4- -2-fluoropyridine

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

Metahation of 2-fluoropyridine with lithium diisopropylamide (LDA) gives 2-fluoro-3-hthiopyridine, thereby providing entry to 3-substituted pyridines (388). This technique has been used to make fluorine analogues of the antitumor eUipticines (389). 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

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

None of the 3-halogenopyridines yield 2-piperidinopyridine. This substance was obtained as the only product from the reaction of 2-fluoropyridine (24, X = F) with lithium piperidide under the same conditions in 97% yield. Finally, it was found that 4-chloropyridine (32, X = Cl) was converted in 95% total yield into a mixture of 0.4% of 3-piperidino- (29, Y = NC5H10) and 99.6% of 4-piperidino-pyridine (34, Y = NCsHio)- Thus, in contrast to the amination with potassium amide, 4-chloropyridine reacts with lithium piperidide almost exclusively via the addition product 33 (X = Cl, Y = NC5H10). 

Fluorination of pyridine (90TL775), uracil (90T3093), and octaethyl-porphyrin [88JCS(P1)1735] has been described using cesium fluorooxysulfate. The outcome of the former was strongly dependent on the solvent. For example, with pyridine in methanol no fluorination was observed and 2-methoxypyridine was obtained. 2-Fluoropyridine was isolated when cyclohexane was the solvent (90TL775). 

Nitrosonium tetrafluoroborate has been proposed as an alternative to NaN02/HBF4. 2-Fluoropyridine is obtained in 69% yield on warming a CH2C12 mixture of NOBF4 with 2-NHrpyridine (90EUP430434). 

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 ease of dehalogenation of C H X by Ni(ll)/ IMes HCl 1/NaO Pr decreased in the order 1 > Br > Cl F. Subsequent work showed that a 1 1 combination of Ni and NHC in the presence of NaOCHEt resulted in enhanced reactivity towards aryl fluorides [6], Again, the A-mesityl substituted ligand IMes HCl 1 imparted the highest level of catalytic activity. Table 8.2 illustrates that hydrodefluorination is sensitive to both the nature of the substituents on the aromatic ring and the specific regioisomer. Thus, 2- or 4-fluorotoluene (Table 8.2, entry 2) proceeded to only 30% conversion after 15 h, whereas quantitative conversion of 2-fluoroanisole (Table 8.2, entry 3) and high conversion of 3-fluoropyridine (Table 8.2, entry 5) was achieved in only 2-3.5 h. The reactivity of 2-fluoropyridine was compromised by more efficient nucleophilic aromatic substitution. 

Carbon and Proton NMR Data. 13C and 11NMR chemical shift and coupling constant data for 2-fluoropyridine, 2-fluoroquino-lines, and 2-fluoroquinoxoline are provided in Scheme 3.62. 

The solid produced by action of bromine trifluoride on pyridine in carbon tetrachloride ignites when dry. 2-Fluoropyridine reacts similarly. 

Halogen substituents are of course easy to introduce to heteroaromatic rings, and they also enhance the acidity of the ring protons. n-BuLi will, for example, lithiate the tetrafluoropyridine 179 at —60°C in ether ° but with pyridine itself it leads to addition/reoxidation products . Addition to the ring is the major product with 2-fluoropyridine 180, though some metaUation can be detected selectivity in favour of metaUation is complete with LDA in THF at —75 °C or with phenyUithium and catalytic -Pr2NH at —50°C (Scheme 90) . Similar results are obtained with quinolines . 

In the total synthesis of 1-fluoroellipticine (56), 1-ethoxy-1-tributylstannylethene was once again used as a two-carbon building block. The 4-pyridylbromide 54 was assembled by applying a metalation/halogen-dance strategy starting from 2-fluoropyridine <92JOC565>. 

Fluoropyridine 2/(19F, 1SN) of -52.64 Hz in (CD3)2CO indicating coupling mechanism strongly influenced by proximity of N and F lone pairs 79CC478... 

Pyridine is converted into perfluoropiperidine (82) in low yield by reaction with fluorine in the presence of cobalt trifluoride (50JCS1966) quinoline affords (83) under similar conditions (56JCS783). Perfluoropiperidine can be obtained electrochemically. This is useful, as it may be readily aromatized to perfluoropyridine by passing it over iron or nickel at ca. 600 °C (74HC(14-S2)407). Recently, pyridine has been treated with xenon difluoride to yield 2-fluoropyridine (35%), 3-fluoropyridine (20%) and 2,6-difluoropyridine (11%), but it is not likely that this is simply an electrophilic substitution reaction (76MI20500). 

A simple example of the Balz-Schiemann reaction is the preparation of 2-fluoropyridine by diazotization of 2-aminopyridine in HF-pyridine at 0°C, and then allowing the salt to warm up to 20°C [88JFC(38)435] there are many other examples [81CJC2608, 81JOC4567 82JHC1245 84H(22)1105 85H(23)1431, 85H(23)1969, 85JHC145 87LA857]. Chloro,... 

Fig. 5. 19F/15N IMPEACH MBC spectrum of a mixture of 2- and 3-fluoropyridine. The accordion optimisation range was varied from 4 to 50 Hz the Fx frequency domain was digitised using 64 increments of the evolution time, ti. The Fi doublet splitting for the 2-fluoropyridine correlation of 70bs = 728 Hz (see text) is clearly visible while the smaller one for the 3-fluoropyridine correlation is no longer resolved. Reproduced from Ref. 27 by permission of J. Wiley Sons.

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