Transition Metal Catalyzed Heterocycle Synthesis

Review Paper

Michael Ko

4/14/14



























[R] Heterocycles are important for their biological activity for drugs and natural product
synthesis. Studies have been focused on synthesizing these heterocyclic compounds by
developing new reaction mechanisms and pathways. There are a few ways to produce these
heterocycles and the method of interest for many are the transition metal catalyzed reactions. The
reason for this is because these metals can aid in direct formation of very diverse heterocycles
from common starting materials under simple conditions. There are two main processes for
heterocyclic synthesis which are carbon-carbon bond and carbon-R bond formation into
heterocycles. The two main processes for heterocyclic synthesis, can be broken up into other
subcategories which are the five classes. These five classes are ring closing metathesis,
cycloisomerization of dienes, cyclization of alkenes, allenes, and alkynes, Heck, Suzuki, and
Stille reactions, and allylic cyclization.
[1] A search for the development of a synthetic route to biologically active heterocycles
have taken precedence. Isoquinoline are heterocycles and their derivatives are found throughout
many natural products. Their precursors, isoquinoline-N-oxides, are also very important as they
are used in pharaceuticals, chiral scaffolds in Lewis basic organocatalysis, and charge-transfer
and metal sensors. The use of transition metals helped develop a new pathway for the synthesis
of these isoquinoline-N-oxides because the previously used pathway suffered from poor atom
economy and were not environmentally friendly.
[2] Isoxazoles are of great interests for their uses in medicinal chemistry and materials
science. The previously used methods that use cycloaddition reaction between alkynes and nitrle
oxides to generate these isoxazoles, but required harsh conditions and did not have chemo or
reigoselectivities. [3] Many natural products, biologically active compounds, and functional
materials are highly substituted isoxazoles. [4] These natural products have stereospecific
polyhydroxylated aminocyclopentane motifs. While there are studies on the synthesis of these
polyhxydroxylated aminocyclopentanes, methods for stereo and enantiocontrolled reactions are
in great demand.
Alkyne derived heterocycle[1]
The formation of the isoquinoline-N-oxides from o-alkynylbenzaldoximes were
conducted through electrophilic metal-catalyzed cyclization. Various electrophilic metal
catalysts were screened for overall conversion and product yield. The diverse conditions and
catalysts tested confirmed that Au(IMes)OTf and AgOTf turned out to be most efficient in
producing the product in 30 minutes at room temperature. Au(IMes)OTf had 96% yield in 30
minutes at room temperature and AgOTf had 85% yield in 30minutes at room temperature. The
other metal catalysts had equal yields, but the conditions required heat or longer reaction times.
Further studies were conducted on Au(IMes)OTf and AgOTf along with varying the o-
alkynylbenzaldoximes as the alkynl groups were changed with different substituents. Depending
on the substituent on the alkyne group, the conditions and yields changed. Table 1 shows..
Isoxazoles [2],[3],[5]
The synthesis of disubstituted isoxzoles began with the metal catalyst screen which
yielded AgBF
4
with THF as the solvent as the most efficient combination for the highest yield
(80%). The results lead to a proposed mechanism which is shown in scheme 2. The optimized
metal catalyst was then treated to various alkynyl oxime ethers. The reaction with the phenyl
alkyne gave good yield and also showed a trend. The alkyl group on the triple bond gave good
yields, but the groups that contained an oxygen gave an even higher yield. The chelation of the
oxygen provides to increase the activity of the catalyst. The results also showed that the
conditions used were useful for electron poor, electron rich, and hydrogen groups.