The catalytic activity of a series of ruthenium(II) complexes in azide−alkyne cycloadditions has been evaluated. The [Cp*RuCl] complexes, such as Cp*RuCl(PPh3)2, Cp*RuCl(COD), and Cp*RuCl(NBD), were among the most effective catalysts. In the presence of catalytic Cp*RuCl(PPh3)2 or Cp*RuCl(COD), primary and secondary azides react with a broad range of terminal alkynes containing a range of functionalities selectively producing 1,5-disubstituted 1,2,3-triazoles; tertiary azides were significantly less reactive. Both complexes also promote the cycloaddition reactions of organic azides with internal alkynes, providing access to fully-substituted 1,2,3-triazoles. The ruthenium-catalyzed azide−alkyne cycloaddition (RuAAC) appears to proceed via oxidative coupling of the azide and alkyne reactants to give a six-membered ruthenacycle intermediate, in which the first new carbon−nitrogen bond is formed between the more electronegative carbon of the alkyne and the terminal, electrophilic nitrogen of the azide. This ...

https://pubs.acs.org/doi/pdf/10.1021/ja805956e

Ruthenium-catalyzed azide-alkyne cycloaddition: scope and mechanism.

Inspired by the need for green and sustainable chemistry, modern synthetic chemists have been seeking general and practical ways to construct complex molecules while maximizing atom economy and minimizing synthetic steps. Over the past few decades, considerable progress has been made to fulfill these goals by taking advantage of transition metal catalysis and chemical reagents with diverse and tunable reactivities. In recent years, haloalkynes have emerged as powerful and versatile building blocks in a variety of synthetic transformations, which can be generally conceived as a dual functionalized molecules, and different reaction intermediates, such as σ-acetylene-metal, π-acetylene-metal, and halovinylidene-metal complexes, can be achieved and undergo further transformations. Additionally, the halogen moieties can be retained during the reaction processes, which makes the subsequent structural modifications and tandem carbon-carbon or carbon-heteroatom bond formations possible. As a consequence, impressive effort has been devoted to this attractive area, and some elegant work has been done over the past several years. This Account highlights some of the recent progress on the development of efficient and practical synthetic methods involving haloalkyne reagents in our laboratory and in others around the world, which showcase the synthetic power of haloalkynes for rapid assembly of complex molecular structures. The focus is primarily on reaction development with haloalkynes, such as cross-coupling reactions, nucleophilic additions, and cycloaddition reactions. The designed approaches, as well as serendipitous observations, will be discussed with special emphasis placed on the mechanistic aspects and the synthetic utilities of the obtained products. These transformations can lead directly to heteroatom-containing products and introduce structural complexity rapidly, thus providing new strategies and quick access to a wide range of functionalized products including many synthetically useful conjugated cyclic and acyclic structures that have potential applications in natural product synthesis, materials science, and drug discovery. Importantly, most of these protocols allow multiple bond-forming events to occur in a single operation, thereby offering opportunities to advance chemical synthesis and address the increasing demands for economical and sustainable synthetic methods. We anticipate that a deep understanding of the properties of haloalkyne reagents and the underlying working mechanism can lead to the development of novel catalytic systems to answer the unsolved challenges in haloalkyne chemistry, which, in turn, may be also instructive for other research areas. We hope this Account will help to provide a guideline for researchers who are interested in this fertile area.

http://pubs.acs.org/doi/pdf/10.1021/ar5001499

Haloalkynes: a powerful and versatile building block in organic synthesis.

