Synthesis of Alkyl Fluorides

The synthesis of alkyl fluorides Is best accomplished by heating an allyl chlorlde/bromlde In the presence of a metallic fluoride such as AgF, HggFg, CoFg or SbFg. The reaction is termed as Swarts reaction. 

The fact that fluoride is a poor leaving group in aliphatic nucleophilic substitutions and the high volatility of fluoroaliphatic compounds are the keys to the Finkelstein synthesis of alkyl fluorides. An alkyl iodide, bromide, or tosylate is heated in a polar solvent vith an alkali fluoride and the volatile alkyl fluoride is removed by distillation during the reaction [30] (Scheme 2.11). For safe handling of primary alkyl fluorides it must be kept in mind that the even-membered compounds of this series are toxic, because they can be oxidatively metabolized to the poisonous fluoroacetate [31]. 

Alkyl fluorides are valuable compounds for study as well as convenient precursors for the construction of complex organic architectures with a high degree of functionalization. A range of routes have been devised for the synthesis of these compounds, and a number of reviews on the synthesis of alkyl fluorides have appeared [1-6], One of the most direct routes to the preparation of an alkyl fluoride would be the deoxyfluorination of alcohols. Fundamentally, this would be analogous to a fluorine version of the Appel reaction, and while the Appel reaction is one of the most successful approaches to the synthesis of alkyl chlorides and bromides [7], it has been challenging to extend the chanistry to the preparation of aUcyl fluorides [6],... 

The formal addition of HF to alkenes would be an attractive approach to the synthesis of alkyl fluorides. To circumvent the issues surrounding the use of hazardous HF for this reaction, a two-step approach has been developed (Example 7.7) [27]. The first step in the process consisted of a rhodium-catalyzed anti-Markovnikov hydroboration of an alkene in order to generate an intermediate alkylboronate. The second step entailed the use of a silver salt to promote a fluorodeboronation of the intermediate. The result of this two-step process was an overall hydrofluorination of an unactivated alkene. In related work, the regi-oselectivity of the hydrofluorination reaction was reversed using a cobalt-catalyzed process (Markovnikov selective) (Scheme 7.14) [28]. 

The Hiyama coupling offers a practical alternative when selectivity and/or availability of other reagents are problematic. Hiyama et al. coupled alkyltrifluorosilane 74 with 2-bromofuran 73 to give the corresponding cross-coupled product 75 in moderate yield in the presence of catalytic Pd(Ph3P)4 and 3 equivalents of TBAF [65]. In this case, more than one equivalent of fluoride ion was needed to form a pentacoordinated silicate. On the other hand, alkyltrifluorosilane 74 was prepared by hydrosilylation of the corresponding terminal olefin with trichlorosilane followed by fluorination with C11F2. This method provides a facile protocol for the synthesis of alkyl-substituted aromatic compounds. 

Moissan and his colleague Meslans then tried other methods for C —F bond synthesis.121 Alkyl fluorides could not be made via reactions of alcohols with hydrogen fluoride or phosphorus fluorides. However, silvcr(l) fluoride was found to function as a halogen-exchange reagent and several alkyl fluorides were made and characterized, all being fairly resistant to alkaline hydrolysis. 

Aliphatic carbamates (readily available from alcohols and sodium cyanate)313 have also been submitted to fluorodediazoniation16,90 314 to give alkyl fluoroformates 890 which are useful tools in peptide synthesis and also valuable precursors of alkyl fluorides.315... 

Halide exchange reactions ( transhalogenation or Finkelstein reaction) have been, until recently, of particular synthetic importance only in the synthesis of alkyl (and strongly activated aryl) fluorides or iodides, where thermodynamic stability (for the fluorides) and solubility differences (for the iodides) shift the reversible exchange processes in the desired direction. With the advent of phase transfer catalysis (PTC) and transition metal catalysis (mainly homogeneous) this important family of reactions has been extended to practically all aromatic and aliphatic halides. 

Not within the scope of this section are the synthesis of a-fluoro sulfides from dithioace-tals, their reduction to alkyl fluorides, and the synthesis of glycosyl fluorides from (phenyl-sulfanyl)glycosides. ... 

Perfluoroalkanesulfonamides have been claimed as intermediates for the synthesis of fluorinated surfactants. Their synthesis by reaction of the corresponding perfluoroalkanesulfonyl fluoride (or chloride) with liquid ammonia is prototypical for the synthesis of alkylated perfluoroalkane-sulfonamide surfactants. This reaction initially forms a complex ammonium salt as shown in Scheme 18.2. The desired amide is obtained by dissolving the crude product in dioxane and... 

