Non-enolizable Aldehydes Research Articles

Synthetic applications of biologically important Mannich bases: An updated review

Mannich bases are the beta-amino ketones carrying compounds. Mannich reaction is a nucleophilic addition reaction (nucleophiles such as halogen ions (I-, Br-, Cl- ), the hydroxide ion (OH- ), cyanide ion (CN-), ammonia and water, which involves the condensation of three components, viz., ammonia or a primary amine or a secondary amine or with amides, a non-enolizable aldehyde, usually formaldehyde and a compound containing an active hydrogen atom. These three compounds condense with the concomitant release of the water molecule to produce a new base known as a mannich base, in which the active hydrogen is replaced by an amino methyl group. During the past decades, there has been a great deal of interest in the synthesis of mannich bases. Mannich base can be synthesized by using microwave irradiation, one pot, catalyst-free, retrospective asymmetric synthesis, solvent-free and ultrasonic-assisted synthetic techniques. The literature studies enlighten the fact that mannich bases are a key step in the synthesis of a wide variety of natural products, pharmaceuticals and so forth. Mannich bases play a vital role in the coordination chemistry and the development of metal complexes. Mannich bases have remained an important and popular area of research due to their simple synthesis, adaptability and diverse range of applications. Thus, mannich bases and their derivatives may be further used for enormous biological applications with potent effects.

Ultrasound mediated synthesis of aldimines from non-enolizable aldehydes at room temperature

A user-friendly, energy efficient method of synthesizing N-sulfonyl aldimines at room temperature (25‒28°C) from readily available and inexpensive reagents has been developed. The method employs ultrasonication from common laboratory ultrasonic cleaner to mediate the reaction. FeCl3 as catalyst and molecular sieves as water scavenger have produced excellent yields of aldimines with short reaction time. The reaction set-up does not require inert atmosphere or anhydrous solvent thereby saving resources and time. The easily scalable method works well for the condensation of aromatic non-enolizable aldehydes and sulfonamides.

Synthesis of pH Dependent Pyrazole, Imidazole, and Isoindolone Dipyrrinone Fluorophores using a Claisen-Schmidt Condensation Approach.

Methine-bridged conjugated bicyclic aromatic compounds are common constituents of a range of biologically relevant molecules such as porphyrins, dipyrrinones, and pharmaceuticals. Additionally, restricted rotation of these systems often results in highly to moderately fluorescent systems as observed in 3H,5H-dipyrrolo[1,2-c:2',1'-f]pyrimidin-3-ones, xanthoglows, pyrroloindolizinedione analogs, BODIPY analogs, and the phenolic and imidazolinone ring systems of Green Fluorescent Protein (GFP). This manuscript describes an inexpensive and operationally simple method of performing a Claisen-Schmidt condensation to generate a series of fluorescent pH dependent pyrazole/imidazole/isoindolone dipyrrinone analogs. While the methodology illustrates the synthesis of dipyrrinone analogs, it can be translated to produce a wide range of conjugated bicyclic aromatic compounds. The Claisen-Schmidt condensation reaction utilized in this method is limited in scope to nucleophiles and electrophiles that are enolizable under basic conditions (nucleophile component) and non-enolizable aldehydes (electrophile component). Additionally, both the nucleophilic and electrophilic reactants must contain functional groups that will not inadvertently react with hydroxide. Despite these limitations, this methodology offers access to completely novel systems that can be employed as biological or molecular probes.

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.

One-pot enol silane formation-Mukaiyama aldol reactions: Crossed aldehyde-aldehyde coupling, thioester substrates, and reactions in ester solvents

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a trialkylamine base promote both in situ enol silane/silyl ketene acetal formation and Mukaiyama aldol addition reactions between a variety of reaction partners in a single reaction flask. Isolation of the required enol silane or silyl ketene acetal is not necessary. For example, crossed aldol reactions between α-disubstituted aldehydes and non-enolizable aldehydes yield β-hydroxy aldehydes in good yield. In a related reaction, the common laboratory solvent ethyl acetate functions as both an enolate precursor and a green reaction solvent. When thioesters are employed as enolate precursors, high yields for additions to non-enolizable aldehydes are routinely observed.

Decarboxylative difluoromethylation of aldehydes with PhSO2CF2COOK: A facile and efficient access to difluoromethylated carbinols

A novel decarboxylative difluoromethylation reaction of PhSO2CF2COOK with aldehydes under metal- and ligand-free conditions has been developed. The reaction is very mild and tolerates a wide range of aldehydes (both enolizable and non-enolizable aldehydes), providing a facile and efficient method for the synthesis of structurally diverse difluoromethylated carbinols in moderate to excellent yields.

