Mutual Cooperation in the Formal Allyl Alcohol Nucleophilic Substitution and Hydration of Alkynes for the Construction of γ‐Substituted Ketones

Mutual cooperation in the formal allyl alcohol nucleophilic substitution reaction and hydration of an alkyne has been utilized in the presence of a gold catalyst to give a series of γ‐functionalized ketones with high to excellent yields. This reaction actually involved an intramolecular O?H insertion cyclization of an alkyne to form the dihydrofuran intermediate, which was followed by the nucleophilic addition ring‐opening of a dihydrofuran to give the target compound.     

Palladium‐Catalyzed Carbonylative Reactions of 1‐Bromo‐2‐fluorobenzenes with Various Nucleophiles: Effective Combination of Carbonylation and Nucleophilic Substitution

A systematic study on the carbonylative transformation of 1‐bromo‐2‐fluorobenzenes with various nucleophiles has been performed. Different types of double nucleophiles, such as N?N, N?C, O?C, and N?S, can be effectively applied as coupling partners. The corresponding six‐membered heterocycles were isolated in moderate to good yields.     

Nucleophilic Aromatic Substitution Reactions of meso‐Bromosubporphyrin: Synthesis of a Thiopyrane‐Fused Subporphyrin

meso‐Bromosubporphyrin undergoes nucleophilic aromatic substitution (S_NAr) reactions with arylamines, diarylamines, phenols, ethanol, thiophenols, and n‐butanethiol in the presence of suitable bases to provide the corresponding substitution products. The S_NAr reactions also proceed well with pyrrole, indole, and carbazole to provide substitution products in moderate to good yields. Finally, the S_NAr reaction with 2‐bromothiophenol and subsequent intramolecular peripheral arylation reaction affords a thiopyrane‐fused subporphyrin.     

Novel Nucleophilic Substitution Reactions of 5‐Halo‐4‐Sulfur‐Substituted 5,6‐Dihydro‐2‐Pyridones

The title compounds ( 3 , 8 , 9 and 10 ) were efficiently synthesized, and their substitution reactions with various nucleophiles were carried out. The effects of leaving group, sulfur‐substituent, solvent, reaction temperature, and the nature of the nucleophiles on the reactivity and S_N2/S_N2′ regioselectivity were studied and rationalized with semi‐empirical calculations.     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

β‐Cyclodextrin Immobilized onto Dowex Resin: A Unique Microvessel and Heterogeneous Catalyst in Nucleophilic Substitution Reactions

The catalytic activity of β‐cyclodextrin immobilized on Dowex resin as an efficient solid‐liquid phase transfer catalyst was developed for the synthesis of alkyl thiocyanates and phenacyl derivatives in water. The nucleophilic substitution reactions were performed under mild reaction condition and gave the products in excellent yields. Furthermore, the catalyst could be recycled by facile separation without any loss of activity.     

Iridium‐Catalyzed Intermolecular Asymmetric Dearomatization of β‐Naphthols with Allyl Alcohols or Allyl Ethers

An Ir‐catalyzed intermolecular asymmetric dearomatization reaction of β‐naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]₂ (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β‐naphthalenone compounds bearing an all‐carbon‐substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee . The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.     

PPh3⋅HBr‐DMSO Mediated Expedient Synthesis of γ‐Substituted β,γ‐Unsaturated α‐Ketomethylthioesters and α‐Bromo Enals: Application to the Synthesis of 2‐Methylsulfanyl‐3(2 H)‐furanones

An efficient chemoselective general procedure for the synthesis of γ‐substituted β,γ‐unsaturated α‐ketomethylthioesters from α,β‐unsaturated ketones has been achieved through an unprecedented PPh₃?HBr‐DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of α‐bromoenals from enals. Furthermore, AuCl₃‐catalyzed efficient access to 3(2H)‐furanones from the above intermediates under extremely mild conditions are described.     

Gold‐Catalyzed Fluorination–Hydration: Synthesis of α‐Fluorobenzofuranones from 2‐Alkynylphenol Derivatives

The Au^I‐catalyzed fluorination–hydration of 2‐alkynylphenol derivatives in the presence of Selectfluor [1‐chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo‐[2.2.2]octane bis(tetrafluoroborate)] has been developed. This method provides straightforward access to α‐fluorobenzofuranones with the construction of C?O, C=O, and C?F bonds in a single step on the basis of an Au^I/Au^III redox catalytic cycle. Several control experiments, including the asymmetric variant of this reaction, were also conducted to gain insight into the reaction mechanism.     

Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Base‐Controlled Selectivity in the Synthesis of Linear and Angular Fused Quinazolinones by a Palladium‐Catalyzed Carbonylation/Nucleophilic Aromatic Substitution Sequence

A new approach for the facile synthesis of fused quinazolinone scaffolds through a palladium‐catalyzed carbonylative coupling followed by an intramolecular nucleophilic aromatic substitution is described. The base serves as the key modulator: Whereas DBU gives rise to the linear isomers, Et₃N promotes the preferential formation of angular products. Interestingly, a light‐induced 4+4 reaction of the product was also observed.     

