Step Economy Research Articles

2 + 4] Annulation of Alkyl(phenyl)phosphinic Chlorides with Enones: Stereoselective Synthesis of δ-Phosphinolactones

Various δ-phosphinolactones (δ-phostines) are efficiently and diastereospecifically synthesized in good to excellent yields from direct [2 + 4] annulation of alkyl(phenyl)phosphinic chlorides and α,β-enones in the presence of LiHMDS. The annulation involves deprotonation, Michael addition, and nucleophilic substitution and features readily available materials, good to excellent yields, diastereospecificity, atom and step economy, wide substrate scope, easy separation, and mild conditions.

Ru-Catalyzed Synthesis of α,β-Unsaturated Acylsilanes and Its Applications in C–N Bond Formation

α,β-Unsaturated acylsilanes have multifunctional sites and can be used in many transformations. However, the existing methods for preparing them generally suffer from problems, such as low atom and step economy, a narrow substrate scope, etc. Herein, an efficient and general method for accessing α,β-unsaturated acylsilanes through Ru-catalyzed cross-metathesis has been developed. This method is applied to various acylsilanes, especially those β-alkyl-α,β-unsaturated acylsilanes, which are difficult to prepare with the classical methods. In addition, the utilities of the products have been demonstrated through two distinct C-N bond formation reactions.

Asymmetric Assemblies of 1,3-Dienes, Sulfuric Diamide, and Aldehydes to Access 1,3-Diamines through Relay Amine/Palladium Catalysis

A relay catalytic protocol using pyrrolidine and palladium catalysis has been developed for asymmetric synthesis of 1,3-diamine derivatives from 3-substituted 1,3-dienes, sulfuric diamide, and aldehydes. This one-pot, three-component reaction features the advantages of a high atom step economy and operational simplicity, providing an efficient and straightforward access to valuable 1,3-diamines incorporating quaternary and tertiary stereogenic centers with moderate to good enantioselectivity.

Photocatalytic direct borylation of carboxylic acids

The preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is generally realized through the extra step synthesized redox-active ester intermediate or in situ generated carboxylic acid covalent derivatives above 150 °C reaction temperature. Here, we report a direct decarboxylative borylation method of carboxylic acids enabled by visible-light catalysis and that does not require any extra stoichiometric additives or synthesis steps. This operationally simple process produces CO2 and proceeds under mild reaction conditions, in terms of high step economy and good functional group compatibility. A guanidine-based biomimetic active decarboxylative mechanism is proposed and rationalized by mechanistic studies. The methodology reported herein should see broad application extending beyond borylation.

Selective Construction of All-Carbon Quaternary Centers via Relay Catalysis of Indole C-H Functionalization/Allylic Alkylation.

Herein, a novel [Rh]2-catalyzed three-component reaction of readily accessible indoles, diazo compounds, and allylic compounds is developed via a relay carbene-induced C-H functionalization and allylic alkylation process, affording diverse C3-substituted indoles bearing all-carbon quaternary centers in good yields with high atom and step economy. Moreover, good enantioselective control is achieved using a (-)-DIOP type ligand, thus providing an efficient method for constructing enantioenriched indole derivatives bearing an all-carbon quaternary stereocenter.

Quinazolinones/Benzothiadiazines as Amidyl/Aminyl Radical Precursors for Controlled Cascade Cyclization via Photocatalyzed PCET.

Quinazolinones/benzothiadiazines were used as amidyl/aminyl radical precursors for cascade cyclizations via a photoredox-catalyzed proton-coupled electron transfer (PCET) process for the first time. A controlled synthesis of isoindole-fused quinazolinones/benzothiadiazines was carried out via quinazolinone amidyl/benzothiadiazine aminyl radical addition to the C-C triple bond under mild conditions. This transition-metal-free method provides an efficient and broad substrate scope for the synthesis of isoindole-fused quinazolinones/benzothiadiazines with step economy and atom efficiency.

