Multicomponent synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives.

Herein, we report a one-pot greener methodology for the synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives by the multicomponent reaction of arylglyoxal monohydrate, 2-amino-1,4-naphthoquinone, and indole in acetonitrile medium under reflux conditions in the presence of 10 mol% sulfamic acid as a catalyst in 20-30 min of reaction time. Three new bonds have formed (2 C-C, 1 C-N) in this methodology. Bioactive moieties such as indole, pyrrole and naphthoquinone are present in our product. This methodology is also applicable in gram-scale synthesis. A wide variety of substrates were tested to find the generality of the methodology and good yield of the products were obtained in a very short reaction time. Along with the operational simplicity of the methodology, purification process of the products is easier by simple recrystallization process. All the synthesized products were characterized by spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, and HRMS.

Multicomponent Reactions Using C,N-Binucleophilic Nature of Aminopyrazoles: Construction of Pyrazole-Fused Heterocycles.

Synthesis of pyrazole-fused heterocycles has gained considerable attention in recent years due to their wide applications in medicinal chemistry. Aminopyrazoles are versatile building blocks for the synthesis of pyrazole-fused heterocycles by multicomponent reactions. Due to the presence of multiple reaction sites, they have fascinating chemical reactivity. Thus, they have been extensively used in multicomponent reactions for the construction of pyrazole-fused heterocycles. Although few review articles on the preparation and applications of aminopyrazoles are known in the literature, to date there is no dedicated review article on the construction of pyrazole-fused heterocycles exploring the reactivity of amino pyrazoles as C,N-binucleophiles in multicomponent reactions. Considering this, herein the multicomponent reactions for the construction of pyrazole-fused heterocycles exploring C,N-binucleophilic nature of amino pyrazoles have been reported.

Domino Reaction for the Synthesis of Pyrazole/Isoxazole Fused Naphthyridine Derivatives Involving Indole Ring Opening and Double Ring Formation.

Herein, a hitherto unreported approach for the synthesis of pyrazole/isoxazole-fused naphthyridine derivatives by a three-component domino reaction of arylglyoxal monohydrate, 5-amino pyrazole/isoxazole, and indoles in acetic acid medium has been reported. In this method, four bonds (2 C-C and 2 C-N) form in one-pot with the concomitant formation of two new pyridine rings via indole ring opening and double cyclization reactions. This methodology is also applicable in gram-scale synthesis. The reaction mechanism was studied by isolating and characterizing the reaction intermediates. Along with complete characterization of all the products, the structure of the product 4o was unambiguously confirmed by single crystal X-ray diffraction.

One-pot multicomponent synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives.

A simple, facile, and efficient green methodology has been developed for the synthesis of benzophenazine tethered tetrahydropyridopyrimidine derivatives by the one-pot four-component reaction of cinnamaldehyde/crotonaldehyde, 2-hydroxy-1,4-naphthoquinone, 1,3-dimethyl-6-amino uracil, and o-phenylenediamine in ethanol medium under reflux conditions using p-TSA as a catalyst. In this environmentally benign methodology, three C-N and two C-C bonds are formed in one pot. The hybrid products have three bioactive moieties such as benzophenazine, tetrahydropyridine, and pyrimidine. Operational simplicity, metal-free conditions, wide substrate scope, readily available starting materials, moderate to good yields of the desired products, presence of pharmaceutically active moieties, and easy purification process are the notable features of this methodology.

Multicomponent Synthesis of Fluorescent Thiazole-Indole Hybrids and Thiazole-Based Novel Polymers.

Herein, we report an efficient multicomponent reaction for the synthesis of trisubstituted thiazoles involving a one-pot C-C, C-N, and C-S bond-forming process from the readily available starting materials. The reaction of arylglyoxal, indole, and aryl thioamides in the acetic acid medium under sealed heating conditions provided 3-(2,4-diarylthiazol-5-yl)-1H-indoles (4) in good to excellent yields. Using a similar reaction strategy, the reaction of arylglyoxal, aryl thioamide, and 2,5-dihydroxy-1,4-benzoquinone provided structurally interesting bis-thiazoles having dihydroxy-1,4-benzoquinone linker (9). All of the products were fully characterized by spectroscopic techniques. We also recorded single-crystal X-ray diffraction (XRD) of compounds 4b and 9a for unambiguous structure determination. Indole-linked trisubstituted thiazoles (4) exhibit prominent fluorescence properties. The relative fluorescence quantum yields of all of the thiazole-linked indoles were measured in the dimethyl sulfoxide (DMSO) medium with respect to quinine sulfate in 0.1 M H2SO4 as reference. The scope of this reaction was further explored by preparing novel polymers 11a and 11b using naphthalene/benzene-1,4-bis(carbothioamide) in multicomponent polymerization.

