Lewis Base-Boryl Radicals Enabled Borylation Reactions and Selective Activation of Carbon-Heteroatom Bonds.

ConspectusThe past decades have witnessed tremendous progress on radical reactions. However, in comparison with carbon, nitrogen, oxygen, and other main group element centered radicals, the synthetic chemistry of boron centered radicals was less studied, mainly due to the high electron-deficiency and instability of such 3-center-5-electron species. In the 1980s, Roberts and co-workers found that the coordination of a Lewis base (amines or phosphines) with the boron center could form 4-center-7-electron boryl radicals (Lewis base-boryl radicals, LBRs) that are found to be more stable. However, only limited synthetic applications were developed. In 2008, Curran and co-workers achieved a breakthrough with the discovery of N-heterocyclic carbene (NHC) boryl radicals, which could enable a range of radical reduction and polymerization reactions. Despite these exciting findings, more powerful and valuable synthetic applications of LBRs would be expected, given that the structures and reactivities of LBRs could be easily modulated, which would provide ample opportunities to discover new reactions. In this Account, a summary of our key contributions in LBR-enabled radical borylation reactions and selective activation of inert carbon-heteroatom bonds will be presented.Organoboron compounds have shown versatile applications in chemical society, and their syntheses rely principally on ionic borylation reactions. The development of mechanistically different radical borylation reactions allows synthesizing products that are inaccessible by traditional methods. For this purpose, we progressively developed a series of NHC-boryl radical mediated chemo-, regio-, and stereoselective radical borylation reactions of alkenes and alkynes, by which a wide variety of structurally diverse organoboron molecules were successfully prepared. The synthetic utility of these borylated products was also demonstrated. Furthermore, we disclosed a photoredox protocol for oxidative generation of NHC-boryl radicals, which enabled useful defluoroborylation and arylboration reactions.Selective bond activation is an ideal way to convert simple starting materials to value-added products, while the cleavage of inert chemical bonds, in particular the chemoselectivity control when multiple identical bonds are present in similar chemical environments, remains a long-standing challenge. We envisaged that finely tuning the properties of LBRs might provide a new solution to address this challenge. Recently, we disclosed a 4-dimethylaminopyridine (DMAP)-boryl radical promoted sequential C-F bond functionalization of trifluoroacetic acid derivatives, in which the α-C-F bonds were selectively snipped via a spin-center shift mechanism. This strategy enables facile conversion of abundantly available trifluoroacetic acid to highly valuable mono- and difluorinated molecules. Encouraged by this finding, we further developed a boryl radical enabled three-step sequence to construct all-carbon quaternary centers from a range of trichloromethyl groups, where the three C-Cl bonds were selectively cleaved by the rational choice of suitable boryl radical precursors in each step. Furthermore, a boryl radical promoted dehydroxylative alkylation of α-hydroxy carboxylic acid derivatives was achieved, allowing for the efficient conversion of some biomass platform molecules to high value products.

Boryl Radical as a Catalyst in Enabling Intra- and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules.

Cascade radical cyclization constitutes an atom- and step-economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox-active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium-based N-heterocyclic carbene (NHC)-boryl radical is capable of catalyzing cascade cyclization reactions in both intra- and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo- and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a ß-elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Boryl Radicals Enabled a Three-Step Sequence to Assemble All-Carbon Quaternary Centers from Activated Trichloromethyl Groups.

The construction of diversely substituted all-carbon quaternary centers has been a longstanding challenge in organic synthesis. Methods that add three alkyl substituents to a simple C(sp3) atom rely heavily on lengthy multiple processes, which usually involve several preactivation steps. Here, we describe a straightforward three-step sequence that uses a range of readily accessible activated trichloromethyl groups as the carbon source, the three C-Cl bonds of which are selectively functionalized to introduce three alkyl chains. In each step, only a single C-Cl bond was cleaved with the choice of an appropriate Lewis base-boryl radical as the promoter. A vast range of diversely substituted all-carbon quaternary centers could be accessed directly from these activated CCl3 trichloromethyl groups or by simple derivatizations. The use of different alkene traps in each of the three steps enabled facile collections of a large library of products. The utility of this strategy was demonstrated by the synthesis of variants of two drug molecules, whose structures could be easily modulated by varying the alkene partner in each step. The results of kinetic and computational studies enabled the design of the three-step reaction and provided insights into the reaction mechanisms.

