Wolff-Kishner Research Articles

Preparation of ABNO on Scale and Analysis by Quantitative Paramagnetic NMR

A practical, safe, and scalable synthesis of the stable nitro-oxide radical catalyst ABNO was developed. This process is chromatography-free and avoids the Wolff–Kishner reduction. 1H NMR data for this paramagnetic compound were obtained that allowed an assessment of its chemical purity. Impact sensitivity test data for solid ABNO are also reported.

Nickel-catalyzed cross-coupling of aldehydes with aryl halides via hydrazone intermediates.

Traditional cross-couplings require stoichiometric organometallic reagents. A novel nickel-catalyzed cross-coupling reaction between aldehydes and aryl halides via hydrazone intermediates has been developed, merging the Wolff-Kishner reduction and the classical cross-coupling reactions. Aromatic aldehydes, aryl iodides and aryl bromides are especially effective in this new cross-coupling chemistry.

Synthesis, Conformational Properties and DFT Computational Studies of Polymethyl‐Substituted [3.3]Metacyclophanes

AbstractPolymethyl substituted [3.3]metacyclophanes (MCPs) 4 a–d, were synthesized by the TosMIC coupling method followed by Wolff–Kishner reduction of the corresponding polymethyl‐substituted [3.3]MCP‐2,11‐diones (3 a–d). 1H NMR spectroscopy reveals that both 5,6,7,14,16‐pentamethyl[3.3]MCP‐2,11‐diones (3 a and 3 b) undergo conformational changes relative to the NMR time scale in solution at room temperature but that the anti conformer is preferred. Reduced 5,6,7,14,16‐pentamethyl[3.3]MCP (4 a and 4 b) adopt fixed syn–conformations in solution at room temperature. X‐ray analysis showed that in the solid state, 5,6,7,14,15,16‐hexamethyl[3.3]MCP‐2,11‐dione 3 a adopts the anti‐conformation and reduced 5,6,7,14,16‐pentamethyl[3.3]MCP‐2,11‐diones 4 b adopts a syn‐(chair‐chair) conformation. A series of electrophilic substitution reactions such as formylation, acetylation and nitration were carried out with 5,6,7,14,16‐pentamethyl[3.3]MCP 4 b to study their conformational isomers. The formyl, acetyl and nitro derivatives of 5,6,7,14,16‐pentamethyl[3.3]MCP are fixed to adopt syn‐conformations in solution at room temperature. The conformational isomers of the metacyclophanes and derivatives obtained from density functional theory (DFT) methods were used to estimate the total energies and energy minimized structures of the different conformations.

Synthesis and characterization of styryl-BODIPY derivatives for monitoring in vitro Tau aggregation

New synthetic strategy to synthesize α-methyl BODIPY derivatives from dipyrromethanes is reported. The method involves regioselective formylation of dipyrromethane followed by modified Wolff-Kishner reduction. The photophysical, electrochemical and computational studies of α-methyl BODIPY derivatives have been investigated in detail. The α-methyl BODIPY derivative was utilized further to prepare biologically important functionalized styryl-BODIPY library in high yield using microwave assisted Knoevenagel condensation. These synthesized dye derivatives were screened to find a potential candidate to track real-time in vitro tau protein fibrillization. Quinoxaline functionalized styryl-BODIPY derivative (5i) exhibited significant fluorescence enhancement upon binding to tau fibrils. Furthermore, tau-5i conjugate was systematically characterized by emission, aggregation kinetics, fluorescence microscopy and Atomic Force Microscopy techniques. Cell culture studies proved that compound 5i was cell permeable and non-toxic to live cells. In addition, a mechanism by which 5i interacts with tau fibrils has been elucidated which can be potentially exploited to further develop reporting dyes and inhibitors for tau aggregates.

Total Synthesis and Antifungal Activity of Palmarumycin CP17 and Its Methoxy Analogues.