Recent Advances in Room-Temperature Direct C–H Arylation Methodologies

AbstractIn recent decades, direct C–H arylation has become a preferred tool for biaryl coupling over traditional cross-coupling methods owing to its operationally simple protocol, inherent atom and step economy, and reduced metallic waste. Several elegant methods have been developed that offer the facile transformation of usually inert Csp2–H bonds into Csp2–Csp2 bonds in a single synthetic operation. Despite many merits, a major drawback to this chemistry comes from the low reactivity of aryl C–H bonds, which often mandate harsh reaction conditions compromising sustainability. Hence, developing reaction protocols that require milder conditions has become an important goal in this area of research. This review article comprehensively highlights the synthesis and mechanistic aspects of direct C–H arylation reactions, which proceed at or below room temperature.1 Introduction2 Concepts and Examples2.1 Transition-Metal-Catalyzed Procedures2.1.1 Pd Catalysis2.1.2 Other Metal-Based Procedures2.1.3 Additive-Free Procedures2.2 Direct Arylation Polymerization2.3 Photocatalyzed Procedures2.3.1 Organometallic C–H-Activation-Based Procedures2.3.2 Radical-Addition-Based Procedures2.4 Transition-Metal-Free Procedures2.4.1 Base-Mediated Procedures2.4.2 Iodonium- and Diazonium-Salt-Based Procedures2.5 Electrocatalyzed Procedures3 Summary and Outlook

Isocyanide-Based Multicomponent Reactions in Water: Advanced Green Tools for the Synthesis of Heterocyclic Compounds.

Reaction rate acceleration using green methods is an intriguing area of research for chemists. In this regard, water as a "green solvent" plays a crucial role in the acceleration of some organic transformations and reveals exclusive selectivity and reactivity in comparison with conventional organic solvents. In particular, multicomponent reactions (MCRs) as sustainable tools lead to the rapid generation of small-molecule libraries in water and aqueous media due to the prominent role of the hydrophobic effect. MCRs, as diversity-oriented synthesis (DOS) methods, have great efficiency with simple operations, atom, pot, and step economy synthesis, and mechanistic beauty. Among diverse classes of MCRs, isocyanide-based multicomponent reactions (I-MCRs), as sustainable and versatile reactions, have gained considerable attention in the synthesis of diverse heterocycle rings, especially in drug design because of the peculiar nature of isocyanide as a particular active reactant. I-MCRs that are performed in water are mild, environmentally friendly, and easily controlled, and have a reduced number of workup, purification, and extraction steps, which fit well with the advantages of "green" chemistry. Performing these powerful organic transformations in water and aqueous media is accompanied by acceleration owing to negative activation volumes, which originate from connecting several reactants together to generate a single product. It should be noted that the combination of MCR strategy and aqueous phase reaction is of growing interest for the development of sustainable synthetic techniques in organic conversions. However, an exclusive account focusing on the recent progress in eco-friendly I-MCRs for the construction of heterocycles in water and aqueous media is particularly lacking. This review highlights the progress of various kinds of I-MCRs in water and aqueous media as benign methods for the efficient construction of vital heterocyclic scaffolds, with a critical discussion of the subject in the period 2000-2021. We hope that this themed collection will be of interest and beneficial for organic and pharmaceutical chemists and will inspire more reaction development in this fascinating field.

Copper‐Catalyzed Multicomponent Reaction to Construct Fluorinated Indole‐quinoxalin‐2(1H)‐ones and Their Biological Evaluation

AbstractA practical and mild three‐component reaction of indoles, quinoxalin‐2(1H)‐ones, and CF3SO2Na is disclosed for the facile access of various 3‐[2‐(trifluoromethyl)1H‐indol‐3‐yl]quinoxalin‐2(1H)‐ones using low‐cost and catalytic amount of CuF2 as the catalyst. This strategy exhibits high site‐selectivity, step economy, and broad substrates scope. Synthetic utility was demonstrated by the one‐pot two‐step synthesis of N‐alkyl triazoles compounds via a click chemistry. To evaluate the antiproliferative activity of these compounds, A549 s (human lung adenocarcinoma cells) and HUVECs, as a model of toxicity, were used in MTT assay. The outcomes disclosed for 6‐CO2Me and a N‐alkyl triazole derivatives were of potent antiproliferative effect against A549 s (IC50 = 4.7 and 14.9 μM, respectively) with slight cytotoxicity in HUVECs. Morphological study was conducted by AO/EB dual staining, indicated hydrochloride 6‐CO2Me derivative was capable of inducing apoptosis of A549 cells.

