Organo-fluorine chemistry II
The introduction of fluorine remains an important specialism in organic chemistry for modulating the physical properties of molecules involved in programmes ranging from bioorganic chemistry to performance materials. Consequently fluorinated organics are of major commercial significance to the pharmaceuticals, agrochemicals, materials and polymer industries with the fluorine fine chemicals industry servicing these industrial sectors. New innovations and insights into the synthesis and the nature and behaviour of organo-fluorine compounds continue to intrigue and this Thematic Series offers a glimpse into the level of activity in the area. The first “Organo-fluorine chemistry” series in 2008 presented ten contributions representing a wide range of this chemistry and this series continues that trend exploring the synthesis and properties of a new range of organo-fluorine compounds. This subject is now firmly embedded as a special interest area of the Beilstein Journal of Organic Chemistry. Contributions have been received from research groups in Australia, China, Germany, Japan, North America, Ukraine and the United Kingdom, representing a particularly international research community.
See also the Thematic Series:
Organo-fluorine chemistry III
Organo-fluorine chemistry
See organo-fluorine videos at Beilstein TV.
- Full Research Paper
- Published 20 Apr 2010
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Figure 1: Boronolide (1), boronolide analogues 2–3 and gem-difluoromethylenated analogues 4–7.
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Scheme 1: Retrosynthetic analysis of target molecules 4–7.
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Scheme 2: Synthesis of target molecules 4–5.
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Scheme 3: Synthesis of target molecules 6–7.
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- Review
- Published 20 Apr 2010
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Figure 1: Conformational effects associated with C–F bonds.
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Figure 2: HIV protease inhibitor Indinavir (17) and fluorinated analogues 18 and 19. In analogue 18 the gauche...
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Figure 3: Cholesteryl ester transfer protein inhibitors 20 and 21. In the fluorinated analogue 21, nO→σ*CF hy...
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Figure 4: HIV reverse transcriptase inhibitor 22 and acid-stable fluorinated analogues 23–25. The F–C–C–O gau...
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Figure 5: Dihydroquinidine (26) and fluorinated analogues 27 and 28. Newman projections along the C9–C8 bonds...
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Figure 6: The neurotransmitter GABA (29) and fluorinated analogues (R)-30 and (S)-30. Newman projections of (R...
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Figure 7: The insect pheromone 31 and fluorinated analogues (S)-32 and (R)-32. The proposed bioactive conform...
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Figure 8: Capsaicin (33) and fluorinated analogues (R)-34 and (S)-34.
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Figure 9: Asymmetric epoxidation reaction catalysed by pyrrolidine 35. Inset: the geometry of the activated i...
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Figure 10: The asymmetric transannular aldol reaction catalysed by trans-4-fluoroproline (41), and its applica...
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Figure 11: The asymmetric Stetter reaction catalysed by chiral NHC catalysts 49–52. The ring conformations of ...
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Figure 12: A multi-vicinal fluoroalkane.
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Figure 13: X-ray crystal structures of diastereoisomeric multi-vicinal fluoroalkanes 55 and 56. The different ...
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Figure 14: Examples of fluorinated liquid crystal molecules. Arrows indicate the orientation of the molecular ...
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Figure 15: Di-, tri- and tetra-fluoro liquid crystal molecules 60–62.
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Figure 16: Collagen mimics of general formula (Pro-Yaa-Gly)10 where Yaa is either 4(R)-hydroxyproline (63) or ...
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Figure 17: Enkephalin-related peptide 64 and the fluorinated analogue 65. The electron-withdrawing trifluorome...
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Figure 18: The C–F bond influences the conformation of β-peptides. β-Heptapeptide 66 adopts a helical conforma...
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Figure 19: The conformations of pseudopeptides 69 and 70 are influenced by the α-fluoroamide effect and the fl...
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- Preliminary Communication
- Published 20 Apr 2010
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Scheme 1: Fluorinated molecular tweezers.
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Scheme 2: Synthesis of non-fluorinated and fluorinated syn-bis-quinoxalines.
