1,3-dipolar Cycloaddition also known as Huisgen reaction

The 1,3-dipolar cycloaddition which is also known as Huisgen cycloaddition or Huisgen reaction, it is a member of the larger class of cycloadditions. It is name back to the German Chemist Rolf Huisgen (June 13, 1920) science his big contributions in chemistry specially in German and Austria. It can be summarized as the reaction between 1,3-dipolar species with dipolarophile to form a five-membered ring. It is a powerful tool for the formation of heterocyclic rings, since the great diversity in each of 1,3-dipole and dipolarophile species within the reaction as we shall see shortly.

Introduction

As mentioned before, 1,3-dipolar cycloaddition is the single most important method for the construction of five-membered heterocyclic rings in organic chemistry. It is a concerted reaction, concerted reactions is a term used for reactions in which the bond making and bond breaking occurs simultaneously, one of it is benefits is stereospecific creation of new chiral centers in organic molecules. When 1,2-disubstituted alkene is involved in concerted 1,3-dipolar cycloaddition reaction, two new chiral centers are formed on the alkene in a stereospecific manner because of the syn attack on the double bond. This is shown for reactions of the two types of 1,3-dipoles (allyl anion type and propargyl/allenyl anion type) Scheme 1, also see table 1. Thus the relative stereochemistry at C-4 and C-5 is always controlled by the geometric relationship of the substituents on the alkenes for the concerted 1,3-dipolar cycloadditions. Depending on the structure of the dipole, up to four contiguous chiral centers can be formed in 1,3 dipolar cycloaddition reaction in a single step and the challenge nowadays for the 1,3-dipolar cycloaddition reactions is to control the absolute stereoselectivity of the reaction by the application of chiral metal catalysts.

The development of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions that has been achieved up to 2000 will be discussed in my blogger at future posts. After this introduction to the basics of metal-catalyzed 1,3-dipolar cycloaddition posts will be divided according to the metal catalysts applied for the reactions.

From Cycloaddition Reactions in Organic Synthesis, by S. Kobayashi and K. A. Jorgensen, Copyright © 2001 Wiley-VCH Verlag GmbH
Asymmetric synthesis is a stimulating academic challenge, but since it has become clear that most chiral drugs can be administered safely only in the enantiomerically pure form, the industrial need for asymmetric methods has made research in asymmetric synthesis absolutely necessary. This has driven a renaissance in the discipline of organic chemistry, because all of the old-established reactions need to be reinvestigated for their application in asymmetric synthesis. This has also applied to the 1,3-dipolar cycloaddition reaction and during the past 15 years there has been enormous interest in asymmetric 1,3-dipolar cycloaddition reactions. Most of the research performed has, however, been on diastereoselective reactions that imply optically active substrates. Unlike the broad application of asymmetric catalysis in carbo- and hetero-Diels-Alder reactions, which has evolved since the mid-nineteen-eighties, the use of enantioselective metal catalysts in asymmetric 1,3-dipolar cycloaddition reactions between alkenes and nitrones remained almost unexplored until 1993.

Basic Aspects for 1,3-dipolar Cycloaddition Reactions

1.     1,3-dipoles

The first reactant for Husigen reaction is 1,3-dipoles, they are three-atoms pi-electron systems containing 4 electrons delocalized over three atoms. They consists elements from main groups IV, V and VI. The parent 1,3-dipoles consist of elements from the second row and the central atom is limited to N or O. Some of the examples of 1,3-dipoles are azides, ozone, nitro compounds, diazo compounds, some oxides (like azoxide compounds, carbonyl oxides, nitrile oxides, nitrous oxide, nitrones), some imines (like azomethine imine, nitrilimines, carbonyl imines), some ylides (like azomethine ylide, nitrile ylide, carbonyl ylide). Table 1 shows the important 1,3-dipoles classified also by their type.

However, 1,3-dipolar cycloaddition reactions have only been explored for five types of dipole shown in scheme 2. Most studies in this fields have been on nitrones. One of the reasons for this is probably because nitrones are readily available compounds that can be obtained from aldehydes, amines, imines and oximes. Moreover, most acyclic nitrones are stable compounds that can be stored under ambient conditions. Cyclic nitrones tend to be less stable, but there are also examples on the applications on

these. Azomethine ylides are unstable and have to be prepared in situ. Several methods have been developed for the synthesis of the azomethine ylides, for example proton abstraction from imine derivatives of alpha-amino acids, thermolysis or photolysis of aziridines and dehydrohalogenation of imonium salts. As for nitrones, azomethine ylides have found broad applications in synthesis. Carbonyl ylides are a less common type of 1,3-dipole, which have found only limited application in synthesis, although access to carbonyl ylides via rhodium carbenes has accelerated the development in this area, and over the past three years the first examples of metal-catalyzed asymmetric reactions have appeared. Nitrile oxides on the other hand are, in close competition with nitrones, the most commonly applied 1,3-dipole for the synthesis of five-membered heterocyclic rings. They are easy available from aldoximes or primary nitro compounds, but most nitrile oxides must be prepared in situ, because of high reactivity and rapid dimerization. The high reactivity of nitrile oxides is probably one reason for the very few examples of catalytic control of this reaction.

2.    Dipolarophile

It is an unsaturated system -the second reactant- that undergoes 1,3-dipolar cycloaddition reaction with 1,3-dipoles. Alkenes, alkynes and their diverse derivatives may react as dipolarophiles.





My next post will be about Understanding the Mechanism of 1,3-dipolar Cycloaddition Reaction. Keep visiting my blogger...