The 100 most-cited articles in Organic Letters, 2019

A mild, practical protocol for the decarboxylative alkylation of heteroarenes has been accomplished via iron photocatalysis. A diverse range of carboxylic acids readily undergo oxidative decarboxylation and then couple with a broad array of heteroarenes in this transformation. The photoexcited state lifetimes of iron complexes are typically much shorter than those of iridium and ruthenium complexes. Here we describe our effort on iron photocatalysis by utilizing the intramolecular charge transfer pathway of iron-carboxylate complexes.

Efficient thermally activated delayed fluorescence materials based on the multiple resonance effect were synthesized by nucleophilic substitution and electrophilic C-H borylation, featuring a small energy gap between the singlet and triplet state, high photoluminescence quantum yield, and narrow emission band. Organic light-emitting diodes employing these materials as emitters exhibited sky-blue emission with a high external quantum efficiency of 21.4% and a narrow full width at half-maximum of 33 nm.

Described is a cross-electrophilic, deaminative coupling strategy harnessing Katritzky salts as a new species of electrophile in Ni/photoredox dual catalytic reductive cross-coupling reactions. Distinguishing features of this arylation protocol include its mild reaction conditions, high chemoselectivity, and adaptability to a variety of complex substrates [i.e., pyridinium salts derived from amines and partners derived from (hetero)aryl bromides].

A photoinduced, phosphoranyl radical-mediated protocol for the direct N-O cleavage of strained cycloketone oximes via a polar/SET crossover process was developed for the first time. This visible-light-driven direct N-O activation mode for oxime offers beneficial features such as streamlined synthetic process and versatile photochemical reactivities. Consequently, the alkenes and α-trifluoromethyl alkenes with varied electronic and structural features acted as competent radical receptors in this protocol, enabling facile accesses to a range of elongated cyano and/or gem-difluoroalkene-bearing compounds.

Cp*Cobalt(III)-catalyzed enantioselective C-H amidation of ferrocenes using monoprotected amino acids (MPAAs) as chiral ligands was developed. The reaction was performed under mild conditions in high yields (up to 97%) with moderate enantioselectivity (up to 77.5:22.5 er), providing a promising strategy to create planar chirality via base-metal-catalyzed enantioselective C-H activation.

A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate the formation of an alkyl radical, and controlling its fate was key to the success of this reaction.

A novel and practical fluoroalkyl radical-initiated cascade reaction was developed to access diverse 2-fluoroalkylbenzothiazoles by reacting various fluoroalkyl radical sources, including perfluoroalkyl iodide (IC n F 2 n +1, n = 3–8, 10), ICF(CF 3 ) 2, ICF 2 COOEt, ICF 2 CF 2 Cl, or ICF 2 CF 2 Br, tetramethylethane-1,2-diamine (TMEDA), and 2-isocyanoaryl thioethers in tetrahydrofuran under nitrogen atmosphere and blue-light irradiation conditions. Furthermore, this one-pot protocol could well be expanded to access various 2-fluoroalkylbenzoselenazoles starting from (2-isocyanophenyl)(methyl)selane, perfluoroalkyl iodides (IC n F 2 n +1, n = 3–8) or ICF 2 COOEt and TMEDA.

We have successfully developed a green and efficient multicomponent reaction protocol to synthesize S -aryl dithiocarbamates under visible light. Most appealingly, the reaction can proceed smoothly without adding any transition-metal catalysts, ligands, or photocatalysts while minimizing chemical wastes and metal residues in the end products. The advantages of this method meet the requirements of sustainable and green synthetic chemistry, and it provides a straightforward way to create valuable S -aryl dithiocarbamates.

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert -butyl, and alkynyl fragments in order to improve physicochemical properties. However, bceause of the difficulty of synthesis, most BCP analogues prepared only bear 1,3-“ para ”-substituents. We report the first selective synthesis of 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on synthesis of other “ ortho / meta -substituted” BCPs via similar mechanisms.

An efficient strategy for the synthesis of benzofuro[2,3- b ]pyrazines was developed. These tricyclic scaffolds were formed through a multistep cascade sequence, which includes double insertion of isonitriles and chemoselective bicyclization. In this reaction, a nanopalladium was used as a recyclable catalyst. Product 3w exhibited excellent anticancer activity toward T-24 (IC 50 = 12.5 ± 0.9 μM) and HeLa (IC 50 = 14.7 ± 1.6 μM) cells. We also explored the action mechanism of 3w on T-24 cells.

A regioselective, intermolecular 1,2-alkylarylation of alkenes with aryl halides and alkyl oxalates has been developed via photoredox/nickel dual catalysis. This dual-catalytic protocol involves a radical relay process, where radical addition is followed by a nickel-assisted coupling, forging two consecutive C-C bonds in a single operation. The mild and redox-neutral conditions allow for good compatibility in the scope of olefins, (hetero)aryl halides, as well as alkyl oxalates.

Manganese-photocatalyzed activation of the Si-H bond in silanes for the hydrosilylation of alkynes has been developed. The mild protocol operates efficiently with high regioselectivity ( anti-Markovnikov) and stereoselectivity ( Z/ E ratio ranges from 92:8 to >99:1), providing a wide range of Z-vinylsilanes in high yields. Moreover, visible-light-induced manganese-catalyzed activation of the Ge-H bond for E-selective alkyne hydrogermylation is reported for the first time.

The use of additive-free conditions is an ideal approach to prepare organoselenium reagents from readily available unsaturated substrates. Thus, we report the electro-induced aminoselenation and oxyselenation of styrenes without any acids or oxidants as additives. This transformation is compatible with various functional groups, which leads to vicinal difunctionalized organoselenium compounds. Our strategy improves the potential of this protocol for use in the pharmaceutical industry. Based upon the preliminary mechanism studies, we propose two possible pathways.

