The 50 most-cited articles in Organic Letters, 2021

A general and metal-free visible-light-induced decarboxylative arylation procedure at room temperature was described for the construction of acylated heterocyclic derivatives, such as benzimidazo/indolo[2,1- a ]isoquinolin-6(5 H )-ones, aroylazaspiro[4.5]trienones, thioflavones, and so on. This practical arylation procedure was conducted by using 2,4,5,6-tetra(9 H -carbazol-9-yl)isophthalonitrile (4CzIPN) as a photocatalyst under mild conditions, which avoided the use of an additional base, traditional heating, and metal reagents.

Three emissive bridged-triphenylamine derivatives are designed and synthesized by incorporating carbon (DQAO), oxygen (OQAO), and sulfur (SQAO) atoms with two carbonyl groups. The fully bridged geometry and unique frontier molecular orbital distribution reveal its potential as narrowband thermally activated delayed fluorescence emitters. DQAO-, OQAO-, and SQAO-based organic light-emitting diodes exhibit the maximum external quantum efficiency (EQE max ) of 15.2%, 20.3%, and 17.8% for blue, green, and yellow, respectively.

A novel visible-light-induced radical tandem trifluoromethylation/cyclization of unactivated alkenes with sodium perfluoroalkanesulfinates (R f = CF 3, C 3 F 7, C 4 F 9, C 6 F 13, C 8 F 17 ) under air atmosphere has been developed. A range of quinazolinones containing unactivated alkene moiety and sodium perfluoroalkanesulfinates were compatible with this transformation, leading to a variety of perfluoroalkyl-substituted quinazoline alkaloids. Remarkably, the experiment can be carried out without any metal catalyst, strong oxidant, or external photosensitizer.

An iron-catalyzed deconstruction/hydrogenation reaction of alcohols through C-C bond cleavage is developed under the irradiation of visible light, to produce ketones or aldehydes as the products. Linear alcohols and cycloalkanols with different ring sizes are suitable substrates, containing tertiary, secondary, and primary alcohols bearing a wide range of substitutes. Complex natural alcohols can also perform the transformation selectively. The mechanism investigation reveals an unpresented reaction procedure that involves chlorine radical as a key intermediate, which is generated from [FeCl4]- through ligand to metal charge transfer (LMCT). The study illustrates new possibilities for iron photocatalysis, especially for various deconstruction/functionalization reactions.

A mild and efficient visible-light-induced radical difluoromethylation/cyclization of unactivated alkenes toward the synthesis of substituted quinazolinones with easily accessible difluoromethyltriphenylphosphonium bromide has been developed. The transformation has the advantages of wide functional group compatibility, a broad substrate scope, and operational simplicity. The benign protocol offers a facile access to pharmaceutically valuable difluoromethylated polycyclic quinazolinones.

A novel and efficient strategy for trifluoromethylthiolation and dearomatization of activated alkynes with stable and readily available AgSCF 3 has been developed. Reported herein is the unprecedented electrochemical generation of the SCF 3 radical in the absence of persulfate for the synthesis of SCF 3 -containing spiro[5,5]trienones in good yields via a 6- exo -trig radical cyclization.

An efficient visible-light-assisted, copper-catalyzed sulfonylation of aryl halides with sulfinates is reported. In our protocol, a single ligand Cu I photocatalyst formed in situ was used in the photocatalytic transformation. Diverse organosulfones were obtained in moderate to good yields. This strategy demonstrates a promising approach toward the synthesis of diverse and useful organosulfones.

Herein, we report a method that combines hydrogen atom transfer and photoredox catalysis to achieve the dehydrogenative difluoroallylation of amides, ethers, and alkyl aldehydes. This operationally convenient method transforms a broad scope of substrates into the corresponding gem -difluoroalkenes via the construction of C(sp 3 )–C(sp 3 ) or C(sp 3 )–C(sp 2 ) bonds. Excellent functional group compatibility and high selectivity make this method have a wide range of substrate types and render it suitable for late-stage modification of pharmaceutical intermediates.

