Trimethyl Orthoformate Research Articles

Microwave-Assisted, Green Synthesis of 4(3H)-Quinazolinones under CO Pressure in γ-Valerolactone and Reusable Pd/β-Cyclodextrin Cross-Linked Catalyst

The development of alternative, green solvents is an important and ongoing challenge. Our latest contribution to the field is the use of γ-valerolactone in aminocarbonylative coupling reactions for the clean synthesis of several 4(3H)-quinazolinones under microwave irradiation. The palladium-catalyzed, four-component carbonylative coupling reactions of o-iodoanilines, trimethyl orthoformate and a variety of amines have been carried out under CO pressure (2.5 bar). This protocol was found to be highly efficient and selective for 4(3H)-quinazolinones, which were isolated in good yields in the presence of two different, recyclable Pd catalysts which were prepared under ultrasound irradiation; a novel lead-free Pd/Boehmite catalyst and a β-cyclodextrin - cross linked Pd catalyst.

Development of a Leuckart–Wallach Reaction in Flow for the Synthesis of Abemaciclib

The development of a route for a key building block in the synthesis of abemaciclib is described. The route proceeds through a Leuckart–Wallach reductive amination in flow followed by an Ullmann amination with aqueous ammonia. Key to the Leuckart–Wallach reductive amination was the addition of trimethyl orthoformate for water removal, running the reaction continuously in a pipes-in-series reactor for rapid heat-up, and building a kinetic model to understand time and temperature parameters for the feed tank storage. The product of the Leuckart–Wallach reductive amination is forward processed in batch and telescoped with the Ullmann amination and subsequent workup. The development resulted in a robust process that has successfully been run on the production scale.

An unexpected course of a palladium catalyzed three-component reaction leading to steroid chroman ketals

A previously reported Pd-catalyzed MCR of 4-pentyn-1-ol derivatives with salicylaldehyde and methyl orthoformate follows an unexpected course when carried out with the 5α- and 5β-epimers of 4,5-secocholestan-5-ol, leading to chroman ketals. The homologation of the alkynol and the restriction of its conformational equilibrium trigger a drastically different reaction course.

Stereoselective synthesis of tri- and tetrasubstituted tetrahydropyrans from syn- and anti-1-R-2-(4-bromophenyl)-5-methylhex-4-en-1-ols and some chemical transformations of the products

Tri- and tetrasubstituted tetrahydropyranes fused to one and two heterocycles with various functional groups (COOEt, Br, MeC=CH2) were synthesized in stereoselective fashion by reactions of syn- and anti-1-R-2-(4-bromophenyl)-5-methylhex-4-en-1-ols (R = Bu, PhCH2) with trifluoromethanesulfonic acid, aldehydes in the presence of boron trifluoride–diethyl ether complex (Prins reaction), and salicylaldehydes in the presence of trimethyl orthoformate and p-toluenesulfonic acid. The obtained compounds were brought into Suzuki coupling with thiofen-2-ylboronic acid, hydrolysis, and reduction of the ester group with lithium tetrahydridoaluminate. The resulting carboxylic acid was converted to carboxamide, and the alcohol was oxidized to aldehyde which was converted to oxime. The steric configuration of substituents remained unchanged in all chemical transformations.

Quantitative assessment of the effect of anhydrous zinc chloride catalysis on the synthesis of some imine derivatives in toluene

Imines are formed when any primary amines react with an aldehyde or a ketone under specific conditions. The classical synthesis reported by Schiff involves the condensation of a carbonyl compound with an amine under azeotropic distillation. In the 1990s an in-situ method for water elimination was developed using dehydrating solvents such as tetramethyl orthosilicate or trimethyl orthoformate another way to remove the water by-product is to use substances that function as Bronsted-Lowry or Lewis acids like ZnCl2, TiCl4, MgSO4, H3COOH, Mg(ClO4)2 to activate the carbonyl group of benzaldehyde, catalyse the nucleophilic attack by amines, and dehydrate the system, and eliminate water as the final steps. Anhydrous zinc chloride has been extensively used in literature for its affordability and reliability, however there is limited information if any, of its quantitative effects in synthesis, this has prompted this present study. The reaction involved the condensation between 4-Methoxybenzaldehyde and para- substituted aniline derivatives (4-chloroaniline, 4-nitroaniline and 4-methylaniline) in toluene. The reaction process was evaluated to determine the effect of temperature, concentration of anhydrous zinc chloride and effect of microwave assisted synthesis on the yield of the products. Results show that increasing the concentration anhydrous zinc chloride at elevated temperature increases the yield of the imine derivatives studied.Keywords: Imines, anhydrous zinc chloride, toluene, microwave assisted synthesis