A general electrohemical strategy for the combined trifluoromethylation/C(sp 2 )–H functionalization using Langlois’ reagent as the CF 3 source under oxidant-free conditions was developed. Using Mn salts as the redox mediator, this method provides an efficient and sustainable means to access a variety of functionalized heterocycles bearing a CF 3 moiety. Detailed mechanistic studies are consistent with the formation of CF 3 -bound high oxidation state Mn species, suggesting a transition-metal-mediated CF 3 transfer mechanism for this trifluoromethylation/C(sp 2 )–H functionalization process.

A visible-light-promoted redox neutral γ,γ-difluoroallylation of cycloketone oxime ethers with trifluoromethyl alkenes through C-C and C-F bond cleavage has been achieved, which affords various cyano-substituted gem-difluoroalkenes in generally good yields. The reaction provides a facile protocol for forming gem-difluoroalkene functionality and a cyano group while incorporating them into one molecule. The conversion of the resulting cyano-substituted gem-difluoroalkenes to cyclic monofluoroalkenes via a second C-F bond cleavage was also described.

An approach for efficient synthesis of C-glycosyl amino acids is described. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C-C bond formation, and its applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.

An unprecedented cascade reaction of benzoyl sulfoxonium ylides with α-diazocarbonyl compounds leading to the formation of highly functionalized naphthalenones containing a β-ketosulfoxonium ylide moiety is presented. Promisingly, the naphthalenone derivative thus obtained was found to be a versatile intermediate toward diversely functionalized naphthalene derivatives including substituted 1-naphthol, 2-hydroxynaphthalen-1(2 H)-one, naphthalen-1,2-dione, and 2-(methylsulfinyl)naphthalen-1-ol.

The catalyst-free electrochemical di- and trifluoromethylation/cyclization of N-substituted acrylamides was realized under external oxidant-free conditions. The strategy provides expedient access to fluoroalkylated oxindoles and 3,4-dihydroquinolin-2(1 H)-ones with ample scope and broad functional group tolerance by mild, direct electrolysis of sodium sulfinates in an undivided cell. Detailed mechanistic studies provided strong support for a SET-based reaction manifold.

A Ni-catalyzed reductive deaminative arylation at unactivated sp 3 carbon centers is described. This operationally simple and user-friendly protocol exhibits excellent chemoselectivity profile and broad substrate scope, thus complementing existing metal-catalyzed cross-coupling reactions to forge sp 3 C–C linkages. These virtues have been assessed in the context of late-stage functionalization, hence providing a strategic advantage to reliably generate structure diversity with amine-containing drugs.

Herein, a practical Cu-catalyzed selenodifluoromethylation protocol was developed, using readily available diselenides as the selenium source under external-oxidant-free conditions. Various structurally diverse 4-seleno-substituted α,α-difluoro-γ-lactams were obtained in moderate to excellent yields. Easy scaleup and the potential for product derivatization make this method attractive for the preparation of other valuable fIuorinated γ-lactams. Mechanistic studies suggest that the catalytic system may involve a radical pathway.

The first example of ancillary (P,N)-ligand-enabled gold-catalyzed C-N cross-coupling reactions of aryl iodides with amines is reported. The high generality of the reaction in de novo synthesis, late-stage modifications, and cascade processes to access functionalized indolinones and carbazoles underscores the synthetic potential of the presented strategy. Monitoring the reaction with ESI-HRMS and NMR provided strong evidence for the in situ formation of putative high valent Au(III) intermediates.

The first example of oxidative C-H fluoroalkoxylation of quinoxalinones with fluoroalkyl alcohols under transition-metal and solvent-free conditions is described. This approach provides the synthesis of fluoroalkoxylated quinoxaline derivatives with good to excellent yields under mild reactions conditions. This method can also be extended to the facile and efficient synthesis of histamine-4 receptor.

Direct construction of N–C axial chirality via Pd-catalyzed atroposelective C–H olefination of N -arylindoles is reported. The crucial role of chiral amino acid as a cocatalyst in the regio- and stereocontrol has been disclosed. In this reaction, a wide range of arylindoles and functional alkenes could be well tolerated. Moreover, the practicality and synthetic value of this process were demonstrated by the divers and simple transformations of the products.

A series of Mn(I) catalysts containing imidazole-based chiral PNN tridentate ligands with controllable “side arm” groups have been established, enabling the asymmetrical hydrogenation of unsymmetrical benzophenones with outstanding activity (up to 13 000 TON) and excellent enantioselectivity (up to >99% ee ). This protocol uses K 2 CO 3 as an industrially desirable base and features a wide substrate scope and functional group tolerance. Moreover, the imine group in the catalyst is crucial for accessing high activities and good enantioselectivities.

A systematic study to include 3 J HH couplings into DP4 formalism ( J -DP4) led to the development of three alternative strategies. The d J -DP4 (direct) approach involves a new DP4-like equation including an additional probability term given by 3 J HH . The i J -DP4 (indirect) approach explores the original DP4 method with a restricted conformational search. Despite both strategies performing better than DP4, their combined use (i J /d J -DP4) provided the best results, with a 2.5-fold performance improvement at similar or lower computational cost.

Herein, a novel fluorescent probe by integrating 4-azide-1,8-naphthalic anhydride and spiropyran was obtained. NT-N 3 -SP was capable of specifically monitoring H 2 S by azide reduced. Upon irradiation by alternate ultraviolet and visible light, both the structure and emission of spiropyran moiety in NT-N 3 -SP can be reversibly tuned. Importantly, the alternation will be interrupted in the presence of SO 2 . Additionally, NT-N 3 -SP was successfully used for detection of H 2 S/SO 2 in cells and mice.

