Perfluoroalkylation nucleophilic

For medium-scale synthesis of fine chemicals and pharmaceuticals, especially, a variety of methods for nucleophilic perfluoroalkylation have assumed an important role. For nucleophilic perfluoroalkylation, either perfluoroalkyl carbanions, carba-nionoid , or perfluoroalkyl metal species must be generated, stabilized, and reacted with suitable electrophiles [33]. 

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Nucleophilic Perfluoroalkylation of Nitrones The reaction of a,N-diaryl nitrones with (trifluoromethyl)trimethylsilane (TMSCF3) gives O-trimethylsilyl ethers of a-(trifluoromethyl)-hydroxylamines. This reaction is initiated by potassium ten -butoxide. Removal of the trimethylsilyl group on acid treatment leads to a-(trifluoromethyl)hydroxylamines, whereas catalytic hydrogenation gives a-(trifluoromethyl)amines (Scheme 2.194). 

The stereoselectivity of all these nucleophilic perfluoroalkylations are generally better than those observed with non fluorinated organometallic species, especially for Grignard reagents. 

Whereas haloalkanes are widely used for the electrophilic alkylation of a broad variety of nucleophiles, perfluoroalkyl bromides or iodides do not act analogously as electrophilic perfluoroalkylation reagents (Figure 2.7). For example, the reaction of perfluoroalkyl iodides with aliphatic alcoholates does not yield the expected alkyl perfluoroalkyl ether (analogous to the Williamson ether synthesis) but mostly the hydrofluorocarbon resulting from the reduction of the iodide [1]. In contrast, perfluoroalkyl iodides and bromides have been used as preparatively useful electrophilic iodination or bromination reagents [2]. 

Scheme 2.116 Nucleophilic perfluoroalkylation of aliphatic or aromatic substrates by perfluoroalkyl anions generated by fluoride addition [43, 44] (TDAE = tetrakis(diurethylamino)ethylene).

Scheme 2.123 Nucleophilic perfluoroalkylation by reductive activation of perfluoroalkyl iodides with TDAE [57, 58].

If equimolar quantities of tetramethylammonium fluoride and a threefold excess of Me3SiCF3 or its homologues are used the perfluoroalkyltrimethyl silane acts as an effective source of nucleophilic perfluoroalkyl equivalents for nucleophilic substitution of aliphatic triflates [90] (Scheme 2.136). This method enables the simple synthesis of partially fluorinated alkane structures which are of interest in the chemistry of liquid crystals and other functional materials. 

Sodium nitrite in dimethylformamide acts as a nucleophile and reacts with perfluoropropene to generate a perfluoroalkyl nitrite anion The intermediate carbanion undergoes intramolecular nitrosation with loss of carbonyl difluoride to give tnfluoroacetic acid upon hydrolysis [5] (equation 6)... 

The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

Oxiranes with a single perfluoroalkyl chain are regioselectively opened by nucleophilic reagents at the more accessible carbon [d4] (equation 30). 

Replacement of iodine in (perfluoroalkyl)ethyl iodides predominates over the usual conversion to olefins when the reagent is very nucleophilic and weakly basic Soft nucleophiles like sodium thiocyanate and sodium thiolates react well in displacements [46, 47] (equation 42)... 

The reaction of perfluoroalkyl iodides with electron donor nucleophiles such as sodium arene and alkane sulfinates in aprotic solvents results in radical addition to alkenes initiated by an electron-transfer process The additions can be carried out at room temperature, with high yields obtained for strained olefins [4 (equations 3-5)... 

FITS reagents), has undergone considerable development recently [141,142,143, 144, 14S. These compounds, available fromperfluoroalkyhodides (equation 76), are very effective electrophilicperfluoroalkylating agents They react with carban-lons, aromatic compounds, alkenes, alkynes, silyl enol ethers, and other nucleophiles under mild conditions to introduce the perfluoroalkyl moiety mto organic substrates (equation 77) (see the section on alkylation, page 446). 

