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Heterocycles are very important scaffolds since many of them exhibit building blocks properties and good biological activities. Various chemical methods have been utilized for their synthesis and out of them, the environmentally benign approaches are highly demanding in view of the importance of green chemistry. There are vast pieces of literature available on sustainable and multi-component synthetic approaches, but it is difficult for a researcher to keep up with research. Therefore, a review article in sustainable and multi-component synthesis of heterocycle was highly required. Herein, we have compiled the work of literatures related to multi-component reaction under solvent free condition, ultrasound assisted, water or ionic liquid mediated conditions.

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.

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.

An efficient iodine-mediated method is developed for the synthesis of functionalized 2-(methylthio)-4

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).

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 (ERβ).

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,β-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.

A facile, efficient and atom-economic synthesis of highly substituted benzo[h]qninolines was established by reaction of 2-methyl-5-nitrobenzonitrile with suitably functionalized 2H-pyran-2-ones under basic conditions. We observed that the presence of a thiomethyl group at the C-4 position of pyran provides 6-aryl-4-(2-cyano-4-nitrobenzyl)-2-oxo-2H-pyran-3-carbonitrile exclusively without any trace of benzo[h]quinolines. Depending on the nature of the functional group at C-4 of the pyran ring, different products were achieved. To probe the mechanism, we performed control experiments and isolated 3-(1-amino-7-nitro-3-thiophen-2-yl-naphthalen-2-yl)-3-piperidin-1-yl-acrylonitrile, which, on further treatment with base, provided the benzo[h]quinolines. The structure of one the products was characterized by single-crystal X-ray diffraction.

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.

A base-mediated carbocyclization study has been performed between two allowed Baldwin cyclization modes (6-exo-trig and 6-exo-dig) and it was found that 6-exo-trig cyclization was preferred over 6-exo-dig. Allyl cyanide was found to be suitable and efficient pronucleophile for this investigation and two sp2–sp2 transition-metal-free C−C bond formations took place in a single operation to yield two differently functionalized biaryl compounds.

A water-mediated regioselective synthesis of 6,7-diaryl-5-oxo-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine-6-carbonitriles was performed by the reaction of 2-[1-cyano-2,2-bis(methylsulfanyl)vinyl]benzonitrile with 1-aryl-2-(imidazolidin-2-ylidene)ethanones under basic conditions. This reaction involves an unprecedented (4+2) annulation.

We have developed a new, metal free methodology for the synthesis of 3,4-diamino-2-methylsulfanyl-naphthalene-1-carbonitrile by reaction of 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile and nitromethane under basic conditions followed by reduction of nitro group. We explored the synthetic potential of 3,4-diamino-2-(methylthio)-1-naphthonitrile for the construction of different class of highly functionalized fused polycyclic N-heterocycles, such as 3H-naphtho[1,2-d]imidazoles, benzo[f]quinoxalines and 3H-naphtho[1,2-d][1,2,3]triazoles. 2-(1-Cyano-2,2-bis(methylthio)vinyl)benzonitrile also provides arylated naphthalenes and carbazole depending on use of functionalized 4-nitrotoluenes as a carbanion source. The structure of some of the compounds was confirmed by single crystal X-ray technique.

A base-promoted strategic synthesis of various functionalized thiomethylated-benzenes has been established from aryl/heteroaryl/cyclopropyl methyl ketone. We can directly access the thiomethylated-benzene nucleus embedded with diverse functional group by the reaction of 3,3-bis(methylthio)-1-arylprop-2-en-1-ones and 2-(1-aryl/cyclopropyl)ethylidene)malononitriles in the presence of sodium hydride in THF at reflux temperature. These precursors are easily accessible from aryl methyl ketones. Various functional groups like alkyl, aryl, nitrile, amine, aroyl and thiomethyl can be directly installed to the benzene ring. The one-pot approach for the construction of thiomethylated-benzene nucleus was also developed. The structure of the synthesized compound was confirmed by X-ray crystallography.

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.

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.

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.

Both one pot and step wise synthesis of methyl 3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylates 6 have been delineated by the reaction of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles 3, methyl mercaptoacetate and hydrazine hydrate. During the stepwise synthesis, functionalized thieno[3,2-c]pyran-4-ones 4 were isolated and treated with hydrazine hydrate to afford the desired products. Analogously, condensation–cyclisation of 5 with hydrazine hydrate delivered identical products, thieno[3,2-c]pyridin-4-ones 6, in excellent yields. The structure of isolated product 6 was ascertained by spectroscopic and single crystal X-ray diffraction analyses.

A microwave directed, simple and efficient synthesis of 3′-amino-5′-(sec.amino)-[1,1′:2′,1′′-teraryl]-4′-carbonitriles has been delineated through ring transformation reaction of 6-aryl-2-oxo-4-sec.amino-2H-pyran-3-carbonitriles by benzyl cyanide under basic conditions. Reaction of 6-aryl-4-sec.amino-2-oxo-2H-pyran-3-carbonitriles and benzyl cyanide in DMSO and KOH as a base at 15 °C provides (2E,4E)-5-aryl-6-oxo-6-phenyl-3-sec.amino-hexa-2,4-dienenitriles. Reaction of 6-phenyl-4-(piperidin-1-yl)-2-oxo-2H-pyran-3-carbonitrile and benzyl cyanide in DMF and sodamide at 100 °C provides 1,5-diphenyl-3-(piperidin-1-yl)cyclopenta-2,4-diene-1,2-dicarbonitrile. Use of microwave irradiation diverts the regioselectivity and changes the course of reaction and 1,2-teraryls was isolated. The structure of one of the compound was confirmed by single crystal X-ray and the nature of weak interactions in the compound has been addressed using ab initio, atoms in molecules (AIM) and Hirshfeld surface analysis.

An efficient synthesis of 1,2,3,4-tetrahydroquinolines with donor and acceptor group has been delineated by base mediated ring transformation of 6-aryl-4-substituted-2H-pyran-2-one-3-carbonitriles by N-boc-3-piperidone followed by consecutive deprotection of Boc group under acidic conditions. This reaction involves 2 new bond formations namely C4a-C5 and C8a-C8 in order to create the nucleus. Various donor and acceptor functional groups like aryl, heteroaryl, nitrile, methylsulfanyl and secondary amine were installed in 1,2,3,4-tetrahydroquinolines. We extended our approach to synthesize the fused 1,2,3,4-tetrahydroquinolines by using 2-oxobenzo[h]chromenes as precursor. Further, we synthesized fused and isolated quinolines through aromatization of 1,2,3,4-tetrahydroquinolines by DDQ in excellent yields. Single-crystal X-ray analysis of the Boc protected tetrahydroisoquinoline 6t showed the steric hindrance between N-Boc and aryl group.

Both one pot and step wise synthesis of methyl 3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylates 6 have been delineated by the reaction of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles 3, methyl mercaptoacetate and hydrazine hydrate. During the stepwise synthesis, functionalized thieno[3,2-c]pyran-4-ones 4 were isolated and treated with hydrazine hydrate to afford the desired products. Analogously, condensation–cyclisation of 5 with hydrazine hydrate delivered identical products, thieno[3,2-c]pyridin-4-ones 6, in excellent yields. The structure of isolated product 6 was ascertained by spectroscopic and single crystal X-ray diffraction analyses.