Reaction Of Enals Research Articles

NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles.

This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,β-unsaturated acylazolium intermediates and their subsequent reactivity with (bis)nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. This key intermediate can be generated by the addition of NHCs to α,β-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,β-unsaturated acylazoliums to form various five and six-membered heterocycles and carbocycles. Moreover, suitably substituted nucleophiles can add to this intermediate and result in valuable products following cascade processes. Employing chiral NHCs in the process can result in the enantioselective synthesis of valuable compounds. In 2013, we developed a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. This reaction takes place under mild conditions with low catalyst loading. Interestingly, employing enolizable aldehydes as the bisnucleophiles in this annulation afforded chiral 4,5-disubstituted dihydropyranones in spite of the competing benzoin/Stetter pathways. Moreover, the use of cyclic 1,3-dicarbonyl compounds such as 4-hydroxy coumarin/pyrazolone afforded the coumarin/pyrazole-fused dihydropyranones. In addition, a [3 + 2] annulation for the synthesis of spiro γ-butyrolactones was demonstrated using 3-hydroxy oxindoles as the bisnucleophile. The interception of α,β-unsaturated acylazolium intermediates with malonic ester derivatives having a γ-benzoyl group resulted in the enantioselective synthesis of functionalized cyclopentenes via a cascade process involving a Michael-intramolecular aldol-β-lactonization-decarboxylation sequence. The use of cyclic β-ketoamides as the coupling partner for catalytically generated α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of spiro-glutarimide and the reaction proceeds in a Michael addition-intramolecular amidation pathway. We have recently demonstrated the enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters by the reaction of enals with dinitrotoluene derivatives bearing electron-withdrawing groups, under oxidative conditions. This atom-economic cascade reaction proceeds in a Michael/Michael/lactonization sequence tolerating a range of functional groups. This technique was also used for the N-H functionalization of indoles for the enantioselective synthesis of pyrroloquinolines following the aza-Michael/Michael/lactonization sequence. The use of α-arylidene pyrazolinones as the bisnucleophiles for the tandem generation of dienolate/enolates combined with the NHC-catalyzed generation of α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. It is reasonable to believe that the chemistry of α,β-unsaturated acylazoliums, catalytically generated through NHCs, will continue to flourish and will lead to amazing results. Future challenges in this area include the applications of this key intermediate in the synthesis of biologically active natural products and drugs.

Carbene-catalyzed enal γ-carbon addition to α-ketophosphonates for enantioselective access to bioactive 2-pyranylphosphonates.

A carbene-catalyzed enantioselective [4+2] cycloaddition reaction between α,β-unsaturated aldehydes and α-ketophosphonates is developed. The reaction affords chiral 2-pyranylphosphonates with excellent enantioselectivities. The optically enriched phosphonate products bear multiple functional groups, including unsaturated lactone and phosphonate moieties that often lead to unique bio-activities. Preliminary studies show that the products from our reactions exhibit anti-bacterial (X. oryzae pv. oryzae) and anti-viral (Tobacco Mosaic Virus) activities for potential use in plant protection.

Asymmetric Traceless Petasis Borono‐Mannich Reactions of Enals: Reductive Transposition of Allylic Diazenes

AbstractThe traceless Petasis borono‐Mannich reaction of enals, sulfonylhydrazines, and allylboronates, catalyzed by chiral biphenols, results in an asymmetric reductive transposition of the in situ generated allylic diazene. Acyclic 1,4‐diene products bearing either alkyl‐ or aryl‐substituted benzylic stereocenters are afforded in excellent yields and enantiomeric ratios of up to 99:1. The use of crotylboronates in the reaction results in concomitant formation of two stereocenters in either a 1,4‐syn or anti relationship from the corresponding E‐ or Z‐crotylboronate used in the reaction. The use of β‐monosubstituted enals in the asymmetric traceless Petasis borono‐Mannich reaction of crotylboronates installs tertiary methyl‐bearing stereocenters in good yields and high enantioselectivities.

