Current Organocatalysis - Volume 8, Issue 2, 2021

Background: Acetylation of protic nucleophiles is used to protect these functional groups. Most of the methods described in the literature use solvents, one or more equivalent of toxic bases or expensive and toxic catalysts. Therefore, new methodologies, above all, greener and more economical procedures, are still in demand. Objective: An eco-efficient method was developed for the acetylation of alcohols, phenols, thiols, amines, and carbohydrates, using acetic anhydride and a catalytic amount of the environmentally benign and inexpensive FeCl3.6H2O, under solvent-free conditions. Methods: Acetylation of a variety of protic nucleophiles was performed using 0.2 mol % of FeCl3.6H2O as the catalyst, and 1.2 equivalent of Ac2O as the acetylating agent at room temperature and under solvent-free conditions. Results: This procedure appears to be highly efficient and promoted rapid and quantitative acetylation under simple and minimum manipulation. Chromatography or recrystallization was generally not necessary for the purification of products. Conclusion: This eco-friendly protocol appears to be potentially universally applicable in organic design to protect protic nucleophiles and isscalable for industrial fields.

Background: Four members of N,N-disulfo-1,1,3,3-tetramethylguanidinium chlorometallates [DSTMG]n[X], where n= 1 or 2; X= FeCl4 - , Zn2Cl6^2-, NiCl4^2-, MnCl4^2- were synthesized as solid Brønsted-Lewis acidic compounds and studied the catalytic activity with the most acidic salt for threecomponent synthesis of 1,2-dihydro-1-aryl-3H-naphth[1,2-e][1,3]oxazin-3-ones. Methods: N,N-disulfo-1,1,3,3-tetramethylguanidinium chlorometallates of the four transition metal cations such as Fe(III), Zn(II), Ni(II) and Mn(II) were prepared after treatment of the parent ionic liquid N,N-disulfo-1,1,3,3-tetramethylguanidinium chloride [DSTMG][Cl] with the respective metal chlorides in different mole fractions at 75 ºC. The synthesis of 1,2-dihydro-1-aryl-3H-naphth[1,2- e][1,3]oxazin-3-ones was carried out via three-component reaction of 2-naphthol, aromatic aldehydes and urea under neat condition at 90 ºC using 7 mol% of the [DSTMG][FeCl4] catalyst. Results: The characterization of synthesized chlorometallates was done using spectroscopic and other analytical techniques, including thermogravimetric analysis and Hammett acidity studies. Among the four salts, the salt of Fe(III) ion was observed as the strong Brønsted acidic hydrophobic salt and thus chosen for the catalytic study. Conclusion: A new type of chlorometallates of guanidinium cation with composition [DSTMG]n[X], where X= FeCl4^- /Zn2Cl6^2-/ NiCl4^2-/ MnCl4^2- and n= 1 or 2 were developed as –SO3H functionalized solid acids with varied thermal stability (150-250 ºC) and physisorbed water (0-20%) as observed from the thermogravimetric study. From them, the most Brønsted acidic Fe(III) salt was employed as an efficient recyclable heterogeneous catalyst for the one-pot synthesis of 1,2-dihydro-1-aryl-3Hnaphth[ 1,2-e][1,3]oxazin-3-ones in neat condition.

Background: The present method is facile, green and effective for the synthesis of 2- amino-3-cyano-4H-pyran derivatives which are obtained by one-pot three-component condensation reactions of aromatic aldehydes, malononitrile and methyl acetoacetate using diammonium hydrogen phosphate (DAHP) in aqueous ethanol at room temperature. Methods: 2-Amino-3-cyano-4H-pyrans were synthesized through a one-pot three-component tandem Knoevenagel cyclocondensation reaction of aromatic aldehydes, malononitrile, and methyl acetoacetate in the presence of 10 mol% of DAHP as a catalyst under aqueous ethanol medium at room temperature. All obtained structures were confirmed by their physical constant, IR, ¹H NMR, ¹³C NMR spectroscopy, and also elemental analyses for new derivatives. Results: Three-component synthesis of 2-amino-3-cyano-4H-pyrans catalyzed by DAHP with aromatic aldehydes, malononitrile and methyl acetoacetate in aqueous ethanol medium at room temperature was prepared. The achieved derivatives (nine entries) were well synthesized in excellent yields. Conclusion: The present method is straightforward, quick, and most efficient green protocol for the synthesis of 2-amino-3-cyano-4H-pyran derivatives using highly inexpensive, easily handle and, nontoxic DAHP as an efficient catalyst in aqueous ethanol medium at room temperature.

