Hydrotrifluoromethylthiolation of Unactivated Alkenes and Alkynes with Trifluoromethanesulfonic Anhydride through Deoxygenative Reduction and Photoredox Radical Processes

An ongoing challenge in trifluoromethylthiolation reactions is the use of less expensive and easily available trifluoromethylthio sources. Herein, we disclose an unprecedented usage of trifluoromethanesulfonic anhydride (Tf₂O) as a radical trifluoromethylthiolating reagent. Hydrotrifluoromethylthiolation of unactivated alkenes and alkynes with Tf₂O in the presence of PMePh₂ and H₂O under visible‐light photoredox catalysis gave the addition products. The trifluoromethylthio radical (^.SCF₃) was first formed from Tf₂O through a photoredox radical processes and deoxygenative reduction of PMePh₂, and H₂O serves as the H‐atom donor for the hydrotrifluoromethylthiolation reaction. This reaction provides a new strategy for radical trifluoromethylthiolation.     

Metal Free Access to Polysubstituted Pyrimidines via Nitrile Activation and [2+2+2] Cycloaddition

Tf₂O mediated intermolecular / intramolecular [2+2+2] cycloaddition between alkynes and nitriles has been developed for efficient construction of polysubstituted pyrimidines and bicyclopyrimidines. In presence of Tf₂O, aza-allene species were generated in situ through nitrile activation and subsequently participated in the [2+2+2] cycloaddition, which was fully supported by deuteration experiments. The reaction had good substrate extensibility with moderate to excellent yield including trimethylsilylalkynes. The method was utilized as a synthetic tool in the preparation of a luminescent metal complex.     

Probing the steric limits of rhodium catalyzed hydrophosphinylation. P-H addition vs. dimerization/oligomerization/polymerization

The reactivity of secondary phosphine oxides containing bulky organic fragments in hydrophosphinylation reactions has been investigated using several rhodium based catalysts. Upon heating in a focused microwave reactor, HP(O)(2-C₆H₄Me)₂ adds to prototypical terminal alkynes affording a complex mixture containing 1,2 and 1,1-addition products. Addition of a second ortho-substituent (HP(O)Mes₂) completely suppresses the hydrophosphinylation reaction for alkyl and aryl substituted alkynes. Variations in the temperature, catalyst loading, solvent, and microwave power were unable to induce an addition reaction in the case of HP(O)Mes₂. While this secondary phosphine oxide did not participate in the hydrophosphinylation reaction, it promoted the polymerization of phenylacetylene. HP(O)R₂ substrates are not commonly thought of as innocent ligands for rhodium complexes in reactions involving alkynes due to facile hydrophosphinylation. While this is certainly true for diphenylphosphine oxide, the chemistry presented herein suggests that HP(O)Mes₂ and related bulky secondary phosphine oxides have great potential as valuable ligands for rhodium catalyzed transformations involving alkynes due to their lack of reactivity towards the addition reaction.     

Chemoselective glycosylations using sulfonium triflate activator systems

A novel chemoselective glycosylation sequence is described that employs the recently developed BSP/Tf₂O and DPS/Tf₂O reagent systems to activate thioglycosides. In the first glycosylation event a relatively armed thioglycoside is activated with the BSP/Tf₂O activator system and condensed with an acceptor thioglycoside to yield the thiodisaccharide, which is activated with the more potent DPS/Tf₂O activator in the next glycosylation event. Quenching of (N-piperidino)phenyl(S-thiophenyl)sulfide triflate, which is formed upon activation of the first thioglycoside, with triethyl phosphite is crucial for a productive glycosylation.     

