Study On The Asymmetric Mannich Reaction And Tandem Nucleophilic Substitution/C(sp~2)-N Cross-coupling Reaction Sequence Of 3-aminooxindoles

Part one: Study on the organocatalytic asymmetric Mannich reaction of 3-aminooxindoles with in situ generated N-Boc protected aldimines for the synthesis of vicinal oxidole-diaminesObject: To achieve highly stereoselective synthesis of newly structural of chiral vicinal oxidole-diamines and establish the related compound library,and to develop an effective complementary methodology for the synthesis of chiral tetra-substituted 3-aminooxindole compounds.Method: The optimal organocatalytic asymmetric reaction conditions were established by screening various reaction factors and using the chiral bifunctional thiourea catalysts.Under the optimal reaction conditions,the highly stereoselective construction of a wide range of newly structural of chiral vicinal oxidole-diamines was achieved by the asymmetric Mannich reaction of 3-aminooxindoles with in situ generated N-Boc protected aldimines.And the related spirocyclic oxindole derivatives were synthesized through the derivatization of the compounds.The structure of the synthetic new compounds was characterized by NMR,HRMS and X-ray crystallo-graphic analysis.Result:(1)The optimal organocatalytic reaction conditions were established as follows: 10 mol% of bifunctional thiourea-tertiary amine derived from(R,R)-cyclohexyl ethylenediamine as the catalyst,1,1,1-trichloroethane as solvent,the saturated aqueous solution of Na2CO3 as base,1:1.5 as the ratio of 3-aminooxindoles and in situ generated N-Boc protected aldimines and 25 oC as the reaction temperature.(2)Under the optimal reaction conditions,20 newly structural of chiral vicinal oxidole-diamines were obtained with excellent yields and high stereoselectivities(up to 94:6 dr and 96% ee).(3)A class of spirocyclic oxindole compound was synthesized from the derivatization of chiral vicinal oxidole-diamine with two steps.(4)The absolute configuration of the major stereoisomer 3n was determined as(C5R,C11S)by the X-ray crystallo-graphic analysis Based on this result,a possible transition state of the reaction was also proposed.Conclusion:(1)A strategy for the highly stereoselective synthesis of chiral vicinal oxidole-diamines has been developed and the chiral tetra-substituted oxindole library was further enriched.(2)This study provides an effective complementary methodology for the synthesis of chiral tetra-substituted 3-aminooxindole compounds.Part two: Study on the synthesis of 2,3'-spirobi[indolin]-2-ones enabled by a tandem nucleophilic substitution/C(sp2)-N cross-coupling reaction sequence of 3-aminooxindoles with 2-bromobenzyl bromidesObject: To develop an efficient strategy for the synthesis of structurally novel spiro [pyrrolidine-3,2'-oxoindole] derivatives and further enrich the library of spirocyclic oxindole compounds.Method: The optimal tandem reaction conditions mediated by opper salts were established via the screen of various reaction factors.Under the optimal reaction conditions,the synthesis of a series of 2,3'-spirobi[indolin]-2-ones was achieved by a tandem nucleophilic benzylation/C(sp2)-N cross-coupling reaction sequence of 3-aminooxindoles with 2-bromobenzyl bromides.Result: The optimal tandem reaction conditions were established as follows: 5 mol % of Cu Br as the catalyst,4 equiv.of tBu ONa as the base,DMF as solvent,1:1.2 as the ratio of 3-aminooxindoles and 2-bromobenzyl bromides and 100 oC as the reaction temperature.(2)Under the optimal reaction conditions,24 newly structural of 2,3'-spirobi[indolin]-2-ones were obtained with 44-86% yields.(3)Based on the previous literature reports and the reaction results,a possible reaction mechanism of this tandem reaction process was proposed.