Dehydroxylative Alkylation of α-Hydroxy Carboxylic Acid Derivatives via a Spin-Center Shift.

A strategically distinct dehydroxylative alkylation reaction of α-hydroxy carboxylic acid derivatives with alkenes is developed. The reaction starts with the attack of a 4-dimethylaminopyridine (DMAP)-boryl radical to the carbonyl oxygen atom, followed by a spin-center shift (SCS) to trigger the C-O bond scission. The resulting α-carbonyl radicals couple with a wide range of alkenes to furnish various alkylated products. This strategy allows for the efficient conversion of a wide array of α-hydroxy amides and esters derived from several biomass molecules and natural products to value-added compounds. Experimental and computational studies verified the reaction mechanism.

Stereoselective Copper-Catalyzed Direct Aldol Reaction of ß, γ-Unsaturated α-Ketoesters with Coumaran-3-Ones.

An efficient direct aldol reaction between coumaran-3-ones and ß, γ-unsaturated α-ketoesters by virtue of a chiral copper complex is developed. A series of coumaran-3-one derivatives containing chiral tertiary alcohol structures are obtained in excellent yields and stereoselectivities.

Selective N-monomethylation of primary anilines with the controllable installation of N-CH2D, N-CHD2, and N-CD3 units.

The selective N-monomethylation of primary anilines was realized by the use of the Me3N-BH3/N,N-dimethylformamide (DMF) system as the methyl source. This method also allows for the controllable introduction of N-CH2D, N-CHD2, and N-CD3 units with high levels of deuterium incorporation using Me3N-BH3/d7-DMF, Me3N-BD3/DMF and Me3N-BD3/d7-DMF systems, respectively.

New Radical Borylation Pathways for Organoboron Synthesis Enabled by Photoredox Catalysis.

Radical borylation using N-heterocyclic carbene (NHC)-BH3 complexes as boryl radical precursors has emerged as an important synthetic tool for organoboron assembly. However, the majority of reported methods are limited to reaction modes involving carbo- and/or hydroboration of specific alkenes and alkynes. Moreover, the generation of NHC-boryl radicals relies principally on hydrogen atom abstraction with the aid of radical initiators. A distinct radical generation method is reported, as well as the reaction pathways of NHC-boryl radicals enabled by photoredox catalysis. NHC-boryl radicals are generated via a single-electron oxidation and subsequently undergo cross-coupling with the in-situ-generated radical anions to yield gem-difluoroallylboronates. A photoredox-catalyzed radical arylboration reaction of alkenes was achieved using cyanoarenes as arylating components from which elaborated organoborons were accessed. Mechanistic studies verified the oxidative formation of NHC-boryl radicals through a single-electron-transfer pathway.

Selective α-Monomethylation by an Amine-Borane/N,N-Dimethylformamide System as the Methyl Source.

A new and practical α-monomethylation strategy using an amine-borane/N,N-dimethylformamide (R3 N-BH3 /DMF) system as the methyl source was developed. This protocol has been found to be effective in the α-monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R3 N-BH3 donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH2 -, CD2 H-, and CD3 - units using Me2 NH-BH3 /d7 -DMF, Me3 N-BD3 /DMF and Me3 N-BD3 /d7 -DMF systems, respectively. Further application of this method to the facile synthesis of anti-inflammatory flurbiprofen and its varied deuterium-labeled derivatives was demonstrated.

Radical Borylation/Cyclization Cascade of 1,6-Enynes for the Synthesis of Boron-Handled Hetero- and Carbocycles.

A synthetic method to construct boron-handled cyclic molecules was developed based on a radical borylation/cyclization cascade of 1,6-enynes. The process was initiated by the chemo- and regio-controlled addition of an N-heterocyclic carbene-boryl radical to an alkene or alkyne, followed by ring closure to afford boron-substituted cyclic skeletons. Further molecular transformations of the cyclic products to synthetically useful building blocks were also demonstrated.

Amide synthesis by nucleophilic attack of vinyl azides.

A method for the synthesis of amide-containing molecules was developed using vinyl azides as an enamine-type nucleophile towards carbon electrophiles, such as imines, aldehydes, and carbocations that were generated from alcohols in the presence of BF3 ⋅OEt2 . After nucleophilic attack of the vinyl azide, a substituent of the resulting iminodiazonium ion intermediate migrates to form a nitrilium ion, which is hydrolyzed to afford the corresponding amide.

