Pyrroles radical substitution

Reviews dealing with a specific reaction or property from the heterocyclic point of view have been rarer—tautomerism (continued from Volume 1), free radical substitution, metal catalysts and pyri-dines, acid-catalyzed polymerization of pyrroles, and diazomethane reactions have been covered in this volume. 

Quantitative investigations of the kinetics of these a-coupling steps suffered because rate constants were beyond the timescale of normal voltammetric experiments until ultramicroelectrodes and improved electrochemical equipment made possible a new transient method calledjhst scan voltammetry [27]. With this technique, cyclic voltammetric experiments up to scan rates of 1 MV s are possible, and species with lifetimes in the nanosecond scale can be observed. Using this technique, P. Hapiot et al. [28] were the first to obtain data on the lifetimes of the electrogenerated pyrrole radical cation and substituted derivatives. The resulting rate constants for the dimerization of such monomers lie in the order of 10 s . The same... 

Intramolecular radical substitution of pyrroles and indoles has been well studied this is exemplified in Schemes 90 <1997TL7937> and 91 <2000TL10181>. Intramolecular radical acylation of l-(-halogenoalkyl)-2-methylsulfonyl-5-substituted pyrroles leads to bicyclic ketones with displacement of the sulfonyl moiety <2000TL3035>. Similar cyclizations can be achieved using acyl selenide precursors to generate an acyl radical... 

Attempted addition of malonate monoester 1017 to pyrrole led to the formation of ester 1018 in 65% yield, presumably through a sequence of events involving radical substitution followed by decarboxylation, as shown in Scheme 196 <2003TL6853>. 

Pyrrole itself tends to give tars under radical conditions. A 2-toluensulfonyl-substiment can be displaced by radicals. Electrophilic radical substitution of 1-phenylsulfonylpyrrole occurs at an a-position the formation of a pyrrol-2-ylacetic acid is typical. 3-Substituted pyrroles are attacked by radicals at C-2. ... 

There are few examples of radical substitution of benzofnran or benzothiophene perfluoroalkylation of benzofuran is one snch, as illnstrated. This process can also be applied to 2-snbstitution of thiophene, pyrrole, imidazole and indole. 

There has been increasing interest in radical substitution and cyclization reactions of pyrroles and indoles. Both 2- and 3- carboethoxypyrroles undergo radical cyclizations (at C5 and C2, respectively) with appropriately placed iodoalkyl substituents. 

Pyrrole itself undergoes a,a -disubstitution. Diazo-acetoacetic ester can be used in this reaction. The mechanism of this reaction, which may be a radical substitution or involve the intermediate formation of a ketene, is uncertain, but it is interesting to note that a number of pyrroles react readily with diketene, giving G-acetoacetyl derivatives, and that ketene converts 2,4-dimethylpyrrole into 2-acetyl-3,5-dimethylpyrrole . In view of these results, the earlier report that diphenylketene converted pyrrole into 1-diphenylacetylpyrrole must be questioned. 

A reaction of uncertain character which deserves mention is that between pyrroles and ethyl diazoacetate in the presence of copper powder , 253, This carbethoxymethylation might be a radical substitution or it might proceed through an initial adduct... 

The rarity of free radical substitutions into pyrrole has been remarked upon (p. 81). With triphenylmethyl, addition occurs giving 2,5-di-tri-... 

Pyridine presents a great contrast to pyrrole as regards its ability to undergo substitution. Electrophilic substitutions are less numerous, varied and important than with the pyrroles. On the other hand, nucleophilic substitutions are of great consequence, and radical substitutions are more widely and significantly represented. 

During the vinylation of 2-arylpyrroles in the presence of the same radical trap, the ESR signals of vinyl-tert-butylnitroxyl and spin adducts of f-BuNO with the adducts of 2-substituted pyrrole radicals to acetylenes have been detected. N-Centered radicals of 2-arylpyrrole are quite stable and are observed directly in the ESR spectra (Scheme 2.40) [496]. 

Brown has also predicted, from localization energy calculations, that pyrrole and glyoxaline should react with radicals mainly at the 2-position, whereas pyrazole should be most reactive at the 3-position. Browm and Heffernan s calculation that the orientation in pyrimidine substitution should be 4 > 2 > 5 is in agreement with the results from the p-nitrophenylation of pyrimidine. ... 

Tolylsulfones of indoles, pyrroles, pyrazoles, furans, thiophenes, indolines, and dibenzofurans react with tributyltin hydride under radical conditions by t/wo-substitution. The most likely mechanism appears to be addition of the RjSiv radical to the ring, followed by elimination of the sulfonyl group, but an electron-transfer mechanism cannot be excluded (Equation (61)).199... 

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

The 5-dig-mode of cyclization has been applied in the synthesis of N-heterocycles. For example, treatment of the /i-allenyl dithiosemicarbazide 37 with Bu3SnH and AIBN in hot benzene furnishes the substituted 3H-pyrrole 38 in 41% yield and the isomeric heterocycle 39 in 30% yield (Scheme 11.13) [68], Iminyl radical 40 is formed via Bu3Sn addition to the thiocarbonyl group of the radical precursor 37 and fragmentation of the adduct (not shown). Nitrogen-centered radical 40 adds 5-dig-selectively to provide substituted allyl radical 41. The latter intermediate is trapped by Bu3SnH to furnish preferentially product 38 with an endocydic double bond. 

A novel aromatic substitution reaction with electron-deficient radicals, which avoids the use of stannanes, is promoted by the addition of tetra-n-butylammonium bromide [54]. Iodoacetonitrile and iodoacetic esters react with pyrroles and indoles in good to high yield upon photolysis in the presence of 2-methyloxirane and sodium thiosulphate (Scheme 6.34). 

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