Wolff-Kishner Research Articles

Synthesis, Conformational Properties and DFT Computational Studies of [3]Metacyclo[3](1,3)pyrenophanes

AbstractTwo new 6,17‐di‐tert‐butyl‐[3]metacyclo[3](1,3)‐pyrenophane‐2,11‐diones 8 a–b were synthesized by the coupling reaction of 1,3‐bis(bromomethyl)‐7‐tert‐butylpyrene 5 with the corresponding TosMIC‐adducts 7 a–b in CH2Cl2 and water under phase‐transfer conditions, followed by acid treatment. Wolff–Kishner reduction of 8 a–b afforded in good yields the corresponding 6,17‐di‐tert‐butyl‐[3]metacyclo[3](1,3)‐pyrenophanes 9 a–b. The spectroscopic data of both 8 a and 8 b show that they adopt anti‐conformations. In contrast, both pyrenophanes 9 a and 9 b adopt syn‐conformations. Variable‐temperature 1H NMR studies were carried out to determine the conformational behavior of the pyrenophanes. A single crystal X‐ray structure of 8 a shows that it also has an anti‐conformation in the solid state. Density functional theory (DFT) computations of 8 a–b and 9 a–b were used to determine their energy‐minimized structures and the total energies of their different conformers.

Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity.

Amphipathic perylene derivatives are broad-spectrum antivirals against enveloped viruses that act as fusion inhibitors in a light-dependent manner. The compounds target the lipid bilayer of the viral envelope using the lipophilic perylene moiety and photogenerating singlet oxygen, thereby causing damage to unsaturated lipids. Previous studies show that variation of the polar part of the molecule is important for antiviral activity. Here, we report modification of the lipophilic part of the molecule, perylene, by the introduction of 4-, 8-, and 12-carbon alkyls into position 9(10) of the perylene residue. Using Friedel-Crafts acylation and Wolff-Kishner reduction, three 3-acetyl-9(10)-alkylperylenes were synthesized from perylene and used to prepare 9 nucleoside and 12 non-nucleoside amphipathic derivatives. These compounds were characterized as fluorophores and singlet oxygen generators, as well as tested as antivirals against herpes virus-1 (HSV-1) and vesicular stomatitis virus (VSV), both known for causing superficial skin/mucosa lesions and thus serving as suitable candidates for photodynamic therapy. The results suggest that derivatives with a short alkyl chain (butyl) have strong antiviral activity, whereas the introduction of longer alkyl substituents (n = 8 and 12) to the perylenyethynyl scaffold results in a dramatic reduction of antiviral activity. This phenomenon is likely attributable to the increased lipophilicity of the compounds and their ability to form insoluble aggregates. Moreover, molecular dynamic studies revealed that alkylated perylene derivatives are predominately located closer to the middle of the bilayer compared to non-alkylated derivatives. The predicted probability of superficial positioning correlated with antiviral activity, suggesting that singlet oxygen generation is achieved in the subsurface layer of the membrane, where the perylene group is more accessible to dissolved oxygen.

Decomposition of Alkynyl Hydrazones: Synthesis of Allenoates, Dihaloallenoates, and Angularly Fused Tricyclic Azepines.

An unprecedented decomposition of unprotected alkynyl hydrazones is attempted that has provided allenoates, tetrasubstituted α,γ-dihaloallenoates, and functionalized tricyclic azepines. A reaction of alkynyl hydrazones with N-halosuccinimides captures the electrophile in 2-fold that delivers fully substituted dibromo- and diiodoallenoates in good yields. In addition, a DABCO-promoted Wolff-Kishner reduction of hydrazones, followed by isomerization, provides versatile allenoates under mild conditions. In contrast, a similar decomposition with ambiphilic DBU furnishes a completely different tricyclic azepine scaffold in excellent yield and diastereoselectivity.

