Reactifs de Grignard vinyliques γ fonctionnels : III. Addition a quelques derives carbonyles

Δt^α,β-Butenolides can be obtained by carbonation of γ-functionally substituted vinylic Grignard reagents, prepared by addition of organomagnesium compounds to α-acetylenic or α-allenic alcohols. By addition to aldehydes and ketones, these vinylic Grignard reagents yield diols, which give unsaturated ethers by cyclization reactions.     

Catalyzed selective direct α- and γ-alkylation of aldehydes with cyclic benzyl ethers by using T(+)BF4- in the presence of an inexpensive organic acid or anhydride

The cross dehydrogenative coupling (CDC) of cyclic benzyl ethers with aliphatic and α,β-unsaturated aldehydes has been developed. The mild reaction conditions, in which an N-oxoammonium salt derived from TEMPO (2,2,6,6-tetramethyl-1-piperidinoxyl) is employed as the oxidant in combination with a Cu catalyst, allow the use of relatively redox-unstable aldehydes under oxidative CDC conditions. The addition of a catalytic amount of trifluoroacetic acid (TFA) or Ac(2)O facilitates the reaction and increases the efficiency and selectivity. In contrast to the expected α-alkylation obtained with aliphatic aldehydes, α,β-unsaturated aldehydes led preferentially to the more challenging γ-alkylated products. The utility of the developed methodology was demonstrated by the synthesis of isochromane-derived bioactive compounds, such as the dopamine antagonist sonepiprazole.     

Cu(I)-catalyzed decarboxylative aldol-type and Mannich-type reactions for asymmetric construction of contiguous trisubstituted and quaternary stereocenters

The catalytic asymmetric decarboxylative aldol-type reaction between aldehydes and cyanocarboxylic acids and Mannich-type reaction between aldimines and cyanocarboxylic acids were developed. α,α,β-Trisubstituted-β-hydroxy nitriles bearing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate enantio- and diastereoselectivity in the presence of 10 mol % CuOAc–TANIAPHOS (or DTBM-SEGPHOS) complex in the aldol-type reaction. α,α,β-Trisubstituted-β-amino nitriles containing contiguous all-carbon quaternary and trisubstituted stereocenters were produced with moderate to high enantio- and diastereoselectivity using 5 mol % CuOAc–(R)-DTBM-SEGPHOS complex in the Mannich-type reaction. These reactions proceed through Cu(I)-catalyzed decarboxylative nucleophile generation, followed by the addition of the resulting chiral Cu-ketenimide to aldehydes or imines. Because the reactions proceed under very mild conditions at nearly neutral pH, the reactions are applicable to a wide range of substrate combinations, including both aromatic and aliphatic substrates. Finally, α,α,β-trisubstituted-β-amino nitriles were converted to β^2,2,3-amino acid derivatives through simple acidic hydrolysis without any racemization and epimerization.     

Lead(IV) acetate mediated cleavage of β-hydroxy ethers: enantioselective synthesis of α-acetoxy carbonyl compounds

α-Acetoxy aldehydes or α-acetoxy ketones can be efficiently synthesized by treating 2,3-epoxy primary alcohols with lead tetraacetate. The reaction, which proceeds with complete regio- and stereoselectivity facilitates the enantioselective synthesis of α-acetoxy carbonyl compounds from allyl alcohols, via Sharpless epoxidation. Cyclic β-hydroxy ethers, with an oxygenated five-, six- or seven-membered ring, are transformed into α-acetoxy ethers.     

Mesoporous aluminosilicate-catalyzed Mukaiyama aldol reaction of aldehydes and acetals

A mesoporous aluminosilicate (Al-MCM-41) was found to be an effective heterogeneous catalyst for the reaction of both aldehydes and acetals with silyl enol ethers or ketene silyl acetals to give the corresponding aldol adducts in moderate to high yields. The remarkable high catalytic activity of Al-MCM-41 over amorphous silica-alumina and aluminum-free mesoporous silicate was observed in the reaction. The solid acid catalyst could be recovered easily by filtration and the recovered catalyst was reusable in the same reactions without a significant loss of catalytic activity.     