Visible Light-Mediated C(sp2)-H Selenylation of Amino Pyrazole and Amino Uracils in the Presence of Rose Bengal as an Organophotocatalyst.

Herein, we report an efficient methodology for the synthesis of alkyl, benzyl, and phenyl selenoethers of aminopyrazoles and aminouracils by C(sp2)-H functionalization in the presence of visible light and Rose Bengal as an organophotocatalyst. The reaction of amino pyrazole/iosothiazole/isoxazole or amino uracils with 0.5 equivalent of diphenyl/dibenzyl/diethyl diselenides in the presence of visible light in acetonitrile medium and a catalytic amount of Rose Bengal provided the corresponding phenyl, benzyl, or ethyl selenoethers in good to very good yields. We have also utilized some of the selenylated aminopyrazoles for the preparation of pyrazole-fused dihydropyrimidines tethered with arylselenoethers by a catalyst-free one-pot three-component reaction. The notable features of this methodology are metal-free reaction conditions, good to very good yields, use of an organic photocatalyst, and wide substrate scope; it is also applicable to gram-scale synthesis and provides selenoethers of medicinally important heterocycles such amio-pyrazole, isoxazole, isothiazole, and uracils.

Synthesis of styryl-linked fused dihydropyridines by catalyst-free multicomponent reactions.

Herein, we report a rapid catalyst-free three-component reaction of 2-hydroxy-1,4-naphthoquinone, cinnamaldehydes and 3-aminopyrazoles in ethanol medium under reflux conditions for the easy access of styryl-linked dihydropyridines fused with naphthoquinone and pyrazole moiety. A wide variety of cinnamaldehyde derivatives and 3-aminopyrazoles were found suitable for this three-component reaction. All the products were fully characterized by spectroscopic tools and by recording single crystal XRD of one of the product. Catalyst-free reaction conditions, short reaction time, good yields of the products, easy purification process, formation of three new bonds (Two C-C and one C-N) in one-pot and products having four different bioactive moieties are the notable features of this methodology.

Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs).

One-pot multiple bond-forming reactions under metal-free conditions have tremendous potential in organic and medicinal chemistry considering their synthetic efficiency and eco-friendliness. In this direction, organocatalysis, i.e. application of organic molecules as catalysts, in multicomponent reactions is one of the best combinations for the preparation of complex molecules in minimum steps under green reaction conditions. Thiourea-based organic molecules show excellent catalytic activity in various transformations by their unique double H-bonding activation process. Chiral organic molecules having a thiourea backbone are well-recognized catalysts for the enantioselective synthesis of diverse products from asymmetric two- or multicomponent reactions. Simultaneous dual activation of the electrophile and the nucleophile in an MCR by using bifunctional thiourea-based chiral organocatalysts has gained considerable interest in recent times. Although several review articles are available in the literature on organocatalysis, asymmetric domino reactions, or multicomponent reactions using various organocatalysts, however, to date there has been no dedicated review article on this emerging topic, i.e. asymmetric multicomponent reactions catalysed by thiourea-based organocatalysts. Thus, this review aims to highlight the recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions.

Regioselective synthesis of pyrimidine-fused tetrahydropyridines and pyridines by microwave-assisted one-pot reaction.

A regioselective three-component reaction of α,ß-unsaturated aldehydes, cyclic 1,3-dicarbonyls and 6-aminouracils in the presence of FeCl3·6H2O as catalyst under microwave irradiation has been demonstrated. Three-component reaction of α,ß-unsaturated aldehydes like cinnamaldehyde/crotonaldehyde, cyclic 1,3-diketones such as 2-hydroxy-1,4-naphthaquinone/dimedone and 6-aminouracils provides regioselective pyrimidine-fused tetrahydropyridines tethered with cyclic 1,3-diketones. On the other hand, replacing cyclic 1,3-diketones by 4-hydroxycoumarin and keeping all other conditions the same provided a two-component pyrimidine-fused pyridines. The salient features of this methodology are operational simplicity, short reaction time, good-to-moderate yields of the products, easy purification method and regioselective products having medicinally important heterocyclic rings such as pyrimidine, tetrahydropyridine or pyridine.