Total synthesis of naturally occurring spirobisnaphthalene palmarumycin CP17 and its methoxy analogues was first achieved through Friedel-Crafts acylation, Wolff-Kishner reduction, intramolecular cyclization, ketalization, benzylic oxidation, and demethylation using the inexpensive and readily available methoxybenzene, 1,2-dimethoxybenzene and 1,4-dimethoxybenzene and 1,8-dihydroxynaphthalene as raw materials. Demethylation with (CH3)3SiI at ambient temperature resulted in ring A aromatization and acetal cleavage to give rise to binaphthyl ethers. The antifungal activities of these spirobisnaphthalene derivatives were evaluated, and the results revealed that 5 and 9b exhibit EC50 values of 9.34 µg/mL and 12.35 µg/mL, respectively, against P. piricola.

ChemInform Abstract: Methyl Hydrazinocarboxylate as a Practical Alternative to Hydrazine in the Wolff—Kishner Reaction.

Herein we describe a facile protocol for the reduction of aromatic ketones and aldehydes to the corresponding methylene unit. The procedure involves isolation of a carbomethoxyhydrazone intermediate that is easily decomposed to the reduced product without the requirement for large quantities of pernicious hydrazine.

Convenient synthesis, anticancer evaluation and QSAR studies of some thiazole tethered indenopyrazoles

A convenient one-pot synthesis of twelve new thiazole tethered indeno[1,2-c]pyrazol-4-ones (3a–3l) was carried out by three-component reaction between 1,3-diketones, thiosemicarbazide and α-bromoketones in high yields. Wolff-Kishner reduction of indeno[1,2-c]pyrazol-4-ones (3a–3l) led to the formation of corresponding indeno[1,2-c]pyrazoles (4a–4l) in moderate-to-good yields. The structures of all the synthesized indenopyrazoles were elucidated by IR, 1H NMR, 13C NMR and mass spectral techniques. In vitro cytotoxicity of thiazole tethered indenopyrazoles (3a–3l & 4a–4l) was evaluated against different human cancer cell lines, viz. human renal carcinoma (A498), human colorectal adenocarcinoma (HT29), human breast adenocarcinoma (MCF-7), human hepatocellular carcinoma (HepG2) and normal cell line, i.e., normal rat kidney epithelial (NRK). Among all the tested derivatives, 4a, 4d and 4h exhibited better activity against HT29 cancer cell line. The statistically significant QSAR models were developed for all the cancer cell lines using multiple linear regression analysis to understand the observed activity trend on structural basis.

A Hydrazine-Free Wolff–Kishner Reaction Suitable for an Undergraduate Laboratory

A Wolff–Kishner reaction that does not require hydrazine has been developed. The reaction sequence has two steps: formation of a carbomethoxyhydrazone from methyl hydrazinocarboxylate and acetophenone, then decomposition of this intermediate by treatment with potassium hydroxide in triethylene glycol. Purification is by filtration through a plug of silica encased in the barrel of a plastic syringe. The reaction sequence can be completed within a day-long laboratory class (8 h).

Synthesis and conformational studies of 9-benzyloxy-18-substituted [3.3]metacyclophanes

A series of syn-[3.3]metacyclophanes (MCPs) containing internal substituted benzyloxy group have been synthesized by the modified TosMIC coupling reaction followed by acid treatment and Wolff–Kishner reduction. anti-Mono- and di-benzyloxy[3.3]MCPs are synthesized by O-benzylation of the corresponding hydroxy[3.3]MCPs, which are obtained by demethylation of methoxy[3.3]MCPs with BBr3at room temperature. An interesting and intriguing result was obtained when syn-6,15-di-tert-butyl-9-methoxy-18-methyl[3.3]MCP-2,11-dione was treated with TMSI to afford the formation of a dihydrobenzofuran ring by a nucleophilic intramolecular cyclization reaction. The1H NMR and X-ray analysis of 6a confirms that it adopts a syn (chair–chair) conformation in both solution and solid state.

