TMSOTf Research Articles

Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin

Treatment of the protected and unprotected nucleosides with 1,3-dibromo-5,5-dimethylhydantoin in aprotic solvents such as CH2Cl2, CH3CN, or DMF effected smooth bromination of uridine and cytidine derivatives at C-5 of pyrimidine rings as well as adenosine and guanosine derivatives at C-8 of purine rings. Addition of Lewis acids such as trimethylsilyl trifluoromethanesulfonate enhanced the efficiency of bromination.

Microwave-assisted one-pot radiosynthesis of 2′-deoxy-2′-[18F]fluoro-5-methyl-1-β-d-arabinofuranosyluracil ([18F]-FMAU)

[(18)F]-FMAU is a PET tracer being evaluated for imaging cell proliferation. Current multi-step procedures of [(18)F]-FMAU synthesis are time-consuming, resulting in low radiochemical yield and inconvenient applications for the clinic. We have previously reported the use of Friedel-Crafts catalysts for an improved synthesis of [(18)F]-FMAU. In this study, we investigated the efficiency of microwave-assisted radiosynthesis of [(18)F]-FMAU in comparison with conventional thermal conditions. A simplified one-pot synthesis of [(18)F]-FMAU was developed under microwave conditions. Various reaction times, temperatures, and microwave powers were systematically explored to optimize the coupling reaction of 2-deoxy-2-[(18)F]fluoro-1,3,5-tri-O-benzoyl-d-arabinofuranose ([(18)F]-sugar) and bis-2,4-(trimethylsilyloxy)-5-methyluracil (silylated uracil) in the presence of a Friedel-Crafts catalyst, trimethylsilyl trifluoromethanesulfonate (TMSOTf). Microwave significantly enhanced the coupling efficiency of [(18)F]-sugar and silylated uracil by reducing the reaction time to 10 min (6-fold reduction as compared to conventional heating) at 95 °C. Base hydrolysis followed by high-performance liquid chromatography purification produced the desired [(18)F]-FMAU. The overall radiochemical yield was 20 ± 4% (decay corrected, n=3). Radiochemical purity was >99% and specific activity was >400 mCi/μmol. The α/β anomer ratio was 1:2. The radiosynthesis time was about 90 min from the end of bombardment. A reliable microwave-assisted approach has been developed for routine synthesis of [(18)F]-FMAU. The new approach affords a simplified process with shorter synthesis time and higher radiochemical yield as compared to conventional heating. A fully automated microwave-assisted synthesis of [(18)F]-FMAU can be readily achieved under new reaction conditions.

Efficient activation of thioglycosides with N-(p-methylphenylthio)-ε-caprolactam-TMSOTf

[Display omitted] N-(p-Methylphenylthio)-ε-caprolactam (1) in combination with trimethylsilyl trifluoromethanesulfonate (TMSOTf) provides an efficient thiophilic promoter system, capable of activating different thioglycosides. Both ‘armed’ and ‘disarmed’ thioglycosyl donors were activated for glycosidic bond formation. Notably, this reagent combination works well in reactivity-based one-pot oligosaccharide assembly strategy.

Reversal of Anomeric Selectivity with O‐Glycosyl Trichloroacetimidates as Glycosyl Donors and Thiols as Acceptors Under Acid/Base Catalysis

AbstractBoron trifluoride or trimethylsilyl trifluoromethanesulfonate catalysed the generation of thioglycosides from O‐glucopyranosyl or O‐galactopyranosyl trichloroacetimidates and thiols giving mainly or exclusively α‐thioglycosides. However, the same reactions with phenylboron difluoride as catalyst are highly β‐selective. An SN2‐type reaction course under acid/base catalysis is invoked by these and previous results.

Synthesis of tetra- and hexasaccharide fragments corresponding to the O-antigenic polysaccharide of Klebsiella pneumoniae

The preparation of linear tetra- (1) and hexasaccharides (2), containing the repeating unit [→3)-β-Galf-(1→3)-α-Galp-(1→] present in the O-polysaccharide of the lipopolysaccharide of Klebsiella pneumoniae is described. The key step in their synthesis is the α-selective galactopyranosylation of 3-OH di- and tetrasaccharide acceptors (20 and 22) with a disaccharide trichloroacetimidate donor 19 in the presence of trimethylsilyl triflate in a diethyl ether–CH2Cl2 mixture as solvent.

