One-pot Access Research Articles

Copper-Catalyzed Aerobic Cross-Dehydrogenation Coupling of Indoles for Synthesis of 2,3'-Bisindoles.

2,3'-Bisindoles with C-C linkages have attracted interest in medicinal chemistry, yet their synthesis is intricate with many steps. Notably, direct C-H/C-H cross-coupling of non-directed heteroaromatics remains challenging, often requiring precious metals and oxidants to enhance coupling efficiency. Herein, we present a copper-catalyzed C-H/C-H cross-coupling method for N-substituted indoles without directing groups, facilitated by molecular oxygen under gentle conditions. It showed reasonable functional group compatibility and provided one-pot access to a variety of 2,3'-bisindoles derivatives in moderate to good yields.

Rh(III)- or Ru(II)-Catalyzed C-H Annulation with Vinylene Carbonate and an Unexpected Aerobic Oxidation/Deprotection Cascade to Yield Cinnolin-4(1H)-ones.

Transition metal-catalyzed C-H annulation reactions have been extensively utilized for the synthesis of cinnolines, especially the N-protected ones; however, none of them can yield cinnolin-4(1H)-ones, a significant class of bioactive skeletons. Herein, we disclose one-pot access to cinnolin-4(1H)-ones through Rh(III)- or Ru(II)-catalyzed C-H activation/annulation of N-aryl cyclic hydrazides with vinylene carbonate, followed by an O2/K2CO3-promoted aerobic oxidation/deprotection cascade. The π-conjugation of the directing groups plays a crucial role in facilitating this transformation. Notably, seven-membered enolic Rh species IMC is characterized via electrospray ionization mass spectroscopy for the first time, which, along with systematic control experiments, provides compelling evidence for the mechanistic pathway encompassing alkenyl insertion, β-oxygen elimination, protonation, and dehydration.

Quick Access to Protoberberine and Tetrahydroprotoberberine Derivatives/Analogues with One-Pot Sequential Isochromenylium-Mediated Annulation.

A one-pot access to the protoberberine and tetrahydroprotoberberine scaffold has been developed from easily available primary amine-functionalized o-alkynylbenzaldehydes. The core skeleton of protoberberine was afforded via in situ generation of isochromenylium by Ag(I) catalysis, subsequent cyclization to isoquinolinium, and final hydride reduction by a continuous operation procedure. The newly developed step-economic protocol shows excellent regio- and stereoselectivity and is capable of achieving those previously unavailable derivatives/analogues with electron-deficient substituents, providing a robust tool for medicinal investigations of protoberberines and derivatives.

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic β-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

Hypervalent Iodine Promoted Selective [2 + 2 + 1] Cycloaddition of Aromatic Ketones and Methylamines: A One-Pot Access to 1-Pyrrolines.

Herein, a versatile highly regioselective three-component annulation of simple aromatic ketones and methylamines using a hypervalent iodine reagent for polyarylated 1-pyrrolines has been described in good to excellent yields. Meanwhile, unsymmetrical 1-pyrroline isomers could be realized and synthesized. Such an intriguing one-pot two-step tandem assembly strategy with green conditions and high regioselectivity shows predictable inspiration in related annulation reactions.

Boron-mediated one-pot access to salicylaldehydes via ortho-C-H hydroxylation of benzaldehydes.

A novel protocol has been devised for the ortho-C-H hydroxylation of benzaldehydes. Directed by a transient imine group, the borylation of benzaldehydes, sequentially followed by the hydroxylation, furnishes diverse salicylaldehydes in a one-pot manner. The resultant salicylaldehydes could be readily applied in the downstream synthesis to produce bioactive molecules.

Oxidative Tandem Cyclization of Aromatic Acids with (Benzo)thiophenes: One-Pot Access to Planar Sulfur-Containing Polycyclic Heteroarenes for Lipid-Droplet-Targeted Probes.

The efficient construction of π-conjugated polycyclic heteroarenes represents a significant task in the field of functional materials. A one-step oxidative tandem cyclization of aromatic acids with (benzo)thiophenes was developed to access planar sulfur-containing polycyclic heteroarenes. This protocol undergoes intermolecular cross-dehydrogenative coupling followed by intramolecular Friedel-Crafts acylation and provides a facile pathway to planar polycyclic compounds from inexpensive reactants. The synthesized heteroarenes serving as lipid-droplet-targeted probes exhibit outstanding performance with favorable biocompatibility and photostability.

