Indoles cyanation

These modified Rosenmund von Braun reaction conditions were also used by Gopalsamy et al. for the rapid cyanation of the 1,3,4,9-tetrahydropyrano-[3,4-fc]indole skeleton while searching for potent and selective Hepatitis C virus polymerase inhibitors (Scheme 74) [84]. 

In contrast, the cyanation of the side chain is not observed for indole derivatives (Scheme 114) [209]. 

The synthesis of a C-labelled version of naratriptan (3b) is highlighted in Scheme The indole ring of naratriptan hydrochloride (3) was oxidatively cleaved using sodium periodate to give ketoformanilide 45. Cyanation of 45 with potassium [ C]cyanide in aqueous ethanol gave the intermediate amidine 46, which was reduced directly with NaBH4 in acetic acid to afford C-labelled naratriptan (3b), which was isolated as the hydrochloride salt. 

The evidence for transient radical-cations from N-substituted indoles has been furnished by the observation of regiocontrolled anodic cyanation of the indole ring.193,194 Substitution in the 2-position dominates, although some 3-substitution takes place. When the 1,2,3-positions of indole were blocked, no cyanation occurred, but the products of anodic oxidation have not been isolated.194... 

Review.1 Use of this reagent in organic synthesis has been reviewed. The report includes cyanation of indoles, pyrroles, and enamines. 

Indole, like benzothiophene, reacts with electrophiles to give preferentially -substituted products. Bromination241-243 in dioxane or pyridine, nitration by ethyl nitrate,244 chlorination by sulfuryl chloride,245 iodination in aqueous solution,246, 247 Vilsmeier and Reimer-Tiemann formylations,248-261 diazo coupling,252 thio-cyanation,263 and nitrosation254 all give the 3-substituted indoles, practically free from other isomers. 

Yoshida K (1979) Regiocontrolled anodic cyanation of nitrogen heterocycles. Pyrroles and indoles. J Am Chem Soc 101 2116-2121... 

Recently, evidence for the transient ex istence of cation-radicals from simple pyrroles and indoles has been furnished by the observation of anodic regiospecific cyanation of these heterocycles.455 Both heterocycles are preferentially cyanated at the 2-position. Methyl side chains at these positions are also activated to cyanation and deuteration. Indole cation-radicals have been generated by photoionization in an aqueous medium.456 Unsubstituted at N, their lifetime in neutral solution is 10-6sec before they lose the N-proton however, it is longer in more acidic conditions.456 The photophysical properties of indole, its cation-radical, and neutral radical have been the subject of a recent theoretical analysis.457 On anodic oxidation of 2,3-diphenyl indole in acetonitrile, the initially formed cation-radicals dimerize to a product identified, primarily on the basis of 13C NMR, as 3-(5-indolyl)-indolenine (141).458... 

Hypervalent iodine(lll) was shown to catalyze the direct cyanation of iV-tosylpyrroles and -indoles under mild conditions, without the need for any prefunctionalization <2007JOC109>. Phenyliodine(m) bis(trifluoroacetate)-induced oxidative regioselective coupling of pyrroles in the presence of bromotrimethylsilane gave a series of electron-rich bipyrroles <2007S2913>. 

Other reactions such as the anodic cyanation or alkoxylation of electron-rich heterocycles such as pyrroles and indoles [85] or of electron-donating substituted azines [86] are important, but are not discussed in detail here, because this subject is well covered in electrochemistry textbooks. 

In methanolic cyanide solution V-substituted pyrroles [165, 213] are substituted in the 2-position by a nitrile group when both 2- and 5-positions carry a methyl group, cyanation initially [215] takes place in the 2- and 5-positions, but these compounds are unstable and the final substitution occurs in the side chain [214, 215]. iV-substituted indoles... 

