Tunable Regioselective Allylic Alkylation/Iodination of Imidazoheterocycles in Water.

The switchable roles of allylic alcohol and molecular iodine as reagents and catalysts have been demonstrated in the regioselective allylic alkylation and iodination of imidazoheterocycles employing the mixture of allylic alcohol-I2. First, we have explored the catalytic activity of iodine for the allylation of imidazoheterocycles using allylic alcohol in an aqueous medium. The allylation of a library of imidazoheterocycles and other electron-rich heterocycles like indole, pyrazole, 4-hydroxy coumarin, and 6-amino uracil has been achieved by employing this methodology. The efficiency of the I2 catalyst for N-allylation of azoles has also been demonstrated. Next, we have shown that this mixture of allylic alcohol and I2 could be beneficial for the iodination of imidazoheterocycles under room temperature. Mechanistic studies indicate that the activation of allylic alcohol by molecular iodine took place probably through halogen bonding, and NMR studies show that the reaction did not proceed through allylic ether formation.

Influence of steric hindrance on the 1,4- versus 1,6-Michael addition: synthesis of furans and pentasubstituted benzenes.

We described the influence of steric hindrance on the 1,4- versus 1,6-Michael addition reaction on 2-(3,3-bis(methylthio)-1-arylallylidene)malononitriles. An efficient and direct synthesis of trisubstituted furans was achieved through the reaction of 2-(3,3-bis(methylthio)-1-arylallylidene)malononitriles and acetone under mild conditions in good to moderate yield by the 1,4-Michael addition. Further exploration of the reaction with a sterically hindered aryl group containing 2-(3,3-bis(methylthio)-1-arylallylidene)malononitriles afforded biaryls by an in situ generated nucleophile through the 1,6-Michael addition. The synthetic utility of furan is further explored. These precursors are easily accessible from aryl methyl ketones. Various functional groups like alkyl, aryl, nitrile, amine, aroyl, and thiomethyl can be directly installed in the benzene and furan rings. A one-pot approach for the construction of a benzene nucleus was also developed. The structure of two compounds was confirmed by X-ray crystallography.

Iodine/DMSO-mediated one-pot access towards 1-aryl-2-(pyrazol-5-yl)ethane-1,2-diones via a domino reaction from functionalized pent-2-ene-1,5-diones.

A facile one-pot cascade synthesis involving simultaneous in situ pyrazole formation followed by iodine/DMSO-mediated oxidation has been established to afford 1-aryl-2-(3-aryl)-1H-pyrazol-5-yl-ethane-1,2-diones. Primarily, a two-pot approach has been established which includes the reaction of 3-methylthio-1,5-diaryl-2-pentene-1,5-diones with hydrazine in the first step to afford pyrazole, which was eventually oxidized in the next steps in the presence of iodine in DMSO. Furthermore, we performed both steps in the same pot to afford 1,2-dicarbonyl compounds in good yield. The structure of one of the compounds was confirmed by single crystal X-ray analysis. DMSO served as a solvent as well as an oxidant. Moreover, N-substituted hydrazines provided 1-(1-substituted-3-aryl-1H-pyrazol-5-yl)-2-arylethane-1,2-diones regioselectively. Furthermore, for synthetic application, 1-aryl-2-(3-aryl)-1H-pyrazol-5-yl-ethane-1,2-diones were treated with o-phenylenediamine to afford pyrazole-functionalized quinoxaline in good yield. A control reaction was carried out to understand the mechanism of product formation.

Ru(II)-Catalyzed Weakly Coordinating Carbonyl-Assisted Dialkynylation of (Hetero)Aryl Ketones.

Functionalized aryl(heteroaryl) ketones are present in many natural products as key structural components and serve as basic synthetic building blocks for various organic transformation reactions. Therefore, the development of an effective and sustainable route for making these classes of compounds remains challenging yet highly desirable. Herein, we report a simple and efficient catalytic system for dialkynylation of aromatic/heteroaromatic ketones via a double C-H bond activation in the presence of less expensive ruthenium(II)-salt as a catalyst using the weakly and native carbonyl group as the desired directing group. The developed protocol is highly compatible, tolerant, and sustainable toward various functional groups. The synthetic utility of the developed protocol has been demonstrated through the scale-up synthesis and functional group transformation. Control experiments support the involvement of the base-assisted internal electrophilic substitution (BIES) reaction pathway.

Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies.

Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2'-pyrrolidin]-2-one/spiro[indoline-3,3'-pyrrolizin]-2-one 23a-f, 24a-f, and 25a-g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a-h, various substituted chalcones 21a-f, and 22a-c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.