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Figure 1: (a) Thermal ellipsoid image of the tweezer molecular 16c in the structure 16c · CH3CO2C2H5; thermal...
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Figure 2: Electrostatic potential surfaces of 16a–c (Spartan 06 [41]: B3LYP/6-31G*//B3LYP/6-31G*; legend in kcal/...
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Figure 3: 1H NMR spectra (CD2Cl2, 500 MHz) of 16c (host [black]) upon titration with N,N,N′,N′-tetramethyl-p-...
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- Preliminary Communication
- Published 20 Apr 2010
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Figure 1: General strategy of using a chemically aminoacylated suppressor tRNA and an in vitro translation sy...
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Figure 2: Structures of non-canonical amino acids. a. (S)-ethylglycine, b. (S)-2-amino-4,4-difluorobutanoic a...
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Scheme 1: General scheme for the synthesis of an N-(4-pentenoyl) amino acid cyanomethyl ester.
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Scheme 2: General scheme of synthesis of mono-2′(3′)-O-[N-(4-pentenoyl)aminoacyl]-pdCpAs and 2′-3′-bis-O-[N-(...
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Figure 3: Denaturing PAGE of ligation products of truncated suppressor tRNA and fluorinated aminoacyl-pdCpAs ...
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- Published 26 Apr 2010
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Scheme 1: The C–F bond forming Prins reaction leading to 4-fluoropyrans [10].
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Figure 1: X-ray crystal structure of syn-5a.
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Scheme 2: Ring opening hydrogenation of an oxa-Prins product.
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Figure 2: X-ray crystal structure of the major bicyclic tetrahydropyran diastereoisomer 9b.
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Scheme 3: Reaction using (E)-11a and (Z)-11b hex-3-en-1-ols with 4-nitrobenzaldehyde to generate 4-fluorotetr...
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Figure 3: X-ray crystal structure of the minor anti-piperidine product 14d.
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- Published 06 May 2010
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Scheme 1: Synthesis of novel tricyclic heterocycles from pentafluoropyridine.
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Scheme 2: Synthetic route to dioxa-diaza-anthracene derivatives.
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Scheme 3: Reactions of tetrafluoropyridazine 3 with sodium phenoxide.
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Scheme 4: Synthesis of dioxa-1,2-diaza-anthracene scaffold 5.
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Scheme 5: Mechanism of formation of 5.
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Scheme 6: Reactions of dioxa-1,2-diaza-anthracene scaffold 5 with nucleophiles.
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Figure 1: Molecular structure of 4-allylamino-3-fluoro-9,10-dioxa-1,2-diaza-anthracene (9b).
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- Published 10 May 2010
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Scheme 1: Electrophilic [4 + 4] dimerization of oxetanes 1a–c under action of BF3·OEt2 catalyst.
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Figure 1: ORTEP drawing of compounds 2a and 2b with thermal ellipsoids drawn to the 50% probability level.
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Scheme 2: Reaction of 1d with BF3·OEt2.
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Scheme 3: Reaction of 2,2-bis(trifluoromethyl)-4-alkoxyoxetanes 1b, c with methanol.
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Scheme 4: Reaction of oxetane 1c with alcohols.
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Scheme 5: Putative mechanism for the reaction oxetanes 2a–d with BF3·OEt2 and alcohols.
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Scheme 6: Reaction of thietanes 4a, b with H2SO4 to generate 5.
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Figure 2: ORTEP drawing of 5 with thermal ellipsoids drawn to the 50% probability level.
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Scheme 7: Reaction of 4c with H2SO4.
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Scheme 8: Putative mechanism for the formation bicyclic ether 5.
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- Published 14 May 2010
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Scheme 1: Diels–Alder reaction of diene 2 with 4 and 6. aThe other isomers of 7a and 7b were isolated in 8% a...
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Scheme 2: Synthetic concept toward multi-substituted gem-difluoroisoquinolinones.
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Figure 1: Comparison of coupling constant of vinyl protons.
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Scheme 3: Diels–Alder reaction with 9 and 6. aCombined yield of two isomers.
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- Published 08 Jun 2010
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Figure 1: Vicinal difluoride containing building blocks.
