Additions fluoromethyl

Rios [41], Wang [42], and Cordova [43] developed independently, almost at the same time, the formal fluoromethyl addition to enals. The authors took advantage of the easy removal of the bis-sulfonyl moiety. As shown in Scheme 33.13, the reaction between fluoro-bis(phenylsulfonyl)methane (FBSM, 62) and enals (6) was efEciently catalyzed by 27 and the results in terms of yield and enantioselectivities... 

This enhanced reactivity of fluoromethyl cyanide is undoubtedly due to the inductive effect of the fluorine atom which produces an electron deficit on the carbon atom linked to the nitrogen, and presumably increases still further the polarity of the carbon-nitrogen bond, so that the electron displacements can be pictured as (IX). The increased polarity of the carbon-nitrogen bond will obviously facilitate polar addition of hydrogen chloride and alcohols (or phenols). 

B. Fluoromethyl phenyl sulfone (2). To a 3-L, three-necked, round-bottomed flask, equipped with an overhead stirrer, thermometer, and 1-L addition funnel with sidearm are added Oxone (221.0 g, 0.36 mol) (Note 9) and water (700 mL). The mixture is cooled to 5°C and a solution of the crude fluoromethyl phenyl sulfide (1) in methanol (700 mL) is placed in the addition funnel and added in a slow stream to the stirring slurry. After addition of the sulfide, the reaction mixture is stirred at room temperature for 4 hr, (Note 10) and the methanol is removed on a rotary evaporator at 40°C. The remaining solution is extracted with methylene chloride (2 x 500 mL). The combined organic layers are dried over magnesium sulfate, concentrated to ca. 150 mL, filtered through a plug of silica gel (230-400 mesh, 300 mL, 10 x 6.5 cm), and washed with an additional 500 mL of methylene chloride (Note 11). The colorless filtrate is concentrated and the resulting oil or solid is dried under vacuum (0.1 mm) at room temperature to provide 29 g of crude fluoromethyl phenyl sulfone (2) as a solid... 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

Hi. Lysine. Gamma radiolysis of aerated aqueous solution of lysine (94) has been shown, as inferred from iodometric measurements, to give rise to hydroperoxides in a similar yield to that observed for valine and leucine. However, attempts to isolate by HPLC the peroxidic derivatives using the post-column derivatization chemiluminescence detection approach were unsuccessful. This was assumed to be due to the instability of the lysine hydroperoxides under the conditions of HPLC analysis. Indirect evidence for the OH-mediated formation of hydroperoxides was provided by the isolation of four hydroxylated derivatives of lysine as 9-fluoromethyl chloroformate (FMOC) derivatives . Interestingly, NaBILj reduction of the irradiated lysine solutions before FMOC derivatization is accompanied by a notable increase in the yields of hydroxylysine isomers. Among the latter oxidized compounds, 3-hydroxy lysine was characterized by extensive H NMR and ESI-MS measurements whereas one diastereomer of 4-hydroxylysine and the two isomeric forms of 5-hydroxylysine were identified by comparison of their HPLC features as FMOC derivatives with those of authentic samples prepared by chemical synthesis. A reasonable mechanism for the formation of the four different hydroxylysines and, therefore, of related hydroperoxides 98-100, involves initial OH-mediated hydrogen abstraction followed by O2 addition to the carbon-centered radicals 95-97 thus formed and subsequent reduction of the resulting peroxyl radicals (equation 55). 

Methylene-l,3-benzoxazin-2-ones 194 were found to be susceptible to addition to the exocyclic double bond. On heating under reflux in ethanol, oxazinones 194 were transformed to the 4-ethoxy derivatives 195. Treatment of 194 with l-chloromethyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4), an electrophilic fluorinating reagent, in the presence of methanol, led to the 4-fluoromethyl-4-methoxy-substituted compounds 196 (Scheme 34) <2003T8163>. 

Anesthesia is achieved rapidly and smoothly with sevoflurane, and recovery is more rapid than with isoflurane. However, sevoflurane is chemically unstable when exposed to carbon dioxide absorbents in anesthesia machines, degrading to an olefinic compound (fluoromethyl-2,2-difluoro-l-[trifluoromethyl]vinyl ether, also known as compound A) that is potentially nephrotoxic. In addition, sevoflurane is metabolized by the liver to release fluoride ions, raising concerns about potential renal damage. 

Fluoromethanol (4) and symmetrical bis(fluoromethyl) ethers (5) are obtained from paraformaldehyde in hydrogen fluoride.205,209 Dissociation of fluoromethanol creates the electrophilic species [HOCH2 + ]F, which then attacks the 7r-bond of an alkene (electrophilic addition).209... 

Fluoromethyl ethers may additionally be attacked by a further alkene molecule under the reaction conditions, which then inserts between the C-F bond of the fluoromethyl group. Thus, 1,1-dihaloethene and the hydrogen fluoride/formaldehyde reagent react to form the symmetrical ether 6. 

Furan-2,3.4-tricarboxylic acid,155 2-(trifluoromethyl)furandicarboxylic acids.152 and tris(tri-fluoromethyl)-2-furoic acid.156 even in excess hydrogen fluoride and under forcing reaction conditions, give exclusively the corresponding poly(trifluoromethyl)furans. e.g. formation of 14 no addition of fluorine to the ring carbons occurs. 

