Letters in Organic Chemistry - Volume 15, Issue 6, 2018

Background: Up to date, numerous attempts for the synthesis of potentially interesting medicinally important heterocyles and organic compounds by application of a wide range of homogeneous and heterogeneous catalysts under green conditions have been made and published. The abundance and variety of diseases and the needs of mankind for treatment of them have made these attempts inevitable. Furthermore, among highly active catalysts, nano-sized Lewis acids play an outstanding role in organic synthesis. Considering all the above facts, herein, numerous potentially interesting biologically active organic products have been synthesized and reported by the use of magnetic iron oxide nanoparticles under green conditions with good to excellent yields. Methods: An efficient and environmentally adapted synthetic route to tri-substituted methanes syntheses by the use of Fe3O4 nanoparticles as a green and recyclable Lewis acid catalyst is introduced. The chemical structures of all obtained products were deduced and confirmed by their 1H NMR, 13C NMR, IR spectroscopies, and elemental analyses (C, H, N, S). Results: In this study, magnetic iron oxide nanoparticles (Fe3O4 NPs) as an highly efficient, recyclable and eco-friendly heterogeneous Lewis acid catalyst have been successfully applied to the green and promoted synthesis of a newly prepared type of tri-substituted methane derivatives containing 4- hydroxycoumarin, arylaldehydes, and N,N-dimethylbarbituric acid under mildly solvent-free conditions via a Domino reaction. In some cases, condensed products via Knoevenagel coupling reaction are only obtained under given conditions. This procedure using Fe3O4 NPs has some advantages synthetically and from industrially point of view including obtaining excellent yields of products, short reaction times, green and safety protocol, ease of handling, and capability of catalyst for reuse. Conclusion: By this achievement, the scope of organic products and potentially biological active compounds has been developed. One-pot synthesis of products under green conditions using reusable magnetic Fe3O4 nanoparticles as catalyst with high yields could attract the interests of chemists and industrialists. In addition, the presence of 4-hydroxycoumarin and N,N-dimethylbarbituric acid scaffolds as important biological and pharmacological fragments in the chemical structure of products makes them more significant for pharmacologists, and their biological and pharmacological activities could be evaluated in future.

Background: Phorboxazole is a polycyclic natural product which exhibits antitumor activity. The synthesis of C20-C26 segment of phorboxazoles, possessing 5 contiguous stereocenters, is described. Methods: A double diastereoselective aldol reaction using an Evans chiral oxazolidinone with a chiral aldehyde generates the C23-C25 stereocenters. Chain extension via Horner-Wadsworth-Emmons olefination and subsequent functional group manipulation set the stage for introduction of C26 stereocenter via a Sharpless asymmetric dihydroxylation. A Roskamp homologation serves to introduce C20-C21 carbons. Results: The acyclic segment was generated in 13 steps, 7.6% overall yield was obtained from the precursors 4 and 5. Examination of the 3JH-H coupling constants for several of the compounds revealed that they exist in predominantly one conformer. Conclusion: The linear molecules 13, 17, and 18 serve as additional examples of acyclic molecules with defined conformation. The defined conformations of these molecules are due to the presence of a bulky “inductor group”.

Fluorescence and photoisomerization studies on donor-acceptor substituted phenyl conjugated molecules [e.g. 2-[(1E)-2-(4-nitrophenyl)ethenyl]furan (trans-1) and 2-[(1E)-2-(4-aminophenyl)- ethenyl]furan (trans-2)] in solvents of varying polarity suggest that ethenylfuran trans-1, with strong electron acceptor, exhibits large solvatochromic red shifted fluorescence maximum, highly dipolar excited state, and photostability. On the other hand, ethenylfuran trans-2 with electron donor amino substituent, is photoreactive and undergoes trans-cis photoisomerization. These results suggest that, in such systems, highly dipolar excited state does not favor trans-cis photoisomerization.

Classical methods for the synthesis of diarylmethylpiperazine drugs generally lead to the generation of high levels of waste. In this study, we have developed a simple and efficient route to the anti-histamine drugs Meclizine 1, Buclizine 2, Clocinizine 3, Cinnarizine 4, Flunarizine 5 and Flotrenizine 6. The advantage of this route lies on the replacement of harmful alkyl halides by readily available alcohols to achieve the N-alkylation of the piperazine unit. This procedure was further extended to the synthesis of other diarylmethylpiperazine drugs and derivatives.

