The 50 most-cited articles in Organic Letters, 2020

Simple nucleophiles with structural similarities to known hydroboration catalysts can readily mediate the formation of BH 3 and borohydride species from pinacolborane (HBpin). Alkyne and alkene hydroboration reactions were successfully mediated by nucleophiles through BH 3 generation, with BH 3 -catalyzed hydroboration found to dominate catalysis. NMR spectroscopy and kinetic analyses showed that the nucleophiles NaO t Bu, Na[N(SiMe 3 ) 2 ], n Bu 2 Mg, and n BuLi only promoted the formation of BH 3 and were not “true” hydroboration catalysts.

A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds.

Although many chiral molecules exhibiting circularly polarized luminescence (CPL) have been reported recently, few molecular design guidelines are known for increasing the dissymmetry factor for CPL ( g lum ). We demonstrate that a figure-eight-shaped molecule with D 2 symmetry has excellent chiroptical properties (Φ f = 0.08, | g lum | = 1.5 × 10 –2 ), which are attributed to the parallel arrangement of μ and m as well as a good | μ |/| m | ratio.

An efficient, photoredox-catalyst-free radical alkylation of quinoxalin-2(1 H )-ones has been described. This reaction utilizes 4-alkyl-1,4-dihydropyridines (R-DHPs) as alkyl radical precursors and acetoxybenziodoxole (BI-OAc) as an electron acceptor to undergo single-electron transfer with photoexcited R-DHPs. The benign conditions allow for good compatibility in the scope of both quinoxalin-2(1 H )-ones and R-DHPs. The synthetic value of the protocol was also demonstrated by the successful functionalization of natural products and drug-based complex molecules

Herein, we describe an efficient, practical photocatalytic deoxygenation/defluorination protocol for the synthesis of γ,γ-difluoroallylic ketones from commercially available aromatic carboxylic acids, triphenylphosphine, and α-trifluoromethyl alkenes. The protocol has good functional group tolerance and a broad substrate scope. Using this method, we accomplished the late-stage functionalization of several bioactive molecules.

Paired electrolysis has a limited reaction scope for organic synthesis because it is often not compatible with reactions involving short-lived intermediates. We addressed this limitation using alternating current electrolysis (ACE). Using trifluoromethylation of (hetero)arenes as a model reaction, we showed that the yield was improved from 13% using paired electrolysis to 84% using ACE. We have also developed a theory for guiding the rational design of reaction parameters for future applications of ACE.

Abstract Aryl sulfinates are precursors to a diverse number of sulfonyl-derived arenes, which are common motifs in pharmaceuticals and agrochemicals. Here, we report a site-selective two-step C–H sulfination sequence via aryl sulfonium salts to access aryl sulfonamides. Combined with site-selective aromatic thianthrenation, an operationally simple one-pot palladium-catalyzed protocol introduces the sulfonyl group using sodium hydroxymethylsulfinate (Rongalite) as a source of SO22–. The hydroxymethyl sulfone intermediate generated from the catalytic process can be employed as a synthetic handle to deliver a variety of sulfonyl-containing compounds.

We report herein a general and practical copper-catalyzed fluorosulfonylation reaction of a wide range of abundant arenediazonium salts to smoothly prepare various arenesulfonyl fluorides using the 1,4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct as a convenient sulfonyl source in combination with KHF 2 as an ideal fluorine source and without the need for additional oxidants. Interestingly, the electronic character of the arene ring in the starting arenediazonium salts has a significant impact on the reaction mechanistic pathway.

The rhodium(III)-catalyzed coupling of C–H substrates with iodonium ylides has been realized for the efficient synthesis of diverse cyclic skeletons, where the iodonium ylides have been identified as efficient and outstanding carbene precursors. The reaction systems are applicable to both sp 2 and sp 3 C–H substrates under mild and redox-neutral conditions. The catalyst loading can be as low as 0.5 mol % in a gram-scale reaction. Representative products exhibit cytotoxicity toward human cancer cells at nanomolar levels.

