Palladium/Brønsted Acid‐Catalyzed α‐Allylation of Aldehydes with Allylic Alcohols

A simple, highly efficient, and readily scalable direct α‐allylation of aldehydes with allylic alcohols that is co‐catalyzed by palladium and a Brønsted acid has been developed.     

Anaerobic Palladium‐Catalyzed Chemoselective Oxidation of Allylic and Benzylic Alcohols with α‐Bromo Sulfoxide as a Co‐oxidant

A chemoselective palladium‐catalyzed anaerobic oxidation of allylic and benzylic alcohols using an α‐bromo sulfoxide as a co‐oxidant is described for the first time. The catalyst system is simple and has a long life because of the allowance of phosphane ligands under the non‐aerobic conditions. The advantages of the described method include no overoxidation of primary alcohols to carboxylic acids because of the mild conditions applied, the tolerance of oxygen‐sensitive functionalities such as a carbon‐carbon double bond, an organothio group, or a diorganoamino group and the effective preparation of α,β‐unsaturated aldehydes and ketones, resulting from the oxidation of primary and secondary allylic alcohols, since a competitive Heck reaction with the co‐oxidant does not occur.     

One‐Step Catalytic Enantioselective α‐Quaternary 5‐Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized α‐Quaternary Proline Derivatives

The highly enantioselective cascade reaction between N‐protected α‐cyanoglycine esters and α,β‐unsaturated aldehydes is disclosed. The reaction represents a one‐step entry to polysubstituted 5‐hydroxyproline derivatives having a quaternary α‐stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two‐step entry to functionalized α‐quaternary proline derivatives.     

Organocatalytic Enantioselective Aziridination of α‐Substituted α,β‐Unsaturated Aldehydes: Asymmetric Synthesis of Terminal Aziridines

The first example of a highly enantioselective organocatalytic aziridination of α‐substituted α,β‐unsaturated aldehydes is presented. The reaction is catalyzed by simple chiral amines and gives access to highly functional terminal azirdines containing an α‐tertiary amine stereocenter in high yields and enantiomeric ratios (95.5:4.5–98:2).     

A General Approach to the Synthesis of β2‐Amino Acid Derivatives via Highly Efficient Catalytic Asymmetric Hydrogenation of α‐Aminomethylacrylates

A new strategy was developed for the synthesis of a valuable class of α‐aminomethylacrylates via the Baylis–Hillman reaction of different aldehydes with methyl acrylate followed by acetylation of the resulting allylic alcohols and S_N2′‐type amination of the allylic acetates. Asymmetric hydrogenation of these diverse olefinic precursors using rhodium(Et‐Duphos) catalysts provided the corresponding β²‐amino acid derivatives with excellent enantioselectivities and exceedingly high reactivities (up to >99.5% ee and S/C=10,000). The first hydrogenation of (Z)‐configurated substrates was studied for the synthesis of β²‐amino acid derivatives. The high influence of the substrate geometry and steric hindrance on the reactivity and enantioselectivity was also disclosed for this reaction. This protocol provides a highly practical, facile and scalable method for the preparation of optically pure β²‐amino acids and their derivatives under mild reaction conditions.     

Catalytic Asymmetric Synthesis of Phosphoryl‐1,4‐dihydropyridazines via an Enantioselective Allylic Alkylation/1,3‐Dipolar Cycloaddition/Rearrangement Reaction Sequence

A novel methodology has been developed for the synthesis of chiral phosphoryl‐1,4‐dihydropyridazine derivatives based on an asymmetric allylic alkylation/intramolecular 1,3‐dipolar cycloaddition/rearrangement reaction sequence, various chiral 3‐phosphoryl‐4‐aryl‐1,4‐dihydropyridazine‐5‐carboxylates were achieved in high yields with high enantioselectivities. Moreover, chiral 4,5‐dihydropyridazinone derivatives were also facilely furnished by the reduction of the allylic alkylation products of Morita–Baylis–Hillman carbonates and α‐diazophosphonates.

     

Organocatalytic Highly Enantioselective Synthesis of β‐Formyl‐α‐hydroxyphosphonates

The cross‐aldol reaction between enolizable aldehydes and α‐ketophosphonates was achieved for the first time by using 9‐amino‐9‐deoxy‐epi‐quinine as the catalyst. β‐Formyl‐α‐hydroxyphosphonates were obtained in high to excellent enantioselectivities. The reaction works especially well with acetaldehyde, which is a tough substrate for organocatalyzed cross‐aldol reactions. The products were demonstrated to have anticancer activities.     

