Alkylation Of Pyrazoles Research Articles

Highly Selective N-Alkylation of Pyrazoles: Crystal Structure Evidence for Attractive Interactions.

Inspired by crystal structures, we designed and achieved a catalyst-free Michael reaction for the preparation of an N1-alkyl pyrazole in a high yield (>90%) with excellent regioselectivity (N1/N2 > 99.9:1). The scope of this protocol has been extended to accomplish the first general regioselective N1-alkylation of 1H-pyrazoles to give di-, tri-, and tetra-substituted pyrazoles in a single step. The resulting pyrazoles bear versatile functional groups such as bromo, ester, nitro, and nitrile, offering opportunities for late-stage functionalization. This efficient methodology will have an impact on drug discovery, as several Food and Drug Administration-approved drugs are pyrazole derivatives. A working hypothesis for the regioselectivity is proposed. X-ray crystal structures of the products that highlight the attractive interactions are discussed. This report provides a rare source for the further elucidation of the attractive interactions because the isomeric ratios and the crystal structures are directly related.

Engineered Enzymes Enable Selective N-Alkylation of Pyrazoles With Simple Haloalkanes.

Selective alkylation of pyrazoles could solve a challenge in chemistry and streamline synthesis of important molecules. Here we report catalyst‐controlled pyrazole alkylation by a cyclic two‐enzyme cascade. In this enzymatic system, a promiscuous enzyme uses haloalkanes as precursors to generate non‐natural analogs of the common cosubstrate S‐adenosyl‐l‐methionine. A second engineered enzyme transfers the alkyl group in highly selective C−N bond formations to the pyrazole substrate. The cosubstrate is recycled and only used in catalytic amounts. Key is a computational enzyme‐library design tool that converted a promiscuous methyltransferase into a small enzyme family of pyrazole‐alkylating enzymes in one round of mutagenesis and screening. With this enzymatic system, pyrazole alkylation (methylation, ethylation, propylation) was achieved with unprecedented regioselectivity (>99 %), regiodivergence, and in a first example on preparative scale.

Synthesis and Antimicrobial Activity of 4-Arylthio- and 4 Alkylthiofunctionalized Pyrazolo[1,5-a]pyrazines

The reaction of pyrazolo[1,5-a]pyrazine-4(5H)ones with phosphorus tribromoxide in boiling benzene yielded 4-bromopyrazolo[1,5-a]pyrazines, and the thionation with phosphorus pentasulfide in pyridine at 90 °C led to pyrazolo[1,5-a]pyrazine-4(5H)thiones. The synthesized bromine derivatives are electrophilic, and thiones are nucleophilic substrates. Their subsequent structural modification in the first case was carried out by interaction with thiophenols, and in the second case was conducted with functional halogenoalkanes. It was shown that bromides react with substituted thiophenols in dimethylformamide in the presence of potassium carbonate at 90 °C to form 4-arylthiopyrazolo[1,5-a]pyrazines with yields of 65–83 %. 4-S-methyl-functionalized derivatives of pyrazole[1,5-a]pyrazines with yields of 60–78 % were easily obtained by the alkylation of pyrazole[1,5-a]pyrazin-4(5H)thiones with a-bromoketones, bromoacetic acid, ethyl bromoacetate and bromoacetonitrile in the K2CO3—DMF system at room temperature. The composition of all synthesized compounds is in agreement with the results of elemental analysis and mass spectra. Their structure is confirmed by NMR 1H and 13C spectra. In particular, in the NMR 1H spectra of 4-arylthiopyrazolo[1,5-a]pyrazines, in addition to the characteristic signals of the pyrazole and pyrazine nuclei, signals of protons of thioaryl substituents are present in the range of 7.04 –8.05 ppm, and in NMR spectra of the 1H 4-S-methylfunctionalized derivatives of pyrazole[1,5-a]pyrazines signals of exocyclic methylene protons are present at 4.11– 5.02 ppm. Promising derivatives with antibacterial activity against the test cultures S. aureus (MIC = 7.8 g/mL), M. luteum (MIC = 3.9 g/mL), and antifungal activity against the test culture of fungus A. niger (MIC = 7.8 g/mL) were determined among 4-S-substituted pyrazole[1,5-a]pyrazines as a result of studies of the antimicrobial activity.

AQUEOUS N -METHYLMORPHOLINE N -OXIDE AS A NEW MEDIUM FOR ALKYLATION OF PYRAZOLES

It is shown that alkylation of pyrazoles with (E)/(Z)-1,3-dichlorobut-2-enes can be carried out in an alkaline aqueous medium in the presence of N-methylmorpholine N-oxide. In some cases, this technique may substitute phase-transfer catalysis. Conformational analysis of the reaction products showed that a mixture of (E)/(Z) isomers is formed in a ratio of 9:1.

Aqueous N-methylmorpholine N-oxide as a new medium for alkylation of pyrazoles

It is shown that alkylation of pyrazoles with (E)/(Z)-1,3-dichlorobut-2-enes can be carried out in an alkaline aqueous medium in the presence of N-methylmorpholine N-oxide. In some cases, this technique may substitute phase-transfer catalysis. Conformational analysis of the reaction products showed that a mixture of (E)/(Z) isomers is formed in a ratio of 9:1.

Alkylation of pyrazoles with ethyl chloroacetate under phase-transfer catalysis and hydrolysis of the esters obtained

Alkylation of pyrazoles with ethyl chloroacetate under phase-transfer catalysis and hydrolysis of the esters obtained

Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.

