Synthesis of Fused Cyclopentenones through Palladium‐Catalyzed Cyclization of 2‐Iodoaryl Allenols

A versatile strategy for the synthesis of fused cyclopentenones, key structural motifs in biologically relevant compounds such as indenones and indole alkaloids, has been established successfully through regioselective palladium‐catalyzed cyclization of 2‐iodoaryl allenols.

     

Divergent Reactivity of 2‐Azetidinone‐Tethered Allenols with Electrophilic Reagents: Controlled Ring Expansion versus Spirocyclization

A dual reactivity of 2‐azetidinone‐tethered allenols may occur by judicious choice of the electrophilic reagents, namely halogenating versus selenating reagents. Using common substrates, structurally different compounds, namely tetramic acids (from N‐bromosuccinimide) or spirocyclic seleno‐β‐lactams (from N‐phenylselenophthalimide), can be readily synthesized by these divergent protocols.     

Acid‐Catalyzed Synthesis of α,β‐Disubstituted Conjugated Enones by a Meyer–Schuster‐Type Rearrangement in Allenols

A novel, direct and simple methodology to gain access to α,β‐disubstituted conjugated enones from α‐allenols in a sustainable metal catalysis context, considering the inexpensiveness and environmentally friendliness of iron(III) species and protons, has been developed.

     

Gold‐Catalyzed Efficient Formation of α,β‐Unsaturated Ketones from Propargylic Acetates

An efficient gold‐catalyzed method for the preparation of α,β‐unsaturated ketones from propargylic acetates has been developed. Under mild reaction conditions, β‐monosubstituted enones were formed mostly with excellent E‐selectivity. β,β‐Disubstituted enones can be prepared from propargylic acetates derived from ketones. The high efficiency and mild nature of this reaction render it a viable alternative for the synthesis of α,β‐unsaturated ketones.     

Highly Enantioselective Epoxidation of α,β‐Unsaturated Ketones Catalyzed by Primary‐Secondary Diamines

The asymmetric epoxidation of α,β‐unsaturated ketones has been achieved by using functional and readily accessible primary‐secondary diamines as the catalysts, giving the useful alkyl epoxy products with good yields and high enantioselectivities (up to 99% ee).     

Bicyclic O,P Ligands for Catalytic Asymmetric 1,4‐Addition to α,β‐Unsaturated Ketones

A new class of bicyclic O,P ligands has been prepared and evaluated in the 1,4‐addition to α,β‐unsaturated ketones. The best results with the bicyclic ligand were obtained using a lower catalyst loading than what has been reported with similar ligands when adding a Grignard reagent to 2‐cyclohexenone.     

A Phosphine‐Catalyzed Regioselective [3+2] Cycloaddition of Ethyl 5,5‐Diarylpenta‐2,3,4‐trienoate with Aromatic Aldehydes and α,β‐Unsaturated Carbonyl Compounds

Tributylphosphine‐catalyzed regioselective [3+2] cycloadditions between ethyl 5,5‐diarylpenta‐2,3,4‐trienoate 1 and various aromatic aldehydes 2 to produce a wide variety of polysubstituted 2,5‐dihydrofurans 3 , and between 1 and β‐unsubstituted α,β‐unsaturated carbonyl compounds 5 to give polysubstituted cyclopentenes 6 with a quaternary carbon center, are reported. In both cases the reaction partners approach each other via the sterically less hindered orientation to afford the target products in excellent regioselectivity. The reaction mechanism involved first the generation of a zwitterionic intermediate between the butatriene 1 and PBu₃. For the formation of 2,5‐dihydrofurans 3 , the preferred cyclization mode encompassed the nucleophilic attack of the α‐position of butatriene to the aldehydic carbon of 2 , followed by the ring closure between the aldehydic oxygen of 2 and the γ‐position of butatriene, which is the first report of a normal [3+2] cycloaddition between cumulenes and aldehydes. For the formation of cyclopentenes 6 , the reaction involved attack of the γ‐position of the butatriene to the electron‐deficient β‐position of the α,β‐unsaturated carbonyl compounds 5 , followed by the ring closure between the α‐position of 5 and the α‐position of butatriene, which shows a different regioselectivity to the previously reported [3+2] cycloadditions between butatriene and olefins.

