Umpolung Isomerization in Radical Copolymerization of Benzyl Vinyl Ether with Pentafluorophenylacrylate Leading to Degradable AAB Periodic Copolymers.

This study revealed that benzyl vinyl ether (BnVE) shows a peculiar isomerization propagation in its radical copolymerization with an electron-deficient acrylate carrying a pentafluorophenyl group (PFA). The co-monomer pair inherently exhibits the cross-over propagation feature due to the large difference in the electron density. However, the radical species of PFA was found to undergo a backward isomerization to the penultimate BnVE pendant giving a benzyl radical species prior to propagation with BnVE. The isomerization brings a drastic change in the character of the growing radical species from electrophilic to nucleophilic, and thus the isomerized benzyl radial species propagates with PFA. Consequently, the two monomers were consumed in the order AAB (A: PFA; B: BnVE) and the unique periodic consumption was confirmed by the pseudo-reactivity ratios calculated by the penultimate model: r11 =0.174 and r21 =6600 for PFA (M1 ) with BnVE (M2 ). The pentafluorophenyl ester groups of the resulting copolymers are transformed into ester and amide groups by post-polymerization alcoholysis and aminolysis modifications. The unique isomerization in the AAB sequence allowed the periodic introduction of a benzyl ether structure in the backbone leading to efficient degradation under acid conditions.

Modular Synthesis of Fully-Substituted and Configuration-Defined Alkyl Vinyl Ethers Enabled by Dual-Functional Copper Catalysis.

Here we present a modular, chemo-, regio-, and stereoselective synthesis of fully-substituted and configuration-defined alkyl vinyl ethers (AVEs) using simple chemical feedstocks. The distinctive approach involves the chemo- and regioselective functionalization of the CF2 unit in gem-difluorinated cyclopropanes with O-H and C-H nucleophiles in a specific order. The resulting highly functionalized cyclopropanyl ethers then undergo a stereoselective ring-opening process to produce fully-substituted and configuration-defined AVEs. These AVEs are rarely accessible through conventional methods and are easily transformable. Mechanistic experiments indicate that the success of this method relies on the use of dual-functional copper catalysis, which is involved in both the functionalization of the CF2 unit and the subsequent ring-opening process.

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers.

In this study, we develop the synthesis methods of fluoroalkenes and fluoroenynes via Suzuki-Miyaura and Sonogashira cross-coupling reactions using novel multihalogenated fluorovinyl ethers, which are easily prepared from the reaction between phenols and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane). These reactions make use of the unique structure of multihalogenated fluorovinyl ethers, which contains a reactive bromine atom, to afford a series of fluoroalkenes and fluoroenynes in moderate to high yields.

Regio- and Z-Selective Alkyne Hydroamination and Hydrophenoxylation using Tetrafluoro-λ6 -Sulfanyl Alkynes under Superbasic, Naked Anion Conditions.

Alkyne hydroamination is an effective approach for the production of enamines and enamine-containing N-heterocycles. However, stereoselectivity control is a considerable challenge in this reaction because of the electronic repulsion between an incoming nitrogen lone pair and the alkyne π-system. Herein, we propose a methodology involving ß-regio- and Z-selective alkyne hydroamination by using tetrafluoro-λ6 -sulfanyl (SF4 ) alkynes under superbasic, naked anion conditions. The reaction is compatible with a wide variety of N-heterocycles, including indoles, carbazoles, pyrazoles, and imidazoles, and selectively furnishes SF4 -linked Z-vinyl enamines with ß-regioselectively. Moreover, the method can be extended to the ß- and Z-controlled, base-mediated alkyne hydrophenoxylation with phenols to provide SF4 -linked Z-vinyl ethers in high yields. As the SF4 unit has attracted attention as a bioisostere for alkynes, p-benzenes, bicyclo[1.1.1]pentyl (BCP) groups, and cubanes in medicinal chemistry, this chemistry represents an effective approach to creating novel drug candidates incorporating SF4 -containing molecules.

Catalytic Living Ring-Opening Metathesis Polymerization Using Vinyl Ethers as Effective Chain-Transfer Agents.

