Methylene Reagents Research Articles

Sulfur Activated α-Methylene Reagents in Asymmetric Catalysis

Sulfur Activated α-Methylene Reagents in Asymmetric Catalysis

NiO Nanoparticles: An Efficient Catalyst for the Multicomponent One‐Pot Synthesis of Novel Spiro and Condensed Indole Derivatives

An efficient catalytic protocol for the synthesis of novel spiro[indoline‐3,4′‐pyrano[2,3‐c]thiazole]carbonitriles and condensed thiazolo[5′′,4′′:5′,6′]pyrano[4′,3′:3,4]furo[2,3‐b]indole derivatives is developed in a one‐pot three‐component approach involving substituted 1H‐indole‐2,3‐diones, activated methylene reagent, and 2‐thioxo‐4‐thiazolidinone under conventional heating and microwave irradiation. This paper describes the use of NiO nanoparticles as catalyst for the synthesis of novel spiro and condensed indole derivatives by Knoevenagel condensation followed by Michael addition. The advantageous features of this methodology are operational simplicity, high yield processing, and easy handling. The particle size of NiO nanoparticle was determined by XRD. After reaction course, NiO nanoparticles can be recycled and reused without any apparent loss of activity.

C–H Insertion Catalyzed by Tetratolylporphyrinato Methyliridium via a Metal–Carbene Intermediate

C–H insertion reactions between different substrates and diazo reagents were catalyzed by tetratolylporphyrinato methyliridium (Ir(TTP)CH3). The highest yields were achieved for reactions between the bulky diazo reagent methyl 2-phenyldiazoacetate (MPDA) and substrates containing electron-rich C–H bonds. An intermediate metalloporphyrin complex was identified as a metal–carbene complex, Ir(TTP)(═C[Ph]CO2CH3)(CH3) (4), using 1H NMR and UV/vis absorption spectroscopy. The presence of 4 was further supported by computationally modeling the absorption spectra with time-dependent DFT (6-31G(d,p)/SBKJC basis set, PBE0 functional). Kinetic studies for C–H insertion reactions using different substrates showed substantial differences in the rate of MPDA consumption, suggesting that carbene transfer is rate-limiting. Furthermore, primary kinetic isotope effects of 3.7 ± 0.3 and 2.7 ± 0.4 were measured using toluene and cyclohexane, respectively. These data are consistent with a mechanism that involves direct C–H in...

Condensation Reactions of 3-Oxo-2-arylhydrazonopropanals with Active Methylene Reagents: Formation of 2-Hydroxy- and 2-Amino-6-substituted-5-arylazonicotinates and Pyrido[3,2-c]cinnolines via 6π-Electrocyclization Reactions

3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either 2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino-6-phenyl-5-p-tolyl-azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly, other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles 2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3-phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2–c]cinnoline-3-carboxylate (11), via a novel 6π-electrocyclization pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a–c to yield pyridazinones 13a–c.

Seeking a Mechanistic Analogue of the Water–Gas Shift Reaction: Carboxamido Ligand Formation and Isocyanate Elimination from Complexes Containing the Tp′PtMe Fragment

A series of stable, isolable Tp'Pt(IV) carboxamido complexes of the type Tp'PtMe(2)(C(O)NHR) (R = Et, (n)Pr, (i)Pr, (t)Bu, Bn, Ph) has been synthesized by addition of amide nucleophiles to the carbonyl ligand in Tp'Pt(Me)(CO) followed by trapping of the Pt(II) intermediate with methyl iodide as the methylating reagent. These compounds mimic elusive intermediates resulting from hydroxide addition to platinum-bound CO in the Water-Gas Shift Reaction (WGSR). Seeking parallels to WGSR chemistry, we find that deprotonation of the carboxamido NH initiates elimination and the isocyanate-derived products form; the resulting platinum fragment can be protonated to reoxidize the metal center and generate Tp'PtMe(2)H, the synthetic precursor to Tp'Pt(Me)(CO). Mechanistic studies on the formation of and elimination from Tp'PtMe(2)(C(O)NHR) suggest a stepwise process with deprotonation from a Pt(IV) species as the key step prompting elimination.

The Green Synthesis of 7-Methoxy-3, 4, 5, 6-Tetrahydro-2H-Azepine by <I>ε</I>-Caprolactam and Dimethylcarbonate as Methyl Reagents

The Green Synthesis of 7-Methoxy-3, 4, 5, 6-Tetrahydro-2H-Azepine by <I>ε</I>-Caprolactam and Dimethylcarbonate as Methyl Reagents

ChemInform Abstract: N‐Methylation of NH‐Containing Heterocycles with Dimethyl Carbonate Catalyzed by TMEDA.