Iodine-Mediated Synthesis of 2-(Methylthio)-4H-chromen-4-ones and Study of Their Halogenation Reactions.

An efficient iodine-mediated method is developed for the synthesis of functionalized 2-(methylthio)-4H-chromen-4-ones by intramolecular cyclization of easily accessible 1-(2-benzyloxy-aryl)-3,3-bis-methylsulfanyl-propenones. The synthesized chromen-4-ones turn out to be a key precursor for various kinds of chemical reactions. Mechanistically, we observed that iodine-mediated intramolecular cyclization of ketene dithioacetal proceeded through a radical pathway. 3-Halo-2-(methylthio)-4H-chromen-4-ones were achieved via various two- or one-pot halogenation approaches.

Step-wise and one-pot synthesis of highly substituted conjugated trienes from 2-oxobenzo[h]chromenes/2H-pyran-2-ones.

A mild and efficient route for the synthesis of conjugated trienes via nitroethane-mediated ring contraction of 2-oxobenzo[h]chromenes/2H-pyran-2-ones followed by decarboxylative rearrangement of the obtained spirobutenolides and butenolides is described. The (E)-isomer of trienes was obtained by step-wise and one-pot approaches from 2-oxobenzo[h]chromenes. Butenolides 4a-l as new substrates have been developed for the construction of trienes. The mixture of the (E)- and (Z)-isomers of spirobutenolides undergoes decarboxylative rearrangement in the presence of sodium ethoxide as a base to yield the (E)-isomer of trienes, while the (E)-isomer of butenolides reacts to give a mixture of (2E,4E)- and (2E,4Z)-isomers of trienes in an almost steady ratio of 45 : 55 or 1 : 1.2. The structure and geometry of the obtained butenolides and trienes were confirmed by single-crystal X-ray analysis.

Base mediated synthesis of functionalized 2-(alkynyl)arylnitriles and their molecular docking study with aromatase receptor.

A simple, efficient, and transition metal-free approach to synthesize functionalized 2-(alkynyl)benzonitriles has been developed using suitably functionalized 2H-pyran-2-ones and 4-phenyl/trimethylsilanyl-but-3-yn-2-ones as precursors. The reaction proceeds in the presence of a base at room temperature to yield internal as well as terminal alkynes. The structure of the synthesized compound was confirmed by single-crystal X-ray analysis. The molecular docking study was performed to evaluate the binding mode of action of newly synthesized alkyne derivatives with known human breast cancer target receptor aromatase (PDB ID: 3EQM).

Correlation of drug resistance with single nucleotide variations through genome analysis and experimental validation in a multi-drug resistant clinical isolate of M. tuberculosis.

BACKGROUND: Genome sequencing and genetic polymorphism analysis of clinical isolates of M. tuberculosis is carried out to gain further insight into molecular pathogenesis and host-pathogen interaction. Therefore the functional evaluation of the effect of single nucleotide variation (SNV) is essential. At the same time, the identification of invariant sequences unique to M. tuberculosis contributes to infection detection by sensitive methods. In the present study, genome analysis is accompanied by evaluation of the functional implication of the SNVs in a MDR clinical isolate VPCI591. RESULT: By sequencing and comparative analysis of VPCI591 genome with 1553 global clinical isolates of M. tuberculosis (GMTV and tbVar databases), we identified 141 unique strain specific SNVs. A novel intergenic variation in VPCI591 in the putative promoter/regulatory region mapping between embC (Rv3793) and embA (Rv3794) genes was found to enhance the expression of embAB, which correlates with the high resistance of the VPCI591 to ethambutol. Similarly, the unique combination of three genic SNVs in RNA polymerase ß gene (rpoB) in VPCI591 was evaluated for its effect on rifampicin resistance through molecular docking analysis. The comparative genomics also showed that along with variations, there are genes that remain invariant. 173 such genes were identified in our analysis. CONCLUSION: The genetic variation in M. tuberculosis clinical isolate VPCI591 is found in almost all functional classes of genes. We have shown that SNV in rpoB gene mapping outside the drug binding site along with two SNVs in the binding site can contribute to quantitative change in MIC for rifampicin. Our results show the collective effect of SNVs on the structure of the protein, impacting the interaction between the target protein and the drug molecule in rpoB as an example. The study shows that intergenic variations bring about quantitative changes in transcription in embAB and in turn can lead to drug resistance.

A [5 + 1] annulation strategy for the synthesis of multifunctional biaryls and p-teraryls from 1,6-Michael acceptor ketene dithioacetals.