A multicomponent sulfonylation of O-acyl oximes via iminyl radicals with the insertion of sulfur dioxide under photoredox catalysis is achieved. This multicomponent reaction of O-acyl oximes, potassium metabisulfite, alkenes, and nucleophiles under visible-light irradiation is efficient, giving rise to a range of sulfones in moderate to good yields. A broad reaction scope is presented with good functional group compatibility.

A sustainable synthesis of quinazoline and 2-aminoquinoline via acceptorless dehydrogenative annulation is presented. The reaction is catalyzed by earth-abundant well-defined manganese complexes bearing NNS ligands. Furthermore, a one-pot synthetic strategy for the synthesis of 2-alkylaminoquinolines through sequential dehydrogenative annulation and N-alkylation reaction has also been demonstrated.

A dehydrogenative annulation of 2-arylindazoles with maleimides for the switchable synthesis of indazolo[2,3- a ]pyrrolo[3,4- c ]quinolinones or spiroindolo[1,2- b ]indazole-11,3′-pyrrolidinones is presented. Mechanistically, the formation of the title compounds involves a Rh(III)-catalyzed C–H metalation of 2-arylindazole, followed by maleimide insertion and intramolecular cyclization. Interestingly, the selectivity to form the fused or spiro compounds could be switched by resorting to different additives. The notable features of this protocol include simple substrates and excellent atom economy and regioselectivity.

A first example of low-energy blue-light-mediated formal Doyle–Kirmse reaction for gem -difluoroallylation of aryl diazoesters has been developed. A variety of highly functionalized gem -difluoroallyl containing esters bearing transformable sulfur and bromine groups were efficiently assembled with broad substrate scope under mild, catalyst-free, and additive-free conditions. The reaction represents a practical and environmentally friendly approach for C–CF 2 bond formation based on rearrangement strategy, which will find potential applications among drug discovery and development.

This article describes direct photoalkylation of electron-rich aromatic compounds with diazo compoiunds. C-2 alkylated indoles and pyrroles are obtained with good yields even though the photocatalyst (Ru(bpy)3Cl2) loading is as low as 0.075 mol %. For substrates bearing electron-withdrawing substituents the addition of a catalytic amount of N,N-dimethyl-4-methoxyaniline is required. Both EWG-EWG and EWG-EDG substituted diazo esters are suitable as alkylating agents. The reaction selectivity and mechanistic experiments suggest that carbenes/carbenoid intermediates are not involved in the reaction pathway, instead radical formation is proposed.

Presented in this work is a novel methodology for the synthesis of selenated benzofurans (or benzothiophenes) via AgNO 2 -catalyzed radical cyclization of 2-alkynylanisoles (or 2-alkynylthioanisoles), Se powder, and arylboronic acids. This method enables the construction of a benzofuran (benzothiophene) ring, two C–Se bonds, and a C–O(S) bond as well as the cleavage of a C–O(S) bond in a single step. Preliminary mechanistic studies imply that the AgNO 2 -catalyzed cyclization proceeds via an aryl selenium radical intermediate.

C-centered radical cyclization under electrochemical conditions is a feasible strategy for constructing cyclic structures. Reported herein is the electrochemical synthesis of highly functionalized 1-naphthols using alkynes and 1,3-dicarbonyl compounds by (4 + 2) annulation of C-centered radical. Electrolysis was conducted with Cp 2 Fe as redox catalyst, thereby eliminating the use of oxidants and transition-metal catalysts. The synthesized 1-naphthol compounds showed good antitumor activity in vitro, and further studies indicated that compound 3bl induced tumor cell apoptosis.

The unusual nonbifunctional outer-sphere strategy was successfully utilized in developing an easily accessible N -heterocyclic carbene manganese (NHC-Mn) system for highly active α-alkylation of ketones with alcohols. This system was efficient for a wide range of ketones and alcohols under mild reaction conditions, and also for the green synthesis of quinoline derivatives. The direct outer-sphere mechanism and the high activity of the present system demonstrate the potential of nonbifunctional outer-sphere strategy in catalyst design for acceptorless dehydrogenative transformations.

Difunctionalization of olefins represents a powerful synthetic tool and yet a challenging task. This work describes an electrochemically enabled fluoroalkylation-migration reaction of unactivated olefins in the absence of a strong oxidant or heavy metal catalyst, affording fluorinated (hetero)aryl ketones in good yields and excellent regioselectivities. The efficient and sustainable electrochemical strategy provides a rapid access to a dual functionalized fluorine-containing heterocyclic manifold.

A novel ruthenium-catalyzed [5 + 1] annulation of 2-alkenylanilines with sulfoxonium ylides was developed for the rapid assembly of highly functionalized quinolines. This new catalytic process employs challenging but synthetically ideal free amino functionality to achieve alkenyl C-H activation with sulfoxonium ylides as one-carbon coupling partners. Various 2-acylquinolines could be obtained with good yields and excellent functional group tolerance. Moreover, the potential synthetic application of this methodology was exemplified by several chemical transformations.

Despite the central role of germacrene A in sesquiterpene biosynthesis and its widespread occurrence in nature, its complete NMR characterization is still pending. This problem was solved through enzymatic preparation of germacrene A isotopomers that allowed for a full signal assignment to all three conformers. The obtained materials gave insights into the stereochemical course of the Cope rearrangement to β-elemene and uncovered the Cope rearrangement as a new EI-MS fragmentation reaction.

cross-coupling reaction has been developed using redox-active esters prepared in situ from alkyl carboxylates and N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (PITU). This undivided cell one-pot method enables C-C bond formation using inexpensive, benchtop-stable reagents with isolated yields up to 95% with good functional group tolerance, which includes nitrile, ketone, ester, alkene and selectivity over other aromatic halogens.