A Bodipy derivative with twisted π-conjugation system is demonstrated that shows efficient intersystem crossing (ISC) (singlet oxygen quantum yield Φ Δ = 55%) and a long-lived triplet state (τ T = 197.5 μs) with high energy ( E T 1 = 1.44–1.53 eV). This is superior to the conventional heavy-atom-enhanced ISC in a reference Bodipy compound, which results in much shorter triplet state lifetime (3.3 μs) and lower triplet-state energy (1.2 eV).

An unprecedented carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent was developed, thus providing the β-trifluoromethyl-α-substituted ketones with a broad scope and moderate to high chemical yields. Notably, this process includes a single-electron-transfer process and utilizes the persistent N-heterocyclic-carbene-bound radical as a key intermediate to trigger the cascade radical cross-coupling.

A mild and efficient protocol for the intramolecular aromatic C-H oxygenation of 2-biphenylcarboxylic acids has been achieved via iron photocatalysis. The 2-biphenylcarboxylic acids with a diverse array of substituents at both phenyl rings could furnish the oxygenation products in good to excellent yields. We speculate that the aryl carboxylate-iron(III) complexes should generate the aroyloxy radicals and iron(II) upon visible light irradiation.

Transition-metal-catalyzed activation of inert C–H bonds and subsequent C–C bond formation have emerged as powerful synthetic tools for the synthesis of elaborate cyclic molecules. In this report, we introduce an efficient synthetic method of 3,4-unsubstituted isocoumarins adopting an electron-deficient Cp E Rh complex as the catalyst. The use of vinylene carbonate as a vinylene transfer reagent enables the direct construction of isocoumarins from readily available benzoic acids, without any external oxidants as well as bases. The reaction mechanism is evaluated by computational analysis to find an unprecedented “rhodium shift” event within the catalytic cycle.

A highly efficient, cheap, and organic alternative to the commonly used iridium photosensitizer (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 ( [Ir–F] ) is presented for visible-light energy transfer catalysis. The organic dye 2CzPN surpasses [Ir–F] in selectivity while at the same time being easily accessible in one step. The catalyst is recyclable and, due to its uncharged nature, soluble in nonpolar solvents such as toluene. Furthermore, the scope of molecular scaffolds that are compatible substrates for visible-light catalyzed dearomative cycloadditions is expanded.

Transition-metal-catalyzed C-H activation followed by oxidative annulation with alkynes has been an efficient synthetic tool for the assembly of various polyaromatic scaffolds. Despite the substantial progress in this field, it is still a significant challenge to achieve the synthesis of nonsubstituted vinylene-fused compounds. In this contribution, we report a Rh-catalyzed C-H/C-H vinylene cyclization adopting vinylene carbonate as a "vinylene transfer" agent. This protocol achieves the direct annulative π-extension of imidazole- and pyrazole-fused aromatics.

Reported in this paper is a step economical method toward the general synthesis of 3-vinyl chromones via the reactions between readily available o -hydroxyphenyl enaminones and various alkenes. The domino C–H alkenylation and chromone annulation of the enaminones are involved, which enables the synthesis of 3-vinyl chromone products using both terminal and internal alkenes via a key process of transient C–H halogenation.

A copper-free Sandmeyer-type fluorosulfonylation reaction is reported. Utilizing Na 2 S 2 O 5 and Selectfluor as the sulfur dioxide and fluorine sources, respectively, aryldiazonium salts were transformed into sulfonyl fluorides. The one-pot direct synthesis of sulfonyl fluorides from aromatic amines was also realized via in situ diazotization. The practicality of this method was demonstrated by the broad functional group tolerance, gram-scale synthesis, and late-stage fluorosulfonylation of natural products and pharmaceuticals.

