Phase Transfer Catalysis Conditions Research Articles

The Surprising Reactivity of Chloromethyl Chlorosulfate with Active Methylene Compounds

AbstractCondensation of chloromethyl chlorosulfate (1) with alkyl 1,3‐keto esters under phase‐transfer catalysis (PTC) conditions led to methylene bridged bis‐acetoacetates through a sequential chloromethylation‐β‐elimination‐Michael addition process. The latter compounds further evolved towards polyfunctional dihydrofuran and tetrahydropyran derivatives by competitive chloromethylation/chlorination reaction. In aprotic organic solvent, chlorination of the methylene active group is the main process and proceeded by reaction of the enolate of acetoacetate with the chlorine atom bound to the sulfonyl group of 1. The reactivity of some other active methylene compounds under PTC conditions was investigated. Acetylacetone reacted similarly to ethyl acetoacetate providing O‐heterocycles while ethyl cyanoacetate gave diethyl 2,4‐dicyanoglutaric acid diethyl ester together with 2‐diethyl 1,2‐dicyanocyclopropane‐1,2‐dicarboxylate. A plausible reaction mechanism is proposed whose the key feature is the competitive halogenation/chloromethylation of the intermediate methylene bridge dimeric active methylene compounds followed by intramolecular cyclization.

Enantioselective Synthesis of (R)-Sitagliptin via Phase-Transfer Catalytic aza-Michael Addition.

The highly enantioselective synthesis of (R)-sitagliptin has been achieved through a series of key steps, including the aza-Michael addition and Baeyer-Villiger oxidation. The enantioselective aza-Michael addition involved the reaction of tert-butyl β-naphthylmethoxycarbamate with (E)-1-(4-methoxyphenyl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one, utilizing a quinine-derived C(9)-urea ammonium catalyst under phase-transfer catalytic conditions. The aza-Michael addition successfully introduced chirality to the amine in (R)-sitagliptin with 96% ee. The subsequent Baeyer-Villiger oxidation of the aza-Michael adduct led to the formation of 4-methoxyphenyl ester. Hydrolysis and amide coupling were then employed to construct the amide moiety. Further deprotections were performed to complete the synthesis of (R)-sitagliptin (7 steps, 41%, 96% ee).

Functionalization of the position 5 of thiopyran fragment of 4-(diethoxyphosphoryl)-4,7-dihydro-5 Н-thiopyrano[3,4-b]furan

Alkaline hydrolysis of ethyl 4-(diethoxyphosphoryl)-4,7-dihydro-5 Н -thiopyrano[3,4- b ]furan-5-carboxylate proceeded selectively at the ester group. The acid obtained formed the corresponding acid chloride when treated with thionyl chloride. The acid chloride was used for acylation of glycine, α- and β-alanine esters. Under the conditions of phase transfer catalysis this acid chloride formed acyl azide which under mild conditions undergoes rearrangement to isocyanate. The latter reacted with primary amines to give ureas, and with the amino acid esters in forms ureidoesters. Reducing of acid chloride with sodium borohydride led to the corresponding alcohol. It was converted to chloride which in the reactions with sodium azide and iodide gives usual substitution products. When treated with potassium thiocyanate it formed thiocyanate. Iodide in the reaction with triethyl phosphite gave the corresponding phosphonate. Oxidation of alcohols with Collins reagent and acetic acid-DMSO system was studied.

Efficient Regioselective Synthesis of Novel Ensembles of Organylselanyl-Functionalized Divinyl Sulfides and 1,3-Thiaselenoles under Phase Transfer Catalysis Conditions

Efficient regioselective synthesis of novel ensembles of organylselanyl-functionalized 1,3-thiaselenoles and divinyl sulfides in high yields under phase transfer catalysis conditions was developed. The methodology is based on the generation of sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate, which were involved in a nucleophilic addition reaction with activated alkenes such as acrylonitrile, acrylamide, methyl vinyl ketone, methyl, and ethyl acrylates. In the case of methyl vinyl ketone, the reaction was accompanied by the hydrogenation of the carbonyl group. Methylene chloride was involved in the nucleophilic substitution reaction with sodium [(Z)-2-(vinylsulfanyl)ethenyl]selenolate and 1,3-thiaselenol-2-ylmethylselenolate to afford new polyunsaturated compounds with several sulfur and selenium atoms.

