The 50 most-cited articles in Organic Letters, 2023

Hantzsch esters (HEs) are widely recognized as sources of hydride ions (H-) and sacrificial electron donors in their ground state. Here, we report the application of HE as a mediator in [2π+2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with alkenes under photo conditions. Through this strategy, various substituted bicyclo[2.1.1]hexanes can be efficiently prepared.

An organoelectrophotocatalytic approach for the C–H silylation of heteroarenes through dehydrogenation cross-coupling with H 2 evolution has been developed. The organoelectrophotocatalytic strategy is carried out under a simple and efficient monocatalytic system by employing 9,10-phenanthrenequinone both as an organocatalyst and as a hydrogen atom transfer (HAT) reagent, which avoids the need for an external HAT reagent, an oxidant, or a metal reagent. A variety of heteroarenes can be compatible in satisfactory yields with excellent regioselectivity.

Sulfur-arylation of sulfenamides is reported. This reaction proceeds via a Chan-Lam-type coupling with commercially abundant boronic acids to give sulfilimines. A broad scope was established with a variety of readily accessible aryl and alkyl sulfenamide and boronic acid inputs. Synthetic utility and functional group compatibility were further demonstrated through the direct late-stage introduction of sulfilimines into approved drugs. Derivatization of the sulfilimine products provided access to medicinally relevant sulfoximines and sulfondiimines.

The elaboration of step-economy and catalytic approaches for accessing diverse fluorinated heterocyclics is highly desirable. Described herein is a radical-polar crossover enabled three-component cyclization to polysubstituted fluoropyrazoles by using CF 2 Br 2 as a novel C1F1 synthon. Mechanistic experiments revealed that the in situ generation of the reactive intermediate gem -difluorovinylimine ion is the key to this transformation. This protocol unlocks the novel reactivity of CF 2 Br 2 and adds significant synthetic values to fluorine chemistry.

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

A practical electrochemically driven method for fluorosulfonylation of both aryl and alkyl thianthrenium salts has been disclosed. The strategy does not need external redox reagents or metal catalysts. In combination with C-H thianthrenation of aromatics, this method provides a new tool for the site-selective fluorosulfonylation of drugs.

In this investigation, an unprecedented transition-metal-free and redox-neutral synthesis of sulfilimines was realized through the S-arylation of readily obtainable sulfenamides employing diaryliodonium salts. The pivotal step encompassed the resonance between bivalent nitrogen-centered anions, engendered postdeprotonation of sulfenamides under alkaline conditions, and sulfinimidoyl anions. The experimental outcomes demonstrate that sulfinimidoyl anionic species function as efficacious nucleophilic reagents, affording sulfilimines with notable to exceptional yields and superlative chemoselectivity, all executed within a transition-metal-free protocol and under exceptionally mild conditions.

We disclose a transition-metal-free NaI/PPh 3 -mediated direct C–H alkylation of azauracils using N -(acyloxy)pthalimides (NHPIs) as readily available alkyl surrogates under visible light irradiation. Detailed mechanistic studies reveal formation of a photoactivated electron donor–acceptor (EDA) complex between NaI/PPh 3, TMEDA, and alkyl NHPI ester and establish the crucial role of TMEDA in increasing the activity of the photoredox system. The reaction demonstrates a broad scope, scalability, and appreciable functional group tolerance. A variety of azauracils are shown to undergo alkylation by primary, secondary, and tertiary NHPI esters under mild conditions, furnishing the desired products in good to excellent yields.

The visible-light-induced photoredox carbon radical formation from aqueous sulfoxonium ylides has been demonstrated for the first time. While direct reduction of sulfoxonium ylides by H 2 O efficiently generates the corresponding hydrocarbon compounds, the use of additional alkenes as radical acceptors alters the chemical reactivity to achieve alkene carboarylation of N -arylacrylamides. Mechanistic studies reveal two different reaction pathways involved in the carbon radical formation from aqueous sulfoxonium ylides resulting in reduction to release dimethyl sulfone and carboarylation to form DMSO.

