Alkyl Triflates Research Articles

Backside versus Frontside SN2 Reactions of Alkyl Triflates and Alcohols.

Nucleophilic substitution reactions are elementary reactions in organic chemistry that are used in many synthetic routes. By quantum chemical methods, we have investigated the intrinsic competition between the backside SN2 (SN2-b) and frontside SN2 (SN2-f) pathways using a set of simple alkyl triflates as the electrophile in combination with a systematic series of phenols and partially fluorinated ethanol nucleophiles. It is revealed how and why the well-established mechanistic preference for the SN2-b pathway slowly erodes and can even be overruled by the unusual SN2-f substitution mechanism going from strong to weak alcohol nucleophiles. Activation strain analyses disclose that the SN2-b pathway is favored for strong alcohol nucleophiles because of the well-known intrinsically more efficient approach to the electrophile resulting in a more stabilizing nucleophile-electrophile interaction. In contrast, the preference of weaker alcohol nucleophiles shifts to the SN2-f pathway, benefiting from a stabilizing hydrogen bond interaction between the incoming alcohol and the leaving group. This hydrogen bond interaction is strengthened by the increased acidity of the weaker alcohol nucleophiles, thereby steering the mechanistic preference toward the frontside SN2 pathway.

Metal- versus ligand-centered reactivity of a cobalt-phenylenediamide complex with electrophiles.

A new series of [CoIII-CF3]n+ complexes supported by a bidentate redox-active ligand is presented. The cationic [Co-CF3]+ complex was first obtained by reacting [CpCo(tBuUreaopda)] (Cp = cyclopentadienyl, opda = o-phenylenediamide) with an electrophilic trifluoromethyl source, for which the redox-active phenylenediamide ligand serves as a 2e- reservoir to generate [CpCp(tBuUreabqdi)(CF3)]+ (bqdi = benzoquinonediimine). Electrochemical studies of [Co-CF3]+ revealed two reversible 1e- reductions. Chemical reduction with 1 or 2 equiv. reducing agent enabled isolation of the neutral and anionic complexes, respectively, where the [CoIII-CF3] bond remains intact in all three oxidation states (n = +1, 0, -1). Structural analysis shows systematic changes to the redox-active ligand backbone upon reduction, consistent with sequential ligand-centered electron transfer in the series [bqdi]0 to [s-bqdi]˙- to [opda]2-. In contrast, the reaction of [CpCo(tBuUreaopda)] with alkyl triflates resulted in ligand-centered alkylation at the ureayl groups instead of the targeted Co-alkyl bond formation, suggesting less favorable bond formation at cobalt and greater nucleophilic accessibility of the ligand compared to the metal center.

Cover Feature: Synthesis of Partially Fluorinated Alkyl Triflates by Electrochemical Fluorination (Simons Process) (Chem. Eur. J. 64/2023)

Cover Feature: Synthesis of Partially Fluorinated Alkyl Triflates by Electrochemical Fluorination (Simons Process) (Chem. Eur. J. 64/2023)

Synthesis of Partially Fluorinated Alkyl Triflates by Electrochemical Fluorination (Simons Process).

A scalable straightforward synthesis of monofluoro- and difluoromethyl triflate CF3 SO2 OCH2 F (MH2F ) and CF3 SO2 OCHF2 (MHF2 ) through electrochemical fluorination (ECF, Simons process) of methyl triflate MH3 in anhydrous hydrogen fluoride at nickel anodes is presented. The ECF method is also feasible for the preparation of the deuterated analogues CF3 SO2 OCD2 F (MD2F ) and CF3 SO2 OCDF2 (MD2F ). Surprisingly, no H/D exchange occurs during ECF of CF3 SO2 OCD3 (MD3 ); this provides further evidence for a NiF3 /NiF4 -mediated ECF mechanism. The ECF of selected partially fluorinated ethyl triflates is described, and electrochemical fluorination of CF3 SO2 OCH2 CF3 (EH2F3 ) leads to the until now unknown chiral CF3 SO2 OCHFCF3 (EHFF3 ). The analogous fluoromethyl and fluoroethyl nonaflates are also accessible by ECF. This study contains detailed spectroscopic, structural, and thermal data on (fluoro)methyl and fluoro(ethyl) triflates.

