Aldol-type Condensation Research Articles

A Regioselective, One-Pot, Transition-Metal-Free α-Alkylation of Quinone Monoacetals for Various Organic Transformations.

Regioselective reactions of biologically significant quinones are challenging. An unprecedented advancement in quinone monoacetal (QMA) chemistry is proposed for constructing regioselective and less explored α-alkylated QMAs through the Morita-Baylis-Hillman (MBH) reaction. Electrophilic QMAs were transformed to nucleophilic umpolung reagents for aldol-type condensation with several electrophiles. Mechanistic studies reveal that solvent (TFE:water (1:1)) and in situ-generated potassium acetate accelerate the reaction. The ensuing MBH adducts were scalable and underwent several post-synthetic transformations and late-stage functionalization.

Biomimetic and Concise Total Syntheses of Prenylated and Bicyclo[2.2.2]diazaoctane-Containing Indole Alkaloids Including Taichunamide A, Notoamide N and Versicolamide B.

Total syntheses of the title prenylated indole alkaloids together with seven others are reported. Biogenetic considerations have been employed in devising the reaction sequences leading to these targets with, in the opening stages, electrochemically-derived indole-3-carboxaldehyde 15 being subject to an aldol-type condensation reaction involving diketopiperazine derivative 19. This led, after prototopic shifts, intramolecular Diels-Alder cycloaddition and hydrolysis/deprotection steps, to the racemic forms of the bicyclo[2.2.2]diazaoctane-containing natural product stephacidin A (2) and its C6 epimer 3. Epoxidation of the last compound afforded, following rearrangement of the primary oxidation products, a mixture of (±)-taichunamide A [(±)-4] and (±)-versicolamide B [(±)-7]. Related protocols allowed for the conversion of (±)-stephacidin A [(±)-2] into (±)-notoamide B [(±)-5]. Analogous aldol condensation, nucleophilic reduction, and epoxidation steps led to the formation of (-)-notoamide E and its conversion into notoamide C as well as the indole fragmentation product amoenamide E. A late-stage chlorination reaction applied to (±)-stephacidin A provided access to the spirocyclic oxindole (±)-notoamide N [(±)-6].

One-Pot Dual C-C Bond-Forming Cascade Process via Suzuki Coupling and Intramolecular Cyclocondensation: An Access to Functionalized Naphthalenes.

Naphthyl ketones encompass a class of essential compounds of biological and industrial significance. The development of synthetic strategies to achieve naphthyl ketones in single-step reactions from readily available materials is highly desirable. Herein, domino one-pot synthesis of functionalized naphthyl ketones via intermolecular Suzuki-Miyaura coupling, followed by intramolecular distal aldol-type condensation with the γ-methyl/methylene groups is reported. The present strategy displayed a comprehensive substrate scope and good functional group tolerance and enabled access to a variety of substituted naphthyl ketones, including aromatic-aliphatic hybrid frameworks of interesting structural features starting from the easily accessible starting materials such as α-iodoenone and 2-formylphenylboronic acids as well as 2-formylphenylboronic acid pinacol esters.

Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease

Down-regulation of Cisd2 in the liver has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and increasing the level of Cisd2 is therefore a potential therapeutic approach to this group of diseases. Herein, we describe the design, synthesis, and biological evaluation of a series of Cisd2 activators, all thiophene analogs, based on a hit obtained using two-stage screening and prepared via either the Gewald reaction or by intramolecular aldol-type condensation of an N,S-acetal. Metabolic stability studies of the resulting potent Cisd2 activators suggest that thiophenes 4q and 6 are suitable for in vivo studies. The results from studies on 4q-treated and 6-treated Cisd2hKO-het mice, which carry a heterozygous hepatocyte-specific Cisd2 knockout, confirm that (1) there is a correlation between Cisd2 levels and NAFLD and (2) these compounds have the ability to prevent, without detectable toxicity, the development and progression of NAFLD.

Synthesis of 2-(5-(2-Aminopropyl)-2-hydroxyphenyl)acetic Acid, a Metabolite of the Drug 5-APB

5-(2-Aminopropyl)benzofuran (5-APB), also known as “Benzo Fury,” is a novel psychoactive substance (NPS) belonging to a new class of synthetic phenethylamines. It acts by disrupting serotonergic circuits as a serotonin–norepinephrine–dopamine reuptake inhibitor and is classified as an entactogen, similar to MDMA and MDA. Despite its popularity among users, recent toxicity events have been associated with the consumption of 5-APB and other benzofurans, highlighting the need for a better understanding of their pharmacodynamics and toxicity. One way to achieve this is by developing the synthesis of 5-APB metabolites as biomarkers of exposure. In this study, we present a six-step synthesis for one of the 5-APB metabolites, 2-(5-(2-aminopropyl)-2-hydroxyphenyl)acetic acid (1), involving methylation, formylation, Aldol-type condensation, reduction, and hydrolysis reactions. The compound was obtained in an overall yield of 11%.