An efficient strategy for the preparation of aryl phosphonates via blue-light-promoted single electron transfer process of an EDA complex between phosphites and thianthrenium salts has been demonstrated. The corresponding substituted aryl phosphonates were obtained in good to excellent yields, and the byproduct thianthrene can be recovered and reused in quantity. This developed method realizes the construction of aryl phosphonates through the indirect C-H functionalization of arenes, which has potential application value in drug discovery and development.

'-tetramethylethylenediamine (TMEDA) that can form a self-assembled tetrameric electron donor-acceptor (EDA) complex with diaryliodonium reagents (DAIRs) and furnish aryl radicals upon visible light irradiation. This practical mode of activation of DAIRs enables arylation of an array of heterocycles under mild conditions to provide the respective heteroaryl-(hetero)aryl assembly in moderate to excellent yields. Detailed mechanistic investigations comprising photophysical and DFT studies provided insight into the reaction mechanism.

A novel visible-light-promoted selective sulfonylation and selenylation of dienes with selenosulfonates has been developed. This technology provides mild access to a wide range of sulfonyl benzo[ b ]azepinones and seleno-benzo[ b ]azepines. Preliminary mechanistic studies suggest that the sulfonylation involves a sulfonyl radical engaged cascade process, and the selenylation is accomplished through a sequential oxidation/electrophilic cyclization process. The large-scale operation and late-stage modification experiment reveal the promising utility of this protocol.

Organoelectrophotocatalytic generation of acyl radicals from formamides and aldehydes to synthesize acylated 3-CF 3 -2-oxindoles has been developed. This protocol features a monocatalytic system using 9,10-phenanthrenequinone (PQ) both as a catalyst and as a hydrogen atom transfer (HAT) reagent, which avoids the use of an external HAT reagent, metal reagent, and oxidant. A variety of acylated 3-CF 3 -2-oxindoles have been obtained in satisfactory yields from CF 3 -substituted N -arylacrylamides via a tandem radical cyclization.

In this work, we developed a metal-free and redox-neutral strategy for the selective S-alkylation of sulfenamides under basic conditions to yield sulfilimines. The key step involves the resonance between bivalent nitrogen-centered anions, generated after deprotonation of sulfenamides under alkaline conditions, and sulfinimidoyl anions. Our sustainable and efficient approach employs sulfur-selective alkylation of readily accessible sulfenamides and commercially available halogenated hydrocarbons, resulting in the successful synthesis of 60 sulfilimines in high yields (36–99%) and short reaction times.

Sulfur-(hetero)arylation of sulfenamides with commercially abundant (hetero)aryl iodides by Ullmann-type coupling with inexpensive copper(I) iodide as the catalyst is reported. A broad scope of reaction inputs was demonstrated, including both aryl and alkyl sulfenamides and highly sterically hindered aryl and 5- and 6-membered ring heteroaryl iodides. Relevant to many bioactive high oxidation state sulfur compounds, the (hetero)arylation of S -methyl sulfenamides is reported, including for complex aryl iodides. Smiles rearrangement of electron-deficient S -heteroaryl sulfilimines is also disclosed.

A simple and efficient Pd-catalyzed oxidative cyclization system is developed for the chemo- and regioselective synthesis of 3,4-dihydro-benzothiadiazine 1,1-dioxides, which are formed through aminosulfonylation of ortho -iodoanilines with SO 2 . DABSO is utilized as the source of SO 2, and the organic compound O 2 acts as an oxidant. This direct C–S, S–N, and C–N functionalization is highly efficient, and broad functional group tolerance is observed, resulting in moderate to excellent yields of 3,4-dihydro-benzothiadiazine 1,1-dioxides. Furthermore, this method is amenable to gram-scale synthesis.

Recent advances in single-atom insertion reactions have opened up new synthetic approaches for molecular diversification. Developing innovative strategies to directly transform biologically relevant molecules, without any prefunctionalization, is key to further expanding the scope and utility of such transformations. Herein, the direct access to quinazolines and pyrimidines from the corresponding unprotected 1 H -indoles and 1 H -pyrroles is reported, relying on the implementation of lithium bis(trimethylsilyl)amide (LiHMDS) as a novel nitrogen atom source in combination with commercially available hypervalent iodine reagents. Further application of this strategy in late-stage settings demonstrates its potential in lead structure diversification campaigns.

