4- Fluoropyridines reactions

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]... 

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). 

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). 

A similar reaction of 1,2,4-triazole with 2-cyano-3-fluoropyridine 33 gave 3-[l,2,4]-triazol-l-yl-pyridine-2-carboni-trile 34 in a yield of 92% after purification (Equation 7) <2004JME2995>. 

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,... 

Reaction of 2-chloropyridine gives 2-chloro-6-fluoropyridine as the major product which arises from the preferential substitution of hydrogen over chlorine and would be unexpected on the basis of the nucleophilic substitution mechanism described above. The product obtained was suggested, therefore, to arise from the addition of fluorine to the most electron rich carbon-nitrogen double bond, followed by elimination of HF [155]. 

An efficient fluorinating agent is 1 -fluoropyridin-2( 1 //)-one (1) obtained by the reaction of fluorine with 2-trimethylsiloxypyridine.28,29... 

The reaction of estrone with the parent 1-fluoropyridinium triflate (la), followed by acetylation, gives a mixture of 3-acetoxy-2-fluoro- and 3-acetoxy-4-fluoroestra-l, 3,5(10)-trien-17-one (16 and 17) in 73 % yield.56 Treatment of 3,17/ -diacetoxyandrosta-3,5-diene with 1 -fluoropyridin-ium triflate and acetic acid in 1,2-dichloroethane at 77 °C provides 17/5-acetoxy-6a-fluoro- and 17/J-acetoxy-6/ -fluoroandrost-4-en-3-one in 81% total yield.57... 

Fluorodediazoniation in anhydrous hydrogen fluoride has been also applied to the synthesis of fluorinated heterocycles, especially pyridines 2. In this case, the reaction is more sensitive to the reaction conditions. For example, diazotization must be performed at lower temperatures than usual and the dediazoniation temperature must be raised slowly in order to obtain good yields. Workup is also important addition of dichloromethane prior to neutralization with ammonia32 as well as treatment of the organic phase with calcium hydride before distillation33 has been recommended, particularly for 4-fluoropyridines (4-fluoropyridine itself forms 4-fluoro-l-(4-pyridyl)pyridinium fluoride if not stored in a sealed tube with cooling33 or stabilized as the hydrochloride32). 

As in the case of fluoropyridines, problems of addition are overcome by LDA metalation. Thus 2-, 3-, 5-, 6-, and 7-fluoroquinolines lead, after TMSC1 quench, to modest to good yields of products 22-26 of chemoselec-tive DoM reaction (Scheme 8) [79JOM( 171)273]. 

Similar behavior of lithium-bromide exchange (-60°C) and homo-transmetalation (metalation of a substrate by one of Li derivatives) (-40°C) was observed in reactions of 4-bromo-3-fluoro- and 3-bromo-2-fluoropyridine with n-BuLi (86T2253). Under similar conditions, 2,3-dibromopyridine undergoes partial bromine migration, yielding, after... 

Systematic studies on 3-fluoropyridine, the first mono halopyridine to be shown to undergo the DoM process [72CR(C)(275)1535], showed that metalation regioselectivity was dependent on reaction conditions (solvent, temperature, time, metalating agent). 

Amminolysis of 3-halopyridines, generally a difficult reaction, can be effected via N-oxide derivatives. Thus, metalation-ary aldehyde condensation on 3-fluoropyridine (38) affords carbinols 122 which, upon standard sequential oxidation reactions, affords the N-oxide ketone 123 (Scheme 38) (84TH1). Treatment with dimethyl amine afforded the 3-amino derivative 124, thus completing this high overall yield sequence. 

In a clear demonstration of such advantage, 2-fluoropyridine (11) has been converted into the 3-substituted derivative 190 (Scheme 55) (88JOC2740). Thus, metalation of 11 followed by iodination gave the 3-iodopyridine 189 which, upon the application of standard SRNi reaction conditions, furnished 190 in almost quantitative yield. This reaction adds an umpolung dimension to substition chemistry of halopyridines formed by DoM processes. 

Fluoropyridines have been prepared by direct reaction of fluorine diluted in an inert gas and dissolved in a polyhalogenated solvent (91BCJ1081). Presumably these reactions involve attack by free halogen atoms as distinct from the ionic halogenation at lower temperatures which gives p-orientation (cf. Section 3.2.1.4.7). Under similar conditions (Br2,450°C) quinoline gives 2-bromoquinoline. 

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