Design, synthesis, biological evaluation on immune cell proliferation, crystal structures, spectroscopic characterizations, DFT calculations, ADME analysis, and molecular docking studies with COX of novel tetrazole-Galactopyranosyl analogues

The new 5-(substituted)-3-(1,2,3,4-di-O-isopropylidene-(D)-galactopyranose) tetrazoles(1c-8c) have been achieved by using as starting materials substituted tetrazole (1b-8b) and 1,2,3,4-di-O-isopropylidene-6-O-p-tolylsulfonyl-alpha-D-galactose (A) via N-alkylation reactions under phase transfer catalysis (PTC) conditions. All the obtained compounds were characterized by nuclear magnetic resonance spectroscopy. The molecular and crystal structures of two compounds (5b and 5c) were examined by single crystal X-ray crystallography. The Density Functional Theory estimations for compound 5c at the DFT/B3LYP level via 6-31+G(d, p) replicate the structure and geometry. Finally, HOMO and LUMO analysis was used for the charge transfer interface of the structure. Against Cytochrome c Peroxidase (2 × 08), the compounds 3c and 7c interacted with the least binding energy of -9.73kcal/mol and -9.13kcal/mol along with the inhibition constant of 74.23nM and 204.28nM, respectively. All the synthesized compounds showed the excellent anticancer activity and have potential to be used as immunomodulatory agents. The compounds 1c, 3c, 4c, 5c, 6c, 7c and 8c caused an immunostimulatory effect, while compound 2c showed an immuno inhibitory effect.

Synthesis, X-ray Crystal Structure, Anticancer, Hirshfeld Surface Analysis, DFT, TD-DFT, ADMET, and Molecular Docking of 3-Phenyl-1,2,4-triazolo[3,4-h]-13,4-thiaza-11-crown-4

In this work, we describe the synthesis of new macrocycles derived from 3-phenyl-1,2,4-triazole-5-thione 1 in a heterogeneous medium using liquid-solid phase transfer catalysis (PTC) conditions. The structures of the two compounds (3 and 4) isolated were elucidated based on spectral data (1H-NMR, 13C-NMR) and confirmed in the case of 3-phenyl-1,2,4-triazolo [3,4-h]-13,4--thiaza-11-crown-4 (3) by a single-crystal X-ray diffraction analysis. Furthermore, the experimental spectral and the X-ray geometrical parameters were compared with their corresponding predicted ones obtained at the B3LYP/6-311++G(d,p) level of theory. The intercontacts between crystal units were investigated through Hirshfeld surface analysis. The drug-like macrocycles were predicted using ADMET and drug-likeness properties, which showed that 3 may act as an inhibitor of DNA-dependent protein kinase (DNA-PK). This assumption was confirmed by the well-binding fitting of 3 into the binding site of DNA-PK and the formation of a stable 3-DNA-PK complex with a binding energy of -7 kcal-mol-1. Finally, the anticancer activity of 3 was assessed by an MTT assay against A549 cells, which showed that 3 has moderate anticancer activity compared to that of the doxorubicin reference drug.

Synthesis of 3,4-Dihydropyridin-2-ones via Domino Reaction under Phase Transfer Catalysis Conditions

3,4-dihydropyridin-2-ones are of considerable importance due to the large number of these core structures exhibiting a diverse array of biological and pharmacological activities. The Michael-type addition of 1,3-dithiane-2-carbothioates to α,β-unsaturated N-tosyl imines, followed by intramolecular annulation driven by a sulfur leaving group, provides a practical reaction cascade for the synthesis of a variety of substituted 3,4-dihydropyridin-2-ones. In this work, the reaction was carried out under solid–liquid phase transfer catalysis (SL-PTC) conditions at room temperature, in short reaction times in the presence of cheap Bu4N+HSO4– and solid KOH. The new PTC method exhibited adequate functional group tolerance, proving to be a green and reliable method and easy to scale up to furnish rapid access to 3,4-dihydropyridin-2-ones after desulfurization from simple, readily available starting materials.

Synthesis, X-Ray, Spectroscopic Characterization, Hirshfeld Surface Analysis, Molecular Docking, and DFT Calculations of a New Series of 3-Hydrazono and 3-Phenylhydrazono Isatin Derivatives

Two novel N-alkylated isatin derivatives (2–3) were synthesized under phase-transfer catalysis conditions. Their condensation with hydrazine hydrate and phenylhydrazine in refluxing ethanol as solvent generates two series of isatin derivatives (3-hydrazono and 3-phenylhydrazono) (4–7). The structures synthesized are elucidated using UV/Vis, FTIR, 13C-NMR, 1H-NMR, and single crystal X-ray diffraction techniques of 2, 3, and 5. The experimental data were compared with the predicted ones obtained at the B3LYP/6-31G(d,p) level of theory. Relatively, good agreements were found between the calculated and experimental results. The intermolecular contacts in 2, 3, and 5 were investigated through the Hirshfeld surface analysis. The expected inhibitory efficiency of 2, 3, and 5 against cyclooxygenase-2 (COX-2) are investigated by their molecular docking into the binding site of COX-2, which revealed that 2 might have strong inhibition efficacy against COX-2 compared to 3.

