Halopyridines Fluoropyridines

Amines or ammonia replace activated halogens on the ting, but competing pyridyne [7129-66-0] (46) formation is observed for attack at 3- and 4-halo substituents, eg, in 3-bromopyridine [626-55-1] (39). The most acidic hydrogen in 3-halopyridines (except 3-fluoropyridine) has been shown to be the one in the 4-position. Hence, the 3,4-pyridyne is usually postulated to be an intermediate instead of a 2,3-pyridyne. Product distribution (40% (33) and 20% (34)) tends to support the 3,4-pyridyne also. 

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. 

Aqueous titanium (III) chloride reductively removes cyano and halo groups from substituted pyridines by a two-electron process and promotes reduction of pyridyl ketones and aldehydes to glycols by a one-electron-transfer process.49 a useful review of the reactions of halopyridines with lithiating reagents is now available.50 Choice of reaction conditions can be critical thus, depending on the conditions, 3-fluoropyridine can be converted into either 2- or 4-lithio-3-fluoropyridine and therefore be used as a precursor of both 2,3- and 3,4- disubstituted pyridines. 

The mechanism of this reaction was discussed in several publications. It was demonstrated that under workup with triethylamine in CH2CI2 or CH2Br2, trifiate salt 14 gives a mixture of three compounds 2-halopyridine 15, compound 16, and 2-fluoropyridine (Scheme 6.7). Similarly, it was demonstrated that salts 12 give 2-diethylaminopyridines, 2-phenylaminopyridines, or 2-(2-furyl and 3-furyl) pyridines when they are reacted with Et2NH, benzene, or furan. 

It was shown that 2-halopyridines 44 containing chlorine substituent in position 3, can be selectively converted into 2-fluoropyridines 45 by treatment with KF [41] (Scheme 14). The reactions were conducted at elevated temperature (100-200 °C) producing final pyridines 45 in 14-94 % yields (Table 3). 

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