Direct Enantioselective Three‐Component Kabachnik–Fields Reaction Catalyzed by Chiral Bis(imidazoline)‐Zinc(II) Catalysts

A direct three‐component reaction of aldehydes, amines and diaryl phosphites was catalyzed by a zinc(II) complex of 1,3‐bis(imidazolin‐2‐ly)pyridine (pybim) giving the corresponding α‐aminophosphonates in good yield with good enantioselectivity. The reaction was applied to a wide variety of aromatic aldehydes to give products with excellent yields (up to 99%) and enantiomeric excesses (up to 93% ee).     

Synthesis of γ‐Fluoro‐α, β‐unsaturated Carboxylic Esters from Saturated α‐Fluoro Aldehydes

γ‐Fluoro‐α, β‐unsaturated carboxylic esters 7a, 7b and 7d and 4‐fluoro‐4‐phenylbut‐3‐enoic ester ( 8 ) are obtained by two alternative pathways from 2‐fluoro aldehydes 5a—d , either by Horner—Wadsworth—Emmons reaction or by Wittig reaction. The aldehydes 5a—d are prepared by Swern oxidation of the corresponding fluorohydrins 4a—d . These are available from α‐olefins by bromofluorination, bromineby‐acetate replacement and subsequent hydrolysis.     

Polymer‐Supported Bisacetoxybromate(I) Anion –‐An Efficient Co‐Oxidant in the TEMPO‐Mediated Oxidation of Primary and Secondary Alcohols

A polymer‐bound reagent for the efficient oxidation of primary alcohols to aldehydes and secondary alcohols to ketones in the presence of a catalytic amount of 2,2,6,6‐tetramethyl‐1‐piperidinyloxyl (TEMPO) is described. The oxidation process is particular mild and allows one to prepare aldehydes with α‐chirality without racemization. This also includes the synthesis of α‐aminoaldehydes. In most cases, work‐up of this heavy metal‐free oxidation is achieved by simple filtration followed by removal of the solvent. Insight into the role of the bromate(I) anion in the oxidation process was gained from the TEMPO‐mediated oxidation of benzaldehyde in the presence of the hypochlorite anion loaded on an anion exchange resin.     

Aldehyde‐Catalyzed Transition Metal‐Free Dehydrative β‐Alkylation of Methyl Carbinols with Alcohols

Different to the borrowing hydrogen strategy in which alcohols were activated by transition metal‐catalyzed anaerobic dehydrogenation, the direct addition of aldehydes was found to be an effective but simpler way of alcohol activation that can lead to efficient and green aldehyde‐catalyzed transition metal‐free dehydrative C‐alkylation of methyl carbinols with alcohols. Mechanistic studies revealed that the reaction proceeds via in situ formation of ketones by Oppenauer oxidation of the methyl carbinols by external aldehydes, aldol condensation, and Meerwein–Ponndorf–Verley (MPV)‐type reduction of α,β‐unsatutated ketones by substrate alcohols, affording the useful long chain alcohols and generating aldehydes and ketones as the by‐products that will be recovered in the next condensation to finish the catalytic cycle.     

Iridium‐Catalyzed Allylic Amination Route to α‐Aminoboronates: Illustration of the Decisive Role of Boron Substituents

The development of a new route to α‐aminoboronates using an iridium‐catalyzed allylic amination on boronated substrates is described. Unlike the boronate group, the trifluoroborato substituent was found to govern the regioselectivity exclusively in favor of branched products. The transformation of an allylic substitution product into an α‐aminoboronic ester in an efficient way validated the implementation of this approach.     

Straightforward Synthesis of Allylated Keto Esters: The Palladium‐Catalysed Haloketone Alkoxycarbonylation/ Allylation Domino Reaction

The palladium‐catalysed α‐chloro ketone methoxycarbonylation and allylic alkylation reactions can be efficiently combined to provide a new catalytic domino reaction. The first, carbonylative, step generates the β‐keto ester, which acts as the nucleophile in a subsequent allylation step. The use of allyl phenates in combination with Xantphos ligand are the key features allowing one to obtain the allylated β‐keto esters in good yields     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Efficient Synthesis of β,γ‐Alkynyl α‐Amino Acid Derivatives by Ag(I)‐Catalyzed Alkynylation of α‐Imino Esters

The first catalytic synthesis of β,γ‐alkynyl α‐amino acid derivatives was achieved by direct addition of terminal alkynes to α‐imino esters in the presence of an Ag(I) salt under mild reaction conditions.     