Background: Ketone is abundant in many natural products and pharmaceuticals. It is believed to be one of the important functional groups in organic chemistry. To date, several research approaches have been made to access ketone from readily available starting materials. One such notable transformation consists of the conversion of a carboxylic acid into the corresponding ketone in a one-pot manner. Objective: We aimed to develop a simple one-pot reaction for the conversion of a carboxylic acid into ketone. This reaction could be useful to convert all types of carboxylic acid to ketone in a facile manner. Methods: In this procedure, a carboxylic acid was converted into the corresponding trimethylsilyl ester using trimethylsilyl chloride in the presence of a base. A suitable organometallic reagent interacted with the ester formed at -20°C to produce the corresponding ketone. Results: Under the optimized reaction conditions, various aromatic, aliphatic and heteroaromatic carboxylic acids were converted into the corresponding ketones using organolithium reagents, in a one-pot manner. Moderate to good yields of the desired ketones were observed in most of the transformations. Conclusion: Conversion of a carboxylic acid into ketone has been reported in a one-pot fashion, where carboxylic acid has been transformed into its silyl ester. Organolithium reagents were used as nucleophiles for reaction purposes. It was observed that the organomagnesium reagents were not useful for this transformation. Aliphatic, aromatic and heteroaromatic carboxylic acids have been converted into the ketones following a simple process.

Background and Objective: Spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives are an important heterocyclic compounds. These compounds shows wide range of biological properties and exhibits varied pharmaceutical applications. Pyranopyrazoles, which are basically fused heterocyclic compounds and act as vasodilators, hypertensive, hypoglycaemic and anticancer agents. Methods: An efficient and micelle-promoted surfactant catalyzed synthesis of spiro[indoline- 3,4′-pyrano[2,3-c]pyrazole] derivatives have been achieved via one-pot four-component reaction of hydrazine hydrate (phenyl hydrazine), ethyl acetoacetate, malononitrile (ethyl cyanoacetate) and isatin under thermal conditions (at 60°C) in water as a solvent. Results: Sodium lauryl sulphate (SLS) used has been found to be an efficient and green catalyst. The compounds reported during this work were obtained in excellent yield, in a short duration of time and ease of work up. They were purified by recrystalization from ethanol and also the synthesized compounds were characterized by various spectroscopic techniques. Conclusion: The method offers several advantages such as safe, cost-effective and catalyst easily recovered and reused for a minimum of five cycles, that confirms its good stability. Short reaction times, high yield and usage of eco-friendly catalyst and solvent are the key features of this methodology.

Aims: Using Selectorfluor® for the oxidation of urazoles and sulfides as well as the oxidation of alcohols under mild conditions. Background: [1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)] so-called Selectorfluor®, is a reagent/catalyst that is donor of the electrophilic fluorine atom. Selectorfluor ® is a colorless salt which was first introduced in 1992. This year, Banks et al. prepared a salt from the reaction of dichloromethane with dabco and sodium tetrafluoroborate, and then reacted it with fluorine gas to prepare the Selectorfluor®. Objective: Unlike the highly hazardous F2, the Selectorfluor® is a stable, non-hygroscopic, easy to handle and commercially available reagent that has many applications in organic reactions. Methods: Substrate [alcohols, urazoles or sulfides (1 mmol)] was added to the mixture of Selectorfluor ® (0.708 g, 2 mmol), KBr (0.236 g, 2 mmol), and 0.2 g wet SiO2 (50%). The mixture was ground with a mortar and pestle for 10-15 minutes. Then, the product was extracted with CH2Cl2 (2×10 mL). The solution was dried with anhydrous sodium sulfate and filtered again. Simple distillation of the CH2Cl2 gave the crude product. Aldehyde/ketones and sulfoxides were purified by short column chromatography on silica gel with EtOAc/n-hexane (1:3 to 1:5). Urazoles were purified by the sublimation method. Results: Some advantages of these oxidation reactions using the Selectorfluor®/KBr system are: a) both reagent and catalyst are safe and easy to handle; b) the procedure is solvent-free; c) the reaction is carried out at room temperature; d) yields are good to excellent; e) work-up is convenient since the reagent/catalyst residue is ionic and insoluble in the organic solvents. Conclusion: Selectorfluor® is a safe and stable reagent that is easy to work with, although it is slow and lazy in reaction, and it cannot react well at room temperature. The literature survey shows that the best conditions for a reaction are acetonitrile reflux and that the solvent-free is not very desirable conditions.

