Reductive N-heteroannulation Research Articles

Discussion Addendum for: Synthesis of Indoles by Palladium Catalyzed Reductive N-Heteroannulation of 2-Nitrostyrenes: Methyl Indole-4-carboxylate

Discussion Addendum for: Synthesis of Indoles by Palladium Catalyzed Reductive N-Heteroannulation of 2-Nitrostyrenes: Methyl Indole-4-carboxylate

Synthesis and biological evaluation of new penta- and heptacyclic indolo- and quinolinocarbazole ring systems obtained via Pd0 catalysed reductive N-heteroannulation

A short route, involving a tetramolecular condensation reaction and a Pd/C catalyst-H(2)-mediated reductive N-heteroannulation as the key-steps, has been found for the synthesis of some new penta- and heptacyclic indolo- (12), quinolino- (13) and indoloquinolinocarbazole (11) derivatives. HF-DFT (B3LYP) energy profiles and NMR calculations were carried out to help in the understanding of the experimental results. N-Alkylated indoloquinolinocarbazoles (16b, 17a, 17b and 18) were prepared and screened essentially toward some cancer-(G-quadruplex, DNA, topoisomerase I) and CNS-related (kinases) targets. Biological results evidenced 13 as a potent CDK-5 and GSK-3β kinases inhibitor, while di- or triaminopropyl-substituted indoloquinolinocarbazoles 17b or 18 targeted rather DNA-duplex or telomeric G-quadruplex structures, respectively.

Attempted synthesis of 3-hydroxy-2-octadecylindole. Proposed structural revision of previously prepared 3-hydroxy-2-octadecylindole and a proposed structure of fistulosin

A synthetic route to 3-hydroxy-2-octadecylindole, the putative structure of the novel indole alkaloid fistulosin, starting from 2-nitro-1-iodobenzene was examined. Key steps include formation of a 1-stannylsubstituted 1-methoxy-1-alkene from a Fischer chromium carbene, intermolecular Kosugi–Migita–Stille coupling, and a palladium-catalyzed reductive N-heteroannulation. Demethylation of 3-methoxy-2-octadecylindole, a possible immediate precursor to 3-hydroxy-2-octadecylindole, was unsuccessful and gave instead methyl 2-(1-oxononadecanyl)aminobenzoate. The structure of the isolated alkaloid was suggested to be 2-(1-oxooctadecanyl)aminobenzoate by comparison of analytical data with a synthetic sample. In addition, oxidation of 2-octadecylindole gave a 2,2′-dimer, a compound identical to previously prepared 3-hydroxy-2-octadecylindole.

Synthesis of tryptophan derivatives via a palladium-catalyzed N-heteroannulation

Tryptophan derivatives were prepared from 2-(2-nitrophenyl)-2-propen-1-yl substituted pyrazines, derived from Schöllkopf’s chiral auxiliary, using a palladium-catalyzed, carbon monoxide-mediated reductive N-heteroannulation reaction. A diastereomeric ratio of products ranging from 4:1 to >30:1 was observed.

Palladium-catalyzed synthesis of quinoxaline derivatives

A palladium-catalyzed reductive N-heteroannulation of enamines derived from 2-nitrobenzenamines forming mixtures of 1,2-dihydroquinoxalines and 3,4-dihydroquinoxalin-2-ones is described. The reactions are performed using bis(dibenzylideneacetone)palladium(0), 1,3-bis(diphenylphosphino)propane, and 1,10-phenanthroline in DMF under 6 atm of carbon monoxide at 70 °C.

Palladium-Catalyzed Synthesis of 3-Indolecarboxylic Acid Derivatives

Indoles having an ester functionality in the 3-position were prepared from 2-(2-nitrophenyl)propenoic acid derivatives via a palladium-catalyzed reductive N-heteroannulation using carbon monoxide as the ultimate reducing agent. The starting materials were prepared either by a Stille coupling of 2-halo-1-nitrobenzenes with ethyl 2-(tributylstannyl)-2-propenoate or by vicarious nucleophilic substitution of nitrobenzenes followed by a Knoevenagel-type condensation with an aldehyde. Synthesis of an example of a 3-nitrile- and a 3-sulfone-substituted indole is also described using the same type of methodologies.

A short synthesis of koniamborine, a naturally occurring pyrano[3,2- b]indole

An expedient synthesis of the alkaloid koniamborine, the only to date isolated naturally occurring pyrano[3,2- b]indole is presented. The key pyrano[3,2- b]indole forming step is a palladium-catalyzed reductive N-heteroannulation of 2-(4-methoxy-2-nitrophenyl)-(4 H)-pyrane-4-one.