Radical hydroboration for the synthesis of organoboron compounds.

Organoboron compounds demonstrate diverse applications in the fields of organic synthesis, materials science, and medicinal chemistry. Compared to the conventional hydroboration reaction, radical hydroboration serves as an alternative approach for the synthesis of organoborons via different mechanisms. In radical hydroboration, a boryl radical is initially generated from homolytic cleavage of a B-H or a B-B bond, which is then added to an unsaturated double bond to deliver a carbon radical. Subsequent hydrogen atom transfer or reduction of the carbon radical to form a carbanion followed by protonation gave the final product. Over the past few years, numerous efforts have been made for efficient synthesis of boryl radicals and the expansion of substrate scope of the radical hydroboration reaction. Here, we discuss the recent advancement of radical hydroboration and its associated mechanisms. Numerous radical hydroboration strategies employing N-heterocyclic carbene borane, bis(pinacolato)diboron and pinacolborane as the boron source were illustrated. Thermochemical, photochemical and electrochemical strategies for the generation of boryl radicals were also discussed in detail.

Leech Poecilobdella manillensis protein extract ameliorated hyperuricemia by restoring gut microbiota dysregulation and affecting serum metabolites.

BACKGROUND: Hyperuricemia (HUA) is a public health concern that needs to be solved urgently. The lyophilized powder of Poecilobdella manillensis has been shown to significantly alleviate HUA; however, its underlying metabolic regulation remains unclear. AIM: To explore the underlying mechanisms of Poecilobdella manillensis in HUA based on modulation of the gut microbiota and host metabolism. METHODS: A mouse model of rapid HUA was established using a high-purine diet and potassium oxonate injections. The mice received oral drugs or saline. Additionally, 16S rRNA sequencing and ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics were performed to identify changes in the microbiome and host metabolome, respectively. The levels of uric acid transporters and epithelial tight junction proteins in the renal and intestinal tissues were analyzed using an enzyme-linked immunosorbent assay. RESULTS: The protein extract of Poecilobdella manillensis lyophilized powder (49 mg/kg) showed an enhanced anti-trioxypurine ability than that of allopurinol (5 mg/kg) (P < 0.05). A total of nine bacterial genera were identified to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which included the genera of Prevotella, Delftia, Dialister, Akkermansia, Lactococcus, Escherichia_Shigella, Enterococcus, and Bacteroides. Furthermore, 22 metabolites in the serum were found to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which correlated to the Kyoto Encyclopedia of Genes and Genomes pathways of cysteine and methionine metabolism, sphingolipid metabolism, galactose metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. Correlation analysis found that changes in the gut microbiota were significantly related to these metabolites. CONCLUSION: The proteins in Poecilobdella manillensis powder were effective for HUA. Mechanistically, they are associated with improvements in gut microbiota dysbiosis and the regulation of sphingolipid and galactose metabolism.

Orthogonal aerobic conversion of N-benzyl amidoximes to 1,2,4-oxadiazoles or quinazolinones.

Concise synthesis of 1,2,4-oxadiazoles was achieved by heating N-benzyl amidoximes with K3PO4 in DMF at 60 °C under an O2 atmosphere via benzylic C-H oxygenation. On the other hand, aerobic treatment of N-benzyl amidoximes with Cs2CO3 in DMSO at 100 °C could result in oxidative skeletal rearrangement to deliver quinazolinones as a major product. This orthogonal product selectivity could be realized by difference of the reaction temperature as well as selection of the solvents and inorganic bases.

Boryl Radical-Promoted Dehydroxylative Alkylation of 3-Hydroxyoxindole Derivatives.

A boryl radical-promoted dehydroxylative alkylation of 3-hydroxy-oxindole derivatives is achieved. The reaction starts from addition of 4-dimethylaminopyridine (DMAP)-boryl radical to the amide carbonyl oxygen atom, which induces a spin-center shift process to promote the C-O bond cleavage. The elimination of a hydroxide anion from a free hydroxy group is also accomplished. Capture of the generated carbon radical with alkenes furnishes a variety of C-3 alkylated oxindoles. This method features a simple operation and broad substrate scope.

Boryl radical catalysis enables asymmetric radical cycloisomerization reactions.