Cs₂CO₃-Initiated Trifluoro-Methylation of Chalcones and Ketones for Practical Synthesis of Trifluoromethylated Tertiary Silyl Ethers.

It was found that 1,2-trifluoromethylation reactions of ketones, enones, and aldehydes were easily accomplished using the Prakash reagent in the presence of catalytic amounts of cesium carbonate, which represents an experimentally convenient, atom-economic process for this anionic trifluoromethylation of non-enolisable aldehydes and ketones.

1,5-Electrocyclization of conjugated azomethine ylides derived from 3-formyl chromene and N-alkyl amino acids/esters.

A novel strategy has been developed for the synthesis of chromeno[3,4-b]pyrrol-4(3H)-one and substituted pyrrole derivatives through 1,5-electrocyclization of conjugated azomethine ylides. This is the first example of the preparation of highly substituted pyrrole derivatives from chromene-3-carboxaldehydes (non-enolizable aldehydes) and N-alkyl amino acids/esters. This method is simple and applicable to a diverse range of substrates.

A kinetically controlled direct aldol addition of α-chloro thioesters via soft enolization

Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr2·OEt2 and i-Pr2NEt. At −78°C the reaction proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover, excellent stereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based aldol addition.

Modular synthesis of tetra-substituted furans from alkynes, Weinreb amides, and aldehydes

A method for the modular one-pot synthesis of tetra-substituted furans utilizing alkynes, Weinreb amides, and non-enolizable aldehydes has been developed. Under this titanium promoted method, furans were prepared in moderate yields with high levels of regioselectivity. The system showed good chemoselectivity tolerating aromatic and aliphatic bromides, chlorides, and fluorides, heteroaromatics, alkenes, and silyl ethers.

Mild Cleavage of N–O Bond of 3,6-Dihydro-1,2-oxazines by Condensation of Aldehydes in Aqueous Media

The nonreductive cleavage of a model 3,6-dihydro-1,2-oxazine by condensation of 2,2-dimethoxyacetaldehyde under aqueous conditions is investigated. Depending on the pH of the solution, the reaction leads either to the N-acylated 1,4-amino alcohol or to the corresponding stable hemiaminal. The formation of the former is believed to proceed through iminium to oxaziridine rearrangement and not through enamine formation, as confirmed by the use of nonenolizable aldehydes. This procedure allows a very mild, nonreductive cleavage of N–O bonds.

Role of hydroxyl groups on the aromatic ring in the reactivity and selectivity of the reaction of β-phenylethylamines with non-enolizable aldehydes

The influence of hydroxyl groups on the β-phenylethylamine aromatic ring was studied during its reaction with non-enolizable aldehydes. Computational calculations established that the degree of hydroxylation generates differences in the activation patterns of the ring (different reaction pathways) and in the nucleophilicity of the nitrogen atoms (different reaction yields). Cyclic aminals, benzoxazinephanes, or tetrahydroisoquinolines were obtained in the reaction with formaldehyde, and Schiff’s bases or tetrahydroisoquinolines were produced in the reaction with other non-enolizable aldehydes. The product obtained depends on the degree of hydroxylation of the ring of the starting phenylethylamine.

Nucleophilic difluoro(phenylsulfonyl)methylation of carbonyls with PhSO2CF2H reagent in the presence of in situ generated substoichiometric amount of base

The reactions between carbonyl compounds and PhSO2CF2H using substoichiometric amount of base in situ generated from N(TMS)3 and catalytic amount of Me4NF have been investigated. It is found that both enolizable and non-enolizable aldehydes are suitable substrates to undergo nucleophilic difluoro(phenylsulfonyl)methylation. Compared to the previously reported trifluoromethylation of carbonyls with CF3H under the similar reaction conditions, the unique reactivity of PhSO2CF2H is attributed to its higher acidity than CF3H and the reversibility of its addition reaction with ketones under basic conditions.

Efficient Entry to the [2.2.2]-Diazabicyclic Ring System via Diastereoselective Domino Reaction Sequence

A domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition for the synthesis of [2.2.2]-diazabicyclic structures is reported. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and nonenolizable aldehyde substrates (nine examples total). Progress toward the synthesis of malbrancheamide B, a protypical member of the [2.2.2]-diazabicyclic natural product family, is also disclosed.

