Aminosulfur Trifluoride Research Articles

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor 1 (BMS-986169), which relies upon a stereospecific SN2 alkylation strategy and a robust process for the preparation of its phosphate prodrug 28 (BMS-986163) from parent 1 using POCl3. A deoxyfluorination reaction employing bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo.

Deoxyfluorination of α- N -phthaloyl cycloalkanones with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor)

Abstract The deoxyfluorination of α- N -phthaloyl cyclobutanone with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) produced a gem -difluoride product together with a vic -difluoride bearing a cyclopropane ring. In contrast, the deoxyfluorination of the corresponding α- N -phthaloyl cyclopentanone produced the gem -difluoride only. Furthermore, the deoxyfluorination of the corresponding α- N -phthaloyl cyclohexanone produced an intramolecular cyclization product with two fluorine atoms as the main product, which provided the starting material after workup. Cationic species formed through neighboring group participation are most likely the key intermediates in these reactions. Control experiments using N -benzoyl congeners produced oxazole or oxazoline derivatives, indicating that the presence or absence of a hydrogen atom on the protected amine moiety was critical to determining the reaction path.

Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

Mycobacterium tuberculosis survival in cells requires mycobactin siderophores. Recently, the search for lipid antigens presented by the CD1a antigen-presenting protein led to the discovery of a mycobactin-like compound, dideoxymycobactin (DDM). Here we synthesize DDMs using solution phase and solid phase peptide synthesis chemistry. Comparison of synthetic standards to natural mycobacterial mycobactins by nuclear magnetic resonance and mass spectrometry allowed identification of an unexpected alpha-methyl serine unit in natural DDM. This finding further distinguishes these pre-siderophores as foreign compounds distinct from conventional peptides, and we provide evidence that this chemical variation influences the T cell response. One synthetic DDM recapitulated natural structures and potently stimulated T cells, making it suitable for patient studies of CD1a in infectious disease. DDM analogs differing in the stereochemistry of their butyrate or oxazoline moieties were not recognized by human T cells. Therefore, we conclude that T cells show precise specificity for both arms of the peptide, which are predicted to lie at the CD1a-T cell receptor interface.

Direct nucleophilic fluorination of carbonyl groups of benzophenones and benzils with Deoxofluor

The carbonyl groups of diaryl ketones and diaryl diketones were directly fluorinated with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) under neat conditions to give the corresponding gem-difluorides and tetrafluorinated derivatives in moderate to high yields.

Fluorination of triptolide and its analogues and their cytotoxicity

The reaction of triptolide and its analogues with a fluorinating agent, that is, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) or (diethylamino)sulfur trifluoride (DAST), was studied. One of the fluorinated products, 14beta-dehydroxy-14beta-fluoro triptolide, was found to be more cytotoxic than the parent natural triptolide.

Controlled conversion of phenylacetic acids to phenylacetonitriles or benzonitriles using bis(2-methoxyethyl)aminosulfur trifluoride

A mild, efficient, and practical method for the one-step synthesis of benzonitriles from phenylacetic acids using bis(2-methoxyethyl)aminosulfur trifluoride is described. The reaction was easily extended to the synthesis of the corresponding phenylacetonitriles by inclusion of triethylphosphine.

Direct, Facile Synthesis of Acyl Azides and Nitriles from Carboxylic Acids Using Bis(2‐methoxyethyl)aminosulfur Trifluoride.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Direct, facile synthesis of acyl azides and nitriles from carboxylic acids using bis(2-methoxyethyl)aminosulfur trifluoride

A mild, efficient, and practical method for the one-step synthesis of acyl azides from carboxylic acids using bis(2-methoxyethyl)aminosulfur trifluoride is described. The reaction was easily extended to the synthesis of the corresponding nitriles by the inclusion of phosphorous reagents. The method can be applied to the synthesis of optically active nitriles in high yields, and is compatible with fluorous phosphines.

One‐Pot Route to New α,α‐Difluoroamides and α‐Ketoamides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

One-pot route to new alpha,alpha-difluoroamides and alpha-ketoamides.

