Indolic substrates

Two synthetic approaches on intact indoles are notable. In one, the indole substrate is converted into the /6-arenetricarbonylchromium complex. The -acetyl and 1 -ethoxy-carbonyl derivatives are cleaved to indoles, whereas the... 

Watanabe s group at Tosoh Corporation reported the coupling of a chlorine-substituted indole and piperazine using a 24/Pd-based catalyst, Eq. (167) [134]. The indole substrate, which was prepare via a novel palladium-catalyzed cycliza-tion, was aminated in 94% yield. 

In the laboratory of F.E. Ziegler, the cyclization of a chiral aziridinyl radical into an indole nucleus was utilized to prepare the core nucleus of the potent antitumor agent FR-900482. In the early stages of the synthetic effort, the VUsmeier-Haack formylation was chosen to install an aldehyde functionality at the C3 position of a substituted indole substrate. The initial iminium salt was hydrolyzed under very mildly basic conditions to minimize the hydrolysis of the... 

A copper-catalyzed coupling reaction between free N-H indole substrates and tetrahydroisoquinolines gave l-(indol-3-yl)isoquinoline derivatives <05JA6968>. 

A regioselective Friedel-Crafts 3-acylation of indoles was reported that utilized diethyl aluminum chloride as a Lewis acid mediator <04S2277>. A facile, 3-cyanoacetylation of indoles has been reported <04S2760>. Treatment of indole substrates with cyanoacetic acid in acetic anhydride led to the formation of the corresponding 3-cyanoacetylindoles. This reaction was also investigated with pyrroles and anilines. 

Indoles undergo Michael additions in the presence of acid catalysts. Gold-catalyzed conjugate additions of indoles with enones led to the formation of indol-3-yl propanones <04SL944>. With 3-substituted indole substrates, the reactions proceeded to give the corresponding 2-substituted indoles. Homotryptamines were formed in a one-pot sequence that involved a Michael addition by indole substrates to acrolein imine derivatives followed by a reductive amination of the indole propionaldehyde intermediates <04TL3803>. 

A novel 2-arylation of A -substituted indoles has been reported <04OL2897>. Treatment of indole substrates with palladium acetate, triphenylphosphine, cesium acetate and aryl iodides led to the formation of 2-arylindoles. 

A detailed study of the Suzuki reaction of benzene-ring substituted bromoindoles was published <04JOC6812>. The highest yields were obtained with indole substrates containing a tosyl nitrogen protecting group. Palladium-catalyzed carbonylation reactions of unprotected bromoindoles allowed for the synthesis of indolecarboxamides. For example, treatment of 5-... 

Lithiation reactions involving lV-methyl-3-substituted indoles are sometimes useful for introducing electrophiles regioselectively to C2. Comins [77] and Adam [78] reported regioselective C2-lithiations of indole substrates containing... 

After realizing that our hypotheses about oxidative cross-coupling reactions were not as unique as assumed, we quickly turned our attentirai to intermolecular oxidative amination reactions. In the carbazole example, regioselectivity was coti-trolled by the presence of a Lewis base that was attached near the C—H bmid that would be cleaved, resulting in a metallacyle intermediate. For die development of an intramolecular reaction, we chose to take advantage of the selectivity that is often observed in the selective metalation of electron-rich heteroarenes. At the time, the palladation of indoles was presumed to operate by an electrophilic aromatic substitution mechanism. (This has since been demonstrated to be incorrect, vide infra.) We hypothesized that regioselective palladation of an indole substrate could be followed by a subsequent C—N bond reductive elimination. At the time, the exact mechanism by which the intermediate containing Pd—C and Pd—N bonds could be formed was not clear, nor was the order of the two metalation steps, but the overall process seemed plausible. 

While none of the reactions produced 2-amino- or 3-aminoindoles, reactions performed in toluene contained several isomers of 2- and 3-tolylindole, presumably the result of oxidative C-H/C-H cross-coupling between the indole substrate and the solvent. Remarkably, we did not detect products resulting from indole/indole homocoupling, and we only observed toluene/toluene homocoupled products at long reaction times. 

To explore the possibility of forging the quaternary center via a cycHza-tion in this manner, hexahydro-l,5-methanoazocino[3,4-lt]indole substrate 83 first had to be constructed (Scheme 23). 

With the appropriate indole substrate 83 now in hand, attention of the Dolby group turned to installation of the ethylene bridge between the alkyl nitrogen and the indole 3-position to construct the desired quaternary center contained in the core of akuamnuline alkaloids. Toward this end, chlor-oacetamide 217 obtained via treatment of the indole 83 with chloroacetyl chloride, was subjected to sodium hydride in DME at room temperature (Scheme 25). No product of cyclization was seen under these conditions. Amine 83 was also treated with ethylene oxide to provide aminoethanol 219 this alcohol was then activated as a sulfonyl ester. Efforts to affect cyclization in this manner also proved unsuccessful. 

Heck Annulation. PolyheterocyUc systems such as pyrido[2, 3 -t( ]pyridazino[2,3-fljindoles 291 are available by Heck annulation reactions using nicotinyl-indole substrates (Scheme 100). ... 

A one-pot intramolecular Heck reaction followed by oxidation was developed to both install a benzoyl group and join the benzoyl group to Cl on the carbazole moiety thereby synthesizing carbazoles of the form 281. It is instructive to reveal that this method is compatible with over 20 indole substrates (14T312). 

N-Triisopropylsilylethyiiyl pyrrole (77) could be alkylated with excellent C3 selectivity by protected amino cyclopropane 78 in the presence of scandium(III) triflate in excellent yield. Although most examples were conducted with indole substrates, both pyrroles and electron-rich arenes were compatible (130L3738). 

Swern oxidation of various indolic substrates has been described, and a range of products resulting from overall oxidation at the 2-position have been observed. For example, indolylpropanol 1809 [R = (CH2)30Hj is oxidized with DMSO and either trifluoroacelic anhydride or oxalyl chloride to give the unsaturated aldehyde 1810 [R = (CH2)2CH0] [1333]. 

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