Copper-catalyzed oxidative sulfenylation and alkylation of indolin-2-ones for direct construction of sulfur-substituted quaternary carbons

A rapid and green one-pot access to S-substituted quaternary carbon centers from commercially available feedstock chemicals has been established, providing complex molecules with high chemoselectivity by the use of air as the terminal oxidant.

One-pot synthesis of 4-pyrimidone-2-thioether through base/acid-mediated condensation of S-alkylisothiourea and β-ketoester.

4-Pyrimidone-2-thioethers can be useful synthetic precursors to densely functionalized pyrimidines, commonly encountered in bioactive molecules. A convenient one-pot access to 4-pyrimidone-2-thioethers is reported herein, which utilizes a sequential base- and acid-mediated condensation of alkylisothioureas with β-ketoesters. Owing to mild reaction conditions, good to excellent functional group tolerance and yields are achieved. The utility of this approach is demonstrated by the synthesis of the crucial adagrasib intermediate on a 200 gram scale.

Regioselective Transition Metal-Free Catalytic Ring Opening of 2H-Azirines by Phenols and Naphthols; One-Pot Access to Benzo- and Naphthofurans.

Benzofuran and naphthofuran derivatives are synthesized from readily available phenols and naphthols. Regioselective ring openings of 2H-azirine followed by in situ aromatization using a catalytic amount of Brønsted acid have established the novelty of the methodology. The involvement of a series of 2H-azirines with a variety of phenols, 1-naphthols, and 2-naphthols showed the generality of the protocol. In-depth density functional theory calculations revealed the reaction mechanism with the energies of the intermediates and transition states of a model reaction. An alternate pathway of the mechanism has also been proposed with computer modeling.

One-Pot Access to Boron-Doped Fused Heterocycles via Domino Cyclization of Bis-Diazidoboranes with Isonitrile.

Boron-doped fused heterocycles have shown great potential in the field of functional materials. This study reports on the synthesis of a new class of bis-diazidoboranes and the discovery of their cycloaddition reaction with isonitriles. Triply fused boron-doped heterocyclic compounds were constructed in a one-pot process through a domino cycloaddition, providing an effective route for constructing complex boron-doped heterocyclic systems.

One-pot access to indazole fused-phenanthridinones via Rh(III)-catalyzed [4+2] annulation

An efficient synthesis of indazole fused phenanthridinones via Rh(III)-catalyzed inert C(sp2)-H activation/[4 ​+ ​2] annulation of 3-aryl-1H-indazoles with iodonium ylides has been developed, providing a strategy to access multi-conjugated π-system tetracyclic and pentacyclic aza-heterocyclics with the favorable photoluminescence properties. This “one-pot” reaction features high efficiency, excellent regioselectivity, a broad substrate compatibility and could be easily scaled up. Furthermore, the obtained products exhibited low toxicity in MDCK cells as well as selectively labeled the zebrafish larvae, which indicated that the titled products could be potentially utilized as biofluorescent probes or fluorescent dyes.

Oxidation of Thiols with IBX or DMP: One-Pot Access to Thiosulfonates or 2-Iodobenzoates and Applications in Functional Group Transformations.

o-Iodoxybenzoic acid (IBX) and Dess-Martin periodinane (DMP) are employed for thiol to thiosulfonate conversion at rt. DMP is better than IBX in terms of reaction rate, conversion, and required equivalents. IBX-mediated oxidation of benzyl thiols produced thiosulfonates, whereas DMP afforded O-benzyl esters. The one-pot conversion of a thiol to an ester is unprecedented; this atom-economic transformation has potential for functional group transformations (FGTs), e.g., an alcohol and an aldehyde are accessed from benzyl thiol.

Indeno-Annulation of o-Formyl-Ynones, o-Bis-Ynones, and p-Bis-o-Formyl-Ynones with Dimethyl Acetone-1,3-Dicarboxylate: One Flask Cascade Synthesis of Functionally Endowed 9-Fluorenols and Indeno[1,2-b]fluorenols.

A mild, scalable, one-pot access to multifunctional 9-fluorenols from o-formyl-ynones and o-bis-ynones on reaction with dimethylacetone-1,3-dicarboxyate through tandem Michael addition-Aldol condensation cascade has been conceptualized and executed. The scope and utility of this synthetic approach have been further amplified for one-pot entry into functionally enhanced, higher order fluorenols like pentacyclic indeno[1,2-b]fluorene-6,12-diols and further to indeno[1,2-b]fluorene-6,12-diones through the implementation of "double indeno-annulation" tactic on p-bis-o-formyl ynones and dimethylacetone-1,3-dicarboxylate. Besides several green attributes, the current approach is also compatible with the emerging time and energy economy features and is a swift gateway to build complexity.