A visible-light-photocatalyzed 1,2-arylalkylation of N -(arylsulfonyl)acrylamides with ketone-based dihydroquinazolinones is described. The formal C–C bond cleavage of aliphatic ketones is unified with tandem radical alkylation/1,4-aryl migration/desulfonylation to forge two different types of vicinal C–C bonds and construct an all-carbon quaternary α-stereocenter, thus enhancing the carbogenic complexity and tolerating diverse functionalities. Additional to telescopic synthesis and product diversification, this method features a radical dicarbofunctionalization of conjugated N -(arylsulfonyl)acrylamides with a nucleophilic alkyl radical precursor (dihydroquinazolinone) utilizing oxygen as a green oxidant at ambient temperature.

An unprecedented protocol for a Rh(III)-catalyzed [3 + 2] annulation from simple and readily available enaminones and iodonium ylides has been developed. The novel strategy allows for access to a new class of structurally diverse tetrahydro-indolones with high efficiency and a broad substrate scope. In addition, this transformation represents the first example of the selective Rh(III)-catalyzed alkenyl C-H bond functionalization and annulation of enaminones. Finally, the potential applications of this protocol are demonstrated through gram-scale reaction and late-stage modification.

A novel Rh(III)-catalyzed cascade alkenyl C-H activation/[3 + 2] annulation/pinacol rearrangement reaction of enaminones with iodonium ylides has been developed. This methodology provides a new and straightforward synthetic strategy to afford highly functionalized 2-spirocyclo-pyrrol-3-ones in satisfactory yield from readily available starting materials under mild conditions. Moreover, gram-scale reactions and further derivatization experiments are implemented to demonstrate the potential utility of this developed approach.

An efficient and metal-free approach for the synthesis of sulfilimines from sulfenamides with aryne and cyclohexyne precursors has been developed. The reaction proceeds through unusual S-C bond formation, which offers a novel and practical entry to access a wide range of sulfilimines in moderate to good yields with excellent chemoselectivity. Moreover, this protocol is amenable to gram-scale synthesis and is applicable to the transformation of the products into useful sulfoximines.

Sulfilimines are key intermediates to common motifs in medicines and agrochemicals. Typically, this class of compounds are prepared by imidation of thioethers, transition-metal-catalyzed or base-promoted sulfur alkylation and transition-metal-catalyzed sulfur arylation. Here, we report a practical and efficient base-mediated sulfur arylation reaction for the preparation of sulfilimines. A wide range of N -acyl and N -aryl sulfenamides react with various diaryliodonium salts smoothly to afford the sulfilimines in high yields with excellent chemoselectivities.

A straightforward cross-coupling of aryl thioether with aryl bromide with the aid of nickel salt, magnesium, and lithium chloride in tetrahydrofuran at ambient temperature was accomplished. The one-pot reactions proceeded efficiently via C-S bond cleavage to produce the desired biaryls in modest to good yields, avoiding the use of pregenerated or commercial organometallic reagents.

Switchable multicomponent reactions have been attractive tools for the construction of compound libraries with skeleton diversity and complexity by slightly changing the reaction conditions. Described herein is a regioselectivity-switchable formal [1 + 2 + 2] cycloaddition reaction from difluoroalkyl compounds, enaminones, and RNHNH 2, ultimately using 1-methylindazol-3-amine as a traceless mediator to switch the inherent regioselectivity of 1,3,4-trisubstituted pyrazole formation to 1,4,5-trisubstituted pyrazoles. Remarkable features of this work include mild conditions, simple operation, and broad scopes.

Deconstructive alkynylation of an unstrained ketone catalyzed by an organic photocatalyst under blue light irradiation is reported for the first time. A broad substrate scope with up to 63 examples, excellent functional group tolerance, and gram scale reaction demonstrated the practicality of this novel alkynylation method. The dihydroquinazolinone derivative of trifluoroacetophenone had been proved to have potential as a novel trifluoromethylation reagent after working well for the trifluoromethylation reaction with various alkynyl bromides.

