Cycloaddition Reactions Of Alkynes And 1,2-Difunctiotnalizations Of N-Aryl Acrylamides

As a common motif in pharmaceutical and natural products as well as very important intermediates in organic synthesis, the synthesis of nitrogen-containing heterocyclic compounds is focused by many chemists. In contrast to the common ring sizes(five- and six-membered rings), seven-membered rings are difficult to access by direct cyclization reactions due to a combination of entropic factors and the development of nonbonded interactions in the transition state. The development of efficient methods for the synthesis of seven-membered-rings are of the most important aspects of organic synthesis.The cycloaddition reaction is a fundamental, straightforward and powerful transformation for the construction of numerous complex ring systems in organic synthesis, which allows several new bonds to be formed in one reaction in a regio-and stereocontrolled fashion, and occupies a central position among the available tools of synthetic organic chemistry. Main advantages of the tandem reaction are that the reaction is often fast, clean, highly atom-economic, not involve workup and isolation of intermediates, as well as achieves much complexity in effectively one step.This dissertation mainly focuses on the construction of nitrogen-containing heterocyclic compounds through the cycloaddition reactions of alkynes with aziridines and 1,2-difunctiotnalization of N-arylacrylamides. This dissertation is divided into seven parts as follows:In chapter 1, recent advances in the synthesis of nitrogen-containing heterocyclic compounds, especially the nitrogen-containing seven-membered-rings and five-membered-rings systems, such as azepines, azepinones, diazepines, oxepines, oxazepanes and oxindoles.In chapter 2, a practical method for the synthesis of azepines, a seven-membered-heterocyclic ring system, was developed by hexafluoroantimonic acid-catalyzed formal [3+2+2] cycloaddition of aziridines with two alkynes. The combination of HSb F6 superacid catalyst with CH2Cl2 solvent was the most effective catalytic system. This method could be applicable to two same or different terminal alkynes for the [3+2+2] cycloaddition with aziridines, and furnished the corresponding azepine derivatives in good yields with good levels of chemo-and regio-selectivity control. The mechanism was also discussed according to the results of the in situ HMRS and 1H NMR analysis.In chapter 3, a new, efficient protocol for 2,3-dihydro-1H-azepine synthesis by silver-catalyzed [5+2] cycloaddition of γ-amino ketones with alkynes was established. This method had a broad substrate scope with respect to the substituents, and allowed four new chemical bonds formation in one-step leading to the seven-membered-ring systems through release of H2 O as the only accompanying product. Most importantly, the significance of the azepine skeleton as a structural element would render this method attractive for both synthetic and medicinal chemistry, thus paving the way for the synthesis of other complex biologically act ive heterocyclic systems.In chapter 4, a new Rh(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes using a Cu(OAc) 2 oxidant for building a spirocyclic ring system was described, which included the functionalization of an aryl C(sp2)-H bond and addition/protonolysis of an alkene carbon-carbon double bond. Extensive screening of various reaction parameters revealed that a combination of 5 mol% of [Cp*Rh Cl 2]2, 20 mol% of Ag Sb F6, 1.2 equiv of Cu(OAc)2 and 3 equiv of H2 O in the medium CH2 Cl CH2Cl at 80 oC for 12 h was found to be the best choice for the annulation of pyrroles with alkynes. This method was applicable to a wide range of 5-aryl-2,3-dihydro-1H-pyrroles and diverse internal alkynes, giving the assembly of the spiro [indene-1,2’-pyrrolidine] architectures in good yields and with excellent regioselectivity. Moreover, DFT calculations were carried out to better understand the exclusive regioselectivity observed.In chapter 5, a metal-free oxidative tandem coupling of activated alkenes with carbonyl C(sp2)-H bonds and aryl C(sp2)-H bonds using TBHP(tert-butyl hydroperoxide) was developed for the synthesis of 3-(2-oxoethyl)indolin-2-ones. This method allowed 1,2-difunctionalization of the carbon-carbon double bond in N-arylacrylamides by the simultaneous formation of two C(sp2)-C(sp3) bonds. The kinetic isotope experiments implied that the cleavage of the carbonyl C(sp2)-H bond was the rate-limiting step. Moreover, the free radical mechanism was supported by some control experiments. Most importantly, this present work provided a new method for the oxidative coupling of alkenes with aldehydes, and represented one of the most efficient straightforward ways to functionalized oxindole synthesis.In chapter 6, DTBP(di-tert-butyl peroxide) was utilized to mediate oxidative 1,2-difunctionalization of N-arylacrylamides. This reaction was a new oxidative coupling strategy for alkene difunctionalization facilitated by Lewis acids. The optimized conditions is 3 mol% of Ir Cl3, 2 equiv of DTBP at 120 oC for 12 h. This method allowed the formation of two C(sp3)-C(sp3) and C(sp2)-C(sp3) bonds to access functionalized oxindoles. The control experiments suggested that the current reaction included a radical process. The kinetic isotope expe riments implied that cleavage of the benzyl C(sp3)-H bond cleavage was the rate-limiting step. Moreover, Lewis acids were used to stabilize the radical intermediates.In chapter 7, a mild and general alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes was illustrated for the assembly of alkyl-substituted alkynes. Extensive screening of various reaction parameters revealed that a combination of 1 mol% of Pd Cl2(PPh)3, 4 mol% of Cu Cl, and 6 equiv of Et3 N in the medium toluene at room temperature for 12 h was optimal for the 1,2-difunctionalization of N-(2-iodophenyl)-N-arylacrylamides. This method represented a new way to various functionalized oxindoles via the use of transient σ-alkylpalladium(II) complexes in organic synthesis through 1,2-alkynylation/arylation of N-arylacrylamides.