Synthesis of chiral malonates by α-alkylation of 2,2-diphenylethyl tert-butyl malonates via enantioselective phase-transfer catalysis.

An efficient synthetic approach for chiral malonates was established via enantioselective phase transfer catalysis. The α-alkylation of 2,2-diphenylethyl tert-butyl α-methylmalonates with (S,S)-3,4,5-trifluorophenyl-NAS bromide as a phase-transfer catalyst under phase-transfer catalytic conditions successfully produced corresponding α-methyl-α-alkylmalonates; these compounds are versatile chiral building blocks containing a quaternary carbon center in high chemical yields (up to 99%) with excellent enantioselectivities (up to 98% ee). α,α-Dialkylmalonates were selectively hydrolyzed to the corresponding chiral malonic monoacids under basic (KOH/MeOH) and acidic conditions (TFA/CH2Cl2), showing the practicality of the method.

Regio- and Stereoselective One-Pot Synthesis of New Heterocyclic Compounds with Two Selenium Atoms Based on 2-Bromomethyl-1,3-thiaselenole Using Phase Transfer Catalysis

To date, not a single representative of 2,3-dihydro-1,4-thiaselenin-2-yl selenides has been described in the literature. The reaction of 2-bromomethyl-1,3-thiaselenole with potassium selenocyanate at low temperature was accompanied by a rearrangement with ring expansion leading to six-membered 2,3-dihydro-1,4-thiaselenin-2-yl selenocyanate, which was used for the generation of sodium dihydro-1,4-thiaselenin-2-yl selenolate. The latter intermediate was involved in situ in the nucleophilic substitution and addition reactions under phase transfer catalysis conditions. The nucleophilic substitution reactions with alkyl halides gave alkyl, allyl and propargyl 2,3-dihydro-1,4-thiaselenin-2-yl selenides in 93–98% yields. The addition reactions of dihydro-1,4-thiaselenin-2-yl selenolate anion to alkyl acrylates, acrylonitrile and alkyl propiolates proceeded in a regio- and stereoselective fashion affording corresponding functionalized 2,3-dihydro-1,4-thiaselenin-2-yl selenides in 93–98% yields. Thus, the regio- and stereoselective one-pot synthesis of a novel family of 2,3-dihydro-1,4-thiaselenin-2-yl selenides has been developed based 2-bromomethyl-1,3-thiaselenole, potassium selenocyanate, alkyl halides and compound with activated double and triple bonds.

Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso-Moramide-A Novel Potentially Powerful Analgesic †.

To develop potent and safer analgesics, we designed and synthesized a novel enantiomerically enriched ethereal analog of (R)-iso-moramide, namely 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one. The titled active agent can potentially serve as a powerful synthetic opiate with an improved affinity and selectivity toward opioid receptors (ORs). This hypothesis was postulated based on docking studies regarding the respective complexes between the designed ligand and µ-OR, δ-OR, and κ-OR. The key step of the elaborated asymmetric synthesis of novel analog involves lipase-catalyzed kinetic resolution of racemic 1-(morpholin-4-yl)propan-2-ol, which was accomplished on a 10 g scale via an enantioselective transesterification employing vinyl acetate as an irreversible acyl donor in tert-butyl methyl ether (MTBE) as the co-solvent. Next, the obtained homochiral (S)-(+)-morpholino-alcohol (>99% ee) was functionalized into corresponding chloro-derivative using thionyl chloride (SOCl2) or the Appel reaction conditions. Further transformation with N-diphenylacetyl-1-pyrrolidine under phase-transfer catalysis (PTC) conditions using O2-saturated DMSO/NaOH mixture as an oxidant furnished the desired levorotatory isomer of the title product isolated in 26% total yield after three steps, and with 89% ee. The absolute configuration of the key-intermediate of (R)-(–)-iso-moramide was determined using a modified form of Mosher’s methodology. The preparation of the optically active dextrorotatory isomer of the titled product (87% ee) was carried out essentially by the same route, utilizing (R)-(–)-1-(morpholin-4-yl)propan-2-ol (98% ee) as a key intermediate. The spectroscopic characterization of the ethereal analog of iso-moramide and the enantioselective retention relationship of its enantiomers using HPLC on the cellulose-based chiral stationary phase were performed. Moreover, as a proof-of-principle, single-crystal X-ray diffraction (XRD) analysis of the synthesized 2-[(2R)-2-(morpholin-4-yl)propoxy]-2,2-diphenyl-1-(pyrrolidin-1-yl)ethan-1-one is reported.