A new type of ketene dithioacetal, 2-(3,3-bis-methylsulfanyl-1-arylallylidene)malononitriles containing 1,4 and 1,6-Michael acceptors, were synthesized to study their reactivity for the synthesis of a new molecular entity. We report a [5 + 1] annulation strategy for the construction of multifunctional biaryls and p-teraryls by the selection of a suitable nucleophilic source. The reaction of p-nitrotoluene with 2-(3,3-bis-methylsulfanyl-1-aryl-allylidene)malononitriles under basic conditions produces p-teraryls in good yields, while the use of nitroethane as the nucleophile source provides functionalized biaryls through cyclization, followed by denitration. This reaction requires mild conditions and exhibits good functional group tolerance.

Synthesis of alkynes from non-alkyne sources.

Alkynes are a very important class of compounds and used as precursors for the assembly of a variety of carbocycles and heterocycles. Alkynes are classified into two classes: terminal alkynes and internal alkynes. Terminal alkynes were used as one of the precursors for the synthesis of internal alkynes. Besides, various elimination reactions were conducted to obtain alkynes. Various applications of alkynes are known but no compiled review is reported so far regarding their synthesis. Therefore, we have compiled the literature available for the synthesis of various functionalized alkynes from non-alkyne sources in this review. We have not discussed the synthesis of internal alkynes from terminal alkynes. Based on the available literature, the synthesis of alkynes can be classified into three major types of reactions: (a) synthesis of alkynes through α,ß-elimination, (b) synthesis of alkynes through carbene rearrangement and (c) synthesis of alkynes via miscellaneous approaches. In this review, we have focused on the different methods available for these transformations including their scope, limitations and recent developments. We have also discussed the mechanism involved during the reaction.

Transition metal-free synthesis of sterically hindered allylarenes from 5-hexene-2-one.

A simple, efficient and transition metal-free strategy was established for the synthesis of highly functionalized, sterically hindered allylarenes (6, 7 & 8) by base-mediated ring transformation of 2-oxo-6-aryl-4-(methylthio/sec-amino)-2H-pyran-3-carbonitriles (3/4) with 5-hexene-2-one (5). This provides a method for the synthesis of allylarenes functionalized with different electron donating and withdrawing groups in one pot. The structures of isolated products 6c and 7a were ascertained by spectroscopic and single crystal X-ray diffraction analyses. In addition, we have performed a molecular docking study to predict the biological activity of the synthesized molecules for binding to estrogen receptor alpha (ERα) and estrogen receptor beta (ERß).

Synthesis of Highly Functionalized Spirobutenolides via a Nitroalkane-Mediated Ring Contraction of 2-Oxobenzo[ h]chromenes through Denitration.

A facile synthesis of highly functionalized spirobutenolides was carried out by a nitroalkane carbanion-induced ring opening and relactonization via a denitration reaction of 2-oxo-5,6-dihydro-2 H-benzo[ h]chromene-3-carbonitriles and 2-oxo-2,5-dihydrothiochromeno[4,3- b]pyran-3-carbonitriles. However, when nitroethane was used as a nucleophile source in lieu of nitromethane, a mixture of ( E)- and ( Z)-isomers of the corresponding spirobutenolides was obtained in a different ratio. The structure and geometry of the product were confirmed by single-crystal X-ray diffraction. The isolated ( E)- and ( Z)-butenolides with the treatment with sodium ethoxide in DMF at room temperature provided highly substituted trienes via an allylic ring opening followed by decarboxylation.

Synthesis, biological evaluation and molecular docking study of 1-amino-2-aroylnaphthalenes against prostate cancer.

A series of functionalized naphthalene was synthesized and screened against human prostate cancer cell line (PC-3). The in vitro antiproliferative activity of the synthesized compounds was evaluated by monitoring their cytotoxic effects against PC-3 cells by using MTT assay. We observed that compound 5f resulted in more than 50% cell death at 14 µM. Treatment of PC-3 cells with 5f provides apoptosis by flow cytometry. Western blotting showed decreased expression of pro-caspase 8 and 9. Our study shows that cancer cell treated with 5f has higher concentration of reactive oxygen species as compare to untreated sample, which facilitate cancerous cell to enter apoptosis. Exact mechanism by which ROS is generated after 5f treatment is still under study. Molecular docking study further strengthens the results obtained from in vitro experiments. Compound 5f can be considered as a promising leads for anticancer agent against prostate cancer cells due to its potent cytotoxic activity and apoptotic effect.

Base controlled diverse reactivity of allyl cyanide for synthesis of multi-substituted benzenes.

A base controlled regioselective 1,6-cyanoallylation of suitably functionalized 2H-pyran-2-ones has been demonstrated for the synthesis of various multi-substituted benzenes through a tandem process. We observed that lithium hydroxide provides a major product from α-attack and a minor product from γ-attack of allyl cyanide, while the use of sodium hydride as a base exclusively provides the product by γ-attack of allyl cyanide. We have also performed NMR experiments to understand the mechanistic pathway. The structure of the compound was confirmed by single crystal X-ray analysis.