The construction of (hetero)biaryls, which are ubiquitous scaffolds among medical substances, functional materials, and agrochemicals, constitutes a key application of cross-coupling methods. However, these usually require multiple synthetic steps. Herein, we report a simple photoinduced and catalyst-free C-H/C-H (hetero)arylation cross-coupling through aryl thianthrenium salts, which are formed site-selectively by direct C-H functionalization. The key to this approach is the UV-light, which can disrupt the C-S bond to form thianthrene radical cations and aryl radicals.

A transition-metal-free one-pot three-component annulation between diaryliodonium triflates, cyclic and acyclic aliphatic amines, and carbon disulfide providing a convenient and efficient access to biologically relevant S -aryl dithiocarbamates is developed. The reaction does not require metal, base, or any other additive and operates under mild and ambient conditions. This methodology is robust, scalable, and exhibits a broad substrate scope. The in silico analysis revealed that the majority of the compounds have a drug-likeness and good ADMET characteristics.

-disubstituted aryl bioisosteres has gained considerable momentum in drug development programs. Carbon-carbon bond formation via transition-metal-mediated cross-coupling represents an attractive strategy to generate BCP-aryl compounds for late-stage functionalization, but these typically require reactive organometallics to prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed functionalization of BCP redox-active esters with (hetero)aryl bromides via the action of a photoactive electron donor-acceptor complex are reported.

A versatile approach for the alkynylation of a variety of aliphatic hydrogen donors, including alkanes, is reported. We used tetrabutylammonium decatungstate as photocatalyst to generate organoradicals from C-H/Si-H bonds via hydrogen atom transfer. The latter intermediates underwent SOMOphilic alkynylation by methanesulfonyl alkynes to afford internal alkynes upon loss of a sulfonyl radical. The effect of different radicofugal groups on the reaction outcome was evaluated and rationalized via a combined experimental and computational approach.

By employing CuOAc as the catalyst, we realize a four-component reaction of 1,3-enynes, diselenides, DABCO·(SO 2 ) 2, and cycloketone oxime esters, providing facile access to diverse cyanoalkylsulfonylated allenyl selenides in moderate to good yields. This reaction features high functional group tolerance and a broad substrate scope, enabling the regioselective, sequential formation of C–SO 2 and C–Se bonds under mild reaction conditions. Moreover, the utility of this methodology is further illustrated through the late-stage functionalization of drug-based molecules.

A facile photocatalyzed strategy for difunctionalization of styrenes in the presence of CS 2 and amines providing β-keto dithiocarbamates has been developed. In the case of 4-nitrostyrene and 2-vinylpyridine, however, only 2-arylethylthiocarbamates are interestingly formed without the aid of photoredox catalysis/TBHP.

A cascade reaction between enaminones, hydrazines, and dimethyl sulfoxide (DMSO) for the synthesis of 1,4-disubstituted pyrazoles catalyzed by molecular iodine in the presence of Selectfluor has been realized. DMSO plays a dual role as the C 1 source and the reaction medium. In addition, the synthesis of 1,3,4-trisubstituted pyrazoles using aldehydes as alternative C 1 building blocks has also been achieved.

A novel electrochemical radical selenylation of alkenes and activated arenes without external oxidants is reported. The diselenide was fully transformed into Se-centered radicals through electrochemical Se-Se bond activation. Three-component radical carbonselenation was successfully realized using styrenes to trap the RSe radical. Besides, the direct coupling of RSe radicals with activated arenes was further developed. Using this atom-economic protocol, diversity of unsymmetric aryl-aryl, aryl-alkyl, and alkyl-alkyl selenoethers was obtained regioselectively, which has potential application in biological chemistry.

Excited-state palladium catalysis is an efficient process for the alkylation of diverse organic compounds via the generation of alkyl radicals from alkyl bromides and iodides. However, the generation of alkyl radicals from more stable alkyl chlorides remains challenging. Herein, we demonstrate the excited-state palladium-catalyzed synthesis of oxindoles and isoquinolinediones via alkylation/annulation reaction by overcoming inherent limitations associated with unactivated C(sp 3 )–Cl bond activation at room temperature.

