An Expedient Green Synthesis of 7-Arylbenzo[c]acridine-5,6(7H,12H)- dione Derivatives Mediated by Achiral Nicotinic Acid

Chemical composition of fingerprints includes the presence of salts, ions, fatty acids, lipids, amino acids, nucleobases, nucleotides, and nucleic acids. Many methods used to detect latent fingerprints on porous surfaces such as paper exploit the reactivity of amino acids with a number of different reagents, including ninhydrin and lawsone (2-hydroxy-1,4-naphthoquinone; HNQ). HNQ, also known as hennotannic acid, is a natural yellow-orange dye present in the leaves of henna plant (Lawsonia inermis) as well as in the flower of water hyacinth (Eichhornia crassipes). It is used as natural dye to color hair and skin. HNQ has been shown to react with amino acids, accordingly used to detect fingerprints on paper. HNQ has also been shown to be a sensor for the detection of anions (changes its color from yellow to orange-red in the presence of anions such as OH-, CN-, etc.). The presence of nucleobases, nucleotides and/or nucleic acids that are also part of the chemical composition of fingerprints, has not been exploited to detect latent fingerprints. In this study we propose utilize the reactivity of HNQ, nucleobases and nucleotides to detect and enhance the detection of latent fingerprints. HNQ reacts with amines and form Schiff-bases that are expected to be strongly colored, whose colors can be further enhanced upon exposure to a base (NH3) or anions (OH- and/or CN). In this regard, we have synthesized a series of HNQ-amine derivatives using microwave green synthetic methods (reactants dissolved in methanol and the reaction carried out at 150°C for 5 min). The compounds formed in the above reactions are strongly colored as judged visually and by spectrophotometry. Under similar conditions, adenine and guanine bases or adenosine and guanosine nucleosides (with amine substituents) also react with aromatic aldehydes to form Schiff-bases. The aromatic aldehyde derivatives of these purine nucleobases or nucleosides are expected to be highly fluorescent. Again, we have synthesized a series of aromatic imine derivatives of adenine, guanine, adenosine and guanosine as above. As judged visually and by spectrophotometry, these compounds exhibit strong fluorescence. The spectroscopic characterization of the compounds described above is on-going. Further, we have used these compounds to detect and enhance detection of latent fingerprints. The latter involved (a) application of powdered HNQ, adenine, guanine, adenosine or guanosine on latent fingerprints or cyanoacrylate coated latent fingerprints, (b) powder deposition aromatic amines or aldehydes, (c) followed by microwave synthesis of Schiff-base derivatives directly on the surface of the fingerprints using a commercially available domestic microwave oven (medium power for 3–10 min). The resulting fingerprints developed as above with HNQ and aromatic amines are strongly colored. Further exposure of thus formed colored fingerprints to NH3 strongly enhanced their color. The fingerprints developed as above using purine nucleobases or nucleosides with aromatic aldehydes were strongly fluorescent. Through this study, we have successfully synthesized Schiff-base derivatives of HNQ and aromatic amines as well as purine nucleobases or nucleosides and aromatic aldehydes. Further, we also suggest a novel method for the detection of latent fingerprints and its successful application on nonporous surfaces using the newly synthesized compounds.