Background: For the green synthesis of furocoumarins in water, PEG-OSO3H was used as a recyclable catalyst for the one-pot synthesis in water. To avoid the use of toxic lachrymators and unstable phenacyl bromides, we prepared them in-situ and directly condensed with 4-hydroxycoumarins. Objective: PEG-OSO3H was found to be an efficient and reusable catalyst for the microwave irradiated one-pot synthesis of 3-Aryl-furo[3,2-c]coumarins in PEG-water as a greener reaction medium. This method was found to be rapid, simple, eco-friendly and obtained relatively higher yield than other reported methods. Methods: Aromatic ketones (5 mmol), NBS (5mmol) were added in the solution of PEG-OSO3H (10 mol%) in 10 ml water and irradiated under ultrasound at 80-85°C. Then, the solution of 4- hydroxycoumarin (5 mmol) and the solution of acetic acid and ammonium acetate (1 ml) were added into it. The reaction mass was further irradiated for 3 min. From the reaction mixture, ethyl acetate (3 x 10ml) was extracted and the combined ethyl acetate phase was concentrated under reduced pressure to obtain corresponding 3-Aryl-furo[3,2-c]coumarins. The aqueous layer was reused for the next reactions. Results: It was observed that electrons withdrawing groups (-NO2,-F etc.) on the benzene ring of aromatic ketones increased the rate of reactions as well as the yield of the products. The IR spectrum of compound 4a showed prominent peaks at 1737cm-1C=O stretching for lactone. 1H NMR of compound 4c showed characteristic singlets for –CH3 of methoxy group at 3.94 ppm. The above spectral data confirmed the structure of the compound. The 13C NMR spectrum of 4b also showed the peaks of CH3, at 23.25 ppm. Conclusion: PEG-OSO3H has been found to be an efficient and reusable catalyst for the microwave irradiated one-pot synthesis of 3-Aryl-furo[3,2-c]coumarins in PEG-water as a greener reaction medium. This method found to be rapid, simple, eco-friendly and obtained relatively higher yield than other reported methods.

Background: Catalyzed organic reactions avoiding the use of metal salts, metal complexes and organometallic compounds have tremendous applications especially within sensitive biological systems. The current work is an effort towards metal and solvent-free organo-catalyzed reactions. Objective: Unprecedented, one-pot regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles through azide-aldehyde (3+2) organo-click cycloaddition under metal and solvent-free conditions is described. Methods: The method presents a convenient approach towards the synthesis of functionally versatile 1,4-disubstituted 1,2,3-triazoles from easily accessible substrates using recyclable 1,8-diazabicyclo[ 5.4.0]undec-7-ene (DBU)-based ionic liquids as catalysts. Results: 1,4-disubstituted 1,2,3-triazoles were obtained in moderate to excellent yield using azidealdehyde (3+2) organo-click cycloaddition under metal and solvent-free conditions. Conclusion: The procedure reported herein for the synthesis of 1,4-disubstituted 1,2,3-triazoles is straightforward, greener, devoid of tedious workups and chromatographic separation.

Background: Synthetic chemists have utilized base catalyzed halogen dance reactions ever since their discovery by Bunnet et al. Many modifications under various conditions have enabled synthetic chemists to build substituted heterocyclic targets with rich structural diversity. Methods: Using DFT-Cam-B3LYP/ land2dz computations and focusing on Hannes Frohlich et al. Halogen dance reactions of iodothiophenes, a new iodo-bridged transition state is proposed. This iodo- bridged TS was then used to put forth 8 possible isomerization as well as 8 possible disproportionation paths. Results & Discussion: All mechanistic pathways were then thoroughly investigated based on TS’s energy and protonation/deprotonation steps to find the most suitable pathways. Collectively, these mechanistic pathways were joined like a jigsaw puzzle to yield, for the first time, a comprehensive cascade-like pattern for base-catalyzed halogen dance in iodothiophenes. Conclusion: The present work may shed light on a dynamic domino mechanism that may well dominate the organic chemistry of iodothiophenyl anions. Trends like this may reveal mechanistic pathways in base digestion of halogenated aromatic compounds in CS2.

