Cycloaddition Reactions in Organic Synthesis

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For example, consider the cycloaddition of diazomethane to three dipolarophiles: methyl acrylate , styrene or methyl cinnamate. Hence, cycloaddition gives the substitution at the C-3 position regioselectively. For methyl cinnamate, the two substituents Ph v. COOMe compete at withdrawing electrons from the alkene. Thus, cycloaddition yields the carboxyl group on C-3 and the phenyl group on C-4 regioselectively. Steric effects can either cooperate or compete with the aforementioned electronic effects.

Sometimes steric effects completely outweighs the electronic preference, giving the opposite regioisomer exclusively. For example, diazomethane generally adds to methyl acrylate to give 3-carboxyl pyrazoline. However, by putting more steric demands into the system, we start to observe the isomeric 4-carboxyl pyrazolines.

The ratio of these two regioisomers depends on the steric demands. Additionally, some cycloadducts can be cleaved to reveal the linear skeleton, providing another route toward the synthesis of aliphatic compounds. These reactions are tremendously useful also because they are stereospecific, diastereoselective and regioselective. Several examples are provided below. Cycloaddition between a nitrile oxide and an alkene yields the cyclic isoxazoline product, whereas the reaction with an alkyne yields the isoxazole.

Nitrile oxide-alkyne cycloaddition followed by hydrogenation was utilized in the synthesis of Miyakolide as illustrated in the figure below. Ylides are regarded as positively charged heteroatoms connected to negatively charged carbon atoms, which include ylides of sulfonium , thiocarbonyl , oxonium , nitrogen , and carbonyl. One of the earliest examples of carbonyl ylide synthesis involves photocatalysis.

Another early example of carbonyl ylide synthesis by photocatalysis was reported by Olah et al.

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Carbonyl ylides can be synthesized by acid catalysis of hydroxypyrones in the absence of a metal catalyst. A cycloaddition reaction with a dipolarophile lastly forms the oxacycle. This approach is less widely employed due to its limited utility and requirement for pyrone skeletons. Dihalocarbenes have also been employed to generate carbonyl ylides, exploiting the electron withdrawing nature of dihalocarbenes.

The carbonyl ylide can be generated upon reaction of the dihalocarbenes with ketones or aldehydes. Subsequent cycloaddition reaction with an alkene or alkyne dipolarophile can afford oxygen-containing five-membered rings. Popular catalysts that give modest yields towards synthesizing oxacycles include Rh 2 OAc 4 and Cu acac 2. The universality and extensive use of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl molecules, for synthesizing oxygen-containing five-membered rings, has spurred significant interest into its mechanism. Several groups have investigated the mechanism to expand the scope of synthetic molecules with respect to regio- and stereo-selectivity.

However, due to the high turn over frequencies of these reactions, the intermediates and mechanism remains elusive. The generally accepted mechanism, developed by characterization of stable ruthenium-carbenoid complexes [46] and rhodium metallocarbenes, [47] involves an initial formation of a metal-carbenoid complex from the diazo compound. Elimination of nitrogen gas then affords a metallocarbene. An intramolecular nucleophilic attack by the carbonyl oxygen regenerates the metal catalyst and forms the carbonyl ylide. The carbonyl ylide can then react with an alkene or alkyne, such as dimethyl acetylenedicarboxylate DMAD to generate the oxacycle.

However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles. Therefore, a persistent metallocarbene can influence the stereoselectivity and regioselectivity of the 1,3-dipolar cycloaddition reaction based on the stereochemistry and size of the metal ligands.

The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole and alkynyl or alkenyl dipolarophiles has been extensively investigated with respect to regioselectivity and stereoselectivity.

1,3-Dipolar cycloaddition reactions

As symmetric dipolarophiles have one orientation for cycloaddition, only one regioisomer , but multiple stereoisomers can be obtained. These regioisomers and stereoisomers may be predicted based on frontier molecular orbital FMO theory , steric interactions , and stereoelectronic interactions. Regioselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkynyl or alkenyl dipolarophiles is essential for generating molecules with defined regiochemistry.

