Current Microwave Chemistry (v.3, #3)

Meet Our Editorial Board Member by Jiaxi Xu (177-177).

Microwave Assisted Synthesis, Biological Characterization and Docking Studies of Pyrimidine Derivatives by Sanjay K. Rathwa, Manoj N. Bhoi, Mayuri A. Borad, Kinjal D. Patel, Dhanji P. Rajani, Smita D. Rajani, Hitesh D. Patel (178-186).
Background: Microwave-assisted organic synthesis has rapidly evolved in the last decade as a well-organized utensil for synthetic chemists. The pyrimidine scaffold still residues as one of the most valuable class of compounds for the synthesis of clinically useful drugs. Molecular docking is frequently used to forecast the binding orientation. The probability of binding of protein to pyrimidine analogues is fascinating and Docking is used to bring out new ligands for biological targets with a known 3D structure.
Methods: Pyrimidine derivatives 5a-5i was synthesized from Chalcones through condensation reaction with guanidine hydrochloride in presence of basic medium via both conventional and Microwave assisted method. In vitro anti-malarial activity against P. falciparum strain, the synthesized compounds were also screened for antibacterial activities against Gram-positive bacteria and Gram-negative bacteria, then done antifungal activity. Molecular modeling study of synthesized compounds as well as the marketed drug pyrimethamine was performed by Glide 5.0 (Schrodinger Maestro 8.5).
Results: Microwave assisted is a very good method for the synthesis of pyrimidine derivatives, in reverence to less time and giving excellent yields as compare to the conventional method. Our results indicated that analogue 5g and 5i show the most pronounced excellent anti-malarial activity, IC50 Value 0.55, 0.70 (?g/mL) respectively. On the other hand Compound 5a, 5d, 5f, 5g, 5h and 5i possesses good activity against Gram negative and Gram positive bacteria. And compound 5c, 5e and 5f shown excellent antifungal activity.
Conclusion: We conclude microwave assisted synthesis is an excellent method as camper to conventional heating. The experimental activity profiles were furthermore validated by docking studies thru the inhibition of P. falciparum dihydrofolate reductase (PfDHFR), a probable target for the improvement of new anti-malarial agents.

Microwave Assisted ZrSiO2 Mediated One-Pot Synthesis of Spiro[chromene- 4,3'-indoline] Derivatives by Mayuri A. Borad, Manoj N. Bhoi, Bhakti N. Patel, Hitesh D. Patel (187-193).
Background: Microwave-assisted organic synthesis has been a powerful and expedient tool for quick organic synthesis which has vital advantages such as simplicity in process, cumulative rate of reaction, high reaction yields, and less amount of side product etc. Multicomponent reactions have developed chemical transformations for powerful bond-forming in organic, combinatorial and medicinal chemistry. The spirooxindole system possesses prominent biological properties and played a very vital role as a core structure of many synthetic pharmaceuticals. Isatin and its derivatives are a leading molecule for designing latent bioactive agents. Isatin and its derivatives are used as precursors due to having numerous applications and great biological characteristics. Fused chromenes derivatives have established more attention because of their high potential biological application. Here, we have described a one-pot synthesis of diverse spiro[chromene-4,3'-indoline] derivatives using ZrSiO2 mediated three-component reactions of substituted phenols with isatin and malononitrile.
Methods: We have used microwave assisted method for synthesis. We have taken mixture of phenol derivatives, Isatin, Malononitrile, the catalyst, ZrSiO2 (10 mol %) and 5 ml methanol was placed into a 25 mL round bottomed flask. The reaction mixture was irradiated under microwave radiations at 100 °C, 300 W for 3-7 min. The progress of the reaction was monitored by thin layer chromatographic plate. After consumption of all starting materials the mixture was poured into water and then extracted with ethyl acetate. The organic layer was washed with brine and evaporated under reduced pressure. The combined aqueous layer was filtered to recycle the catalyst. Filtered catalyst washed with methanol two or three times to remove the strains and tars, and then dried in an oven. Compounds were isolated by column chromatography, elution gradient 15% Ethyl acetate: hexane as pure yellow solid with 80-90% of yield. The catalyst was reused up to three cycles with slight decrease of catalytic activity. Antibacterial activity of synthesized compound was carried out on Nutrient- agar plates by well-diffusion assay against test culture.
Results: The one pot three-component cyclization reaction of phenol derivatives, isatin and malononitrile in the presence of ZrSiO2 (10 mol %) as catalyst in methanol was performed and the reaction was completed in 3-7 minutes by using microwave irradiation to afford 2-amino-2'-oxospiro [chromene-4,3'-indoline]-3-carbonitrile 4a in good yields.
First, we optimized catalyst for finding best catalyst in very short reaction time with high yields. Reactions using ZrSiO2 in methanol give desirable yield with 88 % in very short time. A sensible decrease in the product yield was observed only after the third recycle of the catalyst. The structures of all the newly synthesized compounds were confirmed by various spectroscopy techniques. All the synthesized compounds were screened through antibacterial activity. Most of the synthesized compounds found to be active against Gram negative bacteria and Gram positive bacteria.
Conclusion: We have presented a series of 2-amino-2'-oxospiro[chromene-4,3'-indoline]-3-carbonitrile derivatives that have been synthesized by microwave assisted reaction by isatin, malononitrile and various phenol derivatives. We have described a facile, one pot, three component, and environmentally benign protocol using ZrSiO2 as a prompt catalyst which can be reused. Most important of all, the synthesized derivatives can be used for the development of new antibacterial drugs because compounds 4f, 4b and 4d exhibited promising activity as compared to streptomycin.

