Enolizable Aldehydes Research Articles

Preparation of hyperbranched polyglycerol groups modified by sulfonic acid tags supported on magnetized kappa-carrageenan: A sustainable solid acid for the synthesis of 1-amidoalkyl-2-naphthols

In this study, the magnetization of kappa-carrageenan (Carr) and its modification by hyperbranched polyglycerol-sulfonic acid tags (PGly-SO3H) was found to be a good strategy to fabricate a bio-inspired solid acid as a heterogeneous nanocatalyst for the synthesis of 1-amidoalkyl-2-naphthols from aldehydes, 2-naphthol, and acetamide. The catalyst was produced by embedding Fe3O4 nanoparticles into carrageenan shell and modifying the as-produced Fe3O4@Carr with PGly tags. Then, the Fe3O4@Carr was modified by chlorosulfonic acid (Cl-SO3H) to obtain the Fe3O4@Carr-PGly-SO3H nanoparticles. The morphology and structure of Fe3O4@Carr-PGly-SO3H nanoparticles were studied by FT–IR, XRD, FE-SEM, EDX-mapping, TEM, VSM, and TGA. Aromatic aldehydes with electron-donor/ electron-acceptor substituents, heterocyclic aldehydes, and enolizable aldehyde gave the corresponding 1-amidoalkyl-2-naphthols with 85–96 % isolated yields within 15–35 min, under solvent-free conditions. The acidic content of Fe3O4@Carr-pPGly-SO3H nanoparticles was found to be 3.5 mmol H+/g, which determined by titration. As shown by TEM images, the Fe3O4 core facilitates the efficient magnetic separation. The use of a benign support material, ease of catalyst preparation and recovery, heterogeneous nature (on the basis of hot-filtration experiment), solvent-free conditions, and reusability of the nanoparticles (5 times) are some of the green aspects of the present study.

Asymmetric α‐Pentadienylation of β‐Ketocarbonyls and Aldehydes by Synergistic Pd/Chiral Primary Amine Catalysis†

Comprehensive SummaryDirect alkylation with skipped enynes or cyclopropropylacetylenes represents an ideal process for the installation of pentadienyl group in terms of atom‐ and step‐economy. The development of catalytic asymmetric versions has been frequently pursued and most of the successes have been achieved with enolizable aldehydes. We herein describe a synergistic chiral primary amine/Pd catalysis for asymmetric α‐pentadienylation of β‐ketocarbonyls and aldehydes with skipped enynes or cyclopropropylacetylenes. The reaction features the construction of acyclic all‐carbon quaternary centers with high enantioselectivity, and good functional group tolerance and scalability.

Gold-Catalyzed Addition of β-Oxo Enols at Tethered Alkynes via a Non-Conia-ene Pathway: Observation of a Formal 1,3-Hydroxymethylidene Migration.

With the relay process of Ag(I)/Au(I) catalysts, a one-pot synthesis of skeletally rearranged (1-hydroxymethylidene)indene derivatives from 2-alkynylbenzaldehydes and α-diazo esters is described. This cascade sequence involves Au(I)-catalyzed 5-endo-dig attack of highly enolizable aldehydes at the tethered alkynes, leading to carbocyclizations with a formal 1,3-hydroxymethylidene transfer. On the basis of density functional theory calculations, the mechanism likely involves formation of cyclopropylgold carbenes, followed by an appealing 1,2-cyclopropane migration.

Development of an α'-hydroxy enone for the aminocatalytic asymmetric formal conjugate addition of aldehydes to acrylates, vinyl ketones and acrolein.

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C-C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α'-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl-vinyl ketones and acrylates, respectively.

Potassium Base-Promoted Diastereoselective Synthesis of 1,3-Diols from Allylic Alcohols and Aldehydes through a Tandem Allylic-Isomerization/Aldol-Tishchenko Reaction.

This study reports the first base-promoted aldol-Tishchenko reactions of allylic alcohols with aldehydes initiated by allylic isomerization. The reaction enables the diastereoselective synthesis of a variety of 1,3-diols with three contiguous stereogenic centers. Unlike commonly reported systems, our method allows the use of readily available allylic alcohols as nucleophiles instead of enolizable aldehydes and ketones.

Aminocatalytic [8+2] Cycloaddition Reactions toward Chiral Cyclazines

AbstractAn efficient and exceptionally stereoselective synthesis of chiral cycl[3.2.2]azines has been realized by means of the rational design and utilization of novel (E)‐3‐benzylidene‐3H‐pyrrolizines in iminium‐ion‐catalyzed [8+2] cycloaddition reactions. The presented protocol allows for the incorporation of diverse enals, including cinnamaldehydes, enolizable aldehydes, and substrates of extended conjugation. The obtained products contain both an electron‐rich alkenyl pyrrole moiety and an electron‐deficient carbaldehyde substituent, and both moieties can undergo selective transformations with retention of the stereochemical information established in the [8+2] cycloaddition.

