Pentafluoropyridine substitution

Until recently the substitution pattern in pentafluoropyridine was considered to be 4 2 however, several examples have been found where... 

A mechanism in which ketyl radicals play a role was also postulated for the formation of cyclohexylpentafluorobenzene upon irradiation of a cyclohexane solution of hexafluo-robenzene in the presence of benzophenone756. In this case, however, the excited benzophenone abstracts a hydrogen atom from the solvent and the cyclohexyl radical attacks hexafluorobenzene. The resulting radical is transformed further into the substitution product by loss of fluorine and into an addition product by abstraction of a hydrogen atom. Irradiation of a cyclohexane solution of pentafluoropyridine in the presence of benzophenone resulted in the formation of 4-cyclohexyltetrafluoropyridine, while no addition product was observed. 

Similarly, treatment of pentafluoropyridine with various dinucleophiles yields the substitution products 16 (Scheme 12). No cyclization products have been observed (7SRC 1039). 

Although controlled substitution with molecular fluorine is difficult to attain, noteworthy is the recent success in perfluorinating both saturated and unsaturated heterocycles by electrolysis in anhydrous hydrogen fluoride. Cf. T. C. Simmons and F. W. Hoffmann, J. Am. Chem. Soc. 79, 3429 (1957), for the preparation of undecafluoropiperidine (from piperidine). The latter compound can be converted into pentafluoropyridine by passing it over an iron contact at 600° [R. E. Banks, A. E. Ginsberg, and R. N. Haszeldine, J. Chem. Soc. p. 1740 (1961)]. 

The reactivity profile established for pentafluoropyridine, where the 4, 2- and 6-positions are sequentially, regiospecifically substituted by a succession of oxygen-centred nucleophiles, has allowed medicinal chemists to use pentafluoropyridine as a core scaffold for the synthesis of small arrays of biologically active pyridine systems that fall within the Lipinski parameters (see Table 11.3). 

In these cases, while nucleophilic substitution at the 4-position of pentafluoropyridine by guanidine could be achieved readily [46], attack at the less activated 3-position by the weak NH2 nucleophile present on the guanidine moiety made cyclization a less favoured process than elimination. Consequently, in order to achieve cyclization by nucleophilic substitution in the second step, a more reactive second nucleophile is necessary. 

By a similar strategy, an imidazopyridine scaffold 32 was synthesized by reaction of pentafluoropyridine and benzamidine 31 [56] and, in this case, subsequent nucleophilic substitution occurs at the 5 position to give 33, presumably because of interaction of the nucleophile and the imidazo ring NH bond which directs the incoming nucleophile to the less activated site adjacent to pyridine ring nitrogen. 

Chambers, R. D., Hoskin, P. R., Sandford, G., et al. (2001) Synthesis of multi-substituted pyridine derivatives from pentafluoropyridine. J. Chem. Soc., Perkin Trans 1, 2788-2795. 

Substitution reactions of pentafluoropyridine occurred with nucleophiles in the presence of alkali metal fluorides in graphite (84IZV2158). Treatment... 

Nucleophilic aromatic substitution of activated substrates (pentafluoropyridine, octafluorotoluene, hexafluorobenzene, metal arene jc-complexes) by anions of diethyl cyanomethylphosphonate has been achieved. The reaction is carried out with satisfactory yields in DMF, MeCN, or THF at room temperature in the presence of NaH, CsF, KjtX), or CS2CO3." In a similar manner, 3,6-dihalopyridazines react with sodium diethyl cyanomethylphosphonate in refluxing THF to give phosphonosubstituted pyridazines in 22-68% yields. ... 

Nucleophilic aromatic substitution of perhaloarenes such as pentafluoropyridine and octafluorotoluene by anions of diethyl l-(ethoxycarbonyl)methylphosphonate has been reported. The reaction is carried out with satisfactory yields (60-85%) in solid-liquid system using 2-3 eq CsF or NaH as bases or 3 eq K2CO3 in the presence of TEBAC as phase-transfer agent. - ... 

Only in the case of triazines310-312 is complete substitution obtained readily (Eqs. 84,310 and 85312), although a pentasubstitution product has been observed from pentafluoropyridine, usingtetrafluoroethylene.308,313 In... 

