Maya Shankar Singh

Recent developments in solvent-free multicomponent reactions: a perfect synergy for eco-compatible organic synthesis

Multicomponent reactions have gained significant importance as a tool for the synthesis of a wide variety of useful compounds, including pharmaceuticals. In this context, the multiple component approach is especially appealing in view of the fact that products are formed in a single step, and the diversity can be readily achieved simply by varying the reacting components. The eco-friendly, solvent-free multicomponent approach opens up numerous possibilities for conducting rapid organic synthesis and functional group transformations more efficiently. Additionally, there are distinct advantages of these solvent-free protocols since they provide reduction or elimination of solvents thereby preventing pollution in organic synthesis “at source”. The chemo-, regio- or stereoselective synthesis of high-value chemical entities and parallel synthesis to generate a library of small molecules will add to the growth of multicomponent solvent-free reactions in the near future. In this review we summarized the results reported mainly within the last 10 years. It is quite clear from the growing number of emerging publications in this field that the possibility to utilize multicomponent technology allows reaction conditions to be accessed that are very valuable for organic synthesis. Therefore, diversity oriented synthesis (DOS) is rapidly becoming one of the paradigms in the process of modern drug discovery. This has spurred research in those fields of chemical investigation that lead to the rapid assembly of not only molecular diversity, but also molecular complexity. As a consequence multi-component as well as domino or related reactions are witnessing a new spring.

One-Pot Two-Component [3 + 2] Cycloaddition/Annulation Protocol for the Synthesis of Highly Functionalized Thiophene Derivatives

An efficient and experimentally rapid protocol for the synthesis of hitherto unreported 2,3-dicarboalkoxy-4-aroyl/heteroaroyl/alkanoyl thiophenes has been developed via 1-2 (C-S) and 3-4 (C-C) bond connections promoted by 4-dimethylaminopyridine (DMAP). Optimally, the reaction takes only 3-5 min when β-oxodithioester and dialkyl acetylenedicarboxylate are stirred in DCM at room temperature in the presence of DMAP. This method allows a clean and general synthesis of previously inaccessible and synthetically demanding thiophenes containing the ferrocenyl group. The speed, experimental ease, and high yields of this process are improvements over existing methods to access this important substructure.

ortho-Quinone methide (o-QM): a highly reactive, ephemeral and versatile intermediate in organic synthesis

Since its first observation in 1907, ortho-quinone methide (o-QM) has occupied a strategic place within the framework of reactive intermediates in organic synthesis. In recent years, o-QM has enhanced its importance as a versatile reactive intermediate, and its applications in organic synthesis, material chemistry, fine chemicals, and pharmaceuticals are increasing rapidly. This critical review summarizes the key concepts behind o-QMs and provides an overview of current applications in organic synthesis to provide an appropriate background for synthetic, medicinal and combinatorial developments. This review covers the literature from its origin to the mid of 2014 (112 references).

Biginelli and Hantzsch-Type Reactions Leading to Highly Functionalized Dihydropyrimidinone, Thiocoumarin, and Pyridopyrimidinone Frameworks via Ring Annulation with β-Oxodithioesters

An efficient and highly convergent route to dihydropyrimidinones (DHPMs) and hitherto unreported dihydropyridopyrimidinones has been developed by one-pot, three-component cyclocondensation of aromatic aldehydes, β-oxodithioesters, and urea/6-amino-1,3-dimethyluracil in the presence of recyclable SiO2-H2SO4. On the other hand, salicylaldehyde, β-oxodithioester, and urea reacted under similar conditions to afford the 3-aroyl/heteroaroyl-2H-chromen-2-thiones in high yields instead of Biginelli product. The attractive feature of this approach is the synthesis of three important bioactive heterocyclic frameworks from the same β-oxodithioester under the similar reaction conditions, making this new strategy highly useful in diversity-oriented synthesis (DOS).

Regioselective synthesis of tetrahydrothiochromen-5-ones via a one-pot three-component solvent-free domino protocol.

A highly efficient one-pot three-component regioselective synthesis of 4-aryl-3-aroyl-2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones has been developed by annulation of β-oxodithioesters with aldehydes and cyclic 1,3-diketones under solvent-free conditions promoted by P(2)O(5). No cocatalyst or activator is needed in this protocol. The merit of this process is highlighted by its high efficiency of producing three new bonds and a stereocenter in one operation.