Sequential N‐Heterocyclic Carbene‐Catalyzed Reactions of Enals and Cyclic Aryldiene‐1,3‐Diones: Synthesis of Tricyclic Chromenones and Related Compounds

AbstractN‐Heterocyclic carbene (NHC)‐catalyzed synthesis of highly functionalized pyrano[3,2‐c]chromene‐2,5‐dione derivatives, pyrano[3,2‐c]quinoline‐2,5(6 H)‐dione derivatives, and pyrano[4,3‐b]pyran‐2,5‐dione derivatives with potential biological activities is reported. The reaction occurs through a Knoevenagel condensation and NHC‐catalyzed enolate addition in one pot.

ChemInform Abstract: Synthesis of 5,6‐Dihydro‐2H‐pyran‐2‐ones (Microreview)

AbstractReview: [19 refs.

Synthesis of 5,6-dihydro-2H-pyran-2-ones (microreview)

5,6-Dihydro-2H-pyran-2-ones constitute an important class of heterocyclic compounds which also may be considered as α,β-unsaturated δ-lactones. These types of heterocycles have shown a wide range of biological and pharmacological activities including human antitumor,1 , 2 antifungal,3 , 5 antimicrobial,4 anti-inflammatory,4 antistress,4 antibiotic,5antituberculosis,6 antiparasitic,6 antiviral;7 5,6-dihydro-2Hpyran-2-ones are also known as the inducer of a colony stimulating factor in bone marrow stromal cells.5 All this made 5,6-dihydro-2H-pyran-2-ones more attractive both for chemists and pharmacologists. For example, (R)-rugulactone which was firstly reported in 2009 by Cardellina and coworkers possess interesting anticancer properties.2 In addition, 5,6-dihydro-2H-pyran-2-ones as chemical intermediates have widely been applied to the synthesis of numerous organic compounds including heterocycles.8 Nowadays, there are several synthetic routes to the preparation of these heterocycles including intramolecular cyclization, N-heterocyclic carbeneprecatalyst (NHC-precatalyst) reaction of enals and ketones, dicobaltoctacarbonyl-mediated tandem (5+1)/(4+2) cycloaddition, ring-closing metathesis of dienes containing carboxylate group by Grubbs II catalyst, (3+2) cycloaddition reaction, condensation reaction, and biosynthesis pathway.

ChemInform Abstract: The Organocatalyzed Domino Michael—Aldol Reaction Revisited. Synthesis of Enantioenriched 3‐Hydroxycyclohexanone Derivatives by Reaction of Enals with α,α′‐Diaryl‐Substituted Acetone.

AbstractContrary to previously described, it is shown that ketones with pKa <18 can be used as nucleophiles in the organocatalyzed Michael addition to α,β‐unsaturated aldehydes.

The organocatalyzed domino Michael–aldol reaction revisited. Synthesis of enantioenriched 3-hydroxycyclohexanone derivatives by reaction of enals with α,α′-diaryl-substituted acetone

The reaction of enals with α,α′-diaryl-substituted acetones (pKa> 18) catalyzed by (S)-1-(2-pyrrolidinylmethyl) pyrrolidine provides direct access to enantioenriched 2,5,6-trisubstituted-3-hydroxy cyclohexanones.

ChemInform Abstract: N‐Heterocyclic Carbene‐Catalyzed Chemoselective Cross‐Aza‐Benzoin Reaction of Enals with Isatin‐Derived Ketimines: Access to Chiral Quaternary Aminooxindoles.

AbstractIntroduction of halogen substituents onto the isatin phenyl ring suppresses the formation of the corresponding cross‐aza benzoin products almost completely.

Asymmetric synthesis of highly substituted β-lactones through oxidative carbene catalysis with LiCl as cooperative Lewis acid.

The reaction of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position by oxidative NHC catalysis to provide highly substituted β-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two CC bond formations and one CO bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade.