C-allylation of PhO" Na with H2C=CHCH2C1 in a variety of solvents in the presence of different crown ethers is most effective in each case when using poly(vinylbenzo-15-crown-5)polyether. Only in the presence of the crown ethers 15-crown-5 and 18-crown-6 are the anions in potassium phthalimide and sodium saccharinate, respectively, sufficiently activated to bring about nucleophilic aromatic substitution of the 4-fluorine in pentafluoropyridine. The formation of 2,4-dinitrophenol, in addition to the expected ether, from 2,4-dinitrochlorobenzene and potassium 2-propoxide in 2-propanol-benzene (1 1), in the presence of dicyclohexyl-18-crown-6 polyether, has been accounted for on the basis of a nucleophile-radical reaction (5rn1)/ ... 

Syntheses of tri- and tetrafluoro-substituted pyridiniumtrifluoromethylsulfoxides and their hydroxyl(methoxy)-substituted analogues were previously reported in the same reference. Reactions of pentafluoropyridine with pentafluoro- and 4-nitrophenols were also studied. It was found that the first substitution occurs at the C4-position of pentafluoropyridine, subsequently giving a mixture of di- and triphe-noxy-substituted fluoropyridines. 

Dmowski, W. Haas, A. Trifluoromethanethiolate ion. Part 2. Nucleophilic substitution in pentafluoropyridine. Synthesis and characteristics of trifluoromethylthio and trifluoro-methylsulphonyl derivatives. J. Chem. Soa, Perkin Trans. 1 1987, 2119-2124. 

Extensive discussions regarding the factors that affect the regioselectivity of such nucleophilic aromatic substitution processes have been published in the course of developing the chemistry of pentafluoropyridine and related heteroaromatic systems. 

Pentafluoropyridine Reactions of pentafluoropyridine with nucleophiles proceed very readily and, in the vast majority of cases, substitution of fluorine located at the 4-position is achieved regioselectively. Reactions involving a very wide range of oxygen, nitrogen, sulfur, and carbon-centered nucleophiles have been reported and representative examples of such processes are indicated in Table 8.2. Of... 

The great majority of nucleophilic substitution reactions of pentafluoropyridine occur at the 4-position, but there are exceptions. Keto-oximate salts give high proportions of the 2-substituted isomer (Fig. 8.7) and this is postulated to be due to the directing effect of a complex formed between the pyridine ring and the incoming salt. ... 

Tetrafluoropyridine derivatives, synthesized by nucleophilic substitution reactions of pentafluoropyridine are, of course, electron-deficient aromatic ring systems and further nucleophilic substitution can occur. However, few studies exploring the effects of the 4-substituent upon the regiochemistry of further nucleophilic substitution processes have been reported and examples of reactions of various 2,3,5,6-tetrafluoropyridine derivatives with diethylamine are shown in Table 8.3 to illustrate the synthetic possibilities. 

Recently, the reactivity profile of pentafluoropyridine, where reaction at the 4-position is followed by substitution at the 2- and 6-positions selectively, has been used by medicinal chemists for the synthesis of small arrays of biologically active... 

The order of nucleophilic substitution for the displacement of fluorine atoms in pentafluoropyridine, as outlined above, is generally in the order 4 > 2 > 3, but this reactivity can be altered by reaction with bifunctional nucleophiles. Substitution of the 4-position may be followed by attack at the adjacent 3-position due to the geometric constraints of the system as outlined in Fig. 8.9. Similarly, tetrafluor-opyridine derivatives bearing substituents at the 4-position react with appropriate difunctional nucleophiles to give poly functional annelated sy stems. 

A variety of ring-fused systems have been prepared by reaction of pentafluoropyridine and various tetrafluoropyridine systems with difunctional nitrogen nucleophiles. For example, tetrahydropyrido[2,3-Z ]pyrazine and imidazopyridine systems can be prepared by reaction of pentafluoropyridine and appropriate tetrafluoropyridine systems with suitable diamines. The [5,6] and [6,6]-ring-fused systems are also useful substrates for further nucleophilic substitution processes and, consequently, act as versatile scaffolds for the construction of a range of functionalized annelated systems (Fig. 8.10). Of course, such scaffolds are of great interest to the life science industries where access to novel heterocyclic skeletal diversity is a major factor driving the discovery of new chemical entities in lead generation. 

Tetrafluoropyrimidine Perfluorinated diazines (pyrimidine, pyrazine, and pyridazine) are typically 1000 times more reactive toward nucleophiles than pentafluoropyridine. Various reactions of tetrafluoropyrimidine with a small range of nucleophiles have been reported (Fig. 8.15) and, in all cases, nucleophilic substitution occurs selectively at the 4-position, consistent with the mechanistic principles discussed above. 

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