Transition-Metal-Catalyzed Addition of Organosulfur Compounds to Alkynes and Alkenes: Catalysis and Catalyst Poisons.

The addition of heteroatom compounds to alkynes and alkenes is an atom-efficient method of carbon-heteroatom bond formation and is widely used as a fundamental synthetic method for the construction of functional molecules. Nevertheless, examples of transition-metal-catalyzed addition reactions of group 16 heteroatom compounds to carbon-carbon unsaturated bonds have been limited due to the widespread belief that organic sulfur and selenium compounds are representative catalyst poisons. In recent decades, however, several seminal catalytic reactions of sulfur compounds have been developed, providing important insights into catalysis and poisons. Therefore, this paper focuses on the transition-metal-catalyzed addition of organosulfur compounds to alkynes and alkenes, gains comprehensive insights into the catalysis and catalyst poisons, and proposes concepts for the development of transition-metal-catalyzed reactions of group 16 heteroatom compounds.

Intramolecular cyclization reactions of arylpropargyl amides of electron-deficient α,ß-alkenyl carboxylates and related compounds.

Intramolecular cyclization reactions of arylpropargyl amides of electron-deficient α,ß-alkenyl carboxylates such as fumarates and ethenetricarboxylates were investigated. The reaction of the fumaramides with a base, Et3N or DBU in xylenes at 140 °C under air gave benz[f]isoindoline derivatives in 21-63% yields. The benz[f]isoindolines may be produced via the formation of an allenic intermediate, intramolecular Diels-Alder reaction, proton transfer, and dehydrogenation by oxygen. The suitable bases and the product yields depend on the substituents on the benzene ring. On the other hand, the reaction of the amides of fumarate and ethenetricarboxylate by heating in DMSO gave aroyl-substituted pyrrolidine derivatives as major products, probably via addition of water under metal-free conditions. Furthermore, cyclization reactions of H and Me substituted alkyne derivatives were investigated for comparison. The selective formation of various types of products, such as ethyl 2-(1-benzyl-4-formyl-2-oxopyrrolidin-3-yl)acetate and diethyl 2-(1-benzyl-2-oxo-4-vinylidenepyrrolidin-3-yl)malonate, was found, depending upon the alkyne substituents and the reaction conditions. The reaction mechanisms have been discussed using density functional theory (DFT) calculations.

Metal-Free One-Pot Multi-Functionalization of Unsaturated Compounds with Interelement Compounds by Radical Process.

In recent years, the importance of "environmentally friendly manufacturing" has been increasing toward the establishment of a resource-recycling society. In organic synthesis, as well, it is becoming increasingly important to develop new synthetic strategies with resource conservation and the recycling of elemental resources in mind, rather than just only synthesis. Many studies on the construction of frameworks of functional molecules using ionic reactions and transition-metal-catalyzed reactions have been reported, but most of them have focused on the formation of carbon-carbon bonds. However, it is essential to introduce appropriate functional groups at appropriate positions in molecules in order for the molecules to express their functions, and furthermore, the highly selective preparation of multiple functional groups is considered important for the creation of new functional molecules. In this review, we focus on radical reactions with high functional group selectivity and overview the recent progress in practical methods for the simultaneous introduction of multiple functional groups and propose future synthetic strategies that emphasize the recycling of elemental resources and environmental friendliness.

Multicomponent Reactions between Heteroatom Compounds and Unsaturated Compounds in Radical Reactions.

In this mini-review, we present our concepts for designing multicomponent reactions with reference to a series of sequential radical reactions that we have developed. Radical reactions are well suited for the design of multicomponent reactions due to their high functional group tolerance and low solvent sensitivity. We have focused on the photolysis of interelement compounds with a heteroatom-heteroatom single bond, which readily generates heteroatom-centered radicals, and have studied the photoinduced radical addition of interelement compounds to unsaturated compounds. First, the background of multicomponent radical reactions is described, and basic concepts and methodology for the construction of multicomponent reactions are explained. Next, examples of multicomponent reactions involving two interelement compounds and one unsaturated compound are presented, as well as examples of multicomponent reactions involving one interelement compound and two unsaturated compounds. Furthermore, multicomponent reactions involving intramolecular cyclization processes are described.

Diphenyl Diselenide-Assisted Radical Addition Reaction of Diphenyl Disulfide to Unsaturated Bonds upon Photoirradiation.

