HFIP-Mediated Multicomponent Reactions: Synthesis of Pyrazole-Linked Thiazole Derivatives.

The development of one-pot, atom, and step-economic new methods avoiding metal, harsh reaction conditions, and toxic reagents for the synthesis of medicinally important hybrid molecules bearing more than one bioactive moieties is currently one of the hot topics in organic synthesis. Herein, we report a green and efficient room temperature multicomponent reaction for the synthesis of novel pyrazole-linked thiazoles involving a one-pot C-C, C-N, and C-S bond-forming process from the reaction of aryl glyoxal, aryl thioamide, and pyrazolones in 1,1,1,3,3,3-hexafluoroisopropanol, a hydrogen bond donating reaction medium. A set of diverse hybrid molecules bearing thiazole and pyrazole moieties were prepared in good to excellent yields by using this method. This methodology can also be extended to prepare thiazole-linked barbiturates as well as imidazole-linked pyrazoles. All the products were fully characterized by spectroscopic techniques. The notable features of this protocol are room temperature, metal as well as additive-free reaction conditions, use of recyclable solvent, water as the byproduct, wide substrate scope, operational simplicity, easy purification, applicability for gram-scale synthesis, high atom economy, and the presence of two bioactive pyrazole and thiazole moieties in the products.

Synthesis of Selenocyanates and Selenoethers of Amino Pyrazoles and Amino Uracils by In Situ Triselenium Dicyanide from Malononitrile and Selenium Dioxide.

Herein, we report an efficient method for synthesis of novel selenocyanates of amino pyrazole, amino uracil, and amino isoxazole derivatives using in situ triselenium dicyanide from the combination of malononitrile and selenium dioxide in DMSO medium. Using the same combination but changing the stoichiometry of reagents and sequence of addition and temperature, symmetrical selenoethers of amino pyrazoles and amino uracils were prepared in good yields. Furthermore, selenocyanates of amino pyrazoles were utilized for the synthesis of corresponding alkynyl selenides in the presence of CuI and Cs2CO3. The salient features of this methodology are inexpensive starting materials, short reaction time, and good to very good yields. This method is also applicable for the gram-scale synthesis of selenocyanates of amino pyrazoles and amino uracils.

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.

Sc(OTf)3-Mediated One-Pot Synthesis of Coumarin-Fused Furans: A Thiol-Dependent Reaction for the Easy Access of 2-Phenyl-4H-furo[3,2-c]chromen-4-ones.

Herein, we report a simple and efficient method for the preparation of novel thioether-linked coumarin-fused furans from the one-pot three-component reaction of arylglyoxal, 4-hydroxycoumarin, and various aromatic thiols in the presence of Sc(OTf)3 as a catalyst. This methodology is also applicable to cyclic 1,3-dicarbonyls such as cyclohexane-1,3-dione and dimedone. Depending upon the thiols, this methodology can either give a three-component thioether-linked coumarin-fused furan (4) or a two-component furocoumarin product (5). Wide substrate scope, good to excellent yields, and products having more than one pharmaceutically important motif are the salient features of this methodology.

Iodine-Catalyzed Multicomponent Synthesis of Highly Fluorescent Pyrimidine-Linked Imidazopyridines.

Herein, we report a metal-free one-pot three-component reaction of aryl methyl ketones, 2-aminopyridines, and barbituric acids for the synthesis of pyrimidine-linked imidazopyridines using a catalytic amount of molecular iodine in DMSO medium. This process involves a one-pot C-H oxidation, followed by the formation of one C-C and two C-N bonds. A wide variety of aryl methyl ketones and 2-aminopyridines were found to be suitable for this methodology. The UV and fluorescence properties of the synthesized products were studied in water and DMSO media. Most of the synthesized products exhibited very good to excellent fluorescence quantum yield. Among all the products, compounds 4p and 4q showed the maximum fluorescence quantum yield (0.36) in water medium under basic conditions and compound 4c showed the maximum fluorescence quantum yield (0.75) in DMSO medium.

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.

A reversible and efficient probe for dual mode recognition of Al3+ and Cu2+ with logic gate behaviour: Crystal structure, theoretical and in-vivo bio-imaging investigations.