Background: Small ring nitrogen heterocycles like four membered cyclic carbamates play an important role in medicinal chemistry. The aim of the paper is to facilitate the readers with the green synthesis of carbamates. As the previous reported procedure suffer from one or more demerits such as longer reaction times, obsolete work up procedure, poor yields of the products, and the use of toxic and inflammable solvents. Therefore, we planned to develop a green procedure for the synthesis of oxazetidin-2-ones -a four membered cyclic carbamate under non-conventional energy conditions such as microwave.
Methods: A facile and convenient approach to novel 3,4-diphenyl-1,3-oxazetidin-2-ones (four membered cyclic carbamates) building blocks is described here. For the present study N-cyano(?-bromo-?-phenyl)methylanilines(I) have been used for the decarboxylation reaction employing microwave assisted organic synthesis. Their assembly is attained by N-cyano(?-bromo-?-phenyl)methylanilines (I) which undergo reductive decarboxylation to provide four membered cyclic carbamates(II) in good yield.
Results: The nitrile group gets transformed into amide derivative through microwave irradiation which subsequently suffers nucleophilic attack by alcoholic group on C-phenyl moiety to give azetidone moiety. These azetidone have been characterised through their elemental analysis, infrared, proton magnetic resonance, 13CNMR and high resolution mass spectra.
Conclusion: In conclusion, this paper reports a facile, simple and environmentally benign methodology for the synthesis of substituted oxazetidin-2-ones derivatives in good to excellent yields under microwave conditions by using water as a solvent. Short reaction times, simple workup procedures and mild reaction conditions are the key features of this method. Furthermore, the use of microwave makes this protocol highly efficient and economically viable.

Background: Organic reactions accelerated by microwave irradiation is an area of great interest in recent times. Several organic reactions are usually slow under normal or thermal conditions, however, use of microwave irradiation reduces the reaction time significantly. Multi component reactions (MCRs) are of interest due to nature of complex products formed in a one pot reaction.
Methods: The reaction (MCR) is accelerated by montmorillonite K10 catalyst under microwave conditions.
Results: Microwave assisted 'montmorillonite K10' catalysed synthesis of novel 1-(2,7-dimethyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidin-6-yl)ethanone based fused heterocyclic compounds of medicinal interest is reported in this communication. The reaction is carried out by taking an aldehyde, amine and a 1,3 ketone (1:1:1), alongwith montmorillonite K10 (catalytic) in solvent free condition in an ecofriendly manner under microwave irradiation for about 5 mins followed by chromatography. All new compounds obtained in excellent yields are well characterized by 1HNMR, IR, Mass etc.
Conclusion: A very efficient, MCR involving montmorillonite K10 catalyst and microwave irradiation is reported in this communication for the synthesis of several novel 1-(2,7-dimethyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidin-6-yl)ethanone derivatives of medicinal interest.