Methyl Hydrazinocarboxylate as a Practical Alternative to Hydrazine in the Wolff–Kishner Reaction

Herein we describe a facile protocol for the reduction of aromatic ketones and aldehydes to the corresponding methylene unit. The procedure involves isolation of a carbomethoxyhydrazone intermediate that is easily decomposed to the reduced product without the requirement for large quantities of pernicious hydrazine.

Synthesis and Myelostimulatory Activity of a Number of 3,7-Diazabicyclo[3.3.1]Nonane Derivatives

Mannich condensation was used to synthesize new bispidinones, Wolff-Kishner reduction of which produced the corresponding bispidanes. 1H NMR spectroscopy studies showed that these existed in the double chair conformation. The myelostimulatory activity of the compounds synthesized here was assessed.

Application of palladium-catalyzed carboxyl anhydride-boronic acid cross coupling in the synthesis of novel bile acids analogs with modified side chains

Palladium-catalyzed cross coupling of 4-methoxycarbonyl phenyboronic acid with acetylated bile acids in which the carboxyl functions was activated by formation of a mixed anhydride with pivalic anhydride afforded the cross coupled compounds, which were converted in novel side chain modified bile acids by one pot carbonyl reduction/removal of the protecting acetyl groups by Wolff–Kishner reduction. Unambiguous assignments of the NMR signals and crystal characterization of the heretofore unknown compounds are provided.

Use of solar energy for biodiesel production and use of biodiesel waste as a green reaction solvent

Abstract Due to the depletion of fossil fuel energy sources, new alternative energy sources are becoming prevalent in our society. Biodiesel has been recognized as an attractive replacement for depleting energy sources since it is produced mainly from vegetable oils and animal fats, is a renewable resource, and is non-toxic. The synthesis of biodiesel involves heating a triglyceride with methanol (or ethanol) under strongly basic conditions. Since fossil fuels are used for electrical energy in the United States, the amount of electricity required to heat this reaction requires the use of non-renewable resources. An effective means for minimizing the amount of electricity needed to drive chemical reactions to completion is proposed through the use of solar parabolic reflectors. In this study, a technique was developed to incorporate recently proposed solar reflectors developed from satellite dishes into the synthetic procedure for biodiesel. Through the use of our technique, the generation of carbon dioxide waste during biodiesel production has been eliminated. Another area of environmental concern in biodiesel production is the generation of waste by-products (glycerol). A technique has been developed that incorporates the use of recovered biodiesel waste glycerol as the solvent system for Wolff-Kishner reduction reactions. The reduction of isobutyryl chloride has been performed successfully using biodiesel waste glycerol as the solvent system and solar irradiation as the heat source for the chemical reaction.

Gas Phase Thermal Reactions of exo-8-Cyclopropyl-bicyclo[4.2.0]oct-2-ene (1-exo)

The title compound 1-exo (with minor amounts of its C8 epimer 1-endo) was prepared by Wolff-Kishner reduction of the cycloadduct of 1,3-cyclohexadiene and cyclopropylketene. The [1,3]-migration product 2-endo was synthesized by efficient selective cyclopropanation of endo-5-vinylbicyclo[2.2.2]oct-2-ene at the exocyclic π-bond. Gas phase thermal reactions of 1-exo afforded C8 epimerization to 1-endo, [1,3]- migrations to 2-exo and 2-endo, direct fragmentation to cyclohexadiene and vinylcyclopropane, and CPC rearrangement in the following relative kinetic order: kep > k13 > kf > kCPC.

