2- Fluoropyridinium salts

Acyl-2-fluoro-l,4-dihydropyridines 149, easily synthesized by alkylation of 2-fluoropyridinium salts, undergo hydrolysis to form dihydro-2-pyridones 150 in which only the more stable 3,4-/ra t-isomer is formed. 1,4-Dihydropyridines 149 can also be oxidized with DDQ to form 2-pyridones 151 (Scheme 40) <2002JOC7465, 2000CC2459>. 

Reagents i, H2-Pd ii, HN03-AcCH iii, KOH iv, H+ v, LiAlH4 vi,BuaLi vii, TiCl4-LiAlH4 viii, l-methyl-2-fluoropyridinium salts... 

The previously reported biogenetic-type cyclization of nerol and geraniol to limonene using 2-fluoropyridinium salts has been extended to the sesquiter-penoid area. Thus treatment of cw,rran5-farnesol (77) with 2-fluoropyridinium (74), 2-fluorobenzothiazolium (75), or 2-chlorobenzothiazolium (76) salts resulted in the formation of a-bisabolene (78) and y-bisabolene (79) in 55—75% yield. 

The condensation of ketoximes with 2-fluoropyridinium salts leads to salts (157), which on aqueous hydrolysis undergo a Beckmann rearrangement, giving amides (158) in high yields. ... 

Three new synthetic methods for the conversion of alcohols into azides (and hence potentially into amines) have been published. One route involves a further application of the chemistry of 2-alkoxypyridinium salts (formed in situ from an alcohol and the 2-fluoropyridinium salt) in their reaction with azide ion " (Scheme 17). Another extends the utility of the triphenylphosphine-ethyl diazodicarboxylate system, using diphenylphosphoryl azide as azide donor (Scheme 18), but is sensitive to steric hindrance at the alcohol carbon. The third route (Scheme 19) achieves oxygen activation through the alkoxyphosphonium salts (39), which are prepared from the alcohol, a phosphine, and a positive halogen donor such as carbon tetrachloride (with primary alcohols) or Af-chlorodi-isopropylamine (in... 

A new route to thiols employs the l-methyl-2-fluoropyridinium salt (69) which reacts with alcohols to give the 2-alkoxy-derivatives ° (Scheme 49). Treatment with sulphur nucleophiles as shown proceeds with inversion and thiols are available from the products by reduction. 

A-Acyl-4-pyridones can serve as useful acyl group transfer reagents for the esterification of alcohols in >80% yields.Two notable points about these reagents are their effectiveness in the preparation of formate esters (c/. ref. 157), and their much greater rate of reaction with primary alcohols, (c/. ref. 147). Thioesters and amides can also be prepared from such pyridones by reaction with thiols or amines, respectively. Other useful reagents for the direct formation of esters from carboxylic acids and alcohols are 2-fluoropyridinium salts in the presence of caesium fluorideand certain benzoisothiazole derivatives. Primary alcohols can be esterified with 2,2 -bipyridyl-6-yl carboxylates and CsF. Selective esterification of a primary alcohol in the presence of a secondary alcohol can be achieved in acceptable yields with this reagent (c/. ref. 144). 

Fluoropyridinium salt sodium dithionite Replacement of hydroxyl by hydrogen Ketones from a-hydroxyketones... 

Sodium iodide s. under PhgP and 2-Fluoropyridinium salt Nal... 

Fluoropyridinium salt Carboxylic acid fluorides from carboxylic acids... 

Fluoropyridinium salt sodium iodide Iodides from alcohols... 

Alkyl iodides can be prepared by treatment of 2-fluoropyridinium salts with alcohols, followed by inorganic iodide reaction with the 2-alkoxypyridinium intermediates so formed (Scheme 25). A similar sequence involving 2-alkoxy-3-ethylbenzothiazolium salts (63), produced in situ, allows conversion of alcohols into inverted chlorides, bromides, or iodides (Scheme 26) of high optical purity. 

Fluoropyridine. This isomer can be prepared in 54—81% yield by dia2oti2ation of 4-aminopyridine in anhydrous hydrogen fluoride (370,371,400). Eree 4-fluoropyridine readily undergoes self-quaterni2ation to give pyridyl pyridinium salts (401) stabili2ation can be effected as the hydrochloride salt (371,400). Numerous 4-fluoropyridinium salts, eg, 4-fluoro-l-methylpyridinium iodide, have been converted to novel penicillins (387,402). 

The effects of ring substituents and counterions on the preparation and reac-tivity of the Af-fluoropyridinium salts have been reported in detail [74, 75, 76]. 

The A -fluoropyridinium salts produce 2-fluoropyridines on treatment with base. A carbene mechanism has been proposed [78] (equation 36). 

Both stereoselectivity and regioselectivity occur in the reaction of steroid vinyl esters, ethers, and related compounds with A -fluoropyridinium salts [75, 7d] (equation 45). 

A novel route to 2-fluoropyridines involved the base-induced decomposition of substituted N-fluoropyridinium salts. Abstraction of the 2-H produces a singlet carbene (11) that removes F from a counterion. This is in contrast to the reaction with C nucleophiles, which are fluorinated, and is attributed to the high stability of C—F compared to O—F and N—F (89JOC1726). 

The stability of hypofluorites is improved in derivatives having electron-withdrawing substituents, such as 2,2-dichloropropanoyl hypofluorite.48 Various other fluorinating agents have been developed and used, including /V-fluoropyridinium salts such as the... 