A visible-light-mediated deaminative thioesterification of amino acid derived Katritzky salts with thiobenzoic acid has been developed, which provides a novel synthetic method for the synthesis of α-mercapto acid derivatives under mild conditions. This photoredox catalyst-free generation of alkyl radicals via C-N bond cleavage is enabled by the formation of an electron-donor-acceptor (EDA) complex between the Katritzky salt and thiobenzoic acid anion, which represents a new entry for EDA complex chemistry.

By merging C-F and C-C bond activation in the cross-electrophile coupling, we developed an efficient cyanide-free synthesis of diverse functional-group-rich cyano-substituted gem-difluoroalkenes using cyclobutanone oxime esters and trifluoromethyl alkenes as precursors. Notably, this Ni-catalyzed reaction is bestowed with broad substrate scope, low catalyst loading, complete regioselectivities, and high tolerance of a wide range of sensitive functional groups. Preliminary mechanistic studies indicate that an iminyl radical-initiated C-C bond cleavage is involved in the reaction pathway.

Considering the ubiquitous C(sp 3 )–H and the important value of alkylated heteroarenes, developing a universal method for C(sp 3 )–H arylation with heteroarenes is significant. Herein, we proposed a method where Selectfluor can promote the oxidative C(sp 3 )–H arylation with heteroarenes without external photocatalysis under visible-light irradiation. By EPR study, the N–F activation of Selectfluor by blue LED irradiation can generate the N radical cation, which is the key step for this conversion.

Easily accessible green-light activatable (>500 nm) photocages based on red-shifted, π-extended coumarin scaffolds are developed with uncaging efficiencies similar to those of recently introduced BODIPY derivatives. The photocages possess increased aqueous solubility, high absorption coefficients within the 450-600 nm range, and exceptionally high two-photon cross sections.

A carbon nitride material can be combined with homogeneous nickel catalysts for light-mediated cross-couplings of aryl bromides with alcohols under mild conditions. The metal-free heterogeneous semiconductor is fully recyclable and couples a broad range of electron-poor aryl bromides with primary and secondary alcohols as well as water. The application for intramolecular reactions and the synthesis of active pharmaceutical ingredients was demonstrated. The catalytic protocol is applicable for the coupling of aryl iodides with thiols as well.

Two efficient continuous flow iodoperfluoroalkylation methods are described: using 0.05 mol % perylene diimide (PDI) photocatalyst under 450 nm irradiation or substoichiometric triethylamine under 405 nm irradiation. These methods enable dramatically elevated productivity versus batch processes. The triethylamine-mediated method is explored mechanistically and in substrate scope. The gram-scale synthesis of an active pharmaceutical ingredient side chain is also reported in flow, via a photochemical iodoperfluoroalkylation followed by hydrogenolysis.

The in situ formed ruthenium catalytic system ([Ru]/L) was found to be highly selective for the dehydrogenative coupling reaction of 2-aminophenyl ketones with amines to form quinazoline products. The deaminative coupling reaction of 2-aminobenzamides with amines led to the efficient formation of quinazolinone products. The catalytic coupling method provides an efficient synthesis of quinazoline and quinazolinone derivatives without using any reactive reagents or forming any toxic byproducts.

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale.

Palladium-catalyzed transfer semihydrogenation of alkynes using H 2 O as the hydrogen source and Mn as the reducing reagent is developed, affording cis - and trans -alkenes selectively under mild conditions. In addition, this method provides an efficient way to access various cis -1,2-dideuterioalkenes and trans -1,2-dideuterioalkenes by using D 2 O instead of H 2 O.

Cyclopropanation reactions of carbenes with arenes provide a straightforward pathway to norcaradienes or cycloheptatrienes. This reaction normally requires harsh reaction conditions or transition-metal catalysts. In this report, we describe the metal-free visible-light photolysis of aryl diazoacetates in aromatic solvents, which provides access to the norcaradiene ring system in a highly regio- and stereoselective manner. The mild reaction conditions of this approach also allow chemoselective cyclopropanation of substituted arenes without competing C-H functionalization reactions.

A mild, practical method for direct arylation of unactivated C(sp 3 )–H bonds with heteroarenes has been achieved via photochemistry. Selectfluor is used as a hydrogen atom transfer reagent under visible light irradiation. A diverse range of chemical feedstocks, such as alkanes, ketones, esters, and ethers, and complex molecules readily undergo intermolecular C(sp 3 )–C(sp 2 ) bond formation. Moreover, a broad array of heteroarenes, including pharmaceutically useful scaffolds, can be alkylated effectively by the protocol presented here.

A general class of well-defined, air-stable, and readily available Pd(II)-NHC precatalysts (NHC = N-heterocyclic carbene) for Suzuki and Buchwald-Hartwig cross-coupling of amides (transamidation) and esters by selective N-C/O-C cleavage is reported. Since these precatalysts are highly active and the easiest to synthesize, the study clearly suggests that [Pd(NHC)(acac)Cl] should be routinely included during the development of new cross-coupling methods. An assay for in situ screening of NHC salts in this cross-coupling manifold is presented.

Photoinduced transition-metal- and photosensitizer-free cross-coupling of aryl halides (including Ar-Cl, Ar-Br, and Ar-I) with H-phosphonates (including dialkyl phosphonates and diarylphosphine oxides) is reported. Various functional groups were tolerated, including ester, methoxy, dimethoxy, alkyl, phenyl, trifluoromethyl, and heterocyclic compounds. This simple and green strategy provides a practical pathway to synthesize arylphosphine oxides.