Abstract A practical method for N-methylation of NH-containing heterocycles using an environmentally safe and less toxic methylating reagent, dimethyl carbonate, has been developed. N,N,N′,N′-tetramethylethylenediamine (TMEDA), an extremely active organocatalyst for the methylation of imides, indoles, benzimidazoles, and piperazines in conjunction with dimethyl carbonate, can lead to N-methylation products with high conversion. The reaction sequence consists of competing alkylation and acylation pathways and involves TMEDA as a nucleophilic catalyst. A possible reaction mechanism is discussed based on the reaction results.

Thiocarbamide and microwave-accelerated green methylation of cassava starch with dimethyl carbonate

By combining the acceleration strategies of using thiocarbamide as a active catalyst, incorporating dimethyl carbonate (DMC) as a solvent and methylating reagent and applying microwave irradiation as energy resource, methylation of cassava starch can be performed efficiently to a high degree of substitution (DS=0.6) within 4min. The structures of native cassava starch and methylated starch were characterized by 13C NMR spectroscopy. Their thermal property and crystal structure were studied by thermogravimetric analysis (TG and DTG) and powder X-ray diffractometry.

Uses of 2-Amino-5,6-dihydro-4H-cyclopenta [b] thiophene-3-carbonitrile in the Synthesis of Heterocyclic Compounds with Anticonvulsant, Behavioral and CNS Antidepressant Activities

The reaction of the cyclopenta[b]thiophene derivative 3 with phenylisothiocyanate4 gave thiourea derivative 5. The latter was reacted with the active methylene reagents 2a, b and 7 to give pyrimidine derivatives 6a, b and 8. N-Acylation of compound 3 was achieved via its reaction with acetic anhydride 9 to give the acetyl derivative 10. Compound 10 was utilized as a key for the synthesis of different heterocyclic compounds, where arylidene derivative 12 was obtained via its reaction with benzaldehyde11 and thienopyridone derivative 13 was obtained via its intramolecular cyclization using basic catalysis. Finally treatment of 10 with different activated carbonitriles2a, b or with hydrazine derivatives 15a, b afforded thienopyridone derivatives 14a,b and thienopyrimidine derivatives 17a,b, respectively. The newly synthesized compounds were tested for anticonvulsant, behavioral and CNS antidepressant activities.

Study of Mechanism of Ionization Assisted by Methylation in Direct Analysis in Real Time Ion Source

Direct analysis in real time ion source (DART) has been applied to the rapid analysis of solid, liquid and gaseous samples. The compounds with either high volatility or high proton affinity are favorable for DART analysis. However, a lot of natural products such as ginsenosides and ginseng oligosaccharides are difficult to be directly ionized by DART due to their low volatility and proton affinity. Derivatization is very necessary in the analysis of the compounds with low volatility and proton affinity. Tetramethylammonium hydroxide (TMAH) is a frequently used methylation reagent which can be applied to improve the volatility of low volatile compound in GC-MS. In the current work, TMAH was introduced to assist the ionization of ginsenoside and ginseng oligosaccharide in DART. Small amount of ginsenoside standard or ginseng oligosaccharide powder was collected on the end of melting point tubes respectively. Then 5 mu L of liquid from a solution containing 25% solution of TMAH dissolved in MeOH was applied to elute the surface of each melting point tube. Finally, all the end of melting point tubes containing sample powder and TMAH were put on a stainless holder for DART analysis. The solvents were flash evaporated in the DART source at 400 degrees C and the signals of methylated analytes were detected. The mechanism of methylation and ionization in DART was elucidated from the aspects of condensed and gas phase. On the one hand, the methylation enhanced volatility of analytes, on the other hand, a N(CH3)(3)H+ ion was generated to assist the ionization of methylated analytes. Incomplete and complete methylation is the major reaction of ginsenoside, but hypermethylation occurred in ginseng oligosaccharide with the increase of number of hydroxyls. The results showed that the synergy of methylation reaction both in condensed phase and gas phase is the fundamental reason of the generation of methylated ions. The methylation in condensed phase is governed by necleophilic reaction, and radical reaction is the major reaction in gas phase.

A Partial Synthesis of 5,8-O-Dimethylshikonin and 6-Isomer of 5,8-O-Dimethylshikonin

A convenient synthesis of 5, 8-O-dimethylshikonin and the 6-isomer of 5,8-O-dimethylshikonin was developed in 81.8% total yield from shikonin. (R)-4-Methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-ol was prepared in a one-pot two-step approach and then oxidised with ceric ammonium nitrate. This is simpler and the overall yield is higher than previous methods. The reaction conditions are milder and more environmentally friendly to environment, avoiding the use of the toxic and expensive reagents methyl iodide and chloromethyl ether and are more applicable to large-scale preparation. This is important because shikonin and its closely related derivatives have attracted much attention in view of their antitumor activities.