Typical conditions for these processes are simply to stir an aqueous solution of the metal salt of Y with the organic substrate alone, or in a solvent such as chloroform or benzene, in the presence of 5—10 mole % of a quaternary ammonium salt as catalyst. A recent example is to be found in a synthesis of alkyl azides from alkyl iodides (or other halides) using commercially available Aliquat 336 [mainly (1)] as catalyst, and a reaction temperature of 100 °C. The conversion of alkyl methanesulphonates to alkyl halides has been used to synthesize optically active secondary fluorides, chlorides and bromides via an 5 n2 inversion mechanism (the iodides racemize before isolation). Ammonium salt (1), or phosphonium salt (2), are used to catalyse these mesylate displacements. ... 

The combination of silyl enol ethers and fluoride ion provides more reactive anions to give alkylated nitre compounds in good yields after oxidation v/ith DDQ, as shovm in Eq. 9.22. This process provides a new method for synthesis of indoles and oxyindoles fsee Chapter 10, Symhesis of Hatarocydic Compoioids). 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

In 1998, Harmata and co-workers <98T9995> published a new synthesis of 2-alkenyl anilines. The silylated 2,1-benzothiazines 187 could be deprotonated by n-BuLi and alkylated by different electrophiles. The corresponding products could be desilylated by fluoride with concomitant cleavage of the carbon-sulfur bond to give 2-alkenylsulfinanilides that can then be hydrolyzed by base to the anilines 195 in good yields (Scheme 55). 

A simple two-step synthesis of 5H-alkyl-2-phenyloxazol-4-ones has been reported by Trost and coworkers (Scheme 6.209) [377]. a-Bromo acid halides were condensed with benzamide in the presence of pyridine base at 60 °C to form the corresponding imides. Microwave irradiation of the imide intermediates in N,N-dimethylacetamide (DMA) containing sodium fluoride at 180 °C for 10 min provided the desired 5H-alkyl-2-phenyloxazol-4-ones (oxalactims) in yields of 44—82%. This class of heterocycles served as excellent precursors for the asymmetric synthesis of a-hydroxycar-boxylic acid derivatives [377]. 

The potentiality of the present methodology is demonstrated by the synthesis of y-undecalactone, as shown in Scheme 18 [37,47], The treatment of the THP-protected cu-hydroxyalkyl iodide with the anion of methoxybis(trimethylsilyl) methane gave the corresponding alkylation product. Acidic deprotection of the hydroxyl group followed by Swern oxidation produced the aldehyde. The aldehyde was allowed to react with heptylmagnesium bromide, and the resulting alcohol was protected as tm-butyldimethylsilyl ether. The electrochemical oxidation in methanol followed by the treatment with fluoride ion afforded the y-undeealactone. 

Regiospecific mono-C-alkylation (60-90%) of trimethylsilyl enol ethers is promoted by benzyltriethylammonium fluoride [34, 35]. A similar alkylation of tin(IV) enolates is aided by stoichiometric amount of tetra-n-butylammonium bromide and has been utilized in the synthesis of y-iminoketones [36]. Carbanions from weakly acidic carbon acids can be generated by the reaction of their trimethylsilyl derivatives with tetra-n-butylammonium triphenyldifluorosilicate [37] (see also Section 6.3). Such carbanions react readily with haloalkanes. Tautomeric ketones in which the enol form has a high degree of stabilization are O-alkylated to form the enol ether, e.g. methylation of anthrone produces 9-methoxyanthracene [26],... 

Like aldehyde, the ketone function provides sufficient activation on an aromatic ring for the nucleophiUc substitution. Reduction of the carbonyl group after incorporation of the F-fluoride ion yields F-alkyl aromatics [177]. This methodology using F for trimethylammonium exchange, then reduction of the carbonyl compound, have proved to be useful for the synthesis of a [2- F]fluo-rophenol at high specific activity [141] (Scheme 39). 

Cyclizations of o-(a -haloalk oxy)phenols have been widely studied and were used to afford an expedient synthesis of 5-alkyl-2,3-dihydro-l,4-benzodioxins <2004SC2487>. This approach via a nucleophilic substitution was used for the synthesis of 8-substituted-2-hydroxymethyl-l,4-benzodioxane derivatives 164 in an enantiopure form. Use of CsF instead of more basic conditions allowed higher yields and enantiomeric excess (Equation 28) <2001ASC95>. Dry tetrabutylammonium fluoride (TBAF) in THF was required and was basic enough to initiate an intramolecular Sn substitution from the protected phenol 165 to the fluoro-l,4-benzodioxane 166 <1996T6187>. 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

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