One of the most efficient ways to synthesize oxetanes is the light-enabled [2 + 2] cycloaddition reaction of carbonyls and alkenes, referred to as the Paternò-Büchi reaction. The reaction conditions for this transformation typically require the use of high energy UV light to excite the carbonyl, limiting the applications, safety, and scalability. We herein report the development of a visible-light-mediated Paternò-Büchi reaction protocol that relies on triplet energy transfer from an iridium-based photocatalyst to the carbonyl substrates. This mode of activation is demonstrated for a variety of aryl glyoxylates and negates the need for both visible-light-absorbing carbonyl starting materials and UV light to enable access to a variety of functionalized oxetanes in up to 99% yield.

-amidopyridinium salts under visible light irradiation, we discovered that photoinduced intermolecular charge transfer induces a single-electron transfer event without requiring a photocatalyst for the facile functionalization of pyridines. The generality of this method is amenable to various types of 1,4-dihydropyridines radical precursors to generate structurally different radicals such as alkyl, acyl, and carbamoyl radicals, ultimately providing facile access to synthetically valuable C4-functionalized pyridines. A broad range of functional groups are well accommodated under mild and metal-free conditions, and the synthetic utility of the present method is showcased by the late-stage functionalization of a variety of biologically relevant pyridine-based compounds, pharmaceuticals, and peptide feedstocks.

The sustainable cross-dehydrogenative coupling of strong C(sp 3 )–H with N -heteroarenes has been developed using an efficient organic photocatalyst. It features atomic- and step-economy, and acid-free conditions. Mechanism studies suggest a previous elusive energy transfer pathway from photocatalyst to N -heteroarenes and oxidants.

Site-selective transformation of benzylic C–H bonds into diverse functional groups is achieved via Cu-catalyzed C–H fluorination with N -fluorobenzenesulfonimide (NFSI), followed by substitution of the resulting fluoride with various nucleophiles. The benzyl fluorides generated in these reactions are reactive electrophiles in the presence of hydrogen-bond donors or Lewis acids, allowing them to be used without isolation in C–O, C–N, and C–C coupling reactions.

An NHC-catalyzed radical relay enabled the vicinal alkylacylation of alkenes using aldehydes and tertiary α-bromo esters as a versatile route to δ-keto esters bearing an all-carbon quaternary center at the position α to the ester. The protocol was applicable to the reaction of tertiary α-bromoamides to afford δ-keto amides. This protocol enabled the conversion of readily available starting materials to congested and functionalized δ-ketocarbonyls in a single step without using transition metals.

The catalytic C(sp 3 )–H functionalization is highly desirable yet challenging in organic synthesis. Incorporation of the SP(O)(OR) 2 group through C(sp 3 )–H functionalization remains unexplored. We herein report an unprecedented protocol for phosphorothiolation of primary and secondary C(sp 3 )–H via a multicomponent reaction with N -fluoro-substituted amides, elemental sulfur, and P(O)H compounds involving a sequence of amidyl radical generation, 1,5-HAT, and a Cu-catalyzed cross coupling of the resulting carbon radical with (RO) 2 P(O)SH (generated in situ ).

The Cu-catalyzed 1,4-protosilylation and protoborylation of trifluoromethyl-substituted conjugated enynes were developed to access functionalized homoallenylsilanes and homoallenylboronates. This protocol also provides a general method to synthesize optically active homoallenylsilanes and homoallenylboronates in moderate to excellent yields with high enantiomeric excess by using new designed chiral bisoxazoline ligands. Simultaneously, the transformations of homoallenylsilanes and homoallenylboronates were also explored to synthesize useful building blocks.

