Chemistry Reference
In-Depth Information
11
Cycloaddition and
Cycloisomerization Reactions
Cycloaddition reactions are of enormous importance in organic synthesis, but they are necessarily limited
by the Woodward-Hoffman rules. The majority of cycloaddition reactions used in organic synthesis form
six-membered ring carbocycles through the Diels-Alder reaction. Some four-membered rings can be formed,
and a range of five-membered ring heterocycles can be formed by 1,3-dipolar cycloadditions. The use of
transition metals can not only facilitate the formation of these “convenient” ring sizes, but also permit the
formation of other ring sizes.
1
In addition, conventional cycloadditions almost always involve the adding
together of two components, such as a diene and a dienophile, while transition metals can allow three separate
components to be brought together. The participation of the transition metal means that all of these reactions
become formal cycloadditions, and have multi-step mechanisms.
11.1 Formal Six-Electron, Six-Atom Cycloadditions
11.1.1 The [4
+
2] Cycloaddition
The Diels-Alder reaction is a cornerstone of organic synthesis, but it has its limitations. Principal among
these is that diene/alkene pairs without suitable electronic activation react very slowly, if at all. Usually,
an electron-poor alkene is employed. Enormous rate accelerations can be achieved with Lewis-acid catal-
ysis. This form of catalysis requires that the substrate possesses a group conjugated to the alkene that is
capable of coordination to the Lewis acid. An alternative means of catalysis is to use a transition metal,
which works by coordinating directly to the
-systems, bringing them together and forming the bonds one
by one.
An effective catalyst for this reaction with diene-ynes and diene-allenes
2
is Ni(COD)
2
with added phos-
phite ligands. This can result in a reduction of the temperature required for the reaction from 160
◦
Cto
room temperature (Schemes 11.1 and 11.2).
3
Other catalysts, such as rhodium complexes,
4
have also been
used (Schemes 11.2 and 11.3). The use of chiral ligands allows asymmetric cycloadditions (Schemes 11.4
and 11.5).
5,6