A cobalt-catalyzed C–H carbonylation of naphthylamides for the synthesis of benzo[ cd ]indol-2(1 H )-one scaffolds has been developed. The reaction employs a traceless directing group and uses benzene-1,3,5-triyl triormate as the CO source, affording various free ( NH )-benzo[ cd ]indol-2(1 H )-ones in moderate to high yields (up to 88%). Using this protocol, the total synthesis of BET bromodomain inhibitors A and B was accomplished as well.

A rapid synthesis of β-arylethenesulfonyl fluorides is realized using ligand-accelerated Pd(II)-catalyzed nondirected C-H alkenylation of simple arenes. The newly developed electron-deficient 2-pyridone ligand is crucial for this transformation with arenes as limiting reagent. This protocol features a broad substrate scope and good functional group tolerance. Late-stage functionalization of various pharmaceuticals and their further click manipulations demonstrate this procedure to be highly valuable.

An efficient metal-free, photomediated iodo perfluoroalkylation under mild conditions was developed. Using catalytic amounts (10 mol %) of phosphines and blue light irradiation, various olefins are transformed into the corresponding addition products within short reaction times. For this purpose, a modular and convenient 3D printed photoreactor was constructed, which is presented as an open source model. The reaction presumably proceeds upon generation of perfluoroalkyl radicals, which are formed by catalyst-induced absorption enhancement.

The direct diastereo- and enantioselective 1,8-conjugate additions of thiazolones and azlactones, respectively, to para-quinone methides generated in situ from propargylic alcohols have been achieved in the presence of chiral phosphoric acids. The remote stereocontrolled activation protocol provides an efficient and facile approach for the construction of vicinal axially chiral tetrasubstituted allenes and heteroatom-functionalized quaternary carbon stereocenters, which expands the synthetic potential of chiral phosphoric acids.

A nickel-catalyzed carbonylative difluoroalkylation reaction with arylboronic acids under 1 atm of CO has been developed. The reaction proceeds under mild reaction conditions with high efficiency and high functional group tolerance. Preliminary mechanistic studies reveal that the arylacyl nickel complex is the key intermediate to circumvent the formation of labile fluoroacyl nickel, and bimetallic oxidative addition is likely the key step to facilitate the catalytic cycle.

Electrochemical oxidative radical selenylation/1,2-carbon migration and Dowd-Beckwith-type ring-expansion sequences of alkenylcyclobutanols were developed in this study. This approach is environmentally benign and uses shelf-stable diselenides as selenium radical precursors and electrons as oxidizing reagents. The present protocol offers a facile way to prepare β-selenated cyclic ketone derivatives. Under Dowd-Beckwith-type rearrangement, it can afford the corresponding one-carbon ring-expanded ketones.

A new anode strategy for accessing xanthen-9-azoles via an electrochemical C(sp 3 )–H/N–H cross-coupling of xanthenes with azoles is described. This reaction proceeds efficiently with a broad scope of both xanthenes and N–H-free azoles under metal- and additional oxidant-free conditions and represents a new access to direct incorporation of important N -heterocycle units into the resulting xanthenes.

An operationally simple method is disclosed for the decarboxylative cyanation of aliphatic carboxylic acids at room temperature. Riboflavin tetraacetate, which is an inexpensive organic photocatalyst, promotes the oxidation of carboxylic acids upon visible-light activation. After decarboxylation, the generated radicals are trapped by TsCN, yielding the desired nitriles without any further additive, in a redox-neutral process. Importantly, this protocol can be adapted to flow conditions.

A photoredox/amine-cocatalyzed enantioselective radical hydroacylation of enals with α-ketoacids is described. Acyl radicals generated from α-ketoacids act as the acylation reagent with the iminium ions. This strategy provides an efficient way to access synthetically challenging 1,4-dicarbonyl compounds in an enantioselective manner. The reactions of various enals with α-ketoacids show the generality and limitations of this method.

A photoinduced, copper-catalyzed three-component radical cross-coupling of cycloketone oxime esters, alkenes, and terminal alkynes is described for the first time. Key to the success of this process was the integration of photoinduced iminyl radical-mediated C-C bond cleavage with the conceptual simplicity of copper-catalyzed radical cross-coupling. This protocol provides access to cyanoalkyl-containing propargylic compounds in good yields.

A unified strategy to generate acyl radical from oxime ester via selective C–C bond activation is reported. Under visible-light irradiation, single-electron transfer from fac -Ir(ppy) 3 to related oxime takes place followed by a fast β-fragment of C–C bond to yield aryl and aliphatic acyl radicals, subsequently captured by diverse Michael acceptors. More interestingly, the single-electron transfer enables coupling with energy transfer of the excited fac -Ir(ppy) 3 via enone intermediate formed in situ for cyclobutane formation.

Genome mining of the deep sea-derived Streptomyces atratus SCSIO ZH16 enabled the activation of a cyclodepsipeptide gene cluster and isolation of its cinnamic acid-bearing product, atratumycin (1). Atratumycin's structure was elucidated on the basis of extensive spectroscopic experiments, X-ray data, and Marfey's method; a plausible biosynthesis and tailoring modification of 1 are also proposed and investigated. Additionally, atratumycin is active against Mycobacteria tuberculosis H37Ra and H37Rv with MICs of 3.8 and 14.6 μM, respectively.

Highly enantioselective [4 + 2] cyclizations of azadienes with in situ generated ketenes were developed through sequential visible-light photoactivation/isothiourea catalysis, which offers a novel approach for the creation of all-carbon quaternary stereocenters through disubstituted C1-ammonium enolates. The visible-light-induced sustained release of reactive ketene species through Wolff rearrangement of α-diazoketones is crucial for achieving high levels of chemical efficiency and stereoinduction.