HOME-Chemistry: hydrazone as organo-metallic equivalent

Abstract The modern synthetic chemistry heavily relies on the use of stoichiometric organometallic reagents to react with various electrophiles. The dependence on stoichiometric quantities of metals and often organic halides as precursors, in turn both produces copious amounts of metal halide wastes as well as leads to concerns on future metal sustainability. Inspired by the classical Wolff-Kishner reduction, our lab has recently developed a general strategy of HOME-Chemistry , directly using naturally abundant alcohols/aldehydes and ketones as feedstocks with the releasing of innocuous water and nitrogen gas. These reactions include 1,2-carbonyl/imine addition, conjugate addition, carboxylation, olefination, cross-coupling arylation/allylation, alkylation, hydroalkylation and C-heteroatom formations. This article provides a brief summary on this chemistry.

Efficient Synthesis of Novel 1-Substituted β- Carboline Derivatives via Pictet-Spengler Cyclization of 5-Hydroxy-L-Tryptophan

A facile synthesis of novel 1-substituted β-carboline derivatives by using three efficient reaction steps was described. The synthetic route began with the construction of β-carboline frameworks involving the coupling of 5-hydroxy-L-tryptophan with different substituted phenylglyoxal via Pictet-Spengler condensation. Subsequent reduction of carbonyl functionality on carbon-7’ by using Wolff-Kishner reaction followed by N-alkylation afforded a practical access to a series of 1-substituted β-carboline derivatives in moderate yields. These novel derivatives were successfully synthesized without the use of expensive metal catalyst, prolonged reaction hours or critical reaction conditions. The molecular structures of all synthesized derivatives were confirmed by infrared (IR), gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy.

Synthesis and characterization of alkaloid derived hydrazones and their metal (II) complexes

Abstract Alkaloids have been known overtime to have medicinal uses. Exploring alkaloid derived hydrazones and their complexes as potential therapeutic agents with a view to improving the medicinal uses of alkaloids are imperative. 1,8-dichloroacridone hydrazone hydrochloride, 1-chloro pilocarpine nitrate-3-chlorophenyl hydrazone and 1-phenethyl-4-piperidone formyl hydrazone ligands were synthesized via Wolff–Kishner condensation reaction. Five metal (II) complexes of cobalt, nickel and manganese were prepared by stirring the ligands with the respective metal salts. The ligands and complexes were characterized using elemental analyses, molar conductivity, FTIR, 1H and 13C nmr, UV–Vis spectra, melting point and solubility. Antimicrobial activities of the ligands and their complexes were tested against four bacteria (Staphylococcus aureus, Streptococcus faecalis Escherichia coli, Salmonella paratyphimurium) and a fungus (Candida albican). The molar conductance values indicate that they are 1:1 and 1:2 type electrolytes while the elemental analyses of the complexes reveals a 1:1 metal to ligand stoichiometry. The relevant IR bands suggest coordination is through the C=N, C=O, N=C–O and C–N groups. Both 1H and 13C nmr corroborated the elemental analysis while the UV–Vis reveals intra-ligand charge transfer while the complexes exhibited the expected metal transitions bands. A proposed octahedral geometry is supported by spectral data. Only 1, 8-dichloroacridonehydrazone hydrochloride ligand was found to be active against all the organisms. Cobalt and nickel complexes of 1,8-dichloroacridonehydrazone hydrochloride were active against S. paratyphimurium and S. aureus, respectively, while cobalt complex of 1-chloropilocarpinenitrate-3-chlorophenylhydrazone was active against S. faecalis and S. paratyphimurium. The minimum inhibitory concentrations (MIC) were also recorded.

