Iodine Catalysis Research Articles

Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis.

The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3‐fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.

Transition Metal‐free C−H Sulfonylation and Pyrazole Annulation Cascade for the Synthesis of 4‐Sulfonyl Pyrazoles

AbstractA practical protocol for the synthesis of 4‐sulfonyl pyrazoles via the reactions of readily available N,N‐dimethyl enaminones and sulfonyl hydrazines has been developed via the catalysis of molecular iodine in the presence of TBHP and NaHCO3 at room temperature. The pyrazole products have been constructed via the tandem C(sp2)−H sulfonylation and a pyrazole annulation without employing any transition metal catalyst or reagent, thus providing a practical new method for the synthesis of the novel pyrazoles bearing a sulfonyl side chain in the heterocycle.

Generation of Aryl Radicals from Aryl Hydrazines via Catalytic Iodine in Air: Arylation of Substituted 1,4-Naphthoquinones.

Arylated building blocks or heterocycles are key to myriad applications, including pharmaceutical drug discovery, materials sciences, and many more. Herein, we have reported a mild and efficient strategy for generation of aryl radicals by reacting appropriate aryl hydrazines with catalytic iodine in open air. The aryl radicals were quenched by diversely substituted 1,4-napthoquinones present in the reaction mixture to afford diversely substituted 2,3-napthoquinones in moderate to excellent yield. Control experiments provided insights into the putative reaction mechanism.

Iodine-Catalyzed Aerobic Diazenylation-Amination of Indole Derivatives.

A mild strategy for consecutive diazenylation and amination of indole moieties has been demonstrated. The functionalization occurs at C3 and C2 carbon atoms, respectively, at the indole scaffold in the presence of catalytic iodine and air at 40 °C in the 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) solvent. It is noteworthy that the aromatic amines are generated in situ by the reaction of aryl hydrazine with iodine. In general, bright red products are obtained in moderate to good yield. Control reactions are conducted to establish the reaction mechanism.

Tritylium assisted iodine catalysis for the synthesis of unsymmetrical triarylmethanes.

The combined Lewis acid catalytic system, generated from molecular iodine and tritylium tetrafluoroborate effectively catalyzed the Friedel-Crafts (FC) arylation of diarylmethyl sulfides providing an efficient access to various unsymmetrical triarylmethanes. The addition of tritylium and iodine created a more active catalytic system to promote the cleavage of sulfidic C-S bonds.

Computationally Assisted Mechanistic Investigation into Hypervalent Iodine Catalysis: Cyclization of N-Allylbenzamide.

Previous experimental work identified 2-iodoanisole as the best precatalyst for the oxidative cyclization of N-alkenylamides into 2-oxazolines. Herein, we describe our investigation into the effect on the reaction rate based on the structure of the iodoarene precatalyst. We also reveal the mechanism of the cyclization based on DFT modeling and obtain a clear correlation between observed reaction rates and computationally derived activation energies for different iodoarenes. In addition, the rate-limiting step is shown to be the cyclization of the substrate that is zero order in the concentration of the iodoarene precatalyst. The rate of cyclization is found to correlate with the ease of oxidation of the iodoarene; however, the most easily oxidized iodoarenes generate iodine(III) species that decompose readily. Finally, loss of iodoarene from the cyclized intermediate can proceed by either ligand-coupling or SN2 displacement (reductive elimination), and this is shown to be substrate-dependent.

Aerobic Oxidative Sulfenylation of Pyrazolones and Pyrazoles Catalyzed by Metal-Free Flavin-Iodine Catalysis.

Two-component metal-free catalytic oxidative sulfenylation of pyrazolones with thiols has been achieved using the biomimetic flavin and iodine. The methodology is mild and eco-friendly, proceeds in the presence of air or molecular oxygen (1 atm) as the sole sacrificial reagent, and generates water as the only byproduct. The methodology was also extended to the sulfenylation of pyrazoles and electron-rich benzenes and afforded a series of thioethers in good yields.

Mechanism and Origins of Enantioselectivities in Spirobiindane-Based Hypervalent Iodine(III)-Induced Asymmetric Dearomatizing Spirolactonizations.