An NHC-catalyzed atroposelective reaction between ynals and urazoles is disclosed. The reaction establishes a chiral C-N axis via an atroposelective [3 + 2] annulation/desymmetrization process. Our reaction allows efficient access to axially chiral and heteroatom-rich urazole derivatives with potential applications in bioactive molecules and catalysis.

The reduction of nitroarenes to anilines as well as azobenzenes to hydrazobenzenes using a single base-metal catalyst is reported. The hydrogenation reactions are performed with an air-and moisture-stable manganese catalyst and proceed under relatively mild reaction conditions. The transformation tolerates a broad range of functional groups, affording aniline derivatives and hydrazobenzenes in high yields. Mechanistic studies suggest that the reaction proceeds via a bifunctional activation involving metal-ligand cooperative catalysis.

A highly efficient method for the selective formal C-H/C-H cross-coupling of azoles and (hetero)arenes was established through arylsulfonium intermediates under transition-metal catalysis, which produced a variety of 2-(hetero)aryl azoles in good to excellent yields. Advantages of the reaction included mildness, a good functional group tolerance, a wide range of substrates, a high regio- and chemoselectivity, one-pot procedures, and the late-stage functionalization of complex molecules without the use of oxidants, offering a promising strategy for the transition-metal-catalyzed C-H arylation of azoles.

This manuscript describes a visible-light-mediated organophotoredox catalytic process for vicinal difunctionalization of alkenes using heteroatom nucleophiles and aliphatic redox active esters. A wide range of heteroatom nucleophiles including alcohols, water, carboxylic acids, amides, and halogens can be used for this reaction. This radical relay type reaction allows forging of C(sp 3 )–C(sp 3 ) with a carbon-centered radical and C(sp 3 )–heteroatom bonds with a benzyl cation on the vinylarenes with complete regioselectivity in a single step.

Herein, we report an acid-controlled highly tunable selectivity of Rh(III)-catalyzed [4 + 2] and [3 + 3] annulations of N -carboxamide indoles with iodonium ylides lead to form synthetically important tricyclic and tetracyclic N -heterocycles. Here, iodonium ylide serves as a carbene precursor. The protocol proceeds under operationally simple conditions and provides novel tricyclic and tetracyclic scaffolds such as 3,4-dihydroindolo[1,2- c ]quinazoline-1,6(2 H,5 H )-dione and 1 H -[1,3]oxazino[3,4- a ]indol-1-one derivatives with a broad range of functional group tolerance and moderate to excellent yields. Furthermore, the protocol synthetic utility was extended for various chemical transformations and was easily scaled up to a large-scale level.

An electroreductive arylation reaction of aliphatic and aromatic aldehydes as well as ketones with electro-deficient (hetero)arenes is described. A variety of cyano(hetero)arenes and carbonyl compounds, especially aliphatic aldehydes, have been examined, providing secondary and tertiary alcohols in moderate to good yields. Mechanistic studies, including cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and divided-cell experiments, support the generation of aliphatic ketyl radicals and persistent heteroaryl radical anions via cathodic reduction followed by radical-radical cross-coupling.

Ligand-controlled, palladium-catalyzed asymmetric [4+4] and [2+4] cycloaddition reactions of benzofuran-derived azadienes have been developed. Taking advantage of chiral P,N-ligand ( S, R p )-PPFA, we obtained a variety of benzofuro[2,3- c ][1,5] oxazocines in good yields with excellent enantioselectivities via [4+4] cycloaddition reactions. Employing chiral P,P-ligand ( S )-Cl-MeO-BIPHEP, the chemo- and regioselectivities were switched to synthesize tetrahydropyran-fused spirocyclic compounds in good efficiency via [2+4] cycloaddition reactions.

In this work, ruthenium(II)-catalyzed C-C/C-N annulation of 2-arylquinazolinones with vinylene carbonate is reported to synthesize fused quinazolinones. This catalytic system tolerates a wide range of substrates with excellent functional-group compatibility. In this transformation, the vinylene carbonate acts as an ethynol surrogate without any external oxidant involved. Furthermore, preliminary mechanistic studies were conducted, and a plausible catalytic cycle was also proposed.

