The Study Of Palladium-catalyzed Unactivated C(sp~3)-H Nitrooxylation And Cyclization Reactions

Organic nitrates are found in a wide range of active drug molecules and high-energy materials.In addition,nitrate compounds can be used as precursors for the rapid construction of oxygen-containing fragments,as they can be easily reduced to hydroxyl groups.Traditional syntheses of organic nitrates are limited to pre-modified substrates,expensive and toxic reagents as well as harsh reaction conditions.Transition metal-catalyzed C-H bond activation is a green and efficient synthesis strategy,which is attractive due to its short steps and high atomic economy.In this paper,palladium-catalyzed C（sp³）-H bond activation strategy was used to investigate the C（sp³）-H nitrooxylation of ketones,amides and amines.Theγandδ-C（sp³）-H intramolecular cyclization of amines was also investigated with the assistance of nitrates as the practical oxidants.The main content is divided into the following five parts:Part I:Literature on the palladium-catalyzed unactivated C（sp³）-H functionalization reactions of ketones,amides and amines,the synthesis of organic nitrate esters and the palladium-catalyzed C（sp³）-H intramolecular cyclization of amines are introduced in detail.Part II:A palladium-catalyzed,directing group assistedβ-C（sp³）-H nitrooxylation of ketones was developed.Cheap and commercially available Fe（NO₃）₃·9H₂O was used as the source of nitrate group and the oxidant for Pd（II）to Pd（IV）species for the first time.Two（5,6）palladacycle intermediates in the reaction were isolated and characterized,and their catalytic properties were studied.Subsequently,a novelβ-C（sp³）-H nitrooxylation of ketones was also developed by using TBN as the source of nitrate with a trident auxiliary.This method overcame the limitation that ketones must containα-quaternary carbon in the previous work and was compatible with heterocyclic substituents,which extends the scope of ketone substrates.A（5,6,5）palladacycle intermediate was characterized to understand the mechanism.Part III:The palladium-catalyzed C（sp³）-H nitrooxylation reaction was extended to amides,and a ligand-enabled C（sp³）-H nitrooxylation of amides was developed In this method,the carbonyl oxygen of the amide itself played a directing group.Silver nitrate was used as the source of nitrate group.NIS,as an exogenous oxidant,could promote the formation of Pd（IV）species and the subsequent formation of C-O bonds.The use of pyridine-3-sulfonic acid was also critical to the success of the reaction.Varieties of amides and functional groups could be compatible in the reaction.Gram scale experiment further improved the application value of the method.Part IV:A palladium-catalyzed,quinolineamide-directed C（sp³）-H intramolecular cyclization of amines was accidentally developed in the process of further expanding the palladium-catalyzed C（sp³）-H nitrooxylation substrate scope to amines.In this reaction,nitrates,such as cobalt nitrate hexahydrate,were used as the oxidant in the intramolecular cyclization reaction for the first time,and the nitrogen-containing quaternary five-membered rings were constructed.In the substrate extensibility study,it was found that a variety of amines and natural amino acid esters can be used as precursors to form nitrogen-containing heterocyclic structures.Part V:Palladium-catalyzed C（sp³）-H nitrooxylation of amides using quinoline amide and Ns or p-trifluoromethylbenzene sulfonyl（Tfs）protected amino as directing groups were developed respectively.When quinolinamide was used as the directing group,pyridine-2-sulfonic acid was used as the ligand.Due to the poor substrate extensibility of this method,a protected amino-directed C（sp³）-H nitrooxylation was developed,and acridine was the best ligand in this system.In this reaction,the amino group protected by Ns and p-trifluoromethyl benzene sulfonyl（Tfs）was used as the monodentate directing group.