NaCl as a Novel and Green Catalyst for the Synthesis of Biodynamic Spiro Heterocycles in Water Under Sonication

An efficient and novel green catalytic protocol for the synthesis of biologically important spirooxindole derivatives is developed in a one-pot, three-component approach involving substituted isatin, activated methylene reagent, and 3-methyl-1-phenyl-2-pyrazolin-5-one in water under sonication. This report describes the use of sodium chloride as a nonacidic and green catalyst for a variety of substrates. The advantageous features of this methodology are the environmentally benign character, operational simplicity, high yield processing, easy handling, and the fact that the products do not need to be purified.

N-Methylation of NH-Containing Heterocycles with Dimethyl Carbonate Catalyzed by TMEDA

A practical method for N-methylation of NH-containing heterocycles using an environmentally safe and less toxic methylating reagent, dimethyl carbonate, has been developed. N,N,N′,N′-tetramethylethylenediamine (TMEDA), an extremely active organocatalyst for the methylation of imides, indoles, benzimidazoles, and piperazines in conjunction with dimethyl carbonate, can lead to N-methylation products with high conversion. The reaction sequence consists of competing alkylation and acylation pathways and involves TMEDA as a nucleophilic catalyst. A possible reaction mechanism is discussed based on the reaction results.

KAl(SO4)2 · 12H2O as a Recyclable Lewis Acid Catalyst for Synthesis of Spirooxindoles in Aqueous Media

A simple and efficient procedure for the synthesis of spirooxindole has been described that employs a three-component condensation reaction in one pot using isatin, active methylene reagent, and 1,3-dicarbonyl compounds in an aqueous medium.

Identification of Cysteines Involved in the Effects of Methanethiosulfonate Reagents on Human Equilibrative Nucleoside Transporter 1

Inhibitor and substrate interactions with equilibrative nucleoside transporter 1 (ENT1; SLC29A1) are known to be affected by cysteine-modifying reagents. Given that selective ENT1 inhibitors, such as nitrobenzylmercaptopurine riboside (NBMPR), bind to the N-terminal half of the ENT1 protein, we hypothesized that one or more of the four cysteine residues in this region were contributing to the effects of the sulfhydryl modifiers. Recombinant human ENT1 (hENT1), and the four cysteine-serine ENT1 mutants, were expressed in nucleoside transport-deficient PK15 cells and probed with a series of methanethiosulfonate (MTS) sulfhydryl-modifying reagents. Transporter function was assessed by the binding of [(3)H]NBMPR and the cellular uptake of [(3)H]2-chloroadenosine. The membrane-permeable reagent methyl methanethiosulfonate (MMTS) enhanced [(3)H]NBMPR binding in a pH-dependent manner, but decreased [(3)H]2-chloroadenosine uptake. [2-(Trimethylammonium)ethyl] methane-thiosulfonate (MTSET) (positively charged, membrane-impermeable), but not sodium (2-sulfonatoethyl)-methanethiosulfonate (MTSES) (negatively charged), inhibited [(3)H]NBMPR binding and enhanced [(3)H]2-chloroadenosine uptake. Mutation of Cys222 in transmembrane (TM) 6 eliminated the effect of MMTS on NBMPR binding. Mutation of Cys193 in TM5 enhanced the ability of MMTS to increase [(3)H]NBMPR binding and attenuated the effects of MMTS and MTSET on [(3)H]2-chloroadenosine uptake. Taken together, these data suggest that Cys222 contributes to the effects of MTS reagents on [(3)H]NBMPR binding, and Cys193 is involved in the effects of these reagents on [(3)H]2-chloroadenosine transport. The results of this study also indicate that the hENT1-C193S mutant may be useful as a MTSET/MTSES-insensitive transporter for future cysteine substitution studies to define the extracellular domains contributing to the binding of substrates and inhibitors to this critical membrane transporter.

ChemInform Abstract: Rhodium(I)‐Catalyzed Direct Carboxylation of Arenes with CO2 via Chelation‐Assisted C—H Bond Activation.

