Proline‐Tetrazole‐Catalyzed Enantioselective N‐Nitroso Aldol Reaction of Aldehydes with In Situ Generated Nitrosocarbonyl Compounds

A highly enantioselective method (up to 98 % ee) for the preparation of β‐amino alcohols was achieved by using the readily available proline‐tetrazole as the catalyst for the N‐nitroso aldol reaction of aldehydes with in situ generated nitrosocarbonyl compounds. The key to success of this reaction is the use of MnO₂ as an oxidant and catechol as a Brønsted acid additive.     

PEG 400 promoted nucleophilic substitution reaction of halides into organic azides under mild conditions

Abstract

Polyethylene glycol 400 (PEG 400) has been demonstrated as an efficient and eco-friendly reaction medium for the preparation of organic azides from structurally diverse halides by nucleophilic substitution reaction with NaN₃ under mild conditions. The advantages of this protocol are: operational simplicity, environmental safety, broad substrate scope, excellent functional group tolerance, and short reaction time. The PEG 400 can be recovered and reused.     

Synthesis and Reactions of Trifluoromethyl-Substituted 1,3,5-Triazines

A variety of di- and trifluoromethyl-s-triazines are prepared following straightforward synthetic protocols from simple, commercially available starting materials. Trichloromethyl-substituted triazine electrophiles are obtained in good yield and react with amine nucleophiles to afford aminotriazine products in good to excellent yield. The nucleophilic aromatic substitution reaction is broad in scope and proceeds smoothly with both aromatic and aliphatic (primary, secondary, and branched) amines in the presence of non-participating functional groups including alcohols, carboxylic acids, indoles, and common amine protecting groups. Furthermore, most reactions require only a catalytic amount of 4-DMAP with no stoichiometric base and are complete within two hours at ambient temperature.     

cine‐Substitution Reactions of Metallabenzenes: An Experimental and Computational Study

Alkali‐resistant osmabenzene [(SCN)₂(PPh₃)₂Os{CHC(PPh₃)CHCICH}] ( 2 ) can undergo nucleophilic aromatic substitution with MeOH or EtOH to give cine‐substitution products [(SCN)₂(PPh₃)₂Os{CHC(PPh₃)CHCHCR}] (R=OMe ( 3 ), OEt( 4 )) in the presence of strong alkali. However, the reactions of compound 2 with various amines, such as n‐butylamine and aniline, afford five‐membered ring species, [(SCN)₂(PPh₃)₂Os{CH?C(PPh₃)CH?C(CH?NHR′)}] (R′=nBu( 8 ), Ph( 9 )), in addition to the desired cine‐substitution products, [(SCN)₂(PPh₃)₂Os{CHC(PPh₃)CHCHC(NHR′)}] (R′=nBu( 6 ), Ph( 7 )), under similar reaction conditions. The mechanisms of these reactions have been investigated in detail with the aid of isotopic labeling experiments and density functional theory (DFT) calculations. The results reveal that the cine‐substitution reactions occur through nucleophilic addition, dissociation of the leaving group, protonation, and deprotonation steps, which resemble the classical “addition‐of‐nucleophile, ring‐opening, ring‐closure” (ANRORC) mechanism. DFT calculations suggest that, in the reaction with MeOH, the formation of a five‐membered metallacycle species is both kinetically and thermodynamically less favorable, which is consistent with the experimental results that only the cine‐substitution product is observed. For the analogous reaction with n‐butylamine, the pathway for the formation of the cine‐substitution product is kinetically less favorable than the pathway for the formation of a five‐membered ring species, but is much more thermodynamically favorable, again consistent with the experimental conversion of compound 8 into compound 6 , which is observed in an in situ NMR experiment with an isolated pure sample of 8 .     

Direct Dehydroxytrifluoromethoxylation of Alcohols

The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late‐stage trifluoromethoxylation of complex small molecules.     

Facile Access to Fluoroaromatic Molecules by Transition‐Metal‐Free C–F Bond Cleavage of Polyfluoroarenes: An Efficient,Green, and Sustainable Protocol

The creation of new bonds via C–F bond cleavage of polyfluoroarenes has proven to be an important and powerful tool in synthetic chemistry. Using such a strategy, a myriad of valuable partially fluoroaromatic molecules and building blocks can be obtained. The transition‐metal‐free nucleophilic aromatic substitution (S_NAr) strategy has aroused the continuing interest of researchers due to its simple, mild, economical, and environmentally benign characteristics, which have been successfully applied to C–F bond functionalizations. In this account, we present a summary of the recent investigations of polyfluoroarenes involving S_NAr reactions and discuss some of our recent endeavors in the construction of partially fluoroaromatic molecules. Through this strategy, many new bonds including C–C, C–N, C–O, C–S, and C–H bonds can be created. Additionally, brief discussions on the transformation mechanisms are also provided. Finally, we discuss the existing limitations of the S_NAr reactions of polyfluoroarenes as well as our perspective on the future development of this chemistry.

     

Expanding the Palette of Phenanthridinium Cations

5,6‐Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. Some properties rely on phenanthridiniums intercalating into DNA, but the use of these cations as exomarkers for the reactive oxygen species (ROS), superoxide, and as inhibitors of acetylcholine esterase (AChE) do not require intercalation. A versatile modular synthesis of 5,6‐disubstituted phenanthridiniums that introduces diversity by Suzuki–Miyaura coupling, imine formation and microwave‐assisted cyclisation is presented. Computational modelling at the density functional theory (DFT) level reveals that the novel displacement of the aryl halide by an acyclic N‐alkylimine proceeds by an S_NAr mechanism rather than electrocyclisation. It is found that the displacement of halide is concerted and there is no stable Meisenheimer intermediate, provided the calculations consistently use a polarisable solvent model and a diffuse basis set.     

Preparation of THP‐Ester‐Derived Pyridinium‐Type Salts and their Reactions with Various Nucleophiles

Nucleophilic substitution at the anomeric positions of tetrahydropyranyl (THP) and related carbohydrate‐derived esters that proceeded through pyridinium‐type salt intermediates have been developed. Treatment of the 6‐substituted α‐acetoxy‐tetrahydropyrans with TMSOTf (TMS=trimethylsilyl) and 2‐substitutited pyridines, such as 2‐p‐tolylpyridine and 2‐methoxypyridine, led to the efficient generation of cis‐pyridinium‐type salts. These salts reacted with various nucleophiles, such as alcohols, azides, and organozinc reagents, to form nucleophilic‐substitution products. A characteristic feature of these processes was that they took place under mild conditions, which did not affect acid‐labile protecting groups. Furthermore, the reactions that employed azides and C‐nucleophiles generated 2,6‐trans products with high degrees of stereoselectivity.     

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.