[Alpha]-Amino ketones can serve as important intermediates for the synthesis of biologically active molecules, and making these precursors in a practical manner has long been a challenge for organic chemists. The oxygen-carbon-carbon-nitrogen (O-C-C-N) sequence is common in natural and synthetic compounds of biological interest, due in part to their relatedness to peptides. Because of the many known carbonyl transformations, [alpha]-amino ketones have the potential to form various amine derivatives. Herein we present our research endeavors which led to several novel methods of forming this type of functionality. These endeavors culminated with the development of a two-step hydrazidation/N-N bond cleavage technique for forming [alpha]-amino ketals--which can be readily hydrolyzed to [alpha]-amino ketones. / text

1,2-Diazetidine is a four-membered ring heterocyclic compound which has two adjacent nitrogen atoms. However, the syntheses of C-unsubstituted 1,2-diazetidines are rarely reported in the literature. C-unsubstituted 1,2-diazetidines were synthesized through an operationally simple intermolecular vicinal disubstitution reaction between 1,2-dibromoethane and hydrazine with N-arylsulfonyl as the protecting group. Several different types of C-unsubstituted 1,2-diazetidines derivatives were synthesized with either two of the same or two different N-arylsulfonyl groups. The electronic and steric properties were analyzed using Raman spectroscopy and computational calculations. Then, several synthetic applications were demonstrated with 1,2-ditosyl-1,2-diazetidine (DTD). As a synthetic application, a nucleophilic ring-opening reaction of the diazetidine was identified through various thiol selective cleavage of the N‒N bond, resulting in the stereoselective formation of a new class of N-sulfenylimine. Furthermore, DTD underwent FeBr2-catalyzed retro [2+2] ring-opening and sustained release of formaldimine (FI) in situ in a reaction medium which is the simplest imine used amidomethylative reagent. Therefore, the effective available concentration can be controlled at low levels in the reaction medium. Moreover, the sustained release of FI was able to interrupt the amidomethylative process with α- methylstyrene and FeBr2 as the catalyst and resulted in 4-phenyl-1,2,3,6-tetrahydropyrimidine (PTPH) as a product. The PTPH is a neurotoxic compound used to induce Parkinson’s disease in animal models. In addition, sustained release of FI allowed to switch the selectivity from alkene, imine, and imine arrangement into alkene, imine, and alkene arrangement in [2+2+2] cycloaddition reaction and led to form piperidines as a product which is the most observed heterocycle in marketed drug molecules. Chromane derivatives are observed in pharmaceuticals and natural products. Chirally pure chromane derivatives were synthesized through ruthenium-catalyzed chiral transient directing-mediated enantioselective C–H activation. Interestingly, a phosphate was involved in the deprotonation step, the rate-determining step with a 5.3 KIE value.

Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for use against the malaria vector Anopheles gambiae. In the process of producing a library of compounds for assay against An. gambiae, it became clear that employing regioselective acylation techniques (in molecules that feature two nucleophilic, acyclic nitrogen atoms α to one another) would be imperative. Synthesis of the library derivatives proceeded rapidly and after topical assay, we found three compounds that were more toxic than the RH-series leads. One of the three displayed an LD50 value of half that of RH-1266, though patch clamp assay concluded that toxicity was not necessarily linked to inhibition of mosquito K+ channel Kv2.1. The acylation of monoarylhydrazines appears simple, but its regioselectivity is poorly understood when assumed as a function of basicity correlating to nucleophilic strength. We determined the ratio of the rate constants for distal to proximal N-acylation using 19F NMR spectroscopic analysis of reactions of 4-fluorophenylhydrazine with limiting (0.2 equiv) acylating agent in the presence of various bases. Acid anhydrides gave consistent preference for distal acylation. The selectivity of acylation by acyl chlorides when using pyridine gives strong distal preference, whereas use of triethylamine or aqueous base in conjunction with aroyl chlorides showed a moderate preference for proximal acylation. This observation yielded a convenient one-step method to synthesize proximal aroylarylhydrazines in yields comparable or superior to that provided by the standard three-step literature approach. Combined with NMR evidence of the distal nitrogen as the unambigiously stronger base of the two nitrogens, we propose a single electron transfer mechanism that predicts the regiochemistry of arylhydrazines toward acylating agents better than the nucleophilicity model based on pKa values. While synthesizing the acylhydrazine library for assay against An. gambiae, NMR spectroscopy revealed rotational isomerisms of two types: chiral helicity (M)/(P) and acyl (E)/(Z)-isomerism due to hindered rotation. Variable temperature NMR allowed the measurement of N-N bond rotational barriers, as well as estimate the barrier of (E)/(Z) interconversion. We obtained the X-ray crystal structures of four diacylhydrazines to test this hypothesis and revealed both the twist conformation around the N-N bond axis and (E)/(Z)-isomerism around the proximal acyl group. Computation (which agreed with the crystal structures) allowed us to estimate which (E)/(Z)-isomers were most likely being observed in solution at room temperature by NMR spectroscopy. In addition, we were able to calculate transition structures corresponding to N-N bond rotational barriers of (E,Z)- and (Z,Z)-isomers of model molecules and rationalize the difference in coalescence temperatures between (E,Z)- and (Z,Z)-isomers. / Ph. D.