Substrate dependent reaction channels of the Wolff–Kishner reduction reaction: A theoretical study

Wolff–Kishner reduction reactions were investigated by DFT calculations for the first time. B3LYP/6-311+G(d,p) SCRF=(PCM, solvent = 1,2-ethanediol) optimizations were carried out. To investigate the role of the base catalyst, the base-free reaction was examined by the use of acetone, hydrazine (H2N–NH2) and (H2O)8. A ready reaction channel of acetone → acetone hydrazine (Me2C=N–NH2) was obtained. The channel involves two likely proton-transfer routes. However, it was found that the base-free reaction was unlikely at the N2 extrusion step from the isopropyl diimine intermediate (Me2C(H)–N=N–H). Two base-catalyzed reactions were investigated by models of the ketone, H2N–NH2 and OH−(H2O)7. Here, ketones are acetone and acetophenone. While routes of the ketone → hydrazone → diimine are similar, those from the diimines are different. From the isopropyl diimine, the N2 extrusion and the C–H bond formation takes place concomitantly. The concomitance leads to the propane product concertedly. From the (1-phenyl)ethyl substituted diimine, a carbanion intermediate is formed. The para carbon of the phenyl ring of the anion is subject to the protonation, which leads to a 3-ethylidene-1,4-cyclohexadiene intermediate. Its [1,5]-hydrogen migration gives the ethylbenzene product. For both ketone substrates, the diimines undergoing E2 reactions were found to be key intermediates.

Rapid Wolff–Kishner reductions in a silicon carbide microreactor

Wolff–Kishner reductions are performed in a novel silicon carbide microreactor. Greatly reduced reaction times and safer operation are achieved, giving high yields without requiring a large excess of hydrazine. The corrosion resistance of silicon carbide avoids the problematic reactor compatibility issues that arise when Wolff–Kishner reductions are done in glass or stainless steel reactors. With only nitrogen gas and water as by-products, this opens the possibility of performing selective, large scale ketone reductions without the generation of hazardous waste streams.

A simple synthesis of truxene, a building block for optoelectronics and fullerene fragments

Truxene was efficiently synthesized by reduction of truxenone with excess hydrazine hydrate in diethylene glycol at 180°C without added base, a variation of the Huang-Minlon Wolff–Kishner reduction. The proposed mechanism highlights hydrazine as a nucleophile and a base, extracting protons from the hydrazone and diazene intermediates.

Iridium‐Catalyzed Direct Dehydroxylation of Alcohols

AbstractIridium‐catalyzed direct dehydroxylation of alcohols with hydrazine was developed through a combination of the oxidation of alcohols and the Wolff–Kishner reduction. This protocol is simple to perform and highly efficient for a series of primary, benzylic and allylic alcohols.

Facile one-step hydrazine-assisted solvothermal synthesis of nitrogen-doped reduced graphene oxide: reduction effect and mechanisms

Homogeneous colloidal dispersions of nitrogen-doped graphene in N,N-dimethyformamide (DMF) were readily prepared through a facile hydrazine-assisted solvothermal reduction method. The reduced graphene oxide (RGO) sample, prepared at a weight ratio of hydrazine to graphene oxide (GO) of 1.4 : 1 at 180 °C, was found to possess the highest conductivity (2716.2 S m−1) and good dispersibility (0.5 mg mL−1). This work has not only developed an efficient route to prepare high-quality graphene, but also provides a systematic elucidation of the reaction mechanism for the de-oxygenation of GO based on product characterization. It was found that all of the oxygen-containing groups were reduced by hydrazine-assisted solvothermal reduction. The deoxygenation of GO and re-establishment of the conjugated graphene network were significantly promoted by hydrazine de-epoxidation, a Wolff–Kishner–Huang-type reduction, as well as reactions between metastable NHNH2 and hydroxyl groups. The ease of synthesis of nitrogen-doped RGO with both high conductivity and excellent dispersibility will greatly facilitate potential applications.

Short syntheses of (+)-ferruginol from (+)-dehydroabietylamine

Short syntheses of bioactive (+)-ferruginol in five or six synthetic steps starting from commercially available (+)-dehydroabietylamine are described. The oxygenated function at C12 was introduced via a Friedel–Crafts acylation of N-phthaloyldehydroabietylamine followed by Baeyer–Villiger oxidation. Then, overall deprotection of functional groups, reductive deamination or biomimetic oxidative deamination, and final Wolff–Kishner reduction provided (+)-ferruginol in 21 and 23% overall yields, respectively.