A kinetic study of the selective production of difluoromethoxymethane from chlorodifluoromethane

The reaction of chlorodifluoromethane (R-22) with sodium methoxide produces difluoromethoxymethane, an alternative refrigerant with low ozone depleting potential. In this study a kinetic model of the dehydrochlorination process was identified, based on rate data obtained from a semi-batch gas–liquid reactor. The reaction was studied at a reaction temperature of 283–303K, R-22 inlet partial pressures of 40.5–60.8kPa and initial sodium methoxide concentrations between 1.5 and 2.5mol·dm−3. The products obtained were difluoromethoxymethane and trimethyl orthoformate as well as sodium chloride and fluoride salts. The reaction proceeds via a three step mechanism, initiated by an α-elimination and involving a difluoromethylene intermediate. The elimination step has an identified pre-exponential factor of 1.18 × 104dm3·mol−1·min−1 and activation energy of 15.54kJ·mol−1. The reaction yielding the target compound has a pre-exponential factor of 1.15 × 108dm3·mol−1·min−1 and activation energy of 47.67kJ·mol−1. The byproduct formation reaction has a pre-exponential factor of 8.25 × 101(dm3·mol−1)2·min−1 and activation energy of 12.75kJ·mol−1. In a semi-batch system the reaction is strongly inhibited by the formation and accumulation of precipitated sodium salts. This feature was incorporated into the reaction model using an inhibition term.

Stereodirected reactions of salicilaldehyde derivatives with tert-butyl 3(4)-hydroxy-2(3)-(3-methylbut-2-enyl)- piperidine-1-carboxylates as an efficient preparation procedure of tetrahydropyran derivatives fused with a piperidine ring

Reaction of salicilaldehyde and its derivatives with unsaturated cis-, trans-alcohols of the piperidine series in the presence of methyl orthoformate and p-toluenesulfonic acid led to the formation of a new heterocyclic system connecting four fuzed rings (two tetrahydropyrans, a piperidine, and an aromatic ring), 6,6-dimethyl-6а,7,7а,8(9),10,11,11а,12а-octahydrochromeno[3′,4′:5,6]pyranо[3,2-с(b)]pyridine.

Stereoselective synthesis of tetrahydropyran new derivatives underlain by α-allyl ketones

Decarboxylation of α-allyl-substituted acetoacetic esters afforded α-allyl ketones that were reduced with L-selectride [LiBH(s-Bu)3] in alcohols RCH(OH)CH2CH2CH=C(Me)CH2R'. The latter reacted with methyl 4-hydroxy-3-formylbenzoate and methyl orthoformate in the presence of p-toluenesulfonic acid to provide trans-tetrahydropyrano[3,2-с][1]benzopyran. In reaction of the E-isomer of alcohol Me2CHCH(OH) CH2CH2CH=C(Me)CH2CH2Ph with CF3SO3H a stereoselective cyclization occurred with the formation of 2,6-disubstituted tetrahydropyran; Prins reaction with 4-bromobenzaldehyde and salicylaldehyde in the presence of boron trifluoride etherate also proceeded stereoselectively giving a substituted tetrahydropyrano-[3,2-c][1]-benzopyran.