Cesium-saponites as excellent environmental-friendly catalysts for the synthesis of N-alkyl pyrazoles

An easy and efficient procedure for the synthesis of N-alkyl pyrazoles is reported. The reaction is carried out by alkylation of pyrazole with three different alkyl bromides using acetonitrile or dimethylformamide as solvents and different pillared saponites impregnated with cesium as catalysts. The best experimental condition was the use of DMF at 80 °C, the pillared saponite impregnated with cesium carbonate being the most active catalyst. N-Alkyl pyrazoles, which are key intermediates in the synthesis of pharmacologically active compounds, are obtained in almost quantitative yield at very short reaction times. The loading of cesium slightly affected the conversion values.

Work-Up Optimization en Route to an Improved Process To Prepare a Progesterone Receptor Antagonist

When the process to prepare nonsteroidal progesterone receptor antagonist 5 was scaled up, significant problems were encountered, and as a result lower than expected yields were obtained. In particular, the alkylation of pyrazole 2 with chloromethyl methyl sulfide failed to reach completion, and partial degradation of the product occurred during the work-up, resulting in a modest yield of alkylated pyrazole 3a. Further investigation has revealed the root cause of this problem, and an improved, robust process to 5 has been developed.

Novel structural analogs of glyphosate based on azoles. 2*. N-Substituted imidazoles and pyrazoles obtained by alkylation of heterocycles containing carboxyl or phosphoryl groups in the ring

Alkylation of 4(5)-substituted 1H-imidazoles using the corresponding reagents gave imidazole 1,4-isomers containing phosphoryl and carboxyl groups together in the ring and in the alkyl fragment. The alkylation of pyrazoles containing a carboxyl group at positions 3(5) and 4 of the ring using diethyl phosphonomethyltriflate has been studied.

10.1007/s11176-008-1023-0

Alkylation of pyrazoles with 2-chloroethylamine was performed under conditions of phasetransfer catalysis. Depending on the substrate acidity, the electrophilic substitution process may be accompanied by dehydrochlorination of the alkylating agent, so that 6 equiv of 2-chloroethylamine should be used in the alkylation of 3,5-dimethylpyrazole.

Alkylation of pyrazoles with ethylene chlorohydrin under phase transfer catalysis

Alkylation reactions of pyrazoles with ethylene chlorohydrin under phase transfer catalysis were studied. Effect of solvent nature on alkylation process was established. 3(5)-Methylpyrazole alkylation products were isolated and identified.

Experimental and theoretical study of pyrazole N-alkylation catalyzed by basic modified molecular sieves

Herein we report on the experimental and theoretical study of pyrazole alkylation catalyzed by basic mesoporous materials. (Cs)Al-SBA-15 or DEAPTS/MCM-4,1 differing in textural properties and compositions, were found to be efficient catalysts for pyrazole alkylation with different reactive alkyl bromides under thermal activation. They constitute the first examples of modified molecular sieves catalyzing this highly used transformation, showing a higher catalytic activity than other previously reported catalysts. DEAPTS/MCM-41 whose catalytic centers are tertiary amines resulting in the best catalyst for the investigated reactions. Furthermore, the catalytic pyrazole alkylation has been clarified by studying the reaction mechanism using computational approach.

Two convenient regioselective syntheses of 1- N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles

Two regioselective synthetic routes for 1- N-alkyl-3-aryl-4-[pyrimidin-4-yl]-pyrazoles of generic formula 1 were developed. These highly efficient and scalable routes circumvent the generally observed poor regioselectivity for the pyrazole alkylation.

Synthesis of 1-(2-aminoethyl)pyrazoles under phase-transfer catalysis

Alkylation of pyrazoles with 2-chloroethylamine was performed under conditions of phasetransfer catalysis. Depending on the substrate acidity, the electrophilic substitution process may be accompanied by dehydrochlorination of the alkylating agent, so that 6 equiv of 2-chloroethylamine should be used in the alkylation of 3,5-dimethylpyrazole.

Synthesis of N‐Vinylpyrazoles

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Synthesis of N-Vinylpyrazoles

A method is proposed for the alkylation of pyrazoles with dichloroethane in water in the presence of the phase-transfer catalyst benzyltriethylammonium chloride (TEBAC). It was shown that dehydrochlorination of the corresponding N-(β-chloroethyl)pyrazoles in water under conditions of phase-transfer catalysis proceeds smoothly with the formation of N-vinylpyrazoles in 80–90% yield.

Synthesis of N-(2-vinyloxyethyl)pyrazoles

Alkylation of pyrazoles with 2,2′-dichloroethyl ether under conditions of phase-transfer catalysis was studied. The monoalkylation products of 3(5)-methylpyrazoles at 190–200°C undergo intramolecular cyclization to form bicyclic salts. Conditions for dehydrochlorination of N-[2-(2′- chloroethoxy)ethyl]pyrazoles into N-(2-vinyloxyethyl)pyrazoles were found.

Clean and Efficient Microwave‐Solvent‐Free Synthesis of 1‐(2′,4′‐Dichlorophenacyl) Azoles.

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Clean and efficient microwave-solvent-free synthesis of 1-(2′,4′-dichlorophenacyl) azoles

Microwave induced N-alkylation of several azoles with 2,2′,4′-trichloroacetophenone (TCA) under solvent-free conditions allowed to obtain the corresponding 1-(2′,4′-dichlorophenacyl) azoles with satisfactory to good selectivities and yields. TGA and DSC measurements were achieved for the synthesized compounds and showed a close relationship between the thermal behavior and the reaction temperature under microwave heating. Non-purely thermal microwave effects were evidenced during the alkylation of pyrazole and 1H-indazole under the selected conditions.