Synthesis, crystal structure, DFT calculations and Hirshfeld surface analysis of new 2-oxo-1,2-dihydroquinoline-4-carboxylate derivative

• A new 2-oxo-1,2-dihydroquinoline-4-carboxylate derivative has been synthesized. • It is characterized using NMR spectroscopy and X-ray crystallography. • Intercontacts between crystal units are identified by Hirshfeld surface analysis. • Good correlations are obtained between the X-ray data with the predicted ones. Prop-2-ynyl 6‑chloro-1,2-dihydro-2-oxo-1-(prop‑2-ynyl)quinoline-4-carboxylate was synthesized by an alkylation reaction under phase transfer catalysis (PTC) conditions. This compound was characterized through 1 H- and 13 C NMR spectroscopy and single crystal X-ray diffraction techniques. The crystal belongs to the monoclinic space group C2/c. The lattice parameters obtained are: a = 22.3050(12) Å, 11.9577(6) Å, c = 13.4295(7) Å, α = 90°, β = 124.939(2)°, γ = 90° and Z = 4. In addition, Hirshfeld surface analysis (2D and 3D) was performed to understand the different intermolecular interactions in the crystal structure and to determine the percentage contributions of these interactions on the surface. Theoretical calculations were carried out using Density functional theory (DFT) to develop optimized geometry and frontier molecular orbital analysis.

Regioselective Synthesis of Novel Functionalized Dihydro-1,4-thiaselenin-2-ylsufanyl Derivatives under Phase Transfer Catalysis

The regioselective one-pot synthesis of novel functionalized 2,3-dihydro-1,4-thiaselenin-2-ylsufanyl derivatives in high yields based on 2-bromomethyl-1,3-thiaselenole and activated alkenes was developed under phase transfer catalysis conditions. The reactions proceed under mild conditions at room temperature in a regioselective manner with the addition of sodium dihydro-1,4-thiaselenin-2-ylthiolate exclusively at the terminal carbon atom of the double bond of vinyl methyl ketone, alkylacrylates, acrylamide, acrylonitrile, divinyl sulfone, and divinyl sulfoxide. The sodium dihydro-1,4-thiaselenin-2-ylthiolate was generated from 2-[amino(imino)methyl]sulfanyl-2,3-dihydro-1,4-thiaselenine hydrobromide. The latter compound was obtained by the reaction of 2-bromomethyl-1,3-thiaselenole with thiourea, which was accompanied by a rearrangement with ring expansion to the six-membered heterocycle. The obtained 2,3-dihydro-1,4-thiaselenin-2-ylsufanyl derivatives are a novel family of compounds with putative biological activity. The addition products of sodium dihydro-1,4-thiaselenin-2-ylthiolate at one double bond of divinyl sulfone and divinyl sulfoxide, containing vinylsulfonyl and vinylsulfinyl groups, are capable of further addition reactions. A possibility to obtain corresponding alcohol derivatives was shown in the reaction with vinyl methyl ketone.

Facile and green route polymerization of N-vinyl pyrrolidone under ultrasound-aided dual-site phase transfer catalytic conditions

Facile and green route polymerization of N-vinyl pyrrolidone under ultrasound-aided dual-site phase transfer catalytic conditions

Mechanochemical Synthesis Method for Drugs Used in the Treatment of CNS Diseases under PTC Conditions

Phase transfer catalysis (PTC) is an excellent possibility in the synthesis of organic compounds as it allows the reactions to be carried out under the conditions of green chemistry, while maintaining high yields and selectivity. The great advantage of these reactions is also the possibility of carrying out the reactions not only under conventional conditions, but also mechanochemically in solvent-free processes. Bearing this in mind, we decided to develop a new method for the synthesis of known biologically active compounds from the group of long-chain arylpiperazines (LCAPs). The first mortar trials were very promising and prompted us to carry out a series of ball mill reactions. One of the technological problems that we encountered while conducting reactions in the ball mill was the difficulty in extracting the post-reaction mixture. We tested the effects of additives improving the insulation of the product, such as, e.g., starch, zeolites, and silica. Research has proven that with appropriate process conditions using TBAB as a catalyst and in the presence of potassium carbonate and a small amount of Zeolite ZSM5 or silica, aripiprazole can be obtained with a yield of 90% in just five minutes. The obtained results are very promising and it is worth considering them as an alternative to the synthesis of other compounds from the LCAPS group.

