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Cycloaddition Reactions: Overview

Cycloaddition Reactions: Overview

Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new σ bonds formed at the expense of π bonds. The [4 + 2] cycloaddition, known as the Diels–Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.

Cycloaddition Reactions: MO Requirements for Thermal Activation

Cycloaddition Reactions: MO Requirements for Thermal Activation

Thermal cycloadditions are reactions where the source of activation energy needed to initiate the reaction is provided in the form of heat. A typical example of a thermally-allowed cycloaddition is the Diels–Alder reaction, which is a [4 + 2] cycloaddition. In contrast, a [2 + 2] cycloaddition is thermally forbidden.

Cycloaddition Reactions: MO Requirements for Photochemical Activation

Cycloaddition Reactions: MO Requirements for Photochemical Activation

Some cycloaddition reactions are activated by heat, while others are initiated by light. For example, a [2 + 2] cycloaddition between two ethylene molecules occurs only in the presence of light. It is photochemically allowed but thermally forbidden.

Alkenes via Reductive Coupling of Aldehydes or Ketones: McMurry Reaction

Alkenes via Reductive Coupling of Aldehydes or Ketones: McMurry Reaction

The radical dimerization of ketones or aldehydes gives vicinal diols through a pinacol coupling reaction. However, the behavior of titanium metals used for the reaction as a source of electrons is unusual. When the reaction is carried out in the presence of titanium, diols can be isolated at low temperatures. Else titanium further reacts with diols, forming alkenes through the McMurry reaction.

[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction

[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction

The Diels–Alder reaction is an example of a thermal pericyclic reaction between a conjugated diene and an alkene or alkyne, commonly referred to as a dienophile. The reaction involves a concerted movement of six π electrons, four from the diene and two from the dienophile, forming an unsaturated six-membered ring. As a result, these reactions are classified as [4+2] cycloadditions.

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation

Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).

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Related Experiment Video

Updated: May 21, 2025

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

Published on: February 7, 2019

The Ugi Multicomponent Reaction for the One-Step Construction of Macrocycles.

Yi-Ming Chen¹, Xue Li¹, Zhi-Gang Xu¹

¹College of Pharmacy, Chongqing University of Arts and Sciences, NO.319 Honghe Ave. Yongchuan, Chongqing, 402160, China.

Chemical Record (New York, N.Y.)

|March 21, 2025

Summary

The Ugi four-component reaction (4-CR) enables efficient synthesis of diverse and complex macrocycles. This review highlights contemporary examples and cyclization tactics for creating macrocyclic and cage molecules.

Keywords:

Ugi reaction cage peptide macrocycles macrocyclic peptides multicomponent reaction (MCR)

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Area of Science:

Organic Chemistry
Synthetic Chemistry

Background:

Macrocycle exploration advanced with synthetic chemistry in the 20th century.
The Ugi reaction is a powerful four-component reaction (4-CR) known for its functional group tolerance.

Purpose of the Study:

To review contemporary examples of macrocycles synthesized using the Ugi reaction.
To showcase diverse cyclization tactics for macrocycle and cage molecule construction.

Main Methods:

Utilizing the Ugi reaction for macrocyclic framework construction.
Employing various bifunctional reagents for cyclization.
Visually representing reactant contributions using distinct colors for clarity.

Main Results:

Successful synthesis of diverse and complex macrocycles in a single step.
Generation of numerous macrocyclic and cage molecules through varied cyclization strategies.
Enhanced understanding of macrocycle construction via transparent visualization.

Conclusions:

The Ugi reaction is a versatile and efficient method for synthesizing complex macrocycles.
Bifunctional reagents and varied tactics enable a wide array of macrocyclic structures.
Visual aids significantly improve comprehension of complex synthetic pathways.