Transition-metal-free coupling reactions involving gem–diborylalkanes

Due to the increasing demand for the sustainability of modern organic chemistry, the development of green and powerful methods for C-C and C-B bond formation is highly desired. Among them, the transition-metal-free coupling reactions of gem–diborylalkanes emerge as one valuable tool for organic chemists in the last decade. The review covers selected representative examples. A comparison of these reactions with transition-metal-catalyzed reactions is provided. The recent example of α-boryl radical formation from gem–diborylalkanes is also briefly discussed.

C–F bond activation under transition-metal-free conditions

The unique properties of fluorine-containing organic compounds make fluorine substitution attractive for the development of pharmaceuticals and various specialty materials,which have inspired the evolution of diverse C–F bond activation techniques.Although many advances have been made in functionalizations of activated C–F bonds utilizing transition metal complexes,there are fewer approaches available for nonactivated C–F bonds due to the difficulty in oxidative addition of transition metals to the inert C–F bonds.In this regard,using Lewis acid to abstract the fluoride and light/radical initiator to generate the radical intermediate have emerged as powerful tools for activating those inert C–F bonds.Meanwhile,these transition-metal-free processes are greener,economical,and for the pharmaceutical industry,without heavy metal residues.This review provides an overview of recent C–F bond activations and functionalizations under transition-metal-free conditions.The key mechanisms involved are demonstrated and discussed in detail.Finally,a brief discussion on the existing limitations of this field and our perspective are presented.

Direct benzylation reactions from benzyl halides enabled by transition-metal-free photocatalysis

An SN2-based photochemical strategy using dithiocarbamate anion as catalyst was developed for the activation of benzyl halides,which are extremely challenging to be applied as radical precursors in visible light photocatalysis.With this transition-metal-free and oxidant-free protocol,the benzylation(or cyanomethylation)of various heterocycles including quinoxalin-2(1H)-ones,coumarin,2-phenyl-2H-indazole,1-methyl-5-phenylpyrazin-2(1H)-one,1-(fluoromethyl)cinnolin-4(1H)-one,and 2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione could be realized(46 examples,up to 98%yield).Importantly,some biologically relevant 3-benzylquinoxalin-2(1H)-ones were also be synthesized under mild conditions.

Hydrogen-bond-assisted transition-metal-free catalytic transformation of amides to esters

The amide C-N cleavage has drawn a broad interest in synthetic chemistry,biological process and pharmaceutical industry.Transition-metal,luxury ligand or excess base were always vital to the transformation.Here,we developed a transition-metalfree hydrogen-bond-assisted esterification of amides with only catalytic amount of base.The proposed crucial role of hydrogen bonding for assisting esterification was control experiments,density functional theory(DFT)calculations and kinetic studies.Besides broad substrate scopes and excellent functional groups tolerance,this base-catalyzed protocol complements the conventional transition-metal-catalyzed esterification of amides and provides a new pathway to catalytic cleavage of amide C–N bonds for organic synthesis and pharmaceutical industry.

Three-Component Synthesis of 2-Heteroaryl-3-hydroxybenzo[b]- thiophenes under Transition-Metal-Free Conditions

A convenient synthetic route to 2-heteroaryl-3-hydroxybenzo[b]thiophene derivatives via K_(2)CO_(3)-promoted multicomponent cycliza-tion between o-halogenated benzaldehyde,2-methylquinolines and sulfur powder has been demonstrated.This reaction is performed smoothly under simple conditions to give the corresponding products in moderate to good yields.The resultant 3-hydroxybenzo[b]thiophenes have been proved to be versatile building blocks in a range of transition-metal-catalyzed cross-coupling reactions.

