Design and Synthesis of Indazole-Indole Hybrid via tert-Butyl Nitrite Mediated Cascade Diazotization/Isomerization/Cyclization.

In this report, a tert-butyl nitrite (TBN)-mediated straightforward metal-free approach has been presented for the synthesis of a diverse range of C-3-substituted indazole-indole hybrids using readily accessible 2-(indolin-3-ylidenemethyl)aniline derivatives. This strategy is proposed to occur via a diazonium salt intermediate that is capable of cascade isomerization and intramolecular C-N bond formation through a 5-endo-dig cyclization to achieve a wide variety of indazole-indole hybrids in good yields.

Iron-Catalyzed Synthesis of 13-Aryl-13H-indeno[1,2-l]phenanthrene via Double Annulations of 2-Alkynyl Biaryls.

An Fe(III)-catalyzed expedient synthesis of 13-aryl-13H-indeno[1,2-l]phenanthrene is described by a double annulations of 2-alkynyl biaryls, initiated by the activation of acetal. This strategy provides a simple, efficient and regioselective synthesis of varieties of indenophenanthrene derivatives from easily available starting materials under mild conditions in high to excellent yields. A plausible reaction mechanism is proposed.

DDQ/Fe(NO3)3-Catalyzed Aerobic Synthesis of 3-Acyl Indoles and an In Silico Study for the Binding Affinity of N-Tosyl-3-acyl Indoles toward RdRp against SARS-CoV-2.

In the present study, we herein report a DDQ-catalyzed new protocol for the synthesis of substituted 3-acylindoles. Being a potential system for virtual hydrogen storage, introduction of catalytic DDQ in combination with Fe(NO3)3·9H2O and molecular oxygen as co-catalysts offers a regioselective oxo-functionalization of C-3 alkyl-/aryllidine indolines even with scale-up investigations. Intermediate isolation, their spectroscopic characterization, and the density functional theory calculations indicate that the method involves dehydrogenative allylic hydroxylation and 1,3-functional group isomerization/aromatization followed by terminal oxidation to afford 3-acylindoles quantitatively with very high regioselectivity. This method is very general for a large number of substrates with varieties of functional groups tolerance emerging high-yield outcome. Moreover, molecular docking studies were performed for some selected ligands with an RNA-dependent RNA polymerase complex (RdRp complex) of SARS-CoV-2 to illustrate the binding potential of those ligands. The docking results revealed that few of the ligands possess the potential to inhibit the RdRp of SARS-Cov-2 with binding energies (-6.7 to -8.19 kcal/mol), which are comparably higher with respect to the reported binding energies of the conventional re-purposed drugs such as Remdesivir, Ribavirin, and so forth (-4 to -7 kcal/mol).

The synthesis of indole-3-carbinols (I3C) and their application to access unsymmetrical bis(3-indolyl)methanes (BIMs) bearing a quaternary sp3-carbon.

In the present study, the novel synthesis of tert-indole-3-carbinols is reported through the DDQ-mediated oxidation of the allylic C-H bond/aromatization/hydroxylation at the indolyl carbon using water as the hydroxyl source. The reaction is highly efficient and high yielding and it works under mild reaction conditions. Furthermore, the synthetic value of such indole-based tert-carbinols is explored through their use as excellent electrophilic methylene surrogates to develop medicinally important unsymmetrical bis(3-indolyl)methanes containing an all carbon quaternary center.

Iron(III)-catalyzed synthesis of indole-xanthydrol hybrid through oxidative cycloisomerization/hydroxylation reaction.

An efficient one-pot synthesis of an indole-xanthydrol hybrid is described in the presence of catalytic combinations of Fe(NO3)3/FeCl3. This strategy involves a series of reactions such as allylic oxidation, isomerisation, cyclisation and hydroxylation reactions in a tandem manner. This protocol offers several advantages including mild reaction conditions, operational simplicity, high selectivity, good yields and easily accessible starting materials. The synthetic utility of this protocol was further demonstrated by the one-pot synthesis of the highly substituted xanthene containing bis-indolylmethane derivative. The preliminary mechanistic studies reveal that the reaction is initiated by the generation of radicals in the presence of catalytic iron(III)-salts.

Iron-catalyzed alkyne-carbonyl metathesis for the synthesis of 6,7-dihydro-5H-dibenzo[c,e]azonines.

The synthesis of nine-membered rings via alkyne-carbonyl metathesis is reported. The alkyne and acetal units contained in a biaryl substrate undergo the intramolecular alkyne-carbonyl metathesis reaction under FeCl3-catalysis to furnish the unexplored 6,7-dihydro-5H-dibenzo[c,e]azonines. The method provides an alternative to existing routes to nine-membered rings with cheap, non-toxic iron catalysts and milder conditions.

