Selectfluor, fluorination with

Several 2-fluoroerythromycin derivatives have also been prepared by means of electrophilic fluorination with Selectfluor of the enolate of the )S-ketoester fragment (Fig. 45) [121]. Fluorination is stereoselective and leads to the a-fluo-rine compound [122]. Two derivatives of 2-fluoroerythromycin are in clinical development HMR-3562 and HMR-3787). These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 45) [123]. 

The enantiomeric excess of the (S)-proline-catalyzed a-fluorination was generally found to be rather low. For example, the enantiomeric excess of 70 was determined to be 29%. Because of the importance of enantiopure organofluorine compounds we studied the efficiency of several organocatalysts with respect of the asymmetric a-fluorination of cyclohexanone as the model substrate and Selectfluor as the fluo-rinating agent (Scheme 16). Unfortunately, neither (S )-proline nor its derivatives were able to catalyze the a-fluorination with high stereoselectivity. The highest enantiomeric excess was observed with trans-4-hydroxy-(5)-proline (36% ee). 

Electrophilic Fluorination with F-TEDA-BF4 (Selectfluor) A.3.1 Synthesis of the Fluorosteroid 11... 

The asymmetric fluorination of 3-ketoesters has been achieved in 62-90% ee using F-TEDA (Selectfluor) as fluorine source in the presence of 0.5 mol% of the chiral nonracemic titanium-based Lewis acid (5.108). ° A greater range of p-ketoesters are fluorinated with higher ee using catalytic quantities of the palladium-BINAP complex (5.109) and N-fluorobenzenesulfonamide (NFSI). ° In both cases the reaction proceeds through the intermediacy of a chiral enolate. 

A direct fluorination of nucleophilic primary (as well as secondary) amines with Selectfluor fluorinating agent (20), rather than elemental fluorine, has been reported by Singh and Shreeve [133], making small-scale preparations of (non-geminal) organic difluoramines more convenient. 

More recently, a study on the influence of the substituents in the reactivity of 1-aryl-3,5-substituted pyrazoles 22 in microwave-mediated fluorinations with Selectfluor at C-4 of the pyrazole ring was reported [13], In general, deactivated pyrazoles were unreactive or gave lower yields than more electron-rich derivatives (Scheme 8). Moreover, side products derived from fluorination of aryl or methyl substituents at N-1 and C-3 were isolated. Noteworthy, this was not the case at C-5, probably due to the steric interference between the substituent and the fluorine source. Results were compared with those obtained via C-2 fluorination of 1,3-diketones 21 followed by in situ condensation with arylhydrazines (see below). 

A simple, steieocontrolled synthesis of monofluoro ketomethylene dipepdde isosteres has been developed. N-Tritylated ketomethylene dipeptide isosteres, prepared from N-tritylated amino acids, are converted to their Z-TMS enol ethers and fluorinated with Selectfluor. There is cooperative stereocontrol between the allylic N-tritylamine group and the alkyl group at C-2. The method is short (6 steps) and diastereoselective (85->9S%) and enantioselective (>95%),... 

A series of (2R, 55)-N-tritylated ketomethylene peptide isosteres 4a-e were converted to their corresponding TMS-enol ethers 16a-e with NaHMDS/ TMSCl (Scheme 7). Only a single enol geometry could be detected in the nmr and it was assigned as the Z-isomer because of Ae base employed.(i9) These were fluorinated with Selectfluor to give monofluoro ketomethylene peptide isosteres 17a in good yields. 

The asymmetric fluorination of enolates by means of chiral metal complexes has been reported with Selectfluor in the presence of a chiral Lewis acid derived from TADDOL (TiCl2/TADDOL), or with F-A-sulfonimide (NFSI) with palladium complexes and chiral phosphines. 

Fluoronucleosides that have an exocyclic double bond can be prepared from a fluorosulfoxide. This latter compound is obtained by electrophilic fluorination of the corresponding sulfide with Selectfluor (F-TEDA-BF4) (Figure 6.12). ... 

Partially proton-exchanged Na faujasite X, in turn, is the best catalyst for selective monochlorination with tert-butyl hypochlorite.258 NaX, NaY, and NaKL zeolites used in the chlorination of toluene with sulfuryl chloride undergo rapid deactivation because of the accumulation of polychlorinated toluenes in the pores of the catalysts and dealumination.259, 260 Direct electrophilic fluorination of aromatics can be effected by using Selectfluor in the presence of triflic acid.261 Electrophilic fluorination may also be carried out by R2NF and R3N+FA reagents.262 Elemental fluorine may also act as a powerful electrophile in acidic media (sulfuric acid, trifluoroacetic acid, or formic acid), but monosubstituted aromatics give isomeric mixtures.263-265... 

Fluorination of 9-benzyloxy-2-(4-fluorobenzyl)-6-methoxy-3,4-dihy-dro-lH,8H-pyrido[l,2-a]pyrazine-l,8-dione with Selectfluor in the presence of Ce2C03 in MeCN at ambient temperature for 6 h provided 7-fluoro derivative. Reaction of 6-bromo-3,4-dihydro-lH,8H-pyrido[1,2-a]pyra-zine-l,8-diones with phenol cyclohexyl-, and cyclopropylmethanols in the presence of Ce2C03 in DMF in a sealed tube at 25-60 °C for 12-24 h afforded 6-phenoxy, 6-cyclohexyl-, and 6-cyclopropylmethoxy derivatives, respectively (06WOP2006/066414). 

The action of A-chlorosuccinimide, or a source of positive fluorine such as Selectfluor , in aqueous acetonitrile on the alkene 138 (R1 = Me) is to open the azetidine ring by attack at the allylic position to yield the cyclobuten-3-ol 139 (R OH, R2 = H, R3 = Me) <2003JOC5292>. Chlorosulfonyl isocyanate (CSI) reacts with 138 (R = Et) to give both a chlorobutene 139 (R1 = Cl R2 = CONH2 R3 = Et) and the bicyclic reduced pyrimidone 140 (R1 = Et). However, the action of CSI on the more substituted 2-azabicyclo[2.2.0]hex-5-ene 141 provided the reduced mono-cyclic pyrimidone 142 <2003JOC1626>. 

A proposed reaction mechanism for the formation of fluorinated l,3-dihydro-2/7-indol-2-ones is shown in Scheme 72 <20000L639>. Reaction of 3-substituted indole with Selectfluor 310 gave 3-fluoro-37/-indole 312 as an unstable intermediate that underwent loss of HF due to addition of water. A subsequent [l,5]-prototropic shift gave the indol-2-ol 313. Fluorination of intermediate 313 with additional reagent resulted in indol-2-one 311 as the final product. Formation of nonfiuorinated indol-2-one 314 as a minor side product was explained by the tautomerism... 

The synthesis of Fluorogypsetin 322 (Equation 73) and Fluorobrevianamide E 324 (Equation 74) by a novel fluorination cyclization of cyc/o-L-Trp-L-Aas 321 and 323 with Selectfluor have been recently described <2001AGE4461>. 

It is frequently overlooked that, following fluorination, some of these systems, e.g. Selectfluor , are extremely acidic and may, consequently, ionise the carbon-fluorine bond just formed, leading to a carbocation and subsequent reaction with the solvent (see Section IIIA) [65]. 

The electrophilic chlorination of the 1,3-dithiole derivative 464 with 1 or 2 equiv SO2GI2 afforded the corresponding monochloro 465 or 1,2-dichloro derivatives 466, respectively (Scheme 66). With Selectfluor , [l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.3.3]octane bis(tetrafluoroborate)] or Xep5 fluorination of 464 was also achieved <2001J(P1)3399>. 

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