A catalytic living ring-opening metathesis copolymerization (ROMP) method is described that relies on a degenerative, reversible and regioselective exchange of propagating Fischer-carbenes. All characteristics of a living polymerization such as narrow dispersity, excellent molar mass control and the ability to form block copolymers are achieved by this method. The method allows the use of up to 200 times less ruthenium complex than traditional living ROMP. We demonstrate the synthesis of ROMP-ROMP diblock copolymers, ATRP from a ROMP macro-initiator and living ROMP from a PEG-based macro chain transfer agent. The cost-effective, sustainable and environmentally friendly synthesis of degradable polymers and block copolymers enabled by this strategy will find various applications in biomedicine, materials science, and technology.

Recent Advances in Living Cationic Polymerization with Emerging Initiation/Controlling Systems.

While the conventional living cationic polymerization (LCP) provided opportunities to synthesizing well-defined polymers with predetermined molecular weights, desirable chemical structures and narrow dispersity, it is still important to continuously innovate new synthetic methods to meet the increasing requirements in advanced material engineering. Consequently, a variety of novel initiation/controlling systems have be demonstrated recently, which have enabled LCP with spatiotemporal control, broadened scopes of monomers and terminals, more user-friendly operations and reaction conditions, as well as improved thermomechanical properties for obtained polymers. In this work, recent advances in LCP is summarized with emerging initiation/controlling systems, including chemical-initiated/controlled cationic reversible addition-fragmentation chain transfer (RAFT) polymerization, photoinitiated/controlled LCP, electrochemical-controlled LCP, thionyl/selenium halide-initiated LCP, organic acid-assisted LCP, and stereoselective LCP. It is hoped that this summary will provide useful knowledge to people in related fields and stimulate new ideas to promote the development and application of LCP in both academia and industry.

tert-Butyl Esters as Potential Reversible Chain Transfer Agents for Concurrent Cationic Vinyl-Addition and Ring-Opening Copolymerization of Vinyl Ethers and Oxiranes.

tert-Butyl esters are demonstrated to function as chain transfer agents (CTAs) in the cationic copolymerization of vinyl ether (VE) and oxirane via concurrent vinyl-addition and ring-opening mechanisms. In the copolymerization of isopropyl VE and isobutylene oxide (IBO), the IBO-derived propagating species reacts with tert-butyl acetate to generate a copolymer chain with an acetoxy group at the ω-end. This reaction liberates a tert-butyl cation; hence, a polymer chain with a tert-butyl group at the α-end is subsequently generated. Other tert-butyl esters also function as CTAs, and the substituent attached to the carbonyl group affects the chain transfer efficiency. In addition, ethyl acetate does not function as a CTA, which suggests the importance of the liberation of a tert-butyl cation for the chain transfer process. Chain transfer reactions by tert-butyl esters potentially occur reversibly through the reaction of the propagating cation with the ester group at the ω-end of another chain.

Synthesis and Post-Polymerization Modification of Defined Functional Poly(vinyl ether)s.

Living cationic polymerization is known for a good control over chain growth yielding polymers with well-defined molar mass distributions and low dispersities. However, the practical challenges involved in the synthesis of poly(vinyl ether)s limited suitable post-polymerization modifications (PPM) via chemoselective click reactions. Herein the successful controlled cationic polymerization of vinyl ethers bearing pendant CC double and C≡C triple bonds using a single-component initiation under ambient conditions is reported. Furthermore, the PPM via thiol-ene/-yne and copper(I)-catalyzed alkyne-azide cycloaddition reaction of the obtained polymers is successfully realized laying the foundation for the synthesis of unprecedented functional poly(vinyl ether)s.

Cyanovinylation of Aldehydes: Organocatalytic Multicomponent Synthesis of Conjugated Cyanomethyl Vinyl Ethers.

