An efficient metal-free and catalyst-free C-S/C-O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides.

An operationally simple and metal-free approach is described for the synthesis of pyrazole-tethered thioamide and amide conjugates. The thioamides were generated by employing a three-component reaction of diverse pyrazole C-3/4/5 carbaldehydes, secondary amines, and elemental sulfur in a single synthetic operation. The advantages of this developed protocol refer to the broad substrate scope, metal-free and easy to perform reaction conditions. Moreover, the pyrazole C-3/5-linked amide conjugates were also synthesized via an oxidative amination of pyrazole carbaldehydes and 2-aminopyridines using hydrogen peroxide as an oxidant.

Overview of Hydroxychloroquine and Remdesivir on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing pandemic named COVID-19 which causes a serious emergency on public health hazards of international concern. In the face of a critical medical emergency, repositioning of drugs is one of the most authentic options to design an adequate treatment for infected patients immediately. In this strategy, Remdesivir (Veklury), Hydroxychloroquine appears to be the drug of choice and garnered unprecedented attention as potential therapeutic agents against the pandemic realized worldwide due to SARS-CoV-2 infection. These are the breathtaking instances of possible repositioning of drugs, whose pharmacokinetics and optimal dosage are familiar. In this review, we provide an overview of these medications, their synthesis, and the possible mechanism of action against SARS-CoV-2.

Transition-Metal-Free Transfer Hydrogenative Cascade Reaction of Nitroarenes with Amines/Alcohols: Redox-Economical Access to Benzimidazoles.

This report describes an efficient transition-metal-free process toward the transfer hydrogenative cascade reaction between nitroarenes and amines or alcohols. The developed redox-economical approach was realized using a combination of KOtBu and Et3SiH as reagents, which allows the synthesis of benzimidazole derivatives via σ-bond metathesis. The reaction conditions hold well over a wide range of substrates embedded with diverse functional groups to deliver the desired products in good to excellent yields. The mechanistic proposal has been depicted on the basis of a series of control experiments, mass spectroscopic evidence which is well supported by density functional theory (DFT) calculations with a feasible energy profile.

Reagent-Controlled Divergent Synthesis of 2-Amino-1,3-Benzoxazines and 2-Amino-1,3-Benzothiazines.

A reagent-controlled chemoselective process has been devised for the synthesis of 4H-1,3-benzoxazines and related biologically important heterocycles in high yields under mild conditions. These scaffolds could be efficiently constructed using two different chemoselective reactions that rely on the choice of reagents and reaction conditions. The treatment of various 2-amino-arylalkyl alcohols with isothiocyanates afforded thiourea intermediates, which were reacted in situ with molecular iodine in the presence of triethylamine to give 2-amino-4H-1,3-benzoxazines, whereas the corresponding 2-amino-4H-1,3-benzothiazines were obtained by the reaction of thiourea intermediates in the presence of T3P (a mild cyclodehydrating agent) and triethylamine as the base. The described protocol represents the first example for the synthesis of 4H-1,3-benzoxazines via the dehydrosulfurization method using molecular iodine as the reagent.

Pd-Catalyzed Decarboxylation and Dual C(sp3)-H Functionalization Protocols for the Synthesis of 2,4-Diarylpyridines.

The Pd-catalyzed decarboxylation and dual C(sp3)-H bond functionalization approaches have been described for the preparation of symmetrical and unsymmetrical 2,4-diarylpyridines. The developed transformations were realized using nonactivated aromatic ketones and amino acids as C-N sources. The efficacy of the catalyst and reagent combination drives the transformation toward the formation of desired products with high yields and selectivity. The described reaction conditions have seduced the self-reaction of phenylalanine via [2 + 2 + 2] cycloaddition and minimized the formation of 3,5-phenylpyridine as a side product, whereas using glycine as a C-N source, the corresponding 2,6-diarylpyridines were formed as minor products.

A metal- and base-free domino protocol for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines and related scaffolds.

Efficient protocols have been described for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines, 2-aryl thiazin-4-ones and diaryl[b,f][1,5]diazocine-6,12(5H,11H)-diones. These transformations were successfully driven towards the product formation under mild acid catalyzed reaction conditions at room temperature using 2-amino aryl/hetero-aryl alkyl alcohols and amides as substrates. The merits of the present methods also rely on the easy access of rarely explored bioactive scaffolds like 1,3-benzoselenazine derivatives, for which well-documented methods are rarely known in the literature. A broad range of substrates with both electron-rich and electron-deficient groups were well-tolerated under the developed conditions to furnish the desired products in yields up to 98%. The scope of the devised method is not only restricted to the synthesis of 1,3-benzoselenazines, but it was also further extended towards the synthesis of 1,3-benzothiazines, 1,3-benzothiazinones and the corresponding eight membered N-heterocycles such as diaryl[b,f][1,5]diazocine-6,12(5H,11H)-diones.