The addition reaction of interelement compounds with heteroatom-heteroatom single bonds to unsaturated bonds under photoirradiation is an important method for the efficient and atom-economical construction of carbon-heteroatom bonds. However, in practice, the desired addition reaction is sometimes unable to proceed as expected due to the low efficiency of the desired addition reactions or the preferential polymerization of unsaturated compounds. In this study, by combining an interelement compound with homologous heteroatom compounds as a catalyst, we succeeded in suppressing the polymerization of the unsaturated compounds and in attaining a highly selective carbon-heteroatom bond formation through the desired addition reaction. In this paper, we have examined in detail whether such a "catalytic radical reaction" proceeds for unsaturated compounds and found that the dithiolation of some unsaturated compounds (i.e., vinylic ethers, styrenes, and isocyanides) could proceed with the assistance of (PhSe)2 under light. The developed methods in this study are expected to have strong implications in the fields of radical chemistry, heteroatom chemistry, synthetic organic chemistry, and catalyst chemistry as atom-economical methods for carbon-heteroatom bond formation.

Intramolecular Diels-Alder Reactions of α-Bromostyrene-Functionalized Unsaturated Carboxamides.

Intramolecular cycloaddition reactions of α-bromostyrene-functionalized amides of monomethyl fumarate were investigated. The reaction of the amides with Et3N in toluene at 110 °C gave 1,4-dihydronaphthalenes. The 1,4-dihydronaphthalenes may be produced via the intramolecular Diels-Alder reaction, proton transfer, and dehydrobromination by a base, along with C═C bond isomerization by proton transfer. The reaction of amide derivatives with halogen on a benzene ring and alkali metal carbonates in toluene at 110 °C gave naphthalene derivatives directly. Dehydrogenation of various 1,4-dihydronaphthalenes with cesium or rubidium carbonate in toluene at 110 °C gave naphthalene derivatives. The retardation by TEMPO, acceleration by air for some substrates, and density functional theory calculations suggest a radical mechanism caused by intervention of molecular oxygen.

Innovative green oxidation of amines to imines under atmospheric oxygen.

In recent years, the development of environmentally benign molecular construction methods has been of great importance, and especially, resource recycling, high atomic efficiency, and low environmental impact are in high demand. From this point of view, attention has also been focused on the development of one-pot synthesis of pharmaceuticals and functional molecules. Imines are excellent synthetic intermediates of these useful molecules, and the environmentally friendly oxidative synthesis of imines from amines has been energetically developed using oxygen (or air), which is abundantly available on the Earth, as an oxidant. This review focuses on the latest innovative and green oxidation systems of amines to imines under atmospheric oxygen, and their application to one-pot/eco-friendly and sustainable synthesis of pharmaceuticals and functional molecules. In particular, catalytic systems that activate molecular oxygen are categorized and described in detail as transition metal catalytic systems, photoirradiated catalytic systems, and organocatalytic systems.

Transition-Metal-Free Synthesis of Unsymmetrical Diaryl Tellurides via SH2 Reaction of Aryl Radicals on Tellurium.

Although diaryl tellurides are parent organotellurium compounds, their synthesis methods, especially for unsymmetrical ones, are limited. This may be due to the instability of diaryl tellurides and their synthesis intermediates under reaction conditions. Radical reactions are known to exhibit excellent functional group selectivity; therefore, we focused on a bimolecular homolytic substitution (SH2) reaction between the aryl radical and diaryl ditelluride. Aryl radicals are generated from arylhydrazines in air and captured by diaryl ditellurides, resulting in a selective formation of unsymmetrical diaryl tellurides with high yields. The electronic effects of the substituents on both arylhydrazines and diaryl ditellurides on the SH2 reaction of tellurium are also discussed in detail.

Photoinduced Bisphosphination of Alkynes with Phosphorus Interelement Compounds and Its Application to Double-Bond Isomerization.

The addition of interelement compounds with heteroatom-heteroatom single bonds to carbon-carbon unsaturated bonds under light irradiation is believed to be an atomically efficient method to procure materials with carbon-heteroatom bonds. In this study, we achieved the photoinduced bisphosphination of alkynes using the phosphorus interelement compound, tetraphenyldiphosphine monosulfide (1), to stereoselectively obtain the corresponding (E)-vic-1,2-bisphosphinoalkenes, which are important transition-metal ligands. The bisphosphination reaction was performed by mixing 1 and various alkynes and then exposing the mixture to light irradiation. Optimization of the conditions for the bisphosphination reaction resulted in a wide substrate range and excellent trans-selectivity. Moreover, the completely regioselective introduction of pentavalent and trivalent phosphorus groups to the terminal and internal positions of the alkynes, respectively, was achieved. We also found that the novel double-bond isomerization reaction of the synthesized bisphosphinated products occurred with a catalytic amount of a base under mild conditions. Our method for the photoinduced bisphosphination of carbon-carbon unsaturated compounds may have strong implications for both organic synthesis and organometallic and catalyst chemistry.