This work presents the synthesis, characterization, crystal structure and spectroscopic investigations of isophthalohydrazide based probe. Among various tested metal ions, the probe selectively detects Al3+ and Cu2+ in aqueous ethanol via fluorometric and colorimetric methods, respectively. It displays a fluorescence "turn-on" response with Al3+ and visual colour change from colourless to yellow with Cu2+. Sensing mechanism is explored with UV-Vis, fluorescence spectroscopy and 1H NMR titration, and confirmed with computational results. Suppression of CN isomerization and photo-induced electron transfer (PET) along with chelation enhanced fluorescence emission (CHEF) result in "turn-on" fluorescence with Al3+ while ligand to metal charge transfer (LMCT) accounts for visual colour change with Cu2+. Job's plot and HRMS confirm 1:2 (L:M) stoichiometry. The probe also exhibits efficient reversibility and reproducibility with EDTA which are successfully mimicked with combinatorial logic gate and truth table. Additionally, solid state applications and bio-imaging investigation on gut tissue of Drosophila 3rd instar larvae are performed.

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.

Hydrogen Peroxide-Mediated Rapid Room Temperature Metal-Free C(sp2)-H Thiocyanation of Amino Pyrazoles, Amino Uracils, and Enamines.

A rapid metal- and additive-free room temperature method for C(sp2)-H thiocyanation of aminopyrazoles, aminoisoxazole, aminoisothiazole, amino uracils, and aliphatic enamines has been developed in an aqueous medium using hydrogen peroxide as a benign oxidant and ammonium thiocyanate as a thiocyanating agent. On the other hand, the reaction of hydrogen peroxide and ammonium thiocyanate followed by one-pot addition of NaOH provides the corresponding disulfides in the case of amino azoles, and pyrimidine-fused 2-amino thiazoles were observed in the case of aminouracils. The salient features of this method are the use of an eco-friendly oxidant, reaction tunability to access different products, wide substrate scope, and good to very good yields.

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.

One-pot synthesis of pyrimidine linked naphthoquinone-fused pyrroles by iodine-mediated multicomponent reactions.

Herein we report iodine-mediated multicomponent reactions for the synthesis of naphthoquinone-fused pyrroles tethered with a pyrimidine moiety. The reaction of aryl methyl ketones (3) or terminal aryl alkynes (5) in the presence of molecular iodine in DMSO medium followed by sequential addition of barbituric acids (2) and 2-amino-1,4-naphthoquinone (1) provides the corresponding three-component hybrid molecules 4 having naphthoquinone-fused pyrroles tethered with a barbituric acid moiety. This three-component reaction proceeds via metal-free C-H oxidation followed by multi-component cyclization forming three new bonds (2 C-C, 1 C-N) in one pot. Alternatively, the same molecules can also be prepared from the reaction of arylglyoxals, 2-aminonaphthoquinone, and barbituric acids in the presence of a catalytic amount of iodine in methanol medium under reflux conditions. The salient features of these methodologies are: one-pot metal-free method, good yields, wide substrate scope, easy purification of products, and the presence of medicinally important naphthoquinone, pyrrole and pyrimidine moieties in the products.

Cs2CO3-Mediated Rapid Room-Temperature Synthesis of 3-Amino-2-aroyl Benzofurans and Their Copper-Catalyzed N-Arylation Reactions.

Cs2CO3 in dimethylformamide (DMF) is a perfect combination for the rapid room-temperature synthesis of 3-amino-2-aroyl benzofuran derivatives from the reaction of 2-hydroxybenzonitriles and 2-bromoacetophenones in good to excellent yields. Using this one-pot C-C and C-O bond-forming strategy, we prepared a series of 3-amino-2-aroyl benzofuran derivatives within a very short time (10-20 min). This method was also found suitable for gram-scale synthesis. Benzofurans (3) obtained by this Cs2CO3-mediated methodology were then further explored for the development of a tunable base- and ligand-free copper-catalyzed N-arylation methodology using arylboronic acids for the easy access of either mono- or bi-N-aryl derivatives of aminobenzofurans at ambient temperature. The reaction of 3 with malononitrile in DMF medium under microwave heating conditions provided highly fluorescent conjugated alkenes and novel pyridine-fused benzofurans.

