New NCO Heterocyclic Syntheses Enabled by Amphoteric Reactive Intermediates

Abstract

NCO containing heterocycles are common in pharmaceuticals and agrochemicals. Specifically, among aromatic heterocycles, over 50 drugs or agrochemicals possess an N-NCO subunit. Hence, there is high interest in heterocyclic building blocks or syntheses that rapidly assemble heterocyclic cores from simple, readily available reagents. While isocyanates can be excellent building blocks to form a variety of NCO heterocycles, the high reactivity of heteroatom-substituted isocyanates and the lack of intramolecular C-C bond forming reactions has limited their use in synthesis. In this thesis, blocked (masked) isocyanates were used to generate elusive reactive intermediates in situ and enable new reactivity. More specifically, herein simple precursors could first rapidly be functionalized to install a nucleophilic group in the substrate, by taking advantage of the "protected" form of this blocked isocyanate. Then in situ formation of electrophilic isocyanates enabled access to rare amphoteric reactive intermediates possessing three different types of nucleophiles: amines and related nitrogen nucleophiles, metallo-enamines, and organomagnesium groups. These amphoteric reactive intermediates rapidly underwent intramolecular cyclization, thereby demonstrating their utility in heterocyclic syntheses. In Chapter 2, the use of such an amphoteric reactive intermediate is shown in the synthesis of 1,2,4-triazin-3(2H)-ones, a useful bioactive moiety found in pharmaceutical and agrochemicals. This project explored the generation of amphoteric intermediate precursors and their use in controlled intramolecular cyclization. The use of α-bromohydrazones substrates as blocked N-isocyanates enabled the in situ formation of highly electrophilic diazadiene intermediates and exploit their ability to undergo facile addition with nitrogen nucleophiles, such as amines and hydrazine derivatives. The blocked N-isocyanate precursors now tethered to the desired nitrogen nucleophile, undergoes carefully controlled deblocking conditions to liberate the electrophilic N-isocyanate and furnish the amphoteric reactive intermediate which undergoes rapid cyclization to give the desired triazinones. Careful selection of the blocking group enabled the development of a one-pot strategy allowing for rapid assembly of complex molecules under mild, room temperature conditions. This reactivity manifold was then expanded in Chapter 3 to a synthesis of pyrazolones, arguably the most important NNCO-heterocycle, using carbon-centered nucleophiles and N-isocyanates obtained from simple hydrazones. This reaction exploited the chelation of the substrate to a metal cation to attain the required stability to form the carbon centered nucleophile through deprotonation. Subsequent breakage of this chelate allowed deblocking of the electrophilic N-isocyanate and thus the amphoteric reactive intermediate that readily cyclized. Two sets of complementary conditions using Grignard reagents and lithium amides were developed to achieve broad substrate scope. Modulation of the blocking group nature was carried out to enable efficient synthesis of complex substrates and further functionalization of the pyrazolones was achieved by electrophilic quench of the reaction mixture. Building on the knowledge and control gained from this work, the amphoteric reactive intermediate method was then generalized in Chapter 4, through the use of metal-halogen exchange with turbo-Grignard in a Parham type cyclization. Synthesis of benzoxazinone, dihydrophthalazinone and indazolone using N- and O-isocyanates was achieved. The stability afforded by the chelate formed upon deprotonation enabled efficient subsequent metal-halogen exchange and control over the formation of the amphoteric reactive intermediate which rapidly cyclizes into the desired heterocycle. Moreover, the desired cyclization was obtained over the competitive addition of the Grignard reagent to the isocyanate. Synthesis of an isoindolinone then pushed the system to the extreme by using non-chelating C-isocyanate precursors. Efficient cyclization demonstrated that chelation is not strictly necessary for the reaction to proceed cleanly, suggesting that the use of masked isocyanate is a general approach to the formation of NCO heterocycles. Chapter 5 provides mechanistic insight on the pyrazolone synthesis and Parham cyclizations through deuteration studies of key intermediates. Chelate stability across the different systems was investigated, demonstrating considerable stabilization over the non-chelating C-isocyanates. The blocking group ability of different alcohols was probed using the C-isocyanate system, highlighting the reactivity control achievable over these amphoteric intermediate precursors. Finally, Chapter 6 shows how the syntheses developed as part of this thesis have been incorporated into the Pan-Canadian Chemical Library. A repository of virtual compounds synthesizable from synthetic chemistry developed in Canadian institutions, that is then used within these institutions for virtual screening against targets of interest. Virtual libraries were first generated building on the work presented in Chapter 2, which builds on readily available starting materials. Multiple hit compounds were found from virtual libraries when screened against USP5, a target for non-opioid drugs against chronic and acute pain. Synthesis and evaluation of selected hit compounds are ongoing. Overall, this work illustrates how C-N and C-C bond forming reactions of rare amphoteric reactive intermediate enabled by the use of blocked isocyanate can provide access to a variety of heterocyclic ring systems. The importance of these syntheses is highlighted by their incorporation into the Pan-Canadian Chemical Library showing real world application in hit discovery.