Nondirected, Site-Selective Arylation of Quinone Imine Ketals Derived from Arylamines: One-Pot Access to meta-Substituted Anilines.

Herein, we develop a metal-free, nondirected, site-selective, one-pot approach to meta-arylation of arylamines. This Brønsted acid-catalyzed, direct C-C bond formation offers a broad substrate scope and scalability and creates the ideal conditions for overriding the conventional site-selectivity to furnish meta-substituted anilines. Additionally, the protocol applies to the meta-allylation of anilines and has been extended to afford late-stage functionalization and synthesis of medicinally privileged arylated diamines and densely functionalized anilines. The control experiments and density functional theory studies provide evidence for the proposed mechanism and selectivity.

A one-pot access to 2-(N-substituted Amino)-Quinones or 3-indolyl-Quinones from naphthol/hydroquinone

A sequential one-pot approach towards 2-(N-substituted amino)-1,4-quinones or 3-indolyl-quinones from naphthol/hydroquinone with amines or indoles, such as various (hetero)aromatic amine and aliphatic amine, has been developed. The reaction proceeds through oxidation of naphthol/hydroquinone with the CuBr2 or (NH4)2S2O8 oxidant. This reaction provides efficient access to the biologically important and synthetically useful 2-amino-quinones and 3-indolyl-quinones with good yields under mild conditions. The present protocol is simple, practical and shows good functional group tolerance.

Recent Developments in Enantioselective Domino Reactions. Part B: First Row Metal Catalysts

This review updates the field of enantioselective domino reactions promoted by chiral catalysts derived from first row metals, such as zinc, iron, copper, scandium, nickel, cobalt, titanium, chromium and magnesium as special case, published since the beginning of 2019. It illustrates how much a diversity of these catalysts allow an impressive range of novel highly enantioselective domino reactions of many types to be achieved, providing a one-pot access to very complex and functionalized chiral molecules from simple starting materials.

1,2-Metallate Rearrangement Using Indole Boronate Species to Access 2,3-Diarylindoles and Indolines.

A transition metal-free multicomponent reaction using lithiated indole, boronic ester, pyridine, and ethyl chloroformate was developed to access C2,C3 bis-arylated indoles, which are present in several marketed drugs and bioactive compounds. One-pot access to unsymmetrical C2,C3-diaryl indole from the parent indole remains a huge synthetic challenge. Our group was able to achieve this goal through a transition metal-free 1,2-metalate rearrangement of the indole boronate complex. The reaction of indole boronate species with activated pyridine allows 1,2-migration to access pyridyl-indoleboronate species, which will convert to the corresponding indole upon oxidation and indoline after deborylation. The reaction tolerates substituted pyridines, quinolone, isoquinoline, and more. Both aryl and alkyl boronic esters were accommodated under optimized reaction conditions. Apart from mechanistic studies using 11B-NMR, this methodology has been applied to the gram-scale synthesis of several bioactive compounds.

Transition metal-free and temperature dependent one-pot access to phenanthrene-fused heterocycles via a 1,3-dipolar cycloaddition pathway.

A versatile, operationally simple, temperature-dependent, and transition metal-free one-pot protocol has been devised for the preparation of novel phenanthrene-fused pyrazoles. Notably, the overall process involved an intermolecular condensation, an intramolecular 1,3-dipolar cycloaddition, and an aromatization sequence starting from biaryl-2,2'-aldehydes bearing enoate esters with various hydrazine hydrochlorides. Notably, the sequential one-pot three-component operation has also been achieved. Importantly, it was also shown that this protocol was amenable to hydroxylamine hydrochloride as the nitrogen source and furnished phenanthrene-fused isoxazoles. Notably, the temperature dependent nature of this protocol was also demonstrated, which led to the formation of dealkoxylcarbonylated phenanthrene-fused pyrazoles at slightly higher temperatures and longer reaction times. Remarkably, this metal-free protocol effectively constructed two C-N bonds and one C-C bond and exhibited a broad substrate scope.

Pd-catalyzed imine-directed one-pot access to polysubstituted pyrrolesviatandem triple isocyanide insertion/aza-Nazarov cyclization reactions

A novel one-pot method for synthesizing polysubstituted pyrrole derivatives via three-component reactions of alkenyl bromides, amines, and isocyanides is reported by Pd catalysis, without additional ligands, with the orderly insertion of three isocyanide molecules.