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Scheme 1: Synthesis of meso-2,3-difluoro-1,4-butanediol.
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Scheme 2: Monoprotection of 3, and activation of the remaining alcohol.
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Scheme 3: Reaction of 12 leading to defluorinated products.
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Figure 2: Molecular overlay of both conformers of 7.
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Figure 3: Crystal packing of 7 viewed along the b axis. Short contacts (see text) are shown in light blue.
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Figure 4: Crystal structure of 3.
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Figure 5: Crystal packing of 3 viewed along the c axis. H-bonds are shown in light blue.
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- Review
- Published 16 Jun 2010
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Scheme 1: Preparation of the first electrophilic trifluoromethylating reagent and its reaction with a thiophe...
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Scheme 2: Synthetic routes to S-CF3 and Se-CF3 dibenzochalcogenium salts.
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Scheme 3: Synthesis of (trifluoromethyl)dibenzotellurophenium salts.
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Scheme 4: Nitration of (trifluoromethyl)dibenzochalcogenium salts.
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Scheme 5: Synthesis of a sulphonium salt with a bridged oxygen.
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Scheme 6: Reactivity of (trifluoromethyl)dibenzochalcogenium salts.
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Scheme 7: Pd(II)-Catalyzed ortho-trifluoromethylation of heterocycle-substituted arenes by Umemoto’s reagents....
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Scheme 8: Mild electrophilic trifluoromethylation of β-ketoesters and silyl enol ethers.
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Scheme 9: Enantioselective electrophilic trifluoromethylation of β-ketoesters.
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Scheme 10: Preparation of water-soluble S-(trifluoromethyl)dibenzothiophenium salts.
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Scheme 11: Method for large-scale preparation of S-(trifluoromethyl)dibenzothiophenium salts.
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Scheme 12: Triflic acid catalyzed synthesis of 5-(trifluoromethyl)thiophenium salts.
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Scheme 13: Trifluoromethylation of β-ketoesters and dicyanoalkylidenes by S-(trifluoromethyl)benzothiophenium ...
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Scheme 14: Synthesis of chiral S-(trifluoromethyl)benzothiophenium salt 18 and attempt of enantioselective tri...
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Scheme 15: Synthesis of O-(trifluoromethyl)dibenzofuranium salts.
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Scheme 16: Photochemical O- and N-trifluoromethylation by 20b.
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Scheme 17: Thermal O-trifluoromethylation of phenol by diazonium salt 19a. Effect of the counteranion.
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Scheme 18: Thermal O- and N-trifluoromethylations.
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Scheme 19: Method of preparation of S-(trifluoromethyl)diphenylsulfonium triflates.
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Scheme 20: Reactivity of some S-(trifluoromethyl)diarylsulfonium triflates.
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Scheme 21: One-pot synthesis of S-(trifluoromethyl)diarylsulfonium triflates.
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Scheme 22: One-pot synthesis of Umemoto’s type reagents.
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Scheme 23: Preparation of sulfonium salts by transformation of CF3− into CF3+.
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Scheme 24: Selected reactions with the new Yagupolskii reagents.
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Scheme 25: Synthesis of heteroaryl-substituted sulfonium salts.
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Scheme 26: First neutral S-CF3 reagents.
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Scheme 27: Synthesis of Togni reagents. aYield for the two-step procedure.
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Scheme 28: Trifluoromethylation of C-nucleophiles with 37.
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Scheme 29: Selected examples of trifluoromethylation of S-nucleophiles with 37.
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Scheme 30: Selected examples of trifluoromethylation of P-nucleophiles with 35 and 37.
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Scheme 31: Trifluoromethylation of 2,4,6-trimethylphenol with 35.
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Scheme 32: Examples of O-trifluoromethylation of alcohols with 35 in the presence of 1 equiv of Zn(NTf2)2.
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Scheme 33: Formation of trifluoromethyl sulfonates from sulfonic acids and 35.
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Scheme 34: Organocatalytic α-trifluoromethylation of aldehydes with 37.
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Scheme 35: Synthesis of reagent 42 and mechanism of trifluoromethylation.