Microwave Assisted Eco-Friendly Synthesis, Characterization and in vitro Release Behavior of Carboxymethyl Xanthan Gum by Hemant R. Badwaik, Kalyani Sakure, Kartik T. Nakhate, Hemant Dhongde, Pranita Kashayap, Dulal K. Tripathi (203-211).
Background: In recent time, microwave-assisted procedures are becoming popular ecofriendly approaches in the Green Chemistry. In chemical processing, microwave irradiation is evolving as an efficient tool and has been utilized in various fields including polymer chemistry. Microwave irradiation extends its use in the carboxymethylation of polysaccharides like starch, hemicellusose and chitosan. However, to date, no study has reported the microwave-assisted carboxymethylation of xanthan gum. In this background, the aim of the present investigation was to synthesize microwaveassisted carboxymethyl xanthan gum.
Methods: In the present study, eco-friendly synthesis of carboxymethyl xanthan gum was carried out using microwave. The optimum reaction conditions for the carboxymethylation of xanthan gum were studied by independent variation of six parameters. The synthesized gum was characterized by Fourier transform infrared, X-ray diffraction, differential scanning calorimetric analysis and scanning electron microscopy. Further, to evaluate drug release behavior, matrix tablets of diltiazem hydrochloride were prepared.
Results: The results revealed maximum degree of substitution (0.818) with exposure time of 4 min, microwave power of 360 W, 3 g of NaOH, 1.5 g of monochloroacetic acid and alkalization time of 30 min. In characterization studies, non toxic and semi-crystalline nature of carboxymethyl xanthan gum was observed. The drug release data showed a significantly faster release of diltiazem hydrochloride from matrix tablets of carboxymethyl xanthan gum as compared to tablets prepared using xanthan gum.
Conclusion: We suggest that the microwave-assisted carboxymethylation is an efficient Green Chemistry method for the synthesis of carboxymethyl xanthan gum with zero toxicity rating and Super Case II transport.

Microwave Assisted Synthetic Approach of New Pyridine based Benzothiazepines: Their Antibacterial and Antifungal Activities by Navin B. Patel, Hemant R. Patel, Faiyazalam M. Shaikh, Dhanji P. Rajani, Vatsal M. Patel (212-218).
Background: The Present work describe the synthetic protocol of a new series of 2-(4-(2-(5- Ethylpyridin-2-yl)ethoxy)phenyl)-4-(4-substituted)-2,3-dihydrobenzo [b][1,4]thiazepine (5a-j) by the cyclization of chalcones (4a-j) with 2-amino thiophenol by microwave induced solvent free conditions as well as conventional approach.
Methods: The elemental analysis and spectral method (IR, 1H and 13C NMR) were characterized the structure of all synthesized compounds.
Result: These compounds were screened for antibacterial and antifungal activity. Bezothiazepine derivative 5f showed potency (MBC = 50 µg/ml) against gram negative P. aeruginosa and 5i displyed encouraging activity (MFC = 200 µg/ml) against A. niger and A. clavatus.
Conclusion: The solvent less non-conventional microwave induced synthesis of compound (5a-j) has been proven considerable advantageous over conventional methods.