Chemoselective synthesis of m-teraryls through ring transformation of 2H-pyran-2-ones by 2-(1-arylethylidene)-malononitriles.

We have developed a simple, efficient and chemoselective approach for the synthesis of m-teraryls by the reaction of 6-aryl-2-oxo-4-(sec.amino)-2H-pyran-3-carbonitriles and 2-(1-arylethylidene)malononitriles under basic conditions. We used 6-aryl-2-oxo-4-methylsulfanyl-2H-pyran-3-carbonitriles as precursors and successfully afforded 5'-methylsulfanyl-[1,1';3',1'']teraryl-4'-carbonitriles. We tried to understand the difference in the reactivity of structurally symmetrical molecules, such as allyl cyanide, 2-cyanomethylbenzonitrile and 2-(1-arylethylidene)malononitrile. The structure of 4''-methyl-5'-(piperidin-1-yl)-[1,1':3',1''-terphenyl]-4'-carbonitrile was confirmed by single crystal X-ray diffraction analysis.

Chemoselective synthesis of isolated and fused fluorenones and their photophysical and antiviral properties.

Highly functionalized fluorenones were synthesized by an intramolecular cyclization of 2''-halo-[1,1':3',1''-terphenyl]-4'-carbonitriles in the presence of n-butyllithium or lithium aluminium hydride. The precursor was synthesized by ring transformation of 2-oxo-6-aryl/heteroaryl-4-(sec.amino)-2H-pyran-3-carbonitriles or 2-oxobenzo[h]chromenes with o-bromo/chloro/fluoro-acetophenone under basic conditions in moderate yield. We performed the control experiment to understand the proposed mechanism and found that the presence of a secondary amine in the starting material directs the reactivity. The photophysical properties of 3-methoxy-7-(piperidin-1-yl)-5H-indeno[2,1-b]phenanthren-8(6H)-one was explored and solvent dependent emission was observed. These compounds were also tested against HIV-1 and low to moderate activity was observed.

Microwave assisted base dependent regioselective synthesis of partially reduced chromenes, isochromenes and phenanthrenes.

We have reported a microwave assisted base directed regioselective synthesis of partially reduced chromenes, isochromenes and phenanthrenes. Functionalized 4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]-chromen-2-one-3-carbonitriles have been used as precursors, which on reaction with functionalized acetophenones in the presence of KOH in DMF under microwave irradiation yield (Z)-2-(2-aryl-5,6-dihydro-4H-benzo[f]isochromen-4-ylidene)acetonitriles. The use of NaH in DMF provides 3-aryl-1-(piperidin-1-yl)-9,10-dihydro phenanthrene-2-carbonitriles in excellent yield regioselectively. The use of cyclohexanone as a nucleophile source yields (Z)-2-(3,4,7,8-tetrahydro-1H-naphtho[2,1-c]chromen-6(2H)-ylidene)acetonitriles. The structure and geometry of isochromene have been proved without any ambiguity by single crystal X-ray diffraction.

Synthesis of 1-amino-2-aroyl/acetylnaphthalenes through a base mediated one pot inter and intramolecular C-C bond formation strategy.

A new precursor 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile has been synthesized by the reaction of 2-cyanomethylbenzonitrile, carbon disulfide and methyl iodide under basic conditions. The reaction of 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile with various functionalized aryl/heteroaryl methyl ketones or acetone under basic conditions afforded 4-amino-3-aroyl/heteroaroyl/acetyl-2-methylsulfanylnaphthalene-1-carbonitriles in good yields through a (5C + 1C) annulation strategy; this involves sequential intermolecular, followed by intramolecular, C-C bond formation reactions. The structure of the product was confirmed by single crystal X-ray crystallography.

Direct alkenylation of indolin-2-ones by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles: a novel approach.

A direct one-pot base-induced alkenylation of indolin-2-ones has been developed by using 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles. Different bases such as MeONa, NaH and t-BuONa have been used to optimize the reaction conditions to obtain the desired product. NaH in THF was found to be the most suitable for the alkenylation of indolin-2-ones. Reaction in the presence of other bases led to the formation of 1-aryl-3-methoxy/methylthio-5H-dibenzo[d,f][1,3]diazepin-6(7H)-ones. Quantum chemical calculations have been performed to explain the nature of the weak noncovalent interactions operating in the supramolecular architectures of alkenylated indoline-2-ones and to explain the relative stability of one of the tautomers with respect to the others.