Metal-free Synthesis Research Articles

An efficient metal free synthesis of 2-aminobenzothiozoles - a greener approach.

A facile one-pot, metal-free method for the synthesis of 2-aminobenzothiazoles was developed, which includes an initial reaction of electron-deficient 2-haloanilines with aromatic isothiocyanates and the subsequent intramolecular cyclization of the resulting thioureas through the SNAr mechanism. This one-pot, atom-economical, robust, and scalable method avoids the use of reagents such as acid chlorides and Lawesson's reagent that are difficult to handle.

Metal-free synthesis of nitriles from aldehydes usingN-Boc-O-tosylhydroxylamine as a nitrogen source

In this work, an operationally simple, one-pot, metal free synthesis of nitriles from readily available aldehydes has been disclosed.

Metal-free synthesis of an estetrol key intermediate under intensified continuous flow conditions

Development of a scalable and intensified thermolysis process for the preparation of a key intermediate toward estetrol.

P-TSA·H2O catalyzed metal-free and environmentally benign synthesis of 4-aryl quinolines from arylamine, arylacetylene, and dimethyl sulfoxide.

An environmentally benign and metal-free synthesis of 4-aryl quinolines is reported by employing readily available arylamine, arylacetylene, and DMSO in the presence of 20 mol% p-TSA·H2O. In the present protocol, the solvent DMSO serves as a reactant cum solvent for providing the C2 carbon atom of the quinoline skeleton. Notably, the reaction proceeds effectively and efficiently without the involvement of any metal catalyst, ligand, and co-catalyst as additives and inert atmospheric reaction conditions. This method provides high atom economy and good yields, and two C-C and one C-N bonds are formed in a single step through a three-component reaction.

Acridine yellow G as a photo-induced electron transfer catalyzed radical metal-free synthesis of tetrahydrobenzo[b]pyran scaffolds in an aqueous media

We established a green approach for the radical synthesis of tetrahydrobenzo[b]pyran scaffolds by using Knoevenagel-Michael tandem cyclocondensation of aldehyde derivatives, malononitrile, and dimedone. Using visible light as a renewable energy source, a photo-induced electron transfer (PET) photocatalyst was exploited in an aqueous solution. A low-cost, readily available non-metal dye is the goal of this research. The photochemically catalyzed acridine yellow G (AYG) exhibits high yields, energy efficiency, and environmental friendliness, as well as speed-saving characteristics and ease of use. This allows for tracking of environmental and chemical variables over time. In this study, turnover number (TON) and turnover frequency (TOF) of tetrahydrobenzo[b]pyran scaffolds were determined. It is remarkable that gram-scale cyclization is feasible, indicating that it can be applied to industry.

A metal-free synthesis of pyrimidines from amidines with α,β-unsaturated ketones via tandem [3 + 3] annulation and visible-light-enabled photo-oxidation.

A facile metal-free synthesis of multi-substituted pyrimidines from readily available amidines and α,β-unsaturated ketones is reported. The synthesis involved a [3 + 3] annulation to form a dihydropyrimidine intermediate, which was converted to pyrimidine through visible-light-enabled photo-oxidation rather than the usual transition-metal-catalyzed dehydrogenation. The mechanism of the photo-oxidation was studied. This work has provided an alternative approach to pyrimidines with the advantages of easy operation, and mild and green conditions with a broad scope of substrates, circumventing the dependence on transition-metal catalysts and strong bases.

Brønsted acid-promoted ring-opening and annulation of thioamides and 2H-azirines to synthesize 2,4,5-trisubstituted thiazoles.

In this study, a metal-free synthesis of 2,4,5-trisubstituted thiazoles using 2H-azirines and thioamides is disclosed. Under the catalysis of HClO4, the protocol was realized through a novel chemical bond breaking of 2H-azirine, which is usually achieved using a metal catalyst. It provides an efficient and green route for the synthesis of substituted thiazoles with a broad substrate scope. Preliminary mechanistic studies show that such a reaction may involve a ring-opening reaction, annulation, and a hydrogen atom rearrangement process.

Metal-free synthesis of N-sulfonyl imines from benzyl alcohol derivatives and iminoiodinanes via mechanochemistry.

