl[(R,R)-TsDPEN](C5Me5), afforded the corresponding 1,2-diol monosulfonates and N-substituted β-amino alcohols in high yields and with enantioselectivities up to 99%. Transformation of the reduction products to the chiral benzofuryl β-amino alcohols possessing a primary amine group is also described.

ChemInform Abstract: Decarboxylative Substitution of β‐Keto Acids to Benzylic Alcohols Catalyzed by Molecular Iodine.

An efficient method for molecular iodine catalyzed decarboxylative substitution of β-keto acids with benzylic alcohols under mild conditions has been described and valuable α-functionalized ketones were obtained in good to excellent yields.

ChemInform Abstract: A New Iron(III)—Salen Catalyst for Enantioselective Conia‐ene Carbocyclization.

A chiral iron(III)–salen complex based on a cis-2,5-diaminobicyclo[2.2.2]octane scaffold catalyzes asymmetric Conia-ene-type cyclization of α-functionalized ketones containing an unactivated terminal alkyne and produces an exo-methylenecycloalkane possessing a stereodefined quaternary center.

A New Iron(III)–Salen Catalyst for Enantioselective Conia-ene Carbocyclization

A chiral iron(III)-salen complex based on a cis-2,5-diaminobicyclo[2.2.2]octane scaffold catalyzes asymmetric Conia-ene-type cyclization of α-functionalized ketones containing an unactivated terminal alkyne and produces an exo-methylenecycloalkane possessing a stereodefined quaternary center.

General and Regioselective Synthesis of Pyrroles via Ruthenium-Catalyzed Multicomponent Reactions

A general and highly regioselective synthesis of pyrroles via ruthenium-catalyzed three-component reactions has been developed. A variety of ketones including less reactive aryl and alkyl substrates were efficiently converted in combination with different type of amines and vicinal diols into various substituted pyrroles in reasonable to excellent isolated yields. Additionally, α-functionalized ketones gave synthetically interesting amido-, alkoxy-, aryloxy-, and phosphate-substituted pyrroles in a straightforward manner. The synthetic protocol proceeds in the presence of a commercially available ruthenium catalyst system and catalytic amount of base. It proceeds with high atom-efficiency and shows a broad substrate scope and functional group tolerance, making it a highly practical approach for preparation of various pyrrole derivatives.

Iridium-catalyzed 1,3-hydrogen shift/chlorination of allylic alcohols.

Iridium-catalyzed 1,3-hydrogen shift/chlorination of allylic alcohols.