Fluorohydrin synthesis

The addition of a second double bond in the A ring leads to yet a further increase in potency. One published synthesis of this compound begins with the hydrogenation of fluorohydrin (15-2) to the saturated intermediate (16-1). Treatment of that ketone with bromine leads to the dibromide (16-2) this reaction, as noted earher, in fact follows a quite complex pathway involving at one point a 2,2-dibromo derivative. 

In the synthesis of fluorinated alcohols porous aluminum trifluoride has been found to be an efficient substitute for anhydrous hydrogen fluoride in combination with alkali metal acid fluorides for ring-opening reactions of aliphatic 7-oxabicyclo[4.1.0]heptane fluorohydrins under sonification.47... 

Table 5. The Sonochemical Synthesis of Fluorohydrins using the MHF2/A1F3 Reagent47...

An early report describes the synthesis of fluorohydrins. in low yields, from simple epoxides with anhydrous hydrogen fluoride in diethyl ether containing some water. 1,2-Ep-oxycyclohexanc and 2,2-dimethyloxirane were opened to 2-fluorocyclohexanol in 14% yield and 2-fluoro-2-methylpropan-1 -ol in 20 % yield, respectively, by the same method, but these results could not be reproduced (see also Table 12), With acetonitrile as the solvent, simple epoxides are opened to the fluorohydrins.but yields are low due to side reactions such as oligomerization and rearrangement. 

One of the first examples of industrial application of selective direct fluorination was the synthesis of the cytostatic 5 -fluorouracil. In the most commonly used process the precursor uracil is treated with nitrogen-diluted fluorine in hot water and the intermediate fluorohydrin is subsequently dehydrated either by heating the aqueous solution to 100 °C or with sulfuric acid [18] (Scheme 2.6.). 

Ring opening with milder but more selective reagents such as NEtj -SHF or KHFj/lS-crown-G proceeds significantly more slowly but it can be catalyzed by electrophilic transition metal complexes. With a chiral salen catalyst even enantio-selective synthesis of chiral fluorohydrins can be achieved [70]. This type of reaction is of enormous interest for enantioselective synthesis of fluoropharmaceutical compounds (Scheme 2.26). 

Not offered commercially, CF3COOF did not gain as much popularity until the early 80 s when we modified its synthesis and showed that it can be an useful reagent in organic chemistry as for example in the preparation of fluorohydrins or a-fluoroketones (10,11) -(figure 2). 

At that time, there was interest in obtaining the 8-(i )-fluoro derivative, hence, work on the other regioisomer was dropped. The same happened to the other fluorinated aglycones such as the 8,9-difluoro, 8,13-difluoro and 9,13-difluoro derivatives, which were obtained using an intermediate of the synthesis of cz5-1,2-fluorohydrin 28 [35]. 

The argument is closely analogous to that used to explain the regioselectivity of formation of bromoacetoxy compounds (Table 9.2) formed in the addition of bromine to alkenes in acetic acid. Similarly, addition of bromine to alkenes in water produces bromohydrins. Although they are more difficult to synthesize, iodohydrins and fluorohydrins are also known. For a review of the synthesis and reactions of halohydrins, see Rosowsky, A. in Weissberger, A., Ed. Heterocyclic Compounds with Three- and Four-Membered Rings, Part One Wiley-Intersdence New York, 1964 p.l. 

W. Borzecka, I. Lavandera, V. Gotor, Synthesis of enantiopure fluorohydrins using alcohol dehydrogenases at high substrate concentrations,. Org. Chem 78 (2013)... 

From a non-c ohydrate precursor, Davis and Qi achieved the asymmetric synthesis of 2-deoxy-2-fluoro- iylo-D-pyranose (9) (Figure 7) and 2-deoxy-2-fluoro-lyxo-L-pyranose (13). TTie key reaction was the highly diastereoselective fluorination of a chiral enolate using the electrophilic fluorinating agent, N-fluoro(benzenesulfonimide) (NFSi). In another study by Davis (14), the use of a chiral oxazolidinone adjuvant and fluorination with NFSi led to the chiral fluorohydrin 10 (>97% ee), which was oxidized by the Dess-Martin periodinane procedure to the non-racemic a- fluoroaldehyde 11 (94% ee). Conversion of 11 in four steps provided l,2,3-tri-0-acetyl-4-deoxy-4-fluoro-D-arabinopyranose (12) as a 1 1 mixture of anomers which could not be separated by flash chromatography. 

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