New alpha,alpha-difluoroamides (4a-d, 6a-d) and alpha-ketoamides (5a-d, 7a-d) result from one-pot reactions of alpha-ketoacids, RCOCO(2)H (R = C(6)H(5), CH(3), CH(3)CH(2), thienyl) (1a-d) with bis(2-methoxyethyl)aminosulfur trifluoride [(CH(3)OCH(2)CH(2))(2)NSF(3)] (2) (Deoxofluor) or diethylaminosulfur trifluoride [(CH(3)CH(2))(2)NSF(3))] (3) (DAST). Product yields depend on reaction times and the ratio of reagents used. Longer reaction times ( approximately 36 h) with a 1:2 ratio of alpha-ketoacids and 2 or 3 gave major yields of the alpha,alpha-difluoroamides, and shorter reaction times ( approximately l h) produced alpha-ketoamides as the major products. Reactants in a 1:1 ratio resulted in alpha-ketoamides only.

Recent Advances in Nucleophilic Fluorination Reactions of Organic Compounds Using Deoxofluor and DAST

AbstractFor Abstract see ChemInform Abstract in Full Text.

Nucleophilic Fluorination of Amino Alcohols and Diols Using Deoxofluor.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Exploratory Study of the Reaction of Bis(2‐methoxyethyl)aminosulfur Trifluoride (Deoxofluor Reagent) with Diaryl Sulfoxides: Novel Routes to Ar2SF2 and Ar2SF(OTf) via Sulfoxide Activation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Electrophilic fluorinating reagent mediated synthesis of fluorinated alpha-keto Ethers, benzil, and 6,6'-dialkoxy-2,2'-bipyridines.

Interactions of various fluorinated and nonfluorinated alcohols with trans-stilbene in the presence of electrophilic reagents were studied. Under neat conditions, reactions of trans-stilbene (1) with fluorinated alcohols, R(f)OH (R(f) = CF3CH2-, CFH2CH2-, CF3CF2CH2-, CF2H(CF2)3CH2-, (CF3)2CH-, (CF3)3C- (2a-f) in the presence of an electrophilic reagent, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) or N,N-difluoro-2,2'-bipyridinium bis(tetrafluoroborate) (MEC-31), gave alpha-keto ethers (3a-f) and benzil (4) in good to moderate yields. alpha-Keto ether and benzil formation was very much dependent on the reaction time, the degree of fluorination of the alcohols, and whether a solvent such as CH3CN, DMF or DMA was utilized. In solution, alpha-keto ethers and benzil did not form. Interestingly, under neat conditions, nonfluorinated alcohols, ROH (R = CH3-, CH3CH2-, CH3CH2CH2-, CH3CH2CH2CH2-, CH3CH2CH2CH2CH2CH2-) (5g-k) did not react with trans-stilbene in the presence of MEC-31 but gave 6,6'-dialkoxy-2,2'-bipyridines (6g-k), regioselectively, in excellent isolated yields. On the other hand, fluorinated alcohols did not react with MEC-31. Reaction of MEC-31 with an excess of diethylene glycol (7) gave the bipyridine derivative (8) in 88% isolated yield. Reaction of 8 either with diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) readily produced the corresponding difluoro derivative (9) in 85% isolated yield. All new compounds have been characterized by spectroscopic and elemental analysis.

Nucleophilic fluorination of amino alcohols and diols using Deoxofluor

Various fluorinated chiral compounds were synthesized using bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) as a nucleophilic fluorinating reagent. Reactions of Deoxofluor ( 1) with amino alcohols ( 2a– d) and diols ( 2e– g) in methylene chloride at room temperature led to the formation of the corresponding fluoro derivatives ( 3a– g) in good yields.

Exploratory study of the reaction of bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor™ reagent) with diaryl sulfoxides: novel routes to Ar 2SF 2 and Ar 2SF(OTf) via sulfoxide activation

Neither bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor™ reagent) nor HF/pyridine alone can fluorinate diaryl sulfoxides. S-fluorination can be effected by activating the sulfoxide via protonation with HF/pyridine (70:30) to form sulfoxonium ions in equilibrium which are then S-fluorinated in situ with Deoxofluor™ to give Ar 2SF 2 compounds. Conversions depend strongly on steric factors and the reactions require the use of excess Deoxofluor™ and HF/pyridine. NMR data for the resulting diarylsulfur difluorides are gathered and discussed. Sulfoxide activation via diaryl (trifloxy) sulfonium triflate generated in situ from Ar 2SO with triflic anhydride at low temperature represents another strategy for S-fluorination with Deoxofluor™ to generate Ar 2S(OTf)F.

