Fluoro-alcohols

The Kyoto group has developed some interesting chemistry based upon this readily available alcohol. / -Fluoro vinamidinium salts with potential for the synthesis of fluorinated heterocycles were prepared according to Eq. (89) [265]. Treatment of the tosylate of tetrafluoropropanol with n-butyllithium achieves regioselective dehydrofluorination a short reaction time appears to be critical [266]. 

FLUORINECOMPOUNDS,ORGANIC - FLUORINATED AROMATICCOMPOUNDS] (Volll) p-Fluoro-a,a-bis(trifluoromethyl)benzyl alcohol [2402-74-6]... 

A reagent which is primarily of interest as a means of converting alcohols into fluorides has been used to dehydrate C-11 alcohols in high yields. 1 la-Alcohols dehydrate rapidly with 2-chloro-l-diethylamino-l,l,2-trifluoro-ethane reagent at low temperature, while 11 j5-alcohols require refluxing methylene chloride. Traces of fluoro compounds have been detected in the products. 

Without exception the 17-secondary alcohols give three products, the dehydration products with migration of the 13j5-methyl group, the 17a-fluoro derivatives and the 17/5-chlorofluoroacetates. ... 

Careful studies of the reaction of the fluoroamine with the homoallylic alcohols 3 -fluoro-19-hydroxycholest-5-ene and 3a- and 3j5-hydroxy-17j5-acetoxyestr-5(10)-ene which bear on the proposed mechanism have been reported recently. 

The chloroform solution from which the insoluble 21-fluoro compound has been removed is concentrated in vacuo and the residue recrystallized twice from 95% alcohol. The resulting oxetanone (46) has mp 272-274° ... 

In contrast to phosphorus esters, sulfur esters are usually cleaved at the carbon-oxygen bond with carbon-fluorine bond formation Cleavage of esteri nf methanesulfonic acid, p-toluenesidfonic acid, and especially trifluoromethane-sulfonic acid (tnflic acid) by fluoride ion is the most widely used method for the conversion of hydroxy compounds to fluoro derivatives Potassium fluoride, triethylamine trihydrofluoride, and tetrabutylammonium fluoride are common sources of the fluoride ion For the cleavage of a variety of alkyl mesylates and tosylates with potassium fluoride, polyethylene glycol 400 is a solvent of choice, the yields are limited by solvolysis of the leaving group by the solvent, but this phenomenon is controlled by bulky substituents, either in the sulfonic acid part or in the alcohol part of the ester [42] (equation 29)... 

Dehydration to olefins, which sometimes accompanies the reaction of alcohols with DAST [95, 108], is seldom as extensive as with a-fluoroamines (FAR and 1,1,2,3,3,3 hexafluoropropyldiethylamine) but occurs in a few cases to the exclusion of fluonnation, thus, 9a-fluoro-11-hydroxysteroids give 9a fluoro-A -steroids [127, 128] Dehydration accompanied by Wagner-Meerwein rearrangement occurs during the fluonnation of testosterone [129] Intermolecular dehydration to form ethers in addition to fluorides is observed in the reaction of benzhydryl alcohols [104] (Table 6)... 

Carbocation rearrangements occur in the reactions of some secondary alco hols with DAST, thus isobutyl alcohol gives a mixture of isobutyl fluoride and tert-hxAy] fluonde [95] (Table 6), and both bomeol and isoborneol rearrange to the same 3-fluoro-2 2,3-tnraethylbicyclo[2 2 IJheptane (72-74%) accompanied by camphene [95]... 

Reactions of alcohols with sulfur tetrafluoride, because of decomposition and/or polymerization, usually do not give fluorinated products However, in the presence of a hydrogen fluoride scavenger like triethylamine or pyridine, even such sensitive substrates as benzylic alcohols [555], 2-phenylethanol, and 2-furylmethanol [554] can be fluorinated to give the expected fluoro derivatives (equation 73)... 

Asymmetric epoxidation of racemic unsaturated fluoro alcohols by the chiral Sharpless reagent can be exploited for kmetic resolution of enantiomers The recovered stereoisomer has 14-98% enantiomeric excess [55] (equation 50)... 