Copper-Promoted N-Alkylation and Bromination of Arylamines/Indazoles Using Alkyl Bromides as Reagents for Difunctionalization.

Practical copper-promoted N-alkylation and bromination of arylamines/indazoles with alkyl bromides are described; the N-alkylation-C-4-bromination and N-dialkylation-C-4-bromination of arylamines, and N-alkylation-C-3-bromination of indazoles, with alkyl bromides have been analyzed. The full use of alkyl bromides as alkylating and brominating building blocks without atom wastage, indicating excellent atom and step economy, has been highlighted. Eco-friendly oxygen and water are the reaction oxidant and byproduct, respectively.

Hydrogen Transfer Coupling with 100% Atom Economy: Synthesis of 2-Indolyltetrahydronaphthyridine Derivatives.

An iridium-catalyzed hydrogen transfer strategy, enabling straightforward access to tetrahydropyridine derivatives from aryl-1,8-naphthyridines and indolines was developed. This method has unprecedented advantages, including high step economy. In addition, it does not produce any byproducts or require an external high-pressure H2 gas source. The method offers an important platform for the transformation of 1,8-naphthyridines and indolines into functionalized products.

KOtBu-mediated transition-metal-free synthesis of pyrimidines by selective three-component coupling reactions: A mechanistic insight

A KOtBu-mediated strategy for pyrimidine synthesis via selective three-component coupling reactions has been disclosed. This chemistry, in which a series of pyrimidines (20 examples) can be prepared with moderate to excellent yields, has high potential for large-scale operation owing to its metal-free conditions, atom and step economy. According to mechanistic studies, oxidative species can be generated from KOtBu or toluene in the presence of air, which can initiate the oxidation of alcohols to aldehydes (or ketones). Meanwhile, KOtBu not only promotes the condensation-cyclization process, but also triggers the dehydrogenation of dihydropyrimidine ring.

Recent advances in theoretical studies on transition-metal-catalyzed regioselective C-H functionalization of indoles.

Indole compounds are widely found in natural products and drug candidates. The transition-metal-catalyzed regioselective C-H bond functionalization of indoles as the most efficient method for the synthesis of various functionalized indoles has been extensively studied in the past two decades due to its advantages of step economy and atom economy. In general, the catalysts included the transition-metals (Pd, Rh, Ru, Cu, Co, Fe, Zn, and Ga) and these reactions were accomplished with a remarkably wide range of coupling reagents for construction of various C-C and C-X (X = N, O, S) bonds. However, the general and important rules of the regioselectivity are not clear to date. Therefore, a comprehensive analysis through previous reported theoretical studies on transition-metal-catalyzed regioselective C-H bond functionalization of indoles was crucial and significant. In this review, we found that when the C-H bond activation process was the rate-determining step, the regioselectivity ordinarily occurred at the C7 or C4 positions (on benzene ring), and otherwise, the regioselectivity often occurred at C2 position (on pyrrole ring). For indoline substrates, the C-H bond functionalization occurred at the benzene ring. General rules of the regioselectivities for transition-metal-catalyzed C-H bond functionalization of indoles. This review collects major advances in the transition-metal-catalyzed C-H bond functionalization of indoles and indolines.

One-Step Visible Light Photoredox-Catalyzed Purine C8 Alkoxylation with Alcohol.

A cross-dehydrogenation coupling reaction between purines and alcohols, induced by visible light, using an acridinium photocatalyst and air as the sole oxidant, to synthesize a series of C8-alkoxy purine derivatives was developed. This protocol is a green and novel method to construct the C8-O bond on a purine ring with high step and atom economy.

