Synthesis kleferein (3,4-CFP)
3,4-CFP cannot be made by the classic route of phenylpiperazine synthesis :
This is due to the fact that Fluorine and Chlorine are highly electronegative substituents that inactivate the amino group. The amino group loses its nucleophilic features and becomes inactive. The classic route of synthesis from aniline derivatives is impossible. This synthetic difficulty is the reason why such a simple compound is uncovered so late to the world. Researchers led by Professor Martin had to develop an alternative synthetic route:
In the first step, the nucleophilic substitution of the Fluorine atom takes place, resulting in the formation of 3-chloro-4-nitro-piperein. This is reduced to the corresponding aniline, which is then converted into the diazonium salt and 3,4-CFP.
Everything that is good is made the hard way.
- Robert A. Lyon, Milt Titeler, J. D. McKenney, Philip S. Magee, and Richard A. Glennon J. Med. Chem., 1986, 29 (5), pp 630–634