Overlap of the orbitals with the largest coefficients can ultimately rationalize and predict results.

Cycloaddition Reactions in Organic Synthesis | Wiley Online Books

The archetypal regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by carbonyl ylide dipoles has been examined by Padwa and coworkers. The reaction with methyl propiolate affords two regioisomers with the major resulting from the HOMO dipole -LUMO dipolarophile interaction, which has the largest coefficients on the carbon proximal to the carbonyl group of the carbonyl ylide and on the methyl propiolate terminal alkyne carbon.

The reaction with methyl propargyl ether affords one regioisomer resulting from the HOMO dipolarophile -LUMO dipole interaction, which has largest coefficients on the carbon distal to the carbonyl group of the carbonyl ylide and on the methyl propargyl ether terminal alkyne carbon. Regioselectivities of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl compounds may also be influenced by the metal through formation of stable metallocarbenes. In this situation, the metal ligands will influence the regioselectivity and stereoselectivity of the 1,3-dipolar cycloaddition reaction.


The stereoselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles has also been closely examined. For alkynyl dipolarophiles, stereoselectivity is not an issue as relatively planar sp 2 carbons are formed, while regioselectivity must be considered see image of the Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles.

However, for alkenyl dipolarophiles, both regioselectivity and stereoselectivity must be considered as sp 3 carbons are generated in the product species. The endo product is characterized with the dipolarophile substituents being trans to the ether bridge of the oxacycle. Both products can be generated through pericyclic transitions states involving concerted synchronous or concerted asynchronous processes. One early example conferred stereoselectivity in terms of endo and exo products with metal catalysts and Lewis acids.

Addition and Cycloaddition Reactions of Tetracyanoethylene (TCNE) in Organic Chemistry

After many investigations, two primary approaches for influencing the stereoselectivity of carbonyl ylide cycloadditions have been developed that exploit the chirality of metal catalysts and Lewis acids. The first approach employs chiral metal catalysts to modulate the endo and exo stereoselectivity. However, the exact mechanisms are not yet fully understood. The second approach employs a chiral Lewis acid catalyst to induce facial stereoselectivity after the generation of the carbonyl ylide using an achiral metal catalyst.

This strategy has been applied to the synthesis of spirotryprostatin A.

Ozonolysis is a very important organic reaction. Alkenes and alkynes can be cleaved by ozonolysis to give aldehyde , ketone or carboxylic acid products. The 1,3-dipolar cycloaddition between organic azides and terminal alkynes i. The Huisgen reaction generally does not proceed readily under mild conditions. Meldal et al. They also do not react with other functional groups found in nature, so they do not perturb biological systems.

The reaction is so versatile that it is termed the "Click" chemistry. Although copper I is toxic , many protective ligands have been developed to both reduce cytotoxicity and improve rate of CuAAC, allowing it to be used in in vivo studies. For example, Bertozzi et al. The now fluorescently labeled cell membrane can be imaged under the microscope.

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To avoid toxicity of copper I , Bertozzi et al. The angle distortion of the cyclooctyne helps to speed up the reaction by both reducing the activation strain and enhancing the interactions, thereby enabling it to be used in physiological conditions without the need for the catalyst. For instance, Ting et al. The azide-tagged protein is then labeled with cyclooctyne-fluorophore conjugate to yield a fluorescently labeled protein. From Wikipedia, the free encyclopedia.

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Supplementary files

January Learn how and when to remove this template message. See also: Azomethine ylide. Angewandte Chemie. Angewandte Chemie International Edition. Journal of Organic Chemistry. Concerted nature of 1,3-dipolar cycloadditions and the question of diradical intermediates". Tetrahedron Letters. Past and Future". Bibcode : Natur.

A simplified procedure".

Journal of the American Chemical Society. Basicity, acidity and hydrogen bonding. Diazonium and Diazo Groups. Chemische Berichte.