High-intensity ultrasound promoted the aldol-type condensation as an alternative mean of synthesizing pyrazines in a Maillard reaction model system of D-glucose-13C6 and L-glycine

This study evaluated how the generation of pyrazines was promoted by high-intensity ultrasound (HIU) in a Maillard reaction (MR) model system of glucose-glycine. Carbohydrate module labeling (CAMOLA) technique was adopted using D-glucose-13C6 to elucidate the carbon skeleton of both intermediate and final MR products (MRPs). In the D-glucose-13C6-glycine HIU-MR model system, the concentration of 11 types of pyrazines was significantly higher than their counterparts in the thermal MR. Results of CAMOLA analysis showed that a significantly lower proportion of [M]+ in pyrazines with long-length side chains was observed when compared with the pyrazines generated in thermal MR. This phenomenon may suggest the aldol-type condensation was promoted by the HIU, which is a conversion from pyrazines with short-length side chains to those with long-length side chains involving carbonyl compounds. Furthermore, the analysis of isotopomers distribution in 2,3-dimethyl-quinoxaline as the o-phenylenediamine-derivatized 2,3-butanedione indicated that the increased proportion of [M + 4]+ in 2,3-dimethyl-quinoxaline (15.74% ± 0.11%) was attributed to a cleavage of D-glucose-13C6 promoted by the HIU. The above-mentioned findings elucidate that the aldol-type condensation and cleavage of D-glucose contribute to the promoted synthesis of pyrazines. The HIU would generate an extremely high temperature and pressure environment that is favored by the aldol-type condensation as a high-pressure favored reaction. The HIU, therefore, can be further developed as a promising technique to promote flavor generation through the MR.

Contrasting structure-property relationships in amorphous, hierarchical and microporous aluminophosphate catalysts for Claisen-Schmidt condensation reactions

Amorphous aluminophosphates are industrial catalysts that are active in aldol-type condensations, dehydration and alkylation. The intrinsic nature of the active sites present in these materials is poorly understood. Herein we report a comparative investigation of the catalytic active sites in amorphous and crystalline aluminophosphates (AFI topology) and their corresponding iron-containing analogues, employing Claisen-Schmidt condensation of acetophenone and benzaldehyde as the test reaction. Secondary porosity generated via the soft-templating approach in hierarchically-porous HP FeAlPO-5, and the presence of large mesopores in amorphous Am FeAlPO resulted in improved mass-transport and high conversion of carbonyls. The nature and concentration of the active acidic sites within these materials were characterized by pyridine-DRIFTS and propylamine-TPD studies and was shown to play a crucial role in the activation of carbonyl groups and better catalytic performance. Am FeAlPO(5) nearly outperformed HP FeAlPO-5, thus providing a promising alternative for expanding scope in industrial and pharmaceutical applications.

Synthesis of Spiro Oxazolidinedione Analogues Based on Tandem Multicyclizations of 1,3-Dimethylalloxan and Enaminones in Water

AbstractA tandem double-annulation reaction of 1,3-dimethylalloxan with enaminones, generated in situ from alkyl amines and alkyl but-2-ynoates or pent-3-yn-2-ones to give functionalized oxazolidinedione spiro analogues is described. Three of the four carbonyl groups of alloxan have been engaged through a tandem Michael addition, aldol-type condensation, and double intramolecular annulation sequence.

Total Synthesis and Structure–Activity Relationship Studies of Phelligridins C and D, and Phellifuropyranone A

Abstract α-Pyrone polyphenols, phelligridins C and D (meshimakobnols B and A), and phellifuropyranone A, isolated from a Japanese mushroom, are growth inhibitors of cancer cells. Herein, we report full details of the total synthesis of phelligridins C and D. The key reactions of the synthetic pathways were Pd catalyzed cross-coupling and aldol-type condensation. This strategy also enabled the total synthesis of phellifuropyranone A and artificial analogs of phelligridins. Subsequent biological evaluation of these compounds clarified that the whole skeleton of phelligridin C and the catechol group of the left hand side are essential for the cytotoxicity.

Dimension Control in Mixed Linker Metal-Organic Frameworks via Adjusting the Linker Shapes.