One-Pot Construction of Diverse ß-Lactam Scaffolds via the Green Oxidation of Amines and Its Application to the Diastereoselective Synthesis of ß-Amino Acids.

In this study, a simple one-pot construction of ß-lactam scaffolds was successfully achieved via 4,6-dihydroxysalicylic acid-catalyzed organocatalytic oxidation of amines to imines using molecular oxygen. Although some imines are highly unstable and difficult to isolate by conventional methods, the organocatalytic oxidation of amines described herein, followed by their direct reaction with acyl chlorides in the presence of a base, afforded a series of new ß-lactam derivatives with excellent cis selectivity, which could not be synthesized and isolated by previously reported methods. Thus, this one-pot protocol will be one of the powerful methods applicable to the synthesis of various potential drug candidates and functional molecules. Furthermore, the subsequent hydrolysis of these ß-lactams successfully afforded the corresponding ß-amino acids as almost single diastereomers in up to 99% yields.

Clarification on the Reactivity of Diaryl Diselenides toward Hexacyclohexyldilead under Light.

In this study, the reactivity of organochalcogen compounds toward a representative alkyl-lead bond compound under light was investigated in detail. Under light irradiation, the Cy-Pb bond of Cy6Pb2 (Cy = cyclohexyl) undergoes homolytic cleavage to generate a cyclohexyl radical (Cy•). This radical can be successfully captured by diphenyl diselenide, which exhibits excellent carbon-radical-capturing ability. In the case of (PhS)2 and (PhTe)2, the yields of the corresponding cyclohexyl sulfides and tellurides were lower than that of (PhSe)2. This probably occurred due to the low carbon-radical-capturing ability of (PhS)2 and the high photosensitivity of the cyclohexyl-tellurium bond.

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones.

A simple and efficient method for α-brominating lactones that affords α-bromolactones under mild conditions using tetraalkylammonium hydroxide (R4N+OH-) as a base was developed. Lactones are ring-opened with Br2 and a substoichiometric amount of PBr3, leading to good yields of the corresponding α-bromocarboxylic acids. Subsequent intramolecular cyclization over 1 h using a two-phase system (H2O/CHCl3) containing R4N+OH- afforded α-bromo lactones in good yields. This method can be applied at the 10 mmol scale using simple operations. α-Bromo-δ-valerolactone, which is extremely reactive and difficult to isolate, could be isolated and stored in a freezer for about one week using the developed method. Optimizing the solvent for environmentally friendly large-scale syntheses revealed that methyl ethyl ketone (MEK) was as effective. In addition, in situ-generated α-bromo-δ-valerolactone was directly converted into a sulfur-substituted functional lactone without difficulty by reacting it with a sulfur nucleophile in one pot without isolation. This new bromination system is expected to facilitate the industrial use of α-bromolactones as important intermediates.

Highly regio- and stereoselective phosphinylphosphination of terminal alkynes with tetraphenyldiphosphine monoxide under radical conditions.

The homolytic cleavage of the PV(O)-PIII bond in tetraphenyldiphosphine monoxide simultaneously provides both pentavalent and trivalent phosphorus-centered radicals with different reactivities. The method using V-40 as an initiator is successfully investigated for the regio- and stereoselective phosphinylphosphination of terminal alkynes giving the corresponding trans-isomers of 1-diphenylphosphinyl-2-diphenylthiophosphinyl-1-alkenes in good yields. The protocol can be applied to a wide variety of terminal alkynes including both alkyl- and arylalkynes.

Transition-Metal-Free Synthesis of 2-Substituted Benzothiazoles from Nitrobenzenes, Methylheteroaryl Compounds, and Elemental Sulfur, Based on Nitro-Methyl Redox-Neutral Cyclization.

Greener and more sustainable chemical processes are required to address increasing environmental pollution and depletion of natural resources. This paper aims to develop greener and more sustainable modern synthetic chemical processes using redox-neutral cyclization. Redox-neutral cyclization has been shown to promote the efficient synthesis of 2-substituted benzothiazoles from easily available nitrobenzenes, methyl-heteroaryl compounds, and elemental sulfur in the absence of transition-metal catalysts. The 2-substituted benzothiazoles were obtained in reasonable yields through the sulfuration of electron-deficient C-H bonds with elemental sulfur. This synthetic methodology also affords a high atom economy without the use of any external oxidizing and/or reducing reagents.

Photoinduced Cyclizations of o-Diisocyanoarenes with Organic Diselenides and Thiols that Afford Chalcogenated Quinoxalines.

