Stereoselective synthesis of α-difluoromethyl-β-amino alcohols via nucleophilic difluoromethylation with Me3SiCF2SO2Ph

A facile synthesis of anti-α-(difluoromethyl)-β-amino alcohols was accomplished by using a nucleophilic difluoromethylation strategy with Me₃SiCF₂SO₂Ph reagent. Good to excellent chemical yields as well as modest to good diastereoselectivity were achieved in these reactions. We found that the solvent played a crucial role in controlling the diastereoselectivity of the reaction, and an apolar solvent such as toluene helps to improve the diastereoselectivity of the reaction. The anti-α-(difluoromethyl)-β-amino alcohol 3a was demonstrated to be a useful synthetic intermediate to synthesize difluoromethylated oxazolidinone 9.     

Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H‐Containing Alcohols

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)?O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.     

Fluoride-induced nucleophilic (phenylthio)difluoromethylation of carbonyl compounds with [difluoro(phenylthio)methyl]trimethylsilane (TMS-CF2SPh)

A fluoride-induced nucleophilic (phenylthio)difluoromethylation method using TMS-CF₂SPh has been achieved. This new methodology efficiently transfers “PhSCF₂” group into both enolizable and non-enolizable aldehydes and ketones to give corresponding (phenylthio)difluoromethylated alcohols in good to excellent yields. Diphenyldisulfide can also be (phenylthio)difluoromethylated into PhSCF₂SPh in high yield. The reaction with methyl benzoate, however, gives only low yield of (phenylthio)difluoromethyl phenyl ketone. The above-obtained PhSCF₂-containing alcohols can be further transformed into difluoromethyl alcohols using an oxidation-desulfonylation procedure. This new type of nucleophilic (phenylthio)difluoromethylation methodology may have other potential applications in the medicinal and agrochemical fields.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

Silica Chloride Nano Particle Catalyzed Ring Opening of Epoxides by Aromatic Amines

Silica chloride nano particle (nano SiO₂‐Cl), has been found to be heterogeneous catalyst for facile, simple and mild ring opening of epoxides with aromatic amines to afford β‐amino alcohols in dry CH₂Cl₂ at room temperature.     

Well‐defined epoxide‐containing styrenic polymers and their functionalization with alcohols

Polymers containing electrophilic moieties, such as activated esters, epoxides, and alkyl halides, can be readily modified with a variety of nucleophiles to produce useful functional materials. The modification of epoxide‐containing polymers with amines and other strong nucleophiles is well‐documented, but there are no reports on the modification of such polymers with alcohols. Using phenyloxirane and glycidyl butyrate as low molecular weight model compounds, it was determined that the acid‐catalyzed ring‐opening of aryl‐substituted epoxides by alcohols to form β‐hydroxy ether products was significantly more efficient than that of alkyl‐substituted epoxides. An aryl epoxide‐type styrenic monomer, 4‐vinylphenyloxirane (4VPO), was synthesized in high yield using an improved procedure and then polymerized in a controlled manner under reversible addition‐fragmentation chain‐transfer (RAFT) polymerization conditions. A successful chain extension with styrene proved the high degree of chain‐end functionalization of the poly4VPO‐based macro chain transfer agent. Poly4VPO was modified with a library of alcohols and phenols, some of which contained reactive functionalities, e.g., azide, alkyne, allyl, etc., using either CBr₄ (in PhCN at 90 °C for 2–3 days) or BF₃ (in CH₂Cl₂ at ambient temperature over 30 min) as the catalyst. The resulting β‐hydroxy ether‐functionalized homopolymers were characterized using size exclusion chromatography, ¹H NMR and IR spectroscopy, and thermal gravimetric analysis. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1132–1144     

Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Bifunctional Onium and Potassium Iodides as Nucleophilic Catalysts for the Solvent-Free Syntheses of Carbonates,Thiocarbonates, and Oxazolidinones from Epoxides

The catalytic potential of organo-onium iodides as nucleophilic catalysts is aptly demonstrated in the synthesis of cyclic carbonates from epoxides and carbon dioxide (CO₂), as a representative CO₂ utilization reaction. Although organo-onium iodide nucleophilic catalysts are metal-free environmentally benign catalysts, harsh reaction conditions are generally required to efficiently promote the coupling reactions of epoxides and CO₂. To solve this problem and accomplish efficient CO₂ utilization reactions under mild conditions, bifunctional onium iodide nucleophilic catalysts bearing a hydrogen bond donor moiety were developed by our research group. Based on the successful bifunctional design of the onium iodide catalysts, nucleophilic catalysis using a potassium iodide (KI)-tetraethylene glycol complex was also investigated in coupling reactions of epoxides and CO₂ under mild reaction conditions. These effective bifunctional onium and potassium iodide nucleophilic catalysts were applied to the solvent-free syntheses of 2-oxazolidinones and cyclic thiocarbonates from epoxides.     