DDQ/FeCl3-mediated tandem oxidative carbon-carbon bond formation for the Synthesis of indole-fluorene hybrid molecules.

A series of diverse and complex hybrid structures of indole bearing fluorene were obtained in the presence of DDQ with high regioselectivity under mild conditions from biaryl tethered 3-(methylene)indoline in good to excellent yields. The strategy involves tandem allylic Csp3-H oxidation and subsequent intramolecular carbon-carbon bond formation. The yield of the product was dramatically improved in the presence of additives such as FeCl3 and molecular sieves (4 Å). A possible mechanism is proposed for this tandem process.

Iron-catalyzed carboarylation of alkynes via activation of π-activated alcohols: rapid synthesis of substituted benzofused six-membered heterocycles.

An Fe(OTf)3-catalysed carboarylation of alkynes is reported for the straightforward synthesis of densely substituted 1,2-dihydroquinolines from N-propargyl anilides and π-activated alcohols. The reaction provides a new method for the synthesis of highly substituted benzofused six-membered heterocycles by the formation of two carbon-carbon bonds and one ring in a single step. The power of the methodology was further extended to the synthesis of substituted chromene and thiochromene derivatives in high yields. In addition, substituted quinoline derivatives were also achieved in a single step in the presence of FeCl3 through detosylation/aromatisation. A number of control experiments have been performed and a plausible mechanism has also been proposed to explain the formation of the products.

Application of the Povarov Reaction in Biaryls under Iron Catalysis for the General Synthesis of Dibenzo[a,c]Acridines.

A modified Povarov reaction involving 2'-alkynylbiaryl-2-carbaldehydes and aryl amines with tandem oxidation was performed using catalytic FeCl3. The outcome was an efficient general synthesis of dibenzo[a,c]acridines with moderate to high yields. This method offers simplicity in the preparation of substrates, diverse substrate scope, and high atom economy. The generality of the protocol was verified by synthesizing a tribenzo[a,c,h]acridine derivative. Photophysical properties of the synthesized compounds were also studied. The compounds absorb UV light typically in the range 230-330 nm and emit in the visible range of 400-420 nm.

Efficient two-step synthesis of structurally diverse indolo[2,3-b]quinoline derivatives.

A general and efficient synthesis of diverse tetracyclic indolo[2,3-b]quinoline derivatives was achieved through palladium-catalyzed domino carboannulation/cross-coupling and DDQ-mediated double cross-dehydrogenative C-N bond formation. This approach provides a straightforward, atom-economical and concise route to easily access a diverse range of tetracyclic indolo[2,3-b]quinolines and their analogues in excellent yields with good tolerance of functional groups.

Metal-Catalyzed Domino Synthesis of Benzophenanthridines and 6 H-Naphtho[2,3- c]-chromenes.

A new and efficient synthesis of tetracyclic phenanthridines and benzo[ c]chromenes has been described involving a metal-mediated two-step domino strategy. The first step involved efficient palladium-catalyzed domino carbopalladation/cross coupling, and the second step involved iron-catalyzed domino isomerization/cyclodehydration. The important features of this strategy include high yields, generality, wide substrate scope, and broad functional group tolerance. A plausible mechanism has been proposed to explain the formation of the product.

Synthesis of Fused Dibenzofuran Derivatives via Palladium-Catalyzed Domino C-C Bond Formation and Iron-Catalyzed Cycloisomerization/Aromatization.

A range of tetracyclic dibenzofuran derivatives bearing a variety of functional groups was readily synthesized via a two-stage domino strategy starting from propargyl ethers of 2-halo phenol derivatives. The first stage in the strategy involves Pd(0)-catalyzed domino intramolecular carbopalladation/Suzuki coupling via 5-exo-dig cyclization onto the alkyne, leading to 3-methylene-2,3-dihydrobenzofuran derivatives. In the second stage of the domino strategy, an iron(III)-catalyzed cycloisomerization and aromatization reaction produces tetracyclic benzofuran derivatives. This two-step sequence provides efficient access to diversely substituted polycyclic dibenzofuran derivatives in high yields and in an atom-efficient and environmentally friendly manner. Moreover, this strategy was also successfully used for the synthesis of a naturally occurring tetracyclic dibenzofuran, ß-brazan.

FeCl3-catalyzed synthesis of functionally diverse dibenzo[b,f]oxepines and benzo[b]oxepines via alkyne-aldehyde metathesis.

An efficient synthesis of dibenzo[b,f]oxepines and benzo[b]oxepines via FeCl3-catalyzed alkyne-aldehyde metathesis reaction is described. Structurally diverse dibenzo[b,f]oxepines and benzo[b]oxepines have been achieved in good yields with high regio- and chemoselectivity under mild conditions. Notably, among the various catalysts such as Fe(III), Au(III), In(III), Zn(II), Ag(I) and triflic acid, the alkyne-aldehyde metathesis reaction of 2-(2'-phenylethynyl-phenyloxy)-benzaldehyde is only catalyzed by environmentally friendly and sustainable iron(III) chloride.