Synthesis of cyclopropyl glycosides and their use as novel glycosyl donors

Methods for the synthesis of cyclopropyl glycosides and their use as glycosyl donors are described. Cyclopropyl glycosides containing different substituents were prepared by cyclopropanation of the corresponding vinyl glycosides, or by glycosidation of cyclopropyl alcohols that are synthesized by the Kulinkovich reaction. 1-Methyl- and 1-phenyl-substituted cyclopropyl glycosides undergo coupling to Fmoc-protected serine and threonine and to partially protected monosaccharides in the presence of TMS triflate to give glycosidated products.

Selective and Efficient Silylation of Mesoporous Silica: A Quantitative Assessment of Synthetic Strategies by Solid-State NMR

Surface silanol groups in mesoporous silica MCM-41 particles were successfully silylated with trimethylsilyl trifluoromethanesulfonate (TMSOTf). Characterization of modified mesoporous silica materials was conducted using X-ray diffraction, infrared spectroscopy, nitrogen absorption, elemental analysis, and solid-state NMR spectroscopy. In particular, extensive use of 1H, 13C, and 29Si solid-state NMR provided unique insights into the silylation process and served as a key guiding tool for the synthetic effort. Treatment of as-synthesized MCM-41 with TMSOTf was found to selectively and efficiently passivate the external surface of particles without assistance of a base, whereas modification by other silylating reagents, including trimethylchlorosilane (TMCS), N,O-bis(trimethylsilyl)acetamide (BSA), and triethoxymethylsilane (MeSi(OEt)3), yielded lower coverage and/or resulted in partial silylation of the internal surface. The 29Si and 1H solid-state NMR spectra gave accurate concentrations of silicon sites and densities of trimethylsilyl (TMS) groups on the external and internal surfaces of MCM-41. The 1H and 13C NMR spectra revealed the definite structures and concentrations of all organic species present in the silylated samples. These data highlighted the importance of choosing a proper concentration of the silylating reagent and finding the washing and extraction conditions that result in efficient sequestration of the structure directing agent (surfactant) without detachment of grafted species or production of unwanted surface alkoxy groups.

A new solid acid for specifically cleaving the Car[sbnd]Calk bond in di(1-naphthyl)methane

Three catalysts were prepared by impregnating the same volume of pentachloroantimony (PCA), trimethylsilyl trifluoromethanesulfonate (TMSTFMS), or isometric PCA and TMSTFMA into an activated carbon (AC). Di(1-naphthyl)methane (DNM) was used as a coal-related model compound to evaluate their catalytic activity. The results show that CarCalk bond in DNM can be specifically cleaved over each catalyst to afford naphthalene and 1-methylnaphthalene under pressurized hydrogen at temperatures up to 300°C, but as a new solid acid (NSA), PCA–TMSTFMS/AC is significantly more active for DNM hydrocracking than the other two catalysts. FTIR and SEM analyses reveal the strong interactions among PCA, TMSTFMS, and the AC in the NSA. NH3-TPD analysis suggests that the NSA should exhibit appreciably stronger acidity than the other two catalysts. The strong interactions may result in the appreciably stronger acidity of the NSA than that of the other two catalysts and thereby facilitate DNM hydrocracking. It is presumed that H2 was heterolytically cleaved to immobile H− and mobile H+. The addition of mobile H+ to ipso-position of DNM should be crucial step for DNM hydrocracking.

Intramolecular Conjugate Addition of α,β-Unsaturated Lactones Having an Alkanenitrile Side Chain: Stereocontrolled Construction of Carbocycles with Quaternary Carbon Atoms

An efficient method for constructing carbocycles with all-carbon quaternary stereocenters has been developed on the basis of a stereoselective cyclization reaction of α,β-unsaturated lactones having an alkanenitrile side chain. Treatment of the substrate with lithium hexamethyldisilazide (LiHMDS) in the presence of triisopropylsilyl chloride (TIPSCl) led to the generation of the corresponding α-cyano carbanion species which readily underwent an intramolecular conjugate addition reaction. It was found that the combined use of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and triethylamine is also effective for the cyclization ­reaction without using a strong base. Interestingly, different ste­reochemical outcomes were observed in the two cyclization methods.

Formal [4+2] Cycloaddition of di-tert-Butyl 2-Ethoxycyclobutane-1,1-dicarboxylate with Ketones or Aldehydes and Tandem Lactonization

A catalytic amount of tin(IV) chloride catalyzed formal [4+2] cycloaddition reaction of di-tert-butyl 2-ethoxycyclobutane-1,1-carboxylate with ketones or aldehydes to give diethyl 6-ethoxydihydro-2H-pyran-3,3(4H)-dicarboxylates, whereas two equivalents of trimethylsilyl triflate promoted tandem [4+2] cycloaddition and lactonization to afford 3-oxo-2,6-dioxabicyclo[2.2.2]octane-4-carboxylate esters.

