Benzothiazoles 2-nucleophilic substitution

Most recent syntheses of fluorinated benzothiazoles make use of nucleophilic substitution. Potassium fluoride in acetonitrile converted 40 into the 2-fluoro derivative (R = 6-nitro) in 99% yield. When the solvent was dimethylformamide the 2-dimethylamino derivative was formed instead [80JCS(P1)2358], and similar behavior was reported earlier (77BSF171). 

A series of 2-trifluoromethyl and 2-difluoromethyl substituted benzothiazoles 30 has been synthesized by a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with 2-aminobenzenethiol <07TL3251 >. The reaction pathway presumably involves the imidolyl chloride intermediate 29, which undergoes intramolecular nucleophilic substitution by neighbouring thiol under basic conditions to give benzothiazole 30. 

An intramolecular aromatic nucleophilic substitution has been used for the preparation of 2-substituted benzothiazoles (388) in high yields from o-halothioanilides (387), the halogen atoms being iodine, bromide, or chlorine <82TL5093>. This reaction can also be carried out with naphtho-derivatives <89ijc(B)597>. Moreover, in the presence of sodium carbonate, the reaction can be extended to fluorine-substituted substrates (Equation (81)) <89JHC1039>. 

Nucleophilic Substitution. Several nucleophilic replacements in benzo-thiazolium salts (82) and (83) have been reported. The reactions (see Scheme 4) were studied chiefly for the purpose of comparison with those of the analogous thiazolo[2,3-Z ]benzothiazoles (see p. 702). The results agree with the general experience that quaternization of benzothiazole enhances its susceptibility towards nucleophilic reagents. ... 

Nucleophilic Substitution.—Compound (22) is formed when 2-chlorobenzo-thiazole reacts with 2,6-dimethylaniline at 170 °C. The ring N-atom in the initially formed 2-(2,6-dimethylanilino)benzothiazole reacts in preference to the 2,6-dimethylaniline with any remaining 2-chlorobenzothiazole. The reversible... 

Nucleophilic Substitution.—The replacement of halogen in 2-bromo-5-carboxy-4-methylthiazoles (51 R = EtO or PhNH) by a wide variety of nucleophiles (including phenols, thiophenols, dithiocarbamic acids, and sulphinic acids) has provided the appropriate derivatives (52) in high yields, but some anomalies were observed. The products included examples incorporating 1,3,4-thiadiazole or benzothiazole nuclei in the 2-position of... 

Heating thiazole with phenylazotriphenylmethane at 75 °C for 24 hours affords 2-phenyl-5-triphenylmethyl thiazole (75 Scheme 43). The 1-adamantyl radical and other nucleophilic alkyl and acyl radicals react with 2-substituted benzothiazoles in a homolytic ipso substitution yielding the corresponding 2-alkyl or 2-acylbenzothiazole (Scheme 44) (77CC316). 

The palladium-catalyzed decarboxylative coupling of allyl 2-(benzo[c(jthiazol-2-yl)acetates 118 provides a facile approach to 2-(but-3-enyl)benzo[c(jthiazoles 122 <07JA4138>. The reaction is initiated by nucleophilic attack of Pd(0) on the allyl ester to give Pd-7t-allyl complex 119, which undergoes nucleophilic attack at the less substituted allylic carbon from the benzothiazole nitrogen to produce 120. Decarboxylative dearomatization leads to intermediate 121, and a subsequent aza-Cope rearrangement driven by rearomatization affords the final product 122 and accounts for the unusual regioselectivity. This appears to be the first report of a tandem allylation/aza-Cope reaction driven by decarboxylative dearomatization/ rearomatization. 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycies containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyri-dines, quinolines, diazines, imidazoles, benzothiazoles and purines are amongst the systems that have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and y to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because A-protonation of the heterocycle... 

All reactions with nucleophilic reagents mentioned on p 150/151 for thiazole can also be achieved with benzothiazole. Only slight differences are observed. For instance, 2-chlorobenzothiazole reacts about 400 times faster with sodium methoxide or with sodium thiophenolate than 2-chlorothiazole, to give the corresponding substitution products 2-methoxy- and 2-(phenylsulfanyl)benzothiazole. 

Thiadiazoles are weak bases. On quatemization, e.g. with dimethyl sulfate, mixtures of 2- and 3-methyl-1,2,3-thiadiazoles are formed. Electrophilic substitution of the C-atoms could not be achieved. With 1,2,3-benzothiazoles, substitution occurs on the benzene ring. For instance, with nitric acid the 4- and 7-nitro-l,2,3-benzothiadiazoles are obtained. Nucleophiles bring about ring-opening, e.g. ... 

The intramolecular trapping of benzyne intermediates with tethered nucleophiles is a powerful strategy for the synthesis of benzo-fused heterocycles. In this field, 7-functionalized benzoxazoles 59 and benzothiazoles 60 have been prepared by anionic cyclization of the corresponding lithiated benzyne (thio)amides and (thio)carbamates, which were generated from 3-haloaniline derivatives (Scheme 12.34) [55]. Related to this, substituted indolines 61 have also been accessed by benzyne-mediated cyclization-functionalization from Boc-protected (2-bromo-4-methoxy)phenetylamines using Mg(TMP)2 2LiCl as a base. This methodology has also been applied to the preparation of functionalized carbazoles (Scheme 12.34) [56]. 

The ecofriendly solvent-free reactions of o-aminothiophenol and aromatic or aliphatic P-keto esters with microwave irradiation produced 2-substituted benzothia-zoles in excellent yields. The formation of the 2-substituted benzothiazoles probably involves the nucleophilic addition of the thiol group to the keto group of the P-keto ester followed by elimination of ethyl acetate from the resulting adduct. Then it undergoes an intramolecular addition of the o-amino group to the carbonyl group to give an adduct, from which water is eliminated to afford the 2- substituted benzothiazoles (Kamila et al., 2005). 

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