A novel organocatalytic multicomponent cyanovinylation of aldehydes was designed for the synthesis of conjugated cyanomethyl vinyl ethers. The reaction was implemented for the synthesis of a 3-substituted 3-(cyanomethoxy)acrylates, using aldehydes as substrates, acetone cyanohydrin as the cyanide anion source, and methyl propiolate as the source of the vinyl component. The multicomponent reaction is catalyzed by N-methyl morpholine (2.5 mol%) to deliver the 3-(cyanomethoxy)acrylates in excellent yields and with preponderance of the E-isomer. The multicomponent reaction manifold is highly tolerant to the structure and composition of the aldehyde (aliphatic, aromatic, heteroaromatics), and it is instrumentally simple (one batch, open atmospheres), economic (2.5 mol% catalyst, stoichiometric reagents), environmentally friendly (no toxic waste), and sustainable (easy scalability).

Efficient Regioselective Synthesis of Novel Water-Soluble 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium Derivatives by Annulation Reactions of 8-quinolinesulfenyl Halides.

Regioselective synthesis of novel 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives has been developed by annulation reactions of 8-quinolinesulfenyl halides with vinyl chalcogenides (vinyl ethers, divinyl sulfide, divinyl selenide and phenyl vinyl sulfide) and tetravinyl silane. The novel reagent 8-quinolinesulfenyl bromide was used in the annulation reactions. The influence of the substrate structure and the nature of heteroatoms on the direction of the reactions and on product yields has been studied. The opposite regiochemistry was observed in the reactions with vinyl chalcogenides and tetravinyl silane. The obtained condensed heterocycles are novel water-soluble functionalized compounds with promising biological activity.

Hydrogen Bond Donor Catalyzed Cationic Polymerization of Vinyl Ethers.

The synthesis of high-molecular-weight poly(vinyl ethers) under mild conditions is a significant challenge, since cationic polymerization reactions are highly sensitive to chain-transfer and termination events. We identified a novel and highly effective hydrogen bond donor (HBD)-organic acid pair that can facilitate controlled cationic polymerization of vinyl ethers under ambient conditions with excellent monomer compatibility. Poly(vinyl ethers) of molar masses exceeding 50 kg mol-1 can be produced within 1 h without elaborate reagent purification. Modification of the HBD structure allowed tuning of the polymerization rate, while DFT calculations helped elucidate crucial intermolecular interactions between the HBD, organic acid, and polymer chain end.

Synthesis of Fulvene Vinyl Ethers by Gold Catalysis.

Gold-catalyzed cyclization of 1,5-diynes with ketones as reagents and solvent provides diversely substituted vinyl ethers under mild conditions. The regioselectivity of such gold-catalyzed cyclizations is usually controlled by the scaffold of the diyne. Herein, we report the first solvent-controlled switching of regioselectivity from a 6-endo-dig- to 5-endo-dig-cyclization in these transformations, providing fulvene derivatives. With respect to the functional-group tolerance, aryl fluorides, chlorides, bromides, and ethers are tolerated. Furthermore, the mechanism and selectivity are put to scrutiny by experimental studies and a thermodynamic analysis of the product. Additionally, 6-(vinyloxy)fulvenes are a hitherto unknown class of compounds. Their reactivity is briefly evaluated, to give insights into their potential applications.

Intermolecular Carbonyl-olefin Metathesis with Vinyl Ethers Catalyzed by Homogeneous and Solid Acids in Flow.

The carbonyl-olefin metathesis reaction has experienced significant advances in the last seven years with new catalysts and reaction protocols. However, most of these procedures involve soluble catalysts for intramolecular reactions in batch. Herein, we show that recoverable, inexpensive, easy to handle, non-toxic, and widely available simple solid acids, such as the aluminosilicate montmorillonite, can catalyze the intermolecular carbonyl-olefin metathesis of aromatic ketones and aldehydes with vinyl ethers in-flow, to give alkenes with complete trans stereoselectivity on multi-gram scale and high yields. Experimental and computational data support a mechanism based on a carbocation-induced Grob fragmentation. These results open the way for the industrial implementation of carbonyl-olefin metathesis over solid catalysts in continuous mode, which is still the origin and main application of the parent alkene-alkene cross-metathesis.

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step.