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Scheme 36: Trifluoromethylation of β-ketoesters and dicyanoalkylidenes with 42.
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- Review
- Published 18 Aug 2010
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Figure 1: Examples of industrial fluorine-containing bio-active molecules.
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Figure 2: CF3(S)- and CF3(O)-containing pharmacologically active compounds.
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Figure 3: Hypotensive candidates with SRF and SO2RF groups – analogues of Losartan and Nifedipin.
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Figure 4: The variety of the pharmacological activity of RFS-substituted compounds.
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Figure 5: Recent examples of compounds containing RFS(O)n-groups [12-18].
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Scheme 1: Fluorination of ArSCCl3 to corresponding ArSCF3 derivatives. For references see: a[38-43]; b[41,42]; c[43]; d[44]; e[38-43,45-47]; f[38-43,48,49]; g...
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Scheme 2: Preparation of aryl pentafluoroethyl sulfides.
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Scheme 3: Mild fluorination of the aryl SCF2Br derivatives.
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Scheme 4: HF fluorinations of aryl α,α,β-trichloroisobutyl sulfide at various conditions.
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Scheme 5: Monofluorination of α,α-dichloromethylene group.
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Scheme 6: Electrophilic substitution of phenols with CF3SCl [69].
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Scheme 7: Introduction of SCF3 groups into activated phenols [71-74].
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Scheme 8: Preparation of tetrakis(SCF3)-4-methoxyphenol [72].
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Scheme 9: The interactions of resorcinol and phloroglucinol derivatives with RFSCl.
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Scheme 10: Reactions of anilines with CF3SCl.
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Scheme 11: Trifluoromethylsulfanylation of anilines with electron-donating groups in the meta position [74].
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Scheme 12: Reaction of benzene with CF3SCl/CF3SO3H [77].
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Scheme 13: Reactions of trifluoromethyl sulfenyl chloride with aryl magnesium and -mercury substrates.
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Scheme 14: Reactions of pyrroles with CF3SCl.
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Scheme 15: Trifluoromethylsulfanylation of indole and indolizines.
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Scheme 16: Reactions of N-methylpyrrole with CF3SCl [80,82].
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Scheme 17: Reactions of furan, thiophene and selenophene with CF3SCl.
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Scheme 18: Trifluoromethylsulfanylation of imidazole and thiazole derivatives [83].
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Scheme 19: Trifluoromethylsulfanylation of pyridine requires initial hydride reduction.
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Scheme 20: Introduction of additional RFS-groups into heterocyclic compounds in the presence of CF3SO3H.
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Scheme 21: Introduction of additional RFS-groups into pyrroles [82,87].
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Scheme 22: By-products in reactions of pyrroles with CF3SCl [82].
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Scheme 23: Reaction of aromatic iodides with CuSCF3 [93,95].
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Scheme 24: Reaction of aromatic iodides with RFZCu (Z = S, Se), RF = CF3, C6F5 [93,95,96].
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Scheme 25: Side reactions during trifluoromethylsulfanylation of aromatic iodides with CF3SCu [98].
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Scheme 26: Reactions with in situ generated CuSCF3.
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Scheme 27: Perfluoroalkylthiolation of aryl iodides with bulky RFSCu [105].
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Scheme 28: In situ formation and reaction of RFZCu with aryl iodides.
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Figure 6: Examples of compounds obtained using in situ generated RFZCu methodology [94].
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Scheme 29: Introduction of SCF3 group into aromatics via difluorocarbene.
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Scheme 30: Tetrakis(dimethylamino)ethylene dication trifluoromethyl thiolate as a stable reagent for substitut...
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Scheme 31: The use of CF2=S/CsF or (CF3S)2C=S/CsF for the introduction of CF3S groups into fluorinated heteroc...
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Scheme 32: One-pot synthesis of ArSCF3 from ArX, CCl2=S and KF.
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Scheme 33: Reaction of aromatics with CF3S− Kat+ [115].
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Scheme 34: Reactions of activated aromatic chlorides with AgSCF3/KI.