A facile solvent free Claisen-Schmidt reaction: synthesis of α,α'-bis-(substituted-benzylidene)cycloalkanones and α,α'-bis-(substituted-alkylidene)cycloalkanones

Solvent-free Claisen-Schmidt reactions of cycloalkanones with various substituted benzaldehydes (aryl aldehydes) using solid NaOH (20 mol%) and applying a grinding technique were studied. Quantitative yields (96-98%) of α,α'-bis-(substituted-benzylidene)cycloalkanones were obtained. Aliphatic aldehydes also provided α,α'-bis-(substituted-alkylidene)cycloalkanones in very good yields with minor amounts of a-(substituted-alkylidene)cycloalkanones. The catalytic performance of solid NaOH was examined. The molar ratio of NaOH was optimized. The catalytic effect of solid NaOH was also evaluated by comparing it with KOH, NaOAc, and NH(4)OAc and it turns out that 20 mol% of solid NaOH was good enough to catalyze the Claisen-Schmidt reactions of cycloalkanones with various substituted benzaldehydes. Additionally, the regioselectivity of the Claisen-Schmidt reaction of acetone with benzaldehyde was examined. Using the same method, we could synthesize the corresponding bis-benzylidene- and mono-benzylideneacetone separately in 98% and 96% yields, respectively.     

Organophosphorus Reagents in Organocatalysis: Synthesis of Optically Active α-Methylene-δ-lactones and δ-Lactams

In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important α-methylene-δ-lactones and δ-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes catalyzed by (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into α-methylene-δ-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner-Wadsworth-Emmons olefination of formaldehyde. On the other hand, indolo[2,?3-a]quinolizine-framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet-Spengler reaction with tryptamine, followed by Horner-Wadsworth-Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner-Wadsworth-Emmons olefination of formaldehyde is demonstrated to give α-methylene-δ-lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality.     

α,α‐Diarylprolinol Ethers: New Tools for Functionalization of Carbonyl Compounds

α,α‐Diaryl(dialkyl)prolinol ethers constitute a potent organocatalyst family which has been shown to be very general for a broad range of reactions involving enamine and iminium ion activation or a combination of both. The reactions are characterized by an efficient steric control approach and can lead to a variety of α‐, β‐, γ‐, and α,β‐functionalized carbonyl compounds with excellent stereocontrol. As a full expression of their catalytic activity, these compounds are also excellent promoters of elegant cascade processes and valuable catalysts in water‐compatible systems.     

Star polymers by photoinduced copper‐catalyzed azide–alkyne cycloaddition click chemistry

Well‐defined star polymers consisting of tri‐, tetra‐, or octa‐arms have been prepared via coupling‐onto strategy using photoinduced copper(I)‐catalyzed 1,3‐dipolar cycloaddition click reaction. An azide end‐functionalized polystyrene and poly(methyl methacrylate), and an alkyne end‐functionalized poly(ε‐caprolactone) as the integrating arms of the star polymers are prepared by the combination of controlled polymerization and nucleophilic substitution reactions; whereas, multifunctional cores containing either azide or alkyne functionalities were synthesized in quantitatively via etherification and ring‐opening reactions. By using photoinduced copper‐catalyzed azide–alkyne cycloaddition (CuAAC) click reaction, reactive linear polymers are simply attached onto multifunctional cores to form corresponding star polymers via coupling‐onto methodology. The chromatographic, spectroscopic, and thermal analyses have clearly demonstrated that successful star formations can be obtained via photoinduced CuAAC click reaction. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1687–1695     

Synthesis of symmetrical α-alkyl- and α-arylalkylbenzyl and diarylmethyl ethers by HCl-catalyzed intermolecular dehydration

α-Alkyl-, α-arylalkyl-, and α-aryl-substituted benzyl alcohols were converted into the corresponding symmetrical dibenzyl ethers in the presence of a catalytic amount of 10% aqueous HCl both in methylene chloride and under solvent-free conditions. Analogous reactions in dioxane and on heating afforded mainly the corresponding arylalkenes, whereas symmetrical dibenzyl ethers were formed as minor products.     

