Guenter Haufe

(Salen)chromium Complex Mediated Asymmetric Ring Opening of meso‐ and Racemic Epoxides with Different Fluoride Sources

The asymmetric ring opening of five meso- and three racemic epoxides with different fluorinating reagents in the presence of stoichiometric or slightly sub-stoichiometric amounts of Jacobsens enantiopure (salen)chromium chloride complex A gave the corresponding optically active vicinal fluorohydrins. Silver fluoride was used as one of the fluoride sources either in the presence of Bu4N+H2F3− in diethyl ether or in acetonitrile. The latter reactions starting from cyclohexene oxide (1) showed maximum 72% ee in the formed fluorohydrin 2 isolated in 90% yield. From other meso-epoxides such as cyclopentene oxide and cycloheptene oxide the corresponding fluorohydrins were isolated in 80% and 82% yield with 65% and 62% ee, respectively. In case of ring opening under similar conditions of the racemic styrene oxide or phenyl glycidyl ether 83% and 75% of the fluorohydrins with fluorine in the primary position were isolated with 74% ee and 65% ee, respectively. Tetrahydronaphthalene oxide yielded a 2:1 mixture of trans- (23% ee) and cis-2-fluoro-3,4-benzocyclohexenol (2% ee) suggesting competing SN2 and SN1 type ring openings. Other epoxides such as cyclooctene oxide, cis-stilbene oxide and α-methylstyrene oxide did not react or gave the fluorohydrins with very small enantiomeric excess.

A Closer Look at the Bromine–Lithium Exchange with tert-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 tert-butyllithium (t-BuLi). Differing from the common practice to use 2 or more equiv of organolithium, the exact amount of t-BuLi needed for a sufficient exchange reaction is determined for each aryl bromide in a GC-MS-assisted experiment.

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.

Regioselectivity of the ring opening of propene oxides bearing electron-withdrawing substituents at the methyl group with Olah's reagent

Abstract The regiochemistry of the hydrofluorination of terminal epoxides with Olahs reagent (Py·9HF) is dependent on the electron-withdrawing character of the β-substituents. Phenoxy ethers with different substitution patterns of the aromatic ring and several N -heterocycles were examined as β-substituents.

Anti-Selective Aldol Reactions of Pentafluorosulfanylacetic Acid Esters with Aldehydes Mediated by Dicyclohexylchloroborane

Aldol reactions of pentafluorosulfanyl (SF5)-substituted acetic acid esters with both aromatic and aliphatic aldehydes proceeded with excellent anti-diastereoselectivity and good to high yields using dicyclohexylchloroborane/triethylamine. This methodology enabled the synthesis of hitherto unknown α-SF5-β-hydroxy esters. Using a norephedrine-based auxiliary, high asymmetric induction was observed. The stereochemistry of products was assigned by NMR spectroscopy and proved by X-ray diffraction analysis. The intermediate enolate was identified as a highly unstable species.

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)n 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.

Pentafluorosulfanyldifluoroacetic acid: rebirth of a promising building block.

Three novel, easily scalable routes for the synthesis of pentafluorosulfanyldifluoroacetic acid, SF5CF2C(O)OH, are described. Reactions of its acid chloride with amines and alcohols led to a small library of 15 amides and five esters, respectively. The reaction of the acid chloride with phenylmagnesium bromide gave the corresponding acetophenone. Pentafluorosulfanyldifluoroacetonitrile was obtained from pentafluorosulfanyldifluoroacetamide by dehydration with diphosphorus pentoxide.

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.

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 pKa 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.

Synthesis of a Fluorinated Ether Lipid Analogous to a Platelet Activating Factor

The synthesis of racemic 2-fluoro-3-hexadecyloxy-2-methylprop-1-yl 2′-(trimethylammonio)ethyl phosphate (10), a fluorinated analogue of the anticancer active and blood platelet activating ether lipids 8 and 9, has been achieved in a six-step sequence from methallyl alcohol (11). Etherification of 11 with hexadecyl bromide gave allylic ether 12, bromofluorination of which afforded the bromo-substituted fluoride 13, which was subsequently transformed into the acetate 14. Hydrolysis of 14 gave the key intermediate 2-fluoro-2-(hexadecyloxymethyl)propanol (15), which was attached to the phosphocholine residue in the final step. Enzyme-catalyzed deracemization of the fluorohydrin 15 by acetylation with several lipases gave optically active compounds 14 and 15, with a maximum ee of 61% for 15 with Candida antarctica lipase catalysis after 74% conversion. An enantioselective synthesis of 10, based on a planned eight-step synthesis starting from α-methylstyrene, failed. The anticancer activity of racemic 10 has been observed in an in vivo model of methylcholanthrene-induced mouse fibrosarcoma.