The work of Kita et al. on asymmetric oxidative dearomatization of naphthol carboxylic acids to spirolactones mediated/catalyzed by a novel, conformationally rigid μ-oxo-bridged hypervalent iodine(III) species is a landmark discovery in enantioselective iodine(III) catalysis [Kita, Y.; et al. Angew. Chem., Int. Ed. 2008, 47, 3787. DOI: 10.1002/anie.200800464 ; J. Am. Chem. Soc. 2013, 135, 4558. DOI: 10.1021/ja401074u ]. We have investigated the detailed mechanism of this important transformation using density functional theory. Calculations revealed that proton transfer from the pendant carboxylic acid of naphthols to the bridging oxygen atom or the ligand of iodine(III) species, which enhances the nucleophilicity of the carboxylic oxygen and the nucleofugality of the iodoarene, is crucial for the dearomatizing spirolactonization. Halogen bonding between the resulting carboxylate and the electron-deficient iodine(III) center further stabilizes the dearomatizing spirolactonization transition states. Calculations also revealed a long-neglected cleaved μ-oxo iodine(III) species that is more reactive but less selective than the μ-oxo-bridged hypervalent iodine(III) species itself for the oxidative dearomatization of naphthols. The coexistence of two sequential dearomatizing spirolactonization processes in the reaction system results in a lower enantioselectivity. A new stereochemical model that is able to reproduce and rationalize the observed apparent enantioselectivities is proposed.

Hypervalent Iodine(III)-Catalyzed Epoxidation of β-Cyanostyrenes

A convenient approach for the synthesis of β-cyanoepoxides is illustrated by iodine(III)-catalyzed epoxidation of electron-deficient β-cyanostyrenes, wherein the active catalytic iodine(III) species was generated in situ. The epoxidation of β-cyanostyrenes was performed using 10 mol% PhI as precatalyst in the presence of 2.0 equivalents Oxone as an oxidant and 2.4 equivalents of TFA as an additive at room temperature under ultrasonic radiations. The β-cyanoepoxides were isolated in good to excellent yields in a short reaction time.

Molecular Iodine-Catalyzed Selective C-3 Benzylation of Indoles with Benzylic Alcohols: A Greener Approach toward Benzylated Indoles.

Iodine-catalyzed selective C-3 benzylation of indoles with benzylic alcohols is developed. The reaction proceeds with molecular iodine as the catalyst under ligand-, metal-, and base-free conditions and tolerates wide functionalities. The experimental observations account for the halogen-bond activation mechanistic pathway for the molecular iodine catalysis.

A Practical Aryliodine(I/III) Catalysis for the Vicinal Diamination of Styrenes.

2,6-Disubstituted iodoarenes bearing amide-functionalized side arms are reported as new structures in redox-active iodine(I/III) catalysis. In combination with bis-sulfonimides as nitrogen sources and 3-chloroperbenzoic acid (mCPBA) as benign terminal oxidant they catalyze the vicinal diamination of styrenes. The obtained reactivity and selectivity outperform other iodoarene catalyst candidates. This protocol provides a sustainable alternative to previous related protocols for diamination that are based on stoichiometric iodine(III) reagents.

Acyl Radical Smiles Rearrangement To Construct Hydroxybenzophenones by Photoredox Catalysis.

The first visible-light-induced acyl radical Smiles rearrangement to transform biaryl ethers to hydroxybenzophenones under mild and metal-free conditions is reported. Using the dual catalysis of hypervalent iodine(III) reagents and organophotocatalysts, ketoacids readily generate acyl radicals and undergo 1,5- ipso addition. This method can construct electron-deficient and electron-rich hydroxybenzophenones with excellent chemoselectivity and on gram scale. The performance of the reaction in neutral aqueous conditions holds potential for future biomolecule applications.

A Green Synthetic Approach towards Polyarylated Oxazoles via Iodine‐Catalyzed One‐Pot sp3 C−H Functionalization in Water: From Natural Product Synthesis To Photophysical Studies

AbstractA ‘green’ methodology for the convenient synthesis of specific regioisomers of polysubstituted oxazoles through iodine catalyzed, water‐mediated, aerobic oxidative C(sp3)−H functionalization of primary amines has been developed. This mild and regioselective domino procedure does not require toxic peroxides, transition metals and organic solvents. The versatility of this methodology was demonstrated by preparing a natural product, texaline. It is also scalable and has a wide substrate scope. This methodology opens up a simple avenue for the synthesis of polyarylated oxazoles from various readily available amines as well as 1,2‐diketones and acyloins (α‐hydroxyl ketones) in moderate to excellent yields. Furthermore, these highly substituted oxazole molecules showed excellent fluorescence properties and thus have enormous potential to be a new type of fluorescent probe for use in medicinal applications and materials science.