Recent Advances in Nucleophilic Fluorination Reactions of Organic Compounds­ Using Deoxofluor and DAST

Selective fluorination of organic compounds continues to be a stimulating and exciting area of research. While a variety of fluorinating reagents and methodologies have been developed to fulfill the increasing demand for site selective fluorination of organic compounds, applications of Deoxofluor and DAST continue to be used widely. Our interest in applying synthetic methods for introducing fluorine or a fluorinated group into a large variety of organic compounds encouraged this review which highlights recent progress in fluorination reactions using Deoxofluor [bis(2-methoxyethyl)aminosulfur trifluoride] and DAST (diethylaminosulfur trifluoride) as key nucleophilic fluorinating reagents. This review covers the literature for fluorination reactions of organic compounds using Deoxofluor and DAST from January 1999 through July 2002.

New flourinated chitin derivatives: synthesis, characterization and cytotoxicity assessment

New fluorinated chitin derivatives have been synthesized and characterized. Fluorination of chitin was achieved by facile homogenous reaction of chitin solution with diethyl amino sulfur trifluoride (C 4H 10NSF 3). The degree of substitution of the C6-hydroxyl functionality of N-acetyl-glucosamine repeat unit ranged from 50 to 98%, achieved by varying the reaction time from 1 to 144 h at room temperature. The use of pentafluoropropionic anhydride, trifluoromethylbenzoyl chloride and pentafluorobenzoyl chloride gave fluoro-chitin derivatives with 40, 10 and 5% substitution, respectively. Solid-state nuclear magnetic resonance and Fourier-transform infrared spectroscopy, powder X-ray diffraction, and elemental analysis support the identity of all fluorinated chitin derivatives. The fluorinated chitin derivatives were subjected to MTT assay using human (ATCC CCL-186) and mouse (ATCC CCL-1) fibroblast cell lines. Fluorinated chitin derivatives prepared from C 4H 10NSF 3 at 1, 6, 12, 72 and 96 h showed good cell viability of 80–100% for human fibroblast and 60–70% for mouse fibroblast. The % cell viability for the other fluorinated chitin derivatives were above 60% for both cell lines.

Nucleophilic trifluoromethylation and difluorination of substituted aromatic aldehydes with Ruppert’s and Deoxofluor™ reagents

Efficient, high yield syntheses of 2,2,2-trifluoro-1-( N, N-dialkylaminophenyl)-ethanols ( 3a, b) and 2,2,2-trifluoro-1-(hydroxyaryl)ethanols ( 6c– g) by reacting Ruppert’s reagent, (trifluoromethyl)trimethylsilane (TMSCF 3), with appropriate substrates in the presence of a catalytic amount of cesium fluoride are described. A versatile route to the synthesis of substituted aryl difluoromethane derivatives ( 8h– l, 10m, 12n, o, 14p) and the reactivity of substituted aromatic aldehydes towards bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor™) were also investigated.

Focus: N,N-Diethylaminosulfur trifluoride (DAST, Et2NSF3) and related reagents

N,N-Dialkylaminosulfur trifluorides were first prepared in 1964 [1] and have since been developed as mild, easily handled fluorinating agents. [2] DAST, [38078–09–0], the most widely used member of this family of reagents, is a pale yellow liquid that reacts violently with water. DAST is readily obtained from commercial sources (e.g. Aldrich or Lancaster) and can also be prepared by the reaction of N,N--di-ethylaminotrimethylsilane with sulfur tetrafluoride, followed by distillation of the crude product under reduced pressure. [3] DAST is known to be thermally unstable, undergoing either explosion or detonation when heated to > 9°ºC. [4] The more thermally stable bis(2-methoxy-ethyl) aminosulfur trifluoride (Deoxo-Fluor™, [202289–38–1]) has recently been made commercially available (Aldrich; Air Products and Chemicals) and is reported to have similar reactivity to DAST.[5]