[(SIPr)Ag(CF2H)]: A Shelf-Stable,Versatile Difluoromethylation Reagent

Due to its unique physical and electrophilic properties, the difluoromethyl group (−CF₂H) has been playing an irreplaceable role in the field of pharmaceutical and agrochemical industry. Methods that could efficiently incorporate the difluoromethyl group into the target molecules are increasing in the recent years. Developing a stable and efficient difluoromethylating reagent is thus highly attractive. In this review, we describe the development of a nucleophilic difluoromethylation reagent [(SIPr)Ag(CF₂H)], including its elemental reaction, difluoromethylation reaction with different types of electrophiles, and its application in the synthesis of a nucleophilic and an electrophilic difluoromethylthiolating reagent.     

Silver(I)‐Catalyzed Three‐Component Reaction of Propargylic Alcohols,Carbon Dioxide and Monohydric Alcohols: Thermodynamically Feasible Access to β‐Oxopropyl Carbonates

A silver(I)‐catalyzed three‐component reaction of propargylic alcohols, CO₂, and monohydric alcohols was successfully developed for the synthesis of β‐oxopropyl carbonates. As such, a series of β‐oxopropyl carbonates were exclusively produced in excellent yields (up to 98 %), even under atmospheric pressure of CO₂. The silver catalyst works efficiently for both the carboxylative cyclization of propargylic alcohols with CO₂ and subsequent transesterification of α‐alkylidene cyclic carbonates with monohydric alcohols; thus this tandem process performs smoothly under mild conditions. This work provides a versatile and thermodynamically favorable approach to dissymmetric dialkyl carbonates.     

Gold(I)‐Catalyzed Glycosylation with Glycosyl ortho‐Alkynylbenzoates as Donors: General Scope and Application in the Synthesis of a Cyclic Triterpene Saponin

Glycosyl ortho‐alkynylbenzoates have emerged as a new generation of donors for glycosidation under the catalysis of gold(I) complexes such as Ph₃PAuOTf and Ph₃PAuNTf₂ (Tf=trifluoromethanesulfonate). A wide variety of these donors, including 2‐deoxy sugar and sialyl donors, are easily prepared and shelf stable. The glycosidic coupling yields with alcohols are generally excellent; even direct coupling with the poorly nucleophilic amides gives satisfactory yields. Moreover, excellent α‐selective glycosylation with a 2‐deoxy sugar donor and β‐selective sialylation have been realized. Application of the present glycosylation protocol in the efficient synthesis of a cyclic triterpene tetrasaccharide have further demonstrated the versatility and efficacy of this new method, in that a novel chemoselective glycosylation of the carboxylic acid and a new one‐pot sequential glycosylation sequence have been implemented.     

Extensive Studies on the AIEt3／THF-Promoted Diastereoselective Tandem Rearrangement／Reduction of a-Hydroxy （Amino） Heterocyclopropane： An Efficient Approach to 2-Quaternary 1,3-Diheteroatom Units

A facile and highly diastereoselective method for the construction of 2-quaternary 1,3-amino alcohols and 1,3-diols has been developed on the basis of the AlEt3/THF-promoted tandem rearrangement/reductive reaction of α-hydroxy (amino) aziridines (epoxides). The progressive achievement in this article included that both 2-epimers of the units could be constructed from the initially same substrate. Also a stereochemistry assignment we reported previously was corrected.     

Iron‐containing ionic liquid as an efficient and recyclable catalyst for the synthesis of C3‐substituted indole derivatives

A facile and efficient protocol for the synthesis of C3‐substituted indole derivatives has been developed under mild condition. The iron‐containing ionic liquid, 1‐(2‐hydroxyethyl)‐1,4‐diazabicyclo[2.2.2] octanylium tetrachloroferrate ([Dabco‐C₂OH][FeCl₄]) as a recyclable catalyst has been successfully used in the synthesis of trisindolines, bis(3‐indolyl) methanes and β‐indolyl alcohols for the first time. The products of trisindolines and bis(3‐indolyl) methanes are easily separated and purified without chromatographic technique. The catalyst was recycled six times without significant activity loss.     