A mild, efficient, and one-pot protocol for three-component carbosilylation of alkenes with imidazoheterocycle and silanes has been developed by merging iron(II) and visible-light photocatalysis. This C-C and C-Si bond-forming method provides functionalized organosilicon derivatives having imidazoheterocycles moieties in good yields. The reaction possibly proceeds through a radical pathway.

A mild transition-metal- and photosensitizer-free photoredox system based on the combination of NaI and PPh 3 was found to enable highly selective reduction of nitroarenes. This protocol tolerates a broad range of reducible functional groups such as halogen (Cl, Br, and even I), aldehyde, ketone, carboxyl, and cyano. Moreover, the photoredox catalysis with NaI and stoichiometric PPh 3 provides also an alternative entry to Cadogan-type reductive amination when o -nitrobiarenes were used.

Diverse C-P cross-couplings of arylthianthrenium salts with diarylphosphines producing various triarylphosphines via highly selective C-S bond cleavage are reported. In the absence of catalyst, the reaction of arylthianthrenium salts with diarylphosphines undergoes phosphinative ring opening exclusively via the cleavage of an endocyclic C-S bond of a thianthrene skeleton. The use of a palladacycle catalyst under otherwise the same conditions enables the phosphination via the cleavage of an exocyclic C-S bond with significantly higher speed.

Stereoselective reactions at the anomeric carbon constitute the cornerstone of preparative carbohydrate chemistry. Here, we report stereoselective C-arylation and etherification reactions of anomeric trifluoroborates derived from BMIDA esters. These reactions are characterized by high anomeric selectivities for 2-deoxysugars and broad substrate scope (24 examples), including disaccharides and trifluoroborates with free hydroxyl groups. Taken together, this new class of carbohydrate reagents adds the palette of anomeric nucleophile reagents suitable for efficient installation of C–C bonds.

Enantioselective 7- exo -trig cyclocarbopalladation-initiated carbonylation cascade reactions, leading to seven-membered dibenzo[ b, d ]azepin-6-ones containing a thermodynamically controlled stereogenic axis, have been realized for the first time. A series of 7-acetate- or 7-acetamide-substituted dibenzo[ b, d ]azepin-6-ones are obtained under atmospheric pressure of CO in good yields with excellent diastereo- and enantioselectivities. The calculated energy difference between the diastereoisomers generated from the stereogenic biaryl axis and the stereogenic center is approximately 2.8 kcal/mol, which agrees with the excellent diastereoselectivity observed.

A sustainable and cost-effective manner for the photocatalytic annulation reaction of N -sulfonyl ketimines with N -arylglycines to synthesize imidazolidine-fused sulfamidates (31 examples) by employing CsPbBr 3 as a heterogeneous photocatalyst has been developed. The catalyst CsPbBr 3 can be simply recovered from the reaction mixture and reused at least five times without an obvious reduction in its photocatalytic reactivity, exhibiting a high catalyst economic feature.

We develop a visible light-promoted divergent cycloaddition of α-diazo esters with hexahydro-1,3,5-triazines, leading to a series of aziridine and imidazolidine frameworks in average good yield, by simply changing the reaction media used. It is noteworthy that the reaction occurs under sole visible light irradiation without the need for exogenous photoredox catalysts. More significantly, a reasonable reaction mechanism was proposed on the basis of the control experiments and density functional theory calculation results.

Monofluoroalkenes normally act as metabolically stable bioisosteres for amide groups (−NH–CO−) and have widespread applications in drug discovery. Additionally, they are widely used as building blocks in organic synthesis. In this study, the Cu/Pd-catalyzed cis- borylfluoroallylation of alkynes was achieved, providing a modular and general tactic for the preparation of monofluorinated alkene scaffolds with high regioselectivity and stereoselectivity. Moreover, an array of synthetic building blocks can be generated by downstream transformations.