Background: Blockade of kainate receptors is an emerging strategy to treat neurodegenerative diseases, including Parkinson's disease as well as to treat epilepsy. In particular, non-competitive antagonists of kainate receptors are promising due to the expected good safety profile. We present here synthesis, experimental and computational studies of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5- yl)benzamide which is an intermediate in the synthesis of hypoxanthine derivatives which were designed as non-competitive antagonists of kainate GluK1/GluK2 receptors. Method: The title compound was obtained in a five-step synthesis protocol and characterized used X-ray crystallography and experimental and computed spectra. Results: The presented detailed X-ray studies of the title compound confirm the reaction course. The title compound crystallizes in triclinic P-1 space group. The asymmetric unit comprises two independent molecules of the compound (A and B) and a DMF solvent molecule. The interpretation of IR spectra was facilitated by Potential Energy Distribution (PED) analysis. The low value of HOMO-LUMO gap indicates that the studied compound is relatively reactive. Conclusion: The title compound is a well-characterized intermediate which will be subjected to cyclization to hypoxanthine derivative designed as non-competitive antagonist of kainate GluK1 and GluK2 receptors.

A green and efficient approach to aryl azides, in very short reaction times and excellent yields, has been developed via the reaction of arylboronic acids with sodium azide under CuI catalysis in neat Water Extract of Banana (WEB). The entire process provided compensations over conventional heating in that reactivity of the less reactive arylboronic acids was induced as well as the reaction time was reduced. We have described and permitted to have the first synthesis of aryl azides in natural feedstock extract WEB in the absence of organic co-solvents as well as external base, promoters/ additives, ligands and so on.

Background: Esters of fatty acids with alcohols especially polyols (polyhydroxy alcohols) have found considerable applications as synthetic greases, synthetic lubricants, in cosmetics, food, and paint industries. Industrial or conventional esterification is carried out by the condensation of carboxylic acids with alcohols in the presence of an acid catalyst of homogenous nature. The development of heterogeneous / solid acid catalysts owing to their safe handling, stability, facile recovery and recycling ability for esterification reactions has been a subject of great scientific interest. However, the reported methods have been used for the esterification of acids with mono-alcohols. To the best of our knowledge, there is no report on the use of graphene-based carbocatalysts for the esterification of fatty acids with polyhydroxy alcohols. Methods: The desired sulfonated graphene oxide (SGO) was synthesized by following the two step approach in which first step involves the synthesis of graphene oxide (GO) from oxidation of graphite followed by sulfonation with sulfanilic acid under diazotization conditions to give SGO. Esterification of fatty acids with polyhydroxy alcohols was carried out using 5 wt % of SGO as a catalyst in toluene at 110 °C for 6 h. Results: A number of experiments were performed to optimize the reaction parameters for esterification of 2,2-dimethyl-1,3-propanediol (DMPD) with caproic acid (C6 acid) as model example. The optimum condition for the esterification was found to be 5 wt % SGO, 6 h reaction time, and 110 °C. After optimizing the reaction parameters, the scope of the reaction was further extended to a variety of long chain fatty acids. The presence of electron releasing ethyl group in 2-ethylhexanoic acid had poor effect on the conversion. Conversion and selectivity were determined by GC-MS. Conclusion: The present paper demonstrates the preparation of SGO from GO and sulfanilic acid through diazotization route. The synthesized solid acid carbocatalyst was used in the esterification of fatty acids with polyhydroxy alcohols for bio-lubricant applications, which is an important branch of green chemistry. Importantly, the carbocatalyst showed excellent recyclability, which suggested high stability of sulfonic acid groups in SGO.

The importance and wide application of hydrazones are due to a broad spectrum of biological activities that they possess. The biological activity generally depends on the pH values of the media which have influence on the extent of ionization of organic compounds. The dissociation process of five 4-methoxybenzaldehyde benzoylhydrazones in aqueous sodium hydroxide media was determined using UV spectroscopy method, at room temperature. The influence of the substituents in the pposition of benzoyl moieties was investigated. Prediction of the deprotonation site in the hydrazone molecule was made by using the deprotonation enthalpy values calculated using the AM1 and PM3 semiempirical methods. The dissociation process took place in one step as a result of the dissociation of the amide group, or in two steps for 4-methoxybenzaldehyde 4-hydroxybenzoylhydrazone. The changes in the UV spectra with the basicity of the media were used for calculation of the dissociation constant values. One dissociation constant (pKHA) was calculated for hydrazones which contain only an amide group. The first and the second dissociation constants (pKH2A and pKHA −) were determined as a result of the dissociation of the amide and phenolic group of 4-methoxybenzaldehyde 4- hydroxybenzoylhydrazone which contain these groups. The dissociation of amide group of this hydrazone was retarded due to the influence of phenolic group. In order to obtain thermodynamic pKHA values, the measurements were performed at three different ionic strengths (0.10, 0.25, and 0.50 mol/dm3). The first deprotonation site was due to dissociation of phenolic group, while the second one was a result of dissociation of the amide group. The strength of the acid decreased by following the order: 4- chlorobenzoyl- > benzoyl- > 4-methoxybenzoyl- > 4-methylbenzoyl- > 4-hydroxybenzoyl hydrazone. The obtained results demonstrated that the influence of the substituents was not significant, except for 4-methoxybenzaldehyde 4-hydroxybenzoylhydrazone.