Abstract Photoactivation of an electron donor–acceptor encounter complex in an organic solvent cage, a phenomenon that has been described in Mulliken theory, has been known for decades, but it has not been employed as a photoactivation step in the design of photocatalysis for organic synthesis until recent years. We report herein an iododecarboxylation reaction that applies this concept for photoactivation by using a catalyst to facilitate electron transfer and to suppress back electron transfer in the photoexcited state. Under irradiation of 456 nm blue light-emitting diodes, PPh3 catalyzes the iododecarboxylation of aliphatic carboxylic acid-derived N-(acyloxy)phthalimide with lithium iodide as iodine source. The reaction delivers primary, secondary, and bridgehead tertiary alkyl iodides in acetone solvent, and the alkyl iodide products were easily used to generate C–N, C–O, C–F, and C–S bonds to allow various decarboxylative transformations without using transition-metal or organic dye-based photocatalysts. This protocol is applicable to redox-active esters derived from various…

A new electrochemical three-component annulation–iodosulfonylation of 1,5-enyne-containing para -quinone methides ( p -QMs) has been established by using available arylsulfonyl hydrazides and potassium iodide under environmentally benign conditions. The electrosynthesis offers sustainable and efficient access to construct spirocyclohexadienone-containing ( E )-indenes without any additional catalyst or oxidant through a sulfonyl-radical-triggered 1,6-addition and an I + -mediated ipso -cyclization cascade. Notably, potassium iodide plays the triple role of an electrolyte, a redox catalyst, as well as an iodination reagent.

Herein, we describe a visible light-promoted hydroacylation strategy that facilitates the preparation of ketones from alkenes and 4-acyl-1,4-dihydropyridines via an acyl radical addition and hydrogen atom transfer pathway under photocatalyst-free conditions. The efficiency was highlighted by wide substrate scope, good to high yields, successful scale-up experiments, and expedient preparation of highly functionalized ketone derivatives. In addition, this protocol allows for the synthesis of 1,4-dicarbonyl compounds through alkene diacylation in the presence of NiCl 2 ·DME.

Cobalt-catalyzed Markovnikov-selective hydroamination of nonactivated olefins was developed. Hydrogen atom transfer from a catalytically generated cobalt(III)–hydride complex to the olefins proceeded regioselectively, and the nucleophilic addition of benzotriazoles occurred selectively at their N 2 -positions. The synthetic utility of the obtained N 2 -alkylated benzotriazoles as stable amine protecting groups under various reaction conditions was demonstrated, and the products were also transformed into primary amines by zinc-mediated reduction.

Herein we report the design and synthesis of hypervalent trifluoromethylthio-iodine(III) reagent 1 and the elucidation of its structure by NMR spectroscopy and X-ray crystallography. The trifluoromethylthiolation reactions of 1 with various nucleophiles were explored, and this compound was found to be a versatile electrophilic reagent for the transfer of a trifluoromethylthio group (−SCF 3 ). The hydrogen-bonding mode responsible for the activation of 1 by the solvent 1,1,1,3,3,3-hexafluoro-2-propanol was investigated both experimentally and computationally.

A photoinduced, copper-catalyzed, highly enantioselective dual alkylation/arylation and alkynylation of alkene is reported. A single chiral copper(I) complex serves to enable photoredox catalysis and induce enantioselectivity during the reaction. This reaction couples three different components under mild reaction conditions, exhibits a broad substrate scope, and provides facile access to chiral propargylic systems, including those featuring valuable fluorinated substituents.

A chiral tertiary amine-catalyzed asymmetric γ-regioselective (4 + 3) annulation reaction of isatin-derived Morita–Baylis–Hillman carbonates and 1-azadienes was developed, delivering chiral azepane spirooxindoles with excellent stereoselectivity. In addition, by tuning the substituents of Morita–Baylis–Hillman carbonates, the switchable γ-(4 + 3) or α-(4 + 1) annulation reaction with o -quinone methides was observed to furnish benzo[ b ]oxepines or 2,3-dihydrobenzofurans, respectively, under similar catalytic conditions.

