Nucleophilic aromatic substitution ortho-selectivity

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

A convenient synthesis of 2-mercaptobenzothiazoles 44 features an exclusive ortho-selective nucleophilic aromatic substitution reaction of or//zo-haloanilines 41 and subsequent intramolecular cyclization of the intermediate O-ethyl carbonodithioates 43 <05JHC727>. 2-Mercaptobenzothiazoles 44 are readily converted to the corresponding 2-chlorobenzothiazoles 45 upon treatment with sulfuryl chloride. 

The synthesis of halogenated 2(3/f)-benzothiazolethiones 44 is carried out using ortho-selective nucleophilic aromatic substitution reaction of polyhaloanilines 41 with potassium 0-ethyl xanthate 42 <04JOC7371>. 

Zeynep A, Mehmet A, Canan K, SuLhiye Y, Eidem B, Hakan G (2006) Synthesis and potent antimicrobial activities of some novel retinoidal monocationic benzimidazoles. Arch Pharm Chem Life Sci 339(2) 74-80. doi 10.1002/aidp.200500168 Zhu L, Zhang M (2004) Ortho-selective nucleophilic aromatic substitution reactions of polyhaloanilines with potassium/sodium G-ethyl xanthate a convenient aeeess to halogenated 2(37f)-benzothiazolethiones. J Org Chem 69(21) 7371-7374. doi 10.1021/jo049056s Zou R, Ayres K, Drach J, Townsend L (1996) Synthesis and antiviral evaluation of certain disubstituted benzimidazole ribonucleosides. J Med Chem 39(18) 3477-3482. doi 10.1021/ jm960157v... 

The formation of 151 from the phosphonate 171 could be proved only by indirect means. Electron-rich aromatic compounds such as N,N-diethylaniline and N,N,N, N -tetraethyl-m-phenylenediamine U0 1I9> and N-methylaniline 120> are phosphorylated in the para- and in the ortho- plus para-positions by 151. Furthermore, 151 also adds to the nitrogen lone pair of aniline to form the corresponding phosphor-amidate. Considerable competition between nucleophiles of various strengths for the monomeric methyl metaphosphate 151 — e.g. aromatic substitution of N,N-diethylaniline and reaction with methanol or aromatic substitution and reaction with the nitrogen lone pair in N-methylaniline — again underline its extraordinary non-selectivity. 

Arylnitrenium ions are likewise capable of adding to n nucleophiles. With substituted aromatics (e.g., toluene) there exists the possibility of three reactive sites on the nitrenium ion (the nitrogen, ortho- and para-ring positions), along with up to three possible sites on the arene (ortho, para, and meta in the case of a monosub-stituted trap). Thus in a typical case there is the possibility of nine distinct regio-isomers. Obviously, any synthetic utility of such chemistry relies on the ability of the reagents to react in a selective manner. 

Exactly the same sort of mechanism accounts for the reactions of aryl silanes with electrophiles under Friedel-Crafts conditions. Instead of the usual rules governing ortho, meta, and para substitution using the directing effects of the substituents, there is just one rule the silyl group is replaced by the electrophile at the same atom on the ring—this is known as ipso substitution. Actually, this selectivity comes from the same principles as those used for ordinary aromatic substitution (Chapter 22) the electrophile reacts to produce the most stable cation—in this case (3 to silicon. Cleavage of the weakened C-Si bond by any nucleophile leads directly to the ipso product. 

In aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precursor of the natural product isochizandrine [10]. 

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