Investigation Of No Metal Catalytic Addition-cyclization Reactions Of N-arylacrylamides

The functional-group introductions of organic molecules have been a hot topic in the field of organic synthesis. Especially in recent years, the incorporation of the hetero atom functional group into organic molecules for the construction of high-added compounds has attracted much attention and most of which have been widely applied to the field of pharmaceutical, natural products, pesticides and new materials. The subject of this thesis is mainly revolves around “green chemistry”, which is the main direction of the development of chemistry in this new situation. We combined the modern organic synthesis with the environment, by reasonable and careful designing, the high efficiency and high selectivity functional-group introduction approaches have been developed. The main contents and results are listed as following:Part 1, a metal-free（NH₄）₂S₂O₈-mediated addition-cyclization of N-arylacry lamides with halogen atom is developed. In this work, we proposed for the first time that the halogen-containing oxindoles can be constructed in water medium. These molecules are highly valued synthetic intermediates of physostigmine and its derivatives. The advantages of this reaction are its excellent versatility, the use of NH₄X（X = Cl, Br, I） as the green and cheap halide source,（NH₄）₂S₂O₈ as a versatile oxidant, and H2 O as the solvent. In order to find an optimizated reaction conditions, reaction of N-arylacrylamide with NH₄ Cl was investigated by changing oxidants, solvents, time and temperatures, and it was found that the selective monochlorination or aromatic C5 and C7 chlorination can be achieved by simply tuning the reaction conditions. In addition, we also investigated the solubility of the product in water. It was found that in this（NH₄）₂S₂O₈/NH₄Cl/H2 O reaction system, 1.0 m L of solvent is capable of hosting 0.32 mmol of product. Mechanism investigation experiments suggested that the in situ generated molecular halogen is involved in this reaction, and the electrophilic addition-cyclization is the first step in this transformation.Part 2, a transition-metal-free TBHP- or Oxone-mediated addition-cyclization of N-arylacrylamides with α-diketones is developed. We found that the alkylcarbonyl-containing oxindoles were obtained in majority when N-methyl-N-phenyl methylacrylamide was employed to react with asymmetric aromatic/aliphatic α-diketones in the presence of TBHP. Finally, considering the potential applications of these molecules in the field of pharmaceutical industry, we further evaluated the reaction conditions and finally successfully achieved this transformation by using the safe and inexpensive inorganic oxidant oxone（KHSO5）. On the basis of mechanism experimental evidence as well as previous related reports, TBHP and oxone facilitated two mechanistic scenarios are proposed.Part 3, a transition-metal-free K2S₂O₈-mediated addition-cyclization of N-arylacrylamides with disulfides has been developed. This newly developed method is operationally simple, functional group tolerant, scalable, and represents the first example regarding the synthesis of sulfone-containing oxindoles using disulfides as the sulfonylating precursors with oxygen atom incorporation. At the outset of this investigation, N-methyl-N-phenyl methylacrylamide and diphenyl disulfide were chosen as the model substrates, after screening of various conditions, we decided to set reacting 1.0 equiv of N-methyl-N-phenylmethylacrylamide（0.2 mmol） with 1.5 equiv of diphenyl disulfide（0.3 mmol）, 3.0 equiv of K2S₂O₈（0.6 mmol） and in CH3CN/H2O（1:1, 2 m L） at 80 oC under a N2 atmosphere for 24 h as the standard conditions. The N-arylacrylamide substrates with various substituents were tolerated under the optimized conditions. Moreover, a series of disulfides such as diaryl disulfides, diheterocyclic aromatic disulfides and dicycloalkyl disulfides could also be converted into the corresponding sulfone-containing oxindoles. In addition, the radical verification experiments suggested that the reaction is likely to proceed through a radical pathway, and H218O-labeling experiment confirmed that H2 O and K2S₂O₈ can compete to provide an oxygen source in this reaction system.Part 4, a metal-free nitromethane-mediated addition-cyclization of N-arylacrylamides with AIBN has been developed. In addition, a series of N-alkyl-N-（arylsulfonyl）acrylamide substrates could also be converted into the corresponding oxindoles in good yields and with excellent chemoselectivity via one-pot cyanoisopropylation/aryl migration/desulfonylation and C（sp2）-N bond formation. The present approach, which utilizes cheap and readily available CH3NO₂ as both the solvent and oxidant, enabled introduction of the valuable cyano functional group into oxindoles skeleton under simple and mild reaction conditions. On the basis of experimental observations, a plausible reaction mechanism is proposed.Part 5, because of our another interest in the functional-group transformations of organic small molecules, a metal-free potassium tert-butoxide-mediated amine acyl exchange of N,N-disubstituted formamides with aromatic carbonyl derivatives has also been developed. This reaction realized the transformation from formamides to benzamides through the formal amine acyl exchange. This methodology tolerates a wide range of aromatic carbonyl compounds, including aromatic aldehydes, acyl chlorides, unactivated esters, and acid anhydrides, and thus offering a new method for the synthesis of aromatic amide skeletons that are common structural motifs in drug molecules and fine chemicals. We found that the disproportionation reaction of benzaldehyde was significantly suppressed whereas the yield of the amine acyl exchange product was raised up to 70% when anhydrous THF was used as the solvent and the reaction was conducted by a sequential two step operation. Based on a series of mechanism investigation experiments, we proposed that the thermal decarbonylation of N,N-dimethyl formamide under alkaline conditions resulted in the formation of a free dimethylamine, this species addition to C=O of aldehyde to lend an unstable hemiaminal intermediate. Thereafter, through a Cannizzaro-fashion hydride iontransfer, this unstable species would convert to the corresponding amide along with the formation of potassium alkoxide. The potassium alkoxide intermediate could be further oxidized to aldehyde by air（O₂） under the assistance of base, thus being involved in the next reaction cycle.