Adamantanecarboxylic acids, on treatment with sulfur tetrafluoride, react in a conventional manner to give (triiluoromethyl)adamantanes (see Section 8.2.4.1.). However, in the presence of anhydrous hydrogen fluoride in large excess, substitution of bridgehead hydrogen atoms by fluorine occurs in addition to fluorination of carboxylic acid groups di- or trifluoro(tri-fluoromethyl)adamantanes 7 and 8 arc obtained in one step.8 119186... 

Reaction of disodium hexafluorosilicate with (trichloromethyl)benzene at 221 C for 10 hours affords a mixture in which (chlorodifluoromethyl)benzene (35 %) predominates over (dichloro-fluoromethyl)benzene (15%) and (trifluoromethyl)benzene (0.5%).15 In contrast, addition of antimony(V) chloride to the reaction of l-chloro-4-(trichloromethyl)benzene with disodium hexafluorosilicate increases the yield of l-chloro-4-(trifluoromethyl)benzene.lb... 

A neutral diazo compound can be considered as both a nucleophile and an electrophile. Thus, it can be substituted by the combination of an electrophilic moiety and a nucleophilic moiety (X+ Nu ") (Scheme 8). In practice, the diazomethyl group is transformed to the fluoromethyl group by treatment with hydrogen fluoride/pyridine mixture (70 30 w/w) (X = H Nu = F), or to the halofluoromethyl group by addition of A-halosuccinimide in the same medium (X = Cl, Br, I Nu = F), e.g. formation of l.16 The reaction can be performed on secondary diazo alkanes, diazo ketones or diazo esters.16 90 316... 

In addition, fluorine [97, 98], trifluoromethyl hypofluonte [99,100], bisftri-fluoromethyl)peroxide [100, 101], trifluoromethyl disulfide [100], and xenon difluoride [102,103,104] react with phosphines to give the corresponding diflu-orophosphoranes in yields ranging from 25% to near quantitative. Phosphites are fluorinated by carbonyl fluoride [95, 96] or 2-hydroperfluoropropyl azide [7ft5J (equation 15). 

Addition a to a cyano group Benzyltriethylammonium chloride, 239 Nickel, 197 Addition a to halogen Diiodomethane-Samarium, 113 Fluoromethyl phenyl sulfone, 135 Tris(dimethylamino)sulfonium difluo-rotrimethylsilicate, 336 Addition a to oxygen... 

Fluoromethyl phenyl sulfone, 135 Methylthiomethyllithium, 192 Methyl (trifluoromethylsulfonyl) methyl sulfone, 193 Addition a to selenium Potassium permanganate, 258 Other functionalized carbon reagents Allyltriphenylsilane, 13 Dicarbonyl(nitrosyl)-triphenylphosphinecobalt, 101... 

Peptidyl fluoromethyl ketones can readily be synthesized by addition of organometallic reagents to peptide aldehydes and other carbonyl compounds 28 one variation of this reaction is suitable for the stereoselective synthesis of trifluoromethyl ketones. 23,31 ... 

The ratio of the rate constants for the addition of fluoromethyl radicals to ethylene and tetrafluoroethylene at 437 K ... 

In Table 5 (p. 55) we compared the relative rates of addition of methyl, fluoromethyl, difluoromethyl and trifluoromethyl radicals to ethylene and tetra-fluoroethylene. Figure 3 shows the Arrnehius plots for these competitive reactions. These indicate in a very graphic way the fact that this systematic variation in relative rate can be entirely attributed to variation in the activation energy differences. 

Fig. 3 Arrhenius plot for the relative rates of addition of methyl and fluoromethyl radicals to ethylene and tetrafluoroethylene (Low et al., 1976a)...

A solution of chloromethyl l,l,l,3,3,3-hexafluoro-2-propyl ether (754 g, 3.49 moles) in dry tetrahydrothiophene 1,1-dioxide (203 g, 3,49 moles) were stirred and heated to 130°C in a creased flask fitted with a fractional distillation assembly. A distillate (200 ml), b748 56.0° to 62°C, was collected during 5 h. Then the reaction mixture was cooled to room temperature, dry potassium fluoride (100 g, 1.74 moles) was added, and the cycle of operations was repeated 3 times at temperatures between 138° to 185°C to give distillates (100 ml, 100 ml and 50 ml), b746 58° to 61°C, 55.5° to 57°C, and 54.2° to 55.9°C, respectively. From this portionwise addition of potassium fluoride (503 g, 8.7 moles) there was obtained distillates totalling 672 g, b746 54.2° to 62.0°C, which by GLC analysis was about 92% fluoromethyl and 6.8% chloromethyl l,l,l,3,3,3-hexafluoro-2-propyl ether. 

Fluoromethyl- and 2-hydroxymethyl-4-alkylfurans are accessible from a-alkylacroleins and 1-bromo-l-trimethyl-silylethylene in a four-step sequence (Scheme 15) <1996TL7437>. Lithiation and carbonyl addition leads to diallylalcohols 11. Epoxidation and mesylation provides the bis-epoxides 12, which can be transformed into fluoro-methylfurans (X=F) upon treatment with tetrabutylammonium fluoride (TBAF). In the presence of water, hydroxymethylfurans are formed (X = OH). 

A proposed mechanism for the Michael addition reaction is shown in Scheme 10.7. Note that enamine, generated from the reaction of hydroxyacetone and aldolase antibody 38C2, reacts with the activated methylene group in 2-(phenyl)ethyl-2-(tri-fluoromethyl)acrylate. 

---