An expedient and operationally convenient mechanochemical synthesis of aryl/heteroaryl N-sulfonyl imines is reported by reacting iminoiodinanes with numerous aryl/heteroaryl benzyl alcohols in ball milling apparatus (RETSCH 400™) with three 5 mm stainless steel (ss) balls in a 5 mL stainless steel (ss) reaction jar. CHCl3 (η = 0.2-0.4 μL mg-1) was used as a liquid assisted grinding (LAG) auxiliary. This metal catalyst- and base- free synthesis with nominal amounts of solvents (as LAGs) demonstrated an efficient N-sulfonyl transfer reaction from iminoiodinanes to afford the desired compounds in moderate to good yields. Substituted N-sulfonyl imines are crucial as standalone natural product building blocks and drug intermediates as well as precursors of sulfonamides which have been involved in potential small molecule therapy in many therapeutic programs. The putative mechanisms of the transformations are discussed based on control reactions and DFT calculations.

Tertiary amines as a C1 synthon: metal-free synthesis of quinolines and 2-substituted quinolinesvia[3+2+1] aerobic cyclization and C–N bond cleavage

An I2-mediated aerobic cyclization reaction of anilines, alkynes, and tertiary amine has been reported. In this protocol, a novel strategy for the synthesis of quinolines using tertiary amines as a C1 synthonviaC–N bond cleavage.

Base-mediated chalcogenoaminative annulation of 2-alkynylanilines for direct access to 3-sulfenyl/selenyl-1H-indoles.

An efficient and transition metal-free synthesis of 3-sulfenyl/selenyl-1H-indoles via a base-assisted chalcogenoaminative annulation of 2-alkynyl aniline with disulfides/diselenides is described. A series of 2-alkynylanilines were found compatible with dichalcogenides in this transformation providing 3-sulfenyl/selenyl-1H-indoles in good to excellent yields. The presented methodology has the advantages of easily available raw materials, functional group tolerance, and a wide range of substrates that provide access to 3-sulfenylindoles and 3-selenylindoles.

Correction: Triflic acid-catalyzed metal-free synthesis of (E)-2-cyanoacrylamides and 3-substituted azetidine-2,4-diones

Correction for ‘Triflic acid-catalyzed metal-free synthesis of (E)-2-cyanoacrylamides and 3-substituted azetidine-2,4-diones’ by Bapurao D. Rupanawar et al., New J. Chem., 2018, 42, 6433–6440, https://doi.org/10.1039/C7NJ05169G.

Metal-free synthesis of dihydrofuran derivatives as anti-vicinal amino alcohol isosteres.

Dihydrofuran cores are commonly incorporated into synthetically and pharmacologically significant scaffolds in natural product and drug discovery chemistry. Herein, we report a concise and practical strategy to construct spiro-dihydrofuran and amino dihydrofuran scaffolds as anti-vicinal amino alcohol isosteres. Hypervalent iodine (PhI(OAc)(NTs2))-mediated C-H activation of alkynes resulted in two-bond formations with one pi bond cleavage: (i) C(sp2)-N(sp3) and O(sp3)-C(sp2); (ii) C(sp2)-N(sp3) and C(sp3)-C(sp2). The metal-free 5-endo-dig oxidative cyclization provided versatile amino 2,3- and 2,5-dihydrofurans bearing the C5 quaternary carbon. The non-toxicity of all synthesised dihydrofurans was verified via in vitro cell viability assay.

Metal-free synthesis of selenoesters directly from carboxylic acids using bifunctional selenoureas under batch and continuous-flow conditions.

A new metal-free method for the synthesis of selenoesters directly from carboxylic acids in a flow reactor is reported. The carboxylic acids, Michael acceptors, and bifunctional selenoureas (source of selenium and nucleophile, activator of carbonyl group) were reacted to obtain selenoesters (up to 70% yield). An evidence-backed plausible mechanism is also presented.

