Cyanation of pyrroles

Anodic cyanations of N-substituted pyrrole or 2-methylpyrrole derivatives take place in the a-position to the nitrogen atom (Scheme 111) [209] and at the side chain with 2,5-dimethyl or 2,3,4,5-tetramethylpyrrole derivatives (Scheme 112). 

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

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>. 

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] ... 

Construction of the oxazine ring of 783 was achieved by cyanation of the 4-amino-4-ethoxycarbonyl-pyrrol-3-yl C-nucleoside 337 with cyanogen bromide, followed by hydrolysis and cyclization of the ester cyanamide 782 with methanolic potassium hydroxide. Removal of the sugar-protective ketal group gave 783, which possessed immunostimulant properties [85TL5785 86JAP(K)86/260094] (Scheme 205). 

Recyclable [bis(trifluoroacetoxy)iodo]arenes 66 and 70 are excellent reagents for oxidative coupling of thiophenes or pyrroles [79] and for direct oxidative cyanation of heteroaromatic compounds using Me3SiCN as source of cyanide anion [80,81]. 

It is frequently necessary in synthesis to operate on the non-heterocycle portion of a molecule, and palladium technology often succeeds admirably in this regard. For example, N-(4-iodophenyl)pyrrole (200) is cyanated to 201 in excellent yield [146],... 

Dielectrophilic species are 1,4-diketones, certain 1,3-dienes, a,B-unsaturated isocyanates, isothiocyanates, cyanates, and thiocyanates bearing electron-withdrawing (e.g., polyfluorinated and perfluorinated) substituents the most frequently used 1,1-dinucleophiles are water, potassium sulfide, primary amines, and ammonia. From this repertoire of building blocks many combinations are possible. Tetrakis(trifluoro-methyl)furans, thiophenes, and pyrroles have been synthesized from per-fluoro-3,4-dimethylhexa-2,4-diene on addition of water, potassium sulfide, or aniline (90CC1127) (Scheme 39). 

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. 

As a mechanism, primarily formation of an N-acyhminium salt 77 is suggested, followed by (4 - - 1)-cycloaddition of the isonitrile auxihary to give 78. Next, the iminium ion 78 is deprotonated to the cycHc azomethine ylide 79 (a mesoionic system analogous to Miinchnones (cf. p. 175)), which undergoes 1,3-dipolar cycloaddition with ADE. Finally, the cycloadduct 80 collapses with extrusion of cyclohexyl cyanate and formation of the pyrrole 76. 

Miscellaneous Transformations. The hypervalent iodine(III) reagent phenyliodine bis(trifluoroacetate) (PIFA) mediates the selective cyanation reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles, thiophenes, and indoles under mild conditions (eq 42). Nonactivated arylalkenes are effectively converted to tertiary benzylic nitriles in the presence of triflic acid and cyanotrimethylsilane (eq 43). ... 

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