A Complete Degradation of Organophosphates by Microwave-Assisted Hydrolysis by Petr Jansa, Lucie Cechova, Zlatko Janeba (219-226).
Background: Organophosphates form the basis of many well-known insecticides, herbicides, drugs and nerve agents. Since they belong to the most pervasive synthetic chemicals, a highly efficient method for their degradation has been searched for.
Methods: Recently, an efficient microwave-assisted hydrolysis of phosphonate diesters to the corresponding phosphonic acids has been developed. This novel method, employing inexpensive aqueous hydrochloric acid, has been used to study hydrolytic degradation of organophosphates.
Results: The course of the hydrolysis under microwave irradiation was studied on diethyl chlorophosphate, diisopropyl chlorophosphate and paraoxon as model compounds. Subsequently, the complete hydrolysis to benign phosphoric acid has been demonstrated on 20 toxic organophosphates.
Conclusion: The described methodology represents an efficient and environmentally friendly procedure for the degradation of toxic organophosphates with wide range of possible applications, including water detoxification and purification.

Background: Bemzo and naphthopyranes are biologically relevant heterocycles that demonstrate a wide variety of biological activity. 2-amino-4H-chromenes is among the most compounds that exist in drugs. It is well documented that for chiral drugs one enantiomer possesses biological activity while it's enantiomer is either inactive or less active. Catalytic asymmetric synthesis of such scaffold is very rare utilizing expensive catalyst or lengthy reaction procedure. The aim of this article is to develop a simple, green methodology for the asymmetric synthesis of naphthopyran derivatives via the reaction of malononitrile, aromatic aldehydes and ?-naphthol in water under rmicrowave irradiation in the presence of catalytic amount of Zn(L-proline)2.
Methods: We will develop further utility of Zn(L-proline)2 as simple, recyclable, water soluble and easy to be handled chiral catalyst for the asymmetric synthesis of naphthopyrans in a multicomponent reaction of malononitrile, aromatic aldehydes and ?-naphthol in water under microwave heating. The recyclability of the catalyst will be investigated and the enantioselectivity of the products will be determined.
Results: A variety of asymmetric 2-amino-4H-chromenes were obtained in excellent yields and moderate enantioselectivity. The catalyst could be reused up to four times without pronounced decrease in reactivity.
Conclusion: We have developed a simple and environmentally friendly technique for the asymmetric synthesis of 2- amino-4H-chromenes utilizing for the first time Zn(L-proline)2 As asymmetric Lewis acid catalyst through a tandem Michael addition cyclization of aromatic aldehydes, malononitrile and ?-naphthol. The process proved to be green and of high atom economy.

Catalyst Free Microwave Assisted Synthesis of Sulfides in Aqueous Media by Sushilkumar S. Bahekar, Aniket P. Sarkate, Ishwari A. Kale, Pravin S. Wakte (233-237).
Background: Although several methods are reported for the C-S bond formation, the microwave assisted method reported in this work is simple and proceeds with high yields in short time.
Methods: In the synthetic method, the targeted aryl sulfides were synthesized with the help of microwave by reacting halobenzenes, substituted thiophenols and potassium carbonate in the presence of dimethyl sulfoxide and water.
Results: All the aryl sulfides were obtained in good yield (87%-97%) with the help of microwave technique and in the presence of dimethyl sulfoxide: water as a solvent system.
Conclusion: Microwave assisted synthesis will be a useful alternative method for the synthesis of diverse range of aryl sulfides.

Background: Trisubstituted alkenes are synthetically very important and recognised as versatile substrates for Diels-Alder reactions, Michael addition reactions and Morita-Baylis-Hilman reactions. Among the available procedures, Knoevenagel condensation is considered the most efficient method of synthesizing these alkenes. Numerous reaction conditions and catalysts have been reported till date. However, most of these procedures are being phased out to comply with the increasing demands for environmental protection. Clean, expeditious, sustainable and environmentally benign protocol for Knoevenagel condensation is required.
Methods: Solvent free and microwave assisted greener synthetic strategy has been developed by making use of indium(III) triflate as the catalyst.
Results: Under optimized reaction conditions, 25 sets of reactions using nucleophiles such as malonates, malonic acid and acetylacetone have been carried out and all of them have afforded the desired products in excellent yields. In condensation of two bulkier malonates to benzaldehydes, it was observed that the bulkiness of the malonates did not have much effect on the outcome of the reactions. The catalyst can be easily recovered quantitatively and reused.
Conclusion: By making use of water stable and reusable indium(III) triflate, a simple, effective, convenient and environment- friendly protocol for the synthesis of trisubstituted alkenes has been developed. The yields are excellent and the catalyst could be recovered easily and reused. Solvent free condition, microwave irradiation, easy recovery and reusability of the catalyst are the significant features of this greener synthetic strategy.