     

Organocatalytic Asymmetric Sulfa‐Michael Addition to α,β‐Unsaturated Ketones

The highly enantioselective organocatalytic sulfa‐Michael addition to α,β‐unsaturated ketones has been accomplished using benzyl and tert‐butyl mercaptans as the sulfur‐centered nucleophiles. Optically active products are obtained in high yields and good to excellent stereocontrol (up to 96 % ee) from a large variety of enones. Central to these studies has been the use of the catalytic primary amine salt A , derived from 9‐amino‐(9‐deoxy)‐epi‐hydroquinine and D ‐N‐Boc‐phenylglycine, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis with enones.     

Enantiodivergent Brucine Diol‐Catalyzed 1,3‐Dipolar Cycloaddition of Azomethine Ylides with α,β‐Unsaturated Ketones

Enantiodivergent catalyst systems were developed using metals with different ionic radii and a multifunctional brucine diol (BD) ligand. The catalytic use of purported 1:1 Cu‐BD complexes in the 1,3‐dipolar cycloaddition of azomethine ylides with chalcones resulted in the selective formation of endo‐pyrrolidines in 87–96% ees with an absolute stereochemical outcome of (2R,3S,4R,5S). In contrast, an opposite absolute stereochemical outcome was observed by using the catalysts derived from Ag(I) salts and BD. The demonstration of enantiodivergent approaches to a broad class of substrates/reaction types underlines their synthetic value in asymmetric synthesis.

     

Gold(I)‐Catalyzed Carboaminations of Allenes by N‐Allyltetrahydro‐β‐carbolines: An Experimental and Theoretical Study

N‐Allyltetrahydro‐β‐carbolines bearing a pendant allene undergo unprecedented gold(I)‐catalyzed cyclizations proceeding with an allyl migration from the nitrogen to the allene moiety. The initial product of the gold‐catalyzed cyclization evolves either via isomerization or Cope rearrangement, leading to different scaffolds. Density function theory (DFT) calculations established that the allyl migration occurs in an asynchronous suprafacial manner.

     

Platinum‐Catalysed Hydrosilylation of Unsaturated Fatty Acid Esters

Different Pt(IV), Pt(II) and Pt(0) catalysts were screened for the hydrosilylation of fatty acid esters containing terminal as well as internal double bonds. The reaction of terminally unsaturated fatty acid esters proceeded smoothly with short reaction times for nearly all examined catalysts, whereas Pt(IV) species and Pt(II) or Pt(0) species with labile ligands were sufficiently active in the reaction of internally unsaturated compounds. For methyl linoleate, a conjugation of the two internal double bonds before the hydrosilylation was observed. The reaction was carried out in substance as well as in solvent systems permitting a catalyst recycling and reuse. In these systems, however, hydrogenation and double bond isomerisation were found as side reactions.     

Amine‐Catalyzed Asymmetric Epoxidation of α,β‐Unsaturated Aldehydes

The direct organocatalytic enantioselective epoxidation of α,β‐unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid‐derived imidazolidinones catalyze the asymmetric epoxidation of α,β‐unsaturated aldehydes. In particular, protected commercially available α,α‐diphenyl‐ and α,α‐di(β‐naphthyl)‐2‐prolinols catalyze the asymmetric epoxidation reactions of α,β‐unsaturated aldehydes with high diastereo‐ and enantioselectivities to furnish the corresponding 2‐epoxy aldehydes in high yield with up to 97:3 dr and 98 % ee. The use of non‐toxic catalysts, water and hydrogen peroxide, urea hydroperoxide or sodium percarbonate as the oxygen sources could make this reaction environmentally benign. In addition, one‐pot direct organocatalytic asymmetric tandem epoxidation‐Wittig reactions are described. The reactions were highly diastereo‐ and enantioselective and provide a rapid access to 2,4‐diepoxy aldehydes. Moreover, a highly stereoselective one‐pot organocatalytic asymmetric cascade epoxidation‐Mannich reaction, which proceeds via the combination of iminium and enamine activation, is presented. The mechanism and stereochemistry of the amino acid‐ and chiral pyrrolidine‐catalyzed direct asymmetric epoxidation of α,β‐unsaturated aldehydes are also discussed.     