Synthesis and Enhanced Radical Scavenging Activity of a Conformationally Constrained Epigallocatechin Analogue

Abstract The freely rotating single bond between the pyrogallol and chroman substructures in epigallocatechin (EGC) was constrained by reaction of EGC with acetone in the presence of trimethylsilyl trifluoromethanesulfonate to prepare the rigidified analog in good yield. The synthesized analog was examined for free radical scavenging activity toward the galvinoxyl radical and was found to be 27-fold more potent than EGC.

Trends in Stereoselectivity and Regioselectivity for Trimethylsilyl Trifluoromethanesulfonate Addition to Alkynes

Trends in Stereoselectivity and Regioselectivity for Trimethylsilyl Trifluoromethanesulfonate Addition to Alkynes

Synthesis of α-Glycosyl Thiols by Stereospecific Ring-Opening of 1,6-Anhydrosugars

Treatment of 1,6-anhydrosugars with commercially available bis(trimethylsilyl) sulfide in the presence of trimethylsilyl triflate led to the formation of α-glycosyl thiols. All the reactions were highly stereoselective and afforded the α-glycosyl thiols in good to excellent yields. By this procedure, a variety of 1,6-anhydrosugars, differing in their sugar units, glycosidic linkages, and protecting group pattern, were converted smoothly into the corresponding α-glycosyl thiols, which could be of great utility in thioglycoside chemistry. It is noteworthy that 1,6-anhydrosugars carrying the 2-O-acyl group and 1,6-anhydrosugar-containing oligosaccharides could also be ring-opened stereospecifically under the same conditions to give rise to the corresponding 1-thiosugars in high yields. Thus, a very concise and efficient access to α-glycosyl thiols of great value was established.

Synthesis, Isolation and Structural Characterisation of Alkoxytitanium Triflate Complexes

AbstractTreatment of [Ti(OiPr)4] with trimethylsilyl triflate results in the formation of [Ti(OiPr)3(OTf)] (2) in high yield. Subsequent treatment of the triflate derivative 2 with a series of facially coordinating N3‐donor ligands results in the production of a series of charge‐separated metal alkoxide salts of the general formula [{L}Ti(OiPr)3][OTf] {L = tris(pyrazolyl)methane (3a), 1,3,5‐triethyl‐1,3,5‐triazacyclohexane (3b), 1,3,5‐tribenzyl‐1,3,5‐triazacyclohexane (3c), 1,3,5‐tris(p‐fluorobenzyl)‐1,3,5‐triazacyclohexane (3d), and 1,3,5‐tris[(1S)‐1‐phenylethyl]‐1,3,5‐triazacyclohexane (3e)}. The products were characterized by 1H and 13C NMR spectroscopy and in the case of 3a–c by single‐crystal X‐ray diffraction. Reaction of 2 with 1,3,5‐triphenyl‐1,3,5‐triazacyclohexane results in the formation of complex 4 [{L′}2Ti(OiPr)2(OTf)2], which contains two 3,4‐dihydroquinazoline ligands (L′), a result of catalytic activation of the triazacyclohexane ligands by [Ti(OiPr)3(OTf)] towards electrophilic aromatic substitution.

Elucidating the Directing Effect of Lewis Acids on the Reaction Pathway in Formal [3+3] Cyclocondensation Reactions: A Comprehensive In Situ Spectroscopic Study

AbstractDifferent spectroscopic methods were applied in situ as well as ex situ to elucidate the mode of action of the Lewis acids TiCl4 and trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the formal [3+3] cyclization reaction of a 1,3‐bis(silyloxy)‐1,3‐butadiene with fluorinated ketenacetales. Different products were formed depending on the type of Lewis acid employed, which can be explained by their completely different interaction with the ketenacetale. Results of attenuated total reflection infrared (ATR‐IR) and UV/vis spectroscopic studies revealed that TMSOTf interacts with only one site of the ketenacetale, forming an ionic species. In contrast, TiCl4 forms a bischelate complex, which was confirmed by using X‐ray crystal structure analysis. Both reaction pathways were studied by simultaneously applying in situ ATR‐IR/UV/vis spectroscopy in a specifically developed reaction cell. During cooling and subsequent heating of the reaction mixture, formation and structural changes of different intermediates were observed, in particular in the case of the TMSOTf catalyzed reaction. Although the TiCl4 mediated reaction proceeds in only one step, the TMSOTf route comprises two reaction steps. In situ spectroscopic results revealed that the applied workup procedure influences product formation and distribution as well.

