Synthesis of 3-sulfenylindole derivatives from 4-hydroxy-2H-chromene-2-thione and indole using oxidative cross-dehydrogenative coupling reaction and anti-proliferative activity study of some of their sulfone derivatives.

The synthesis of hitherto unreported 3-sulfenylindole derivatives is achieved from 4-hydroxy-2H-chromene-2-thione (1) and indole (2) by employing an oxidative cross-dehydrogenative coupling reaction using a combination of 10 mol% of molecular iodine and 1 equivalent of TBHP in DMSO at room temperature. Then, the 3-sulfenylindole derivatives 3a, 3b, 3d, 3f, 3 h, and 3 k were converted into their corresponding sulfone derivatives because of lead likeness properties. Subsequently, a target prediction and docking study of six sulfone derivatives (5a-f) was performed, and four sulfones, namely 5a, 5d, 5e, and 5f, were selected for further in-vitro studies. The four sulfones mentioned above exhibited prominent anti-proliferative activity on breast cancer (MCF7) cell lines. In addition, this reaction was exergonic through quantum chemical analysis of the mechanistic steps. The salient features of this reaction are mild reaction conditions, good yields, and broad substrate scope.

Synthetic utility of biomimicking vanadium bromoperoxidase and n-tetrabutylammonium tribromide (TBATB) in organic synthesis.

Nature has established a broad spectrum of methods to introduce halogen atoms in organic compounds. Recent developments have revealed that haloperoxidases are one of the major sources responsible for incorporating bromines to produce bromoorganics in nature. Pioneering studies of numerous researchers have unravelled the details of haloperoxidases, mainly vanadium dependent enzyme bromo- and iodo-peroxidases, including reaction mechanism, kinetics and especially biomimicking studies. In this review, we initially have described the scope of biomimicking vanadium bromoperoxidase in producing the bromonium ion and its further utilisation in conducting oxidative bromination or cleavage of various organic molecules. Moreover, by biomicmicking, the synthesis of OATB and the synthetic utility of various organic ammonium tribromides (OATBs) have been discussed. Among such OATBs, n-tetrabutylammonium tribromide (TBATB) has been explored for bromination of organic molecules as well as in the facile removal of several protecting groups and as a potential catalyst in various synthetic transformations. This review attempts to compile a myriad of reactions concerning the catalytic activity of vanadium bromoperoxidases and the usefulness of various OATBs, particularly with special emphasis on TBATB in various organic transformations.

An environmentally benign regioselective synthesis of 2-benzyl-4-arylquinoline derivatives using aryl amines, styrene oxides and aryl acetylenes.

A novel and an expedient metal- and solvent-free synthesis of a wide variety of 2-benzyl-4-arylquinoline derivatives is described from readily available aryl amines, styrene oxides and aryl acetylenes in the presence of 10 mol% molecular iodine. This domino reaction occurs under metal- and solvent-free conditions at 120 °C, which avoids the usage of metal catalyst and as a consequence generation of metal waste. The salient features of this methodology are the use of simple starting materials, ease of handling, high regioselectivity, shorter reaction time, atom-economical, step-economical, the formation of one C-N and two C-C bonds and a wide range of functional groups tolerance.

Metal-free synthesis of quinoline-2,4-dicarboxylate derivatives using aryl amines and acetylenedicarboxylates through a pseudo three-component reaction.

An efficient, useful and one-pot protocol for the synthesis of quinoline-2,4-dicarboxylate scaffolds is accomplished from aryl amines and dimethyl/diethyl acetylenedicarboxylates using 20 mol% molecular iodine as a catalyst in acetonitrile at 80 °C. In addition, the mechanistic explanation for the formation of the desired products is disclosed. The pivotal role of molecular iodine in the formation of the major products, diester quinoline derivatives, and the minor product, triesters, in two cases is described in the mechanism. The notable advantages of this method are non-involvement of a metal catalyst, avoiding of metal contamination in the final product as well as waste generation, use of a low cost and eco-friendly catalyst, ease of handling, high regioselectivity, shorter reaction time, the formation of one C-N and two C-C bonds and a broad substrate scope with good yields.

Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline derivatives using aryl amines, aryl aldehydes and styrene oxides.

An efficient and expedient synthetic protocol is reported for the synthesis of 2,3-diarylquinoline derivatives from readily available aryl amines, aryl aldehydes and styrene oxides using 10 mol% copper(ii) triflate by employing three-component reaction. This approach involves the reaction between the in situ generated imine (derived from the aryl amine and aryl aldehyde) and styrene oxide, which enables the formation of the desired products. The present method has several advantages such as high atom-economy, high regioselectivity, easy handling, consecutive one C-N and two C-C bond formation, shorter reaction time and broader substrate scope with good yields.

Newly synthesized 3-sulfenylindole derivatives from 4-hydroxydithiocoumarin using an oxidative cross dehydrogenative coupling reaction (OCDCR): potential lead molecules for antiproliferative activity.