Synthesis of aminouracil-tethered tri-substituted methanes in water by iodine-catalyzed multicomponent reactions.

An efficient, mild and environmentally benign protocol has been developed for the synthesis of aminouracil-tethered tri-substituted methane derivatives. The three-component reaction of 2-hydroxy-1,4-naphthaquinone, 6-amino-1,3-dimethyluracil and aldehydes in the presence of molecular iodine as catalyst under reflux conditions resulted in aminouracil-tethered tri-substituted methane derivatives 4 in aqueous medium. Similarly, the four-component reaction of 2-hydroxy-1,4-naphthaquinone, o-phenylenediamine, aldehydes and aminouracil derivatives resulted in aminouracil-tethered tri-substituted methane derivatives 6 under the same reaction conditions. The notable features of this protocol are simple experimental procedure, cheap catalyst, readily available starting materials, moderate-to-good yields of the products having biologically active important moieties such as aminouracil, hydroxy-naphthaquinone/benzophenazine.

Synthesis of Pyrimidine Fused Quinolines by Ligand-Free Copper-Catalyzed Domino Reactions.

Herein, we report two novel methods for the synthesis of pyrimidine fused quinolines using a one-pot C-C and C-N bond forming strategy from the reaction of 6-aminouracils with 2-bromobenzaldehydes or 2-bromobenzyl bromide derivatives in the presence of 10 mol % CuCl2 without using any ligand. The reaction of 2-bromobenzaldehyde or its derivatives with 6-aminouracils in the presence of K2CO3 as base and a catalytic amount of CuCl2 in DMF medium under microwave heating conditions provides corresponding pyrimidine fused quinoline derivatives in good yields within 30 min. Alternatively, pyrimidine fused quinoline derivatives have been synthesized from the reaction of 2-bromobenzyl bromides with 6-aminouracil derivatives in the presence of molecular oxygen, CuCl2 (10 mol %), and K2CO3 as base in DMF under reflux conditions. Structures of all the products were unambiguously confirmed by spectroscopic techniques and by recording single crystal XRD of 3a.

Multicomponent synthesis of diverse pyrano-fused benzophenazines using bifunctional thiourea-based organocatalyst in aqueous medium.

A series of pyrano-fused benzophenazines were synthesized using a bifunctional thiourea-based organocatalyst from the one-pot four-component reaction of 2-hydroxy-1,4-naphthoquinone, benzene-1,2-diamines, malononitrile or its derivatives and isatins or aromatic aldehydes in aqueous medium. Metal-free reaction condition, water as solvent, high bond forming efficiency (five new bonds formed in one step), good yields and easy purification process are the notable features of this methodology.

VCl3 catalyzed imine-based multicomponent reactions for the facile access of functionalized tetrahydropyridines and ß-amino carbonyls.

A simple, mild, and highly efficient method has been developed for the preparation of functionalized tetrahydropyridines and ß-amino carbonyls from the multicomponent reactions involving in situ imines and vanadium (III) chloride as a Lewis acid. The multicomponent reaction of two equivalents of aromatic aldehyde, two equivalents of amine, and one equivalent ß-keto ester in the presence of catalytic amount of VCl(3) provides highly atom economic five-component tetrahydropyridines in very good yields. The same catalyst was found useful for the efficient synthesis of a wide variety of ß-amino ketones using direct-type Mannich reaction of aromatic aldehyde, amine, and aromatic ketones. The notable advantages of this method are simple procedure, short reaction time and good yields, and applicable to broad range of substrates.

Effects of substituents in the beta-position of 1,3-dicarbonyl compounds in bromodimethylsulfonium bromide-catalyzed multicomponent reactions: a facile access to functionalized piperidines.

1,3-Dicarbonyl compounds can be converted to Mannich-type products A or highly functionalized piperidines B in the presence of a catalytic amount of bromodimethylsulfonium bromide (BDMS). The combination of aromatic aldehyde, amine, and 1,3-dicarbonyl compounds in the presence of a catalytic amount of BDMS leads to the formation of Mannich-type product A when R is a non-enolizable carbon or an alkoxy group, whereas in cases when R = CH3, the same combination yielded highly functionalized piperidines B. A synthetic study and mechanistic proposal are presented.