Synthesis of 2-Amino-2-deoxy-β-d-mannosides via Stereoselective Anomeric O-Alkylation of 2N,3O-Oxazolidinone-Protected d-Mannosamine: Synthesis of the Trisaccharide Repeating Unit of Streptococcus pneumoniae 19F Polysaccharide.

Cesium carbonate-mediated stereoselective anomeric O-alkylation of a 2N,3O-oxazolidinone-protected d-mannosamine with sugar-derived primary or secondary alkyl triflates afforded the corresponding 2-amino-2-deoxy-β-d-mannosides in moderate to good yields and excellent stereoselectivity. The oxazolidinone ring can be opened with aqueous alkali hydroxide to liberate the amine functionality. This method has been successfully applied to the synthesis of the trisaccharide repeating unit of Streptococcus pneumoniae 19F polysaccharide.

Broadly Applicable Ion Pair-Assisted Nucleophilic Substitution of sp3-Carbon Electrophiles with Alkynyltrifluoroborates.

Alkynyltrifluoroborate nucleophiles react smoothly with a wide range of sp3-carbon electrophiles, including propargyl methanesulfonates and unactivated alkyl triflates, to give Sonogashira-type products, via a novel ion pair-assisted nucleophilic substitution mechanism. An ion pair-organic complex, investigated using computational chemistry and in situ NMR experiments, may play a crucial role in this reaction.

Kinetics of Nucleophilic Substitution of Compounds Containing Multiple Leaving Groups Bound to a Neopentyl Skeleton.

Ammonium salt derivatives with a neopentyl moiety are remarkably stable against Hofmann elimination, but the neopentyl moiety slows nucleophilic substitution, complicating their synthesis. To identify the best leaving group for the synthesis of the ammonium salts, we prepared six 1,1,1-tris(X-methyl)ethane derivatives, where X is chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate (triflate), and studied the kinetics of their reactions with sodium, cesium, or tetramethylammonium azide in deuterated dimethylsulfoxide (DMSO) at 100 °C by NMR spectroscopy. Iodide and bromide were found to be more reactive than p-toluenesulfonate and methanesulfonate. As expected, the best leaving group for nucleophilic substitution was triflate. Despite the usual high reactivity and instability of primary alkyl triflates, neopentyl triflate can be used as a stable but sufficiently reactive reactant for nucleophilic substitution on neopentyl skeletons.

Synthesis, reactivity, and crystallography of a sterically hindered acyl triflate

2,6-Dimesitylbenzoyl triflate (1) has been prepared from the corresponding acid chloride, and its structure and reactivity with some small molecules is described. Notably, methods for cleaving ethereal C–O bonds under mild conditions with regioselectivity, generation of alkyl triflates in situ from ethers, and introduction of m-terphenyl groups via flexible alkoxy linkers to nucleophiles of interest are described. Advantages and limitations of cyclic ether polymerizations are also detailed. Some acylammonium reaction intermediates were also prepared and characterized. An intramolecular Friedel-Crafts acylation competes with other substrates at elevated temperatures, such that haloarenes are not appreciably acylated. Six compounds were characterized by XRD owing to the crystallinity of the 2,6-dimesitylphenyl group, which was used to scrutinize the carbonyl moiety in a variety of functional groups.

Synthesis and characterization of light-fluorous NHC-ligands and their palladium complexes

Light-fluorous ponytails containing perfluoro-n-propyl, perfluoro-n-butyl and perfluoro-t-butoxy groups were used to synthesize light-fluorous α-olefins, branched dialkyl iodides, alkyl triflates, alkyl imidazoles, and dialkyl imidazolium salts. The latter were used to prepare two light-fluorous N,N’-dialkyl-imidazole-2-ylidene diiodo palladium(II) complexes. The fluorous partition coefficients of the light-fluorous olefins, iodides, and triflates were measured in perfluoro(methylcyclohexane)/toluene biphasic system, which revealed that the shorter and environmentally friendlier perfluoroalkyl chains of the light-fluorous ponytails results in lower fluorous partition coefficients, especially as the number of methylene groups increases.

Synthesis of Alkyl Silanes via Reaction of Unactivated Alkyl Chlorides and Triflates with Silyl Lithium Reagents.

