https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.

Multicomponent Reactions with Isocyanides.

Controlled/living radical polymerization: Features, developments, and perspectives

This paper presents a review of living radical polymerization achieved with thiocarbonylthio compounds [ZC(=S)SR] by a mechanism of reversible addition–fragmentation chain transfer (RAFT). Since we first introduced the technique in 1998, the number of papers and patents on the RAFT process has increased exponentially as the technique has proved to be one of the most versatile for the provision of polymers of well defined architecture. The factors influencing the effectiveness of RAFT agents and outcome of RAFT polymerization are detailed. With this insight, guidelines are presented on how to conduct RAFT and choose RAFT agents to achieve particular structures. A survey is provided of the current scope and applications of the RAFT process in the synthesis of well defined homo-, gradient, diblock, triblock, and star polymers, as well as more complex architectures including microgels and polymer brushes.

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Living radical polymerization by the RAFT process

Xanthates and related derivatives have proved to be extremely useful for both inter- and intramolecular radical additions. The broad applicability of the intermolecular addition to un-activated olefins opens tremendous opportunities for synthesis, since various functional groups can be brought together under mild conditions and complex structures can be rapidly assembled. The presence of the xanthate in the product is also a powerful asset for further modifications, by both radical and non-radical pathways. Of special importance is the access to highly substituted aromatic and heteroaromatic derivatives and the synthesis of block polymers through a controlled radical polymerisation mediated by various thiocarbonylthio group containing agents (RAFT and MADIX processes).

Powerful carbon - Carbon bond forming reactions based on a novel radical exchange process

Nitroalkenes, or their β-acetoxynitro precursors, react with α-isocyanoacetate esters in the presence of base to give high yields of 5-unsubstituted pyrroles; some important pyrroles are easily synthesised by this method.

A new synthesis of pyrroles from nitroalkenes

The capability of three chain-transfer agents, O-alkyl-S-(1-ethoxycarbonyl)ethyl xanthates (CH3CHCO2C2H5)S(CS)OZ′, to control the free-radical polymerization of styrene and ethyl acrylate by the MADIX process was examined. The reactivity of the xanthates varied according to the following trend: Z′  CH2CH3 < CH2CF3 < CH[P(O)(OEt)2]CF3. This change in reactivity allowed a lowering of the polydispersity index from 2.0 for Z′  CH2CH3 to 1.15 for Z′  CH[P(O)(OEt)2]CF3 in the case of the polymerization of styrene. 

Evolution of Mw/Mn with conversion during the polymerization of ethyl acrylate in the presence of xanthates X1, X2 and X3. Reaction conditions: [EA]0 = 4.6 M, [X]0 = 5.75 × 10−2M, [AIBN]0 = 1.72 × 10−3M ; T = 80 °C ; solvent: toluene.

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Xanthates as Chain‐Transfer Agents in Controlled Radical Polymerization (MADIX): Structural Effect of the O‐Alkyl Group

The degenerative radical addition-transfer of xanthates onto alkenes allows the rapid assembly of richly functionalized structures. Various families of open-chain, cyclic, and polycyclic compounds can thus be readily accessed. Furthermore, the process can be extended to the synthesis or modification of aromatic and heteroaromatic derivatives by exploiting the possibility of using peroxides both as initiators and stoichiometric oxidants. The modification of existing polymers and the controlled synthesis of block polymers by what is now known as the RAFT/MADIX (reversible addition-fragmentation transfer/macro- molecular design by interchange of xanthate) process is described briefly.

/pdf/fun-with-radicals-some-new-perspectives-for-organic-5g5xdxa7n7.pdf

Fun with radicals: Some new perspectives for organic synthesis*

This review summarises recent work on the dithiocarbonyl group transfer reaction. Xanthates, in particular, have proved to be extremely useful for both inter- and intra-molecular additions. The broad applicability of the intermolecular addition to unactivated olefins opens tremendous opportunities for synthesis, since various functional groups can be brought together under mild conditions and complex structures can be rapidly assembled. The presence of the xanthate in the product is also a powerful asset for further modifications, by both radical and non-radical pathways. Of special importance is the access to highly substituted aromatic and heteroaromatic derivatives and the synthesis of block polymers through a controlled radical polymerisation mediated by various dithiocarbonyl agents (RAFT and MADIX processes).

Samir Z. Zard

Papers

Powerful carbon - Carbon bond forming reactions based on a novel radical exchange process

A new synthesis of pyrroles from nitroalkenes

Xanthates as Chain‐Transfer Agents in Controlled Radical Polymerization (MADIX): Structural Effect of the O‐Alkyl Group

Fun with radicals: Some new perspectives for organic synthesis*

The Degenerative Radical Transfer of Xanthates and Related Derivatives : An Unusually Powerful Tool for the Creation of Carbon-Carbon Bonds