Efficient synthesis of functionalized dihydroquinolines, quinolines and dihydrobenzo[b]azepine via an iron(III) chloride-catalyzed intramolecular alkyne-carbonyl metathesis of alkyne tethered 2-amino benzaldehyde/acetophenone derivatives.

In this study we have developed an efficient synthesis of 1,2-dihydroquinoline and dihydrobenzo[b]azepine derivatives involving the iron(III) chloride intramolecular alkyne-carbonyl metathesis reaction for the first time. Various functionalized 1,2-dihydroquinolines and dihydrobenzo[b]azepines were prepared from easily accessible substrates in the presence of environmentally friendly and inexpensive iron(III) chloride (10 mol%) under mild conditions. The method is applicable to a wide range of substrates containing different functional groups and furnishing products in good to excellent yields. This methodology was further extended to the one-pot synthesis of 3-acyl quinolines via alkyne-carbonyl metathesis/detosylation/aromatization of N-propargyl-2-aminobenzaldehyde/acetophenone derivatives by the addition of NaOH/EtOH. While many Lewis acid and Brønsted acid catalysts were investigated, anhydrous iron(III) chloride turned out to be the best catalyst for this transformation.

Synthesis of substituted phenanthrene by iron(III)-catalyzed intramolecular alkyne-carbonyl metathesis.

An efficient synthesis of functionalized phenanthrenes has been developed for the first time involving an iron(III)-catalyzed intramolecular coupling of 2'-alkynyl-biphenyl-2-carbaldehydes. A broad range of functionalized phenanthrene derivatives could be obtained in the present method in moderate to good yields with high chemo- and regioselectivity. This transformation can also be applied to the synthesis of an angularly fused tetracyclic compound. This method offers several advantages such as high selectivity, mild reaction conditions, and easy availability of starting materials.

Iron-catalyzed synthesis of functionalized 2H-chromenes via intramolecular alkyne-carbonyl metathesis.

An iron-catalyzed intramolecular alkyne-aldehyde metathesis strategy of the alkynyl ether of salicylaldehyde derivatives has been developed which works under mild reaction conditions to produce the functionalized 2H-chromene derivatives. This protocol is compatible toward a wide range of functional groups, such as methoxy, fluoro, chloro, bromo, and phenyl groups. This method provides an atom-economical and environmentally friendly approach for the synthesis of a series of substituted 2H-chromenes.

Iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes: a simple and direct synthesis of functionalized pyrroles.

A simple, convenient, and multicomponent coupling strategy for the synthesis of highly functionalized pyrroles catalyzed by iron(III) salts has been developed. This strategy demonstrated four-component coupling reactions of 1,3-dicarbonyl compounds, amines, aromatic aldehydes, and nitroalkanes without an inert atmosphere. This methodology provides an alternative approach for easy access of highly substituted pyrroles in moderate to very good yields using four simple and readily available building blocks via one-pot tandem reaction. Notably, this method is very cheap, straightforward, and environmentally friendly compared to the existing methods.

Discovery of a novel class of AKT pleckstrin homology domain inhibitors.

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated K(D) values ranging from 0.8 to 3.0 micromol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro K(D)s for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 micromol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.

Iron-Catalyzed 1,5-Enyne Cycloisomerization via 5-Endo-Dig Cyclization for the Synthesis of 3-(Inden-1-yl)indole Derivatives.

An Fe(OTf)3-catalyzed 1,5-enyne cycloisomerization via 5-endo-dig cyclization is described for the synthesis of 3-(1-indenyl)indole derivatives. Since a variety of 1,5-enynes are readily accessible via Heck-Suzuki coupling, this strategy provides a rapid and easy access to a wide range of highly substituted 3-(1-indenyl)indoles in good yields.

Fe-catalyzed novel domino isomerization/cyclodehydration of substituted 2-[(indoline-3-ylidene)(methyl)]benzaldehyde derivatives: an efficient approach toward benzo[b]carbazole derivatives.

A new and efficient protocol to synthesize substituted benzo[b]carbazole derivatives has been demonstrated involving iron-catalyzed domino isomerization/cyclodehydration sequences from substituted 2-[(indoline-3-ylidene)(methyl)]benzaldehyde derivatives. The substrates could be easily made via Pd-catalyzed domino Heck-Suzuki coupling from 2-bromo-N-propargylanilide derivatives in high yields. Notably, the generality and efficiency of this two-stage domino strategy was further exemplified by the synthesis of a polycyclic benzofuran derivative.