The reaction of unactivated secondary and primary alkyl chlorides as well as primary alkyl triflates with silyl lithium reagents to access tetraorganosilanes is reported. These nucleophilic substitutions proceed in the absence of any transition metal catalyst under mild conditions in moderate to very good yields. The silyl lithium reagents are readily generated from the corresponding commercially available chlorosilanes. Enantioenriched secondary alkyl chlorides react with high stereospecificity under inversion of configuration.

Alkylation of Terminal Alkynes under Zinc Lewis Acid Catalysis and Its Mechanistic Studies

AbstractWith a zinc Lewis acid catalyst and proton sponge in toluene, terminal alkynes were found to undergo the alkylation by alkyl triflates to provide unsymmetrical internal alkynes. This is the first example that a simple alkyl chain other than benzylic and norbornyl units can be introduced onto the alkynyl carbon atom under Lewis acid catalysis. Mechanistic studies revealed that the activation of the alkyne by the zinc Lewis acid and proton sponge is the trigger of the reaction to give a monoalkynylzinc species, which successively reacts with the alkyl triflate to afford the internal alkyne. A radical pathway is unlikely in this system.magnified image

Mild Base Promoted Nucleophilic Substitution of Unactivated sp3‐Carbon Electrophiles with Alkenylboronic Acids

AbstractDiverse alkenylboronic acids react smoothly with various sp3‐carbon electrophiles such as unactivated alkyl triflates in the presence of mild bases such as K3PO4. The reaction protocol is very mild and thereby enables high functional group tolerance. This transition metal‐free condition is orthogonal towards the classic transition metal catalyzed Suzuki coupling.magnified image

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to MTMs that proceeds through nucleophilic ring‐opening of Meldrum's acid derivatives followed by O‐alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34 – 92% and allows for variations of the oxo‐ and thioester moieties as well as the substituent at the C(α) position.

N-Heterocyclic carbene copper-catalyzed direct alkylation of terminal alkynes with non-activated alkyl triflates.

(NHC)-Cu-catalyzed C(sp)-C(sp3) bond formation has been successfully achieved under mild conditions. Nonactivated alkyl triflates, which could be easily derived from alcohols, were utilized as C-O electrophiles. Mechanistic studies suggested that copper acetylide was the active species. Scale-up reactions further demonstrated the practicality and efficiency of the developed strategy.

ChemInform Abstract: Site‐Selective N‐Dealkylation of 1,2,3‐Triazolium Salts: A Metal‐Free Route to 1,5‐Substituted 1,2,3‐Triazoles and Related Bistriazoles.

N3-Alkylation of 1-(pivaloyloxymethyl)-1,2,3-triazoles with alkyl triflates carrying latent “click” functionality, followed by a nucleophile-promoted N1-dealkylation of the resulting strongly electrophilic intermediate triazolium salts, provides an efficient route to 1,5-disubstituted 1,2,3-triazoles. The azide and alkyne groups incorporated by N-alkylation can be submitted to further copper-catalyzed azide–alkyne and Huisgen cycloadditions to provide bis(1,2,3-triazoles) with unprecedented 1,5/1,4 substitution patterns.

Site-Selective N-Dealkylation of 1,2,3-Triazolium Salts: A Metal-Free Route to 1,5-Substituted 1,2,3-Triazoles and Related Bistriazoles

N3-Alkylation of 1-(pivaloyloxymethyl)-1,2,3-triazoles with alkyl triflates carrying latent "click" functionality, followed by a nucleophile-promoted N1-dealkylation of the resulting strongly electrophilic intermediate triazolium salts, provides an efficient route to 1,5-disubstituted 1,2,3-triazoles. The azide and alkyne groups incorporated by N-alkylation can be submitted to further copper-catalyzed azide-alkyne and Huisgen cycloadditions to provide bis(1,2,3-triazoles) with unprecedented 1,5/1,4 substitution patterns.

Mechanism of Copper-Catalyzed Hydroalkylation of Alkynes: An Unexpected Role of Dinuclear Copper Complexes.

