Fluorine beneficial effects

In a series of comparative studies Dolle et al. examined the nucleophilic aromatic substitution of a number of nitropyridine derivatives [104—106], The results, as summarized in Scheme 13.14, show that under microwave-enhanced conditions the 2-N02 and 2-+NMe3 groups led to excellent fluorine incorporation whilst the 2-iodo compound was virtually unreactive. Under thermal conditions no fluorination was observed for the 2-chloro and 2-bromo compounds. In a separate study Banks et al. [107] again observed the beneficial effects of nitro and trimethylamino substitution (Scheme 13.15). The authors also developed a novel microwave-enhanced method of producing [18F]-fluoromethane [108]. 

This beneficial effect of fluorination on hydrolytic stability has also been demonstrated with the synthetic prostaglandin SC-46275 (Fig. 70). This compound possesses an anti-secretory activity that protects the stomach mucous membrane. However, its clinical development was too problematic because of the instability of the tertiary allyl alcohol in acidic medium (epimerisation, dehydration, etc.). A fluorine atom was introduced on the C-16 methyl to disfavour the formation of the allylic carbocation. This fluorinated analogue possesses the same biological activity, but does not undergo any degradation or rearrangement, and itepimerises only slowly [165]. 

While other electron-withdrawing substituents may play the same role, fluorine (or a CF3 group) has the advantage of other beneficial effects without engendering too strong disturbances vide supra). 

Choiesteryi Ester Transfer Protein inhibitors Cholesterol ester transfer protein (CETP) is a glycoprotein that transfers choiesteryi ester from HDL (high density lipoprotein) to proatherogenic apolipoproteins (LDL—(low density lipoprotein). Its inhibition has beneficial effects at the level of HDL cholesterol. SC-71952 and torcetrapib are highly fluorinated CETP inhibitors. SC-71952 is a disymmetrical sulfide with 10 fluorine atoms. Torcetrapib contains three CF3 groups (Figure 8.61). ... 

A highly fluorinated androgen agonist, LGD-2941, is in early clinical development for the treatment of several indications related to the beneficial effects of the androgen receptor activation (e.g., hypogonadism). 

The piperidinium benzoyltrifluoroacetone derivative shows even more interesting behavior. In the alcohol mixture, it is completely dissociated. Adding dimethylformamide decreases the degree of dissociation to 47 %, while a solution of this compound in nitrile solvents (in which the benzoylactonate is found to be completely dissociated) even at room temperature, is less than 10% dissociated. The high inherent quantum efficiency of this and closely related fluorinated chelates (J5), and the specific beneficial effect of nitrile solvents has permitted laser action to occur at room temperature with, for example, piperidinium (BTFA)4Eu in acetonitrile 28). 

Finally here it is worth noting that substitution by a fluorine atom does not always produce beneficial effects. For example, Chipperfield has synthesized the symmetric salen complexes shown in the Figure 32 containing copper(II), nickel(II) and oxovanadium(IV) [63]. Fluorination reduces the clearing point, as expected, in all but the oxovanadium complex with n = 6 where it remains constant. However, the mesophases are severely destabilized either disappearing completely or becoming monotropic. 

Biphenyls Wyeth reported a series of simple hydroxyl-biphenyls [60]. It was found that biphenyls bearing a 4 -carbaldehyde and one or more substituents ortho to the carbaldehyde moiety led to ER ligands (e.g. 18) with acceptable ER 3 affinity and good ER 3 selectivity. Attachment of a carbaldehyde oxime moiety gave 19 which showed enhanced ERP affinity [61]. This result suggests a favorable interaction between oximes and His475 in E R[3. Attachment of fluorine ortho to the hydroxyl group had a beneficial effect on ER 3 selectivity. Combination of the structure-affinity/selectivity relationship provided compound 20 that showed the best compromise between affinity and selectivity. 

Bollard and Butler (1966) in their discussion of functional elements include several others in addition to the above four. They state that fluorine, iodine, and selenium fall in this class for in some plant species they are metabolized, forming definite organic compounds. Bromine, rubidium, and strontium are also placed in this class because they exert a sparing effect on the utilization of chloride, potassium and calcium. Cobalt may perform that same function. They state further that our knowledge of the beneficial effects produced by aluminum, beryllium, and barium are not as yet adequate to justify including these in the group of functional elements. Further research will probably add other elements to this group. 

Moisture resistance This may be increased on metal and glass substrates by including cross-linking agents, which may yield a more hydrolytically stable polymer or by using hydrophobic monomers such as fluorinated cyanoacrylates. Silane adhesion promoters also improve moisture durability. There is also evidence to suggest that inclusion of some of the anhydrides described above has a beneficial effect. 

Molybdenum- and tungsten-based hydrotreating catalysts supported on AI2O3 are widely used in the industry for HDS and HDN processes. Cobalt and nickel are the promoters of choice for HDS and HDN catalyst system based on MS2 (M = Mo or W), and their presence greatly increases both HDS and HDN activity. For HDN, Ni is the promoter of choice, whereas Co is preferred for HDS. Other additives, such as fluorine, chlorine, boron, and phosphorus, have been incorporated into both promoted and unpromoted MoS2-type catalysts with beneficial effect on HDN and HDS processes [116],... 

A substituted oxazolidinone (XXIV) which had the pharmacological spectrum of a major tranquilizer was reported in a clinical study to worsen psychosis and no beneficial effect was noted. The unusual, fluorinated aminoimidazoline (XXV) has been reported to have the pharmacological properties of a minor tranquilizer. ... 

A proper intake of fluorine is essential for maximum resistance to dental caries (tooth decay), a beneficial effect that is particularly evident during infancy and early childhood, and which persists through adult life. 

The modulation of photophysical properties and dye lifetime that result from ring fluorination can lead beneficial effects for dye-sensitized solar cell performance. A straightforward comparison of photoelectric activity of these cells in which meso-substituted porphyrins featuring variable fluorine and chlorine substitution was published recently [115]. However, the results from this study indicated that chlorine substitution provided an enhanced photocurrent output in comparison to the corresponding fluorinated derivatives. 

Improved enantioselectivities were reached by replacing the BINAP-Ni complexes with bis(oxazoline)-Ni complexes in particular, the catalyst combination Ni(II)/(/ ,/ )-Ph-DBFOX/HFIP/2,6-lutidine was highly efficient in the enantioselective fluorination of aryl acetylthiazolidinones, up to 99% ee (Scheme 44.20). The strong Lewis acid, EtsSiOTf, used in the previous example, was replaced by the relatively strong Brpnsted acid, HFIP (1,1,1,3,3,3-hexa-fluoroisopropyl alcohol pKa = 9.3). The beneficial effect of HFIP is probably a result of an improved turnover of catalysts thanks to a faster release of the fiuorinated product in the transition state. The utility of this catalytic system was further demonstrated in the enantioselective fluorination of nonconjugated enone substrates such as 3-butenoyl derivatives and 3-heteroaryl substrates and of (3-keto esters (up to 99% ee ) and oxindoles (Scheme 44.20). ... 

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