Transition-Metal-Free Catalyzed Dehydrative Coupling of Quinoline and Isoquinoline N-Oxides with Propargylic Alcohols

A novel,green,and transition-metal-free protocol for the facile modification of quinoline and isoquinoline derivatives is introduced,starting from readily available and environmentally benign quinoline and isoquinoline N-oxides with propargylic alcohols in the presence of Na_(2)S_(2)O_(8) or K_(2)S_(2)O_(8) at 100℃.The one-pot transformation features the advantages of good functional group compatibility,short reaction time,operational simplicity,and highly efficient reaction system.This protocol,which produces water as the only byproduct,provides efficient and atom-economical access to a class of fascinating quinoline and isoquinoline products in satisfactory yields.The method is effective on the gram scale,thus highlighting the inherent practicality of this methodology.

Photocatalytic Transition-Metal-Free Direct 3-Acetalation of Quinoxaline-2(1H)-ones

A general transition-metal-free visible-light-promoted 3-acetalation reaction of quinoxaline-2(1H)-ones was developed under mild conditions.By employing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene(4CzIPN)as an inexpensive photocatalyst,and glyoxylic acid acetal as a radical source,various acetalated quinoxaline-2(1H)-ones were constructed in moderate to good yields.Moreover,the versatility of this protocol is highlighted by the successful application in the late-stage modification of drug molecules and the various functionality transformations.The excellent antitumor activity of the acetalated product demonstrated that this streamlined and sustainable approach could have emerged as a powerful strategy for structural modification in medicinal chemistry.

Transition-metal-free synthesis of 1,4-benzoxazepines via[4+3]-cycloaddition of para-quinone methides with azaoxyallyl cations

A formal[4+3]-cycloaddition reaction of ortho-hydroxyphenyl-substituted para-quinone methides(p-QMs)with in-situ generated azaoxyallyl cations is reported.The reaction occurs under very mild reaction conditions(transition-metal free,room temperature,cheap inorganic base)and provides a very efficient route to a series of biologically important 1,4-benzoxazepine derivatives in good to excellent yields.

Transition-Metal-Free Reductive Cross-Coupling Employing Metabisulfite as a Connector:General Construction of Alkyl–Alkyl Sulfones

A multicomponent reductive cross-coupling of unactivated alkyl halides and alkyl tosylates connected via sodium metabisulfite was established for the general construction of alkyl-alkyl sulfones.Neither a metal catalyst nor a metal reductant is required in this“green”reductive cross-coupling.Inorganic sodium metabisulfite served as both the sulfur dioxide source and the robust connector.

Transition-metal-free [3+3] annulation reaction of sulfoxonium ylides with cyclopropenones for the synthesis of 2-pyrones

An efficient and practical synthetic approach was developed for the tandem synthesis of trisubstituted 2-pyrone derivatives from sulfoxonium ylides and cyclopropenones.This[3+3]annulation reaction was carried out under transition-metal-free conditions.A broad range of functional groups were tolerant under mild conditions,and a variety of 2-pyrones were obtained in moderate to good yields.

Iodomethane as an organocatalyst for the aerobic ortho-selective trifluoromethylation of pyridines

Iodomethane is usually used as an electrophilic methylation reagent.Herein,we report its use as a C1 organocatalyst for the aerobic ortho-selective trifluoromethylation of pyridines in the absence of a transition metal.Trifluoroacetic acid(TFA)was employed as an inexpensive,readily available trifluoromethyl source.The reaction efficiently produced a variety of trifluoromethylation products,with good functional group compatibility.Pyridine-containing drug molecules could also be selectively trifluoromethylated for late-stage functionalizations.Mechanistic studies showed that iodomethane selectively reacted with the pyridine starting material,rather than the pyridine product,to generate the corresponding N-methylpyridinium iodide.The decarboxylation of trifluoroacetic acid produced a trifluoromethyl anion,which added to the methylpyridinium iodide,and the subsequent aerobic rearomatization led to the generation of the ortho-trifluoromethylated product.

Lactonization of C（sp2）-H Bonds in Enamides with CO2

Herein, we report a novel synthesis of 1,3-oxazin-6-ones from enamides with CO2 through C--H carboxylation and one-pot cyclization. This transition-metal-free and redox-neutral process features broad substrate scope, good functional group tolerance and facile product derivatization. The nucleophilic attack to CO2 from the electron-rich alkene is demonstrated for this reaction.