Natural product inspired design and synthesis of ß-carboline and γ-lactone based molecular hybrids.

ß-Carboline and γ-lactone moieties have been selected by nature as privileged scaffolds and display a wide range of pharmacological properties. Following nature, we envisaged the preparation of new ß-carboline and γ-lactone based molecular hybrids incorporating both the pharmacophores. In this regard, a water-assisted In-mediated environmentally benign and easy to execute single-step tandem Barbier type allylation-lactonisation process has been devised in order to afford the targeted molecular architectures. It is anticipated that aqueous medium plays the key role in allylation as well as in the subsequent lactonisation process for the diastereo-selective synthesis of these conjugates. It is believed that water drives the reaction pathway through dual activation, it increases the electrophilic character of formyl and ester functionalities and simultaneously enhances the nucleophilic potential of the hydroxyl group to facilitate the in situ intramolecular condensation. Importantly, during this synthetic strategy no column chromatographic purification was required at any stage.

Base-Promoted Domino Reaction of 5-Substituted 2-Nitrosophenols with Bromomethyl Aryl Ketones: A Transition-Metal-Free Approach to 2-Aroylbenzoxazoles.

The reaction of 5-substituted 2-nitrosophenols with bromomethyl aryl ketones and related compounds employing K2CO3 as a base in refluxing THF and DMF at 80 °C, respectively, delivers 2-aroylbenzoxazoles in a single step with yields up to 85%. The new method involves an intermolecular nucleophilic substitution followed by intramolecular 1,2-addition and elimination. It allows an efficient and practical access to 2-aroylbenzoxazoles under transition-metal-free conditions.

Immobilized catalysts for iridium-catalyzed allylic amination: rate enhancement by immobilization.

The first immobilized catalyst for Ir-catalyzed asymmetric allylic aminations is described. The catalyst is a cationic (π-allyl)Ir complex bound by cation exchange to an anionic silica gel support. Preparation of the catalyst is facile, and the supported catalyst displayed considerably enhanced activity compared with the parent homogeneous catalyst. Up to 43 consecutive amination runs were possible in recycling experiments.

2,3-Dihalo-1-propenes as building blocks in Cu(I)-catalyzed domino reactions: efficient and selective synthesis of furans.

The Cu(I)-catalyzed reaction of 2,3-dibromo-1-propenes with ß-ketoesters and 1,3-diketones, respectively, in DMF at 120 °C using Cs2CO3 as a base and hydroquinone as an additive exclusively delivers 2,3,5-trisubstituted furans and related compounds with yields up to 96%. The highly regioselective domino process is based on an intermolecular C-allylation followed by an intramolecular Ullmann type O-vinylation and a double bond isomerization.

Lewis acid mediated vinyl-transfer reaction of alkynes to N-alkylimines by using the N-alkyl residue as a sacrificial hydrogen donor.

A variety of N-alkyl-α,α-dichloroaldimines were vinylated by terminal acetylenes in the presence of Lewis acids such as In(OTf)3 or BF3 ⋅OEt2 and hexafluoroisopropanol (HFIP) as an additive. The reaction proceeds at ambient temperature and leads to geometrically pure allylic ß,ß-dichloroamines. This approach is complementary to previously reported transition-metal-catalyzed vinyl-transfer methods, which are not applicable to aliphatic imines and are restricted to imines that contain an electron-withdrawing nitrogen substituent. In the present approach, terminal alkynes were used as a source of the vinyl residue, and the N-alkyl moiety of the imine acts as a sacrificial hydrogen donor. The additional advantage of this methodology is the fact that no external toxic or hazardous reducing agents or molecular hydrogen has to be used. This new methodology nicely combines a C(sp(2) )C(sp) bond formation, hydride transfer, and an unusual cleavage of an unactivated CN bond, thereby giving rise to functionalized primary allylic amines. A detailed experimental study supported by DFT calculations of the mechanism has been done.

Pharmaceutical potential of phorbol esters from Jatropha curcas oil.

Phorbol esters (PEs) are diterpenes present in Jatropha curcas L. seeds and have a myriad of biological activities. Since PEs are toxic, they are considered to be futile in Jatropha-based biodiesel production chain. In the present study, the extracted PEs from Jatropha oil were used as a starting material to synthesise pharmacologically important compound, prostratin. The prostratin synthesised from Jatropha showed identical mass with that of the reference standard prostratin, as determined by Nano-LC-ESI-MS/MS. Considering the rapid growth in Jatropha biodiesel industry, potential exists to harness large amount of PEs which can be further utilised to synthesise prostratin as a value added product.