An Efficient and Rapid Microwave-Assisted Synthesis of 1-acetyl-1Hindol- 3-yl Acetates by Jay P. Parshotam, John A. Brazier, Richard Bovill, Helen M.I. Osborn (247-257).
Background: The synthesis of indoles, which are often derived from 1-acetyl-1H-indol-3-yl acetates, is of considerable synthetic interest, for example due to their medicinal properties, and their applications within microbiology. Whilst several chemical routes are available for accessing indoles, many are lengthy, and their scope for accessing a range of derivatives has not always been demonstrated. Herein, an optimised method for the synthesis of 1-acetyl-1H-indol-3-yl acetates is presented that is rapid and efficient, and allows entry to a range of functionalised indoxyls.
Methods: 1-Acetyl-1H-indol-3-yl acetates 1 and 7 have been prepared via the microwave-assisted cyclisation and decarboxylation of 2-[(carboxymethyl)amino]benzoic acids 5. The latter were reacted with acetic anhydride using triethylamine as the base and were subjected to microwave irradiation for 1 minute, at 80 °C with initial power of 300 W. Two chemical routes were investigated for access to the key 2-[(carboxymethyl)amino]benzoic acid intermediates 5.
Results: The target 1-acetyl-1H-indol-3-yl acetates 1 and 7 were isolated in 34-71% yield. In particular, synthesis of 1-acetyl-6-(trifluoromethyl)-1H-indol-3-yl acetate 7f and 1-acetyl-7-methyl-1H-indol-3-yl acetate 7h is reported for the first time. Access to the key 2-[(carboxymethyl)amino]benzoic acid intermediates 5 was achieved via two complementary routes, with a two step synthesis that used 2-aminobenzoic acids 4 as the starting materials being the preferred strategy.
Conclusion: The synthesis of 1-acetyl-1H-indol-3-yl acetates 1 and 7 from 2-[(carboxymethyl)amino]benzoic acids 5 has been optimised. By using microwave irradiation, and altering the base, solvent and reaction time, rapid entry to a range of indoxyl derivatives 1 and 7 proved possible, in good yield.

Simplifying Nucleophilic Aromatic Substitutions: Microwave-Assisted Solvent Free Synthesis of 5-Alkylamino-2-nitroanilines by Pedro J. Trejo-Soto, Anuar Flores-Gahona, Rafael Castillo, Alicia Hernández-Campos (258-265).
Background: Substituted 2-nitroanilines are synthetic intermediates used in the synthesis of important bioactive compounds. Nucleophilic aromatic substitution reactions with activated substrates, such as substituted 5-chloro-2-nitroanilines, usually involve the use of a solvent, high pressure conditions and prolonged reaction times. We describe a simple and straightforward protocol to prepare 5-substituted 2-nitroanilines that addresses these drawbacks.
Methods: Utilizing microwave irradiation and solvent free conditions, a series of 5-alkylamino-2- nitroanilines (1-14) have been efficiently prepared by reacting 4,5-dichloro-2-nitroaniline with different primary and cyclic secondary amines.
Results: The reactions proceeded in short periods of time (5-35 min) without side products, facilitating the isolation of 1- 14 in 55-93% yields. Reactions under microwave conditions were faster than those achieved with conventional heating.
Conclusion: This simplified approach can be a suitable alternative to synthetic methods involving conventional heating. The reported methodology can be applied to generate a variety of 5-substituted 2-nitroanilines which serve as precursors to compounds of pharmaceutical interest.