Gold‐Catalyzed Cyclization of 1‐(Indol‐3‐yl)‐3‐alkyn‐1‐ols: Facile Synthesis of Diversified Carbazoles

Efficient cyclization of 1‐(indol‐3‐yl)‐3‐alkyn‐1‐ols in the presence of a cationic gold(I) complex, leading to annulated or specific substituted carbazoles, was observed. Depending on the reaction conditions and substitution pattern, divergent reaction pathways were discovered, furnishing diversified carbazole structures. Cycloalkyl‐annulated [b]carbazoles are obtained through 1,2‐alkyl migration of the metal‐carbene intermediates; cycloalkyl‐annulated [a]carbazoles are formed through a Wagner–Meerwein‐type 1,2‐alkyl shift; carbazole ethers are constructed through ring‐opening of the cyclopropyl group by nucleophilic attack of water or an alcohol.     

Gold‐catalyzed Reactions of 3‐Alkynyloxireno[2, 3‐b]chromenones to Form 3(2H)‐Furanones via a Domino Pathway

3(2H)‐Furanones are efficiently generated from 3‐alkynyl oxireno[2,3‐b]chromenones by an Au/DDQ‐catalyzed domino reaction through a pathway composed of cyclization, C? C cleavage, nucleophilic addition, oxidation, and nucleophilic addition. It was found that stoichiometric AuCl₃ or catalytic Au with stoichiometric DDQ can oxidize the benzylic sp³ C? H bond to facilitate nucleophilic addition.     

Nucleophilic Aromatic Substitution on Pentafluorophenyl‐Substituted Dipyrranes and Tetrapyrroles as a Route to Multifunctionalized Chromophores for Potential Application in Photodynamic Therapy

The application of porphyrinoids in biomedical fields, such as photodynamic therapy (PDT), requires the introduction of functional groups to tune their solubility for the biological environment and to allow a coupling to other active moieties or carrier systems. A valuable motif in this regard is the pentafluorophenyl (PFP) substituent, which can easily undergo a regiospecific nucleophilic replacement (S_NAr) of its para‐fluorine atom by a number of nucleophiles. Here, it is shown that, instead of amino‐substitution on the final porphyrinoid or BODIPY (boron dipyrromethene), the precursor 5‐(PFP)‐dipyrrane can be modified with amines (or alcohols). These dipyrranes were transformed into amino‐substituted BODIPYs. Condensation of these dipyrranes with aldehydes gave access to trans‐A₂B₂‐porphyrins and trans‐A₂B‐corroles. By using pentafluorobenzaldehyde, it was possible to introduce another para‐fluorine atom, which enabled the synthesis of multifunctionalized tetrapyrroles. Furthermore, alkoxy‐ and amino‐substituted dipyrranes were applied to the synthesis of A₃B₃‐hexaphyrins. The polar porphyrins that were prepared by using this method exhibited in vitro PDT activity against several tumor cell lines.     

Broad‐Spectrum Catalysts for the Ambient Temperature Anti‐Markovnikov Hydration of Alkynes

Anti‐Markovnikov alkyne hydration provides a valuable route to aldehydes. Half‐sandwich ruthenium complexes ligated by 5,5′‐bis(trifluoromethyl)‐2,2′‐bipyridine are remarkably active for this transformation. In the presence of 2 mol % metal, a wide range of functionalized aliphatic and aromatic alkynes are hydrated in high yield at ambient temperature.     

Mechanistic Studies on the SCS‐Pincer Palladium(II)‐Catalyzed Tandem Stannylation/Electrophilic Allylic Substitution of Allyl Chlorides with Hexamethylditin and Benzaldehydes

This paper describes a mechanistic study of the SCS‐pincer Pd^II‐catalyzed auto‐tandem reaction consisting of the stannylation of cinnamyl chloride with hexamethylditin, followed by an electrophilic allylic substitution of the primary tandem‐reaction product with 4‐nitrobenzaldehyde to yield homoallylic alcohols as the secondary tandem products. As it turned out, the anticipated stannylation product, cinnamyl trimethylstannane, is not a substrate for the second part of the tandem reaction. These studies have provided insight in the catalytic behavior of SCS‐pincer Pd^II complexes in the auto‐tandem reaction and on the formation and possible involvement of Pd⁰ species during prolonged reaction times. This has led to optimized reaction conditions in which the overall tandem reaction proceeds through SCS‐pincer Pd^II‐mediated catalysis, that is, true auto‐tandem catalysis. Accordingly, this study has provided the appropriate reaction conditions that allow the pincer catalysts to be recycled and reused.