Synthesis of new quinuclidine derivatives via Pd-mediated cross-coupling and cross-benzannulation reactions

New functionalized quinuclidines were prepared via palladium-catalyzed addition reactions of terminal alkynes (donors) to internal alkynes (acceptors). The enantiopure terminal alkynes were derivatives of quincoridine and quincorine, two semi-natural Cinchona alkaloids. The processes exhibited high chemoselectivity and excellent diastereoselectivity, the E-enynes being obtained as single products in almost all cases. The synthesis of new tetra and pentasubstituted benzene derivatives in good yields by [2+2+2] benzannulation of the diynes, obtained by the palladium-catalyzed homodimerization of 10,11-didehydro quincoridine and 10,11-didehydro quincorine, with terminal alkynes and in fair yield by [4+2] benzannulation of an enyne derivative of 10,11-didehydro quincoridine with 2,4-hexane-diyne are reported.     

A mild, expedient, one-pot trifluoromethanesulfonic anhydride mediated synthesis of N-arylimidates

The direct transformation of various secondary amides into N-arylimidates via mild electrophilic amide activation with trifluoromethanesulfonic anhydride (Tf₂O) in the presence of 2-chloropyridine (2-ClPyr) is described. Low-temperature amide activation followed by C-O bond formation with 2-naphthol provides the desired N-arylimidates in short overall reaction times. In contrast, reaction with oxindole proceeds via formation of a C-C bond to give 1-(1H-indol-2-yl)naphthalene-2-ol.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)?H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²) H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂⋅4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²)? H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂?4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

Palladium-catalyzed phosphinylthiolation of terminal alkynes

Phosphinylthiolation of terminal alkynes with Ph₂P(O)SBu or a related compound proceeds in the presence of a palladium–PEt₃ catalyst system. Activity and stereoselectivity are highly dependent on the nature of solvent, ethylbenzene, and n-hexanol (or t-amyl alcohol) being E- and Z-selective, respectively.     

Palladium-catalyzed carbonylative annulation of terminal alkynes: synthesis of coumarins and 2-quinolones

o-Iodophenols and o-iodoaniline derivatives react with terminal alkynes under 1 atm of CO in the presence of pyridine and catalytic amounts of Pd(OAc)₂ to generate coumarins and 2-quinolones, respectively, as the only products. Terminal alkynes bearing alkyl, aryl, silyl, hydroxyl, ester and cyano substituents are effective in these processes affording the desired products in moderate yields. The formation of coumarins and 2-quinolones in this process is in stark contrast with all previously described palladium-catalyzed reactions of o-iodophenols or o-iodoanilines with terminal alkynes and CO, which have afforded chromones and 4-quinolones. Moreover, under our reaction conditions terminal alkynes insert into the carbonpalladium bond instead of undergoing a Sonogashira-type coupling as confirmed by an isotope labeling experiment.     

Z-Selective hydroamidation of terminal alkynes with secondary amides and imides catalyzed by a Ru/Yb-system

A catalyst system formed in situ from bis(2-methallyl)cycloocta-1,5-diene-ruthenium(II) [(cod)Ru(met)₂], 1,4-bis(dicyclohexylphosphino)butane (dcypb) and ytterbium(III) triflate hydrate (Yb(OTf)₃) was found to catalyze the addition of nitrogen nucleophiles to terminal alkynes under mild conditions to stereoselectively form the Z-enamide or Z-enimide products. Various secondary amides and imides could be added across the triple bond of a range of aliphatic and aromatic alkynes. The new bimetallic catalyst system sets new standards with regard to scope and selectivity for the synthesis of Z-configured anti-Markovnikov enamides.     

Intermolecular Pauson–Khand reactions of N-substituted maleimides

Co₂(CO)₈-mediated intermolecular Pauson–Khand reactions of N-substituted maleimides with terminal alkynes are described, producing maleimide-fused cyclopentenones. The transformation differs from other intermolecular Pauson–Khand-type reactions of electron-deficient olefins, which react with Co₂(CO)₈ and alkynes to produce conjugated dienes, or generally require terminal, monosubstituted olefins to generate cyclopentenones. The reaction works well for N-benzyl, N-aryl, and N-alkyl substituted maleimides, and tolerates branching at the 3-position of the terminal alkyne. N–H maleimide, N–CO₂Me maleimide, and maleic anhydride do not take part in the transformation.     