Highly Efficient Molybdenum(II)‐Catalyzed Intramolecular Allylic Alkylation of Arenes

The Friedel–Crafts‐type intramolecular allylic alkylation of simple arenes is performed in the presence of a catalytic amount of [Mo(II) (CO)₄Br₂]₂ (2.5 mol%). The moisture‐tolerant protocol provided a mild and direct access to a large library of functionalized 4‐vinyl‐1,2,3,4‐tetrahydronaphthalenes in high yields.     

Copper‐Catalyzed Oxidative α‐Alkylation of α‐Amino Carbonyl Compounds with Ethers via Dual C(sp3)‐H Oxidative Cross‐ Coupling

A novel copper‐catalyzed oxidative alkylation of α‐amino carbonyl compounds with ethers has been established for the selective synthesis of α‐etherized α‐amino carbonyl compounds. This oxidative alkylation is achieved by dual C(sp³) H bond oxidative cross‐coupling, and its scope is expanded to α‐amino ketones, α‐amino esters and α‐amino amides.

     

Enantioselective Synthesis of α‐Amino‐γ‐sulfonyl Phosphonates with a Tetrasubstituted Chiral α‐Carbon via Quinine‐Squaramide‐Catalyzed Michael Addition of Nitrophosphonates to Vinyl Sulfones

α‐Nitro‐γ‐sulfonyl phosphonates with a key tetrasubstituted chiral α‐carbon center have been synthesized for the first time in high yield and enantioselectivity through a quinine‐squaramide‐catalyzed conjugate addition of α‐nitro phosphonates to aryl vinyl sulfones. Representative examples presented here for the transformation of nitrosulfonyl phosphonates to aminosulfonyl phosphonates, alkylation at the α‐position of the sulfonyl group followed by desulfonation and scale‐up of the conjugate addition highlight the practical applications of the methodology.     

Tris(acetylacetonato)rhodium(III)‐Catalyzed α‐Alkylation of Ketones, β‐Alkylation of Secondary Alcohols and Alkylation of Amines with Primary Alcohols

The tris(acetylacetonato)rhodium(III) catalyst is shown to be a versatile catalyst in the presence of DABCO (1,4‐diazabicyclo[2.2.2]octane) as ligand for the α‐alkylation of ketones followed by transfer hydrogenation, for the one‐pot β‐alkylation of secondary alcohols with primary alcohols and for the alkylation of aromatic amines in the presence of an inorganic base in toluene.     

Antioxidant and prooxidant effects of α‐tocopherol in a linoleic acid‐copper(II)‐ascorbate system

The peroxidation of linoleic acid (LA) in the absence and presence of either Cu(II) ions alone or Cu(II)‐ascorbate combination was investigated in aerated and incubated emulsions at 37°C and pH 7. LA peroxidation induced by either copper(II) or copper(II)‐ascorbic acid system followed pseudo‐first order kinetics with respect to primary (hydroperoxides) and secondary (aldehydes‐ and ketones‐like) oxidation products, detected by ferric‐thiocyanate and TBARS tests, respectively. α‐Tocopherol showed both antioxidant and prooxidant effects depending on concentration and also on the simultaneous presence of Cu(II) and ascorbate. Copper(II)‐ascorbate combinations generally led to distinct antioxidant behavior at low concentrations of α‐tocopherol and slight prooxidant behavior at high concentrations of α‐tocopherol, probably associated with the recycling of tocopherol by ascorbate through reaction with tocopheroxyl radical, while the scavenging effect of α‐tocopherol on lipid peroxidation was maintained as long as ascorbate was present. On the other hand, in Cu(II) solutions without ascorbate, the antioxidant behavior of tocopherol required higher concentrations of this compound because there was no ascorbate to regenerate it. Practical applications: Linoleic acid (LA) peroxidation induced by either copper(II) or copper(II)‐ascorbic acid system followed pseudo‐first order kinetics with respect to primary (hydroperoxides) and secondary (e.g., aldehydes and ketones) oxidation products. α‐Tocopherol showed both antioxidant and prooxidant effects depending on concentration and also on the simultaneous presence of Cu(II) and ascorbate. The findings of this study are believed to be useful to better understand the actual role of α‐tocopherol in the preservation of heterogenous food samples such as lipid emulsions. Since α‐tocopherol (vitamin E) is considered to be physiologically the most important lipid‐soluble chain‐breaking antioxidant of human cell membranes, the results can be extended to in vivo protection of lipid oxidation.