A Closer Look at the Bromine–Lithium Exchange with <i>tert</i>-Butyllithium in an Aryl Sulfonamide Synthesis

A practical protocol for the one-pot synthesis of various aryl sulfonamides, notably of pyridine-core-substituted 7-azaindolyl sulfonamides, is described. A key step is the well-known bromine–lithium exchange reaction of an aryl bromide with <i>tert</i>-butyllithium (<i>t</i>-BuLi). Differing from the common practice to use 2 or more equiv of organolithium, the exact amount of <i>t</i>-BuLi needed for a sufficient exchange reaction is determined for each aryl bromide in a GC–MS-assisted experiment

Ambiphilic Properties of SF₅CF₂CF₂Br Derived Perfluorinated Radical in Addition Reactions Across Carbon–Carbon Double Bonds

The extraordinary properties of the pentafluorosulfanyl (SF₅) group attract attention of organic chemists. While numerous SF₅-substituted compounds have been synthesized, the direct introduction of SF₅(CF₂)_<i>n</i> moieties has remained almost unexplored. Our investigations revealed the ambiphilic character of the SF₅CF₂CF₂ radical. Addition reactions to electron-rich or electron-deficient alkenes profit either from its electrophilic or nucleophilic properties. Thus, the readily available SF₅CF₂CF₂Br proved to be a promising and versatile building block for the introduction of this perfluorinated moiety

Synthesis of SF₅CF₂‑Containing Enones and Instability of This Group in Specific Chemical Environments and Reaction Conditions

The chemistry of the SF₅CF₂ moiety has been scarcely investigated. In this report, we present synthetic pathways to a variety of SF₅CF₂-substituted compounds starting from vinyl ethers and SF₅CF₂C­(O)­Cl. In specific chemical environments and under particular reaction conditions, the SF₅CF₂ moiety is unstable in downstream products resulting in the elimination of the SF₅^– anion and its decomposition to SF₄ and F^–. Surprisingly, the formed F^– can attack the intermediate difluorovinyl moiety to form trifluoromethyl substituted products. This appears to happen when an intermediate neighboring group participation involving a double bond is possible. Under slightly different conditions, the reaction stops at the stage of a difluorovinyl compound

Transannular <i>O</i>‑Heterocyclization: A Useful Tool for the Total Synthesis of Murisolin and 16,19-<i>cis</i>-Murisolin

Transannular <i>O</i>-heterocyclization is applied as a key step in a total synthesis. This highly stereoselective and metal-free transformation introduces four stereocenters in one step. It was chosen to be the pivotal step in the synthesis of Murisolin and 16,19-<i>cis</i>-Murisolin, two annonaceous acetogenins. The efficiency of this synthesis is further illustrated by a stereodivergent late-stage separation of both synthetic routes

Synthesis, ¹⁸F‑Radiolabeling, and in Vivo Biodistribution Studies of <i>N</i>‑Fluorohydroxybutyl Isatin Sulfonamides using Positron Emission Tomography

The effector caspases-3 and -7 play a central role in programmed type I cell death (apoptosis). Molecular imaging using positron emission tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo- and enantiopure isatin sulfonamide-based potent and selective caspase-3 and -7 inhibitors were prepared by cyclic sulfate ring-opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC₅₀ = 11.8 and 0.951 nM for caspase-3 and -7, respectively), which makes them appropriate PET radiotracer candidates. Therefore, <i>N</i>-(4-[¹⁸F]­fluoro-3­(<i>R</i>)-hydroxybutyl)- and <i>N</i>-(3­(<i>S</i>)-[¹⁸F]­fluoro-4-hydroxybutyl)-5-[1-(2­(<i>S</i>)-(methoxymethyl)­pyrrolidinyl)­sulfonyl]­isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10–127 GBq/μmol using [¹⁸F]­fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild-type mice using PET/computed tomography imaging proved fast clearance of the tracer after tail vein injection

Transannular <i>O</i>‑Heterocyclization: A Useful Tool for the Total Synthesis of Murisolin and 16,19-<i>cis</i>-Murisolin

Transannular <i>O</i>-heterocyclization is applied as a key step in a total synthesis. This highly stereoselective and metal-free transformation introduces four stereocenters in one step. It was chosen to be the pivotal step in the synthesis of Murisolin and 16,19-<i>cis</i>-Murisolin, two annonaceous acetogenins. The efficiency of this synthesis is further illustrated by a stereodivergent late-stage separation of both synthetic routes

Asymmetric Synthesis of Monofluorinated 1‑Amino-1,2-dihydronaphthalene and 1,3-Amino Alcohol Derivatives

Enantioenriched 1-amino-4-fluoro-1,2-dihydronaphthalene derivatives are accessed via two complementary synthetic strategies. The careful optimization of the reaction conditions required for the elimination step in one route has allowed both the identification of an anchimerically assisted reaction pathway and, more importantly, access to a divergent reaction pathway toward fluorinated 1,3-amino alcohols from a common intermediate just by adjusting the number of equivalents of base used

Synthesis of α‑(Pentafluorosulfanyl)- and α‑(Trifluoromethyl)-Substituted Carboxylic Acid Derivatives by Ireland–Claisen Rearrangement

Earlier studies have shown that [3,3]-sigmatropic rearrangements of allyl esters are useful for the construction of fluorine-containing carboxylic acid derivatives. This paper describes the synthesis of 3-aryl-pent-4-enoic acid derivatives bearing either a pentafluorosulfanyl (SF₅) or a trifluoromethyl (CF₃) substituent in the 2-position by treatment of corresponding SF₅- or CF₃-acetates of <i>p</i>-substituted cinnamyl alcohols with triethylamine followed by trimethylsilyl triflate (TMSOTf). This Ireland–Claisen rearrangement delivered approximate 1:1 mixtures of syn/anti diastereoisomers due to tiny differences (<0.5 kcal/mol) both in the energy of (<i>Z</i>)/(<i>E</i>)-isomeric ester enolates and in the alternative Zimmerman–Traxler transition states of model compounds as shown by DFT calculations. Acidic reaction conditions have to be avoided since addition of the reagents in opposite sequence (first TMSOTf then Et₃N) led to oligomerization of the cinnamyl SF₅- and CF₃-acetates. Treatment of the corresponding regioisomeric 1-phenyl-prop-2-en-1-yl acetates under the latter conditions resulted in [1,3]-sigmatropic rearrangement and subsequent oligomerization of the intermediately formed cinnamyl esters. When Et₃N was added first followed by TMSOTf, no further reaction of the formed ester was detected

Radical Reactions of Alkyl 2‑Bromo-2,2-difluoroacetates with Vinyl Ethers: “Omitted” Examples and Application for the Synthesis of 3,3-Difluoro-GABA

Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)­phosphonate, [(bromodifluoromethyl)­sulfonyl]­benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na₂S₂O₄-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)­sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the p<i>K</i>_a values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit

Cyclobutyl-Containing Rigid Analogues of Threonine: Synthesis and Physical Chemical Properties

Hitherto unknown <i>cis</i>- and <i>trans</i>-1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids were synthesized in multigram scale. The obtained compounds can be considered as achiral conformationally restricted analogues of threonine with fixed spatial orientation of functional groups. p<i>K</i>_a values are noticeably different for both amino acids. According to the X-ray data the cyclobutane rings in both compounds are almost planar (the corresponding torsion angles are below 7°)