Trihaloisocyanuric Acids Research Articles

Trihaloisocyanuric Acids: Useful Reagents for Halogenation Reactions and Heterocyclic Scaffold Construction

Abstract: Trihaloisocyanuric acids [1,3,5-trihalo-1,3,5-triazine-2,4,6-(1H,3H,5H)-triones] are commercially available or easily prepared solids. They are highly reactive, stable, easily handled, and have an excellent atom economy, transferring up to three halogen atoms to organic substrates. In these regards, the present review summarizes their synthetic applications as safe and convenient reagents. Therefore, electrophilic halogenation reactions of alkenes, alkynes, arenes, heteroarenes, carbonyl compounds, and heteroatoms, as well as radical halogenation involving saturated substrates and in situ halogenated intermediates for Appel-type reactions are presented and discussed. Remarkably, applications of trihaloisocyanuric acids in processes for the construction of heteroarene scaffolds based on electrophilic halo- and oxidative cyclization, multicomponent reactions, and telescopic reactions are also given.

The double halofluorination reaction of alkynes using trihaloisocyanuric acids and Olah's reagent

A simple and efficient method to produce a CF2 group vicinal to a CX2 group (X = chlorine or bromine) through double halofluorination reaction of alkynes using trihaloisocyanuric acid as halogenating agent and Pyridine.(HF)x (Olah's reagent) as fluoride source is presented. The alkynes used were 1-hexyne, 3-hexyne, phenylacetylene, 1-phenyl-1-butyne, and diphenylacetylene, obtaining, mainly, the desired products in 30–88 % yields. Among the trihaloisocyanuric acids studied, the tribromoisocyanuric acid gave the best yields and the most selective reactions, while trichloroisocyanuric acid, although the most reactive, had less selectivity in the reactions studied, giving in some cases several by-products.

Applications of N-Halo Reagents in Multicomponent Reactions: A Still Underrated Approach for the Construction of Heterocyclic Scaffolds

Abstract:Heterocyclic scaffolds are important from both academic and industrial points of view. Due to their biological and pharmacological activities, they are useful intermediates in organic synthesis and have great interest in medicinal and natural products chemistry. N-halo compounds bearing an electron-withdrawing group on nitrogen (e.g., carbonyl, sulfonyl) present the unique chemical properties of the N-X bond that give them broad synthetic utility for diverse organic transformation. In the past years, significant progress has been achieved in the synthesis of heterocyclic compounds with the intermediacy of N-halo compounds. Numerous strategies (e.g., electrophilic cyclizations, asymmetric halocyclizations, oxidative cyclizations, radical processes) were implemented featuring high atom- and step-economy, and more efficient procedures are continually being developed. An interesting approach consists of using Nhalo compounds to promote multicomponent reactions (MCRs), which rapidly became an emerging field in heterocyclic construction. MCRs are recognized for their mild conditions, high convergence, and efficiency. Thus, the present review will focus attention on the main topics and utilization of N-halo compounds (N-halosuccinimides, trihaloisocyanuric acids, N-halosulfonamides, etc.) as green and convenient reagents in heterocyclic construction via MCRs. Examples of the preparation of azoles, pyridines, 1,4-dihydropyridines, chromenes, and xanthenes, among other scaffolds are presented and discussed.

A convenient Hofmann reaction of carboxamides and cyclic imides mediated by trihaloisocyanuric acids

A simple, efficient and pot-economic approach in a single vessel has been developed for conversion of aromatic and aliphatic carboxamides into primary amines with one fewer carbom atom (Hofmann reaction) in 38–89 % yield by reacting with trichloro- or tribromoisocyanuric acid and sodium hydroxide in aqueous acetonitrile. Under the same reaction conditions, cyclic imides gave amino acids (69–83 %). The role of the trihaloisocyanuric acids is the in situ generation of N-haloamides, key-intermediates for the Hofmann reaction. The scalability of the methodology was demonstrated by a multigram-scale transformation of phthalimide into anthranilic acid in 77 % yield.