-ligand scaffold for the N-alkylation of amines with alcohols utilizing the borrowing hydrogen methodology is reported. A broad range of anilines and the more challenging aliphatic amines were alkylated with primary and secondary alcohols. Moreover, the combination of low catalyst loadings and mild reaction conditions provides high efficiency for this atom-economic transformation.

An efficient photocatalytic decarboxylative 3-position alkylation of coumarins by using alkyl N-hydroxyphthalimide esters as alkylation reagents has been developed. A variety of NHP esters derived from aliphatic carboxylic acids (primary, secondary, and tertiary) has been proved to be tolerated for this decarboxylation process, affording a broad scope of 3-alkylated coumarin derivatives in moderate to excellent yields. This protocol was highlighted by its mild conditions, readily available starting materials, operational simplicity, and wide functional group tolerance.

A general protocol for the hydroacylation of styrenes from aliphatic carboxylic acids is reported. These reactions proceed via β-scission of a phosphoranyl radical that is accessed by photoredox catalysis, followed by addition of the resulting acyl radical to the styrenyl olefin. We show that phosphine tunability is critical for efficient intermolecular coupling due to competitive quenching of the photocatalyst by the olefin. Primary, secondary, and structurally rigid tertiary carboxylic acids all generate valuable unsymmetrical dialkyl ketones.

A redox-neutral alkyl Petasis reaction has been developed that proceeds via photoredox catalysis. A diverse set of primary, secondary, and tertiary alkyltrifluoroborates participate effectively in this reaction through a single-electron transfer mechanism, in contrast to the traditional two-electron Petasis reaction, which accommodates only unsaturated boronic acids. This protocol is ideal to diversify benzyl-type and glyoxalate-derived aldehydes, anilines, and alkyltrifluoroborates toward the rapid assembly of libraries of higher molecular complexity important in pharmaceutical and agrochemical settings.

A multicomponent reaction of styrenes, aryldiazonium tetrafluoroborates, sulfur dioxide, nitriles, and water in the presence of a photocatalyst at room temperature is performed. This vicinal aminosulfonylation of styrenes with the insertion of sulfur dioxide under visible light irradiation proceeds efficiently with excellent chemoselectivity, giving rise to the corresponding β-sulfonyl amides in moderate to good yields.

A practical and switchable method for the synthesis of aryl sulfones and sulfoxides via sulfide oxidation was developed. The chemoselectivities of products were simply controlled by reaction temperature using O 2 /air as the terminal oxidant and oxygen source. The broad substrate scope, easy realization of gram-scale production, and the simplification of a sulfide oxidation system render the strategy attractive and valuable.

A palladium-catalyzed cross-coupling of gem -difluorinated cyclopropanes with boronic acids, providing the corresponding arylated/alkenylated/alkylated 2-fluoroallylic scaffolds, is generated. This new approach has good functional group compatibility for both gem -difluorinated cyclopropanes and boronic acids; thus, an array of synthetic building blocks of monofluoroalkene scaffolds including conjugated fluorodiene and skipped fluorodiene gave good yields with high Z -selectivity. Moreover, proficient application was described for monofluoroalkene, whereas the corresponding alkyl fluoride was constructed through hydrogenation.

Abstract The development of an efficient synthetic route toward rim-differentiated C5-symmetric pillar[5]arenes (P[5]s), whose two rims are decorated with different chemical functionalities, opens up successive transformations of this macrocyclic scaffold. This paper describes a gram-scale synthesis of a C5-symmetric penta-hydroxy P[5] precursor, and a range of highly efficient reactions that allow functionalizing either rim at will via, e.g., sulfur(VI) fluoride exchange (SuFEx) reactions, esterifications, or Suzuki–Miyaura coupling. Afterward, BBr3 demethylation activates another rim for similar functionalizations.

A general approach is described for the formation of tetrahydrothiepines using donor-acceptor cyclopropanes. Thiochalcones, functioning as sulfur-containing four-atom building blocks, were reacted in a Lewis acid catalyzed formal (4 + 3)-cycloaddition reaction with donor-acceptor cyclopropanes as three-atom building blocks. Under mild conditions various tetrahydrothiepines were synthesized in good yields in a stereospecific reaction with high functional group tolerance.

In contrast to the well-explored quinone methides (QMs) and aza- ortho -QMs, aza- para -QMs have been rarely studied in terms of their asymmetric transformations. Herein, a highly efficient enantioconvergent asymmetric 1,8-addition of aza- para -QMs is described. Featuring remarkable remote stereocontrol, this reaction provides expedient access to chiral tetrasubstituted allenes bearing an adjacent all-carbon quaternary stereocenter with high enantioselectivity and diastereoselectivity.

The first examples of electrochemical trifluoromethylation and sulfonylation/semipinacol rearrangements of allylic alcohols were developed using cheap and stable RSO 2 Na (R = CF 3, Ph) as reagents. Various β-trifluoromethyl and sulfonated ketones were obtained in moderate to excellent yields. This strategy provides a facile, direct, and complementary approach to construct all-carbon quaternary stereocenters. In addition, the reaction has the advantages of being chemical oxidant-free and metal-free and has safe and mild reaction conditions.

A radical relay strategy for the generation of 3-(methylsulfonyl)benzo[ b]thiophenes through a reaction of methyl(2-alkynylphenyl)sulfanes with sodium metabisulfite in the presence of a photocatalyst under visible light irradiation is developed. This photoinduced sulfonylation proceeds efficiently under mild conditions by using a catalytic amount of sodium methylsulfinate as an initiator. During the reaction process, the methyl radical generated in situ is the key intermediate, which undergoes a radical relay with the combination of sulfur dioxide to afford methylsulfonyl-containing compounds.