Expanded Perlite-Polyphosphoric Acid (EP-PPA) as a Low-Cost Heterogeneous Solid Acid Catalyst for Green and Metal-Free Synthesis of Nitriles from Aldehydes

Expanded Perlite-Polyphosphoric Acid (EP-PPA) as a Low-Cost Heterogeneous Solid Acid Catalyst for Green and Metal-Free Synthesis of Nitriles from Aldehydes

A efficient, metal-free and sustainable synthesis, C-S linked by simple C-H thiocyanation of 4-aminocoumarin or 4-(N-aryl)aminocoumarin derivativess

In the present study, we describe the successful development of a novel and efficient C(sp2)−H thiocyanation reaction of 4-aminocoumarin and 4-(N-aryl)aminocoumarin derivatives with readily available using KSCN as thiocyanating agent and K2S2O8 as an oxidant in ACN under the air atmosphere and room temperature. The most notable point, the reaction proceeded smoothly without the addition of any metal catalyst or strong oxidant and heat, ultimately minimizing the production of chemical waste. The advantages of this reaction met the requirements of green and sustainable synthetic chemistry and may be widely used in organic synthesis and pharmaceutical chemistry.

Metal-free one-pot synthesis of 2-substituted benzimidazoles from N-aryl imines and TMSN3

Iodine-catalysed efficient synthesis of 2-substituted benzimidazoles has been developed under aerobic condition. The one-pot oxidative cascade reactions of anilines, aldehydes and trimethylsilyl azide (TMSN3) lead to the benzimidazoles derivatives in the presence of tert-butyl hydroperoxide (TBHP). Iodine efficiently promoted the cross-coupling strategy to achieve the desired compounds via the sequential CH functionalization and cyclization. The present method features a greener approach, readily accessible reagents, broad substrate scope, high yields of the products, shorter reaction time and mild conditions.

Metal-Free Synthesis of Acyl Glycosides and Application to Oligosaccharide Synthesis.

Oligosaccharides are involved in numerous biological processes. Achieving optimal anomeric selectivity and regioselectivity remains challenging. Herein, we present a method for the oxidative glycosylation of thioglycosides with hypervalent iodine reagents derived from carboxylic acid to form C-O bonds. The reaction of thioglycosides with various hypervalent iodine carboxylates afforded acyl O-glycosyl compounds. These acyl O-glycosyl compounds could react with thioglycoside acceptors to produce disaccharides; trisaccharides and tetrasaccharides could be synthesized by repeating this method.

Metal-Free Synthesis of Thiocyanated Aminonitroalkenes and 2-Aminothiazoles/selenazoles from β-Aminonitroalkenes and N‑Thio/Selenocyanatosaccharin

AbstractA convenient and efficient protocol has been developed for the synthesis of thiocyanated aminonitroalkenes and 2,4,5-trisubstituted thiazoles/selenazoles from β-aminonitroalkenes and N‑thio/selenocyanatosaccharin. This method features simple operation, mild reaction conditions, short reaction time, good functional group compatibility, and metal-free characteristics. The broad applications of polysubstituted thiazoles/selenazoles in organic and medicinal chemistry make this protocol much more practical.

Visible-Light Photoredox-Catalyzed Decarboxylation of α-Oxo Carboxylic Acids to C1-Deuterated Aldehydes and Aldehydes.

The synthesis of high-value-added C1-deuterated aldehydes would improve the availability of deuterated lead compounds for deuterium-labeled drug discovery. Herein, we develop a metal-free synthesis of C1-deuterated aldehydes with D2O from α-oxo carboxylic acids at ambient temperature. Via visible-light photoredox-catalyzed decarboxylation, stoichiometric reductants and oxidants were avoided. Various functional groups were tolerated and resulted in C1-deuterium aldehydes in up to 92% yield and 91-97% D incorporation under mild conditions. This method is also applied to the synthesis of various aldehydes. Primary mechanistic studies indicate that the catalytic pathway occurs via a reductive quenching pathway followed by hydrogen atom transfer.

New metal-free one-pot synthesis of α-2-deoxy-Ulosides by microwave-assisted double Michael Addition of β-enamino ketones

New metal-free one-pot synthesis of α-2-deoxy-ulosides in moderate to good yields by microwave-assisted double Michael addition of various O-nucleophiles to β-enamino ketones in the presence of 12 N HCl. These glycosyl additions occurred with high α-stereoselectivity and were complete in 10–25 min in 51–93% yield. In addition, high α-stereoselectivity was also observed when S-nucleophiles were examined.