The nucleophilic displacement of halogens by pentafluorophenoxide ion resulted in the formation of the corresponding esters [31] (equation 29) (Table 12). Reactions of trifluoromethanesulfinyl fluoride with fluoro alcohols in the presence of sodium fluoride or cesium fluoride are used to prepare sulfmates [32] (equation 30) (Table 12). 

Electrochemically generated trifluoromethyl radicals add to 1-hexyne to give a 1 4 mixture of ( )- and (Z)-l,l,l-trifluoro-2-heptene [22] Kinetic data on the addition of photochemically generated trifluoromethyl radicals to acetylene and substituted acetylenes were reported [2J]. Alcohols and aldehydes add to hexa-fluoro-2-butyne in the presence of peroxide and y-ray initiation [24] (equations 16 and 17). 

A wide variety of a-tnfluoromethyl a-amino acids are readily available from the reaction of 5-fluoro-4-tnfluoromethyl-l,3 azoles with allylic alcohols [138, 139] a-Tnfluoromethyl-subsumted a-amino acids show anubactenal and antihy pertensive activity Some are highly specific enzyme inhibitors (suicide inhibitors) and may be important as bioregulators [140] Furthermore, they are interesting candidates for peptide modification... 

In l-chloro-2-fluoroacenaphthene [58] and in 2,3-dihalo-2,3-dihydrobenzofuran [59, 60], potassium t rt-butoxide eliminates hydrogen fluonde in preference to hydrogen chloride. trares-2-Chloro-3-fluoro-2,3-dihydrobenzofuran loses hydrogen fluoride quantitatively on treatment with sodamide in tert-butyl alcohol [60] (equation 29). 

To a suspension of 500 mg of 6a-fluoro-triamcinolone in 75 ml of acetone is added 0.05 milliliters of 72% perchloric acid and the mixture agitated at room temperature for 3 hours. During this period the crystals gradually dissolve and the clear solution is neutralized with dilute bicarbonate and the acetone removed in vacuo. The resulting crystalline suspension is filtered and the crystals washed with water. The dried material is recrystallized from 95% alcohol to give the pure acetonide. 

A sodium carbonate solution of the crude acetic acid was washed with ether and then acidified with hydrochloric acid the required acid was isolated via an ether extraction and was esterified by refluxing for 6 hr with ethanol (370 ml) and concentrated sulfuric acid (15 ml). Excess alcohol was distilled, the residue diluted with water and the required ester isolated in ether. Distillation finally gave ethyl 2-fluoro-4-biphenylacetate,BP 134°C to 136°C/0.25 mm. 

This ester (70 g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (1 54 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when Ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acid to give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°Cfor 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4-biphenylyl)propionic acid, MP 110°C to 111°C. 

A solution of 0.144 g of the 3-ethy ene glycol ketal of 5Q ,1 1/3,17Q ,21-tetrahydroxy-6/3-fluoro-16Q -methylallopregnane-3,20-dione 21-acetate in 12 ml of chloroform and 0.1 ml of absolute alcohol was cooled to -10°C in an ice-salt bath and a stream of anhydrous hydrochloric acid was gently bubbled through the solution for 2.5 hours while the temperature was maintained between -5°Cand -15°C. The solution wasthen diiuted with 25 ml of chloroform, washed with dilute sodium bicarbonate and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure at BO t or less to give 60 -fluoro-11/3, 170 ,21 -trihydroxy-16Q -methyl-4-pregnene-3,20-dione 21-acetate. 

Coupling to both termini of the 2-methyl-2-propcnyl residue occurs when the complex 5, formed from the iodo compound 4 and stiver tetratluoroborate, is allowed to react with an excess of aldehyde, giving rise to diastcreomerically pure 4-fluoro-2,4,6-trisubstituted tetrahy-dropyrans 617. The details of the reaction and, as well, the origin of stereoselectivity is unclear at present. It would not be surprising if the reaction is restricted to those aldehydes leading in the first step to homoallylic alcohols capable of forming mesomerically highly stabilized carb-enium ions on solvolysis. 

This excellent method of oxidative cleavage (/) of carbon-silicon bonds requires that the silane carry an electronegative substituent (2), such as alkoxy or fluoro. Either hydrogen peroxide or mcpba may be used as oxidant, and the alcohol is produced with retention of configuration (3). Fluoride ion is normally a mandatory additive in what is believed to be a fluoride ion-assisted rearrangement of a silyl peroxide, as shown below ... 

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