Meinert demonstrated that fluorination of pyridine at low temperatures gives the ionic salt N-fluoropyridinium fluoride, a compound that was reported to be explosive at 0°C (Fig. 59) [154]. However, direct fluorination of variously substituted pyridines is possible and good yields of the corresponding 2-fluoro-pyridines (Figs. 60 and 61) [155] are obtained, offering an attractive alternative to the usual halogen-exchange and Balz-Schiemann routes to these products. These reactions probably proceed via N-fluoropyridinium salts (Fig. 62) which are activated towards nucleophilic attack. 

Thiols have also been prepared from alcohols. One method involves treatment with H2S and a catalyst such as A1203,747 but this is limited to primary alcohols. Another method involves treatment with Lawesson s reagent (see 6-11).748 Still another method, involving the use of a fluoropyridinium salt and sodium N,N-dimethylthiocarbamate, can be applied... 

Fluoropyridinium salts, in most cases, are freely soluble in polar solvents such as acetonitrile, but insoluble or sparingly soluble in nonpolar organic solvents.38 39 The solubilities of 1-fluoro-pyridinium triflate, tetrafluoroborate, hexafluoroantimonate and perchlorate in dichloro-methane are 0.63, 0.05, 0.09 and 0.035 mg cm 3, respectively, and of 1-fluoropyridinium triflate in tetrahydrofuran is 1.71 mg cm-3. The salts were dissolved in water and decomposed very slowly at room temperature. When a solution of 1-fluoropyridinium triflate in water was allowed to stand for 14 days at room temperature it decomposed completely to give pyridin-2-ol in 66% yield. 1-Fluoropyridinium salts with non-nucleophilic counteranions are generally stable crystals with high melting points. 

Fluoropyridinium salts with either tetrafluoroborate, hexafluoroantimonate, or hexafluoro-phosphate as a counteranion can be treated with excess base (triethylamine, pyridine, diethyl-amine) at room temperature to give 2-fluoropyridine (bp 125 126°C, d4° 1.131, np° 1.468) in good yield.43 This method has been successfully applied to the preparation of 2-fluoropyridine derivatives 4 possessing electron-donating or -withdrawing substituents using substituted 1-fluoropyridinium tetrafluoroborates.43... 

Ground crystals of 4-/m-bulyl-1 -fluoropyridinium tclrafluoroborale (1.9 g, 7.89 mmol) were added in portions to Et3N (8mL, 79 mmol) with stirring at rt over a period of ca. 30 min. A vigorous exothermic reaction occurred immediately each time a portion of the 1-fluoropyridinium salt was added. After all of the salt had been added, the solution was stirred for an additional 5 min. GC analysis of the mixture showed that 4-(m-butyl-2-fluoropyridinc was produced in 91 % yield. The mixture was acidified with 1 % HC1 and extracted with pentane. The organic layer was dried (anhyd MgS04) and filtered, and the solvent evaporated yield 0.87 g (72%) oil (purity by GC analysis, > 98%). 

The reaction of sulfides bearing an a-hydrogen with 1-fluoropyridinium salts results in the facile formation of a-fluoro sulfides 7.53... 

It was found that the counteranion of the 1-fluoropyridinium salts considerably affects selective fluorinations.54 For example, fluorination with 1-fluoropyridinium triflate (la) was compared to that with l-fluoro-4-methylpyridinium-2-sulfonate (2b) using a steroid 10 containing an acetoxy function and a conjugated trimethylsilyl enol ether as the substrate.54... 

Porphyrins, e. g. 27, are fluorinated by 1-fluoropyridinium salts (2,6-dichloro-1-fluoropyridinium triflate, 3,5-dichloro-l-fluoropyridinium triflate, pentachloro-l-fluoropyridinium triflate) in an organic solvent such as acetonitrile in the presence of a base (e. g., K2C03 or SrC03) with good selectivity at the meso positions and in high yields.64 "" 66... 

The scope of selective fluorination should be broadened considerably on the basis of the present results. The 1-fluoropyridinium salt system should thus make possible the preparation of many useful organo-fluorine compounds. 

Although a number of electrophilic fluorinating reagents are known, most are toxic, unstable, and difficult to handle. These new, stable N-fluoropyridinium salts are readily obtained in 60-80% yield by reaction of a pyridine with F2/N2(l/9) in CH3CN in the presence of sodium triflate. 

Reaction of iV-fluoropyridinium triflate with a base in methylene chloride affords 2-chloropyridine as the major product along with 2-pyridyl triflate and 2-fluoropyridine. This conversion may be explained by a singlet carbene produced through proton abstraction of the fV-fluoropyridinium salt <1996JFC161>. 

The main use of A -fluoropyridinium salts is as fluorinating agents. A recent study of A-fluoropyridinium-2-sulfonates substituted with alkyl or trifluoromethyl groups reveals them to be powerful and selective fluorinating... 

Oxidation of pyridinecarboxylic acids.1 Reaction of a pyridinecarboxylic acid or the ester with 10% F2 in N2 results in oxidation to the corresponding 2-pyridone in 50-75% yield. An N-fluoropyridinium salt is probably an intermediate. 

With the increasing importance of organofluorine compounds in the development of new materials, pharmaceuticals, and agricultural chemicals, N-fluoropyridinium salts should find extensive use as mild and selective fluorinating agents. 

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