The Studies And Applications Of Ring Opening Reactions Of Bridged Aromatic Fused Azepines

In this dissertation the studies of the ene-type cyclization/ring opening reactionsand their applications in the synthesis of novel nitrogen-containing heterocycles werecarried out. The research includes ene-type cyclization and ring-opening reactions ofbridged azepines, and the synthesis of mozavaptan and tolvaptan. It consists of fourchapters.In chapter one, the biological activities and synthetic methodologies of thearomatic-fused azepine derivatives were briefly reviewed.The aromatic-fused azepines possess a7-membered aza-heterocyclic ring-fusedaromatic unit. This framework is often presented in bioactive natural products andpharmaceuticals, and is considered as an important scaffold in medicinal chemistry.Design and synthesis of novel aromatic-fused azepines may provide opportunities toscreen compounds with biological avtivities and new drugs.In chapter two, the competition reaction between the inverse electron-demandaza-Diels–Alder (IADA) and ene-type cyclization of pyrimidine aldehydes andanilines were studied, and a conditions-based divergence strategy of bridged aromaticfused azepines was developed.1. We systematically studied the competition reactions between the IADA andene-type reactions of pyrimidine aldehydes and anilines. We found that the same setof starting materials may either undergo IADA or ene-type reaction depending on thereaction conditions such as the amount of acidic catalyst, solvent, and reaction temperature. To gain insights into the process of the two reactions, a DFT study wascarried out.2. The imino ene-type reaction between2-(allylamino)nicotinaldehydes and amineswas studied. The results showed that both aromatic and aliphatic primary amines weresuitable to this reaction. The substituents on the nitrogen atom of theaminonicotinaldehydes was also investigated. For the alkyl substituents, the reactionwas rapid and gave high yield; the aryl groups led to sluggish reaction and lower yield.When the N atom linker between the ene and the pyridine moity was replaced with Oor S atoms, the ene-type reaction could not occur.3. The application of carbonyl ene-type reaction of2-(allylamino)nicotinaldehydesin the systhesis of oxa-bridged azepines was studied. The results show that a varietyof substrates were suitable to this reaction. A series of novel oxa-bridged azepineswere synthesized in82%-90%yield.In chapter three, we briefly reviewed the ring-opening reactions of cyclicN,O-acetals and N,N-acetals, and systematically investigated the ring-openingreactions of bridged aromatic fused azepines.1. Reductive ring-opening reaction of bridged azepines(1) We systematically studied the selective reductive ring-opening of aza-bridgedpyridoazepines. Using NaBH3CN as the reductant, AcOH as the solvent, the reactioncould proceed quickly to afford the desired products with high to excellent yields. Thesubstituents at the nitrogen atom were found to be the determinants of cleavagedirections (either C-N1bond or the C-N2bond). When both R1and R2wereelectron-donating groups or strong electron-withdrawing groups, the C-N1cleaved2-aminonicotines were obtained; when R2was strong electron-withdrawing group andR1was methyl, the C-N2cleaved pyrido[2,3-b]azepines were obtained. On the basisof these results and considering the precedents in the literatures, a plausiblemechanism involving iminium intermediates was proposed. The reaction directiontowards forming the more stable iminium was favored. The explanation wassupported by deuterium-labeling experiment.(2) The reductive ring-opening reaction of oxa-bridged aromatic-fused azepines was investigated. Oxa-bridged pyridoazepines were subjected to the optimizedconditions to afford expected C-O bond cleaved pyrido[2,3-b]azepin-5-ol productswith high to excellent yields. Further more, the products of oxa-bridged benzazepinescould be readily converted to dehydrated products under the reductive ring-openingconditions.2. Oxidative ring-opening reaction of aza-bridged pyridoazepinesThe oxidative ring-opening reactions of aza-bridged pyridoazepines with NaIO4asoxidant under mild aqueous conditions were investigated. We screened severaloxidative conditions and found that a variety of aza-bridged pyridoazepines with botharomatic and aliphatic substituted groups could be oxidized with NaIO4(1.5equiv) asthe oxidant in30%aq AcOH at25oC to lead to pyrrolidin-2-ones in a moderate tohigh yield. The reaction of N2-alkyl aza-bridged pyridoazepines proceeded faster withhigher yield than that of N2-aryl substrates.3. Cascade reactions involving C O bond cleavage and redox reaction ofoxa-bridged benzazepinesAn acid-catalyzed C-O bond cleavage/1,5-hydride transfer process (internal redoxprocess) of oxa-bridged benzazepines was studied. With the optimized reactionconditions (10%aq H2SO4at90oC), a series of benzazepinones were prepared fromoxa-bridged benzazepines. But under the existence of NO2at the C-7, this internalredox process could be completely suppressed by a strong electronwithdrawing groupsuch as NO2at the C-7of the fused benzene ring.4. Grignard addition reactions of oxa-bridged benzazepineThe Grignard addition reactions of oxa-bridged benzazepines were investigated,and a concise synthetic strategy for2,5-disubstituted1-benzazepines was developed.With dichloromethane as the solvent, we investigated the reactions of oxa bridgedbenzazepines with various Grignard reagents, and ring-opening/nucleophilic addtionproducts were obtained with high yields and a moderate to high stereoselectivity. Inall these cases, the stereoselectivity appeared to be particularly sensitive to the sterichindrance of the Grignard reagents. The structures and the ratios of syn/anti of theproducts were confirmed by single-crystal X-ray structure analyses and the1H NMR spectra. Subsequently, oxidation of the benzo[b]azepin-5-ol products to thecorresponding carbonyl compounds has been achieved with the Dess-Martinoxidation.In chapter four, new synthetic strategies of mozavaptan and tolvaptan weredeveloped by using the above ring-opening reactions as the key steps.1. Three new synthetic routes to mozavaptan using the above reductive ringopening and internal redox process as key steps were developed. These routes couldbe complementary to the reported ones.2. A novel synthetic route to the key intermediate of tolvaptan using the aboveinternal redox process as the key step was developed. A key intermediate to tolvaptancould be obtained with excellent overall chemical yield by this four-step procedure.