An expedient and efficient synthetic method was developed for the oxidative cross dehydrogenative coupling reaction between 4-hydroxydithiocoumarin and indole at the C-3 position regio-selectively using a combination of 10 mol% molecular iodine and TBHP in the presence of 10 mol% CuBr2 as an additive at room temperature. Mild reaction conditions, good yields and a broad substrate scope are some of the salient features of the present protocol. Additionally, the synthesized 3-sulfenylindoles derived from 4-hydroxydithiocoumarin were converted into biologically active sulfone derivatives. Interestingly, some of the compounds exhibit anti-cell proliferative activity on breast cancer (MCF-7) cells due to reactive oxygen species (ROS) mediated cell damage.

Reaction behaviour of arylamines with nitroalkenes in the presence of bismuth(iii) triflate: an easy access to 2,3-dialkylquinolines.

We report the reaction behaviour of arylamines with nitroalkenes in the presence of bismuth(iii) triflate (10 mol%) and diacetoxyiodobenzene (10 mol%). We obtained 2,3-dialkylquinoline derivatives instead of the expected 3-alkylindole derivatives. The present reaction is an alternative approach for the synthesis of 2,3-dialkylquinoline derivatives under milder conditions. Furthermore, we establish the mechanistic pathway by theoretical calculations using Gaussian 09 software [B3LYP/6-311+G(d,p)], which shows that the conventional aza-Michael reaction is preferred over Michael addition. Aliphatic nitroalkenes behave in a different manner than aromatic nitroalkenes. An aza-Michael adduct gives rise to an imine by the elimination of water which may tautomerize to the corresponding enamine. The resulting imine and enamine intermediates react together to afford the desired quinoline derivatives. This protocol has the advantages of consecutive formation of one C-N and two C-C bonds, high regioselectivity, broad substrate-scope and good yields.

Iodine monobromide catalysed regioselective synthesis of 3-arylquinolines from α-aminoacetophenones and trans-ß-nitrostyrenes.

A simple and efficient method for regioselective synthesis of 3-arylquinolines is described from α-aminoacetophenones and trans-ß-nitrostyrenes using 20 mol% iodine monobromide as a catalyst in acetonitrile solvent at 80 °C. The present method involves tandem reaction of α-aminoacetophenones and trans-ß-nitrostyrenes, formation of two new C-C bonds and cleavage of one C-C bond in a single step. The salient features of the protocol are metal- and oxidant-free reaction conditions, broad substrate scope, and good yields.

Electronic effect of substituents on anilines favors 1,4-addition to trans-ß-nitrostyrenes: access to N-substituted 3-arylindoles and 3-arylindoles.

A simple and an efficient method for the regioselective synthesis of N-alkyl/aryl/H 3-arylindole derivatives from N-substituted anilines and trans-ß-nitrostyrenes has been described using 10 mol% of bismuth(iii) triflate as a catalyst in acetonitrile at 80 °C. The present protocol profits from the formation of new C-C and C-N bonds, broad substrate scope and moderate to good yields.

An oxidative cross-coupling reaction of 4-hydroxydithiocoumarin and amines/thiols using a combination of I2 and TBHP: access to lead molecules for biomedical applications.

A metal-free I2/TBHP induced highly atom economic and operationally simple oxidative cross-coupling reaction has been developed for the direct synthesis of sulfenamides/sulfanes/disulfides from the reaction of 4-hydroxydithiocoumarin and amines/thiols. The novelties of the present protocol are unprecedented S-C bond formation in addition to S-N and S-S bonds, shorter reaction time, mild and environmentally benign reaction conditions, functional group tolerance and moderate to excellent yields. Moreover, the four newly synthesized compounds namely 4q, 6d, 6e and 7a exhibit anti-proliferative activity against the breast cancer cell line MCF7, and may be lead molecules for future drug development.

Camphorsulfonic Acid Catalyzed One-Pot Three-Component Reaction for the Synthesis of Fused Quinoline and Benzoquinoline Derivatives.

A simple and an efficient one-pot three-component reaction of arylamines, aromatic aldehydes, and cyclic ketones was described for the synthesis of various fused quinoline, benzoquinoline, and naphthoquinoline derivatives by using camphorsulfonic acid as a catalyst. The exploitation of pregnenolone steroid for benzoquinolines and terephthalaldehyde for bis-benzoquinolines synthesis was achieved with 68-75% yields. The reactivity of arylamines and the mechanistic study for the formation of benzoquinoline was described precisely. The present protocol offers a great potential for atom-economy under mild conditions.

K2CO3 catalyzed regioselective synthesis of thieno[2,3-b]thiochromen-4-one oximes: access to the corresponding amine and nitroso derivatives.

An unprecedented and efficient method for the synthesis of useful thieno[2,3-b]thiochromen-4-one oximes is accomplished via a thio[3 + 2] cyclization reaction of 4-hydroxydithiocoumarins and trans-ß-nitrostyrenes in the presence of 10 mol% K2CO3 in ethanol under reflux conditions. Furthermore, hitherto, these precursors were converted into the corresponding 2-amino thieno[2,3-b]thiochromen-4-one and 2-nitroso thieno[2,3-b]thiochromen-4-one derivatives respectively. The salient features of the present protocol are mild reaction conditions, shorter reaction times, good yields and unexpected formation of C-C and C-S bonds in a regioselective manner.

