Periodic Reporting for period 4 - e-Cat (The Electron as a Catalyst)
Reporting period: 2021-04-01 to 2022-03-31
Is the electron a catalyst in synthesis? This fundamental question has been addressed. In the challenging project, e-catalysis and its potential in synthesis have been investigated. The aim was to establish e-catalysis as an independent research branch in organic synthesis. The generality and broad applicability of the concept had to be documented. Different reactions, which have been conducted as non-chain reactions by using transition metals as redox catalysts, have been performed via electron-catalyzed radical chain processes. In view of the foreseen shortage of transition metals we considered the development of transition-metal-free chemistry as important. Preparative and kinetic experimental studies have been supported by theoretical chemistry.
Overall 46 papers resulted. Aryl iodides and bromides are efficiently reduced with Na-alcoholates by e-catalysis. H-atom transfer from the weak C-H bond in Na-alcoholates results in ketyl radical anions, that act as SET-reductants. The sigma-bond activation in anionic radicals served as basis for development of e-catalyzed alkenyl/alkynyl-migrations and allylations. We used ethereal solvents as radical chain reductants and even less activated aryl chlorides could be reduced via this e-catalyzed process.
We studied the electrochemical approach to initiate e-catalyzed transformations. Further, we investigated thermal homolysis of deprotonated pinacols and used non-thermal plasma for initiation of e-catalyzed reactions. We tackled the SET-reduction of acyl azoliums to give ketyl radicals. Via strategy, a synthesis of β-trifluoromethylated alkyl aryl ketones via cooperative NHC/photoredox catalysis was developed. We published the direct α-acylation of alkenes via NHC, sulfinate, and photoredox cooperative triple catalysis. In addition, the dearomative aroylfluorination of benzofurans and indoles was achieved with aroylfluorides using NHC/photoredox catalysis.
The acidity of radical anions has been in focus using theory. We also investigated heteroarene syntheses applying e-catalysis and hydrazones were found to be valuable radical acceptors. Often perfluoroalkyl iodides, that are SET-reduced by radical anions occurring as intermediates in e-catalyzed transformations, were used as C-radical precursors. We also established electron-catalyzed α-perfluoroalkyl-β-heteroarylation of various alkenes with perfluoroalkyl iodides using quinoxalin-2(1H)-ones as radical acceptors. For less reducing radical anions, I(III)-reagents with higher reduction potential were used as radical precursors. Thus, I(III)-chemistry was applied to the regio- and stereoselective perfluoroalkyltriflation of alkynes using phenyl(perfluoroalkyl)iodonium triflates as C-radical precursors. Moreover, a metal-free direct alkene-C-H cyanation was developed. Alkynyl-I(III)-species were used as C-radical trapping reagents of redox-catalyzed alkene amidoalkynylations. To this end, a novel amidyl radical precursor that allows generating an N-radical via SET-oxidation was developed. This N-radical precursor was used in an alkene amidofluorination and in a carboamination of unactivated alkenes.
We introduced alkenyl boron ate complexes as radical acceptors in electron-catalyzed radical-polar crossover reactions. This approach was extended towards the preparation of α-chiral ketones. Amidyl-radical induced radical polar cross/over in vinyl boronates were established. We used the B-ate chemistry in alkaloid synthesis and developed a protocol for the hydrodeboronation of alkyl B-ate complexes. The hydrodeboronation reaction was applied to a radical alkene hydromethylation. B-ate complexes were used in transition-metal free C-H a-arylation or a-alkylation reactions using a novel coupling strategy. We showed that 1,n-bisborylalkanes can be prepared via boron migration using diboron ate complexes. Along these lines, radical 1,2-boron migration is a key step in the 1,3-difunctionalization of allylboronic esters. In addition, catechol diborane was found to be an efficient alkyl radical borylation reagent. For example, mild electron-catalyzed alkene 1,2-perfluoroalkylborylation was realized. Meanwhile, we also found that alkyl iodides and aryl iodides can be converted to the corresponding boronic esters under very mild and practical conditions. Further, conversion of alcohols to their boronic esters (deoxygenative borylation) was achieved by using the same approach. In the B-ate field, we developed a transition-metal-free oxidative cross-coupling of tetraarylborates to biaryls using organic oxidants.
We introduced radical translocating arylating groups for remote C-H arylation of alcohols at unactivated sites and also applied that strategy to the functionalization of α‐C(sp3)‒H bonds in various amides. We further showed that ketenes react with arylsulfonamides to the corresponding amide enolates that upon SET-oxidation and subsequent radical aryl migration provide a-arylated amides. Finally, we entered the area of Fe-H-induced radical alkene hydration and found that nitroarenes can be used in place of dioxygen as radical oxygenation reagents.
We studied the electrochemical approach to initiate e-catalyzed transformations. Further, we investigated thermal homolysis of deprotonated pinacols and used non-thermal plasma for initiation of e-catalyzed reactions. We tackled the SET-reduction of acyl azoliums to give ketyl radicals. Via strategy, a synthesis of β-trifluoromethylated alkyl aryl ketones via cooperative NHC/photoredox catalysis was developed. We published the direct α-acylation of alkenes via NHC, sulfinate, and photoredox cooperative triple catalysis. In addition, the dearomative aroylfluorination of benzofurans and indoles was achieved with aroylfluorides using NHC/photoredox catalysis.