Electrochemical Generation of Stabilized Halogen Cation Pools

Halogen cations such as I+ and Br+ are highly unstable species, although some of them are identified in the gas phase. The electrochemical oxidation provides a powerful method for generating and accumulating highly reactive cationic species in the solution, whereas the chemical methods are not effective because of reversibility of cation generation. We have already reported that some carbocations and onium ions can be generated and accumulated as cation pools at low temperatures (the “cation pool” method). However, halogen cations are very difficult to accumulate in the solution as “cation pools” because they are too unstable. We envisioned that the use of a stabilizing agent that coordinates the cation being generated would solve the problem. Coordination of a neutral molecule gives a positively charged species and coordination of an anionic species gives a neutral species, although the halogen is the +1 oxidation state in both cases. Some stabilizing agents have already been reported. For example, Miller and co-workers reported the generation and accumulation of “I+” cation in acetonitrile (CH3CN), and later we reported the detection of CH3CN−I+ and (CH3CN)2I+ by cold-spray-ionization mass spectroscopy. Shono and co-workers reported that “I+” could be accumulated in trimethyl orthoformate (TMOF). In this paper we report that dimethyl sulfoxide (DMSO) serves as a neutral stabilizing agent and that TfO− anion serves as a negatively charged stabilizing agent in the electrochemical generation and accumulation of halogen cations such as I+ and Br+. We also report their reactions with organic molecules to give the corresponding halogen-containing products, which serve as useful transformations in organic synthesis.

ChemInform Abstract: Investigation of the Reaction of Dithiocarbamic Acid Salts with Trimethyl Orthoformate and Styrene Epoxide.

AbstractThe title reactions proceed in the presence of BF3·OEt2 to give 1,3‐dithietane or 1,3‐dithiolane derivatives in good yields.

Addition of phthalimide and acetone to phosphorylated methylene quinones

New method for synthesis of phosphorylated methylene quinones via bromination of the sterically hindered phenol [prepared via benzylation of secondary chlorophosphines with 4-(methoxymethyl)-2,6-di-tert-butylphenol] with N-bromosuccinimide followed by dehydrobromination with trimethyl orthoformate has been developed. Tertiary phosphine oxides containing the fragment of sterically hindered phenol and amine or acetonyl group have been synthesized for the first time in the reaction of phosphorylated methylene quinones with N- and C-nucleophiles.

Phenylphosphonic Acid (PPA) as an Efficient Catalyst for Synthesis of Symmetry and Asymmetry Formamidines

Introduction: Formamidines are derivatives of the unstable imidic acid having a unique and fascinating spectrum of biological and pharmacological activity. The aim of the present study id to evaluate the phenylphosphonic acid (PPA) as a catalyst for synthesis of symmetry and asymmetry formamidines. Method: A solution of the aniline (0.094 g, 1.0 mmol) and trimethyl orthoformate (0.318 g, 3.0 mmol) in 2.5 mL water as solvent and phenylphosphonic acid (0.015 g, 10 mol%) was heat to 55 oC with natural condition for 15 min. After an appropriate time (TLC) the reaction mixture was washed with cold water, and the product was isolated by filtering. A solution of the aniline (0.094 g, 1.0 mmol, 1 equiv) and DMF-DMA (0.360 g, 3 mmol) in solvent-free condition and phenylphosphonic acid (0.015 g, 10 mol%) was heat to 55 oC with natural condition until completion (TLC). The reaction was cooled to room temperature, and after addition water to the reaction, the product as colorless oil was extracted by CH2Cl2. Result: We had found that both Amberlist-15 and phenylphosphonic acid (PPA) are effective in reaction progress in 45 and 10 min, respectively. But, based on quick reaction time and also easy water separable of the formamidine from water soluble phenylphosphonic acid (PPA), we select PPA as ideal catalyst in synthesis of N, N-diarylformamidine. Conclusion: The reaction of alkyl orthoformates with aromatic amines in the presence of phenylphosphonic Acid (PPA) as a catalyst to produce alkyl N , N -disubstituted Formamidines has been shown to be general. Reaction of orthoformates with an aromatic primary-amine, preferably in the presence of PPA in solvent-free or water-medium condition, gives formamidine in excellent yields.