Asymmetric Phase-Transfer Catalytic aza-Michael Addition to Cyclic Enone: Highly Enantioselective and Diastereoselective Synthesis of Cyclic 1,3-Aminoalcohols.

The highly enantioselective aza-Michael reaction of tert-butyl β-naphthylmethoxycarbamate to cyclic enones has been accomplished by using a new cinchona alkaloid derived C(9)-urea ammonium catalyst under phase-transfer catalysis conditions with up to 98% ee at 0 °C. The resulting aza-Michael adducts can be converted to versatile intermediates by selective deprotection and the cyclic 1,3-aminoalcohols by diastereoselective reduction with up to 32:1, which have been widely used as important pharmacophores in pharmaceutical development.

New gem‑dichlorocyclopropane-pyrazole hybrids with monoterpenic skeleton: Synthesis, crystal structure, cytotoxic evaluation, molecular dynamics and theoretical study

A new series of four gem-dichlorocyclopropane-pyrazole hybrids 3a-d have been synthesized from (R)-carvone, using a two-step procedure consisting of dichlorocyclopropanation under phase transfer catalysis conditions followed by a 1,3-dipolar cycloaddition reaction of the obtained cyclopropanic product with diarylnitrilimines. The structure of the target products 3a-d was fully established via spectroscopic analysis (1H- & 13C NMR and HRMS) as well as an X-ray crystallographic study carried out on compound 3d An attempt to prepare the corresponding thiosemicarbazones was unsuccessful. So, a succinct theoretical study was carried out to explain the non-reactivity of the hybrids 3a-d vis a vis thiosemicarbazide. Furthermore, all the compunds were evaluated for their anticancer activity against HT-1080 fibrosarcoma, breast adenocarcinoma (MCF-7 and MDA-MB231), and lung carcinoma A-549 cells. The four newly synthesized compounds (3a-d) exhibited interesting antiproliferative activities with IC50 values ranging from 25.78 ± 0.24 µM to 37.13 ± 0.47 µM. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells.

Vinylogous and Arylogous Stereoselective Base-Promoted Phase-Transfer Catalysis

Vinylogous enolate and enolate-type carbanions, generated by deprotonation of α,β-unsaturated compounds and characterized by delocalization of the negative charge over two or more carbon atoms, are extensively used in organic synthesis, enabling functionalization and C–C bond formation at remote positions. Similarly, reactions with electrophiles at benzylic and heterobenzylic position are performed through generation of arylogous and heteroarylogous enolate-type nucleophiles. Although widely exploited in metal-catalysis and organocatalysis, it is only in recent years that the vinylogy and arylogy principles have been translated fruitfully in phase-transfer catalyzed processes. This review provides an overview of the methods developed to date, involving vinylogous and (hetero)arylogous carbon nucleophiles under phase-transfer catalytic conditions, highlighting main mechanistic aspects.

Utility of pyrrole‐2‐thioacetohydrazide in synthesis of new heterocyclic compounds with promising antimicrobial activities and molecular docking studies

AbstractOne‐pot synthetic method for [(3‐cyano‐5‐phenyl‐1H‐pyrrol‐2‐yl)sulfanyl]acetic acids 3a,b with excellent yield have been accomplished via a tetrabutylammonium bromide (TBAB) catalyzed reaction of mercaptoacetic acid with 2‐(2‐oxo‐2‐arylethyl) malononitrile under phase transfer catalysis conditions (PTC). The coupling of methyl [(3‐cyano‐5‐phenyl‐1H‐pyrrol‐2‐yl)sulfanyl] acetate 4a,b with hydrazine gave the corresponding 2‐[(3‐cyano‐5‐aryl‐1H‐pyrrol‐2yl)thio] acetohydrazides 5a,b, which reacted with glucose, acetylacetone, carbon disulfide, phenyl isothiocyanate, chloroacetyl chloride or benzaldehyde, to afford the compounds 6a,b–11a,b, respectively ranged from satisfactory to excellent yields. In vitro antibacterial and antifungal activities were assessed with good results. Furthermore, molecular docking experiments were done for the most active compounds against the E. coli MurB enzyme in order to determine the mechanism of their antibacterial activity and showed good binding interactions.

Epoxidation of Allyl Chloride in the Presence of Tungsten Oxo–Peroxo Heteropoly Compounds of P(V), As(V), and Si(IV) Under Phase-Transfer Catalysis Conditions

Epoxidation of Allyl Chloride in the Presence of Tungsten Oxo–Peroxo Heteropoly Compounds of P(V), As(V), and Si(IV) Under Phase-Transfer Catalysis Conditions