An asymmetric synthesis of silicon-stereogenic monohydrosilanes by rhodium-catalyzed dehydrogenative C–H silylation is developed. The process is suitable for the synthesis of various asymmetrically trisubstituted 1 H -benzosiloles and 1 H -benzosilolometallocenes in good yields with excellent chemo-, regio-, and stereocontrol. These selected silicon-stereogenic 1 H -benzosilole compounds exhibit bright blue fluorescence and CPL (circular polarized luminescence) signals, which could be attractive to practitioners of materials science.

Asymmetric functionalization of inert C(sp 3 )–H bonds is a straightforward approach to realize versatile bond-forming events, allowing the precise assembly of molecular complexity with minimal functional manipulations. Here, we describe an asymmetric photocatalytic C(sp 3 )–H bond addition to α-substituted acrylates by using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom transfer (HAT) photocatalyst and chiral phosphoric acid as a chiral proton-transfer shuttle. This protocol is supposed to occur via a radical/ionic relay process, including a TBADT-mediated HAT to cleave the inert C(sp 3 )–H bond, a 1,4-radical addition, a back hydrogen abstraction, and an enantioselective protonation. A variety of inert C–H bond patterns and α-substituted acrylates are well tolerated to enable the rapid synthesis of enantioenriched α-stereogenic esters from simple raw materials.

We report a general photocatalytic protocol for the remote C(sp 3 )–H bond amination of free aliphatic alcohols. The electron transfer between the abundant and inexpensive catalyst FeCl 3 and simple alkanols under blue LED irradiation enables the alkoxy radical formation under mild redox-neutral conditions, with no need for additional oxidant and prefunctionalization. The subsequent selective 1,5-hydrogen atom transfer (HAT) and amination provide a simple and efficient way to access molecular complexity from readily available and bulk alcohols.

A green and sustainable oxime ether formation method via the visible-light-promoted O-H functionalization of oximes with diazo esters is described. The reaction occurs under very mild conditions (catalyst- and additive-free) with a high yield and a high functional group tolerance. When the reaction was performed with a cyclic ether as the solvent (e.g., THF, 1,4-dioxane, tetrahydropyran, ect.), an interesting photochemical three-component reaction product was obtained in good yields.

The synthesis of NH-free pyrroles via Pd-catalyzed annulation of enaminones and alkenes is reported. With the catalysis of Pd(II), the activation of triple C(sp 2 )–H bonds, including one internal C(sp 2 )–H bond in enaminone, has been activated to provide various pyrroles. The interesting evolution of hydrogen gas from the reactions has been observed by a hydrogen detector.

Asymmetric ruthenium-catalyzed C–H alkylations were enabled by a chiral C2-symmetric carboxylic acid. The mild cooperative ruthenium(II) catalysis set the stage for the assembly of chiral tetrahydrocarbazoles and cyclohepta[ b ]indoles with high levels of enantioselectivity at room temperature. Mechanistic studies by experiment and computation identified a fast C–H ruthenation, along with a rate- and enantio-determining proto-demetalation. The asymmetric induction was governed by weak attractive secondary dispersion interactions as found in NCI analysis of the key transition states.

We describe an efficient photoredox system, relying on decatungstate/disulfide catalysts, for the hydrofunctionalization of styrenes. In this methodology the use of disulfide as a cocatalyst was shown to be crucial for the reaction efficiency. This photoredox system was employed for the hydro-carbamoylation, -acylation, -alkylation, and -silylation of styrenes, giving access to a large variety of useful building blocks and high-value molecules such as amides and unsymmetrical ketones from simple starting materials.

The asymmetric synthesis of P -stereogenic phosphinates through allylic alkylation of H -phosphinates has been developed. With H -phosphinates and allylic acetates as the starting materials, a variety of allylic P -chiral phosphinates were accessed in high enantioselectivities of up to 92% ee and generally high yields. In addition, a further study demonstrated the applicability of this protocol, including the scale-up synthesis and facile transformation of chiral products from phosphinates to phosphine oxides with organolithium reagents under mild reaction conditions.

A simple and efficient mechanochemical-induced approach for the synthesis of 1,2-diketoindolizine derivatives has been developed. BaTiO 3 was used as the piezoelectric material in this transformation. This method features no usage of solvent, simple experimental operation, scalable potential, and high conversion efficiency, which make it attractive and practical.