An iron-catalyzed borrowing hydrogen strategy has been applied in the synthesis of β-branched carbonyl compounds. Various secondary benzylic and aliphatic alcohols have been used as alkylating reagents under mild reaction conditions. The ketones have been isolated in good to excellent yield. Deuterium labeling experiments provide evidence that the alcohol is the hydride source in this reaction and that no reversible step or hydrogen/deuterium scrambling takes place during the process.

-oxide (TTSO)-mediated site-selective silylation of arenes has been realized via a thianthrenation/Pd-catalyzed silylation sequence. This method features a broad substrate scope and wide functional group tolerance under mild conditions and allows the synthesis of a set of (hetero)arylsilanes with operationally simple manipulations. The application and generality of the approach were further demonstrated by the late-stage functionalization of marketed drugs. This reaction also represents the first example of a Pd-catalyzed silylation reaction of aryl sulfonium salts.

The Co(III)-catalyzed redox-neutral annulation of benzamides and acrylamides with vinylene carbonate for the synthesis of isoquinolinones and pyridinones has been developed. This protocol employing inexpensive Co(III) as the catalyst tolerated diverse functional groups and substitution patterns, affording the target products with good to excellent yields. The synthetic utility of this transformation was demonstrated by a three-step synthesis of gusanlung D, 8-oxopseudopalmatine, and oxopalmatine.

gem -Difluoroalkene bearing a carbonyl group is a challenging target to synthesize by conventional methods. Herein we report a mild and concise route to access the target compounds through the visible-light-mediated direct β-C–H gem -difluoroallylation of aliphatic aldehydes and cyclic ketones. Upon a synergistic combination of photoredox catalysis and organocatalysis, various α-CF 3 alkenes were employed as the gem -difluoroallylation reagents via the C–F bond cleavage.

The first base metal-catalyzed transfer hydrogenation of alkynes with methanol is described. An air and moisture stable manganese pincer complex catalyzes the reduction of a variety of different alkynes to the corresponding ( Z )-olefins in high yields. The reaction is stereo- and chemoselective and scalable.

A strategy to functionalized spiro[4.5]trienones, by domino silver-catalyzed decarboxylative acylation or alkylation/ ipso -cyclization of N -arylpropiolamides with α-keto acids/alkyl carboxylic acids, is presented. This transformation offers a wide range of substituted 3-acyl/alkyl-spiro[4.5]trienones in high yields with a broad substrate scope. The approach was further extended to access fused tricyclic frameworks, 6,7-dihydro-3 H -pyrrolo[2,1- j ]quinoline-3,9(5 H )-diones.

Abstract Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an enantioselective C–H functionalization method using our chiral RhJasCp complex for the synthesis of the biaryl atropisomer types that can be accessed from three different five-membered-ring heterocycles.

A feasible arylaminomethyl radical-triggered tandem annulation reaction has been developed toward a large variety of poly fused heterocycles, tetrahydroimidazo[1,5- a ]quinoxalin-4(5 H )-ones, by reacting diverse quinoxalin-2(1 H )-ones with various N -arylglycines in green solvent (DMC) in the presence of CsPbBr 3 under white-light irradiation conditions.

A visible-light-driven photoredox-catalyzed multicomponent reaction of 2-vinylanilines, sulfonyl chlorides, and sulfur ylides is described. This protocol features redox-neutral mild conditions, a broad substrate scope, and good functional group tolerance, providing access to various sulfonated 2,3-disubstituted indolines. The product can be transformed to a diverse range of functionalized indoles by a selective aromatization/nucleophilic substitution process. Mechanistic investigations suggest that both sulfonyl chlorides and sulfur ylides serve as radical sources, and the reaction proceeds through a sequential radical addition/addition/thermal S N 2-substitution process.

A mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the well-established two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the long-standing challenge of the installation of sterically demanding side chains into α-amino acids.