This study describes the syntheses of 2,3-bis(selanyl)quinoxalines via the photoinduced cyclizations of o-diisocyanoarenes with diaryl or dialkyl diselenides, in addition to providing a detailed discussion of the corresponding mechanism and revealing that the developed procedure can also be applied to prepare 2-thiolated quinoxaline derivatives from o-diisocyanoarenes and thiols. The developed technique does not need the use of additives or metal catalysts and features the advantages of a high conversion, a broad substrate scope, and mild reaction conditions, thereby rendering it a valuable addition to the quinoxaline synthesis toolbox.

Phosphorus-Recycling Wittig Reaction: Design and Facile Synthesis of a Fluorous Phosphine and Its Reusable Process in the Wittig Reaction.

This study shows that phosphorus sources can be recycled using the appropriate fluorous phosphine in the Wittig reaction. The designed fluorous phosphine, which has an ethylene spacer between its phosphorus atom and the perfluoroalkyl group, was synthesized from air-stable phosphine reagents. The synthesized phosphine can be used for the Wittig reaction process to obtain various alkenes in adequate yields and stereoselectivity. The concomitantly formed fluorous phosphine oxide was extracted from the reaction mixture using a fluorous biphasic system. The fluorous phosphine was regenerated by reducing the fluorous phosphine oxide with diisobutylaluminum hydride. Finally, a series of gram scale phosphorus recycling processes were performed, which included the Wittig reaction, separation, reduction, and reuse.

Photoinduced Syntheses and Reactivities of Phosphorus-Containing Interelement Compounds.

The photoinduced reactions of tetraphenyldiphosphine disulfide with a range of organic dichalcogenides successfully afforded a series of phosphorus(V)-chalcogen interelement compounds via a radical process. The relative reactivities of the organic dichalcogenides (i.e., (PhS)2, (PhSe)2, and (PhTe)2) toward the PIII or PV groups in the diphosphine analogues under light were investigated in detail, and a convenient method was developed to form P-S or P-Se interelement compounds from tetraphenyldiphosphine disulfide and (PhS)2 or (PhSe)2 upon photoirradiation. Furthermore, the relative photochemical properties and reactivities of tetraphenyldiphophine (P-P interelement compound) and its analogues toward photoinduced radical addition reactions were also discussed. The formed P-E (E = S, Se) interelement compounds could be utilized for ionic reactions, and they could be transformed into various phosphine reagents via one-pot processes.

Reductive Rearrangement of Tetraphenyldiphosphine Disulfide To Trigger the Bisthiophosphinylation of Alkenes and Alkynes.

The facile synthesis of organophosphorus compounds is of great importance for the development of new synthetic methods by using air-stable sources of phosphorus. In this respect, a synthetic method that is based on a reductive rearrangement and is capable of converting air-stable pentavalent phosphorus compounds into reactive trivalent phosphorus compounds is a powerful tool. Tetraphenyldiphosphine disulfide, which is a shelf-stable solid, was the focus of this study, and it was shown to undergo reductive rearrangement to trigger the bisthiophosphinylation of a variety of alkenes, such as terminal, cyclic, internal, and branched alkenes, 1,3-dienes, and terminal alkynes when exposed to light without any catalyst, base, or additive.

Synthesis of Bis(phosphanyl)alkane Monosulfides by the Addition of Diphosphane Monosulfides to Alkenes under Light.

Bis-phosphanated compounds are regarded as the most ubiquitous privileged ligand structures in transition-metal catalysis. The development of highly atom economical reactions is of great importance for their syntheses because less atom economical methods often require complicated purification procedures under inert atmospheres to remove excess starting materials and byproducts. Herein, the photoinduced addition reactions of diphosphane monosulfides bearing PV (S)-PIII single bonds to alkenes is disclosed. These reactions require only equimolar amounts of the diphosphane monosulfide relative to the alkene and facilitate highly selective introduction of two different types of phosphorus-containing groups, such as thiophosphoryl and phosphanyl groups, into a variety of alkenes without any catalyst, base, or additive.

2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Ugi Reactions with Molecular Oxygen via Homo- and Cross-Coupling of Amines.

Metal-free, oxidative four-component Ugi reactions (U-4CRs) were conducted to synthesize dipeptides from two different amines, isocyanides, and carboxylic acids using 2,4,6-trihydroxybenzoic acid catalyst in O2 atmosphere. The organocatalytic U-4CRs proceed via oxidative cross-coupling of benzylamines with other aliphatic or aromatic amines to form imines, followed by condensation with isocyanides and carboxylic acids. The U-4CRs via cross-coupling of amines are rare, and the simple, metal-free procedures are advantageous for further applications in drug and heterocycle syntheses.