N-Heterocyclic carbene-catalyzed chemoselective cross-aza-benzoin reaction of enals with isatin-derived ketimines: access to chiral quaternary aminooxindoles.

A chemo- and enantioselective cross-aza-benzoin reaction between enals and isatin-derived ketimines is disclosed. The high chemoselectivity (of the acyl anion reaction over enal α- and β-carbon reactions) is enabled by the electronic and steric properties of the N-heterocyclic carbene organocatalyst.

ChemInform Abstract: Enantioselctive N‐Heterocyclic Carbene Catalyzed Aza‐Benzoin Reaction of Enals with Activated Ketimines.

AbstractVarious differently substituted chiral aza‐benzoin products are synthesized (24 examples).

ChemInform Abstract: NHC‐Catalyzed Reactions of Enals with Water as a Solvent.

AbstractThe NHC‐catalyzed reaction of enals (I) with chalcones (II) in water leads to trisubstituted cyclopentenes (III).

ChemInform Abstract: NHC‐Catalyzed Reaction of Enals with Hydroxy Chalcones: Diastereoselective Synthesis of Functionalized Coumarins.

The N-heterocyclic carbene-catalyzed annulation of enals with 2′-hydroxy chalcones afford cyclopentane-fused coumarin derivatives with an excellent level of diastereocontrol. The reaction tolerates a broad range of functional groups; 25 examples are given, and a preliminary mechanistic investigation is provided.

Enantioselective N‐Heterocyclic Carbene Catalyzed Aza‐Benzoin Reaction of Enals with Activated Ketimines

Enantioselective N‐Heterocyclic Carbene Catalyzed Aza‐Benzoin Reaction of Enals with Activated Ketimines

Enantioselective N‐Heterocyclic Carbene Catalyzed Aza‐Benzoin Reaction of Enals with Activated Ketimines

α-Aminoketone, vielseitige Bausteine für die organische Synthese, wurden mit der Titelreaktion hergestellt. Eine freie Hydroxygruppe am NHC-Katalysator war entscheidend für die Reaktion, und die mögliche konkurrierende Reaktion über ein Homoenolat oder ein Enolat wurde mit diesem Katalysator nicht beobachtet (siehe Schema). As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

ChemInform Abstract: One‐Step Formation Both of C—N and of C—O Bonds of N‐Alkoxyamides Through NHC‐Catalyzed Three‐Component Reactions of Enals, Nitrosoarenes, and Enones.

AbstractThe present new reaction proceeds by aza‐benzoin condensation of α,β‐unsaturated aldehydes and nitrosoarenes followed by oxo‐Michael addition of intermediate N‐hydroxylamide to α,β‐unsaturated ketones to provide the title compounds in good yields.

ChemInform Abstract: γ‐Amino Alcohols via Organocascade Reactions Involving Dienamine Catalysis.

AbstractProlinol‐catalyzed reaction of enals with azadicarboxylates followed by treatment with Hantzsch ester and NaBH4 allows a new access to optically active γ‐amino alcohols.

Enantioselective, NHC‐Catalyzed Annulations of Trisubstituted Enals and Cyclic N‐Sulfonylimines via α,β‐Unsaturated Acyl Azoliums

All aboard please! A new reaction of enals and cyclic sulfonylimines, as the nucleophiles(!), is the first highly enantioselective NHC-catalyzed annulation of trisubstituted enals. The catalytically generated α,β-unsaturated acyl azolium undergoes a reaction with the enamine tautomer of the imine via an aza-Claisen rearrangement as the key CC bond-forming step. High yields and enantioselectivities were achieved using β-, α,β-, and β,β′-substituted enals.

ChemInform Abstract: Access to Spirocyclic Oxindoles via N‐Heterocyclic Carbene‐Catalyzed Reactions of Enals and Oxindole‐Derived α,β‐Unsaturated Imines.

AbstractUnder conditions A), the title reaction affords bicyclic lactam structures with all carbon spiro centers.