Halofluorination

A wide variety of reagent systems have been developed to carry out this synthetically useful reaction (Table 3.10). 

The reaction has been used extensively for the introduction of fluorine into steroids [277], where a curious anomaly arises between BrF and IF addition. As indicated, stereospecific anti addition occurs in most reactions but syn addition of BrF or IF to carbohydrates has been observed [278]. Halofluorination of alkynes proceeds as expected, although further reaction of the resulting alkene derivative can occur. 

CSSO3OF reacts with alkenes to give fluoroalkyl sulphates [284], 

NIS-NH4HF2-AIF3 Ichihara, J., Funabiki, K., and FFanafusa, T. (1990) Tetrahedron Lett., 31, 3167 3170. 

HfPOA Ittf blljuiup-updi d- itfll % ldnhtf 

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Y.S. Choe, P.J. Lidstrdm, D.Y. Chi, T.A. Bonasera, M.J. Welch, J.A. Katzenellenbogen, Synthesis of 11-beta-[F-18]fluoro-5-alpha-dihydrotestosterone and 11-beta-[F-18]fluoro-19-nor-5-alpha-dihydrotestosterone—Preparation via halofluorination-reduction, receptorbinding, and tissue distribution, J. Med. Chem. 38 (1995) 816-825. 

Addition of Fluoride and a Different Halogen (Halofluorination Reactions)... 

Halofluorinations take place, as a rule, regioselectively (Markovnikov addition), the olefinic carbons can be substituted with a variety of substituents ranging from alkyl or aryl groups to different electron-withdrawing functions see for example refs 31 and 178-180. Bromo-fluorination of 4-/m-butyl-l-methylcyclohexene with /V-bromosuccinimide in 70% hydrogen fluoride/pyridine gave two stereoisomers 1 and 2.181... 

As a rule, alkynes react in bromo- and iodofluorinations by monoaddition because vinylic a./f-halofluorides as electron-deficient alkenes are generally less reactive. However, some aryl-conjugated alkenes, such as cinnamate or stilbene derivatives 3 or 5, respectively,184 may also be halofluorinated by hydrogen fluoride/pyridine/A-halosuccinimide reagent.185... 

Halofluorination of Alkencs with A-Halosuccinimide/Triethylaminc Tris(hydrogen Fluoride) General Procedure 96 187... 

Table 8. Halofluorination of Cycloalkenes with Triethylaminc Tris(hydrogen Fluoride) A -Halosuccinirrnde 6 1...

Table 10. Halofluorination of Alkynes with 70% Hydrogen Fluoride/Pyridine/A-Halosuccinimidc at Room Temperature31...

Halofluorinations can also be carried out with transannular oxygen participation in the case of unsaturated bicyclic epoxides. Thus, 9-oxabicyclo[6.1,0]non-4-ene (7) is attacked stereo-specifically by A -halosuccinimide and triethylamine tris(hydrogen fluoride) (or 70% HF/py-ridine), to give endo,e fo-2-fluoro-6-halo-9-oxabicyclo[3.3.1]nonane 8 (main product) and eHr/o,eWo-2-fluoro-5-halo-9-oxabicyclo[4.2.1]nonane 9.194... 

Furthermore, it has been found that larger carbocyclic 1,5-dienes195 or norbornadiene96,173 196 give halofluorinations with transannular participation of the second re-bond. A synthetically interesting example of a comparative study of selectivities in bromofluorinations of unsaturated... 

Various applications of halofluorinations are described in reports on the synlhesis of modified natural products and bioactive compounds,197 199 see also reviews.28 29-200 201... 

Furthermore, the halofluorination method can also be modified to prepare vicinal difluorides by a one-pot two-step reaction. Halofluorination followed by nucleophilic halogen-fluorine exchange is carried out simply by adding silver(I) fluoride to a solution of the initially formed a-fluoro-/J-haloalkanes, effecting the exchange in situ202 203 (Table 12). 

Halofluorination with Stoichiometric Equivalents of Halogen Fluorides (Positive Halogen and HF or Its Salts)... 

The combination of A/-halosuccinimides with polyfluorinated ammonium salts, in particular A/-halosuccinimide-triethylamine trisfhydrogen fluoride)42 (Method C), is convenient and effective for the halofluorination of alkenes. These easy-to-handle reagents allow work to be carried out at room temperature in conventional glass apparatus, while Olah s reagent requires polyethylene equipment. The reaction of various alkenes with A -halosuccinimide-triethylamine trisfhydrogen fluoride) in dichloromethane or diethyl ether at 0 C is complete within 3-5 hours giving the halogen fluoride addition products in 70-95% yield. 

