Indole reaction with carbenes

Catalysts generated from A-heterocyclic carbenes 23-25 (Figure 7) have been shown to efficiently catalyze the coupling of aryl and heteroaryl halides with indoles. Reactions conducted with the terf-butoxide base, which is typically used for the C—N coupling, did not occur, but reactions with NaOH as base occurred to high conversion85. Although 4-bromotoluene and bromobenzene reacted with numerous substituted indoles under these conditions, electron-rich and orf/zo-substituted aryl bromides reacted slowly and in low or moderate yields. 

Arylamines and diaryl ethers. Polyhaloarenes have been employed in A-arylation. By using certain carbene ligands, rapid reaction with chloroarenes at room temperature has been demonstrated. The (dba)2Pd-t-BujP system has a wide scope of arylation including that of indole and carbamates." (Formation of Al-dimethylaminoindole from 2-chlorophenylacetaldehyde MA-dimethylbydrazone is novel." ) A more complicated ligand for arylation of amines by aryl chlorides is 1."... 

No isolable cyclopropane-containing products have been obtained by the reaction of indoles with carbenes (cf. section 13.10) but a dichlorocyclopropane is believed to be an intermediate in the pathway which leads from 2,3-dimethylin-dole to 3-chloro-2,4-dimethylquinoline the second product arises via nucleophilic attack by the indolyl anion on the electrophilic dichlorocarbene. In the comparable reaction of indole itself, only the second pathway operates and 3-formylindole, the hydrolysis product of the 3-dichloromethyl-substituted heterocycle, is isolated. 

Ylides derived from imidazolium- and triazolium-substituted indole anions belong to the class of conjugated mesomeric betaines. Their tautomers are N-heterocyclic carbenes, which undergo trapping reactions with sulfur, selenium, and triethylborane, respectively. Deprotonation of the salts 45a—c with NaOH/EtOH produces the ylides 46a—c which are in tautomeric equihbrium with carbenes 47a—c (Scheme 36) (2014T8672). 

In the case of the 4-(indol-2-yl)-lH-l,2,4-triazolium bromide 51, all attempts to isolate the corresponding carbene 53 or its tautomers 52 failed. However, the carbene tautomer 53 was trapped by reaction with sulfur to form product 54 (Scheme 38) (2014T8672). 

Reactions of carbenes other than cyclopropanation can also be performed, and recent examples include the ring expansion of five-ring heterocycles, such as the indoles (18), to their six-membered counterparts (19), and the production of formamides from secondary amines (Scheme 7), both with dichlorocarbene. The latter method is of interest because of its relation to the catalysis of dichlorocarbene generation by tertiary amines in two-phase systems. Recent work indicates that such catalysis is possible because the carbene, after generation at the phase boundary, is transferred into the organic phase (to undergo reaction) in the form of the N-ylid adduct (20). 

Ciamician and Dennstedt reacted the potassium salt of pyrrole with chloroform in ether and isolated, after much purification, 3-chloropyridine, which was confirmed by crystallization with platinum. While the pyrrole salt can be used as the base, the chloroform carbene is typically formed with an alkali alcohol. Forty years later, Robinson and co-workers made 3-chloroquinolines from indoles using the Ciamician-Dennstedt reaction. ... 

Feldman reported a route to dihydropyrroles, pyrroles, and indoles via the reaction of sulfonamide anions with alkynyliodonium triflates <96JOC5440>. Thus, upon nucleophilic addition of the anion of 91 to the p-carbon of the alkynyliodonium salt, the alkylidene carbene 92 is generated which can the undergo C-H insertion to the desired product 93. 

This [3 + 2] addition approach has been extended successfully to indole derivatives. The ready availability of the precursor tosylanilides provides a novel and useful complement to the current approach (94MI3). However, me(a-substituted tosylanilide yields a mixture of two regioisomeric indoles 107a and 107b in different ratios depending on the nature of substitutents (Scheme 30). Furthermore, the reaction of o-methyltosylamide with 102 does not produce any detectable amount of the desired indole, plausibly due to the repulsive peri-type steric interactions as indicated in 108, which would be unavoidable as the carbene approaches the CH bond. 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

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