New 4-trichlorobenzene [1] - Triazole And - A - Homo - Steroid Synthesis Of Heterocyclic Compounds

Steroids and related derivatives occur widely in nature. Their significance connected with many life processes has well been documented. However, the traditional extraction method for achieving steroidal natural products cannot meet with the ever increasing utilities of this class of compounds, thus the development of new synthetic methods has become a necessity. The diversity of biological activity is associated with the diversity of chemical structure. For example, steroids in which one or several C replaced by one or more nitrogen atoms (leading to azasteroids) often put up a new activity. In particular, conversion of the steroidal A-ring into azepine ring has proved to be a valuable change. The present dissertation describes a novel and efficient methods for accessing a series of3-aza-A-homocholestane derivative, which show unprecedented characters both in the fusion mode and substitution pattern.The first chapter summarizes the classification of steroidal natural products, with focus on the uses and synthetic methods of A-azepine-steroids. In addition, the research in the field of1,3-dipolar cycloadditions with the1-aza-2-azoniaallenium ions as cationic1,3-dipoles are briefly reviewed. Especially, the application of these newly emerging reactive intermediates in the assembly of N-containing five-membered heterocycles is introduced.The second chapter describes firstly the synthesis of the precedentless pentacyclic compounds, i.e.[1R-[1α(R*),3aβ,3bα,5aβ,12aα,12bβ,14aα]]-1-(1,5-dimethylhexyl)-1,2,3,3a,3b,4,5,11.12,12a.12b.13.14,14a-tetradecahydro-8-sub stitued-12a,14a-dimethyl-9-(2,4,6-trichlorophenyl)-cyclopenta[5,6]naphtho[2,1-d][1,2,4]triazolo[1,5-a]azepinium hexachloroantimonates58. Starting from the easily available dihydrocholesteranone50, the2,4,6-trichlorophenyl hydrazone53was prepared by the usual condensation method. The a-chlorination of53with t-BuOCl as the chlorination agent gave the corresponding a-chloroazo compound55in96%yield. Then, dechlorination under the action of a Lewis acid like SbCl5generated the short-lived1-aza-2-azoniaallenium salt56, which underwent the cycloaddition with the pre-added nitrile with spontaneous1,2-shift rearrangement. This reaction sequently resulted in the insertion of an N atom in the six-membered A ring. Thus, this constitutes a new and efficient strategy leading to the formation of the triazolo fused A-aza-homocholesterane derivatives58. To ultimately ascertain the structural determination, single crystals of one of the products, namely58a, was grown and subjected to X-ray diffraction analysis, whereby providing unerring structural proof. On the bases of the above results, and for the sake of future physiological activity evaluation, we modified our method to the synthesis of the neutral [1,2.4]triazolo[1,5-a]azepine analogies. Thus. the (5α)-cholestan-3-one’s ethoxycarbonyl hydrazone60was prepared and allowed to react as described for58. Under comparable conditions. a set of [1,2,4]-triazolo-annulated3-aza-A-homocholestane compounds65or their picrates66were obtained in moderate yields. It has been observed that different substituted1-aza-2-azoniaallenium salts exhibited variable reactivity in this polar cycloaddition. Similarly, the nitrile or alkyne dipolarophiles behaved quite differently depending on the different stereo and electronic feature. According to our experimental data, together with investigations from our previous work, the mechanism with respect to the polar1,3-dipolar cycloaddition and1,2-shift were discussed.Besides this study, we attempted the transformation of (5α)-cholestan-3-one to a-acylated products68which were condensed with hydrazine to furnish the pyrazolo fused cholestane derivatives70. Scope and limitations of this synthesis remains to be investigated.In the third chapter, the application of azocarbenium ions for the synthesis of1,2,4-triazolo annulated bi-or tricyclic heterocycles was explored.. Thus,[1,2,4]-triazolo-[1,5-a][1]benzazepines80and [1,2,4]triazolo-[1,5-a]quinoline derivatives86were successfully synthesized starting from a-tetralone and2,3-dihydro-1-indanone. Oxidation of a-tetralone ethoxycarbonylhydrazone74with lead tetraacetate afforded the bicyclic geminal ethyl azoester75. On addition of equimolecular aluminum trichloride, the azocarbenium salt76was believed to be generated in situ as a reactive intermediate, which could be trapped to the C=N triple bond of the pre-added nitriles by cycloaddition. These cycloadducts underwent smooth1,2-aryl-shift with concurrent ring enlargement and insertion of a nitrogen atom to the carbon skeleton to afford the [1,2,4]-triazolo-[1,5-a][1]benzazepinium picrates80in23～56%yields, upon hydrolytic removal of the N-ethoxycarbonyl group and subsequent treatment of the alkalescent heterocycles with picric acid finally. Analogously, the novel4,5-dihydro-[1,2,4]-triazolo-[1,5-a] quinolinium picrates87have also been prepared starting from2,3-dihydro-1-indanone in moderate overall yields. In light of the above results, we concluded that under the same conditions the ring-expansion5â†'6seems to proceed more readily than that of6â†'7. Efforts were also made to extend this approach to the cyclobutanone system, aiming at achieving4â†'5membered-ring expansion to yield [1.2.4]-triazolo-[1,2-b]-pyrrolidines. However, all experiments failed so far.The fourth chapter is the experiment part, providing the details both in the experimental procedures and characterization data including IR. NMR. HRMS and/or microelemental analysis.