Laser-induced fluorescence and infrared spectroscopic studies on the specific solvation of tris(1-(2-thienyl)-4,4,4-trifluoro-1,3-butanedionato)europium(III) in an ionic liquid

The extraction constant and the two-phase stability constant (K_D,Mβ₃) of tris(2-thenoyltrifluoroacetonato)europium(III) between 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([C₄mim][Tf₂N]) as an ionic liquid and an aqueous phase were determined by considering the extraction equilibria including anionic tetrakis(2-thenoyltrifluoroacetonato)europate(III). Specific solute-solvent interactions between the neutral Eu(III) chelate and [C₄mim][Tf₂N] molecules were revealed from the relationships between the distribution constant of the enol form of 2-thenoyltrifluoroacetone (Htta) as a proton chelate and the distribution constant (K_D,M) of the neutral Eu(III) chelate because the [C₄mim][Tf₂N] system gave the high K_D,Mβ₃ value compared with those in conventional molecular solvents such as benzene and 1,2-dichloroethane. The coordination environment of Eu³⁺ in the neutral Eu(III) chelate in [C₄mim][Tf₂N] was investigated by time-resolved laser-induced fluorescence spectroscopy and infrared absorption spectroscopy. Both methods consistently indicated that not only the Eu(III) chelate extracted but also Eu(tta)₃(H₂O)₃ synthesized as a solid crystal were almost completely dehydrated in [C₄mim][Tf₂N] saturated with water. Consequently, the higher K_D,M or extractability of the neutral Eu(III) chelate in the [C₄mim][Tf₂N] system can be ascribed to the dehydration of the Eu(III) chelate, which is caused by the specific solvation with [C₄mim][Tf₂N] molecules.     

Hydrothiolation of terminal alkynes with diaryl disulfides and diphenyl diselenide: selective synthesis of (Z)-1-alkenyl sulfides and selenides

A simple, stereoselective and efficient method for the hydrothiolation of terminal alkynes with diaryl disulfides and diphenyl diselenide has been developed. In the presence of CuI, rongalite, and Cs₂CO₃, a variety of disulfides underwent the reaction of terminal alkynes stereoselectively to afford the corresponding (Z)-1-alkenyl sulfides in moderate to excellent yields. It is noteworthy that hydroselenations of 1,2-diphenyldiselane with alkynes are also conducted smoothly to afford (Z)-1-alkenyl selenides in good yields under the standard conditions.     

Synthesis of 3-substituted benzo[g]isoquinoline-5,10-diones: a convenient one-pot Sonogashira coupling/iminoannulation procedure

A series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines were prepared by coupling of terminal alkynes with the tert-butylimine of 3-bromo-1,4-dimethoxy-2-naphthaldehyde in the presence of a Pd-catalyst and subsequent Cu-catalyzed cyclization of the intermediate 3-alkynyl-2-naphthylcarbaldehyde. A CAN-mediated oxidative demethylation yielded the corresponding 2-azaanthraquinones in excellent yields. Since this methodology proved to be limited to alkynes bearing aromatic groups, an alternative and more general Pd-catalyzed coupling procedure was developed, starting from 3-bromo-1,4-dimethoxy-2-naphthaldehyde. For more acidic terminal alkynes, like phenylacetylene, a combination of Pd(OAc)₂/P(t-Bu)₃/CuI (2/6/1) with potassium carbonate in DMF gave a complete conversion within 24 h. For less acidic acetylenes, 2 equiv of alkyne and caesium carbonate as a base were required in order to obtain complete conversion of the starting material within 24 h. These altered Sonogashira conditions also allowed the isolation of a benzo[f]indenone as an interesting side product in case Bu₄NCl was added to the reaction mixture. The 3-alkynyl-1,4-dimethoxy-2-naphthaldehyde acquired after completion of the Pd-catalyzed coupling could be cyclized by adding a solution of ethanolic ammonia and an extra equivalent of potassium carbonate to the reaction mixture. As such, this consecutive one-pot coupling/iminoannulation procedure was a convenient alternative to the Larock isoquinoline procedure, enabling the isolation of a series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines.     

