SNAr displacement reactions

It is important to note that SNAr displacement reactions of heteroatom functional groups other than halides have been demonstrated on purine substrates, including mesitylenesulfonates <20000L927>, sulfones (see Section 10.11.7.5), nitro substituents <2006S2993>, and T-azoles (see Section 10.11.7.3.2). Halopurines have been reduced using sodium naphthalenide <1997T6295>. 

There is certain similarity in the order of reactivities between SNAr displacement reactions and oxidative additions in palladium chemistry. Therefore, the ease with which the oxidative addition occurs for these he ter o aryl chlorides has a comparable trend. Even a- and y-chloroheterocycles are sufficiently activated for Pd-catalyzed reactions, whereas chlorobenzene requires sterically hindered, electron-rich phosphine ligands. 

Mechanistic features of SNAr displacement reactions involving amino nucleophiles have been the object of many investigations, a major point of interest being the occurrence of base-catalyzed paths. Strongly activated aryl halides react readily with ammonia and with primary and secondary amines to give the corresponding arylamines. Thus, for example, 2,4-dinitrofluorobenzene is used to tag the amino end of a peptide or protein chain. 

Haloacridines and 6-halophenanthridines readily undergo SnAr displacement reactions by analogy to the corresponding pyridine, quinohne, and isoquinohne compounds. 

New tri- and tetracyclic compounds containing the pyridazine moiety were synthesized in a multistep reaction sequence from commercially available pyridazine 173 <00AP231>. Acid chloride 173 reacted- readily with 174 to yield 175. Cyclized product 176 was then produced by treatment of tethered pyridazine 175 with sodium hydride in an intramolecular SNAr displacement. 

By taking advantage of the C(2) activation, 2-allyloxy-3-iodopyridine (173) was prepared by an SNAr displacement of 2-chloro-3-iodopyridine with sodium allyloxide [137]. 2-Chloro-3-iodopyridine was prepared by orrto-lithiation of 2-chloropyridine followed by iodine quench. The intramolecular Heck reaction of allyl ether 173 under Jeffery s ligand-free conditions resulted in 3-methylfuro[2,3-6]pyridine (174). 

Activated nitro and halo substituents have been efficiently replaced by a variety of alkyl groups via SsAx reaction with carbanions. Examples include the displacement of the nitro group in compounds (10 X = 4-PhCO, 4-MeOCO, 4-CN, 4-N02, 4-PhS02, 3,5-(CF3>2) by the anion of 2-nitropropane in HMPA at room temperature (equation 2),83 and the reaction of p-dinitrobenzene with several ketones, esters and nitriles (RH equation 3) in Bu OK/liquid NH3 at -70 C.84 Interestingly, under the latter reaction conditions, p-chloronitrobenzene gave the product of alkylation rather than of SNAr displacement of chloride, as in equation (4).85 Further examples include the dehalogenation of p-halonitrobenzenes by 9-fluorenyl anions in DMSO at room temperature,34 and dehalogenation and denitration reactions by the carbanions of phenyl- and diphenyl-acetonitrile in DMSO or under PTC conditions.86... 

In the case of the SNAr nucleophilic displacement reaction shown in Fig. 2,19F was found to be an useful probe nucleus (19). Since fluorine is the leaving group, the disappearance of the 19F signal offers a window through which to observe reaction progress. Shown in Fig. 2 is a typical spectrum... 

Quinazolines undergo many of the same reactions as pyrimidines, such as SwAr reactions, using a chloride as the leaving group. For example, Chenard and co-workers chemoselectively converted quinazolinethione 99 to chloride intermediate 100. Subsequent SNAr displacement of the chloride with amines led to the formation of aminoquinazolinones 101 <01JMC1710>. 

Fluoropurines have also been prepared by SNAr displacement of 2-nitropurine derivatives, using tetra-A-butyl ammonium fluoride (TBAF) as the fluoride source [14], A variation on this method proved particularly useful for the introduction of an T radiolabel into 2-fluoroadenosine 10, since the Balz-Schiemann reaction is poorly applicable to radiochemistry and the displacement of 2-iodo- or 2-fluoropurines with radioactive fluoride ion is inefficient [15] (Scheme 3). 