An electrochemical oxidative difunctionalization of allyl alcohols for the synthesis of β-trifluoromethyl ketones is achieved through a 1,2-migration process. A series of β-trifluoromethyl ketones can be facilely obtained utilizing CF 3 SO 2 Na as a radical source, eliminating the use of metals and sacrificial chemical oxidants. Importantly, this protocol not only realizes aryl migration but also offers alkyl-migration products. Additionally, an electrochemically catalyzed ring expansion and gram-scale reaction demonstrated the synthetic usefulness of this protocol.

A hypodiboric acid system for the reduction of nitro groups on DNA-chemical conjugates has been developed. This transformation provided good to excellent yields of the reduced amine product for a variety of functionalized aromatic, heterocyclic, and aliphatic nitro compounds. DNA tolerance to reaction conditions, extension to decigram scale reductions, successful use in a DNA-encoded chemical library synthesis, and subsequent target selection are also described.

A rhodium-catalyzed annulation between aroyl sulfoxonium ylides and anthranils has been developed to synthesize 10 H -indolo[1,2- a ]indol-10-one derivatives. This reaction started with an unpredented (4 + 1) annulation toward N -(2-formylphenyl) indolones, proceeding with the sequential ortho -amination of the C–H bond in aroyl sulfoxonium ylides by anthranils and the insertion of N–H to carbene. Finally, the Aldol condensation constructed the second indole ring. This procedure features the formation of two C–N bonds and one C═C bond in one pot.

-heterocyclic-carbene (NHC)-catalyzed atroposelective acylation of amino bisphenols to provide access to a wide range of 1,1'-biaryl-2,2'-amino alcohols (NOBIN analogs) in high yield and with uniformly excellent enantioselectivity. This catalytic system is shown to proceed through a combination of desymmetrization and secondary kinetic resolution to produce the axially chiral products in excellent enantioselectivity.

To challenge the limits of nitro groups associated with a tetrazole ring, the polynitrotetrazoles, 2,5-bis(dinitromethyl)-2 H-tetrazole, and 2-(dinitromethyl)-5-(trinitromethyl)-2 H-tetrazole as well as their salts, were designed, synthesized, and characterized. The neutral compounds were also studied by natural bonding orbital (NBO) and Hirshfeld surface calculations. The heats of formation were calculated with Gaussian 03 and combined with experimentally determined densities in order to obtain the detonation properties of the energetic materials with the EXPLO5 program. They exhibit high densities, good oxygen balances, positive heats of formation, and excellent detonation properties.

The enantio- and diastereoselective synthesis of 1,2-difluorides via chiral aryl iodide-catalyzed difluorination of cinnamamides is reported. The method uses HF-pyridine as a fluoride source and mCPBA as a stoichiometric oxidant to turn over catalyst, and affords compounds containing vicinal, fluoride-bearing stereocenters. Selectivity for 1,2-difluorination versus a rearrangement pathway resulting in 1,1-difluorination is enforced through anchimeric assistance from a N- tert-butyl amide substituent.

A nickel-catalyzed electrochemical cross-coupling reaction of aryl bromides with dialkyl phosphites, ethyl phenylphosphinate, and diphenylphosphine oxide has been developed. This reaction utilizes a simple undivided cell with inexpensive carbon electrodes to synthesize aryl phosphonates, aryl phosphinates, and arylphosphine oxides at room temperature. This protocol provides a mild and efficient route for the construction of C-P bond in moderate to high yields with broad substrate scope.

A tandem radical relay strategy was realized for the first Cu(I)-catalyzed enantioselective phosphinocyanation of styrenes. In this reaction, t BuOOSiMe 3 generated in situ from t BuOOH serves as a radical initiator to trigger t -butoxy radical production upon oxidization of L*Cu(I) species via proton-coupled-electron transfer (PCET) pathway, which leads to sequential phosphinoyl radical and benzyl radical formations. The resultant β-cyanodiarylphosphine oxides could be easily converted to a series of chiral γ-amino phosphine ligands.

A Co(III)-catalyzed novel [4 + 2] annulation of N-chlorobenzamides with maleimides has been reported. Mostly, maleimides are known to furnish the Michael-type or 1,1-type cyclized products while treating with amides. In this reaction, maleimides furnished [4 + 2] annulated products in good yields at room temperature while being treated with the internal oxidizing N-chlorobenzamide as a directing group. The developed methodology is compatible with a variety of functional groups. The [4 + 2] annulated products obtained are featured in some biologically active molecules.

The first organocatalyzed asymmetric dearomative cycloaddition between 2-nitrobenzofurans and isatin-derived Morita-Baylis-Hillman carbonates has been developed. Using a modified cinchona alkaloid as the catalyst, a series of structurally diverse cyclopenta[ b]benzofuran derivatives with three contiguous stereocenters, including a spiro-quaternary chiral center, could be smoothly obtained in excellent results (all cases >20:1 dr, up to 99% yield and 98% ee). The utility of this method was showcased by the versatile transformations of the product.

Unactivated alkyl chlorides are abundant building blocks in organic synthesis, but they have been rarely engaged in cross-electrophile coupling. Herein, we report a Ni/Ti-cocatalyzed reductive allylic defluorinative cross-coupling between trifluoromethyl alkenes and unactivated alkyl chlorides and bromides, enabling the efficient preparation of diverse functional-group-rich gem -difluoroalkenes. Notably, synthesis of the gem -difluoroalkene analogues of azaperone, haloperidol, and benperidol was also accomplished using our method as a key step.