The use of polymer-based catalysts has increased because of their high potential application as an effective catalyst in organic reactions. They have benefits such as high efficiency and reactivity, simple separation, and safety compared to other heterogeneous catalysts. The objective of the current research is to prepare solid polymer-based catalysts, poly(aniline-co-m-phenylenediamine) (PAmPDA), and its superparamagnetic nanocomposite. Then, the catalytic activity of the resulting superparamagnetic nanocomposite was investigated in the synthesis of 1H-pyrazolo[1,2-b]phetalazine-5,10-diones and 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives. A series of some 1H-pyrazolo[1,2-b]phetalazine-5,10-diones and 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives was tested for its antibacterial properties against the Staphylococcus aureus and E. coli bacteria. PAmPDA copolymer was synthesized in a 1:2 molar ratio of Ani to mPDA via radical oxidative polymerization at room temperature. Superparamagnetic PAmPDA@Fe3O4nanocompo-site was synthesized from a mixture of Fe(II), Fe(III) solution, and PAmPDA copolymer via the in-situ co-precipitation technique. 1H-pyrazolo[1,2-b]phetalazine-5,10-diones were synthesized via one-pot three-component condensation reaction of Phthalhydrazide, aromatic aldehyde derivatives, and malono-nitrile in the presence of PAmPDA under solvent-free conditions at 80 °C. The synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives was carried out via a one-pot three-component condensa-tion reaction of maleic hydrazide, aromatic aldehyde derivatives, and malononitrile in the presence of PAmPDA under reflux conditions at EtOH/H2O 1:1. The antibacterial activity of some derivatives was tested against Gram-positive and Gram-negative bacteria. First, superparamagnetic PAmPDA@Fe3O4 nanocomposite was synthesized and characterized successfully, and then the resulting nanocatalyst was used for the synthesis of pyrazolo[1,2-b]phthalazine and pyrazolo[1,2-a]pyridazine. We obtained the maximum yield of the desired 1H-pyrazolo[1,2-b]phthalazine-5,10 dione derivatives with 0.05 g of catalyst at 80°C, under solvent free conditions, whereby the reaction was complete within 30 min. A wide range of 1H-pyrazolo[1,2-b]phthalazine-5,10 dione derivatives were synthesized in good to excellent yield. On the other hand, pyrazolo[1,2-a]pyridazine derivative was synthesized successfully in high yield using PAmPDA as a nanocatalyst. The antibacterial activity of some derivatives, according to the data (inhibition zone%), showed good ac-tivity against Staphylococcus aureus and E. coli. In this research, PAmPDA was used for mild preparation of 1H-pyrazolo [1,2-a]pyridazine-5,8-diones & 1H-pyrazolo[1,2-b]phetalazine-5,10-diones derivatives with excellent yields and short reac-tion times. The attractive features of this protocol are simple procedure, cleaner reaction, and the use of recyclable nanocatalyst. Satisfactory yields of products and easy workup make this a useful protocol for the green synthesis of this class of compounds. The antibacterial activity of some derivatives, according to the data (inhibition zone%), showed good activity against Staphylococcus aureus and E. coli.

The goal of this thesis is to develop new carbon-carbon bond forming reactions using inexpensive and simple coupling partners like aryl halides (pseudohalides), sulfonyl derivatives, Grignard reagents, alkenes and alkynes with metal catalysis, preferably under environmental friendly conditions. A brief review of different cross-coupling reactions is presented applying noble metal catalysts like palladium and nickel. The importance of sustainability and hence the development of alternative iron-catalysis is discussed. The history of iron-catalyzed cross-coupling reactions and their applications to the synthesis of natural products, significant new developments in the field are visited. On our side, we have shown that 2-methylpropene-, prop-2-ene-, 1-methylprop-2-ene- and but-2-enesulfonyl chlorides can be used as electrophilic partners in palladium-catalyzed desulfinylative C-C cross-coupling reactions with both hard and soft nucleophiles. Alk-2-enesulfonate esters can also be used as electrophilic partners in allylic arylations and allylic alkylations. The regioselectivity of the reaction depends on the nature of the catalyst. With PdCl2(PhCN)2, (E)-crotylderivatives are formed with high regioselectivity using either 1-methylprop-2-ene- or but-2-enesulfonyl chlorides. We found also the alk-2-enesulfonyl chlorides that are electrophilic partners in palladium-catalyzed C-C coupling reactions can also be used as nucleophilic partners towards carbonyl compounds by Umpolung. In the presence of a catalytic amount of palladium and a transmetallating agent such as diethylzinc, sulfonyl chlorides can be coupled both with aldehydes and ketones to form homoallylic alcohols in good yields. In the case of unsymmetrical sulfonyl chlorides, regioselectivity depends on the polarity of the solvent and generates selectively products of γ-addition. Most useful is our discovery of conditions permitting the desulfinylative C-C cross-coupling of inexpensive alkanesulfonyl chlorides and Grignard reagents. Above 65 °C, the iron-catalyzed reaction generates products of C-C coupling rather than sulfones. It does not require any expensive and/or toxic ligand. This procedure was also applied to the ligand free iron-catalyzed couplings of alk-2-enesulfonyl chlorides with aromatic and aliphatic Grignard reagents. We have also discovered the synergic effect of iron and copper salts in palladium-free Sonogashira-Hagihara cross-coupling reaction of a wide range of aryl iodides, aromatic and aliphatic alkynes. Together with Dr. R. Loska we have studied the iron-catalyzed Mizoroki-Heck cross-coupling reaction with styrenes. In the presence of iron(II) chloride and potassium tert-butoxide in dimethyl sulfoxide, aryl and heteroaryl iodides undergo stereoselective Mizoroki–Heck C-C cross-coupling reactions with electron-rich alkenes at 60 °C giving the corresponding (E)-alkenes. The best yields were obtained upon addition of a ligand such as proline or picolinic acid. Aryl bromides and pyridinyl bromides are also coupled with styrenes but in lower yields. Finally, we have explored iron-catalyzed C-H activation. Ligand and solvent free-conditions have been developed for the iron-catalyzed oxidative C-C cross-coupling of tertiary amines and terminal alkynes. FeCl2 catalyzes the coupling to generate propargylamines using tert-butylperoxide as oxidant. High chemoselectivity was observed for the aminomethyl group and was attributed to a steric factor.