In this context, we describe a novel method to control the dimensionality and, further, the morphology in three mixed linker metal-organic frameworks (MOFs) TMU-70, TMU-71, and TMU-49 via altering the linker shapes. The compatibility between the shape of linkers used in the mixed linker framework, specifically linker angles, can directly affect the dimensionality of the resulting networks from 2D to 3D. Using incompatible linkers (one bent and one linear) together with binodal SBU directed the structure to form 2D networks, while 3D networks were obtained through applying linkers with the same shape. Further, the 2D and 3D MOFs were fabricated through the coordination modulation strategy. The impact of various modulators on the size and morphology of the structures has been examined. The 2D MOFs produced only nanorods through application of different capping agents owing to their preferred crystal growth, while the 3D networks led to rod and plate morphologies. Also, the catalytic performance of MOFs in an aldol-type condensation reaction was estimated. High and fast catalytic activity is detected in nanoscale rod-shaped catalysts.

A novel 3D pillar-layered metal-organic framework: Pore-size-dependent catalytic activity and CO2/N2 affinity

The structure–activity relationship plays the main role in the applicability of Metal-organic Frameworks (MOFs) in different areas including catalysis. Regarding to this herein a novel pillar-layered MOF (TMU-52) that is isostructural to our recently reported TMU-25 is introduced. The structure of this framework was analyzed using X-ray crystallography, FT-IR spectroscopy, Thermogravimetric and elemental analyses. According to the similar organic and inorganic backbone, a comparative study was done on catalytic manner of TMU-25 and TMU-52 toward in aldol-type condensation reaction. TMU-52 was designed through replacing the biphenyl core in the pillar linker of TMU-25 with phenyl group as a better candidate heterogeneous catalysis. The selectivity of the TMU-52 was higher owing to its narrower channels. CO2/N2 affinity of these structures was also investigated.

Stereochemistry in the Reaction of the myo-Inositol Phosphate Synthase Ortholog Ari2 during Aristeromycin Biosynthesis.

The myo-inositol-1-phosphate synthase (MIPS) ortholog Ari2, which is encoded in the aristeromycin biosynthetic gene cluster, catalyzes the formation of five-membered cyclitol phosphate using d-fructose 6-phosphate (F6P) as a substrate. To understand the stereochemistry during the Ari2 reaction in vivo, we carried out feeding experiments with (6S)-d-[6-2H1]- and (6R)-d-[6-2H1]glucose in the aristeromycin-producing strain Streptomyces citricolor. We observed retention of the 2H atom of (6S)-d-[6-2H1]glucose and no incorporation of the 2H atom from (6R)-d-[6-2H1]glucose in aristeromycin. This indicates that Ari2 abstracts the pro-R proton at C6 of F6P after oxidation of C5-OH by nicotinamide adenine dinucleotide (NAD+) to generate the enolate intermediate, which then attacks the C2 ketone to form the C-C bond via aldol-type condensation. The reaction of Ari2 with (6S)-d-[6-2H1]- and (6R)-d-[6-2H1]F6P in vitro exhibited identical stereochemistry compared with that observed during the feeding experiments. Furthermore, analysis of the crystal structure of Ari2, including NAD+ as a ligand, revealed the active site of Ari2 to be similar to that of MIPS of Mycobacterium tuberculosis, supporting the similarity of the reaction mechanisms of Ari2 and MIPS.

A Green Protocol for the Synthesis of α‐Diazo‐β‐hydroxyesters and One‐Pot Conversion to β‐Keto‐Esters and Imidazo[1,2‐a]pyridine‐3‐carboxylates

AbstractA new solvent cum reagent system comprising of water extract of banana ash and dimethylsulfoxide (WEB‐DMSO) has been engaged for the first time to promote the aldol type condensation reaction of aldehydes with ethyl diazoacetate. The condensation reaction has smoothly undergone producing a range of α‐diazo‐β‐hydroxy esters in good to excellent yields. The solvent system has been reused up to five times without loss of its catalytic activity. Further, two one‐pot sequential reactions have been developed in the same reaction medium. First, the methodology has been extended to synthesize β‐keto esters through Pd catalyzed 1,2‐hydrogen migration. Secondly, β‐keto esters have been converted to imidazo[1,2‐a]pyridine‐3‐carboxylates by using N‐bromosuccinimide and 2‐aminopyridines in a one‐pot fashion.

The LANCA three-component reaction to highly substituted β-ketoenamides - versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives.

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to β-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-β-ketoenamides. β-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of β-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of β-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile β-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key β-ketoenamides show a unique substitution pattern – not easily accomplishable by alternative methods – and therefore many subsequent reactions are possible.

