C-F bond formation

D. O Hagan, M. Onega, Fluorinase mediated C- F bond formation, an enzymatic tool for PET labelling, Chem. Commun. (2006) 652-654. 

Senn HM, O Hagan D, Thief W (2005) Insight into Enzymatic C-F Bond Formation from QM and QM/MM Calculations. J Am Chem Soc 127 13643... 

The AsF3 and F2 molecules were desorbed as gases into the vacuum chamber and As was left in the matrix of (CH)X film. For electrochemical doping, it has been found that doping levels above 8 mole % led to an irreversible conductivity loss, with IR evidence of C-F bond formation. Between 1 to 7 mole % dopant, the conductivity was stable for several weeks in dry air since the polymer no longer reacts with oxygen [118]. 

Termination also occurs if ligand exchange produces a weaker Lewis acid which is unable to reactivate the covalent adduct. In this case, addition of another aliquot of the stronger acid may reactivate the system. For example, hydroxy or alkoxy groups are exchanged in polymerization systems based on boron trifluoride and adventitious water or alcohol, respectively. Termination occurs infrequently by irreversible cleavage of B—F bond from the BF3OH anion, with irreversible C—F bond formation [Eq. (127)]. 

Selective introduction of a fluorine atom into organic compounds is important due to the unique biological and physical properties of fluorinated compounds. One useful method for C-F bond formation is desulfurative fluorina-tion realized by a cleavage of C-S bonds of dithioacetals. Thus, 1,3-ditholane derivatives undergo a facile reaction... 

Scheme 10 C-F bond formation from Pd(II) complexes (a) Proposed reductive elimination step in the synthesis of p-fluoronitrobenzene, (b) No fluoroaromatic compound was observed for aryl groups lacking the strong electron-withdrawing nitro substituent...

In a similar approach, MacMillan reported an operationally simple procedure for the enantiocontrolled C-F bond formation. The enantiose-lective a-fluorination of aldehydes was based on the use of imidazolidinone I as the active catalyst. MacMillan proposed the use of M-fluorobenzene-sulfonimide 3 (NFSI) as a fluorinating agent (Seheme 18.5 B). A similar mechanism has been proposed for both ehlorination and fluorination with the MaeMillan eatalyst, in which the imidazolindinone enamine reacts with the halogen source, although this mechanism has not been proven... 

Abstract Direct sp C-H bond functionalization is an efficient, straightforward, and powerful method to construct new C-X (X=C, N, F, S) bonds from nonfunctionalized aliphatic motif of organic molecules, which has been used in late-stage modification of complex molecules. In this chapter, the recent developments of silver-mediated direct sp C-H functionalizations are reviewed, categorized by C-C bond formation (C-H insertion), C-N bond formation (intramolecular and intermolecular amination/amidation), C-F bond formation, and C-S bond formation. 

Although much attention has been paid to silver catalysis in the past several years and significant progress has been achieved in this field of silver-mediated sp C-H bond transformations, compared to the catalysis with other transition metals, the reports in this field are still very limited. In this chapter, we have reviewed a variety of important silver-catalyzed sp C-H transformations, including C-C bond formation, C-N bond formation, C-F bond formation, and C-S bond formation. A... 

In contrast, C-F bond-formation was observed when 53 was treated with an excess of electrophilic fluorinating reagents (e.g., Xep2) at 80°C in nitrobenzene (Eq. 43b). Under these conditions, <5% of the biaryl product 55 was produced. The mechanism of this transformation (particularly the role of the reagents in promoting C-F coupling) has not been fully elucidated. 

In the same year (2013), Doyle and co-workers reported an intramolecular version of the cyclization of the allenes.They combined allene chemistry with fluorination, and their report represents the first example of tandem C-C and C-F bond formation for the palladium-catalyzed carbofluorination of allenes. The intramolecular Heck-fluorination cascade provides mono-fluoromethylated heteroarenes, an important class of products in medicinal chemistry, in good yields (Scheme 2.88). The intermolecular variants for the three-component coupling of allenes, aryl iodides, and AgF were reported as well. Mechanistic studies indicate that C-F bond formation occurs by an outer sphere attack of fluoride on an allylpalladium fluoride intermediate. 

Scheme 3.10 Sequential C-B and C-F bond formation. (Adapted with permission from ref. 74 2013 Wiley-VCH Verlag GmbH.)...

The only a-alkyl substrate (R = n-Pr, X = S) reacted with poor yield (15%) and enantioselectivity (11% ee). The unique combination of the catalytic components was specifically chosen to offer a dual activation of the substrate and reagent the formation of the activated nickel-enolate complex was assisted by the presence of the noncoordinating Bronsted base, while the Lewis acidic EtsSiOTf activated NFSI to become a stronger nucleophile, without interfering with the formation of the enolate. C-F bond formation resulted from the reaction between the activated substrate and the activated electrophile, prior to product release. 

Type of reaction C-F bond formation Reaction conditions Acetonitrile, room temperature Synthetic strategy Direct fluorination of C(sp )-H group Catalyst Vanadium(III) oxide (V2O3)... 

Fluorination of organic compounds using fluoride ion can be catalyzed by enzymes (Fig. 10.38). For example, fluorinase from Streptomyces cattleya catalyzes C—F bond formation in the reaction of S-adenosyl-L-methionine with fluoride to yield 5 -fluoro-5 -deoxyadenosine. " Although their substrate scope is hmited at present, these kinds of enzymes may come to play an important role for fluorination in the future due to the ease, mildness and safety of the reaction conditions and the use of fluoride as fluorine source. 

Scheme 7.8 Palladium-catalyzed C—F bond formation under the flow conditions.

Replacement of other groups with the fluoride ion can be illustrated by the palladium-catalyzed C-F bond formation affording a number of 4-fluoro-quino-lines 70 from the corresponding 4-susbstituted quinolines bearing OTf group (Scheme 27) [45]. 

Noel T, Maimone T, Buchwald S (2011) Accelerating palladium-catalyzed C-F bond formation use of a microflow packed-bed reactor. Angew Chem Int Ed 50 8900-8903... 

Recently, a palladiumotalyzed C—F bond formation in a CsF microflow packed-bed reactor for the conversion of aryl triflates 20 to aryl fluorides 21 was presented by Noel et al. (Figure 6.10 and Table 6.3) [8]. A 5 ml reagent loop was filled with a solution of aryl triflate substrate, Pd catalyst, and ligand 19 in... 

The palladium-catalyzed C—F bond formation could be accelerated in a CsF packed-bed microreactor, which enables the handling of large amounts of the fluorine source [22], Increasing the temperature resulted in an accelerated fluorination process, with 130 °C being identified as the optimal reaction temperature (Figure 11.4). Further increase of the temperature resulted in lower yields probably due to catalyst decomposition or ligand dissociation. It was also found that elevated temperatures could reduce the catalyst loading. 

---