A Pd-catalyzed formal [5 + 3] intermolecular cycloaddition reaction of isatin-derived α-(trifluoromethyl)imines with aryl substituted vinylethylene carbonates (VECs) has been reported, affording trifluoromethyl-group-containing spirooxindoles fused with an eight-membered ring as a single diastereoisomer in good yields in the presence of a Brønsted acid in a one-pot manner under mild conditions. The asymmetric version of this reaction has been also realized using a chiral phosphine ligand along with the further transformation of the obtained product to give a spirooxindolo pyrrolidine derivative upon oxidation.

Given the versatility and value of the structurally diverse organohalides and CF 3 -containing compounds in organic synthesis, we reported a green, oxidant-free electrochemical method using undivided electrochemical cells for radical bromination, chlorination and trifluoromethylation–formyloxylation of the various alkenes with readily available halogen radical (NaCl, NaBr), trifluoromethyl radical (CF 3 SO 2 Na) sources, and DMF as formyloxylation reagents. The protocol is operationally simple and robust and the Cl –, Br – or CF 3 – was directly oxidized at the anode, obviating the need for exogenous chemical oxidants.

A photoinduced copper-catalyzed three-component reaction involving carbohalide, alkene and amine has been developed, leading to valuable fluoroalkyl-containing amines. A sole inexpensive CuCl is used as the photo- and coupling catalyst. A broad array of substrates are capable coupling partners. The diverse method is compatible with a broad range of functional groups and can be further applied to the late-stage functionalization of bioactive pharmaceuticals.

By using silver complexes with bulky ligands such as DavePhos or N -heterocyclic carbenes, propargylic alcohols are smoothly converted with CO 2 into a unique class of unexplored cyclic alkylidene carbonates. These systems, for the first time, also achieve the direct carboxylative cyclization of primary propargylic alcohols. The silver-DavePhos catalyst is further applied for the bis-carboxylative cyclization of primary propargyl derivatives, thereby providing an effective route to a series of previously inaccessible and industrially relevant α-alkylidene cyclic carbonates.

An easy-to-handle Ni-catalyzed three-component reductive arylacylation of alkenes using isobutyl chloroformate as a CO source was described. This reaction operates under mild reaction conditions without the need to use toxic CO gas or metal carbonyl reagents. In addition, this method allows for rapid synthesis of 3,3-disubstituted oxindoles with an all-carbon quaternary stereocenter containing a ketone group in good yields with broad substrate scope.

An efficient electro-oxidative C-H/N-H activation with 1,3-diynes has been achieved with a robust earth-abundant cobalt catalyst. The electrochemical C-H functionalization was accomplished with ample scope and remarkable functional group compatibility in a simple undivided cell. This protocol avoids the utilization of stoichiometric and cost-intensive chemical oxidants in C-H activation, thus forming hydrogen as the only byproduct.

Thiocyanate compounds are key intermediates in the synthesis of pharmaceuticals and other sulfur-containing organic compounds. Herein, we first report an electrochemical protocol to synthesize vinyl thiocyanates from decarboxylative coupling of cinnamic acids with NH 4 SCN in aqueous solution. This method provides thiocyanation products with broad functional group tolerance under ambient conditions.

Catalytic enantioselective chemical reactions involving highly reactive radical species remain largely unexplored. We report herein for the first time a novel enantioselective radical ring-opening cyanation of redox-active oxime esters by dual photoreodox and copper catalysis. This mild protocol shows good functional group tolerance and broad substrate scope, producing a wide range of optically active alkyl dinitriles with high yields and excellent enantioselectivities, which are difficult to access traditionally.

An unprecedented Rh(I)-catalyzed, amino-group-assisted C–H carboxylation of 2-arylanilines with CO 2 under redox-neutral conditions has been developed. This reaction was promoted by a phosphine ligand with t -BuOK as the base and did not require the use of additional strong organometallic reagent. It enabled an efficient direct conversion of a broad range of 2-(hetero)arylanilines including electron-deficient heteroarenes to various phenanthridinones. Possible intermediates of the reaction were also evaluated in the preliminary mechanistic studies.

A fast and simple method for deoxyfluorination of carboxylic acids is presented. The protocol employs commodity chemicals (PPh 3, NBS, fluoride), affording products in excellent yields under mild conditions. Acyloxyphosphonium ion, the key reaction intermediate, was identified by NMR spectroscopic methods. Brønsted acidic conditions are essential for efficient C–F bond formation. The protocol displays scalability, high functional group tolerance, chemoselectivity, and easy purification of products. Deoxyfluorination of active pharmaceutical ingredients was established.

A metal-, base-, and additive-free amide bond formation reaction was developed under an organic photoredox catalyst. This green approach showed excellent functional selectivity without affecting other functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles. This method featured a broad substrate scope, good compatibility with water and air, and high yields (≤95%). The potential utilities were demonstrated by the synthesis of important drug molecules such as paracetamol, melatonin, moclobemide, and acetazolamide.

A sustainable synthesis of 5-fluoromethyl-2-oxazoles by use of electrochemistry has been demonstrated. Hypervalent ArIF 2 is generated by direct electrochemical oxidation of iodoarene ArI in Et 3 N·5HF and mediates the fluorocyclization of N -propargylamides to 5-fluoromethyl-2-oxazoles. The stoichiometry in ArI turned out to be a key parameter in controlling the product selectivity. This electrochemical protocol provides access to fluorinated oxazoles starting from simply available N -propargylamides with yields up to 65% and offers a green alternative over conventional reagent-based approaches.

A regioselective and stereoselective difluoromethylation of enamides with bench-stable and easily accessible difluoromethyltriphenylphosphonium bromide is described. A broad array of synthetically important and geometrically defined β-difluoromethylated enamides bearing various functional groups are obtained with up to 91% yield.