Synthesis and characterization of cinnamylidene acetone – A study on tuning of band gap by vibrational spectroscopic tools

The title molecule Cinnamylidene acetone (CA) was synthesized through a single step base catalyzed aldol type condensation between acetone and cinnamaldehyde. The prepared molecule has been characterized using NMR (1H and 13C) spectral analysis, FTIR, UV–Vis and Elemental analysis. The complete vibrational characterization of the molecule was performed using experimental (FTIR and FT-Raman) spectra and calculations at DFT level. In order to carry out a detailed vibrational spectroscopic analysis of CA, Fourier Transform Infrared and Fourier Transform Raman spectra recorded in condensed phase were used. To determine the optimized geometry and vibrational wavenumbers, Density functional theory calculations in the B3LYP/6-31G** level have been carried out followed by scaling using the scaled quantum mechanical methodology. A root mean square deviation of 6.53 cm−1 has resulted from the scaled quantum mechanical treatment. The ultraviolet visible spectra of the title compound dissolved in various solvents were recorded in the range of 300–600 nm. The natural bond orbital and frontier molecular orbital analyses were also performed using B3LYP/6-31G** method. These studies revealed a reduction in the band gap of CA in comparison with that of cinnamaldehyde (CY).

Concise total syntheses of phelligridins A, C, and D.

We have established a concise and scalable synthetic pathway for phelligridins A (1), C (2) and D (3). The synthetic highlights were Suzuki–Miyaura coupling and aldol-type condensation of α-pyrone. Phelligridin A was synthesized in four steps, while phelligridins C and D were each synthesized in six steps. Furthermore, we have revealed that the whole structure is essential for the cytotoxicity of phelligridins.

Enantiomeric pairs of ternary copper(ii) complexes and their aldol-type condensation products: synthesis, characterization, and anticancer and epigenetic properties.

Chiral enantiomers [Cu(phen)(l-ser)(H2O)]NO31 and [Cu(phen)(d-ser)(H2O)]NO32 (ser = serinato) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz. l- and d-[Cu(phen)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0-2) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1-4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.

BF3·Et2O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects

We report novel insights into the cascade rearrangement of destabilized vinyl cations deriving from the BF3·Et2O-induced decomposition of cyclic α-diazo-β-hydroxy ketones in turn prepared by aldol-type condensation of cycloalkanones with diazoacetone. Complexation of the hydroxy group of the α-diazo-β-hydroxy compound with the Lewis acid is the first event, followed by the generation of the cycloalkanylidenediazonium salt that, after nitrogen loss, produces the highly reactive vinyl cation. The subsequent ring expansion results in the formation of a cycloalkenyl vinyl cation that affords the allylic cation by 1,2-methylene shift and ring contraction. The cation can then trap the solvent, the fluoride or the hydroxide released from the [BF3OH]− to afford different reaction products. The effect of both solvent and substrate ring size on products types and ratios were analyzed and discussed from a mechanistic point of view.

Synthesis and DSSC application of donor-acceptor stilbenoid dendrimers with triphenylamine as core and benzothiazole as surface unit

Abstract The π-conjugated donor-acceptor stilbenoid dendrimers are successfully synthesized in high yields by either Aldol-type condensation or Wittig reaction with triphenylamine as donor and benzothiazole as acceptor. The molar extinction coefficient increases with increase in the number of the conjugated π-bridges. All the stilbenoid dendrimers exhibit quasi-reversible oxidation reduction signal in cyclic voltammetry. The highly π-conjugated stilbenoid dendrimers exhibit better current generating capacity and light energy harvesting efficiency than the other dendrimers, when used as additives in dye-sensitized solar cells. Stilbenoid dendrimer 7 shows the maximum power conversion efficiency (ɳ) of 5.08%.

Efficient synthesis of chalcone-4′-sulfonyl chlorides and fluorides

A library of 4′-chloro- and 4′-fluorosulfonyl-substituted chalcones was prepared via the aldol-type condensation reactions of 4-acetylbenzene-1-sulfonyl halides with various aromatic aldehydes, either in absolute ethanol or glacial acetic acid, in the presence of dry HCl. This represents the first examples of chalcone sulfonyl halides in which the phenone ring bears one of these functional groups. The reactivity of the chalcone sulfonyl halides were strongly dependent on the styrene ring substituents; sulfonyl chlorides reacted with most nucleophiles (e.g. amines, alcohols), while sulfonyl fluorides reacted only with charged nucleophiles (e.g. phenolates).