In this paper, a new access to several chiral 3-aminoglycals as potential precursors for glycosylated natural products is reported from a common starting material, (-)-methyl-L-lactate. The stereodivergent strategy is based on the implementation of a ring-closing metathesis of vinyl ethers as key step of reaction sequences developed.

Integrative Pericyclic Cascade: An Atom Economic, Multi C-C Bond-Forming Strategy for the Construction of Molecular Complexity.

An all-pericyclic manifold is developed for the construction of topologically diverse, structurally complex and natural product-like polycyclic chemotypes. The manifold uses readily accessible tertiary propargyl vinyl ethers as substrates and imidazole as a catalyst to form up to two new rings, three new C-C bonds, six stereogenic centers and one transannular oxo-bridge. The manifold is efficient, scalable and instrumentally simple to perform and entails a propargyl Claisen rearrangement-[1,3]H shift, an oxa-6π-electrocyclization, and an intramolecular Diels-Alder reaction.

Living Cationic Polymerization of Vinyl Ethers through a Photoinduced Radical Oxidation/Addition/Deactivation Sequence.

A new photoinitiating system for living cationic polymerization of vinyl ethers is reported. In the current approach, visible-light irradiation of dimanganese decacarbonyl (Mn2 (CO)10 ) in the presence of an alkyl bromide results in the formation of carbon-centered radicals. The photochemically generated radicals were then oxidized by diphenyliodonium ions to the corresponding cations. These cations can add vinyl ether monomers, which are then rapidly deactivated by the bromide anions to give α-halide functional end groups. Poly(vinyl ether) chains are then grown through successive photoinduced radical oxidation/addition/deactivation (PROAD) in a controlled manner. The living nature of the system is evaluated through kinetics studies and block copolymer formation.

Scope and limitations of the dual-gold-catalysed hydrophenoxylation of alkynes.

Due to the synthetic advantages presented by the dual-gold-catalysed hydrophenoxylation of alkynes, a thorough study of this reaction was carried out in order to fully define the scope and limitations of the methodology. The protocol tolerates a wide range of functional groups, such as nitriles, ketones, esters, aldehydes, ketals, naphthyls, allyls or polyphenols, in a milder and more efficient manner than the previously reported methodologies. We have also identified that while we are able to use highly steric hindered phenols, small changes on the steric bulk of the alkynes have a dramatic effect on the reactivity. More importantly, we have observed that the use of substrates that facilitate the formation of diaurated species such as gem-diaurated or σ,π-digold-acetylide species, hinder the catalytic activity. Moreover, we have identified that the use of directing groups in unsymmetrical alkynes can help to achieve high regioselectivity in the hydrophenoxylation.

Unique Curing Properties through Living Polymerization in Crosslinking Materials: Polyurethane Photopolymers from Vinyl Ether Building Blocks.

Photopolymers with unique curing capabilities were produced by combining living cationic polymerization with network formation and restricted polymer motion. A vinyl ether diol was synthesized as a functional building block and reacted with isophorone diisocyanate to form a highly functionalized vinyl ether polyurethane as a model system with high crosslinking ability. When using a cationic photoinitiator, fast polymerization is observed upon short UV irradiation. Curing proceeds in the absence of light and under ambient conditions without oxygen inhibition. Cationic active sites become trapped dormant species upon network-induced vitrification and surprisingly remain living for several days. The polymerization can be reactivated by additional UV irradiation and/or raised temperature. The curing behavior was studied in detail by using UV and FT-NIR coupled rheology and photo-DSC to simultaneously study spectroscopic and mechanical information, as well as thermal effects.

Discovery of a new class of cinnamyl-triazole as potent and selective inhibitors of aromatase (cytochrome P450 19A1).

Synthesis of a novel class of natural product inspired cinnamyl-containing 1,4,5-triazole and the potent inhibition of human aromatase (CYP 450 19A1) by select members is described. Structure-activity data generated provides insights into the requirements for potency particularly the inclusion of an aryl bromide or chloride residue as a keto-bioisostere.

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions.

Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers, which are found embedded in a number of natural products.