Outer‐sphere reduction of hexacyanoferrate(III) by enolizable and nonenolizable aldehydes in alkaline medium

AbstractOuter‐sphere reduction of hexacyanoferrate(III) by some enolizable/nonenolizable aldehydes (viz., aliphatic, heterocyclic, and aromatic aldehydes) in alkaline medium has been studied spectrophotometrically at λmax = 420 nm. The reactions are first order each in [aldehyde] and [Fe(CN)63−]. The rate increases with an increase in [OH−] in the oxidation of aliphatic and heterocyclic aldehydes, whereas it is independent of [OH−] in the reaction with aromatic aldehydes. The intervention of free radicals in the reaction mixture was carried out using both acrylonitrile and acrylamide scavenger in two different experiments. The kinetic results indicate that the oxidation of benzaldehyde in aqueous medium proceeds at a slower rate than the aliphatic aldehydes (other than formaldehyde) and furfural. The values of third‐order rate constant (k3) at 308 K in the oxidations of some aliphatic aldehydes and furfural follow the order (CH3)2CH > CH3CH2 > CH3 > C4H3O > H. The rate constants correlate with Taft's σ* value, the reaction constant being negative (–9.8). The pseudo–first‐order rate constants in the oxidations of benzaldehyde and substituted benzaldehydes follow the order NO2 > H > Cl > OCH3. The Hammett plot is also linear with a ρ value (0.6488) for meta‐ and para‐substituted benzaldehydes. The kinetic isotope effect for benzaldehyde (kH/kD = 1.93 at 303 K) was obtained. The rate‐determining step is the outer‐sphere formation of Fe(CN)64− and free radicals, which is followed by the rapid oxidation of free radicals by Fe(CN)63− to give products. The kinetic data and hence thermodynamic parameters have been used to distinguish enolizable and nonenolizable aldehydes. An attempt has also been made to correlate kinetic data with hydration equilibrium constants of some aliphatic aldehydes. © 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 494–505, 2012

Methyltrioxorhenium Catalyzed Synthesis of Dinitrones from Primary Diamines and Non-Enolizable Aldehydes

Green Chemistry is the design of chemicals and processes that reduce or eliminate the use and generation of hazardous substances, and consequently reduce the risk to human health and the environment. Nitrones have various applications, such as building blocks in the synthesis of natural and biologically active compounds and molecular weight regulators in radical polymerization. In this work, dinitrones were successfully synthesized in a one-pot process from primary diamines and proper aromatic aldehydes employing methyltrioxorhenium (MTO) as catalyst and urea-hydrogen peroxide adduct (UHP) as oxidizing agent. Diamines, such as 1,6-diaminohexane and 1,12-diaminododecane were reacted with benzaldehydes bearing various substituent, such as 4-chloro, 4-nitro, 4-methoxybenzaldehyde, and also furfural. The resulting N,N' -bis (benzylidene)-1,6-hexanediamine N,N' -dioxides or N,N' -bis (benzylidene)-1,12-dodecanediamine N,N' -dioxides (or substituted benzylidenes) were separated with 45-60 % yields. The main advantage of the one-pot process is the elimination of need for several separation and purification steps and reduction in consumption of chemicals and waste production. The products selectively were characterized by 1H-NMR, 13C-NMR, FT-IR spectroscopies, and elemental analysis (CHNS).

Nucleophilic trifluoromethylation with organoboron reagents

Potassium trialkoxy(trifluoromethyl)borates are shown to behave as convenient reagents for nucleophilic trifluoromethylation of non-enolizable aldehydes and N-tosylimines to give CF3-substituted alcohols and N-tosylamines in good yields.

ChemInform Abstract: Magnesium Metal Mediated Reductive Trifluoromethylation of Aldehydes with Phenyl Trifluoromethyl Sulfone.

AbstractThe method is suitable for enolizable and non‐enolizable aldehydes via formation of a CF3‐ species.

ChemInform Abstract: Diastereoselective Synthesis of Tetrahydrofurans from Aryl 3‐Chloropropylsulfoxides and Aldehydes.

AbstractSulfoxides of type (I) smoothly react with electron‐rich nonenolizable aldehydes to afford trans‐substituted tetrahydrofurans with high stereoselectivity.

ChemInform Abstract: Alkylation of Carbonyl Compounds with Dialkylzirconocene Complexes Promoted by Potassium t-Butoxide.

Abstract Potassium t -butoxide promotes alkylation of non-enolizable ketones and aldehydes by zirconocene dialkyls. The reaction proceeds with loss of cyclopentadienide ion from the metal center.