Studies Of A Novel Tandem Hoffmann Elimination-Diels-Alder Cyclization And Design And Synthesis Of Novel Pyrimidine-fused Heterocyclic Scaffolds

This dissertation is divided into two parts. In the first part, a novel intra-molecular tandem Hoffmann elimination-Diels-Alder cyclization reaction of N-alkyl indoloazapines and their analogs with α,β-unsaturated aldehydes was studied. In the second part, three novel pyrimidine-fused heterocyclic scaffods were designed and synthesized. These scaffolds are useful in preparation of libraries of priviledged structures in drug discovery. In part one, Chapter One summarizes tandem Diels-Alder cyclizations in the literature. Reactions of N-alkyl indoloazapines with saturated aldehydes have been systematically studied by Kuehne et al. They involve a tandem Hoffmann elimination-Diels-Alder cyclization, in which the Hoffmann elimination product indoloacrylate part from the indoloacrylate-enamine intermediate is used as the diene while the enamine within the same molecule as the dienophile. In Chapter Two, a novel anti-Kuehne tandem Hoffmann elimination–Diels-Alder cyclization is described. Reaction of N-alkyl indoloazapines with α,β-unsaturated aldehydes in refluxing toluene led to novel tetracyclic products in 48-92% yields. All these compounds were characterized by NMR spectra, MS and elemental analysis. The reaction results can be summarized as follows: 1) Reaction of indoloazepines containing N-substitutents, such as benzyl, allyl, ethyl, with α, β-unsaturated aldehydes could proceed to give the expected tetracyclic compounds; 2) The reaction is highly stereoselective; 3) The existence of β-substituents on α, β-unsaturated aldehydes facilitates this reaction while α-substituents hinder it. To explain the above results, an anti-Kuehne's Hoffmann elimination-Diels-Alder cycylization mechanism was proposed. The key to this mechanism is an intramolecualr Diels-Alder reaction by indoloacrylate (dienophile)-dienamine (diene) intermediate generated in situ. As a subsequence, the synthesis of natural alkaloid (±)-andranginine was attempted and its ABCE skeleton has been prepared. In Chapter Three, 3-benzazepine-1-carboxylate and its thieno analogs were synthesized. Following a three-step reaction sequence involving Pictet-Spengler cyclization, ring-expansion and reduction, the desired methyl 2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylate derivatives were obtained from β-phenyl-ethanamine hydrochloride. In the ring-expansion stage, a simple 'one-pot'ring enlargement method was developed. it involves reactions of a-chloromethyl-tetrahydroisoquinoline with alkylating reagents such as benzyl or allyl bromide under basic conditions. The keys were proposed to be the formation of aziridinium salt and subsequent bond breaking between the nitrogen and tertiary carbon atoms. This one-pot reaction provides a convenient way to prepare 3-benzazepine in high yields. Thienoazepine derivatives were synthesized from β-(thiophen-3-yl)ethanamine hydrochloride in a similar manner. The newly discovered intramolecular tandem Hoffmann elimination-Diels-Alder cyclizations were applied to 3-benzazepine-1-carboxylate and its thieno analogs. Unfortunately, no desired products were obtained. Chapter Four to Seven deal with design and synthesis of novel privileged structures. In Chapter Four, the application of privileged structures and pyrimidine-fused heterocycles in drug design were reviewed. Priviledged structures represent a class of molecules capable of binding to multiple receptors with high affinity. As a structural component of key biomolecules, pyrimidinemoiety has been widely employed in design of privileged structures in medicinal chemistry. In Chapter Five, an efficient method for rapid preparation of 5,6-dihydroindolo[2,1-h]pteridine scaffods has been developed. The key step involves the intramolecular cyclization of an iminium ion intermediate derived from the reaction of 4-chloro-6-(1H-indol-1-yl)-pyrimidin-5-amine with aldehydes or ketones. The key precursor 4-chloro-6-(1H-indol-1-yl)-pyrimidin-5-amine was prepared by three steps of reactions involving indoline substitution, nitro reduction and oxidation aromation from commercially available 5-amino-4, 6-dichloro-pyrimidine. The one-pot reaction of imine formation of this key precursor with aldehydes or ketones and cyclization under the catalysis of trifluoroacetic acid led to 5,6-dihydroindolo[2,1-h]pteridine derivatives in 47-98% yields. The cyclization represents a special Pictet-Spengler type reaction involving an aromatic amine. In the acidic condition, aminopyrimidine condensed with an aldehyde or ketone to form the iminium ion intermediate, which was attacked by the electron-rich 2-position carbon atom of the indole ring to result in the desired product. To test the scope of this cyclization and as a special case, an electon-withdrawing ester group was introduced into the 3-position of indole moiety. The results demonstrated that various substituents including electron-donating or withdrawing group might be tolerated. Similarly, the substitution of 4-chloro atom in the cyclized products by an amine symbolized the ease of convertion by other nucleopliles, which further increases the structural diversity of this new scaffold. Based on the results in chapter five, we envisioned that if indoline-substituted aminopyrimidine instead of indole-substituted one reacted with an aldehyde or ketone, the cyclization would be forced to occur on the benzene ring of indoline due to the absence of the electron-rich indole 2-carbon. The details of this study is described in Chapter Six. Following the cyclizationconditions described in Chapter Five, indoline-substituted aminopyrimidine reacted with a series of aldehydes or ketones respectively to give the expected tetracyclic 4-chloro-5, 6-dihydro-pyrimido[4,5-b][1,4]benzodiazepine derivatives. This strategy was applied to tetrahydroquinoline-substituted aminopyrimidine system. It was found that reactivity of tetrahydroquinoline-substituted aminopyrimidine was lower compared to that of indoline-substituted aminopyrimidine, especially in the reactions with ketones. The results were explained by two possible factors, the steric hindrance and/or the bond angle strain. On the bases of the aboved results, we have designed a combinatorial library containing 1000 to 2000 5, 6-dihydro-pyrimido[4,5-b][1,4]benzo-diazepines with various substituents. In Chapter Seven, the above cyclization strategy was applied to the 5-pyrrolyl-substituted amino-pyrimidine system. Starting from 5-amino-4,6-dichloro-pyrimidine, the required precursor was prepared in two steps. The new aminopyrimidine reacted with aldehydes or ketones under the catalyzation of p-TsOH to result the desired 1-chloro-5,6-dihydropyrrolo-[1,2-f]pteridine derivatives. In a similar manner, the chloro atom on the newly formed cyclized products is highly reactive towards a nucleophile, such as an amine. Based on these results, a combinatorial library containing about 600 5, 6-dihydropyrrolo[1,2-f]pteridine derivatives was designed.