Ring strain energies: substituted rings, norbornanes, norbornenes and norbornadienes

Silver-Catalyzed Csp−H and Csp−Si Bond Transformations and Related Processes

2.3.1. IMDA Reactions of Acetylenic Sulfones 4512 2.3.2. IMDA Reactions of Allenic Sulfones 4513 2.3.3. IMDA Reactions of Dienyl Sulfones 4513 3. 1,3-Dipolar Cycloadditions 4514 3.1. With Azides 4514 3.2. With Diazo Compounds 4515 3.3. With Nitrones 4516 3.4. With Nitrile Oxides 4519 3.5. With Mesoionic Compounds 4519 3.6. With Other 1,3-Dipoles 4519 4. [2 + 2] Cycloadditions 4520 4.1. With Alkenes and Dienes 4520 4.2. Intramolecular [2 + 2] Cycloadditions 4522 4.3. With Imines, Enamines, Ynamines, And Enol Ethers 4522 4.4. Other [2 + 2] Cycloadditions 4523 5. Miscellaneous Cycloadditions 4524 6. Ene Reactions 4524 7. Cyclizations of Bis(allenic) Sulfones and Their Congeners 4526

Cycloadditions and cyclizations of acetylenic, allenic, and conjugated dienyl sulfones.

Ruthenium-catalyzed [2 + 2] cycloadditions of 2-substituted norbornenes.

Ruthenium-catalyzed [2 + 2] cycloadditions between bicyclic alkenes and alkynyl halides.

The ruthenium-catalyzed [2 + 2] cycloadditions of 7-substituted norbornadienes with an alkyne have been investigated. The cycloadditions were found to be highly regio- and stereoselective, giving only the anti-exo cycloadducts as the single regio- and stereoisomers in good yields. The results on the relative rate of different 7-substituted norbornadienes in the Ru-catalyzed [2 + 2] cycloadditions with an alkyne indicated that the reactivity of the alkene component decreases dramatically as the alkene becomes more electron deficient. Ab initio computational studies on the ruthenium-catalyzed [2 + 2] cycloadditions provided important information about the geometries and the arrangements of the four different groups on the Ru in the initial Ru-alkene-alkyne pi-complex, 14, and in the metallacyclopentene 15. Based on our computational studies, we also found that the first carbon-carbon bond formed in the [2 + 2] cycloaddition is between the C(5) of the alkene and the C(b) (the acetylenic carbon attached to the ester group) of the alkyne 8. Our computational studies on the potential energy profiles of the cycloadditions showed that the activation energy relative to the reactants for the oxidative addition step is in the range of 9.3-9.8 kcal/mol. The activation energy relative to the metallacyclopentene for the reductive elimination step is much higher than for the oxidative addition step (in the range of 25.9-27.6 kcal/mol).

Ruthenium-catalyzed [2 + 2] cycloadditions between 7-substituted norbornadienes and alkynes: an experimental and theoretical study.

Study on the reactivity of the alkene component in ruthenium-catalyzed [2 + 2] cycloadditions between an alkene and an alkyne. Part 1.

The ruthenium-catalyzed [2 + 2] cycloadditions of norbornadiene with a variety of alkynes have been investigated. Electronic effect of the alkyne component has shown to play an important role on the rate of the cycloaddition, and the reactivity of the alkyne component increases dramatically as the alkyne becomes more electron deficient. Increase in the steric bulk of the alkyne component decreases the reactivity of the alkyne component. It was also found that chelation effect of propargylic alcohols greatly enhanced the reactivity of the alkyne component in the ruthenium-catalyzed [2 + 2] cycloadditions.

Robert W. Jordan

Papers

Ruthenium-catalyzed [2 + 2] cycloadditions of 2-substituted norbornenes.

Ruthenium-catalyzed [2 + 2] cycloadditions between bicyclic alkenes and alkynyl halides.

Ruthenium-catalyzed [2 + 2] cycloadditions between 7-substituted norbornadienes and alkynes: an experimental and theoretical study.

Study on the reactivity of the alkene component in ruthenium-catalyzed [2 + 2] cycloadditions between an alkene and an alkyne. Part 1.

Study on the reactivity of the alkyne component in ruthenium-catalyzed [2 + 2] cycloadditions between an alkene and an alkyne.