Synthetic and Reactions Routes to Tetrahydrothieno[3,2-b]Quinoline Derivatives (Part IV)

Abstract:This review describes the synthesis and chemical reactivity of tetrahydrothieno[3,2-b] quinoline derivatives from through many of the reagents such as; 1, 2-dihydropyridine-3-carbonitrile; 1,6-dihydropyrimidine-5-carbonitrile; 2,3-dihydropyridazine-4-carbonitrile; 3-amino-thiophene-2-carboxylate; 3-amino-thiophene-2-carbonitrile; 3,4-diaminothieno[2,3-b] thiophene-2,5-dicarbo- nitrile; 2-(3-bromo-1-iodoisoquinolin-8-yl) benzonitrile and 3-mercapto-benzo[g]quinolin-4(1H)-one derivatives. The synthesis of the tetrahydrothieno [3, 2-b] quinoline derivatives were explained through the following chemical reactions: Aldol condensation, alkylation, cyclocondensation, dehydration, chlorination, Wolff-Kishner reduction, acylation, Friedlander reaction and intramolecular cyclization.

Ruthenium(II)-catalyzed deoxygenation of ketones.

The classical Wolff-Kishner reduction plays a key role in organic synthesis to convert carbonyl functionalities into methylene groups; however, it generally requires harsh reaction conditions and a strategy with wider applications demands further development. Herein, a ruthenium-catalyzed Wolff-Kishner type reduction of ketones is developed with 31 examples under mild conditions. This strategy tolerates aryl and alkyl ketones with reactive functional groups including halogens, hydroxyls, carboxylic acid, unsaturated functional groups, and so on. The corresponding methylene products were obtained in 32% to 95% yields while using water or methanol as solvents.

Synthesis, structures and DFT calculations of 9-Methoxy[3.3] metaparacyclophanes and their Lewis acid–catalyzed reactivity

The synthesis of 6-tert-butyl-9-methoxy-14,15,17,18-tetramethyl[3.3]MPCP 11, via the TosMIC cyclo-condensation reaction followed by Wolff-Kishner reduction is described. Lewis acid (AlCl3-MeNO2) catalyzed reactions of 11 led only to de-tertbutylation and demethylation of the C(9)-methoxy group. A DFT analysis of the conformations of all of the synthesized [3.3]MPCPs products is also presented and a study of their Lewis acid-mediated properties. The contrast between the reactions of 11 with those of the corresponding [2.2]MPCPs is presented as is a DFT computational analysis of the various conformers of the molecules described herein.

Catalytic asymmetric total syntheses of (R)-bgugaine and (R)-irnidine

An enantioselective total synthesis of ( R )-bgugaine and the first enantioselective total synthesis of ( R )-irnidine are reported. The key steps are the asymmetric ‘clip-cycle’ formation of the pyrrolidine ring in 94:6 e.r., which is common to both natural products, followed by Liebeskind–Srogl coupling and Wolf-Kishner reduction. The route yields ( R )-bgugaine and ( R )-irnidine in 6 steps and in overall yields of 33% and 18% respectively.

Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification.

We report a novel reductive interrupted Fischer indolization process for the concise assembly of the 20-oxoaspidospermidine framework. This rapid complexity generating route paves the way toward various dihydroindole Aspidosperma alkaloids with different C-5 side chain redox patterns. The end-game redox modulations were accomplished by modified Wolff–Kishner reaction and photo-Wolff rearrangement, enabling the total synthesis of (−)-aspidospermidine, (−)-limaspermidine, and (+)-17-demethoxy-N-acetylcylindrocarine and the formal total synthesis of (−)-1-acetylaspidoalbidine.

Mitigating Chemical Paths to Capacity Fade in Organic Flow Batteries

In this issue of Chem, Michael Aziz, Roy Gordon, and collaborators report soluble, functionalized anthraquinones that serve to deactivate and recover from chemical reactions that lead to capacity fade in organic redox flow battery electrolytes. The result is an unprecedented low rate of capacity fade of

Synthesis, characterization, antibacterial and DNA photocleavage study of 1-(2-Arenethyl)-3, 5-dimethyl-1H-pyrazoles

Abstract 1-(2-Arenethyl)-3, 5-dimethyl-1H-pyrazoles (4a-g) were obtained by Wolff-Kishner reduction of 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-1-arylethanones (3a-g). The synthesized compounds were characterized by analyzing their IR, 1H, and 13C-NMR spectral data. Intermediates (3a-g) were synthesized by the solid phase reaction of 3, 5-dimethylpyrazole with different substituted phenacyl bromides under basic condition by adopting reported procedure. All synthesized compounds were screened in vitro for their anti-bacterial potential against four bacterial strains and it was found that the compounds 4c and 4g bearing methoxy and nitro group, respectively, exhibited good level of inhibitory potential which was about 25% of the standard drug, Ciprofloxacin- against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains. Further, DNA photocleavage ability was also explored and it was observed that compounds bearing halogen group (4d, 4e and 4f) displayed good DNA photocleavage activity.