DABCO-Promoted three-component regioselective synthesis of functionalized chromen-5-ones and pyrano[3,2-c]chromen-5-ones via direct annulation of α-oxoketene-N,S-arylaminoacetals under solvent-free conditions

An efficient and convergent route to 3-aroyl-4-aryl-2-arylamino-4,6,7,8-tetrahydrochromen-5-ones and hitherto unreported 3-aroyl-4-aryl-2-arylamino-4H-pyrano[3,2-c]chromen-5-ones has been developed by an one-pot three-component domino coupling of α-oxoketene-N,S-arylaminoacetals, aromatic aldehydes, and dimedone/4-hydroxycoumarin in the presence of DABCO under solvent-free conditions in high yields. Further, suitably substituted pyrano[3,2-c]chromen-5-ones undergo intramolecular aromatic nucleophilic substitution (SNAr) to give pentacyclic pyrano[3,2-c]chromenoquinolines in excellent yields. The merit of this cascade Knoevenagel condensation/Michael addition/cyclization sequence is highlighted by its high atom-economy, good yields, efficiency of producing three new bonds (two C–C and one C–O), and one stereocenter in a single operation. The protocol avoids the use of expensive catalysts, toxic organic reagents/solvents, and anhydrous condition. In particular the attractive feature of this approach is the synthesis of three important bioactive heterocyclic frameworks from the same α-oxoketene-N,S-arylaminoacetal under the similar reaction conditions making this new strategy highly useful in diversity oriented synthesis (DOS).

InCl3‐Driven Regioselective Synthesis of Functionalized/Annulated Quinolines: Scope and Limitations

The efficient, regioselective synthesis of functionalized/annulated quinolines was achieved by the coupling of 2-aminoaryl ketones with alkynes/active methylenes/α-oxoketene dithioacetals promoted by InCl(3) in refluxing acetonitrile as well as under solvent-free conditions in excellent yields. This transformation presumably proceeded through the hydroamination-hydroarylation of alkynes, and the Friedländer annulation of active methylene compounds and α-oxoketene dithioacetals with 2-aminoarylketones. In addition, simple reductive and oxidative cyclization of 2-nitrobenzaldehyde and 2-aminobenzylalcohol, respectively, afforded substituted quinolines. Systematic optimization of the reaction parameters allowed us to identify two-component coupling (2CC) conditions that were tolerant of a wide range of functional groups, thereby providing densely functionalized/annulated quinolines. This approach tolerates the synthesis of various bioactive quinoline frameworks from the same 2-aminoarylketones under mild conditions, thus making this strategy highly useful in diversity-oriented synthesis (DOS). The scope and limitations of the alkyne-, activated methylene-, and α-oxoketene dithioacetal components on the reaction were also investigated.

Molecular Docking and in Vitro Antileishmanial Evaluation of Chromene-2-thione Analogues.

Leishmaniases are an epidemic in various countries, and the parasite is developing resistance against available drugs. Thus, development of new drugs against Leishmania is an open area of investigation for synthetic organic chemists. To meet this challenge, a series of chromene-2-thione derivatives have been synthesized and docked into the active site of trypanothione reductase (TryR) enzyme required for redox balance of the parasite. These were screened on promastigote, axenic amastigote, and intracellular amastigote stages of Leishmania donovani and found to show high levels of antileishmanial activity together with minimal toxicity to human peripheral blood mononuclear cells. Compounds 3b and 3k were found to be the most active among the tested compounds. Although the compounds show moderate antileishmanial activity, they identify a chemical space to design and develop drugs based on these chromene-2-thione derivatives against the Leishmania parasite.

4-Dimethylamino pyridine-promoted one-pot three-component regioselective synthesis of highly functionalized 4H-thiopyrans via heteroannulation of β-oxodithioesters.

A highly convergent and regioselective heteroannulation protocol for the synthesis of hitherto unreported highly substituted 2-amino-4-(aryl/alkyl)-5-(aroyl/heteroaroyl)-3-(cyano/carboalkoxy)-6-methylthio-4H-thiopyran derivatives has been developed. This one-pot three-component domino coupling of β-oxodithioesters, aldehydes, and malononitrile/ethyl or methyl cyanoacetate is promoted by 4-dimethylamino pyridine (DMAP) in solvent (dichloromethane (DCM)) as well as under solvent-free conditions. Systematic optimization of reaction parameters identified that the three-component coupling (3CC) protocol is tolerant to a wide array of functionality providing densely functionalized 4H-thiopyrans in excellent yields. The merit of this cascade Knoevenagel condensation/Michael addition/cyclization sequence is highlighted by its high atom-economy, excellent yields, and efficiency of producing three new bonds (two C-C and one C-S) and one stereocenter in a single operation.

Catalyst-free one-pot four-component domino reactions in water–PEG-400: highly efficient and convergent approach to thiazoloquinoline scaffolds

A cost-effective and eco-friendly straightforward synthesis of highly diversified thiazoloquinoline scaffolds is successfully achieved via one-pot four-component cascade reaction utilizing α-enolic dithioesters, cysteamine, aldehydes, and cyclic 1,3-diketones in water–PEG-400. The new efficient domino protocol generates two rings by the concomitant formation of C–C (two), C–N (two), and C–S multiple bonds presumably involving a sequence of N,S-acetal formation, Knoevenagel reaction, aza–ene reaction, imine–enamine/keto–enol tautomerization, and N-cyclization as key steps. The merit of this protocol is highlighted by its easily available and economical starting materials, operational simplicity, efficient utilization of all the reactants, clean reaction profile, simple workup procedure, and tolerance of a wide variety of functional groups.