Abstract:A green and efficient protocol was developed for the one-pot three-component synthesis of novel 2-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-(arylamino)-1H-indene-1,3(2H)-dione derivatives by the reaction of 4-hydroxycoumarin, ninhydrin and aromatic amines in the presence of guanidine hydrochloride as an organocatalyst under solvent-free conditions. The present approach offers several advantages such as low cost, simple work-up, short reaction times, chromatography-free purification, high yields and greener conditions.

Background: In this research, pyridinium hydrogen sulfate ionic liquid (PHSIL) was employed as a green, efficient and reusable catalyst for the synthesis of 1,8-dioxo-decahydroacridines. Different primary amines and aromatic aldehydes were subjected to the reaction with 5,5-dimethyl- 1,3-cyclohexanedione (dimedone) in the presence of this catalyst and the corresponding products were achieved in excellent yields and short reaction times. Two important advantages of the study were easily separation of ionic liquid from the reaction mixture by water extraction and a high recycling capability of up to six times. Methods: Different primary amines and aromatic aldehydes were subjected to the reaction with 5,5-dimethyl-1,3- cyclohexanedione (dimedone) in the presence of, pyridinium hydrogen sulfate ionic liquid (PHSIL) catalyst and the corresponding 1,8-dioxo-decahydroacridines derivatives were achieved in excellent yields and short reaction times. Results: Having established optimum conditions as follows: aldehyde (1 mmol), amine (1 mmol), PHSIL (0.65 mmol), CH3CN (3 mL) at 80°C, a series of 1,8-dioxo-decahydroacridines were synthesized via the one-pot three component reaction between various aromatic aldehydes and amines with dimedone. The aromatic aldehydes containing electrondonating and electron-withdrawing groups afforded 1,8-dioxo-9-aryl-10-aryl-decahydroacridines with high yields within short reaction times in comparison with other conventional procedures. The presence of substituent on the amine has the same effect. All compounds were identified by melting point (in some cases), IR spectra, 1H- and 13C-NMR and elemental analysis. Conclusion: In summary, pyridinium hydrogen sulfate ionic liquid was used as a green catalyst for the synthesize of 1,8- dioxo-decahydroacridines. Various derivatives of acridinediones were synthesized in high yield. Short-time reaction, high yield, stability, reusability up to six times, relatively non-toxicity of the catalyst, economically viable and one-pot synthesis of acridinedione derivatives are the important advantages of the reported method. Keywords: 1, 8-dioxo-decahydroacridines, green chemistry, ionic liquid, pyridinium hydrogen sulfate, reusability.