TiCl3/PhN2-mediated radical addition of ethers to aldimines generated in situ under aqueous conditions

Ti(III)-mediated one-electron reduction of phenyldiazonium cation, followed by phenyl radical α-H atom abstraction from ethers, leads to one-pot radical addition of ethers to the C-atom of imines generated in situ from the corresponding aldehydes and imines under aqueous conditions. The reaction is not limited to aromatic aldehydes and may be applied to imines generated in situ from formaldehyde and enolizable aldehydes.     

An amine-catalyzed enantioselective [3+2] cycloaddition of azomethine ylides and α,β-unsaturated aldehydes: applications and mechanistic implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β-unsaturated aldehydes catalyzed by α,α-diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2-alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5-alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.     

Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross-Aldol Reactions of Two Different Aldehydes

The aldol reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry. Asymmetric direct cross-aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self-aldol reaction and over reaction. We found that trifluoromethyl-substituted diarylprolinol, α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol ( 1 ), is an effective organocatalyst that promotes several cross-aldol reactions of aldehydes with excellent diastereo- and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α-alkyl-α-oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.     

Triflic acid catalyzed reductive coupling reactions of carbonyl compounds with O-, S-, and N-nucleophiles

Highly efficient metal-free reductive coupling reactions of aldehydes and ketones with a range of nucleophiles in the presence of triflic acid (1-5 mol%) as the catalyst are presented. The reactions can be performed at ambient temperature without exclusion of moisture or air. A range of symmetrical and unsymmetrical ethers were obtained by this method in high yields and short reaction times. For the first time, the influence of additional functionalization has been studied. Furthermore, the formation of thioethers from ketones (by addition of unmodified thiols) and of sulfonamides from either aldehydes or ketones has been achieved under catalytic conditions.     

Addition reaction of arylboronic acids to aldehydes and α,β-unsaturated carbonyl compounds catalyzed by conventional palladium complexes in the presence of chloroform

Arylboronic acids react with aldehydes and α,β-unsaturated carbonyl compounds in the presence of a base and a catalytic amount of a palladium(0) complex with chloroform, affording the corresponding addition products in good yields, and chiral benzhydrol was obtained with up to 43% e.e. using (S,S)-bppm as a ligand. General palladium complexes have no catalytic activity without chloroform. Because chloroform is essential for this reaction, these reactions would be promoted by dichloromethylpalladium(II) species.     

How good is CuAAC “click” chemistry for polymer coupling reactions?

¹H NMR and SEC analyses are used to investigate the overall efficiency of Copper Catalyzed Azide Alkyne Cycloaddition (CuAAC) “click” coupling reactions between alkyne‐ and azide‐terminated polymers using polystyrene as a model. Quantitative convolution modeling of the entire molecular weight distribution is applied to characterize the outcomes of the functional polymer synthesis reactions (i.e., by atom transfer radical polymerization), as well as the CuAAC coupling reaction. Incomplete functionality of the azide‐terminated polystyrene (∼92%) proves to be the largest factor compromising the efficacy of the CuAAC coupling reaction and is attributed primarily to the loss of terminal bromide functionality during its synthesis. The efficiency of the S_N2 reaction converting bromide to azide was found to be about 99%. After taking into account the influence of non‐functional polymer, we find that, under the reaction conditions used, the efficiency of the CuAAC coupling reaction determined from both techniques is about 94%. These inefficiencies compromise the fidelity and potential utility of CuAAC coupling reactions for the synthesis of hierarchically structured polymers. While CuAAC efficiency is expected to depend on the specific reaction conditions used, the framework described for determining reaction efficiency does provide a means for ultimately optimizing the reaction conditions for CuAAC coupling reactions. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 75–84     