Aminocatalytic [8+2] Cycloaddition Reactions toward Chiral Cyclazines.

An efficient and exceptionally stereoselective synthesis of chiral cycl[3.2.2]azines has been realized by means of the rational design and utilization of novel (E)-3-benzylidene-3H-pyrrolizines in iminium-ion-catalyzed [8+2] cycloaddition reactions. The presented protocol allows for the incorporation of diverse enals, including cinnamaldehydes, enolizable aldehydes, and substrates of extended conjugation. The obtained products contain both an electron-rich alkenyl pyrrole moiety and an electron-deficient carbaldehyde substituent, and both moieties can undergo selective transformations with retention of the stereochemical information established in the [8+2] cycloaddition.

Three-component radical homo Mannich reaction

Aliphatic amine, especially tertiary aliphatic amine, is one of the most popular functionalities found in pharmaceutical agents. The Mannich reaction is a classical and widely used transformation for the synthesis of β-amino-carbonyl products. Due to an ionic nature of the mechanism, the Mannich reaction can only use non-enolizable aldehydes as substrates, which significantly limits the further applications of this powerful approach. Here we show, by employing a radical process, we are able to utilize enolizable aldehydes as substrates and develop the three-component radical homo Mannich reaction for the streamlined synthesis of γ-amino-carbonyl compounds. The electrophilic radicals are generated from thiols via the desulfurization process facilitated by visible-light, and then add to the electron-rich double bonds of the in-situ formed enamines to provide the products in a single step. The broad scope, mild conditions, high functional group tolerance, and modularity of this metal-free approach for the synthesis of complex tertiary amine scaffolds will likely be of great utility to chemists in both academia and industry.

Stereospecific Asymmetric Synthesis of Tertiary Allylic Alcohol Derivatives by Catalytic [2,3]-Meisenheimer Rearrangements.

Chiral acyclic tertiary allylic alcohols are very important synthetic building blocks, but their enantioselective synthesis is often challenging. A major limitation in catalytic asymmetric 1,2‐addition approaches to ketones is the enantioface differentiation by steric distinction of both ketone residues. Herein we report the development of a catalytic asymmetric Meisenheimer rearrangement to overcome this problem, as it proceeds in a stereospecific manner. This allows for high enantioselectivity also for the formation of products in which the residues at the generated tetrasubstituted stereocenter display a similar steric demand. Low catalyst loadings were found to be sufficient and the reaction conditions were mild enough to tolerate even highly reactive functional groups, such as an enolizable aldehyde, a primary tosylate, or an epoxide. Our investigations suggest an intramolecular rearrangement pathway.

Synthesis of 1,2-Diamine Bifunctional Catalysts for the Direct Aldol Reaction Through Probing the Remote Amide Hydrogen

Background: While proline can catalyze the asymmetric direct aldol reactions, its catalytic activity and catalyst turnover are both low. To improve the catalytic efficiency, many prolinebased organocatalysts have been developed. In this regard, prolinamide-based bifunctional catalysts have been demonstrated by us and others to be highly efficient catalysts for the direct aldol reactions. Results: Using the β-acetamido- and β-tosylamidoprolinamide catalysts, the highly enantio- and diastereoselective direct aldol reactions between enolizable ketones and aldehydes were achieved (up to >99% ee, 98:2 dr). A low catalyst loading of only 2-5 mol % of the β-tosylamidoprolinamide catalyst was needed to obtain the desired aldol products in good to high yields and high stereoselectivities. Methods: By carefully adjusting the hydrogen bonding ability of the remote β-amide hydrogen of the 1,2-diamine-based prolinamide bifunctional catalysts, the catalytic activity and the asymmetric induction of these catalysts were significantly improved for the direct aldol reaction between aldehydes and enolizable ketones. Conclusion: Some highly efficient 1,2-diamine-based bifunctional prolinamide catalysts have been developed through probing the remote β-amide hydrogen for its hydrogen bonding capability. These catalysts are easy to synthesize and high enantioselectivities may be achieved at very low catalyst loadings.

Synthesis of Multisubstituted Pyrroles from Enolizable Aldehydes and Primary Amines Promoted by Iodine.