ABSTRACTPolyfunctionalized heterocyclic compounds have an important role in the drug discovery process and analysis of drugs in late development. Piperidines and their analogues have received attention owing to their biological activities, because of the importance of these heterocycle compounds, there is still a need to improve the ways for green synthesis of these compounds. In this study, lactic acid was applied as a green and efficient catalyst for the one-pot five-component synthesis of highly substituted piperidines from the reaction between aromatic aldehydes, aromatic amines, and b-ketoester at ambient temperature. This methodology has a number of advantages such as: use of easy access and green catalyst, short reaction times, high yields, and easy work-up (just simple filtration).

Mesoporous silica nanoparticles in an efficient, solvent-free, green synthesis of acridinediones

The synthesis of a wide variety of α-amino amidine derivatives was accomplished through a one-pot three-component reaction from aromatic aldehydes, aromatic amines and isocyanides, catalyzed by bromodimethylsulfonium bromide (BDMS), in good yields. Some of the salient features of the present protocol are: mild reaction conditions, shorter reaction times, non-aqueous work-up procedure and no need for chromatographic separation.

An efficient, green, high yielding, and quick method for the synthesis of N-substituted decahydroacridine-1,8-diones was achieved by multicomponent reaction between various aromatic aldehydes (1a–q), dimedone (2), and various aromatic amines (2a–d) using ChCl:Urea deep eutectic solvent as a recyclable organocatalyst and medium. The reaction conditions are relatively mild and do not require additional metals, acid catalysts, or organic solvents. The mild reaction conditions, experimental simplicity, straightforward purification procedures, excellent yields with short reaction times, as well as the application of green chemistry principles, are the advantages of this methodology. This simple ammonium deep eutectic solvent, easily synthesized from choline chloride and urea, is relatively inexpensive and biodegradable, making it applicable for industrial use. The deep eutectic solvent was easily separated and reused without loss of activity, and thus provides a good alternative. The synthesized 10-(substituted phenyl)-9-(substitutedphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8 (2H,5H)-diones (4a–l) were screened for their in vitro antimicrobial activity against four bacterial Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and three fungal strains (Candida albicans, Aspergillus niger and Aspergillus flavus). Among them, the 9-(N,N-Dimethylphenyl)-3,3,6,6-tetramethyl-10-(3-pyridyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4f), 10-(4-Bromophenyl)-9-(3-hydroxy-4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4i) and 9-(4-Nitrophenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4k) show good antimicrobial activity.

For the first time, an elegant, metal‐free and concise route using a pseudo five‐component reaction of dimethyl acetylenedicarboxylate, mono/bis‐ aromatic aldehydes and amines with trifluoroacetic acid as an effective organocatalyst to afford novel and diverse substituted bis‐2,5‐dihydrofuran‐3‐carboxylates in good yields at ambient temperature has been described. The prominent features of this protocol are the energy sustainability, wide range of functional group tolerance, shorter reaction time, no column chromatographic purification, facile experimental and work‐up procedure. The present one‐step, cascade synthetic approach is straightforward that could avoid hazardous reagents/solvents and is turned to be a benign chemistry for the preparation of potent bis‐ O ‐heterocyclics on a multigram scale.