Fluorinated alkenes and alkynes are highly activated toward nucleophilic attack and reaction with bifunctional nucleophiles is a fruitful area for the synthesis of heterocycles. A review on perfluoroalkyl(aryl)acety-lenes contains many examples (91RCR501). 

Perfluoroalkyl carbanions, generated by reversible nucleophilic addition of a fluoride anion to fluoroalkenes, react with dry benzenediazonium chloride in dimethyl formamide, giving phenylazoperfluoroalkanes in 41-53% yield (Dyatkin et al., 1972). The dianion obtained from 1,2-dinitrobenzene with dipotassium cyclo-octatetraenide reacts in a complex way with arenediazonium salts, forming 4-aryl-azo-2-nitrophenol in 46-58% yield (Todres et al., 1988). 

Furthermore, Saveant et al. have shown elegant examples of electrochemi-cally induced nucleophilic substitution of perfluoroalkyl halides. The reaction mechanism is a slightly modified version of the classical SRNI mechanism in... 

Our early work examined the reaction of PCTFE with sulfur, selenium and phosphorous nucleophiles 9 to achieve high levels of functionalization through a well-precedented (in the case of perfluoroalkyl iodides)20"24 one electron transfer, radical anion chain process. While such a reaction demonstrated the feasibility of using one-electron processes for the functionalization of PCTFE, the carbon-sulfur linkage remained susceptable to oxidation. 

Fluorination has a particularly profound effect on the additions of nucleophiles to per-fluorinated alkenes where the intermediate is anionic. Such processes are dramatically assisted by the strongly stabilizing influence of perfluoroalkyl groups substituted at the incipient anionic site.66 Similar to carbocations (see Section 1.4.), the effect of fluorination in such systems is often ambiguous when monofluorination is involved. a-Halogens generally stabilize anions in the order bromine > chlorine > fluorine, which is the exact opposite to the inductive electron-withdrawing order of the substituents. This effect reflects the importance of l7t-repulsion.67... 

Spontaneous perfluoroalkylation ofenamines occurs in the presence of fluor-mated perhalogenoalkanes [143, 144] This condensation is interpreted by a SET process (mechanism analogous to equation 57 with a neutral nucleophile in place of a charged nucleophilic reagent). Formation of chlorodifluoromethylcyclo... 

Peptidyl fluoromethyl ketones are widely used as fairly potent inhibitors for a variety of proteases, including serine, cysteine, and aspartyl proteases. Unlike other halomethyl ketones (Section 15.1.3), fluoromethyl ketones are reversible transition-state mimics. The electron-withdrawing fluorine(s) next to the carbonyl group enhances the electrophilicity of the a-fluoroalkyl ketone functionality, thereby making the carbonyl more susceptible to nucleophilic attack. a-Fluoroalkyl ketones are good mimics of peptide bonds due to the small size of the fluorine and the stability of C F bonds. There are three general classes of peptidyl fluoromethyl ketones fluoromethyl ketones (irreversible inhibitors of cysteine proteases), difluoromethyl ketones (reversible inhibitors of both serine and aspartyl proteases), and trifluoromethyl/perfluoroalkyl ketones, which typically exist in hydrated forms and are excellent inhibitors of both serine and cysteine proteasesJ1 ... 

The rates of bromine atom abstraction by tris(trimethylsilyl)silyl radicals from a range of /Jara-substitutcd benzyl bromides has indicated that the silyl radical is nucleophilic. In addition both the polar and spin-delocalization effects of the substituents play a role in the abstraction reaction with the latter effect greater than for H-atom abstractions.166 The perfluoroalkylation of aromatics and alkenes has been investigated using C4F9I as the source of C,. Measurement of rate constants indicated that perfluoroalkyl radicals were 2-3 orders of magnitude more reactive than the corresponding alkyl radicals. This was attributed primarily to the reaction enthalpy and far less to the electrophilic nature of the radicals.167... 

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