1,2,4-Trisubstituted pyrroles were synthesized from enolizable aliphatic aldehydes and primary aliphatic amines by using iodine as the dual Lewis acid/mild oxidant. In the presence of 3.0 equiv of TBHP, enolizable α,β-unsaturated aldehyde, for example, cocal reacted with aromatic primary amines to form C2-iodized N-arylpyrroles. An acetal-containing pyrrole was successfully prepared from 4-aminobutyraldehyde diethyl acetal, which can be converted easily to 5,6,7,8-tetrahydroindolizine derivatives.

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.

A Versatile Catalyst-Free Perfluoroaryl Azide-Aldehyde-Amine Conjugation Reaction.

A tri-component reaction, involving an electrophilically-activated perfluoroaryl azide, an enolizable aldehyde and an amine, reacts readily at room temperature without any catalysts in solvents including aqueous conditions to yield a stable amidine conjugate. The versatility of this reaction is demonstrated in the conjugation of an amino acid without prior protection of the carboxyl group, and in the synthesize antibiotic-nanoparticle conjugates.

Three-Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o-Terphenyls.

An unprecedented organocatalytic three-component domino Knoevenagel/vinylogous Michael reaction starting from simple enolizable aldehydes, malononitrile, and nitroolefins is reported. This facile two-step domino process provides a straightforward stereoselective route to multifunctional vinyl malononitrile products (up to 82 % yield, 85:15 d.r.) containing a nitroalkane moiety, and contributes to the development of sustainability and atom economy. The application of the obtained domino products for synthesis of highly functionalized o-terphenyls (of high interest for materials science and medicinal chemistry) through subsequent new three-step domino reaction involving cyclization-tautomerization-aromatization steps, has been demonstrated.

Efficient Access to All-Carbon Quaternary and Tertiary α-Functionalized Homoallyl-type Aldehydes from Ketones.

β,γ-Unsaturated aldehydes with all-carbon quaternary or tertiary α-centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C1 homologation, 2) Lewis acid mediated epoxide-aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a β,γ-unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.

Efficient Access to All‐Carbon Quaternary and Tertiary α‐Functionalized Homoallyl‐type Aldehydes from Ketones

Abstractβ,γ‐Unsaturated aldehydes with all‐carbon quaternary or tertiary α‐centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C1 homologation, 2) Lewis acid mediated epoxide–aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a β,γ‐unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.

Asymmetric Michael Addition Organocatalyzed by α,β-Dipeptides under Solvent-Free Reaction Conditions.

The application of six novel α,β-dipeptides as chiral organocatalysts in the asymmetric Michael addition reaction between enolizable aldehydes and N-arylmaleimides or nitroolefins is described. With N-arylmaleimides as substrates, the best results were achieved with dipeptide 2 as a catalyst in the presence of aq. NaOH. Whereas dipeptides 4 and 6 in conjunction with 4-dimethylaminopyridine (DMAP) and thiourea as a hydrogen bond donor proved to be highly efficient organocatalytic systems in the enantioselective reaction between isobutyraldehyde and various nitroolefins.

Dynamic Covalent Chemistry of Aldehyde Enamines: BiIII - and ScIII -Catalysis of Amine-Enamine Exchange.

The dynamic exchange of enamines from secondary amines and enolizable aldehydes has been demonstrated in organic solvents. The enamine exchange with amines was efficiently catalyzed by Bi(OTf)3 and Sc(OTf)3 (2 mol %) and the equilibria (60 mm) could be attained within hours at room temperature. The formed dynamic covalent systems displayed high stabilities in basic environment with <2 % by‐product formation within one week after complete equilibration. This study expands the scope of dynamic C−N bonds from imine chemistry to enamines, enabling further dynamic methodologies in exploration of this important class of structures in systems chemistry.

Bicatalyzed Three-Component Stereoselective Decarboxylative Fluoro-Aldolization for the Construction of Elongated Fluorohydrins

A bicatalyzed three-component cascade between simple aliphatic enolizable aldehydes, a fluorine source, and keto acids has allowed the diastereoselective and enantioselective direct synthesis of carbonyl-elongated vicinal fluorohydrins. The obtained complex acyclic functionalized molecules, possessing up to four stereogenic centers controlled in usually >95% ee, hold great promise for further synthetic developments and rapid incorporation in bioactive elaborated structures.

Highly selective intermolecular one-pot three component 1,3-dipolar cycloaddition reaction of aldehydes, with phosphonates and proline

The use of l-proline to act as an organocatalyst in the aldol reaction of acylphosphonates and non enolizable aldehydes failed; however, it reacted with the aldehydes to afford azomethine ylides after decarboxylation that in turn underwent 1,3-dipolar cycloaddition with the acylphosphonates to form a bicyclic hexahydropyrrolo[1,2-c]oxazol-1-ylphosphonates in good yield. No azomethine ylide formation was observed on the reaction of acylphosphonates with proline.