Trihaloisocyanuric Acids: Useful Reagents for Conversion of Benzaldehydes into Benzylidene Dihalides under Appel Conditions

The reaction of substituted benzaldehydes with tribromoisocyanuric acid and triphenylphosphine led to the corresponding benzylidene dibromides (95-99%). Similar reaction using trichloroisocyanuric acid produced benzylidene dichlorides (38-96%).

Trihaloisocyanuric acids in ethanol: an eco-friendly system for the regioselective halogenation of imidazo-heteroarenes

Herein, we describe an efficient, rapid and benign protocol for the direct C(sp2)–H bond halogenation (Cl, Br, I) of 2-arylimidazo[1,2-a]pyridines using trihaloisocyanuric acids in ethanol.

N-Halo Reagents: Modern Synthetic Approaches for Heterocyclic Synthesis

Heterocyclic chemistry is an essential frontier in science and a source of novel biologically active compounds. The development of innovative synthetic methodologies that allows access to different heterocyclic rings is of critical interest to the scientific community. This review will focus on recent applications of N-halo compounds (e.g., N-halosuccinimides, trihaloisocyanuric acids, N-halosulfonamides, etc.) in heterocyclic construction via electrophilic cyclization, asymmetric halocyclization, oxidative cyclization, and radical processes.1 Introduction2 N-Halo Reagent Mediated Heterocyclic Construction and Functionalization2.1 Electrophilic Halocyclizations2.1.1 Asymmetric Halocyclizations2.2 Radical Halocyclizations2.3 Oxidative Halocyclizations2.4 Miscellaneous Halocyclization Reactions3 Summary and Outlook

A general method for the metal-free, regioselective, remote C–H halogenation of 8-substituted quinolines

An operationally simple and metal-free protocol for geometrically inaccessible C5-H halogenation of a range of 8-substituted quinoline derivatives has been established. The reaction proceeds under air, with inexpensive and atom economical trihaloisocyanuric acid as a halogen source (only 0.36 equiv.), at room temperature. Exceptionally high generality with respect to quinoline is observed, and in most instances, the reaction proceeded with complete regioselectivity. Quinoline with a variety of substituents at the 8-position gave, exclusively, the C5-halogenated product in good to excellent yields. Phosphoramidates, tertiary amides, N-alkyl/N,N-dialkyl, and urea derivatives of quinolin-8-amine as well as alkoxy quinolines were halogenated at the C5-position via remote functionalization for the first time. This methodology provides a highly economical route to halogenated quinolines with excellent functional group tolerance, thus providing a good complement to existing remote functionalization methods of quinolin-8-amide derivatives and broadening the field of remote functionalization. The utility of the method is further showcased through the synthesis of several compounds of biological and pharmaceutical interest.

Efficient Direct Halogenation of Unsymmetrical N-Benzyl- and N-Phenylureas with Trihaloisocyanuric Acids

A simple and efficient methodology for the direct halogenation of N-phenylureas was developed using trihaloisocyanuric acids in acetonitrile at room temperature. This protocol proved to be effective for the construction of N-phenylureas with different patterns of substitution. Additionally, less reactive N-benzylureas were halogenated in the presence of a mixture of trifluoroacetic acid and acetonitrile at room temperature.

Reaction of trihaloisocyanuric acids with alkynes: an efficient methodology for preparation of β-haloenol acetates

Reaction of trihaloisocyanuric acids with alkynes: an efficient methodology for preparation of β-haloenol acetates

Ultrasound-assisted tandem reaction of alkynes and trihaloisocyanuric acids by thiourea as catalyst in water

With water as the sole solvent, a green and efficient method has been developed for the synthesis of various α,α-dihaloketones via ultrasound assisted p-tolylthiourea catalyzed tandem reaction of alkynes with trihaloisocyanuric acids. This synthetic route could effectively avoid the use of toxic organic solvents and transition metal catalysts, and the products could be obtained in a very short time at room temperature with good to excellent yields.

