Pyridine-boryl Radicals Mediated Reductive Couping Reactions: Computational Design And Experimental Study

Diborane compounds,as a class of highly useful chemical raw materials in the synthetic chemistry,are widely used in boron chemistry research.In recent years,with the prosperity of radical chemistry,new synthetic methods based on boron radicals have become one of the research hotspots in the field of chemical synthesis.Among them,the homolytic cleavage of the B-B bond of B₂?pin?₂ by the cooperative catalysis of two Lewis bases to produce pyridine-boryl radicals has become a simple and effective approach for the generation of boryl radicals.Based on the pyridine-boryl radicals,the azobenzene,sulfoxide and quinones can be reduced,the reductive coupling of aldehydes with 1,1-diarylethylenes can be realized,the 4-pyridine derivatives and aryl borate esters can be synthesized,and the perfluoroalkylative pyridylation of alkenes can be achieved.Although quite a few synthetic applications of pyridine-boryl radicals have been achieved in recent years,it is still of great significance to develop more reactions using easily available pyridine-boryl radicals.In this thesis,my focus is on developing new synthetic applications of the pyridine-boryl radicals via a combination of computational design and experimental study.We have realized new reactions mediated by pyridine-boryl radicals,including decarboxylative alkylation of N-hydroxyphthalimide esters,and Lewis acid-catalyzed selective reductive decarboxylative pyridylation of N-hydroxyphthalimide esters,reductive coupling of aliphatic aldehydes/ketones with 4-cyanopyridine.The main research results can be summarized as follows:Part ?.The decarboxylative alkylation via the addition of carbon radicals to olefins is one of the most useful tools to construct C-C bonds,due to the broad sources of carboxylic acids and olefins.Traditionally,transition-metal or photoredox catalysts are required in these reactions.Herein,based on quantum chemistry calculations and experimental studies,we developed a new organocatalytic decarboxylative alkylation reaction.At first,our DFT calculations indicate that the N-hydroxyphthalimide?NHPI?esters are very likely to coordinate with the pyridine-boryl radicals to form a radical intermediate,which may trigger the fragmentation of NHPI esters to generate a carbon radical for subsequent radical-alkyene addition reactions.Based on the calculated reaction mechanism,our further experimental studies have demonstrated that pyridine-boryl radicals promoted decarboxylative alkylation of NHPI esters and olefins can be realized.The control experiments?such as radical clock,EPR,nuclear magnetism resonance and high-resolution mass spectrometry?provide supportive evidence for the calculated mechnism.This metal-free decarboxylative alkylation reaction features good functional compatibility,and broad substrate scope illustrated by the transformations of both the alkyl and aryl carboxylic acid derivatives.Part ?.Pyridines are essential structural units that exist in a wide range of biologically active molecules,natural products,and functional materials.Therefore,the development of new synthetic methods for highly efficient construction of pyridine derivatives are of significance in organic synthesis.Traditional functionalization of pyridines,including nucleophilic aromatic substitution?S_NAr?,and transition-metal catalyzed C-H activation,has been broadly investigated.However,sensitive organometallic reagents or transition-metal catalysts are always required in these processes.Moreover,these methods are usually limited by harsh reaction conditions and narrow substrate scope.In recent years,complex pydirine derivatives have also been constructed via radical-mediated processes,such as the radical addition or radical-radical coupling reactions.For example,the classical Minisci-type reactions via the direct addition of carbon radical to heteroaromatic bases is an effective way to construct alkylated pyridines.However,there are still significant challenges in the tunability of regioselectivity of pyridines.Recent theoretical calculations and experiment studies from our group have shown that pyridine-boron radicals have the dual properties of both"boron radicals"and"pyridine precursors",and they can be applied to synthesize4-substituted pyridines under suitable conditions.Here,inspired by our previous work on the radical decarboxylative coupling reaction,we have developed a new Lewis acid-catalyzed selective reductive decarboxylative pyridylation reaction of N-hydroxyphthalimide esters.The combination of DFT calculations and experimental investigations suggests that Lewis acid could promote the regioselectivity of the radical-radical coupling step and lower the activation barrier of the rearomatization of the 1,4-dihydropyridine intermediate.This protocol features good selectivity,excellent functional group compatibility,and a series of 4-substituted pyridine derivatives that could be readily prepared under simple and mild reaction conditions.Part ?.Aliphatic aldehydes and ketones are pervasive structures in natural products.The direct nucleophilic addition reaction of nucleophilic reagents to the carbonyl compounds is a reliable method for the construction of C-C bonds,and provides an efficient approach for generating the alcohol products,which are also frequently encountered as key building blocks in organic synthesis.Currently used approaches mainly rely on the participation of organometallic reagent,transition-metal catalyst or photocatalyst.In this work,we report an organocatalytic reductive coupling reaction of aliphatic aldehydes/ketones with 4-cyanopyridine via a combined computational and experimental study.This metal-free reductive pyridylation reaction features good functional compatibility,and broad substrate scope illustrated by the transformations of both the aliphatic aldehydes,ketones and pyridines.In addition,DFT calculations and control experiments?such as NMR,HRMS and X-ray spectroscopy?suggest that these reactions involve a boryl-radical mediated radical-radical coupling pathway.