2-Fluoropyridine amination

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. 

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). 

Fluoropyridinium salts with either tetrafluoroborate, hexafluoroantimonate, or hexafluoro-phosphate as a counteranion can be treated with excess base (triethylamine, pyridine, diethyl-amine) at room temperature to give 2-fluoropyridine (bp 125 126°C, d4° 1.131, np° 1.468) in good yield.43 This method has been successfully applied to the preparation of 2-fluoropyridine derivatives 4 possessing electron-donating or -withdrawing substituents using substituted 1-fluoropyridinium tetrafluoroborates.43... 

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. 

Fluoropyridines undergo amination in good yield on treatment with lithium aminoborohydride reagents in THF at 65 °C <2003OL3867>. As an example, reaction with 1.1 equiv of lithium piperidinyl borohydride in THF at 65 °C gives 2-piperidinylpyridine in 99% yield (Equation 104). 2-Chloropyridine can also be used as a substrate in the presence of excess borohydride. 

An example of a thermal Balz-Schiemann reaction at room temperature is the preparation of the elusive 4-fluoropyridine (6) from pyridin-4-amine (5). ... 

Usually it is possible to isolate and characterize the arenediazonium tetrafluoroborate intermediate, e.g. 8, and then, in the next step, carry out the thermal decomposition of that intermediate, c.g. the preparation of 2.6-disubstituted 3-fluoropyridines 9 from the corresponding pyridin-3-amines 7 (Tabic 7, see also Vol. If lOa, p 711... 

Lithium aminoborohydride has proven to be a mild reagent to generate 2-dialkylaminopyridines from 2-fluoropyridine. This reaction is generally applicable to the introduction of unhindered secondary amines <03OL3867>. 

The more reactive 2-chloro-3-fluoropyridine (89) is aminated readily by piperazine in boiling -butanol to give —60% of 90 (83JMC16%). The presence of a polar cyano group allows the 2-chloro-3-cyanopyridine (72) to be aminated already at I00°C by methylamine to 2-methylamino-3-cyanopyridine (91) in 63% yield (85SC10I3). An additional 6-chloro group, as in 92, leads, upon amination with ammonia to a mixture of the corresponding amino compounds 93 and 94. With the weakly basic aniline in the... 

Due to these safety problems, the search for new, easy-to-handle electrophilic fluorinating agents has become an important area of research. Some of these new reagents have been tested in the fluorination of enamines to give a-fluoro ketones. These include l-fluoropyridin-2(l//)-one (9), 16 AMluoroquinuclidinium fluoride (NFQNF, 10),117 AMluoropyridinium salts 11, 18 and /V-fluorobis(trifluoromethanesulfonyl)amine (Tf2NF, 12).42... 

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). 

Amides can be readily added to the 2-position of the title compound. One account describes a direct dehydrative process, whereby the pyridine iV-oxide is activated by triflic anhydride (eq 34). The role of a base additive was determined to be key with 2-fluoropyridine, proving to be optimal. Also noteworthy is the application of a similar means of triflate activation in the addition of amine nucleophiles. A separate account describes the amidation of the title compound via reaction with activated isocyanides. The reaction requires the presence of TMSOTf, which, under these conditions, furnishes the corresponding amine directly (eq 35). 

The halogen atom in 3-chloropyridine 1-oxide is very much less activated than those in 2- and 4-halogenopyridine 1-oxides but more so than that in 3-chloropyridine (see below). 3-Fluoropyridine 1-oxide reacts with piperidine or hydrazine more readily than do the chloro- or bromo-compounds . Surprisingly, reaction of amines or hydrazine with 3-halogeno-4-nitropyri-dine 1-oxides causes replacement of halogen and not of the nitro-group " 2. 

For preparing 2- and 4-fluoropyridines diazotization of the amines has been effected in aqueous a, 424, 790, 805 or anhydrous hydrofluoric acid, 806-7, Alternatively, the Schiemann reaction has been used 807-9 or the diazotization has been carried out in fluorosilicic acid , 807, h impossible to state which method is generally to be preferred. Yields are usually poor the best of 2-fluoropyridine (42 per cent) was obtained by using fluorosilicic acid ". 4-Fluoropyridine was obtained in poor yield by diazotizing 4-aminopyridine in hydrofluoric acid 24... 

Resin bound fluoronicotinoate 4 was reacted with a variety of amines under mild conditions (8 eq. amine, 8 eq. K2CO3, DMF, 25 °C). Sinq>le alkyl amines functioned as good nucleophiles in this reaction (8) even morpholine, typically a relatively weak nucleophile (9), gave excellent results under these conditions. Of the aliphatic amines swveyed, only sterically demanding diisopropylamine failed to react with the fluoropyridine substrate. On the odrer hand, aromatic amines, which do not commonly participate in SnAR reactions (]]) did not react under these conditions. 

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