An efficient synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives using nanocrystalline magnesium oxide (nano-MgO) as a catalyst from 2-aminobenzamide and various aldehydes/ketones under aqueous conditions at room temperature is described. Nano-MgO was synthesized by the precipitation and hydrothermal treatment of aqueous salt solution as reported previously. The structure of nano-MgO was characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM) analysis. Simple conditions, environmentally benign, good to excellent yields and comparatively shorter reaction times are the advantages of this protocol.

2,4,5-Triaryl-1H-imidazoles were synthesized from benzyl bromides under Kornblum oxidative condition. The reaction proceeded via an in situ oxidation followed by condensation to afford the desired products in good yields.

Background: Aldehydes were converted to carboxylic acids using sodium hypochlorite as oxidant in a single step, involving microwave assistance and without a metal catalyst in basic media. The use of microwave irradiation increased both conversion and yield due to an easier work-up and the reaction time was reduced. Two advantages of this oxidation are the relatively low cost and low pollution. This oxidative method has been applied to alcohols successfully. Results: Several aryl aldehydes and alcohols containing different substituents were oxidized with moderate to excellent synthetic yields. The effects of various substituents on the aromatic nucleus were examined, finding that not only the nature of the substituent is important but also its position. Microwave irradiation was favorable and considerably reduced the reaction time. Conclusion: A simple and effective preparation of carboxylic acids from the corresponding aldehydes or alcohols in basic media was successfully achieved with inexpensive domestic beach.

In the present study, a new class of triazino-caffeine derivatives with good antimicrobial activities is reported. Eight new triazino-caffeine derivatives were synthesized via Mitsunobu reaction, followed by intramolecular cyclization. Their chemical structures were established on the basis of elemental analysis, IR, 1H NMR, mass spectral data as well as through an alternate synthetic route. The compounds were also screened for their antimicrobial activities, among them, compounds 5c and 5d showed good inhibitory potentials, indicating the importance of morpholine moiety in enhancing antimicrobial activity. Therefore, it is concluded that the triazino-caffeine derivatives developed, show encouraging potentials in their medicinal applications.

Background: Over the last few years, one of the primary focuses of our research group has been the synthesis and biological evaluation CANs featuring structural and/or configurationally alterations on the carbocyclic moiety. We previously reported an enlarged group of diversely functionalized amino cyclopentenols, cyclopentenols and cyclopentenones as useful precursors in the synthesis and posterior biological evaluation of CANs featuring structural and/or configurationally alterations on the carbocyclic moiety; moreover the five-membered carbocycles are common structural units in other natural products and bioactive compounds, for this reason, these compounds presented great interest for their use as building blocks in the development of compounds with potential pharmacological activities. Method: The conversion of benzyl cyclopent-3-enocarboxylate into a mixture of the corresponding hydroxy allylic esters 5a and 5b was efficiently achieved by the employed diphenyl diselenide, H2O2 in dry CH2Cl2 for the synthesis of phenylselenenic acid and electrophilic addition to double bond of 3, and 90% tert-butyl hydroperoxide subsequently being added. Results: The mixture of compounds 5 was obtained in good yields under these conditions, and this was readily separated by column chromatography. Isolated components were identified by 1H and 13C NMR spectral, as well as by its EI HRMS. The corresponding alcohols 5a or 5b were easily transformed in the corresponding 3,5-dinitrobenzoyl derivatives, 6a and 6b, from which single crystals were obtained, permitting unequivocal identification. Conclusion: Using a one-pot method, benzyl cyclopent-3-enecarboxylate was turned into a mixture of corresponding hydroxy allylic derivatives 5a and 5b, employing diphenyl diselenide, H2O2 and tertbutyl hydroperoxide for the formation and subsequent oxidation/elimination of the first-generated alkyl phenyl selenides. The use of these oxidants corresponds to modern trends in organic synthesis, because they are easily available and environmentally friendly reagents, which can be used at a large scale.