N ′-Benzylidene- N -homoallylacetohydrazides were designed and synthesized as novel skeletons for the construction of functionalized tetrahydropyridazines. A series of aryl- and alkylsulfonylated tetrahydropyridazines were obtained in yields of up to 94% employing sulfonyl chlorides as the sulfonyl radical sources under visible-light irradiation. Besides, sulfonylated dihydropyrazoles were also produced from N -allyl- N ′-benzylideneacetohydrazides. Mechanistic investigations indicated that both energy transfer and single electron transfer processes were involved in accomplishing the radical 6/5- endo - trig cyclization to the C═N bond.

We disclose herein an efficient photochemical formal [3+2+1] annulation strategy for the transformation of diazocarbonyl compounds into various fluorinated nitrogen-containing heterocycles. This transformation is characterized by reacting fluoroalkyl radicals with α-diazoketones, which are used as infrequent denitrogenated synthons under visible light. Moreover, a wide range of N-heterocycles containing precious CF 3 and perfluoroalkylated groups are constructed in moderate to good yields. Notably, this photochemical strategy may provide a fruitful path for the synthesis of complex organofluorides via diazo/fluorine/radical chemistry.

The development of mild methodology for converting inert C–H bonds to value-added molecules has been an attractive research topic during the last few decades as it offers efficient preparation. Meanwhile, diaryl ketones hold potent applications in antitumor drugs, the agrochemical industry, and synthetic chemistry. Herein, we report versatile palladium-catalyzed carbonylative cross-coupling reactions of aryl thianthrenium salts with arylboronic acids. Arenes were transformed site selectively via C(sp 2 )–H thianthrenation, and various desired diaryl ketones were produced in good to excellent yields.

Herein, we report a mild and practical protocol for the α-perchloroalkyl β-heteroarylation of alkenes using available chloroform as the dichloromethyl source via α-amino radical-mediated halogen-atom transfer. Various substrates are compatible under mild reaction conditions, providing the corresponding products in moderate to good yields. This strategy gives an efficient and convenient method for the introduction of chloroalkyl motifs into N -heteroarenes. The control experiment demonstrates that the α-amino radical generated in situ is a key intermediate in the transformation.

A new class of iminosulfonylation reagents were developed and extensively used in the 1,2-iminosulfonylation of various olefins. Olefins containing bioactive molecules, such as indomethacin, gemfibrozil, clofibrate, and fenbufen, afforded the desired iminosulfonylation products in synthetically useful yields. Furthermore, the first remote 1,6-iminosulfonylation of alkenes was realized by using oxime ester bifunctionalization reagents. Overall, more than 40 structurally diverse β-imine sulfones were obtained in moderate to excellent yields.

An organo-photocatalytic sulfonylimination of alkenes was developed by employing readily available N -sulfonyl ketimines as bifunctional reagents. This transformation, featuring prominent functional group tolerance, provides a direct and atom-economic approach for the synthesis of valuable β-amino sulfone derivatives as a single regioisomer. In addition to terminal alkenes, internal alkenes participate in this reaction with high diastereoselectivity. N -Sulfonyl ketimines with aryl or alkyl substituents were found to be compatible with this reaction condition. This method could be applied in the late-stage modifications of drugs. Additionally, a formal insertion of alkene into cyclic sulfonyl imine was observed, affording a ring expansion product.

The three-component reactions of enaminones, α-diazo esters/ketones, and t -butyl nitrite (TBN) for the switchable synthesis of isomeric isoxazoles have been realized. The catalysis with Cu(II) salt provides 3,4-disubsituted isoxazoles via [3 + 2] cycloaddition. On the other hand, the catalysis of Ag(I) with identical substrates leads to isomeric isoxazoles with reversed C3 and C4 substitution based on a key [2 + 1] cycloaddition.

Here, we explored the possibility of using radial conjugated π-system of cycloparaphenylenes (CPP) within a donor-acceptor TADF emitter design. 4PXZPh-[10]CPP contains four electron-donating moieties connected to a [10]CPP. In the 15 wt% doped in CzSi film, 4PXZPh-[10]CPP showed sky-blue emission with λPL = 475 nm, ΦPL = 29%, and triexponential emis-sion decays with τPL of 4.4, 46.3 and 907.8 ns. Solution-processed OLEDs using 4PXZPh-[10]CPP exhibited sky-blue emission with an λEL of 465 nm and an EQEmax of 1.0%.

