Fluoroesters

The nitro substituent is also preserved dunng fluoroester reduction with sodium borohydride [S3] (equation 67) Use of diborane itself allows reduction of nitrodifluoroacetanihde to the amine, Al-nitrodifluoroethylaniline [84] (equation 68)... 

Both for primary and secondary a-fluoroesters, the a-protons absorb slightly downfield of analogous aliphatic ketones and somewhat upheld of analogous aromatic ketones. 

Although the fluoride anion is not a good leaving group (because of the great strength of the C-F bond), ketones, imines and jS-fluoroesters easily afford this S-elimination reaction (Fig. 22) [77], The S-elimination process remains efficient for CF2 and CF3 compounds, while the C-F bond is stronger. Indeed, fluorine atoms render more acidic the a proton, which makes easier the formation of the anion. 

The thermal decomposition of 1,1,1,-trifluoroacetone has been studied by Fekete - , and that of fluoroacetone hemiacetal esters by Newallis et Lewis and Newman have reported on the rearrangements of fluoroesters in the gas phase. Thermal reactions of nitrogen-containing fluoro-compounds have included trifluoromethyl cyanide , hexafluoroazomethane , tetrafluorohydra-zine , fluorodiazirines , perfluoropyridazines , fluorochlorodinitrometh-ane and poly(difluoroamino)fluoromethanes - . ... 

A 1-phenylethylamino moiety is used for diastereomeric control not only in addition of nucleophiles to A-(l-phenylethyl)imines but also in diasteroselective Michael addition to a,P-unsaturated esters. Thus, lithium A-(l-phenylethyl)-A-benzylamide 148 is employed for a one-pot tandem Michael addition-fluorination reaction (see Scheme 9.32) [58]. The reaction provides a/i/f-3-amino-2-fluoroesters 149 exclusively, whose diastereoselectivi-ties (64-66% de) to the chiral carbon of the 1-phenylethyl-group are good enough. 

Esters with one or two fluorines at the a-carbon are useful building blocks for construction of interesting and novel biologically active substrates. Alkylation of a-fluorocarboethoxy phosphonium ylides followed by hydrolysis of the resultant phosphonium salt with 5% aqueous sodium bicarbonate provides a useful preparative route to a-fluoroesters. Similarly, acylation/hydrolysis of either a-fluoro phosphonium ylides or a-fluorophosphonate anions gives a general route to 2-fluoro-3-oxo-esters. The a,a-difluoroesters can be prepared by Cu° catalyzed addition of iododifluoroacetates to olefins followed by reduction of the iodo addition adduct. Both terminal and internal olefins participate equally well in the addition reaction. 

Elucidation of the mechanism of toxicity of fluoroacetate in living organisms led to increased interest into the preparation and properties of a-fluoroesters. More recently, the use of fluorine substituted esters as analytical probes and diagnostic tools in metabolic processes has added to their stature as important compounds in biochemistry(7). In addition, a-fluoroesters have served as useful building blocks to more complex and interesting biological substrates. 

The alkylation reaction occurred easily with both primary and secondary halides. When R = Et in the phosphonate carbanion, the alkylated phosphonate suffers partial dealkylation to 0"(R0)P(0)GFR CCX)Et by SN2 attack of the lithium halide produced in the reaction. This side-reaction can be easily suppressed by use of the corresponding isopropyl phosphonate carbanion. Thus, this straightforward alkylation of (3) appeared promising as an entry to a-fluoroesters. Alkylation occurred only at carbon and the absence of hydrogen at the a-carbon in the phosphonate precluded any transylidation process, thus allowing total utility of the phosphonate carbanion only in the desired alkylation reaction without concomitant loss of the phosphonate carbanion in acid-base side-reactions. 

In contrast to the difficulty experienced in the hydrolysis of (5), the phosphonium salts (6) were all easily hydrolyzed by 5% sodium bicarbonate, 5% sodium carbonate or 5% sodium hydroxide to give the a-fluoroester. These results are summarized in Table II. The increased positive charge on phosphorus in(6) compared to (5) facilitates attack by the hydrolysis reagent and allows the overall scheme to succeed. Thus, a-fluoroesters can be readily prepared via alkylation and hydrolysis of (4). The reaction is not as general with (4) (secondary halides did not react), but for primary and activated halides, the reaction does provide a convenient, facile, easily scaled up synthesis for a variety of a-fluoroesters. 

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