Baltz-Schiemann reaction

Fluorinated and iodinated derivatives are usually prepared by halogen exchange reactions, although the Baltz-Schiemann reaction has been applied to the synthesis of 2-fluoroquin-oxaline (66JHC435>. 

The most widely used method for the substitution of nitrogen-containing functional groups by fluorine is the thermal or photochemical decomposition of diazonium salts, the Baltz-Schiemann reaction (see Section 1.1.8 ). 

One of the typical examples of the Baltz-Schiemann reaction is synthesis of fluoro-substituted pyridines 26 from aminopyridines 25 (Scheme 6.10). In this variation, the Baltz-Schiemann reaction is most often used for the synthesis of 2-fluoropyridines. In the first step, a diazonium tetrafluoroborate is generated from 2-aminopyridine, NaN02, and solution of HF and BF3 (HBF4), while subsequent thermal decomposition of the diazonium salt leads to formation of 2-fluoropyridines. In this chapter, we present several literature examples of synthesis of 2-fluoropyridines and examples of specific use of the Baltz-Schiemann reaction for preparation of biologically active derivatives of 2-fluoropyridines. 

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). " ... 

Fluoro-5-methylpyridine, which is often used for the synthesis of herbicides, can be also prepared by the Baltz-Schiemann reaction from the corresponding 2-amino-5-methylpyridine ... 

The Baltz-Schiemann reaction is the most often used method for the synthesis of 3-fluoropyridines. This method utilizes readily accessible 3-nitropyridines as the precursors, since they can be readily reduced into amines and then used in the Baltz-Schiemann reaction. In this section, selected examples applied for the synthesis of practically important compounds are given. For example, the Baltz-Schiemann reaction was used for the synthesis of fluoro-substituted epibatidine analogue 79 (epibatidine is a high-affinity nonselective ligand for nicotinic cholinergic receptor (nAChRs)) (Scheme 6.27). 

Deoxy-3-fluoropyridoxamine 5 -phosphate 86 (a coenzyme Bg analogue) was also synthesized using the Baltz-Schiemann reaction" (Scheme 6.28). First, substituted pyridine 80 was nitrated to form 3-nitropyridine 81, which was subsequently treated with PCI5 to form 2-chloro-5-nitropyridine 82. It was then reduced in two steps to form 3-aminopyridine 84, was converted into 3-fluoropyridine 85 by the Baltz-Schiemann reaction, and afterward was transformed into 3-deoxy-3-fluoropyridoxamine 5 -phosphate (F-PMP) 86. 

Similarly, the Baltz-Schiemann reaction was also used for the synthesis of 3-fluoropyridine-4-carboxylate, which can also be prepared by the nucleophihc sub-... 

The Baltz-Schiemann reaction can also be used for the synthesis of 4-fluoropyridine derivatives. For example, it was successfully applied to the synthesis of... 

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. 

The Baltz-Schiemann reaction is frequently used in synthesis substituted 3-fluoropyridine 58-intermediate for synthesis of biologically active compounds [58-62]. In particular, compound 58 was used for synthesis of compound 59 active against atherosclerosis dyslipidemias [59,60] (Scheme 21). 

Hydroxy-2-chloro-4-fluoroquinolones (95) have been synthesized by Baltz-Schiemann reaction for creation of novel quinolone compounds applied as S-nitrosoglutathione reductase (GSNOR) inhibitors [80] (Scheme 36). 4-Huoropyridinone synthesized by Baltz-Schiemann reaction from 2-chloro-4-fluoropyridine, it is used in synthesis 4-fluorocytisine [81]. 

Bromo-2,3-difluoropyridine (133) it is synthesized by Baltz-Schiemann reaction from 2-amino-5-bromo-3-fluoropyridine (132) [108] (Scheme 49). 

Substituted 2,5-difluoropyridines 206 are obtained from the corresponding aminopyridines 205 by Baltz-Schiemann reaction, which are used in various areas of organic synthesis, including synthesis of biologically active compounds [108, 131-133]. For example, by few steps reaction 2-amino-3-bromo-5-fluoropyridine (205) was converted to biologically active compounds (210) by few steps [133] (Scheme 65). 

The Baltz-Schiemann reaction is still one of the most common methods for direct ring fluorination because of the accessibility to aminated isoquinoline derivatives. The original conditions, which involve the use of tetrafluoroboric acid (fluoroboric acid), are still often employed, [23-27] even though several modified procedures have been reported. For example, Myers synthesized 1-fluoroisoquinoline 2 by the dealkylative diazotization of 1-fcrt-bntyl-aminoisoquinoline 1 with pyridine hydrofluoride instead of HBF4 (Scheme 8) [28]. 

Scheme 13 Reaction of compound 21 with KF 3.2.4 The Baltz-Schiemann Reaction...

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