A facile synthesis of cost-effective triphenylamine-containing porous organic polymers using different crosslinkers

The synthesis of polytriphenylamine networks (PTPAs) was accomplished by FeCl3-promoted one-step oxidative coupling reaction and Friedel–Crafts alkylation in one pot. For the first time, we used the common reagents including trimethyl orthoformate (TMOF), trimethyl orthoacetate (TMOA), triethyl orthoacetate (TEOA) and triisopropyl orthoformate (TIPO) as the crosslinkers, respectively. The highest BET specific surface area is 1543 m2 g−1, for PTPA-4. Its CO2 uptake capacity is as high as 2.65 mmol g−1 at 1.0 bar and 273 K, which makes it promising candidate for applications in environment fields. In addition, this work extends the types of cheap crosslinkers that could be incorporated into porous organic polymers to enhance their porosity.

Investigation of the reaction of dithiocarbamic acid salts with trimethyl orthoformate and styrene epoxide

The reaction of dithiocarbamic acid salts with trimethyl orthoformate in the presence of BF3·OEt2 was investigated to give 4-(N,N-dialkyldithiocarbamato)-2-dialkyliminio-1,3-dithietane tetrafluoroborates in good yields. Additionally, a one-pot procedure for the synthesis of 2-iminium-1,3-dithiolanes from the BF3·OEt2 catalyzed reaction of dithiocarbamic acid salts with styrene epoxide is described.

Application of Chan-Lam cross coupling for the synthesis of N-heterocyclic carbene precursors bearing strong electron donating or withdrawing groups.

Chan-Lam cross coupling allowed efficient synthesis of N,N’-disubstituted ortho-phenylene diamines bearing strong electron donating or withdrawing groups, such as nitro or methoxy groups, with moderate to high yields. These diamines can then be turned into N-heterocyclic carbene precursors after condensation with trimethyl orthoformate. The same strategy can also be utilized for the synthesis of N-monosubstituted aniline derivatives containing a functionalized ortho-aminomethyl group as intermediates for chiral 6-membered ring carbene precursors.

In Situ Formed Acetal-Facilitated Synthesis of Substituted Indene Derivatives from o-Alkenylbenzaldehydes.

A new protocol has been developed for the synthesis of indene derivatives in a diastereoselective manner from o-alkenylbenzaldehydes and enolizable ketones in the presence of trimethyl orthoformate and catalytic triflic acid. This method involves tandem in situ formed acetal-assisted Claisen-Schmidt condensation followed by 5-exo-trig cyclization/Michael addition in one-pot. It has also been shown that the chalcones derived from o-alkenylbenzaldehydes and ketones can effectively be transformed into indene derivatives in the presence of TfOH catalyst alone.

ChemInform Abstract: A Synthesis of Abemaciclib Utilizing a Leuckart—Wallach Reaction.

Abstract A concise total synthesis of CDK 4/6 inhibitor abemaciclib is described. The synthesis uses a Suzuki coupling, followed by a Hartwig–Buchwald amination to join three of the four subunits. The final step is a reductive amination utilizing Leuckart–Wallach conditions. Key to the Leuckart–Wallach reaction was the addition of trimethyl orthoformate to remove water formed during the reaction, allowing the reaction to go to completion.

One-pot three-component synthesis of 3-cyano-4-methyl-2,6-dioxopyridine amino enones

(Z)-5-(Arylaminomethylidene)-4-methyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitriles were obtained by three-component condensation of 4-methyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitrile with aromatic amines and trimethyl orthoformate in DMF. According to X-ray data, in the solid phase they exist as amino enone tautomers.

A synthesis of abemaciclib utilizing a Leuckart–Wallach reaction

A concise total synthesis of CDK 4/6 inhibitor abemaciclib is described. The synthesis uses a Suzuki coupling, followed by a Hartwig–Buchwald amination to join three of the four subunits. The final step is a reductive amination utilizing Leuckart–Wallach conditions. Key to the Leuckart–Wallach reaction was the addition of trimethyl orthoformate to remove water formed during the reaction, allowing the reaction to go to completion.

Pd/C as an efficient heterogeneous catalyst for carbonylative four-component synthesis of 4(3H)-quinazolinones

A relatively mild, operationally simple, phosphine-free and recyclable catalytic system for the carbonylative synthesis of 4(3H)-quinazolinones with 2-iodoanilines, trimethyl orthoformate, and amines as the substrates has been developed.