Reaction of 1-nitroso-2-naphthols with α-functionalized ketones and related compounds: the unexpected formation of decarbonylated 2-substituted naphtho[1,2-d][1,3]oxazoles.

Reactions between 1-nitroso-2-naphthols and α-functionalized ketones such as α-bromo-, α-chloro-, α-mesyloxy-, α-tosyloxy-, and α-hydroxy ketones under basic conditions delivered 2-substituted naphtho[1,2-d][1,3]oxazoles in a single synthetic operation. The product formation was accompanied by the unexpected loss of the C═O group from the α-functionalized ketones. With aryl bromides, allyl bromides, α-bromo diketones, α-bromo cyanides, α-bromoesters, and α-bromo ketoesters as substrates the formation of naphtho[1,2-d][1,3]oxazoles was also observed. The transformations were performed in 1,2-dichloroethane or acetonitrile under reflux and gave the corresponding naphthoxazoles with yields ranging between 52% and 85%.

Copper(I)-catalyzed intramolecular O-arylation for the synthesis of 2,3,4,9-tetrahydro-1H-xanthen-1-ones with low loads of CuCl.

As little as 0.5 mol % CuCl is sufficient to catalyze the intramolecular O-arylation of easily accessible 2-(2-bromobenzyl)cyclohexane-1,3-diones to provide the corresponding 2,3,4,9-tetrahydro-1H-xanthen-1-ones with yields ranging from 83% to 99%.

Cu-catalyzed reaction of 1,2-dihalobenzenes with 1,3-cyclohexanediones for the synthesis of 3,4-dihydrodibenzo[b,d]furan-1(2H)-ones.

The Cu(I)-catalyzed reaction of 1-bromo-2-iodobenzenes and other 1,2-dihalobenzenes with 1,3-cyclohexanediones in DMF at 130 °C using Cs(2)CO(3) as a base and pivalic acid as an additive selectively delivers 3,4-dihydrodibenzo[b,d]furan-1(2H)-ones with yields ranging from 47 to 83%. The highly regioselective domino process is based on an intermolecular Ullmann-type C-arylation followed by an intramolecular Ullmann-type O-arylation. Substituted products are accessible by employing substituted 1-bromo-2-iodobenzenes and substituted 1,3-cyclohexanediones as substrates. Reaction with an acyclic 1,3-diketone yields the corresponding benzo[b]furan.

Copper-catalyzed synthesis of quinazolines in water starting from o-bromobenzylbromides and benzamidines.

Water makes it possible: The Cu(2)O-catalyzed reaction between easily available o-bromobenzylbromides and benzamidines by using Cs(2)CO(3) as the base and N,N'-dimethylethylenediamine (DMEDA) as the additive in water as the solvent gives access to substituted quinazolines in a single step with yields ranging from 57 to 85 % (see scheme).

Cu(I)-catalyzed annulation for the synthesis of substituted naphthalenes using o-bromobenzaldehydes and ß-ketoesters as substrates.

Cu(I)-catalyzed reaction of o-bromobenzaldehydes with ß-ketoesters using Cs(2)CO(3) as a base and 2-picolinic acid as an additive proceeds under mild conditions and gives access to substituted naphthalenes in a single step with yields ranging from 71 to 86%. The new annulation process relies on a domino Knoevenagel condensation/C-arylation/1,2-addition/carboxylic acid cleavage. The annulation can also be achieved with o-iodobenzaldehyde.

Cu(I)-catalyzed domino reactions: efficient and selective synthesis of 4H-chromenes and naphthalenes.

Depending on the ratio of the substrates and the reaction conditions, the Cu(I)-catalyzed domino reaction between bromobenzyl bromides and ß-ketoesters exclusively yields either 4H-chromenes or naphthalenes.

Double C-H activation: the palladium-catalyzed direct C-arylation of xanthines with arenes.

The novel Pd-catalyzed C(sp(2))-H/C(sp(2))-H cross-coupling of unactivated xanthines with unactivated arenes utilizing a combination of Ag(I) and O(2) as oxidants exclusively yields C-8 arylated xanthines in a single synthetic operation.

Influence of bases and ligands on the outcome of the Cu(I)-catalyzed oxidative homocoupling of terminal alkynes to 1,4-disubstituted 1,3-diynes using oxygen as an oxidant.

The efficient Cu(I)-catalyzed oxidative homocoupling of terminal alkynes in the presence of a base using an amine as a ligand and oxygen as an oxidant yields the symmetrical 1,3-diynes with yields of up to 99%. The outcome of the couplings critically depends on the proper choice of base and ligand as well as reaction conditions. Best results were observed with 2.0 mol % CuCl, 1.5 mol % TMEDA or DBEDA, and DBU or DABCO in acetonitrile.