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Scheme 35: Comparative CuSCF3/KI and Hg(SCF3)2/KI reactions.
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Scheme 36: Me3SnTeCF3 – a reagent for the introduction of the TeCF3 group.
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Scheme 37: Sandmeyer reactions with CuSCF3.
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Scheme 38: Reactions of perfluoroalkyl iodides with alkali and organolithium reagents.
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Scheme 39: Perfluoroalkylation with preliminary breaking of the disulfide bond.
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Scheme 40: Preparation of RFS-substituted anilines from dinitrodiphenyl disulfides.
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Scheme 41: Photochemical trifluoromethylation of 2,4,6-trimercaptochlorobenzene [163].
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Scheme 42: Putative process for the formation of B, C and D.
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Scheme 43: Trifluoromethylation of 2-mercapto-4-hydroxy-6-trifluoromethylyrimidine [145].
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Scheme 44: Deactivation of 2-mercapto-4-hydroxypyrimidines S-centered radicals.
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Scheme 45: Perfluoroalkylation of thiolates with CF3Br under UV irradiation.
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Scheme 46: Catalytic effect of methylviologen for RF• generation.
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Scheme 47: SO2−• catalyzed trifluoromethylation.
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Scheme 48: Electrochemical reduction of CF3Br in the presence of SO2 [199,200].
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Scheme 49: Participation of SO2 in the oxidation of ArSCF3−•.
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Scheme 50: Electron transfer cascade involving SO2 and MV.
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Scheme 51: Four stages of the SRN1 mechanism for thiol perfluoroalkylation.
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Scheme 52: A double role of MV in the catalysis of RFI reactions with aryl thiols.
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Scheme 53: Photochemical reaction of pentafluoroiodobenzene with trifluoromethyl disulfide.
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Scheme 54: N- Trifluoromethyl-N-nitrosobenzene sulfonamide – a source of CF3• radicals [212,213].
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Scheme 55: Radical trifluoromethylation of organic disulfides with ArSO2N=NCF3.
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Scheme 56: Barton’s S-perfluoroalkylation reactions [216].
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Scheme 57: Decarboxylation of thiohydroxamic esters in the presence of C6F13I.
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Scheme 58: Reactions of thioesters of trifluoroacetic and trifluoromethanesulfonic acids in the presence of ar...
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Scheme 59: Perfluoroalkylation of polychloropyridine thiols with xenon perfluorocarboxylates or XeF2 [222,223].
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Scheme 60: Interaction of Xe(OCORF)2 with nitroaryl disulfide [227].
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Scheme 61: Bi(CF3)3/Cu(OCOCH3)2 trifluoromethylation of thiophenolate [230].
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Scheme 62: Reaction of fluorinated carbanions with aryl sulfenyl chlorides.
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Scheme 63: Reaction of methyl perfluoromethacrylate with PhSCl in the presence of fluoride.
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Scheme 64: Reactions of ArSCN with potassium and magnesium perfluorocarbanions [237].
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Scheme 65: Reactions of RFI with TDAE and organic disulfides [239,240].
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Scheme 66: Decarboxylation of perfluorocarboxylates in the presence of disulfides [245].
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Scheme 67: Organization of a stable form of “CF3−” anion in the DMF.
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Scheme 68: Silylated amines in the presence of fluoride can deprotonate fluoroform for reaction with disulfide...
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Figure 7: Other examples of aminomethanols [264].
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Scheme 69: Trifluoromethylation of diphenyl disulfide with PhSO2CF3/t-BuOK.
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Scheme 70: Amides of trifluoromethane sulfinic acid are sources of CF3− anion.
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Scheme 71: Trifluoromethylation of various thiols using “hyper-valent” iodine (III) reagent [279].
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Scheme 72: Trifluoromethylation of p-nitrothiophenolate with diaryl CF3 sulfonium salts [280].
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Scheme 73: Trifluoromethyl transfer from dibenzo (CF3)S-, (CF3)Se- and (CF3)Te-phenium salts to thiolates [283].
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Scheme 74: Multi-stage paths for synthesis of dibenzo-CF3-thiophenium salts [61].
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