Solid phase combinatorial synthesis is also applicable to purine nucleosides, as exemplified by the preparation of a library of more than five hundred 2,8-disubstituted guanosine analogues using SNAr displacement of the 2-fluoro group in the protected nucleoside 28, linked to the polystyrene resin with a methoxytrityl group through the ribose C-5 hydroxyl [54] (Scheme 12). The SnAt reactions were successful with primary or secondary alkylamines, but not with anilines or other arylamines. 

The electron-withdrawing character of Cr(CO)3 can be used to promote the displacement of leaving groups on nonactivated aromatic rings in SNAr reactions.117 Perhaps other SNAr reactions can be run, taking advantage of Cr(CO)3 and of PTC activation.117a... 

Benzotriazoles, for example, are accessible from o-aminoaryl-substituted triazenes after a two-step reaction sequence a nucleophilic displacement followed by cleavage/heterocyclization.35 The nucleophilic halide displacement of activated haloarenes is an indispensable tool for the synthesis of highly substituted arenes. Fluoronitroarenes in particular have served as excellent precursors in this transformation. Thus, it was appealing to combine this SNAr reaction with the flexibility of diazonium chemistry. In this case, an immobilized fluoronitrophenyl triazene would be the equivalent of the Sanger reagent. 

In conclusion, SNAr reactions are often facihtated by polar protic solvents such as butanol or by polar solvents in the presence of Brpnsted or Lewis acids. When displacements of halides with amines are used, both polar and protic solvents can solubilize the ammonium halides resulting from the reactions, and lead to the formation of Brpnsted acids. Fluoride or chloride ions are preferred leaving groups for this reaction. Suliinyl and sulfenyl groups require somewhat harsher conditions. 

If SnAr reactions are to be performed, it is advisable to render the scaffold as electron deficient as possible. Thus, thioethers may be oxidized to sulfoxide or sulfonyl groups, and nitrogen-containing functionahties should be amides or nitro groups prior to a substitution. Of course, these derivati-zations are limited by the reactivity of the corresponding heterocycle, since more than one functionality may be displaced, if multiple leaving groups are present. 

An alternative sequence to avoid dimer formation in the synthesis of bosentan has appeared in the patent literature. The SNAr reaction with ethylene glycol is carried out first and the primary alcohol protected as the acetate ester 30. The second displacement with sulfonamide 24 and saponification of the ester protecting group then provide bosentan (l).29 This route is reported to provide the product in high purity and yield, but lacks the advantages of improved throughput afforded by the optimized route. 

Although the vast majority of published resin data consist of 11 and 13C NMR, multinuclear NMR is also possible. Different examples of the use of 19F MAS spectrometry were described in the literature [36, 80]. This nucleus was used to monitor different reactions on solid support, as coupling of fluorobenzyloxycarbonyl with aminoacids and SNAr nucleophilic displacements [80]. 

Thus, carbon 1 of 2,4-dinitrohalobenzene has the lowest electron density, and the halogen in position 1 is easily displaced by a nuclephile in a rate-determining step of an SNAr reaction with hydroxide, alkoxide, and primary or secondary amino compounds [94]. As the nucleophile becomes attached to the carbon, the compound is converted to an unstable nonaromatic species, the Meisenheimer complex [91]. Restoration of aromaticity facilitates elimination of the halogen in a fast step, in this particular case giving 2,4-dinitroanisole. 

A totally different approach to metal-catalyzed SNAr reactions of chlorobenzene involves reversible -coordination of the metal to PhCl, leading to the increase in electron deficiency of the benzene ring, sufficient for nucleophilic displacement of chlorine via the Meisenheimer-type path (Sect. 2.4) [85,86,203]. This way, anisole can be prepared from chlorobenzene in a catalytic manner [86, 203], although with very low catalytic turnover numbers of 2-6 (Eq. 26). 

Furthermore, the stronger C-F bonds, compared with other C-halogen bonds such as the C-Cl, are the actual thermodynamic driving force for Halex reactions towards the fluoroaromatics [57]. The Halex reaction is a nucleophilic aromatic substitution (SNAr) in which chlorine atoms activated by an electron-withdrawing group are displaced by fluorine upon reaction with a metal fluoride under polar aprotic conditions [58]. 

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