Regio‐ and Enantioselective Copper‐Catalyzed 1,4‐Conjugate Addition of Trimethylaluminium to Linear α,β,γ,δ‐Unsaturated Alkyl Ketones

A regio‐ and enantioselective copper‐catalyzed 1,4‐conjugate addition of trimethylaluminium to linear δ‐aryl‐substituted α,β,γ,δ‐unsaturated alkyl ketones was developed. A series of γ,δ‐unsaturated alkyl ketones were obtained in good yields with high regio‐ and enantioselectivity (up to 88% ee and 96:4 dr). Expansion of the reaction scope to substrates containing aromatic heterocycles also afforded good yields and enantioselectivities (up to 91% ee) with very high regioselectivities, exclusively providing the single 1,4‐products.

     

Cinchona Alkaloid‐Catalyzed Enantioselective Amination of α,β‐Unsaturated Ketones: An Asymmetric Approach to Δ2‐Pyrazolines

Δ²‐Pyrazolines are of significant medicinal and synthetic interest due to their therapeutic properties and utility in the synthesis of 1,3‐diamines, yet few asymmetric methods exist to prepare them. An unprecedented and highly enantioselective organocatalytic synthesis of 2‐pyrazolines was achieved through an asymmetric conjugate addition catalyzed by 9‐epi‐amino Cinchona alkaloids followed by deprotection‐cyclization, which furnished chiral 2‐pyrazolines in 46–78% yield and 59–91% ee. This bifunctional catalytic methodology thus provides easy access to a considerable range of optically active 3,5‐dialkyl 2‐pyrazolines.     

Progress in the Palladium‐Catalyzed α‐Arylation of Ketones with Chloroarenes

Non‐ and deactivated chloroarenes can be coupled with a wide range of ketones to yield the corresponding arylmethyl ketones in good to excellent yields using a palladium(II) acetate/n‐BuPAd₂ catalyst system. Depending on the ketone, the chloroarene/ketone ratio and the base, mono or diarylation can be effected selectively.     

A Ruthenium Complex‐Catalyzed Cyclotrimerization of Halodiynes with Nitriles. Synthesis of 2‐ and 3‐Halopyridines

Monohalo‐ and dihalodiynes efficiently undergo [2+2+2] cyclotrimerization with nitriles in the presence of a catalytic amount of the ruthenium complex Cp*RuCl(cod) (10 mol%) to afford the corresponding halopyridines under ambient conditions in good isolated yields (up to 90%). The halopyridines are formed as two separable regioisomers. This is the first example of a direct synthesis of halopyridines from haloalkynes and nitriles.

     

Palladium‐Catalyzed Intramolecular Coupling of Aryl Halides and Ketone Enolates: Synthesis of Hexahydro‐2,6‐methano‐1‐2

The palladium‐catalyzed intramolecular coupling of 2‐haloanilines and ketone enolates is a useful methodology for the synthesis of hexahydro‐2,6‐methano‐1‐2 derivatives. A study about the reaction conditions of the process is reported.     

Nitrones as Trapping Reagents of α,β‐Unsaturated Carbene Intermediates – [1,2]Oxazino[5,4‐b]indoles by a Platinum‐ Catalyzed Intermolecular [3+3] Cycloaddition

Some readily available Boc‐protected 2‐(3‐methoxy‐1‐propynyl)anilines and nitrones in platinum‐catalyzed reactions deliver [1,2]oxazino[5,4‐b]indoles. Twelve examples with yields of 41–95% are reported. Different substituents like nitro, trifluoromethyl, fluoro, bromo, and ester groups are tolerated. With regard to the mechanism, this reaction probably combines an initial intramolecular cyclization/elimination to vinylcarbenoid species and a subsequent stepwise intermolecular [3+3] cycloaddition with the nitrones.     

Base‐Catalyzed Condensation of 2‐Hydroxybenzaldehydes with α,β‐Unsaturated Aldehydes – Scope and Limitations

The base‐catalyzed condensation of α,β‐unsaturated carbonyl compounds with 2‐hydroxybenzaldehydes yielding tetrahydroxanthones and dihydrobenzopyrans has been investigated. A novel access to highly functionalized dihydrobenzopyrans via a mild generation of the dienol of senecialdehyde and subsequent conjugated aldol reaction has been reported.