TEMPO and its derivatives mediated reactions under transitionmetal-free conditions

2,2,6,6-Tetramethyl-l-piperidinyl-N-oxyl(TEMPO)and its derivatives as stable radicals can participate in many reactions.During the process,TEMPO and its derivatives could act not only as the substrates to capture or initiate new radical intermediates to provide new compounds but also as organic catalysts or oxidants for transformations of alkenes,alcohols,aldehydes and so on to synthesize various high valueadded compounds.In this review,we would introduce recent advances of the transformations of different substrates mediated by TEMPO and its derivatives under transition-metal-free conditions.

[4+1]Cyclization of benzohydrazide and ClCF_(2)COONa towards 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d_(5)

A facile synthesis of 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d_(5) via[4+1]cyclization of ClCF_(2)COONa with non-amine compounds containing amino groups is developed.Of note,this is the first time that halofluorinated compounds are used as C1 synthon to construct deuterated nitrogen-heterocyclic compounds.The current protocol features simple operation,readily accessible raw materials,wide substrate scope and valuable products.

A facile access to mono-C-alkynylated-o-carboranes from o-carboranes and arylsulfonylacetylenes

A facile access to mono-C-alkynyl-o-carboranes from o-carboranes and arylsulfonylacetylenes was developed.This facile process tolerates a wide variety of functional groups,occurs at mild conditions in onepot procedure with short reaction time.The obtained mono-C-alkynyl-o-carboranes can be easily derivatized to synthesize 1,2-difunctionalized o-carboranes.This work provides a useful tool for the functionalization of o-carboranes.

Catalyst-Free Imidation of Allyl Sulfides with Chloramine-T and Subsequent [2,3]-Sigmatropic Rearrangement

A facile synthesis of various allyl sulfonamides based on imidation of allyl sulfides with chloramine-T and sub- sequent [2,3]-sigmatropic rearrangement has been achieved without metal catalysts. The reaction completes smoothly within 10 min, providing excellent yields in environment friendly solvent of alcohol. Functional groups such as bromine, hydroxyl, protected amido and aldehyde are tolerant under this condition.

Air-tolerant direct reductive N-methylation of amines using formic acid via simple inorganic base catalysis

The construction of N-methyl amine moieties is an important reaction that has found numerous applications.Development of new methylation agents that are more environmentally benign than classical agents,such as iodomethane and methyl sulfate,is still highly desirable.Herein,we report a convenient protocol for direct reductive N-methylation of amines using formic acid as the methylation agent via simple inorganic base catalysis.The present protocol operates under transition-metal-free and air-tolerant conditions.Both the catalyst,K2 HPO4,and the reductant,polymethylhydrosiloxane(PMHS),are cheap and easily separable from the crude reaction product mixture.Mechanistic investigations suggest that the reaction occur through the formation of an acetal inte rmediate followed by the C-N bond formation.

Visible-light-induced chemoselective reactions of quinoxalin-2(1H)-ones with alkylboronic acids under air/N_(2) atmosphere

A visible-light-induced chemoselective reactions of quinoxalin-2(1 H)-ones with alkylboronic acids in the presence of air(O_(2)) and N_(2)atmosphere was developed under transition-metal free conditions, providing 3-alkylquinoxalin-2(1H)-ones and 3,4-dihydroquinoxalin-2(1H)-ones, respectively. The overall strategy accommodates a broad scope of substituted quinoxalin-2(1H)-ones and alkylboronic acids with good to excellent product yields.

Metal-Free Synthesis of 2-Aminobenzothiazoles via I2-Catalyzed Tandem Cyclization Reaction of Amines and Carbon Disulfide

Comprehensive Summary,A convenient approach for the construction of 2-aminobenzothiazoles via I2-catalyzed tandem cyclization reaction of amines and carbon disulfide has been developed.The present approach starts from simple and readily available starting materials,affording a series of 2-aminobenzothiazoles in up to 89%yields under metal-free conditions.In this work,C—H/N—H functionalization was achieved and multiple C-hetero bonds were successfully constructed in one pot.