Study On The Synthesis Of Fused Heterocycles Based On Domino Reaction

Domino reactions and Multi-component reactions (MCRs) have been highlighted as one of research frontier, widely used for the construction of heterocycles and in total synthesis and combinatorial chemistry. In this thesis, a series of novel heterocyclic compounds involving in more complex structures and in part original nucleus were synthesized based on domino reactions and MCRs. The starting materials have been maximized to convert into the desired compounds, avoiding time-consuming and energy-costing processes that involve multi-step syntheses. So, these reactions have the advantage of atom economy, high synthetic efficiency and environmental friendliness, which offer a valuable addendum to methodology for the synthesis of heterocycles. The discussions and results are listed as following:PartⅠ:The first synthesis of poly-substituted dispiro[4.2.5.2] pentadecane-9, 13-dione based on new, efficient domino autocatalytic reaction has been developed. The symmetric double imines reacted with Meldrum's acid in HOAc to provide poly-substituted spiro[5.5]undecanes with high stereoselectivity. When the reaction was carried out in mixed solvent of HOAc and ethylene glycol, interestingly, new dispiro[4.2.5.2]pentadecanes was furnished with ethylene glycol as a protection reagent of carbonyl group under this mild reaction condition. The chiral 1,2-propanediol (S-) also gave the corresponding dispiro[4.2.5.2]pentadecanes. The key step to spiro[5.5]undecanes was that acetohydrazide from the reaction system catalyzed Diels-Alder reaction between Barbas dienamine and arylidene-Meldrum's acid. The study on the reaction mechanism indicated that acetohydrazide as a self-catalyst was served for the reaction. The methodology provides a new approach to the synthesis of dispiro system. PartⅡ:(a) the novel domino reaction of 1,8-dioxo-2,3,4,5,6,7-hexahydroanthenes with hydrazine hydrate has been developed. The domino reaction involved intermolecular and intramolecular ring-opening/cyclization/rearrangement/ re-ring-opening/re-cyclization/aromatization process. In addition, 1,8-dioxo-2,3,4,5,6,7-hexahydroanthenes with aryl-groups (R1) reacted with hydrazine hydrate to N-amino-1,8-dioxoacridines with good to excellent yields. The reaction chemoselectivity was controlled by the steric effect.(b) A new iodine-promoted domino reaction of 2-aminochromene-3-carbonitriles with various isocyanates was described, and a set of polyfunctionalized N-substituted 2-aminoquinoline-3-carbonitriles with high regioselectivity were successfully synthesized under microwave heating. In this reaction, the ring-opening/recyclization process occurs unexpectedly at the ring of 4H-pyran with different isocyanates. The syntheses were finished within short periods (20-36 min) with good to excellent chemical yields and regioselectivity that avoided tedious work-up isolations.PartⅢ:a novel four-component domino reaction by employing simple aldehydes, cycloketones and cyanoamides has been discovered. Two different Knoevenagel intermediates from the reaction of simple aldehydes, cycloketones and cyanoamides underwent [4+2] cyclization to generate pyrido[3,4-i]quinazoline derivatives possessing original nucleus with concomitant new formation of up to two rings, fiveσbonds and four quaternary carbon centers with one quaternary carbon-amino function. The replacement of their aliphatic counterparts (or cycloketones) with aromatic aldehydes was examined, and the reaction occurred to another direction to form multi-functionalized tricyclo[5.2.2.01,5]undecanes and tricyclo[6.2.2.01,6]dodecane. The reaction is very fast and can be finished within short period and with water or CO2 as the major byproduct, which makes work-up convenient, which show the superiority of atom economy, bond economy and structure economy.PartⅣ:The microwave-assisted synthesis of a variety of new substituted pyrrolidones via the three-component reaction of acetylene esters and aldehydes, amines has been developed. The structure is established by NMR and X-ray analysis, and a possible mechanism for the domino process was proposed. Secondly, a tandem reaction of acetylene esters cyanoamides and thio-isocyanide ester were studied. In order to avoid the formation of by-products, thio-isocyanide was condensed with cyanoamides. Without isolation, the excessive amount of acetic acid and acetylene esters was added into the mixture, providing thiazole ketones in quantitative yields.Part V:The microwave-assisted multi-component tandem reactions of malononitrile were developed. (1) The new domino reaction of malononitrile, cyclic ketones and ammonium acetate was discovered. The reaction underwent a domino intermolecular and intramolecular condensation-addition-cyclization-recyclization sequence. (2) Instead of cyclic ketones, the arones reacted with malononitrile to give the more cyano-substituted pyridine derivatives, which further reacted with ammonium acetate to 1,6-naphthyridine-8-carbonitriles. So the new domino reaction was described. (2) The base-catalyzed A2B2-type reaction of malononitrile (2.0 equiv.) with cyclic ketones (2.0 equiv.) was developed.