2-Oxindoles, especially those 3,3-disubstituted or spiro-fused to other cyclic frameworks, continue to be recognized as valuable compounds for drug discovery. They are present in a large number of natural and unnatural compounds with important biological activities and serve as key intermediates for the synthesis of many kinds of drug candidates.1 In particular, spirooxindoles, having cyclic structures fused at the C3 carbon, move away from the flat heterocycles encountered in many drug discovery programs. For this reason, they are of special interest, being able to potentially provide improved physicochemical properties in their interaction with biological systems.2 As more examples of the enantiospecific biological activity are identified, efficient and reliable asymmetric synthesis of such compounds becomes more and more valuable. In this context, the identification of asymmetric methods that achieve high stereoselectivity in the synthesis of heterocyclic compounds, in particular bearing tetrasubstituted or spiro-stereocenters, remains challenging. In this context, my research was aimed to the synthesis of oxindole-based libraries, exploiting protocols at the cutting edge of synthetic chemistry, such as MCRs and organocatalysis. Considering the great attention around optically active δ-amino-α,β-unsaturated carbonyl compounds as important building blocks in the synthesis of biologically active compounds,3 for my first project I focused my attention on the synthesis of 3-amino-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-ones derivatives via a BINOL-based phosphoric acids organocatalyzed vinylogous Mannich-type reaction.4 The desired products were obtained in general good yields and high enantiomeric excesses considering the challenge in the formation of a quaternary stereocenter consecutive with a bulky tertiary one. The stereochemistry of the final products was assigned by chemical correlation with respect to a reported compound5 and the stereochemical outcome was also rationalized by computational study. Moreover, I studied the Biginelli reaction, a three component cyclocondensation between alkyl acetoacetates, urea and a carbonyl compound, as a practical method for the synthesis of biologically important 3,4-dihydropyrimidine-2(1H)-ones.6 In particular, BINOL-phosphoric acids have been used in the development of the first enantioselective organocatalyzed multicomponent Biginelli-like reaction applied to a ketone, allowing to obtain a small library of spiro[indoline-pyrimidine]-dione derivatives in good yields and enantioselectivity.7 During the second year, I focused my attention on the synthesis of 2-oxindoles spiro-fused with four- and five-membered rings. Considering the recent medicinal chemists' interest in oxindole-based thiazolidine compounds as antitumor agents for the inhibition of the p53-MDM2 PPI,8 a novel synthetic approach towards spirooxindole-fused thiazolidines has been developed, based on two sequential multicomponent reactions (MCRs), namely the Asinger and two different Ugi-type reactions,…

The Schiff bases were prepared with aromatic aldehyde and aromatic amine using cashew shell extract as a catalyst under microwave irradiation. This reaction is rapid, efficient, and solvent-free and involves the one-pot synthesis of Schiff bases under microwave irradiation. The synthesized Schiff bases were characterized by Fourier transform infrared (FTIR) spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, 13C NMR spectroscopy, and gas chromatography-mass spectrometry (GC-MS). The advantages of the preparation of Schiff bases under microwave irradiation are high yield, shorter reaction time, easy, elimination of side products, and quick product isolation. The synthesized Schiff base derivatives are well known for their biological activity like antibacterial and antifungal activity.

A facile and convenient greener route has been introduced for the synthesis of novel 2‐phenyl‐2,3,5,6‐tetraazaaceanthrylene‐1,4(2 H ,5 H )‐dione derivatives via one pot three component reaction of barbituric acid, substituted aryl amines and isatin with ethanol as solvent. The synthesized compounds were characterized by FT‐IR, 1 H NMR and 13 C NMR techniques. The remarkable features of this method are catalyst‐free, short reaction time, good yields and simple purification techniques. The effect of inhibition and possibilities of interaction of 1GQN enzyme on Salmonella typhi with synthesized compounds was explored through molecular docking approach. Pharmacokinetics profile of the synthesized compounds was explored by ADME technique. All the synthesized compounds have also been evaluated for their antibacterial activity against Gram positive and Gram‐negative bacterial strains. The compounds 4a and 4d exhibited significant effect against four human pathogenic bacterial strains with the maximum inhibition zone.

A series of novel 10‐substituted 3,6‐diphenyl‐9‐aryl‐3,4,6,7,9,10‐hexahydroacridine‐1,8(2H,5H)‐dione derivatives 2 were synthesized by condensation of compounds 1 with amines, which the compounds 1 were synthesized by 5‐phenylcyclohexane‐1,3‐dione and aromatic aldehydes according to Knoevenagel, Michael, and cyclization reactions in the presence of a very small amount of l‐proline as catalyzed at room temperature. The structures of all the synthesized compounds were characterized by IR, 1H NMR, and MS. In addition, the molecular structures of compound 1a have been determined by single‐crystal X‐ray diffraction analysis.

1,2-Dimethyl-N-butanesulfonic acid imidazolium hydrogen sulfate as efficient ionic liquid catalyst in the synthesis of indeno fused pyrido[2,3-d]pyrimidines