This article describes a mechanistic study of copper-catalyzed hydroalkylation of terminal alkynes. Relying on the established chemistry of N-heterocyclic carbene copper hydride (NHCCuH) complexes, we previously proposed that the hydroalkylation reaction proceeds by hydrocupration of an alkyne by NHCCuH followed by alkylation of the resulting alkenylcopper intermediate by an alkyl triflate. NHCCuH is regenerated from NHCCuOTf through substitution with CsF followed by transmetalation with silane. According to this proposal, NHCCuH must react with an alkyne faster than with an alkyl triflate to avoid reduction of the alkyl triflate. However, we have determined that NHCCuH reacts with alkyl triflates significantly faster than with terminal alkynes, strongly suggesting that the previously proposed mechanism is incorrect. Additionally, we have found that NHCCuOTf rapidly traps NHCCuX (X = F, H, alkenyl) complexes to produce (NHCCu)2(μ-X)(OTf) (X = F, H, alkenyl) complexes. In this article, we propose a new mechanism for hydroalkylation of alkynes that features dinuclear (NHCCu)2(μ-H)(OTf) (X = F, H, alkenyl) complexes as key catalytic intermediates. The results of our study establish feasible pathways for the formation of these intermediates, their ability to participate in the elementary steps of the proposed catalytic cycle, and their ability to serve as competent catalysts in the hydroalkylation reaction. We also provide evidence that the unusual reactivity of the dinuclear complexes is responsible for efficient hydroalkylation of alkynes without concomitant side reactions of the highly reactive alkyl triflates.

Copper-Catalyzed Hydroalkylation of Terminal Alkynes

We have developed a copper-catalyzed hydroalkylation of terminal alkynes using alkyl triflates as coupling partners and (Me(2)HSi)(2)O as a hydride donor. The hydroalkylation proceeds with excellent anti-Markovnikov regioselectivity and provides exclusively (E)-alkenes. We have demonstrated that both alkyl- and aryl-substituted alkynes can be used as substrates, together with 1° alkyl and benzylic triflates. Finally, the transformation can be accomplished in the presence of a wide range of functional groups. Overall, the new hydroalkylation reaction allows highly efficient and diastereospecific synthesis of (E)-alkenes from readily available terminal alkynes and alkyl triflates. On the basis of a preliminary mechanistic study, we propose that the hydroalkylation reaction involves copper hydride formation, hydrocupration of an alkyne, and alkylation of an alkenyl copper intermediate.

ChemInform Abstract: Mild Copper‐Catalyzed Fluorination of Alkyl Triflates with Potassium Fluoride.

A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45 °C using 2 mol % of the copper catalyst. With 10 mol % of the catalyst, full conversion can be achieved in less than 10 minutes at 45 °C, and thus makes this procedure potentially suited for the preparation of 18F-labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase-transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).

Synthesis and Characterization of 12-Pyridinium Derivatives of the [closo-1-CB11H12]− Anion

Diazotization of [closo-1-CB11H10-1-R-12-NH2](-)[NMe4](+) (4[NMe4]) in neat 4-methoxypyridine leads to 12-(4-methoxypyridinium) zwitterions [closo-1-CB11H10-1-R-12-(4-MeOC5H4N)] (2) in ∼50% yield. Demethylation of 2 with LiCl in dimethylformamide provides access to 12-pyridones 5[NMe4], which can be O-alkylated with alkyl triflates giving 12-(4-alkoxypyridinium) zwitterions, such as 1. This three-step process is more efficient than direct diazotization of amine 4[NMe4] in neat higher 4-alkoxypyridine. The new method was demonstrated for the synthesis of [closo-1-CB11H10-1-C5H11-12-(4-C7H15OC5H4N)] (1c), which exhibits a smectic A phase. Molecular and electronic structures of 4-methoxypyridinium zwitterion 2b and its C(1) isomer [closo-1-CB11H11-1-(4-MeOC5H4N)] (3b) were investigated by single-crystal X-ray diffraction and spectroscopic methods, respectively, and the experimental results were compared to those obtained with density functional theory methods. Lastly, the mechanism for formation of zwitterions 2 was investigated computationally revealing low energy for dediazoniation of the [closo-1-CB11H10-1-R-12-N2] (14) intermediate (ΔG298 ≈ 25 kcal/mol) to form boronium ylide 15, with weak dependence on substituent R. Dinitrogen derivative 14c was observed by (11)B NMR spectroscopy.