We report an organophotoredox-catalyzed stereoselective allylic arylation of MBH acetates with a palette of diaryliodonium triflates (DAIRs) to provide the corresponding trisubstituted alkenes in moderate to good yields. The method could be extended to three-component coupling involving 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a sulfur dioxide surrogate for the synthesis of biologically relevant allylic sulfones. Both of these reactions were carried out under mild conditions featuring broad scope, robustness, and appreciable functional group tolerance.

We report a strategic exploitation of trifluoromethyl thianthrenium triflate (TT-CF 3 + OTf – ) as both electromediator and CF 3 radical precursors for paired electrolysis. Enabled by this strategy, the three-component trifluoromethylheteroaromatization of alkenes and alkynes was realized. The superiority of TT-CF 3 + OTf – to other electrophilic CF 3 reagents is attributed to the cathodic generation of thianthrene (TT) as a mediator, which shifts the heterogeneous oxidation of interest to a homogeneous one.

We have presented a carbonate anion assisted photochemical protocol for the C-X bond activation. Anion-π interactions have been leveraged to generate aryl radicals from easily accessible aryl halides that are further utilized in C-P and C-B bond formation reactions with excellent reactivity and broad functional group tolerance. Spectroscopic investigations and DFT studies were conducted for mechanistic insights. This inexpensive method alleviates the use of a photocatalyst and the need of preactivation of the substrate for the light-induced activation of C-X bonds.

Herein, we disclose a facile and versatile trifluoromethylimination of alkene with a rationally designed N -(diphenylmethylene)-1,1,1-trifluoromethanesulfonamide as a bench-stable and readily accessible carboamination reagent. Enabled by an energy transfer (EnT) process, an array of alkenes were able to be facilely CF 3 -iminated under metal-free photocatalytic conditions. The mild reaction conditions and good functional group compatibility render this protocol highly valuable for the difunctionalization of olefins with structural complexity and diversity.

The iminoacylation of alkenes via photoredox N-heterocyclic carbene catalysis is developed with the employment of alkene-tethered α-imino-oxy acids and acyl imidazoles. The corresponding substituted 3,4-dihydro-2 H -pyrroles were afforded in moderate to good yields with good to high diastereoselectivities in most cases. The reaction involves the 5- exo -trig radical cyclization of an alkene-tethered iminyl radical and the following coupling with a ketyl radical from acyl imidazole under NHC catalysis.

Herein, we report a protocol for the anaerobic oxidation of alcohols, amines, aldehydes, and imines promoted by photoexcited nitroarenes. Mechanistic studies support the idea that photoexcited nitroarenes undergo double hydrogen atom transfer (HAT) steps with alcohols and amines to provide the respective ketone and imine products. In the presence of aldehydes and imines, successive HAT and oxygen atom transfer (OAT) events occur to yield carboxylic acids and amides, respectively. This transformation is amenable to a continuous-photoflow setup, which led to reduced reaction times.

In this study, we present a novel and efficient approach for the oxidative esterification of sulfenamides using phenyliodonium diacetate, enabling the synthesis of sulfinimidate esters and sulfilimines under mild and metal-free conditions, with yields reaching up to 99%. The protocol is readily scalable and compatible with a diverse range of substrates and functional groups, and we demonstrate its potential for late-stage functionalization of pharmacologically relevant molecules. Furthermore, we propose a plausible reaction mechanism to account for the observed sequence of events.

Herein, we describe a novel and efficient photoredox catalytic C α radical addition/defluoroalkylation coupling reaction between α-trifluoromethyl alkenes and N -trifluoroethyl hydroxylamine. A series of gem -difluoroallylated α-trifluoromethylamines were synthesized by the C α radical addition enabled by a 1,2-H shift of the in situ-generated N- trifluoroethyl radical. Notably, this protocol is distinguished by its mild conditions, easy operation, and excellent functional group tolerability.

