C-H Bond Functionalization And The Construction Of Heterocycles Via Visible-Light Photoredox Catalysis

Visible light photoredox catalysis, which relies on the redox ability of excited-state photosensitizers to promote the single-electron-transfer (SET) processes upon irradiation by visible light, has attracted great interest in the synthetic chemistry during recent years. Photoredox reactions occur under extremely mild conditions, with most reactions proceeding at room temperature without presence of highly reactive radical initiators. The irradiation source is typically commercial availiable household light bulb, which is a significant advantage over the specialized equipment required for generate high-energy ultraviolet (UV) light. Additionally, because organic molecules generally do not absorb visible light, there is little potential for deleterious side reactions that might arise from photoexcitation of the substrate itself. Finally, photoredox catalysts are ususlly employed at very low loadings, typically 1.0 mol% or much less, which indicates its promising future in organic chemistry.C-H bond functionalization is always one of the most prevalent research frontiers in organic chemisty for recent years. Therefore, The development of new strategies for promoting C-H bond functionalizaiton under mild and efficient condition is imperative to this research area. We have achieved C-H bond alkylation, sulfonation and trifluoromethylation of enamides, enecarbamates and enol acetates by the strategy of visible light photoredox catalysis, which provides an alternative approach to realize the C-H bond functionalization.Aromatic heterocycles are widely existed in biological active natural products and pharmaceutical molecules. Therefore, the development of environmentally friendly and efficient methods to construct aromatic heterocycles is of great importance in medicinal chemistry. To achieve the syntheses of aromatic heterocycles efficiently by visible light photoredox catalysis, we have developed:(1) the radical cyclization and aromatization of 2-bromo-1,3-dicarbonyl compounds with alkynes under visible-light photoredox to construct polysubstituted naphthols and furans; (2) photoredox neutral somophilic isocyanide insertion to prepare 6-alkyl phenanthridine derivatives; (3) a unified approach to pyridines, quinolines and phenanthridines by visible light promoted iminyl radical formation from acyl oximes.The first part of this dissertation focused on the C-H bond functionalization of enamides, enecarbamates and enol acetates by visible-light photoredox catalysis. Upon visible light irradiation, we firstly achieved C-H bond alkylation of N-vinylpyrrolidinone by using diethyl 2-bromomalonate as the radical precursor and Ir(ppy)2(dtbbpy)PF6 as the photosensitizer. The scope of enamides, enecarbamates and bromedes were then explored and obtained the C(sp2)-H alkylated products with E-configuration exclusively. The catalytic cycle was also proposed in which includes single electron transfer (SET) and tautomerization of N-acyliminium. To explore the diversity of this C-H bond functionalizaiton, we achieved the sulfonation of enamides and enecarbamates with sulfonyl chlorides by the same strategy. In addition, we also developed a mild and practical method to prepare a-sulfonyl and α-trifluoromethyl ketones from enol acetates and sulfonyl chlorides by using visible-light photoredox catalysis.The second part of this dissertation discussed the De Novo synthesis of polysubstituted naphthols, furans and dihydrofurans by photoredox neutral coupling of alkynes with 2-bromo-1,3-dicarbonyl compounds, by using Ir(ppy)2(dtbbpy)PF6 as photosensitizer, we obtained 2-naphthol derivative in 98% yield through the coupling of methyl 2-bromo-3-oxo-3-phenylpropanoate and ethynylbenzene upon visible light irradiation. This transformation worked smoothly for both aryl alkynes and aliphatic alkynes. Furan derivatives were prepared with the same strategy in which 2-bromocyclohexane-1,3-dione derivatives were used as the radical precursor. We found that the electron-rich aryl alkynes were preferable coupling partners compared to the electron-deficient aryl alkynes, which implies the generation of oxonium cation intermediate during the reaction. We also proposed the catalytic cycle that includes the single electron transferred (SET) process. This redox-neutral strategy, which promoted by photosenstizer upon visible light irradiation, are of broad substrate scope and can be carried out at room temperature without any external stoichiometric oxidant. Thus, it is an efficient approach to prepare polysubstituted furans and 1-naphthols.The third part of this dissertation described the photoredox neutral somophilic isocyanide insertion to prepare 6-alkylated phenanthridines. By using fac-Ir(ppy)3 as the photocatalyst and methyl 2-bromopropanoate as the radical precursor, somophilic isocyanide insertion of 2-isocyano-5-methylbiphenyl occurred smoothly and gave 6-alkylated phenanthridine in 92% yield. The use of different functional groups on 2-Isocyano biphenyl derivatives were all gave high to excellent yields. Both acyclic and cyclic a-bromoesters, as well as perfluorobromoalkanes, were appropriate radical precursors in this transformation. A off/on light profile over time was generated to verify the necessity of light and thus suggested the regeneration of the photocatalyst was crucial for the full consumption of the isocyanide. Compared to transition metal catalyzed or radical initiator promoted isocyanide insertions, photoredox neutral somophilic isocyanide insertion is a more efficient approach to prepare 6-alkylated phenanthridines due to its mild and practical conditions which circumvents the use of stoichiometric oxidants and harsh reaction conditions. In addition, we also achieved the first example of visible light-promoted vinyl isocyanide insertion with diaryiodonium salts through the same strategy, which can rapidly access highly substituted isoquinolines. The resultant 1-arylisoquinoline carboxamides and esters are biologically intriguing motif, which can be used as chemical probe, such as PBR ligands.The last part of this dissertation focused on a unified approach to pyridines, quinolines and phenanthridines from acyl oximes by visible light promoted iminyl radical formation. By tuning the electronic properties of acyls on acyl oximes, we demonstrated that p-trifluoromethylbenzoate oxime were competent to generate iminyl radical species through single-electron-transferred (SET) photoredox catalysis. The iminyl radical intermediates could be converted to a range of N-containing six-membered rings, including pyridines, quinolines and phenanthridines, by means of intramolecular SET processes. In addition, we achieved the 5-step rapid and efficient total syntheses of phenanthridine-based natural products including noravicine and nornitidine by using this strategy as the key step. Redox potential of p-trifluoromethylbenzoate oxime was measured by cyclic voltammogram to demonstrate the feasibility of the formation of iminyl radical from the SET process between acyl oximes and photo-excited fac-Ir(ppy)3.