Ruthenium(III) Chloride–Catalyzed Ring Opening of Epoxides with Aromatic Amines

Ruthenium(III) chloride catalyzes the nucleophilic opening of epoxides by anilines, leading to the efficient synthesis of β‐amino alcohols. High regioselectivity can be considered as a noteworthy advantage of this method.     

Rh‐Catalyzed Reaction of Propargylic Alcohols with Aryl Boronic Acids–Switch from β‐OH Elimination to Protodemetalation

It is known that Rh‐catalyzed reaction of propargylic alcohols with aryl metallic reagents undergoes S_N2’‐type reaction affording allenes via a sequential arylmetalation and β‐OH elimination process. Here we report a Rh/Ag‐cocatalyzed reaction of propargylic alcohols with organoboronic acids affording stereo‐defined (E)‐3‐arylallylic alcohols via arylmetalation and protodemetalation with a high regio‐ and stereoselectivity under very mild conditions. The reaction exhibits a good substrate scope and the compatibility with synthetically useful functional groups with no racemization for optically active propargylic alcohols. Such a reaction may also be extended to homopropargylic alcohols with a remarkable regioselectivity and exclusive E‐stereoselectivity.     

Metastable Tetragonal Cu2Se Hyperbranched Structures: Large‐Scale Preparation and Tunable Electrical and Optical Response Regulated by Phase Conversion

Despite the promising applications of copper selenide nanoparticles, an in‐depth elucidation of the inherent properties of tetragonal Cu₂Se (β‐Cu₂Se) has not been performed because of the lack of a facile synthesis on the nanoscale and an energy‐intensive strategy is usually employed. In this work, a facile wet‐chemical strategy, employing HCOOH as reducing agent, has been developed to access single‐crystalline metastable β‐Cu₂Se hyperbranched architectures for the first time. The process avoids hazardous chemistry and high temperatures, and thus opens up a facile approach to the large‐scale low‐cost preparation of metastable β‐Cu₂Se hyperbranched architectures. A possible growth mechanism to explain the formation of the β‐Cu₂Se dendritic morphology has been proposed based on time‐dependent shape evolution. Further investigations revealed that the metastable β‐Cu₂Se can convert into the thermodynamically more stable cubic α‐Cu_2?xSe maintaining the dendritic morphology. An increase in electrical conductivity and a tunable optical response were observed under ambient conditions. This behavior can be explained by the oxidation of the surface of the β‐Cu₂Se hyperbranched structures, ultimately leading to solid‐state phase conversion from β‐Cu₂Se into superionic conductor α‐Cu_1.8Se, which has potential applications in energy‐related devices and sensors.     

Sulfamic acid catalyzed ring opening of epoxides with amines under solvent-free conditions

Sulfamic acid (SA) catalyses the nucleophilic opening of epoxide rings by amines leading to the efficient synthesis of ß-amino alcohols. The reaction works well with aromatic and aliphatic amines in short reaction times and in the absence of solvent. Exclusive trans stereoselectivity is observed for the ring opening of cyclohexene oxide. This method exhibits excellent regioselectivity for preferential nucleophilic attack at the less hindered position during the reaction with unsymmetrical epoxides.     

ZrCl4 as a new and efficient catalyst for the opening of epoxide rings by amines

Zirconium(IV) chloride catalyses the nucleophilic opening of epoxide rings by amines leading to the efficient synthesis of β-amino alcohols. The reaction works well with aromatic and aliphatic amines in short times at room temperature in the absence of solvent. Exclusive trans stereoselectivity is observed for cyclic epoxides. Aromatic amines exhibit excellent regioselectivity for preferential nucleophilic attack at the sterically less hindered position during the reaction with unsymmetrical epoxides. However, in case of styrene oxide, selective formation of the benzylic amine was observed during the reactions with aromatic amines.     

Rhodium‐catalyzed Asymmetric Hydrogenation of α‐Dehydroamino Ketones: A General Approach to Chiral α‐amino Ketones

Rhodium/DuanPhos‐catalyzed asymmetric hydrogenation of aliphatic α‐dehydroamino ketones has been achieved and afforded chiral α‐amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β‐amino alcohols by LiAlH(tBuO)₃ with good yields_. This protocol provides a readily accessible route for the synthesis of chiral α‐amino ketones and chiral β‐amino alcohols.