Pyridine 3-fluoro

B. Kuhnast, B. Lagnel - de Bruin, F. Hinnen, B. Tavitian, F. Dolle, Design and synthesis of a new [ F]fluoropyridine-based haloacetamide reagent for the labeling of oligonucleotides 2-Bromo-N-[3-(2-[ F]fluoro-pyridin-3-yloxy)-propyl]-acetamide, Bio-conj. Chem. 15 (2004) 617-627. 

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. 

The iodo-fluoro-pyridine 119 is lithiated by LDA to give the only possible lithium derivative 120. But iodine is a poor ortho-director and the compound equilibrates by the halogen dance to put the Li atom next to one of the best orffto-directors fluorine.14 Presumably one molecule of 120 removes I from 119 to give 123 from which the 3-1 atom is removed by another molecule of 120 initiating a chain. 

Fluorides are more reactive than the other hahdes, (cf. 3.3.2) for example 2-fluoropyridine can be converted into 2-dialkylamino-pyridines using hthium amides at room temperature. This could be compared with the 130 °C required to displace a-bromine using the potassium salt of pyrazole. Displacement of nitro can be made the means for the synthesis of a- and y-fluoro-pyridines. Of the five fluorines in pentafluoropyridine, the y-fluorine is displaced most rapidly. ... 

There are many example of direct hthiation with the assistance of ortfto-directing groups. Halo-, particularly chloro-, or better, fluoro-pyridines, but even bromo-pyridines undergo hthiation ortho to the halogen, nsing lithinm di-wo-propylamide. 3-Halopyridines react mainly at C-4, and 2- and 4-halo-pyridines necessarily hthiate at a P-position. In the hthiation of methoxy-pyridines, using mesityllithium the 3-isomer metahates at C-2, whereas 3-methoxymethoxypyridine, 3-di-/xo-propylaminocarbonyl- ... 

The rate and activation parameters have been determined for the reaction of potassium methanethiolate with various 2-fluoro- and bromo-pyridines. Although an ortAo-methyl group did not activate the 2- position in 2-bromo- or 2-fluoro-pyridine towards attack by the methanethiolate ion, deactivation of the ortho rather than the para position was observed. At 110°C for the bromo-compounds Ao-Me Xp-Me = 3-9, while Ao-Br A -Br = 2-2. The results have been compared with those obtained using methoxide and benzenethiolate anions in methanol. The relative rates observed in HMPA are the same as those in methanoP . Thio-phenol reacts faster than its anion with a bromopyridine, in methanol, due to a rapid acid-base pre-equilibrium in which the pyridine is protonated. An o-MeO substituent accelerates the replacement of Br, and a small increase is also noted on going from MeOH to DMSO as solvenpii. 

Several aminofluoropyridines are prepared either by the Hofmann reaction or the Curtius degradation. Thus, 2-amino-6-fluoropyridine is easily obtained from either 6-fluoropicolinamide or 6-fluoropicolinic hydrazide. 3-Amino-2-fluoro-pyridine and S-amino-2-fluoropyridine are prepared best from the appropriate 2-fluoropyridine carboxamide rather than from the hydrazide because the a-fluorine atom is easily replaced by hydrazine. 

Treatment of pentachloropyridine with hydrogen fluoride at 180 °C under pressure gives a mixture of trichloro-2,6-difluoro- and dichIoro-2,4,6-tri-fluoro-pyridine. Gas-phase fluorination of pentachloropyridine and of 2,4, 2,4,6-trichlorop3rrimidine with hydrogen fluoride over chromium oxide-fluoride and aluminium oxide-fluoride (or A1203) has also been achieved tetrachloropyrimidine gives 5-chloro-2,4,6-trifluoro- (61%), 5,6-dichloro-2,4-difluoro- (33 %), and 4,5,6-trichloro-2-fluoro-pyrimidine (6 %). ... 

Displacement of nitro-groups by fluoride ion has been reported 2-fluoro-pyridine, 4-fluoropyridine, and 2-fluorothiazoIe (244) were prepared in 60, 60, and 20 % yield, respectively, by treating the corresponding nitro-compound with potassium fluoride in -methyl-2-pyrrolidone or hexamethylphos-phoramide. ... 

Fig. 16 pK values of mono-substituted fluoro pyridines and quinolines (pifa pyridine = 5.17 p Ta quinoline = 4.85). pAT, values of analogous chloro and methoxy pyridines are provided for comparison [17]... 

Although predicted theoretically some years ago, unequivocal experimental evidence for the so-called oxa-benzidine rearrangement is still awaited. However, to the list of reactions suspected of involving this type of rearrangement must now be added the process outlined in Scheme 50, which is useful for the direct arylation of pyrimidine. Similar reactions occur with 2-chloro-3-nitro-pyridine and with 2-chloropyrazine, but not with 2-chloro- or 2-fluoro-pyridine. 

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