Fluorine substitution, effect selectivities

In Section 1.3, the general effects of fluorine substitution on drug activity and selectivity have been treated. As seen frequently with other enzymatic reactions, introduction of fluorine can have dramatic effects on the properties of substrates and inhibitors of MAOs [26]. For example, preliminary studies indicated that fluorination of 5-hydroxytryptamine in the 6- or the 4,6-positions (3,4) causes this predominantly MAO A substrate to be metabolized significantly by platelet MAO B [27]. Although no direct evidence was obtained, this may be caused by increased lipophilicity introduced by fluorine substitution. 

As previously discussed, L-deprenyl (2) is a selective suicide inhibitor of MAO B. As part of a program to develop [ F]-labeled L-deprenyl for PET studies, Fowler and coworkers prepared [ C]-labeled o- and L-4-fluorodeprenyl (37) to study the effects of fluorine substitution on kinetics of uptake and localization [105]. Subsequently, no-carrier-added o,L-4-[ F]-fluoroderprenyl (38) was made by a nucleophilic aromatic substitution reaction [106],... 

As discussed above, many cyclopropylamines are good inhibitors of MAOs. In addition, as discussed in Section 3.2, fluorine substitution had substantial effects on the inhibition of MAOs by such analogues as allylamines. We undertook a broadly based study of the effects of fluorine substituted on the cyclopropyl ring of cyclopropyl amines on potency and selectivity of amine oxidase inhibition. In addition to effects on amine pKg and lipophilicity, we expected additional consequences resulting from altered geometry and ring strain due to the presence of fluorine. 

Fluorine substitution has greatly diminished the (negative) electrostatic potential for the internal double bond, but has had little effect on the potential for the external double bond. The change in selectivity (toward favoring addition onto the external double bond) is a direct consequence given that carbene addition is electrophilic addition. 

Efforts to find optimally reactive, less toxic, less toxic, nonexplosive, more stable and cost-effective chemical reagents capable of the transfer of a fluorine atom site-selectively into a comprehensive range of organic molecules promises to be rewarded with the promotion of 1-fluoro-substituted l,4-diazoniabicyclo[2.2.2]octane salts as versatile fluorinating reagents. 

Conformational Effects of Fluorine Substitution. Mechanisms considered to explain adrenergic selectivities of fluorinated norepinephrine (and related adrenergic agonists) have included 1) an indirect effect of the C-F bond on the conformation of the ethanolamine side-chain or 2) a direct effect of the C-F bond on agonist-receptor interaction. In the first formulation, proposals were made that fluorine situated in a position ortho (position 2 or 6) to the ethanolamine side chain creates a bias for side chain conformations favorable for binding to p- and a-adrener-gic receptors, respectively. 

Fuchikami and Shimizu reported the carbonylative coupling of alkyl halides with PhSnBu3 in 2001 [64], As shown in Scheme 4.31, ketones were synthesized in moderate to good yields. Furthermore, the effect of fluorine substitutents on the selectivity was checked. 

The double-isotopic fractionation method was employed in this study. This procedure consists of the use of deuterium substitution to selectively slow down the rate of one step in a reaction and observing the changes in a second kinetic isotope effect. In this study flie aim is to obtain information from the secondary D KIE at C4 and the fluorine isotope effects, respectively. For that reason, substrates on which the deuterium has been placed at C3 to slow down the step in which the C3-H bond is being broken, have been employed. Then, the extra labels were deuterium at C4 (compound 4) and labeled fluorine (compound 6) (atoms colored red in Fig. 37.1). Compounds 3 and 4 were used to determine the effect of the deuterium at C3 on the secondary D KIE values at C4 (k lk ) (Fig. 37.1). Similarly, compounds 5 and 6 were used to study the influence of the deuterium label at C3 on the leaving group F KIEs... 