Acceptorless double dehydrogenative cross-coupling of secondary and primary alcohols under nickel catalysis is reported. This Guerbet type reaction provides an atom- and a step-economical method for the C-alkylation of secondary alcohols under mild, benign conditions. A broad range of substrates including aromatic, cyclic, acyclic, and aliphatic alcohols was well tolerated. Interestingly, the C-alkylation of cholesterol derivatives and the double C-alkylation of cyclopentanol with various alcohols were also demonstrated.

We report a photochemical method for the chemoselective radical functionalization of tryptophan (Trp)-containing peptides. The method exploits the photoactivity of an electron donor-acceptor complex generated between the tryptophan unit and pyridinium salts. Irradiation with weak light (390 nm) generates radical intermediates right next to the targeted Trp amino acid, facilitating a proximity-driven radical functionalization. This protocol exhibits high chemoselectivity for Trp residues over other amino acids and tolerates biocompatible conditions.

N-N axially chiral skeletons are significant structural motifs in natural products, pharmaceuticals, and functional materials. Herein we disclose a method for the asymmetric synthesis of N-N axially chiral compounds by phase-transfer catalysis. A wide range of N-N axially chiral quinazolinone derivatives were prepared in high yields with excellent stereoselectivities. Furthermore, the synthetic utility of the protocol was proved by large-scale reaction and transformation of the product. Density functional theory calculations provide insight into the mechanism.

An efficient B(C 6 F 5 ) 3 -catalyzed aerobic oxidative C–S cross-coupling reaction of thiophenol with indoles was developed, affording a wide range of diaryl sulfides in good yields. An electron donor–acceptor complex between B(C 6 F 5 ) 3 and indoles was formed, facilitating the photoinduced single-electron transfer (SET) from indole substrates to the B(C 6 F 5 ) 3 catalyst. This protocol demonstrates a new reaction model using B(C 6 F 5 ) 3 as a single-electron oxidant.

O/DMSO-based system for the dehydrogenative coupling of a wide range of alcohols, phenols, thiols, and thiophenols with diverse phosphorus reagents has been developed. This metal- and strong-oxidant-free strategy provides a facile approach to a great variety of organophosphinates and thiophosphates. The simple reaction system, good functional-group tolerance, and broad substrate scope enable the application of this method to the modification of natural products and the direct synthesis of bioactive molecules and flame retardants.

A visible-light-induced radical tandem cyclization/arylation between 2-amino-1, 4-naphthoquinone and N -allyl-2-bromo-2,2-difluoroacetamides has been developed without an external photocatalyst. The transformation could be carried out at room temperature and gave a variety of C-3-functionalized 2-amino-1,4-naphthoquinone derivatives in moderate to excellent yields. Moreover, mechanistic studies revealed that the reaction is driven by the formation of an electron donor–acceptor (EDA) complex.

A palladium-catalyzed asymmetric tandem C–C bond activation/Cacchi reaction between cyclobutanones and o -ethynylanilines was reported. The transient chiral σ-alkylpalladium species generated via enantioselective C(sp 3 )–C(sp 2 ) bond activation of cyclobutanones promotes cyclization of o -ethynylanilines, leading to one-carbon-tethered chiral indanone-substituted indoles. Two C–C bonds and one C–N bond are created with concomitant formation of an all-carbon quaternary stereocenter. Furthermore, a chiral C2-aryl axis can be created in 2,3-disubstituted indole moiety, leading to indanone-substituted indoles with both central and axial stereogenic elements.

High Resolution Image Download MS PowerPoint Slide This work describes the application of pentafluoropyridine (PFP), a cheap commercially available reagent, in the deoxyfluorination of carboxylic acids to acyl fluorides. The acyl fluorides can be formed from a range of acids under mild conditions. We also demonstrate that PFP can be utilized in a one-pot amide bond formation via in situ generation of acyl fluorides. This one-pot deoxyfluorination amide bond-forming reaction gives ready access to amides in yields of ≤94%.