Date of Award

Spring 5-16-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Xiu-Ren Bu, Ph.D.

Second Advisor

Cass Parker, Ph.D.

Third Advisor

James Reed, Ph.D.

Abstract

The synthesis of tetrahydroimidazo[1,5-a]pyridine (rIMP) through the transfer hydrogenation of imidazo[1,5-a]pyridine (IMP) was successfully developed. The simple two-step procedure is the most viable and efficient method that results in a unique conjugated system with pyridine at the 1-position and functionalized phenyl group at the 3-position.

In the synthesis of imidazo[1,5-a]pyridine, the reaction between di-2-pyridil ketone, substituted benzaldehyde and ammonium acetate in acetic acid under N2 was highly successful, resulting in yields ranging from 35-95%. Highest yields were obtained for compounds that had electron withdrawing group on them.

The transfer hydrogenation of IMP using recyclable and inexpensive Pd/C catalyst, hydrazine hydrate in ethanol under N2 was shown to be viable and efficient in the synthesis of rIMP. The reaction conditions for the nitro based IMP were optimized to give singly- or doubly- reduced products, amine-IMP or amine-rIMP, respectively. The optimization of reaction conditions in the synthesis of amine-IMP led to the discovery of 1: 3 mol%: 3 eq ratio of IMP, Pd/C and hydrazine hydrate to obtain high yields. An optimal temperature of 90 oC and a reaction duration of 1.5 hr were established. The optimization of reaction condition for the synthesis of amine-rIMP revealed that of 1: 15 mol%: 15 eq ratio of IMP, Pd/C and hydrazine hydrate lead to high yield. The presence of hydroxy, alkyl and methoxy group was unaffected. The optimized condition for synthesis of amine-rIMP was used on other functionalized IMP. Hydrogenolysis was observed for halogenated (bromine- and chlorine-) IMP to give non-functionalized rIMP. The fluorine atom was not affected by the condition and resulted in fluorine-rIMP. The nitrile group was reduced completely to methyl. The ethoxy and acetaimide groups were unaffected. The thiomethyl group was poisonous to the catalyst.

Anti-proliferative assay on human prostate cancer cell lines, PC3 and DU145 revealed that rIMP is more potent at inhibiting growth of PC3 cells and IMP more potent at inhibiting growth of DU145 cells. Of the various treatments amine-rIMP were more potent at inhibiting PC3 cells than Me-rIMP, amine-IMP and OH-IMP. Amine at the ortho-position was most potent compared to meta- and para-position. Cell growth of PC3 cells was inhibited in a dose-dependent manner.