I2/DMSO mediated multicomponent reaction for the synthesis of 2-arylbenzo[d]imidazo[2,1-b] thiazole derivatives.

Synthesis of a series of 2-arylbenzo[d]imidazo[2,1-b] thiazoles tethered with barbituric acid moiety has been reported from the three component reaction of 2-aminobenzothiazoles, barbituric acids and terminal aryl acetylenes or aryl methyl ketones in the presence of I2 in DMSO medium. Both conventional and microwave heating conditions can be used for this multicomponent reaction. The salient features of this methodology are: (i) formation of one C-C and two C-N bonds in one-pot under metal-free oxidation followed by cyclization, (ii) selective formation of the fused imidazole ring, (iii) wide substrate scope, (iv) easy purification of the products, (v) products having more than one pharmaceutically important motifs and (vi) gram scale synthesis possible.

Synthesis of fused pyrroles containing 4-hydroxycoumarins by regioselective metal-free multicomponent reactions.

The reaction of arylglyoxals, 4-hydroxycoumarin, and aromatic amines such as 7-amino-2-methylchromone, 6/7-aminoflavone, 7-amino-4-methylcoumarin, 1-amino-9-fluorenone, 1-aminoanthraquinone and aniline derivatives in acetic acid medium under microwave conditions provides the corresponding regioselective fused pyrroles having hydroxycoumarin and aryl substituents. Alternatively, we have developed another method using in situ arylglyoxals from acetophenone derivatives by I2/DMSO promoted C-H oxidation followed by one-pot three component cyclization reactions to provide similar fused pyrroles. Using both the methods a series of novel pyrroles fused with pharmacologically important chromone, flavone, coumarin, fluorenone, and anthraquinone moieties were synthesized under metal-free reaction conditions in good to very good yields within a short reaction time. The structures of the synthesized fused pyrroles have been unambiguously confirmed by spectroscopic techniques, mass analysis and single crystal XRD.

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.

Synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3-d]Pyrimidine-2,4-Diones Via One-Pot Three-Component Reactions.

A simple and novel method for the synthesis of 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones has been reported using arylglyoxal-based three-component reactions. Under microwave heating conditions, arylglyoxal, 6-amino uracil, or its derivatives reacts with various thiols in acetic acid medium to provide a series of pyrrolo[2,3-d]pyrimidine-2,4-diones (4) having a thioether and an aryl ring in 5 and 6 positions, respectively. On the other hand reaction of arylglyoxal, amino uracil and malononitrile in place of thiols, provided corresponding 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones (5) with selectively converting one of the -CN to -CONH2 group both in conventional (method A) and microwave heating conditions (method B). This methodology is a simple and efficient protocol for the synthesis of diverse 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones from the readily available starting materials in good yields.

PEG-mediated one-pot multicomponent reactions for the efficient synthesis of functionalized dihydropyridines and their functional group dependent DNA cleavage activity.

Polyethylene glycol (PEG) has been found to be an inexpensive, non-toxic and useful medium for the one pot synthesis of highly functionalized dihydropyridines using multicomponent reactions (MCRs) at room temperature under catalyst free conditions. The notable features of this protocol are: mild reaction condition, applicability to wide range of substrates, reusability of the PEG and good yields. The interaction of the synthesized compounds with pUC19 plasmid DNA was also analyzed. Some of the synthesized compounds showed interesting functional group dependent nuclease activity for plasmid DNA cleavage under physiological conditions.

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.

A mild and regioselective method for alpha-bromination of beta-keto esters and 1,3-diketones using bromodimethylsulfonium bromide (BDMS).

Bromodimethylsulfonium bromide has been found to be an effective and regioselective reagent for alpha-monobromination of beta-keto esters and 1,3-diketones. A wide variety of beta-keto esters and 1,3-diketones undergo chemoselective alpha-monobromination with excellent yields at 0-5 degrees C or room temperature. The notable advantages of this protocol are no need of chromatographic separation, use of less hazardous reagent than molecular bromine, and no added base, Lewis acid, or other catalyst.