Umpolung Difunctionalization of Carbonyls via Visible-Light Photoredox Catalytic Radical-Carbanion Relay.

The combination of photoredox catalysis with the Wolff–Kishner (WK) reaction allows the difunctionalization of carbonyl groups by a radical-carbanion relay sequence (photo-Wolff–Kishner reaction). Photoredox initiated radical addition to N-sulfonylhydrazones yields α-functionalized carbanions following the WK-type mechanism. With sulfur-centered radicals, the carbanions are further functionalized by reaction with electrophiles including CO2 and aldehydes, whereas CF3 radical addition furnishes a wide range of gem-difluoroalkenes through β-fluoride elimination of the generated α-CF3 carbanions. More than 80 substrate examples demonstrate the broad applicability of this reaction sequence. A series of investigations including radical inhibition, deuterium labeling, fluorescence quenching, cyclic voltammetry, and control experiments support the proposed radical-carbanion relay mechanism.

Concise total syntheses of (+)- and (−)-ar-macrocarpene

Concise catalytic asymmetric total syntheses of both the enantiomers of aromatic sesquiterpenes, (+)-ar-macrocarpene (1) and (–)-ar-macrocarpene (ent-1) is featured in 4 steps, 66.0% overall yields from commercially available 5,5-dimethylcyclohexane 1,3-dione 13. The enantioenriched 5,5-dimethyl-3-(p-tolyl)cyclohexanone 10 is found to be the key intermediate, which was obtained from catalytic enantioselective p-tolylboronic acid addition onto enone 11 using Pd(II)-(S,S)-DUPHOS (ent-L5) in >99% ee. Finally, a Wolf-Kishner reduction of cyclohexanone 10 completes straightforward access to naturally occurring sesquiterpenoid, (+)-ar-macrocarpene (1).

Scalable Wolff–Kishner Reductions in Extreme Process Windows Using a Silicon Carbide Flow Reactor

A safe and scalable continuous flow strategy for Wolff–Kishner reductions that employs methanol as the solvent has been developed. The use of low-cost hydrazine as the reducing agent in combination with a caustic base provides an atom-efficient, environmentally friendly method for the deoxygenation of aldehydes and ketones to alkanes. Because of the required harsh and corrosive reaction conditions (200 °C, 50 bar), reactor materials such as stainless steel, glass, or any type of polymer have compatibility problems, rendering this process problematic on a production scale. The use of corrosion-resistant silicon carbide (SiC) as the reactor material opens up the possibility of performing Wolff–Kishner reductions on scale with a considerably improved safety profile. Methanol as the solvent significantly simplifies the workup procedure compared with the generally employed high-boiling solvents such as diethylene glycol. The continuous flow protocol was applied to a number of substrates and provided the desire...

Synthesis, Crystal Structure, DFT Calculations and Hirshfeld Surface Analysis of 5-Bromo-1-decyl-2,3-dihydro-1H- indolin-2-one

In the title compound, C18H26BrNO, the dihydroindolone unit is slightly twisted. The n-decyl chains are fully extended and intercalate to form hydrophobic regions. The polar head groups are associated through C–H···O hydrogen bonds and C–Br···π(ring) interactions. In this study, we efficiently synthesized 5-bromo-1-decylindolin-2-one without isolation of the intermediate hydrazone by the Wolff–Kishner reduction of 2-(5-bromo-1-decyl-2-oxo-2,3-dihydro-1H-indol-3-ylidene)propanedinitrile with hydrazine hydrate.