ChemInform Abstract: Trihaloisocyanuric Acids as Atom‐Economic Reagents for Halogenation of Aromatics and Carbonyl Compounds in the Solid State by Ball Milling.

It is shown that both tribromoisocyanuric acid (TBCA) and trichloroisocyanuric acid (TCCA) are excellent reagents for direct halogenation of electron-rich aromatics under solvent-free, ball-milling conditions. The results are remarkable in light of the fact that chlorination of aromatics without any acid catalyst is heretofore unknown. The procedure is operationally simple, and the reactions occur within a few hours, affording high yields of halogenated products. Similarly, crystalline β-keto dicarbonyl compounds are shown to undergo direct α,α-dihalogenation with TBCA and TCCA with ball milling. Whereas monoketones are found to be unreactive with TBCA/TCCA, addition of 25 mol-% of p-toluenesulfonic acid as a solid catalyst catalyzes the reaction, leading to the formation of α-chloro/bromo ketones in very good isolated yields. The fact that each of the reagents, in principle, serves as a source of three halogen atoms should render solvent-free halogenation of aromatics and carbonyl compounds with TBCA/TCCA an invaluable synthetic protocol.

Trihaloisocyanuric Acids as Atom‐Economic Reagents for Halogenation of Aromatics and Carbonyl Compounds in the Solid State by Ball Milling

AbstractIt is shown that both tribromoisocyanuric acid (TBCA) and trichloroisocyanuric acid (TCCA) are excellent reagents for direct halogenation of electron‐rich aromatics under solvent‐free, ball‐milling conditions. The results are remarkable in light of the fact that chlorination of aromatics without any acid catalyst is heretofore unknown. The procedure is operationally simple, and the reactions occur within a few hours, affording high yields of halogenated products. Similarly, crystalline β‐keto dicarbonyl compounds are shown to undergo direct α,α‐dihalogenation with TBCA and TCCA with ball milling. Whereas monoketones are found to be unreactive with TBCA/TCCA, addition of 25 mol‐% of p‐toluenesulfonic acid as a solid catalyst catalyzes the reaction, leading to the formation of α‐chloro/bromo ketones in very good isolated yields. The fact that each of the reagents, in principle, serves as a source of three halogen atoms should render solvent‐free halogenation of aromatics and carbonyl compounds with TBCA/TCCA an invaluable synthetic protocol.

ChemInform Abstract: Halofluorination of Alkenes Using Trihaloisocyanuric Acids and HF·Pyridine.

AbstractThe reaction proceeds regio‐ and stereoselectively to give the Markovnikov‐type products.

Halofluorination of Alkenes Using Trihaloisocyanuric Acids and HF×Pyridine

Halofluorination of alkenes with a new system (trihaloisocyanuric acids and HF˙pyridine) results in the formation of vicinal halofluoroalkanes. The reaction is regioselective leading to Markovnikov-oriented products and the halofluorinated adducts follow anti-addition in the case of cyclohexene and 1-methylcyclohexene. Reaction yields range from 67-88%.

ChemInform Abstract: Trihaloisocyanuric Acids as Convenient Reagents for Regioselective Halogenation of β‐Dicarbonyl Compounds.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Trihaloisocyanuric acids as convenient reagents for regioselective halogenation of β-dicarbonyl compounds

The reaction of β-dicarbonyl compounds (β-ketoesters and β-diketones) with 0.34 mol equiv of trichloro- and tribromoisocyanuric acids produced regioselectively the corresponding α-monohalo β-dicarbonyl compound. On the other hand, utilization of 0.68 mol equiv of the trihaloisocyanuric acid produced the α,α-dihalo β-dicarbonyl compound.

Trihaloisocyanuric acids/NaX: an environmentaly friendly system for vicinal dihalogenation of alkenes without using molecular halogen

The reaction of alkenes with easily handled trihaloisocyanuric acids / NaX in aqueous acetone produces the corresponding vicinal dihaloalkanes in moderate to excellent yields.