Merging catalyst-free synthesis and iodine catalysis: one-pot synthesis of dihydrofuropyrimidines and spirodihydrofuropyrimidine pyrazolones.

A new and efficient one-pot strategy combining catalyst-free synthesis and iodine catalysis has been developed for the synthesis of dihydrofuropyrimidines and spirodihydrofuropyrimidine pyrazolones. This approach affords products in moderate to high yields (up to 96%) with excellent diastereoselectivities (up to >25 : 1 dr). The reaction is simple to carry out and is metal-free.

Cooperative iodine and photoredox catalysis for direct oxidative lactonization of carboxylic acids.

A new method for the formation of γ- and δ-lactones from carboxylic acids through direct conversion of benzylic C-H to C-O bonds is described. The reaction is conveniently induced by visible light and relies on a mild cooperative catalysis by the combination of molecular iodine and an organic dye.

Front Cover Picture: Enantioselective Iodine(I/III) Catalysis in Organic Synthesis (Adv. Synth. Catal. 1/2019)

Front Cover Picture: Enantioselective Iodine(I/III) Catalysis in Organic Synthesis (Adv. Synth. Catal. 1/2019)

Enantioselective Iodine(I/III) Catalysis in Organic Synthesis

AbstractChiral aryliodine(III) reagents have provided an advanced concept for enantioselective synthesis and catalysis. With the advent of chiral iodine(I/III) catalysis, many different structures have been explored in the area. The currently most prominent catalyst design is based on a resorcinol core and the attachment of two lactic side chains bearing ester or amide groups. This enables a privileged modular catalyst synthesis, in which fine‐tuning with respect to the specific reaction requirement is straightforward. The present overview summarizes the structural variation and optimization of such chiral aryliodine catalysts and discusses structural properties of the active iodine(III) catalyst states. The status quo of enantioselective iodine(I/III) oxidation catalysis with respect to intramolecular and intermolecular reaction control is reviewed, and specific aspects of the individual catalytic cycles are discussed.magnified image

Combining Organocatalysis and Iodine Catalysis: One-Pot Sequential Catalytic Synthesis of Chiral Spirodihydrobenzofuran Pyrazolones and Spirodihydrobenzofuran Oxindoles.

A new and efficient catalytic strategy that combines asymmetric organocatalysis and iodine catalysis was first developed for the one-pot Michael/iodization/SN2 nucleophilic substitution sequential catalytic synthesis of spirodihydrobenzofuran pyrazolones and spirodihydrobenzofuran oxindoles. The approach results in products with moderate to high yields (up to 93%), high to excellent enantioselectivities (up to 99% ee), and excellent diastereoselectivities (up to >99:1 dr). The reaction features simple operation and is metal-free and base-free.

Iodine‐Catalyzed Metal‐Free Oxidative Ring Opening of 1‐Aryltetrahydro‐β‐carbolines: Facile Synthesis of C‐2 Aroyl and Aryl Methanimino Indole Derivatives

Indole derivatives bearing C‐2 substituents have garnered a lot of attention due to their diverse biological activities. Various methods forthe synthesis of these compounds have been reported. Inspired by the hydrolysis of imines, an oxidative ring‐opening reaction of 1‐aryltetrahydro‐β‐carbolines with catalytic iodine in aqueous hydrogen peroxide, and also in the presence of appropriate amines, is described for the generation of 2‐aroyl and arylmethanimine indole derivatives. The reaction proceeds under mild reaction conditions with ethanol as the solvent or under solvent‐free conditions, respectively. This metal‐free strategy facilitates the formation of the desired substituted C‐2 indoles in moderate to excellent yields. The utility of this reaction is demonstrated by a facile multigram‐scale synthesis of Luzindole, a selective melatonin receptor antagonist and an investigational drug against depression and disruption of the circadian rhythm.

Frontispiece: Mechanisms in Iodine Catalysis

Frontispiece: Mechanisms in Iodine Catalysis