The development of functionally distinct catalysts for enantioselective synthesis is a prominent yet challenging goal of synthetic chemistry. In this work, we report a family of chiral N-heterocyclic carbene (NHC)-ligated boryl radicals as catalysts that enable catalytic asymmetric radical cycloisomerization reactions. The radical catalysts can be generated from easily prepared NHC-borane complexes, and the broad availability of the chiral NHC component provides substantial benefits for stereochemical control. Mechanistic studies support a catalytic cycle comprising a sequence of boryl radical addition, hydrogen atom transfer, cyclization, and elimination of the boryl radical catalyst, wherein the chiral NHC subunit determines the enantioselectivity of the radical cyclization. This catalysis allows asymmetric construction of valuable chiral heterocyclic products from simple starting materials.

Application of the Spin-Center Shift in Organic Synthesis.

Spin-center shift (SCS) is a radical process involving 1,2-radical translocation along with a two-electron ionic movement, such as elimination of an adjacent leaving group. Such a process was initially observed in some important biochemical transformations, and the unique property has also attracted considerable interest in synthetic chemistry. Experimental, kinetic, as well as computational studies have been performed, and a series of useful radical transformations have been developed and applied in organic synthesis based on SCS processes in the last 20 years. This Perspective is an overview of radical transformations involving the SCS mechanism.

Stereoselective hydrogen atom transfer to acyclic radicals: a switch enabling diastereodivergent borylative radical cascades.

Radical cascade reactions are powerful tools to construct structurally complex molecules. However, the stereochemical control of acyclic radical intermediates remains a persistent challenge, due to the low differentiation between the two faces of these species. This hurdle further makes stereodivergent synthesis rather more difficult to be accomplished, in particular for intermediates resulted from complex cascades. Here we report an efficient strategy for stereoselective hydrogen atom transfer (HAT) to acyclic carbon radicals, which are generated via N-heterocyclic carbene (NHC)-boryl radicals triggered addition-translocation-cyclization cascades. A synergistic control by the NHC subunit and a thiol catalyst has proved effective for one facial HAT, while a ZnI2-chelation protocol allows for the preferential reaction to the opposite face. Such a stereoselectivity switch enables diastereodivergent construction of heterocycles tethering a boron-substituted stereocenter. Mechanistic studies suggest two complementary ways to tune HAT diastereoselectivity. The stereospecific conversions of the resulting boron-handled products to diverse functionalized molecules are demonstrated.

Sequential C-F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts.

Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, the controllable replacement of one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe a general strategy for sequential carbon-fluorine (C-F) bond functionalizations of trifluoroacetamides and trifluoroacetates. The reaction begins with the activation of a carbonyl oxygen atom by a 4-dimethylaminopyridine-boryl radical, followed by a spin-center shift to trigger the C-F bond scission. A chemoselectivity-controllable two-stage process enables sequential generation of difluoro- and monofluoroalkyl radicals, which are selectively functionalized with different radical traps to afford diverse fluorinated products. The reaction mechanism and the origin of chemoselectivity were established by experimental and computational approaches.

Radical α-addition involved electrooxidative [3 + 2] annulation of phenols and electron-deficient alkenes.

An electrooxidative [3 + 2] annulation of phenols and electron-deficient alkenes for the synthesis of C3-functionalized 2-aryl-2,3-dihydrobenzofuran derivatives was achieved. The ring construction starts by a unique α-addition of carbon radicals derived from anodic oxidation of phenols to electron-deficient alkenes. The subsequent anodic oxidation of the resulting alkyl radical intermediates followed by trapping with the phenolic hydroxy group assembles the 2,3-dihydrobenzofuran core. Such a pathway enables the installation of various electrophilic functionalities including alkoxycarbonyl, alkylaminocarbonyl, trifluoromethyl, and cyano groups at the C-3 of the 2,3-dihydrobenzofuran framework, which is unattainable by other intermolecular reactions. The application of this method for a rapid synthesis of a bioactive natural product is demonstrated.

Copper-Catalyzed Anti-Markovnikov Hydrosilylation of Terminal Alkynes.

A copper-catalyzed anti-Markovnikov hydrosilylation of alkynes with PhSiH3 was reported. This reaction represents a notable and efficient example on copper-catalyzed hydrosilylatioin of alkynes, which shows excellent recognition between the terminal and internal triple bonds. Various (hetero)aromatic and aliphatic substituted terminal alkynes underwent this reaction to afford the (E)-vinylsilanes in high yields and with excellent regioselectivity.