A very impressive example of the synthetic utility of this chemistry is the one-pot enantioselective double G-H activation reaction of 86 to generate chiral spiran 87 (Equation (73)).172 In this case, the phthalimide catalyst Rh2(enantiotopically selective aromatic C-H insertions of diazo ketoesters (Equation (74)).216 Moreover, dirhodium(n) tetrakisIA-tetrafluorophthaloyl- )-/ /-leucinate], Rh2(hydrogen atoms of the parent dirhodium(n) complex are substituted by fluorine atoms, dramatically enhances the reactivity and enantioselectivity (up to 97% ee). Catalysis... 

In contrast to the cathodic reduction of organic tellurium compounds, few studies on their anodic oxidation have been performed. No paper has reported on the electrolytic reactions of fluorinated tellurides up to date, which is probably due to the difficulty of the preparation of the partially fluorinated tellurides as starting material. Quite recently, Fuchigami et al. have investigated the anodic behavior of 2,2,2-trifluoroethyl and difluoroethyl phenyl tellurides (8 and 9) [54]. The telluride 8 does not undergo an anodic a-substitution, which is totally different to the eases of the corresponding sulfide and selenide. Even in the presence of fluoride ions, the anodic methoxylation does not take place at all. Instead, a selective difluorination occurs at the tellurium atom effectively to provide the hypervalent tellurium derivative in good yield as shown in Scheme 6.12. 

The APHA with a fluorine atom at the 3-position of the aryl exhibits a class-II/class-I HDAC selectivity of 176, whereas substitution at the 2-or 4-position gives respectively much lower selectivity ranging from 34 to a value less than 2. It is interesting to note that this meta-effect is much less pronounced when the substituent is a chloro atom and the effect is completely lost when a bromo-atom is introduced (data not shown). 

Carbon-fluorine coupling constants of fluorobenzene and selected substituted derivatives are collected in Table 4.60 [402], Benzenoid JCF couplings are about 245+15 Hz. They depend on both type and position of the substituents Electron withdrawing groups increase while electron releasing ones decrease one-bond carbon-fluorine coupling in fluorobenzene, particularly when they are ortho and para to fluorine. These observations can be explained by cannonical resonance formulae which take ( + )- and (-)-M effects into account. The data of fluoroanilines (( + )-M) and fluorobenzaldehydes (( — )-M) provide typical examples (Table 4.60). 

The alkylation reaction is limited to nitro-substituted arenes and heteroarenes and is highly chemoselec-tive nucleophilic displacement of activated halogens, including fluorine, was not observed. The regio-selectivity is determined by the bulkiness of the silicon reagent. With unhindered silyl derivatives a strong preference for ortho addition was observed, as in the example of equation (6). With bulkier reagents attack took place exclusively at the para position (Scheme 1). The success of this reaction, which could not be reproduced with alkali enolates, was attributed at least in part to the essentially nonbasic reaction conditions under which side processes due to base-induced reactions of nitroarenes can be effectively eliminated.12... 

A similar change in orientation of attack arises with the fluorobromomethyl radicals where the bulkier the radical, the lower the relative rate of attack at the most substituted end of an unsymmetric olefin (Table 13). This increase in selectivity is believed to be primarily due to steric effects. Lone pair repulsion is unlikely to be important in the tribromomethyl radical, and bromine is less electronegative than fluorine. 

Kinetic studies of the substitution reaction of 2-chloro-l-methylpyridinium iodide with phenoxides are consistent with the SnAt mechanism, with rate-determining nucleophilic attack.38 The effects of a variety of ring substituents on the reactivities of 2-fluoro- and 2-chloro-pyridines in reactions with sodium ethoxide in ethanol have been examined. The results were discussed in terms of the combination of steric, inductive, and repulsive interactions.39 Substitution in 2,4,6-trihalopyridines normally occurs preferentially at the 4-position. However, the presence of a trialkylsilyl group at the 3-position has been shown to suppress reaction at adjacent positions, allowing substitution at the 6-position.40 Methods have been reported for the introduction and removal of fluorine atoms for polyfluoropyridines. Additional fluorine atoms were introduced by metallation, chlorination, and then fluorodechlorination, while selective removal of fluorine was achieved by reduction with either metals or complex hydrides or alternatively by substitution by hydrazine followed by dehydrogena-tion-dediazotization.41... 

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