Indoles carbene addition

Table 2.4. Quinoline formation from indoles by carbene addition [42]...

CBz-protected benzimidazole gave primarily oxazinone [31], while 3/f-indoles incorporated two equivalents of imine (Eq. 4) [32]. In these cases it appears that the initially formed zwitterionic ketene-imine adduct could not close, and reacted with additional photo activated carbene or substrate. 

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. 

Photolysis of 3-diazoindole 59a in cycloalkenes, via the addition of carbene 65 to the cycloolefine, gave rise to cyclopropane adduct 66, which can rearrange to indolenines 68 or 69 and then to indoles 70 (66LA17). 

Supercritical carbon dioxide with a minute co-solvent addition is an effective medium for the 1,3-dipolar cycloaddition of azomethine ylides with DMAD to produce substituted pyrroles.67 The 1,3-dipolar cycloaddition of nitrile ylides [e.g. benzonitrile (4-nitrobenzylide) and 4-nitrobenzonitrile(benzylide)] with acrylamides provided a synthesis of 3,4-dihydro-2//-pyrroles with moderate to good yields.68 The Pt(II)-or Au(III)-catalysed 3 + 2-cycloaddition of the transition metal-containing azomethine ylide (63) with electron-rich alkenes provided a carbene complex (64), which yields tricyclic indoles (65) having a substituent at 3-position (Scheme 17).69 The 1,3-dipolar cycloadditions of azomethine ylides with aryl vinyl sulfones are catalysed by Cu(MeCN)4C104-Taniaphos with nearly complete exo- selectivity and enantioselec-tivities up to 85% ee.10 The 3 + 2-cycloaddition of benzol/>]thiophene 1,1-dioxide... 

Carbenoid addition of diazocarbonyl compounds to pyrrole, A -alkylpyrroles, indole, N-alkylindoles, imidazole, and benzimidazole does not result in cyclopropanation, but leads to the formal products of carbene insertion into a heterocyclic C-H bond (see Houben-Weyl, Vol.E19b, ppll58 and 1334). However, Af-acylpyrroles, and Af-acylindoles - " have successfully been converted into 2-azabicyclo[3.1.0]hex-3-ene-exo-6-carboxylates and alkyl-1,la,2,6b-tetrahydrocyclopropa[ ]indole-exo-l-carboxylate, respectively (for an experimental procedure, see Houben-Weyl, Vol.E19b, pll60). 

Except for 3-bromoindole, it is necessary to proceed via the indoline, because treatment of indole with 1,1-dimethyIpropargyl chloride (31) in the presence of base leads to product mixtures resulting from reaction of in situ formed dimethyl-vinylidene carbene. Sheu and co-workers isolated the three products 32, 33 and 34 on reaction of indole-3-carbaldehyde (30) (Scheme 7) [53]. In the main reaction, indole C3 attacks at dimethylvinylidene carbene forming a vinyl anion, which is protonated to give the 3-allenylindolenine. Hydroxide then attacks the carbal-dehyde moiety with loss of formic acid and formation of a 3-allenylindole. Addition of a second equivalent of indole-3-carbaldehyde (30) affords 32 and 33. 

In addition to the above intermolecular reactions, the intramolecular Diels-Alder cycloadditions of furo[3,4-b]indoles have also been reported. Herndon and coworkers [131] used the coupling reaction of the Af-benzylindolynal derivative 396 with Fischer carbenes 397a-b to obtain the carbazoles 398a-b, presumably via the... 

Dimethylvinylidine carbene (52) has been shown to add to indole-3-carbaldehyde (53) to mainly yield /3-(dihydroprenyl)indole (54). Aryl- and heteroaryl-chloro-carbenes (55) have been shown to add to 1-azabuta-1,3-dienes via a formal [4- -1]-cycloaddition, involving a transient azomethine ylide (56) giving rise to the corresponding pyrrole (57). A formal [4 -1- l]-cycloaddition is also observed during the addition of a triplet carbene (dicarboethoxycarbene generated with a triplet sensitizer) to cyclooctatetraene which leads to bicyclo[4.2.1]nonatriene (58). ... 

For the study of the cyclopropanation reaction of indoles with diethyl diazoacetate (EDA), we were inspired by the pioneering work of Welstead [63] and Wenkert [64], They found that the deactivation of the indole nucleus, through electron-withdrawing substituents at Nl, allows the addition of carbene moiety into the 2,3-double bond without the competitive rearrangement that leads to the C-H insertion product (Scheme 4.16). 

Tryptophan offers an indole side chain that can be used for ligation chemistry. A water-compatible rhodium carbene can be added to the indole ring (19) [105,139]. The reactive species is generated in situ by a conjugated diazo compound by a rhodium catalyst like rhodium(II) acetate [63,139,149]. The reaction takes place in the two- and three-position of indole. Thus, a mixture of N-alkylated and C-alkylated product is obtained. It is necessary to add hydroxylamine hydrochloride as an additive to bind to the distal rhodium carbenoid complex. The usage of this salt lowers the pH value below 3.5 and therefore limits the scope of this methodology. As a side reaction, the carbene inserts into the O-H bond of water (Table 6). 

The reaction of a,(3-unsaturated Fischer carbene complexes 42 with cyclic enamines 43 gives cyclopentannulation products 46 with complete regioselectivity by a formal [3-1-2] cycloaddition (Scheme 5.11) [20]. The formal [3-1-2] cycloaddition is assumed to occur in a stepwise manner via the 1,4-addition of cyclic enamines 43 to the alkynyl carbene complexes 42 (formation of iminium intermediate 44), the intramolecular cyclization to the formed iminium moiety from the carbene carbon (formation of intermediate 45), and the hydrolysis reaction. When (—)-8-phenylmenthyl derivatives of Fischer carbene complexes 42 are reacted with indoles 43, the corresponding indolinones 46 are obtained with >97% ee. 

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