Herein, we describe a palladium-catalyzed alkynylation of gem -difluorinated cyclopropanes via C–C bond activation/C–F bond cleavage, followed by C–C(sp) coupling. The new approach proceeds with broad substrate scope under mild reaction conditions, whereas both 1,1-disubstituted and complex-molecule-modified gem -difluorinated cyclopropanes react smoothly with high stereoselectivity. The developed method provides efficient and convenient ways access to diversity of important fluorinated enynes and arenes by slightly modification of the reaction conditions.

We report a facile and economical synthesis of α-fluoroacrylic acids via direct electrochemical defluorinative carboxylation of gem -difluoroalkenes with CO 2 . By using a platinum plate as the working cathode and a cheap nickel plate as the anode in a user-friendly undivided cell under constant current conditions, the reactions proceed smoothly under room temperature, without the use of expensive transition metal catalysts, ligands, external base or reductant, affording the desired adducts in up to 83% yield and 20:1 Z / E ratio, with good functional group tolerance. A cyclic voltammetry study was conducted and suggested a novel ECEC process.

Acyl radicals have been generated from α-keto acids using inexpensive and commercially available 2-chloro-thioxanthen-9-one as the photoredox catalyst under visible light illumination. These reactive species added to olefins or coupled with aryl halides via a bipyridyl-stabilized Ni(II) catalyst, enabling easy access to a diverse range of ketones. This reliable, atom-economical, and eco-friendly protocol is compatible with a wide range of functional groups.

A direct cross-coupling between sodium sulfinates and 2 H -indazoles has been developed under electrochemical conditions. The utilization of a graphite anode and platinum cathode in an undivided cell with a constant current of 7 mA allowed the concurrent oxidations of sulfinates and 2 H -indazoles to sulfonyl radical and radical cationic 2 H -indazoles, facilitating the direct radical–radical coupling strategy to 3-sulfonylated 2 H -indazole derivatives. The transition-metal- and redox-reagent-free synthetic approach should serve as a valuable synthetic tool to achieve heteroaromatic compounds.

An electrochemical oxydihalogenation of alkynes has been developed for the first time. Using this sustainable protocol, a variety of α,α-dihaloketones can be prepared with readily available CHCl 3, CH 2 Cl 2, ClCH 2 CH 2 Cl, and CH 2 Br 2 as the halogen source under electrochemical conditions at room temperature.

An operationally simple mechanochemical C-S coupling of aryl halides with thiols has been developed. The reaction process operates under benchtop conditions without the requirement for a (dry) solvent, an inert atmosphere, or catalyst preactivation. The reaction is finished within 3 h. The reaction is demonstrated across a broad range of substrates; the inclusion of zinc metal has been found to be critical in some instances, especially for coupling of alkyl thiols.

A novel visible-light-induced palladium-catalyzed Heck reaction for bromine sugars and aryl olefins with high regio- and stereochemistry selectivity for the preparation of C- glycosyl styrene is described. This reaction takes place in one step at room temperature by using a simple and readily available starting material. This protocol can be scaled up to a wide range of glycosyl bromide donors and aryl olefin substrates. Mechanistic studies indicate that a radical addition pathway is involved.

)-H cyanation of carboxamides has been described by merging photoredox and copper catalysis in a site-selective and enantiocontrolled manner. The protocol is the integration of photoinduced and nitrogen-centered radical-mediated intermolecular hydrogen atom transfer with chiral copper-complex-catalyzed radical cyanation. This strategy gives enantio-enriched cyanated amides in high yields.

In the micelle of PS-750-M, the presence of 3° amides from the surfactant proline linker mimics dimethylformamide, dimethylacetamide, and N -methyl-2-pyrrolidone. The resultant micellar properties enable extremely fast amide couplings mediated by 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (without hydroxybenzotriazole), rather than expensive and specialized coupling agents. Conditions have been developed wherein products precipitate, and isolation by filtration completely avoids the use of organic solvent. This methodology is scalable and avoids product epimerization.