DBU-Mediated Domino Annulation Reaction of 2-Amino-4H-chromen-4-ones and Aromatic Aldehydes for Synthesis of Polysubstituted 3-Hydroxy-5H-chromeno[2,3-b]pyridinones.

A pseudo-three-component annulation reaction of substituted 2-amino-4H-chromen-4-ones with aromatic aldehydes promoted by DBU was investigated to access polysubstituted 5H-chromeno[2,3-b]pyridines. This reaction included a sequential intermolecular nucleophilic addition/Michael cyclization/intramolecular epoxidation/ring opening/aromatization sequence, which possessed excellent step and atom economy in a single operation for generating 3-hydroxy-5H-chromeno[2,3-b]pyridines from readily available substrates.

Synthesis of β-Arylseleno Sulfoximines: A Metal-Free Three-Component Reaction Mediated by Tetrabutylammonium Tribromide.

A tetrabutylammonium tribromide-mediated three-component reaction of alkenes, diselenides, and sulfoximines has been established herein, providing direct and metal-free access to diverse β-arylseleno sulfoximine derivatives. This regioselective sulfoximido-selenization protocol proceeds efficiently under mild and ambient conditions with generally good yields. This strategy is featured by step and atom economy, practicability, a broad substrate scope, and gram-scale synthesis.

Recent Applications of the Multicomponent Synthesis for Bioactive Pyrazole Derivatives.

Pyrazole and its derivatives are considered a privileged N-heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.

Metal-Free Temperature-Controlled Intermolecular [3 + 2] Annulation to Access Benzo[d]thiazole-2(3H)-thiones and Benzo[d]thiazol-2(3H)-ones.

A facile access to benzo[d]thiazole-2(3H)-thiones and benzo[d]thiazol-2(3H)-ones has been developed through a temperature-controlled intermolecular [3 + 2] annulation of N,N-disubstituted arylhydrazines with CS2 in the presence of DMSO. This protocol can obviate the prefunctionalization of the starting materials. This direct C-S/C-N bond formation reaction was performed in the absence of any external catalysts, transition metals, bases, ligands, and oxidants with high step economy.

Copper catalyzed C-N-bond formation and synthesis of Imidazopyridinone derivatives

The formation of the C–N bond is critical because it allows for the incorporation of nitrogen into organic molecules. Despite significant advances in this area, the formation of the C–N bond continues to be a challenge for organic chemists owing to the need of severe reaction conditions or costly catalysts in many cases. As a result, developing alternate, milder, and less expensive C–N bonding techniques is a challenge. Herein, a series of novel imidazopyridinone derivatives (8a-8e) were synthesized via copper-mediated C–¬N bond-forming reaction. This reaction takes place under mild conditions with high efficiency, step economy, and tolerance for a wide range of functional groups. All synthesized new compounds were analyzed by 1H NMR, 13C NMR and mass spectrometry.

Dual Ligand Enabled Nondirected C-H Chalcogenation of Arenes and Heteroarenes.

Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction of these chalcogen motifs has been restricted to either the use of directing groups or the employment of a large excess of electronically activated arenes, typically employed as a cosolvent. Despite being highly effective, these methods have their own limitations in the step economy and the deployment of an excess amount of arenes. Herein, we report the evolution of a catalytic system employing arene-limited, nondirected thioarylation of arenes and heteroarenes using a complimentary dual-ligand approach. The reaction is controlled by a combination of steric and electronic factors, and the utilization of a suitable ligand enables the generation of products on a complimentary spectrum to that generated by classical methods. The combination of ligands remains imperative in the reaction protocol with theoretical calculations pointing towards a monoprotected amino acid ligand being crucial in the concerted metalation deprotonation (CMD) mechanism by a characteristic [5,6]-palladacyclic transition state, while the pyridine moiety assists in the active catalyst species formation and product release. Combined experimental and computational mechanistic investigations point toward the C-H activation step being both regio- and rate-determining. Interestingly, oxidative addition of the diphenyl disulfide substrate is found to be unlikely, and an alternative transmetalation-like mechanism involving the Pd-Ag heterometallic complex is proposed to be operative.