Halofluorination of Alkenes with the, V-Halosuccinimide-F.t, N 3HF System General Procedure (Method C) 42... 

Silver(I) fluoride dispersed on the surface of finely powdered calcium fluoride shows improved fluoride nuclcophilicity for addition to alkenes in halofluorination reactions.56 For example, hex-1-ene with l,3-dibromo-5,5-dimethylhydantoin and silver(I) fluoride/calcium fluoride in dichloromethane at 20 C gives, within 1 hour, l-bromo-2-fluorohexanc in 90% yield while with silver(I) fluoride, under similar conditions, the yield is only 39%. 

Boron trifluoride and boron trifluoride-diethyl ether complex can be used as a source of fluoride ions in the presence of hypobromites and hypochlorites, e.g. methyl hypobromitc, tert-butyl hypobromite, methyl hypochlorite in carbon tetrachloride at 25 C. The addition of bromine monofluoride" and chlorine monofluoride" to various alkenes is accompanied by the formation of the corresponding alkoxybromides and alkoxychlorides which hinder the isolation of the halofluorinated products.57 jV-Bromo- and A -chloro-substiluted alkyl- and arylamines. -amides, and -imides, A -chloro-A,-methylamine, A -bromo-A -methylamine, A -chloro-A, /V-dimethylamine, A-bromo-A.A-dimethylamine, ACV-dichloro-A -methylamine, V,fV-dibromo-,V-mcthylaminc, A -bromosuccinimide, -V-chlorosuccinimide, Af-bromoacct-amide, A.A -dichlorourethane, can be used in the reaction instead of the hypohalites. The reactions with various alkenes conducted in dichloromethane at room temperature in the presence of boron trifluoride-diethyl ether complex produce bromofluoro and chlorofluoro addition products in 40-80 % yield. However, the reactions are complicated by the addition of A -halo-succinimides and Af.A-dichlorourcthane to the C = C bonds.58... 

Alkenes are converted into the corresponding bromofluorides by reaction w ith 1,3-di-bromo-5,5-dimethylhydantoin and silicon telrafluoride in aqueous dioxane in a highly regio-and stereoselective manner,54 Both A-ehlorosuecinimide and A/-iodosuccinimide arc ineffective in this halofluorination. 

The buildup of chlorine substituents in unsaturated substrate molecules hampers halofluorination that suggests an electrophilic mechanism for the reaction. Esters of acrylic, methacrylic. 

Dediazoniative Halofluorination of Diazo Ketones and Diazoacetates with yV-Halosuccinimide-Pyridinium Poly(hydrogen fluoride)... 

Halofluorination has also been applied to tertiary diazo compounds. For example, biologically active products 2 and 3 were prepared from esters of 6-diazopenicillanic acid not too acid-sensitive esters can be treated with A-bromosuccinimide in 70 % hydrogen fluoride/pyridine317 but acid-sensitive esters [such as (pivaloyloxy)methyl esters] must be reacted with A-bromo- or A-chlorosuccinimide in the presence of tetrabutylammonium hydrogen fluoride.318 319... 

Hydro- or halofluorination of tertiary diazo esters complements the fluorodediazoniation of a-amino adds, since these diazo esters are now available from the corresponding a-amino acids.41... 

The carbomum ion rearrangements that can be observed in halofluorinations are illustrated by the reactions ot norbornene (Table 2) and norbornadiene (Table 3). Product ratios may vary with the different reagent combinations... 

Rearrangements are also observed during halofluorinations with cyclic medium ring dienes [70, 93] (equations 4 and 5) and with the monoepoxide of 1,5-cyclooctadiene [94] (equation 6) during halofluorinations Again, there are differences in product mixture with apparently minor variations in reagents (equation 4)... 

Several groups have employed N-halosuccinimdes for the halofluorination of alkenes. Laurent and co-workers have found that triethylamine tris(hydrofluoride) is a suitable fluoride source for the halofluorination of a number of alkenes (Scheme 70).137 Other examples of halofluorinations include NBS and tetrabutylammonium fluoride as the halogen sources for the formal addition of BrF across funtionalized cyclohexenes138 and the halofluorination of alkenes and alkynes by all three N-halosuccinimides and polymer-supported HF.139... 

Inorganic expl materials have also proven to he amenable to IR spectroscopic analysis. An IR spectrophotometric analysis method for carbon monoxide, carbon dioxide, nitric oxide, nitrous oxide and nitrogen dioxide produced in vacuum stability tests of expls stored together with polymeric materials has been developed (Ref 60). Structural properties, as elucidated by IR absorption, of a variety of new perfluorinated and halofluorinated covalent perchlorates are reported in Ref 42. Characterization of the products of the pyrot reaction of silicon and red lead in oxygen... 

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