An Old Dog with New Tricks: Enjoin Wolff–Kishner Reduction for Alcohol Deoxygenation and C–C Bond Formations

The Wolff–Kishner reduction, discovered in the early 1910s, is a fundamental and effective tool to convert carbonyls into methylenes via deoxygenation under strongly basic conditions. For over a century, numerous valuable chemical products have been synthesized by this classical method. The reaction proceeds via the reversible formation of hydrazone followed by deprotonation with the strong base to give an N-anionic intermediate, which affords the deoxygenation product upon denitrogenation and protonation. By examining the mechanistic pathway of this century old classical carbonyl deoxygenation, we envisioned and subsequently developed two unprecedented new types of chemical transformations: a) alcohol deoxygenation and b) C–C bond formations with various electrophiles including Grignard-type reaction, conjugate addition, olefination, and diverse cross-coupling reactions.1 Introduction2 Background3 Alcohol Deoxygenation3.1 Ir-Catalyzed Alcohol Deoxygenation3.2 Ru-Catalyzed Alcohol Deoxygenation3.3 Mn-Catalyzed Alcohol Deoxygenation4 Grignard-Type Reactions4.1 Ru-Catalyzed Addition of Hydrazones with Aldehydes and Ketones4.2 Ru-Catalyzed Addition of Hydrazone with Imines4.3 Ru-Catalyzed Addition of Hydrazone with CO2 4.4 Fe-Catalyzed Addition of Hydrazones5 Conjugate Addition Reactions5.1 Ru-Catalyzed Conjugate Addition Reactions5.2 Fe-Catalyzed Conjugate Addition Reactions6 Cross-Coupling Reactions6.1 Ni-Catalyzed Negishi-type Coupling6.2 Pd-Catalyzed Tsuji–Trost Alkylation Reaction7 Other Reactions7.1 Olefination7.2 Heck-Type Reaction7.3 Ullmann-Type Reaction8 Conclusion and Outlook

Bimetallic Nanoparticles in Supported Ionic Liquid Phases as Multifunctional Catalysts for the Selective Hydrodeoxygenation of Aromatic Substrates.

Bimetallic iron–ruthenium nanoparticles embedded in an acidic supported ionic liquid phase (FeRu@SILP+IL‐SO3H) act as multifunctional catalysts for the selective hydrodeoxygenation of carbonyl groups in aromatic substrates. The catalyst material is assembled systematically from molecular components to combine the acid and metal sites that allow hydrogenolysis of the C=O bonds without hydrogenation of the aromatic ring. The resulting materials possess high activity and stability for the catalytic hydrodeoxygenation of C=O groups to CH2 units in a variety of substituted aromatic ketones and, hence, provide an effective and benign alternative to traditional Clemmensen and Wolff–Kishner reductions, which require stoichiometric reagents. The molecular design of the FeRu@SILP+IL‐SO3H materials opens a general approach to multifunctional catalytic systems (MM′@SILP+IL‐func).

Bimetallic Nanoparticles in Supported Ionic Liquid Phases as Multifunctional Catalysts for the Selective Hydrodeoxygenation of Aromatic Substrates

AbstractBimetallic iron–ruthenium nanoparticles embedded in an acidic supported ionic liquid phase (FeRu@SILP+IL‐SO3H) act as multifunctional catalysts for the selective hydrodeoxygenation of carbonyl groups in aromatic substrates. The catalyst material is assembled systematically from molecular components to combine the acid and metal sites that allow hydrogenolysis of the C=O bonds without hydrogenation of the aromatic ring. The resulting materials possess high activity and stability for the catalytic hydrodeoxygenation of C=O groups to CH2 units in a variety of substituted aromatic ketones and, hence, provide an effective and benign alternative to traditional Clemmensen and Wolff–Kishner reductions, which require stoichiometric reagents. The molecular design of the FeRu@SILP+IL‐SO3H materials opens a general approach to multifunctional catalytic systems (MM′@SILP+IL‐func).