Trimethylsilyl Trifluoromethanesulfonate-promoted Reductive 2′-O-arylmethylation of Ribonucleoside Derivatives

Arylmethyl groups such as benzyl, p-methoxybenzyl, and 1-pyrenylmethyl groups were introduced to the 2′-O-position of nucleosides by reductive etherification. Combining corresponding aromatic aldehydes with 2′-O-trimethylsilylnucleoside derivatives in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) resulted in moderate to good yields of the 2′-O-arylmethyluridine derivatives, whereas the corresponding cytidine and adenosine derivatives were obtained in low yields. The reaction of ribonucleosides with aliphatic aldehydes did not proceed smoothly. Anomerization of the uridine derivatives by TMSOTf was observed in CH2Cl2, toluene, and CH3CN, but was completely suppressed when the reactions were conducted in 1,4-dioxane.

Comprehensive and Facile Entry into Substituted Amidines via the Condensation of N-Pmc-Substituted Thioamides with Amines Using Mukaiyama Reagent as a Thiophile

A convenient approach is presented for the preparation of substituted amidines through the fusion of N-Pmc-substituted thioamides with amines, facilitated by a variety of thiophilic reagents. Assorted thiophiles were evaluated for their effectiveness as condensation reagents between the two partners, with the Mukaiyama reagent emerging as the optimal candidate for this process. The scope and limitations of this method were explored, revealing interesting synthetic challenges and constraints. Many of these limitations were overcome through the application of alternative reaction pathways in the construction of troublesome products. Treatment of the resultant Pmc-amidines with trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate cleanly afforded the deprotected substituted amidines.

Silicon Lewis Acid Catalyzed [3+2] Cycloaddition Reactions of Hydrazones/Cyclopentadiene: Mild Access to Pyrazolidine Derivatives

AbstractA first and fairly mild metal‐free catalytic route was developed for the [3+2] cycloadditions of different N‐acylhydrazones to cyclopentadiene, providing the synthetically andbiologically important five‐membered cyclic compounds pyrazolidines. The reaction was successfully conducted in high yields (up to 99 %) with high diastereoselectivities (up to 98:2 dr) by using catalytic amounts of TMSOTf (trimethylsilyl triflate) as a readily available Lewis acidic catalyst. The experimental findings were supported by DFT calculations of the reaction mechanism. The theoretical and experimental diastereomeric excess values show good agreement, rendering the computations an efficient tool for predicting the selectivities in these and related reactions.

Facile routes to manganese(II) triflate complexes

Manganese(II) chloride reacts with trimethylsilyl triflate (TMS(OTf) where OTf = (-)OSO(2)CF(3)) in a 1:1 mixture of acetonitrile and tetrahydrofuran, and after recrystallization affords the linear coordination polymer [Mn(II)(CH(3)CN)(2)(OTf)(2)](n). Each distorted octahedral manganese(II) center in the polymeric chain has trans-acetonitriles and the remaining equatorial coordination positions are occupied by the bridging triflate anions. Dissolving [Mn(II)(CH(3)CN)(2)(OTf)(2)](n) in equal volumes of acetonitrile and pyridine followed by recrystallization with diethyl ether yields trans-[Mn(II)(C(5)H(5)N)(4)(OTf)(2)]. The distorted octahedral geometry of the manganese center features monodentate trans-triflate anions and four equatorial pyridines. Exposure of either [Mn(II)(CH(3)CN)(2)(OTf)(2)](n) or [Mn(II)(C(5)H(5)N)(4)(OTf)(2)] to water readily gives [Mn(II)(H(2)O)(6)](OTf)(2). XRD reveals hydrogen-bonding interactions between the [Mn(II)(H(2)O)(6)](2+) cation and the triflate anion. All three of these species are easily crystallized and provide convenient sources of manganese(II) for further synthetic elaboration.

Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with N-gulosyl nitrones

Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with L-gulose-derived chiral nitrones in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate was investigated. The selectivity was strongly influenced by the bulkiness of the C-substituent of the nitrone: for example, C-benzyloxymethyl nitrone afforded four stereoisomers, whereas bulky C-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]nitrone gave a single stereoisomer. The latter product was elaborated to afford key synthetic intermediates for polyoxin C and dysiherbaine.