Fluorinated 2- pyridines synthesis

Blayo AL, Le Meur S, Gree D, Gree R (2008) New enantloselective synthesis of mono-fluorinated pyridines designed for the preparation of chemical libraries. Adv Synth Cat 350 471 76... 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

In principle, this would be the preferred route, but in practice no generally successful procedure is available for the synthesis of highly fluorinated compounds directly by this approach. It has been reported that pentafluoro-pyridine may be obtained in approximately 15% yield by fluorinating pyridine over cesium tetrafluorocobaltate (Eq. 10).45 But it appears that... 

Trifluorothymidine is a fluorinated pyridine nucleoside structurally related to idoxuridine (55). It has been approved by the U.S. FDA and is a potent, specific inhibitor of replication of HSV-1 in vitro. Its mechanism of action is similar to that of idoxuridine. Like other antiherpes drugs, it is first phos-phorylated by thymidine kinase to mono-, di-, and triphosphate forms, which are then incorporated into viral DNA in place of thymidine to stop the formation of late virus mRNA and subsequent synthesis of the virion proteins. 

SYNTHESIS OF RING-FLUORINATED PYRIDINES HForHF-Py, NaNOg... 

Several variations of the Baltz-Schiemann reaction allow synthesis of fluorinated pyridines in almost quantitative yields. For example, 2-fluoropyridines 28 were prepared in 91-94% yields by diazotation of 2-aminopyridines 27 with sodium nitrite in anhydrous HF or HF-pyridine complex (Scheme 6.11). " ... 

A similar synthetic approach was used in the synthesis of polyfluorinated oxygen-and nitrogen-containing macrocycles. Substitution reaction of fluorinated pyridines... 

A similar approach was used in case of aromatic fluorinated heterocycles. Ring-fluorinated pyridines containing one, two, and three fluorine substituents are reviewed in Chapter 6, whUe Chapter 7 focuses on the synthesis and typical chemical transformations of aromatic heterocycles containing perfluoroalkyl groups. 

Palacios and coworkers describe a simple de novo construction of fluorinated pyridines via a stereoselective synthesis of fluorine-containing /3-aminophosphonate intermediates (eq 72). ... 

Thus, treatment of enamines with BuLi yields the lithiated species, which was selectively C-methylated to give the corresponding a-methyl-substituted enamines in good yields. The reaction of the enamines with a, 8-unsaturated ketones is also explored (eq 73). Furthermore, the lithio-enamines undergo 1,2-addition to unsaturated ketones to give intermediates, which, upon cycliza-tion and prototropic rearrangement, provide a regioselective de novo synthesis of fluorinated pyridines. 

TA. Vaganova, I.K. Shundrina, S.Z. Kusov, V.I. Rodionov, E.V. Malykhin, Synthesis and characterization of novel fluorinated pyridine-based polyimides, J. Ruorine Chem. 149 (2013) 57-64. 

The present review contains the literature published since 2009 for 2012. TUI 2009 four reviews on this field have been published, completely [1, 2] or in part [3] devoted to methods syntheses C-F pyridines and perfluoroalkyl pyridines [2,4]. To display full information about synthesis fluorinated pyridines in the present review earlier classical works also are included. 

The reaction has general character. It is applied for the synthesis of various 2-, 3- or 4-fluoropyridines and is full enough described in earlier reviews [1,3,4]. Practical use the Baltz-Schiemann reaction for preparation of pesticides or medicines is described in reviews [6, 7]. Several variations of the Baltz-Schiemann reaction allow synthesis of fluorinated pyridines in almost quantitative yields. For example, 2-fluoropyridines 21 were prepared in 91-94 % yields by diazotization of 2-aminopyridines 20 with sodium nitrite in anhydrous HF or HF-pyridine complex [23] (Scheme 8). 

Synthesis of exo-2-(2 -fluorosubstituted 5 -pyridinyl)-7-azabicyclo[2.2.1]heptanes (28), novel nicotinic receptor antagonists, was based on diazotization reaction of corresponding 2-aminopyridines 27 using HF-pyridine complex [26-29] (Scheme 11). Classical examples of use of this reaction are resulted in earlier works [23-29], Now the Baltz-Schiemann reaction continues to use for synthesis fluorinated pyridines. 

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