Rh-catalyzed direct carboxylation of unactivated aryl C−H bond under atmospheric pressure of carbon dioxide was realized via chelation-assisted C−H activation for the first time. Variously substituted and functionalized 2-arylpyridines and 1-arylpyrazoles underwent the carboxylation in the presence of the rhodium catalyst and a stoichiometric methylating reagent, AlMe2(OMe), to give carboxylated products in good yields. The catalysis is proposed to consist of methylrhodium(I) species as the key intermediate, which undergoes C−H activation to afford rhodium(III), followed by reductive elimination of methane to give nucleophilic arylrhodium(I). This approach demonstrates promising application of C−H bond activation strategy in the field of carbon dioxide fixation.

Analytical characterization of lacquer objects excavated from a Chu tomb in China

This work presents the results of an investigation of the lacquer objects excavated from a Chu tomb in China (Warring States, 481–221 BC). This study is engaged in the examination of the methods and the materials used for the urushi coating on the objects. X-Ray fluorescence and Scanning Electron Microscopy/Energy Dispersive Using X-Ray (SEM/EDX) analyses were applied for the pigment identification. The results show that vermilion was for the red colour, while carbon black was for the black colour. Pyrolysis gas chromatography and mass spectrometry (Py-GC/MS) was applied for the characterization of the lacquer resulting that it is based on urushi. The possibility to classify the drying oil (tung or linseed oil) present in the lacquer is highlighted and discussed in this paper. Py-GC/MS with in-situ hydrolysis and methylation reagent tetramethylammonium hydroxide (TMAH) were performed on reference materials of linseed oil and tung oil as well as on the lacquer object samples. The results show that it is possible to unambiguously identify the drying oil, in our case, linseed oil was identified to retard the rate of hardening.

FIRM FINED FOR CHEMIST’S DEATH

DRUGMAKER SEPRACOR CANADA pleaded guilty in a Canadian court on May 2 to one charge of failing to provide proper workplace ventilation and will pay a U.S.$47,000 fine for the death of chemist Roland Daigle. Daigle died on Oct. 8, 2008, from lung failure after exposure to trimethylsilyldiazomethane (TMSD) in a quality control laboratory at the company’s Windsor, Nova Scotia, facility. The plea and fine were part of a deal in which the prosecutor dropped four other charges against the company, a subsidiary of Sunovion Pharmaceuticals. The other charges involved hazardous material training, use of personal protective equipment, and maintaining the security of the accident scene. The day before he died, Daigle, 46, worked with TMSD, (CH 3 ) 3 SiCHN 2 , when lab fume hoods were not operating because of roof work. TMSD can be used as a methylating reagent in place of diazomethane, which is explosive. When inhaled, diazomethane can also cause fatal lung damage akin to ...

Thiophilic nucleophilic trifluoromethylation of α-substituted dithioesters. Access to S-trifluoromethyl ketene dithioacetals and their reactivity with electrophilic species

The nucleophilic trifluoromethylation of dithioesters bearing a nucleofugal group in α-position, using CF 3TMS under fluoride activation, afforded unprecedented S-CF 3 ketene dithioacetals via a domino process thiophilic trifluoromethylation–β-elimination. The best results were obtained with non-enolisable α-carbamoyloxydithioesters. The higher homologues S-C 2F 5 ketene dithioacetals were prepared by a similar way. These new dithioacetals react with methylating reagents quantitatively and chemoselectively at sulfur to give stable dimethylsulfonium type salts. They react more classically with triflic acid, protonation taking place at the β-carbon to give a dithiolium salt, characterized in solution but non-isolable.

1,2‐Diphosphaacenaphthene 1,2‐Dications: Synthetic, Stereochemical and Computational Study of the Stabilising Role of Naphthalene‐1,8‐diyl Backbone

Syntheses and full characterisation data (including single crystal diffraction) of three 1,2-diphosphonium dicationic species with the naphthalene-1,8-diyl (Nap) backbone are reported. The oxidation of Nap[P(NMe(2))(2)](2) with P(2)I(4) to its 1,2-dication was achieved. meso- and rac-forms of "all carbon" 1,2-diphosphonium dications were obtained in good yields and purity by double alkylation of the parent diphosphine (1,2-diphenyl-1,2-diphosphaacenaphthene) with methyl triflate or trimethyloxonium tetrafluoroborate. Each methylating reagent produces one of the rac- or meso-forms of the dication diastereospecifically. Structural parameters of the new dications are discussed with respect to other phosphorus 1,2-dications. DFT (B3LYP) computations revealed the significant role of the naphthalene backbone in stabilisation of the dicationic motif and helped to assess the energy cost of the steric clash of a variety of groups attached to the peri-positions of naphthalene. The synthesis and single crystal X-ray data of the extremely crowded Nap[P(Se)(OiPr)(2)](2) are discussed, and are contrasted with the unsuccessful synthesis of Nap(PtBu(2))(2) from NapLi(2) and ClPtBu(2).