Direct, economical, and green synthesis of deuterated α-amino phosphine oxides remains an elusive challenge in synthetic chemistry. Herein, we report a visible-light-driven umpolung strategy for synthesizing deuterated α-amino phosphine oxides from isocyanide using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene as the photocatalyst and D 2 O as the deuterium source. Moreover, the streamlined and sustainable methodology can be applied in the modification of amino acids, natural products, and drugs. The strong antiproliferative activity of the desired products indicates that the method could provide a novel privileged scaffold for antitumor drug development.

A metal-free photosensitized three-component reaction of oxime esters, alkenes, and DABCO·(SO 2 ) 2 was developed. This protocol could accommodate a wide substrate scope, including activated and unactivated alkenes and aryl and aliphatic carboxylic acid oxime esters, delivering a broad range of β-amino sulfones in moderate to high yields. The insertion of SO 2 as a linker moiety allows the manipulation of the functionality in the reaction process, expanding the utility of oxime esters as bifunctional reagents.

A novel alkoxycarbonyl-radical-triggered cascade cyclization of 1,7-enynes, with alkyloxalyl chlorides as the ester units, for the synthesis of benzo[ j ]phenanthridines is described. The reaction conditions exhibit excellent compatibility with a broad range of alkoxycarbonyl radical sources and realize the installation of an ester group in the polycyclic compound. This radical cascade cyclization reaction features excellent functional group tolerance, mild reaction conditions, and good to excellent yields.

The reductive cleavage of C(Ar)-X bonds is the key step for the cross coupling of Ar-X with other groups. In this work, under the irradiation of 407 nm LEDs using sodium formate as reductant and thiol as hydrogen atom transfer agent, a variety of (hetero)aryl chlorides, bromides, and iodides could be reduced to corresponding (hetero)arenes. The key intermediates, aryl radicals, could be trapped by either hydrogen, phosphite, or borates. The same reduction conditions can be extended to the deprotection of sulfonamides.

Sulfilimines, the aza analogues of sulfoxides, are of increasing interest in medicinal and agrochemical research programs. However, the development of efficient routes for their synthesis has remained relatively unexplored. In this study, we report a transition metal-free, selective S- arylation reaction between sulfenamides and arynes, enabling the facile preparation of structurally diverse sulfilimines under mild and redox-neutral conditions in good yields. The application value of our method was further demonstrated by scale-up synthesis, downstream derivatization, and robustness screen.

An efficient palladium-catalyzed 2-fluoroallylation of P(O)H compounds with gem -difluorocyclopropanes is presented. The reaction provides a variety of 2-fluoroallylic phosphorus compounds in good yields with high Z selectivity through the sequential C–C bond activation, C–F bond cleavage, and C–P coupling process. Various H-phosphonates, H-phosphinates, and secondary phosphine oxides are all tolerated. In addition, the gram-scale synthesis and the late-stage modification of complex bioactive molecules show practical utilities of the transformation.

A novel trifluoromethylation of (hetero)arenes and polarized alkenes using simple trifluoroacetic anhydride (TFAA) as the low price CF 3 source under photoredox catalysis was developed without using additives such as bases, hyperstoichiometric oxidant, or auxiliaries. The reaction showed excellent tolerance, including to some important natural products and prodrugs, even on the gram scale and extended to ketones. This simple protocol provides a practical utilization of TFAA. Several perfluoroalkylations and trifluoromethylation/cyclizations were successfully achieved under identical conditions.

We present herein a highly atroposelective indolization for the efficient synthesis of 1,1′-biheteroaryls bearing a chiral N–N axis. Under the cooperative catalysis of chiral phosphoric acid and InBr 3, the reactions between 2,3-diketoesters and 1,3-dione-derived enamines resulted in a highly enantioselective construction of 1,1′-pyrrole-indoles with up to 92% yield, 94% enantiomeric excess (ee), or bisindoles in up to 92% ee. Derivatizations of these compounds to diverse functionalized N–N linked axially chiral biheteroaryls have also been demonstrated.

Copper-catalyzed dynamic kinetic resolution of secondary phosphine oxides has been successfully developed, providing a general method for the gram-scale enantioselective synthesis of P -stereogenic cyclic phosphine oxides with high yields and high enantioselectivities. The products could be easily reduced to the corresponding useful P (III)-stereogenic cyclic phosphines. A mechanism of the dynamic kinetic resolution involving the unusual rapid racemization of SPOs has been proposed.