Background: Chiral β-hydroxy esters and α-substituted β-hydroxy esters represent versatile building blocks for pheromones, β-lactam antibiotics and 1,2- or 1,3-aminoalcohols. Objective: Synthesis of versatile α-substituted β-keto esters and their diastereoselective reduction to the corresponding syn- or anti-α-substituted β-hydroxy esters. Assignment of the relative configuration by NMR-spectroscopy after a Curtius rearrangement of α-substituted β-keto esters to 4-substituted 5-methyloxazolidin-2-ones. Methods: Diastereoselective reduction was achieved by using different Lewis acids (zinc, titanium and cerium) in combination with complex borohydrides as reducing agents. Assignment of the relative configuration was verified by ¹H-NMR spectroscopy after Curtius-rearrangement of α-substituted β-hydroxy esters to 4-substituted 5-methyloxazolidin-2-ones. Results: For the syn-selective reduction, titanium tetrachloride (TiCl4) in combination with a pyridine-borane complex (py BH3) led to diastereoselectivities up to 99% dr. High anti-selective reduction was achieved by using cerium trichloride (CeCl3) and steric hindered reducing agents such as lithium triethylborohydride (LiEt3BH). After Curtius-rearrangement of each α-substituted β-hydroxy ester to the corresponding 4-substituted 5-methyloxazolidin-2-one, the relative configuration was confirmed by ¹H NMR-spectroscopy. Conclusion: We have expanded the procedure of Lewis acid-mediated diastereoselective reduction to bulky α-substituents such as the isopropyl group and the electron withdrawing phenyl ring.

Objective: 3,3-Disubstituted indol-2-one derivatives have wider applications in pharmaceuticals and they are key intermediates for the synthesis of many kinds of drug candidates. The development of an efficient and practical method to prepare this class of compound is highly desirable from both environmental and economical points of views. Methods: In order to establish an effective synthetic method for preparing 3,3-disubstituted indol- 2-one derivatives, the bis-condensation reaction of isatin and 1H-indene-1,3(2H)-dione was selected as a model reaction. A variety of natural deep eutectic solvents (NADESs) were prepared and used for this reaction. The generality and limitation of the established method were also investigated. Results: It was found that model reaction can be carried out in natural deep eutectic solvent (NADES) based on choline chloride (ChCl) at 80°C under microwave irradiation. This protocol with a broad substrate applicability afforded various 2,2'-(2-oxoindoline-3,3-diyl)bis(1H-indene- 1,3(2H)-dione) derivatives in high yields. Conclusion: A simple and efficient procedure has been developed for synthesis of 2,2'-(2-oxoindoline- 3,3-diyl)bis(1H-indene-1,3(2H)-dione), spiro[indoline-3,7'-pyrano[5,6-c:5,6-c']dichromene]- 2,6',8'-trione, and spiro[indoline-3,9'-xanthene]trione via bis-condensation between isatin with 1,3- indandione, 4-hydroxycoumarin or 1,3-cyclohexanedione in natural deep eutectic solvent (NADES) based on choline chloride (ChCl) and glycerol (Gl) under microwave irradiation. The salient features of this protocol are avoidance of any additive/catalyst and toxic organic solvent, clean reaction profiles, non-chromatographic purification procedure, and high to excellent yield. Furthermore, the use of NADES as green reaction medium reduces burden on environment and makes the present method environmentally sustainable.

Background: 1,4-benzothiazine carboxylates show wide application in the field of medicinal chemistry. Therefore, we have designed convenient and efficient method for the synthesis of 1,4-benzothiazine carboxylates. Objective: Synthesis of 1,4-benzothiazine carboxylates and its guanidines by simple and facile method using efficient catalyst. Methods: Derivatives of 1,4-benzothiazine carboxylates were synthesized by cyclocondensing β- keto esters with 2-aminobenzenethiols using CAN as a catalyst at room temperature. 1,4-benzothiazine carboxylate, condensed with guanidine hydrochloride in the presence of sodium methoxide in DMF to obtained new 3-substituted-l-4H-benzo[b][1,4]thiazine-2-carboxyguanidines (88-91%). Results: All the products were obtained with good to excellent yields within 40 min. Here, CAN oxidizes aminothiophenol into disulfide and then nucleophilic attack of enolic form of β-ketoesters on the disulphide and 1, 4-benzothiazine acetates, were obtained with good yields. Conclusion: We have designed convenient and efficient method for the synthesis of 1,4-benzothiazine carboxylates. Most remarkable features of this cyclocondensation such as use of efficient catalyst and non-volatile solvent under mild reaction condition to obtain excellent yield.