Study On Silver-Catalyzed Cyclizations And Cyanations With Isocyanides

Isocyanides serve as an important building block in organic synthesis which have display special and flexible properties mainly including coordination to metal centres,α-addition,α-acidity,and as a free radical receptor.It is commonly used for the construction of nitrogen-containing molecules or heterocyclic compounds.Isocyanide-involved cascade reactions,such as the Passerini and Ugi reactions,and their modified heterocyclization reactions,and other reactions are important strategies to access amino acids,peptides,and peptide-based molecules,as well as various heterocycles.However,currently,the reactions of isocyanides are greatly restricted to the multicomponent reactions,such as Passerini and Ugi and their extensions.Therefore,it is necessary to develop new modes of isocyanide reactions to broaden their application in organic synthesis,and for efficient synthesis of chemicals.This has attracted more and more attention of chemists and bacome a hot topic in the contemporary reasearch of isocyanides.Recently,the development of transition metal catalysis with isocyanides has received great attention,especially the study of non-Passerini and Ugi-type reactions,such as bimolecular reactions.However,due to the strong coordination between isocyanide and metals,as well as the uncontrollable over-insertion of isocyanides have become thorny issues and reducing yields and selectivity.Therefore,the exploration of suitable catalytic systems,to effective regulate possible reaction pathways,which has become an important research direction of isocyanide chemistry.At present,the development of novel,efficient,and selective transformations are still a major challenge for organic chemists.Our group has been committed to the development of silver catalysis and has made some progress in the field of isocyanides.The incorporation of silver and isocyanides provides an effective catalytic activation system,which can well regulate the insertion of isonitrile to improve the efficiency and selectivity of the reactions.This provides a possible access to address the current polymetallic polycondensation of isonitriles.At the same time,At the same time,the silver salt of Lewis acidity,single electron oxidation properties also provide a new reaction mode and a possible catalytic environment with isocyanides for the construction of nitrogen-containing compounds,such as heterocyclics,amides,and nitrile derivatives.Recently,significant progress has been made in the direct C–H bond functionalization with isocyanides under the transition metal catalysis.In particular,palladium-catalyzed isocyanide insertion reactions(also referred to as imidization reactions)have been extensively studied and have become a powerful tool in organic synthesis.In view of the silver-catalyzed isocyanide reactions,development related to C–H functionalizations,such as the [3+2] cycloaddition of isocyanides with terminal alkynes,C(sp)–H bond cyanation,and cross-coupling with dicarbonyl compounds has been reported by our group.Although silver has a good controllability for isocyanide insertions,it is still less developed.In addition,although the conversion between isocyanide and cyanide has been well known,the current research on the tandem isocyanide insertion/cyanation is largely limited to palladium catalysis.In this thesis,we focus on developing new modes of silver catalysed isocyanide transformations,including new tandem mode for the synthesis of heterocycles,applications of N-isocyanoiminotriphenylphosphine(NIITP),and inert bonds activation with isocyanides.This mainly includes three parts,seven chapters:The first part: the research background and topic for the thesis.The second part: silver-promoted cyclizations of isocyanides reaction to prepare functionalized heterocyclic derivatives,including the third and fourth chapters of the thesis.Chapter 3: Silver-catalyzed cascade reaction of β-enaminones and isocyanoacetates to construct polysubstituted pyrroles.Chapter 4: Synthesis of imidazole/imidazoline derivatives via [3+1+1] cyclization of isocyanoacetates with nitrosoaromatics.Based on the [3+2] cycloadditions of isocyanoacetates,we have completed two new cyclization reactions of isocyanoacetates with β-enaminones and nitrosoaromatics,respectively under the silver catalysis.β-Enaminone is a stable imine precursor that was used to perform the Mannich cyclization with isocyanoacetate,which followed by steps such as the retro-Michael step and dehydration condensation to produce pyrrole products.In the [3+1+1] annulation of nitroisoaromatics,isocyanoacetates serve as both a 1,3-dipole and C1 synthon.At the same time,the imidazole or imidazoline derivatives could be selectively obtained by simple adjusting the reaction conditions.The third part: study on cyclization and cyanation with N-isocyanoiminotriphenylphosphorane(NIITP),including Chapters 5 to 7.Chapter 5: Silver-promoted intermolecular aminocyanation of alkynes to(Z)-β-aminoacrylonitrilesChapter 6: Silver/molybdenum promoted [3+2] cyclization with non-activated terminal alkyne for the synthesis of 1H-pyrazoles.Chapter 7: Silver(I)-catalytic cross metathesis between C(sp3)–C(O)and N–NC bondsThe solid functionalized isocyanide N-isocyanoiminotriphenylphosphorane(NIITP)is thermally stable and commercial available.However,theie applications have greatly limited to being ligands and involvment in(Ugi)multi-component reactions to access heterocyclics.Learning from the direct cyanations of non-activated terminal alkynes,we further investigated the reactivity of NIITP as a cyano source.Inspired by the efficient interaction of silver,non-activated terminal alkyne and NIITP,a direct aminocyanation reaction of alkyne was achieved for the first time,providing a series of β-aminoacrylonitriles with high selectivity.With DTF calculations we proposed the plausible mechanism involved.The novel cross-metathesis reaction of inert C–C and N–N single bonds(i.e.selective cross-exchange α-functionalized ketones and NIITP)provides an effective method for the synthesis of cyanides.This reaction is also an important advance in transition metal-catalyzed selective cleavage and direct cyanation of inert C–C σ-bonds.At the same time,NIITP can also be used as a stable diazo-replacement reagent “NNC” synthon to provide 1H-pyrazole through the [3+2] cyclization with terminal alkynes.This “NNC” reactivity is an important foundation for NIITP as a cyano donor for achieving intermolecular aminocyanation and cross-metathesis reactions.Subsequent cycloreversion and N–N bond cleavage is the key to complete the isocyano-initiated cyanation strategy.