A novel O-fucosylation strategy preactivated by (p-Tol)2SO/Tf2O and its application for the synthesis of Lewis blood group antigen Lewisa

Based on a preactivation strategy using (p-Tol)₂SO/Tf₂O, a new O-fucosylation method with thioglycoside as donor under mild conditions was reported. High yields and excellent α-stereoselectivities of the fucosylation were obtained with secondary sugar alcohol as acceptors. Moreover, the novel fucosylation strategy was successfully applied to the synthesis of an important Lewis blood group antigen Lewis^a, which was obtained in nine linear steps with 27% overall yield.     

First report of a nano‐Cu2O‐catalyzed protocol for homo‐coupling reaction of terminal alkynes in water/ionic liquid medium

A new, efficient and green protocol for the nano‐Cu₂O‐catalyzed homo‐coupling reaction of terminal alkynes has been developed, using water/ionic liquid as an environmentally friendly solvent. Moreover, the system also allows the synthesis of unsymmetric 1,3‐diynes by cross‐coupling of two different terminal alkynes. It is noteworthy that the nano‐Cu₂O‐catalyzed methodology is a good supplement to copper catalyst for the Glaser‐type homo‐coupling reaction. Copyright © 2016 John Wiley & Sons, Ltd.     

Reaction of CBrF2-CBrF2 with hydrazones of aromatic aldehydes: Novel efficient synthesis of fluorocontaining alkanes, alkenes and alkynes

An olefination of hydrazones of aromatic aldehydes by CBrF₂-CBrF₂ under copper catalysis was investigated. In situ prepared aldehydes hydrazones were converted to (3-bromo-2,2,3,3-tetrafluoropropyl)arenes by reaction with CBrF₂-CBrF₂ in the presence of CuCl. Subsequent elimination of HF by sodium hydroxide resulted in stereospecific formation of fluorocontaining alkenes. Elimination proceeds stereoselectively, only Z-isomers of alkenes are formed. Elimination of two molecules of HF from (3-bromo-2,2,3,3-tetrafluoropropyl)arenes by treatment with potassium tert-butoxide leads to formation of (bromodifluoromethyl)alkynes. As a result a simple and efficient transformation of aromatic aldehydes to range of various fluorinated alkanes, alkenes and alkynes was elaborated.     

Tf2O-catalyzed Friedel–Crafts alkylation to synthesize dibenzo[a,d]cycloheptene cores and application in the total synthesis of Diptoindonesin D,Pauciflorial F,and (±)-Ampelopsin B

By using Tf₂O as a catalyst, we have developed a protocol for the preparation of various dibenzo[a,d]cycloheptene cores via Friedel–Crafts alkylation. Using this method as the key step, we also present concise and useful routes to synthesize the natural products Diptoindonesin D, Pauciflorial F, and (±)-Ampelopsin B. Notably, this process exhibited following very attractive features: (i) the process is metal free, with only catalytic amounts of Tf₂O being employed, and (ii) the process is simple and environmentally conscious, avoiding the use of excess amounts of base, oxidant, or other additives.     

Stereoselectivity investigation on glycosylation of oxazolidinone protected 2-amino-2-deoxy-d-glucose donors based on pre-activation protocol

Diverse 2,3-oxazolidinone protected 2-amino-2-deoxy-d-glucose thioglycosides were prepared and studied as glycosyl donors at low temperature by BSM/Tf₂O pre-activation protocol before the addition of glycosyl acceptors. The stereochemistry outcomes of a series of glycosylations were investigated. Different stereoselectivities of the coupling reactions were obtained, arising from the different protecting groups in the oxazolidinone donors. 4,6-Di-O-benzyl-N-benzyl-oxazolidinone protected thioglycoside donor 1c underwent glycosylation with general β-anomeric selectivity and the stereoselectivity could be also affected by glycosylation conditions.