If the 2-position is blocked, cyanation occurs at the 3-position. Similarly, cyanation of 1-methylpyrazole gives a mixture of the 4- and 5-carbonitrile [228]. The efficient substitution observed for many pyrroles, imidazoles [229], and indoles contrasts markedly the addition reactions observed for furans (cf. Chapter 16) and thiophenes [230]. However, this difference may only be apparent. At least for two of the cases already cited [226], it has been demonstrated [231] that the cyanosubstituted pyrroles arise as a result of elimination during workup of the 2,5-addition product originally formed. For benzo[b]thiophenes, cyanation leads predominantly to substitution products [232] ... 

The synthetically useful ethoxycarbonyl isocyanate reacts with 2-benzimid-azolylacetonitrile or its corresponding acetate ester. Alkyl isocyanates also cyclize the benzimidazol-2-acetate ester [3S70,3S88]. Acyliso(thio)cyanates and a mild base convert 2-methylindolenines (3//-indoles) to a fused pyrimidinedione ring [2695],... 

Indolyl radicals can be generated under standard conditions by reacting 2-bromoindole with tributyltin hydride. 3-Methyl-1-tosylindole can be cyanated at C-2 in good yield by a mixture of TMSCN and PIFA via oxidation of the indole to a cation radical, then addition of cyanide anion. ... 

Indoles and pyrroles are cyanated by the reagent in fairly good yields ... 

Oxidative cyanation of the indole ring at C-2 and C-3 has been observed for W-tosyl indoles on reaction with trimethylsilyl cyanide and phenyliodonium bis-trifluoroacetate in the presence of BF3 [78]. The reaction is distinctive in giving a preference for 2-substitution and is thought to proceed through radical cation intermediates. 

In addition to the several early examples cited by Brown [4], Scheme 2 illustrates some applications of the Reissert indole synthesis. Attempts by Beer and colleagues to improve the decarboxylation step in their synthesis of 5-hydroxyindole (equation 2) were unsuccessful, but these workers were able to synthesize 6- and 7-hydroxyindole via a Reissert method [5]. Uhle described an excellent preparation of 4-chloroindole (equation 2) [6], and Singer and Shive synthesized 7-indolecarboxylic acid (equation 3) [7] and 5-indolecarboxylic acid (equation 4) [8] via a Reissert strategy. As seen, both cyanation steps resulted in decarboxylation and cyanide replacement prior to nitrile... 

Bach reported the C2 selective alkylation of protected tryptophan via a palladium(II)-norbornene system (178, 72% yield) (13JOC12263). Azidirine-substituted indole 179 was prepared by Vedejs in 40% yield by the Stille coupling of an aziridinyl stannane with the corresponding indole (13JOC5061).The direct C2 cyanation of Al-pyrimidylindole was achieved using acetonitrile as the cyanide source with catalytic amounts of copper(II) acetate (180,70%) (13JOC9494). 

Copper has been demonstrated to mediate cyanation of aryl bromides and iodides through the activation of C-CN bonds (Scheme 20). Phenylacetonitrile [64], malononitrUe [65], and even acetonitrile as a reaction solvent [66] have been reported to serve as cyanating agents. 2-Phenylpyridines [67] and indoles [68] are directly cyanated by copper-mediated cyanation reaction using phenylacetonitrile, which is supposedly oxidized first at its benzylic position to give benzoyl cyanide, which further reacts with copper complexes to generate a cyanocopper species responsible for the cyanation event. Nevertheless, detailed mechanisms of these cyanation reactions remain elusive. 

Substituted (indol-2-yl)-ct-allenols show divergent patterns of reactivity under metal catalysis and an intramolecular 1,3-iodine migration has been reported (Scheme 208). Computational methods have addressed rearrangements of acyl, thioacyl, and imidoyl (thio)cyanates to iso(thio)cyanates, acyl iso(thio)cyanates to (thio)acyl isocyanates, and imidoyl iso(thio)cyanates to (thio)acyl carbodiimides, RCX-YCN RCX-NCY RCY-NCX RCY-XCN (X and Y = O, S, NR ). ... 

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