Date of Award

December 2016

Degree Type


Degree Name

Doctor of Philosophy (PhD)




John D. Chisholm


Anilines, Nitrogen alkylation, SHIP, Steroids, Sulfonamides, Trichloroacetimidates

Subject Categories

Physical Sciences and Mathematics


Trichloroacetimidates have frequently been used in the formation of glycosidic bonds and other ethers, which is especially useful for the introduction of ether protecting groups. Trichloroacetimidates have also been used as electrophiles in Friedel-Crafts alkylation reactions. The formation of C-N bonds has also been accomplished utilizing trichloroacetimidates. Most frequently C-N bond formation with trichloroacetimidates is associated with sigmatropic rearrangement of an allylic trichloroacetimidate to an allylic trichloroacetamide. This reaction can proceed thermally or through the use of Lewis acid or transition metal catalysts. Recently, the direct substitution of trichloroacetimidates using nitrogen nucleophiles has been accomplished utilizing transition metal catalysts, which indicates that trichloroacetimidates may be suitable alkylation partners for certain nitrogen nucleophiles.

Trichloroacetimidates are now shown to be effective alkylating reagents for the monosubstitution of anilines using the Brønsted acid catalyst (±)-camphorsulfonic acid. The reaction is especially efficient for electron deficient anilines while electron rich anilines provided lower yields due to competing Friedel-Crafts reactions. A one-pot procedure for generating the trichloroacetimidate in situ followed by displacement with the aniline is also described, and the yields for this one-step process are similar to the two-step protocol. The displacement of a chiral

imidate by 4-chloroaniline led to significant racemization which indicates that the reaction may proceed through a carbocation intermediate.

The alkylation of sulfonamides with trichloroacetimidates under thermal conditions is also described. Primary and secondary trichloroacetimidates are found to be suitable electrophiles under these conditions, while tertiary trichloroacetimidates provide reduced yields. Aryl and alkyl sulfonamides with varying electronic properties were well tolerated under the reaction conditions. A bioactive analog of the analgesic ketoprofen is synthesized using the described methodology. Complete racemization of a chiral trichloroacetimidate is observed under these reaction conditions which is evidence that the reaction proceeds through an SN1 type mechanism.

Pyrroloindoline trichloroacetimidates may react with amine nucleophiles in the presence of catalytic BF3ˑOEt2 to generate pyrroloindoline systems decorated with amines at the C3a position. The natural product kapakahine C is a complex heterocyclic compound containing a substituted pyrroloindoline-pyridoindoline core that may be accessed using this method. A route to the synthesis of the substituted pyridoindoline core of kapakahine C was investigated. Optimization of key reactions in this sequence, including a peptide coupling reaction and oxidative cyclization, was performed. Investigation into completing the synthesis of kapakahine C is ongoing.

The inhibition of the SH2-containing inositol 5’-phosphatase (SHIP) can modulate the dephosphorylation of phosphoinositols. These molecules act as second messengers in a signal transduction cascade, with the placement of phosphorylation on the inositol acting to convey information in the transmission of signals from the cell membrane to the cell nucleus. The

concentration of these phosphates has an effect on cellular function such as cell proliferation, survival, and differentiation.

The synthesis of six aminosteroid SHIP inhibitors is described. Optimization of the key steps in the synthetic sequence was conducted. The synthesis of two quinoline based SHIP inhibitors, which were identified in a high-throughput screening conducted by the National Cancer Institute (NCI), was also completed. Studies were conducted to synthesize these molecules on multi-gram scale. The synthesized compounds were tested for inhibitory activity in a Malachite Green assay.


Open Access