One-Pot Synthesis and Evaluation of Antileishmanial Activities of Functionalized S-Alkyl/Aryl Benzothiazole-2-carbothioate Scaffold.

The synthesis of hitherto unreported S-alkyl/aryl benzothiazole-2-carbothioate is reported from thiols, oxalyl chloride, and 2-aminothiophenols using 10 mol % n-tetrabutylammonium iodide (TBAI) as catalyst in acetonitrile through multicomponent reaction (MCR) strategy. The present protocol favored formation of benzothiazoles and thioesters via simultaneous formation of C-N and C-S bonds in good yields with a wide range of substrates. A few of the synthesized derivatives were evaluated for their antimicrobial activity against the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL). Further, these compounds displayed no toxicity toward macrophage RAW 264.7 cells and are therefore nontoxic and effective antileishmanial leads. In silico docking studies were performed to understand the possible binding site interaction with trypanothione reductase (TryR).

Synthesis of Unsymmetrical Sulfides and Their Oxidation to Sulfones to Discover Potent Antileishmanial Agents.

Unsymmetrical sulfides were first synthesized using combinations of a 1,3-dicarbonyl, an aromatic aldehyde and a thiol in the presence of 10 mol % ethanolic piperidine. These sulfides derivatives were subsequently converted into corresponding sulfones via oxidation in the presence of m-chloroperoxybenzoic acid (m-CPBA) at ice-bath to room temperature. The former reaction was achieved at room temperature through one-pot three-component. The later was obtained in good yields using mild reaction conditions with flexibility in choice from a range of substrates. The antimicrobial properties of the newly synthesized sulfone derivatives were investigated against the protozoan parasite, Leishmania donovani, a causative agent of visceral leishmaniasis (VL). Nine sulfone derivatives were found to be efficacious and exhibited significant antimicrobial activity. Further, these compounds were nontoxic on murine peritoneal macrophages thus eliminating potential cytoxicity in the host cells. These compounds may be indicated as potential leads in the treatment of visceral leishmaniasis.

Beyond conventional routes, an unprecedented metal-free chemoselective synthesis of anthranilate esters via a multicomponent reaction (MCR) strategy.

A hitherto unreported route for the synthesis of anthranilate esters is demonstrated using 2-nitrobenzaldehyde, malonitrile and an alcohol or amine via a metal and oxidant free multicomponent reaction (MCR) strategy. This process simultaneously installs an ester and urea or urethane functionality via CO and CN bond formations via concurrent oxidation of the aldehyde group and reduction of the nitro group involving an intramolecular redox process.

VO(acac)(2)/H(2)O(2)/NaI: a mild and efficient combination for the cleavage of dithioacetal derivatives of sugars.

A wide variety of dithioacetal derivatives of sugars can be cleaved easily into the corresponding open-chain aldehydo sugars using an efficient combination of VO(acac)(2)/H(2)O(2)/NaI at 0-5°C. Some of the salient features of this protocol are mild reaction conditions, good yields, short reaction times, easy work-up procedures, and non-involvement of toxic chemicals.

Tetrabutylammonium tribromide (TBATB): a mild and efficient catalyst for O-isopropylidenation of carbohydrates.

A wide range of O-isopropylidene derivatives can be prepared from the sugars and their derivatives on reaction with acetone at room temperature by employing 2 mol% of tetrabutylammonium tribromide (TBATB) as a catalyst. Good yields, low catalyst loading, mild reaction conditions, and a non-aqueous workup procedure are some major advantages of this protocol.

Bromodimethylsulfonium bromide (BDMS) mediated dithioacetalization of carbohydrates under solvent-free conditions.

A variety of diethyl dithioacetals of sugars can be prepared in very good yields by the reaction of various monosaccharides with ethanethiol in the presence of 3 mol% bromodimethylsulfonium bromide (BDMS) at 0-5°C. Similarly, dipropyl dithioacetal derivatives can also be obtained in good yields using propanethiol under identical reaction conditions. These dithioacetal derivatives were characterized by per-O-acetylation using silica gel-supported perchloric acid. The significant features of the present protocol are good-to-excellent yields, mild, clean, and solvent-free reaction conditions. This method is extremely suitable for the large-scale preparation of dithioacetal derivatives of various sugars.

A simple and convenient synthetic protocol for O-isopropylidenation of sugars using bromodimethylsulfonium bromide (BDMS) as a catalyst.

Various O-isopropylidene derivatives of sugars and acyclic sugars were obtained in very good yields on reaction with acetone at room temperature with a catalytic amount of bromodimethylsulfonium bromide (BDMS). These O-isopropylidene derivatives can also be prepared in good yields on reaction with 2,2-dimethoxypropane (DMP) in acetonitrile using the same catalyst in shorter reaction times. Some of the advantages of this method are high effectiveness, a nonaqueous workup procedure, economic viability, and good yields.

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.