Polymer-supported enantioselective bifunctional catalysts for nitro-Michael addition of ketones and aldehydes

Introduction of an L-amino acid as a spacer and a urea-forming moiety in a polymer-supported bifunctional urea-primary amine catalyst, based on (1R, 2R)-(+)-1,2-diphenylethylenediamine, significantly improves the catalyst's activity and stereoselectivity in the asymmetric addition of ketones and aldehydes to nitroolefins. Yields and enantioselectivities, unprecedented for immobilized catalysts, were obtained with such challenging donors as acetone, cyclopentanone, and α,α-disubstituted aldehydes, which usually perform inadequately in this reaction (particularly when a secondary-amine-based catalyst is used). Remarkably, though in the examined catalysts the D-amino acids as spacers were significantly inferior to the L?isomers, for the chosen configuration of the diamine (match-mismatch pairs) the size of the side chain of the amino acid hardly influenced the enantioselectivity of the catalyst. These results, combined with the reactivity profile of the catalysts with substrates bearing two electron-withdrawing groups and the behavior of the catalysts' analogues based on tertiary (rather than primary) amine, suggest an enamine-involving addition mechanism and a particular ordered C-C bond-forming transition state as being responsible for the catalytic reactions with high enantioselectivity.     

Allylation Reactions of Aldehydes with Allylboronates in Aqueous Media: Unique Reactivity and Selectivity that are Only Observed in the Presence of Water

Zn(OH)₂‐catalyzed allylation reactions of aldehydes with allylboronates in aqueous media have been developed. In contrast to conventional allylboration reactions of aldehydes in organic solvents, the α‐addition products were obtained exclusively. A catalytic cycle in which the allylzinc species was generated through a B‐to‐Zn exchange process is proposed and kinetic studies were performed. The key intermediate, an allylzinc species, was detected by HRMS (ESI) analysis and by online continuous MS (ESI) analysis. This analysis revealed that, in aqueous media, the allylzinc species competitively reacted with the aldehydes and water. An investigation of the reactivity and selectivity of the allylzinc species by using several typical allylboronates ( 6a , 6b , 6c , 6d ) clarified several important roles of water in this allylation reaction. The allylation reactions of aldehydes with allylboronic acid 2,2‐dimethyl‐1,3‐propanediol esters proceeded smoothly in the presence of catalytic amounts of Zn(OH)₂ and achiral ligand 4d in aqueous media to afford the corresponding syn‐adducts in high yields with high diastereoselectivities. In all cases, the α‐addition products were obtained and a wide substrate scope was tolerated. Furthermore, this reaction was applied to asymmetric catalysis by using chiral ligand 9 . Based on the X‐ray structure of the Zn‐ 9 complex, several nonsymmetrical chiral ligands were also found to be effective. This reaction was further applied to catalytic asymmetric alkylallylation, chloroallylation, and alkoxyallylation processes and the synthetic utility of these reactions has been demonstrated.     

The Rabe amination after a century: direct addition of N-heterocycles to carbonyl compounds

A catalytic version of the Rabe electrophilic amination is presented. This kind of reaction was originally employed in 1918 in a key step for the conversion of quinotoxine to quinine. Ketones and α-substituted aldehydes give the corresponding α-aminated carbonyl compounds in moderate yield. α,α-Unsubstituted aldehydes give rise to amino ketones via a novel rearrangement.     

Bu4NI-catalyzed α-acyloxylation reaction of ethers and ketones with aldehydes and tert-butyl hydroperoxide

The reaction of (hetero)aromatic aldehydes or cinnamaldehyde with di-/multi-ethers in the presence of Bu₄NI and tert-butyl hydroperoxide generated corresponding α-acyloxy ethers. Reactions between (hetero)aromatic aldehydes or cyclohexanecarbaldehyde with arylalkyl ketones under similar conditions resulted in α-acyloxy ketones. Collectively, Bu₄NI-catalyzed α-acyloxylation reactions exhibit a broad scope of substrates and a high compatibility with functional groups.