The acidity of radical anions has been in focus using theory. We also investigated heteroarene syntheses applying e-catalysis and hydrazones were found to be valuable radical acceptors. Often perfluoroalkyl iodides, that are SET-reduced by radical anions occurring as intermediates in e-catalyzed transformations, were used as C-radical precursors. We also established electron-catalyzed α-perfluoroalkyl-β-heteroarylation of various alkenes with perfluoroalkyl iodides using quinoxalin-2(1H)-ones as radical acceptors. For less reducing radical anions, I(III)-reagents with higher reduction potential were used as radical precursors. Thus, I(III)-chemistry was applied to the regio- and stereoselective perfluoroalkyltriflation of alkynes using phenyl(perfluoroalkyl)iodonium triflates as C-radical precursors. Moreover, a metal-free direct alkene-C-H cyanation was developed. Alkynyl-I(III)-species were used as C-radical trapping reagents of redox-catalyzed alkene amidoalkynylations. To this end, a novel amidyl radical precursor that allows generating an N-radical via SET-oxidation was developed. This N-radical precursor was used in an alkene amidofluorination and in a carboamination of unactivated alkenes.
We introduced alkenyl boron ate complexes as radical acceptors in electron-catalyzed radical-polar crossover reactions. This approach was extended towards the preparation of α-chiral ketones. Amidyl-radical induced radical polar cross/over in vinyl boronates were established. We used the B-ate chemistry in alkaloid synthesis and developed a protocol for the hydrodeboronation of alkyl B-ate complexes. The hydrodeboronation reaction was applied to a radical alkene hydromethylation. B-ate complexes were used in transition-metal free C-H a-arylation or a-alkylation reactions using a novel coupling strategy. We showed that 1,n-bisborylalkanes can be prepared via boron migration using diboron ate complexes. Along these lines, radical 1,2-boron migration is a key step in the 1,3-difunctionalization of allylboronic esters. In addition, catechol diborane was found to be an efficient alkyl radical borylation reagent. For example, mild electron-catalyzed alkene 1,2-perfluoroalkylborylation was realized. Meanwhile, we also found that alkyl iodides and aryl iodides can be converted to the corresponding boronic esters under very mild and practical conditions. Further, conversion of alcohols to their boronic esters (deoxygenative borylation) was achieved by using the same approach. In the B-ate field, we developed a transition-metal-free oxidative cross-coupling of tetraarylborates to biaryls using organic oxidants.
We introduced radical translocating arylating groups for remote C-H arylation of alcohols at unactivated sites and also applied that strategy to the functionalization of α‐C(sp3)‒H bonds in various amides. We further showed that ketenes react with arylsulfonamides to the corresponding amide enolates that upon SET-oxidation and subsequent radical aryl migration provide a-arylated amides. Finally, we entered the area of Fe-H-induced radical alkene hydration and found that nitroarenes can be used in place of dioxygen as radical oxygenation reagents.
With the B-ate complexes we introduced valuable radical acceptors that show great potential. They allowed the development of new radical methodology, significantly expanding the radical chemical space. In our radical ionic crossover, the valuable boronic ester remains in the product.The potential of the cross over methodology was documented by the development of methods for the preparation of gamma-lactones and alpha-chiral ketones. Further, an a-C-C coupling reaction of boronic esters was developed. This coupling is complementary to existing methodology and does not require any transition-metal catalysis. Again, B-ate complexes turned out to be highly valuable starting materials.
Radical dehalogenations in aryl halides have been mainly conducted using toxic tin hydrides as reagents. We showed that such transformations can be achieved with cheap alcoholates as reagents. Notably, electron-catalyzed reactions can be initiated using electrochemistry or with a Helium plasma. No doubt, the use of a plasma to conduct radical chemistry is unconventional, represents novel methodology and we see potential along those lines.
The radical borylation with catechol diboranes also represents a valuable method. Borylation of alkyl and aryl iodides is practical and should find use in industry. In most projects, we used DFT-calculations for mechanistic analysis.
In the final two funding periods, we investigated radical transformations which proceed via electron transfer processes and use N-heterocyclic carbenes (NHCs) as catalysts. NHCs have been intensively used in ionic organic synthesis but NHC radical catalysis has remained underdeveloped. We found that readily generated acylazolium ions derived from acyl fluorides and the NHC catalyst can be SET-reduced with a redox catalyst and the thus generated persistent ketyl radicals efficiently couple with concomitantly oxidatively generated transient C-radicals. After cross coupling, which is steered by the persistent radical effect, the NHC catalyst is liberated closing the NHC catalysis cycle. The overall transformation represents a redox neutral process and no terminal redox reagent is required. This NHC/radical catalysis has gained great attention in the past two years and we heavily contributed to the development of this emerging area with pioneering and continuous studies.
Radical dehalogenations in aryl halides have been mainly conducted using toxic tin hydrides as reagents. We showed that such transformations can be achieved with cheap alcoholates as reagents. Notably, electron-catalyzed reactions can be initiated using electrochemistry or with a Helium plasma. No doubt, the use of a plasma to conduct radical chemistry is unconventional, represents novel methodology and we see potential along those lines.
The radical borylation with catechol diboranes also represents a valuable method. Borylation of alkyl and aryl iodides is practical and should find use in industry. In most projects, we used DFT-calculations for mechanistic analysis.
In the final two funding periods, we investigated radical transformations which proceed via electron transfer processes and use N-heterocyclic carbenes (NHCs) as catalysts. NHCs have been intensively used in ionic organic synthesis but NHC radical catalysis has remained underdeveloped. We found that readily generated acylazolium ions derived from acyl fluorides and the NHC catalyst can be SET-reduced with a redox catalyst and the thus generated persistent ketyl radicals efficiently couple with concomitantly oxidatively generated transient C-radicals. After cross coupling, which is steered by the persistent radical effect, the NHC catalyst is liberated closing the NHC catalysis cycle. The overall transformation represents a redox neutral process and no terminal redox reagent is required. This NHC/radical catalysis has gained great attention in the past two years and we heavily contributed to the development of this emerging area with pioneering and continuous studies.