Palladium-catalyzed N-heteroannulation of N-allyl- or N-benzyl-2-nitrobenzenamines: synthesis of 2-substituted benzimidazoles

A palladium-catalyzed reductive N-heteroannulation of N-allyl- or N-benzyl-2-nitrobenzenamines, using carbon monoxide as the ultimate reducing agent, affording 2-substituted benzimidazoles has been developed.

Palladium-catalyzed synthesis of 3-alkoxysubstituted indoles

Indoles having an electron-donating alkoxy-group in the 3-position were prepared from 1-(2-nitrophenyl)-1-alkoxyalkene derivatives via a palladium-catalyzed reductive N-heteroannulation using carbon monoxide as the ultimate reducing agent. The required starting materials were prepared by a Stille coupling of 2-halonitroarenes with tributyl(1-ethoxyethenyl)stannane or tributyl(3,4-dihydro-2 H-pyran-6-yl)stannane.

Palladium-catalyzed syntheses of tetrahydrocarbazolones as advanced intermediates to carbazole alkaloids

Two sequential palladium-catalyzed reactions, an intermolecular Stille cross-coupling followed by a recently developed palladium-catalyzed reductive N-heteroannulation, have been employed as the key synthetic steps toward six tetrahydrocarbazolones. The products are advanced intermediates toward a number of naturally occurring carbazole alkaloids.

Synthesis of Fused Indoles by Sequential Heck Reaction and N-Heteroannulation

A new synthetic route to 3,4-fused indoles by two Pd-catalyzed reactions - intramolecular Heck and reductive N-heteroannulation - is reported. Indoles with various ring sizes (6-8) anchored to the 3- and 4- position of the indole nucleus may be prepared by this method. A number of functional groups (e.g., Me, Ph, Ac, CO2Me) tolerate the conditions of this route. Both hetero­atom (N, O) containing and carbocyclic rings may be anellated to the indole moiety with acceptable yields.

Synthesis of fused indoles by sequential palladium-catalyzed Heck reaction and N-heteroannulation

A route to 3,4-fused indoles via two consecutive palladium-catalyzed reactions; an intramolecular Heck reaction followed by a reductive N-heteroannulation is described. Using this route, a number of indoles have been prepared having a variety of ring sizes anchored to the 3- and 4-position of the indole nucleus. Furthermore, a number of functional groups, both carbon and heteroatom substituents can be introduced in (and on) the additional ring without any detrimental effects on the two reactions.

Palladium-catalyzed synthesis of 1,2-dihydro-4(3 H)-carbazolones. Formal total synthesis of murrayaquinone A

Two sequential palladium-catalyzed reactions are the key steps in a novel synthetic route to 1,2-dihydro-4(3 H)-carbazolones. The steps are an intermolecular Stille cross-coupling followed by a reductive N-heteroannulation. A formal total synthesis of murrayaquinone A, employing this sequence, is reported.

Novel palladium-catalyzed synthesis of 1,2-dihydro-4(3 H)-carbazolones

Two sequential palladium-catalyzed reactions are the key steps in a novel synthetic route to carbazolones, an intermolecular Stille coupling followed by a recently developed palladium-catalyzed reductive N-heteroannulation. A number of functionalized 1,2-dihydro-4(3 H)-carbazolones were prepared using this sequence.

Palladium-catalyzed synthesis of fused indoles

A novel route to fused indoles via two consecutive palladium catalyzed reactions, an intramolecular Heck reaction followed by a reductive N-heteroannulation, has been developed. For example, reaction of 2-bromo-3-nitro-1-(3-butenyloxy)benzene with palladium diacetate, and tri(o-tolyl)phosphine in the presence of triethylamine gave a readily separable mixture (18:4:1) of dihydro-4-methylene-5-nitro-2 H-1-benzopyran, 4-methyl-5-nitro-2 H-1-benzopyran, and 4-methyl-5-nitro-4 H-1-benzopyran. Reaction of pure dihydro-4-methylene-5-nitro-2 H-1-benzopyran with palladium diacetate, 1,3-bis(diphenylphosphino)propane, and carbon monoxide in DMF (120 °C, 70 h, 60 psi CO) gave 3,5-dihydro-2 H-pyrano[4,3,2- cd]indole in 63% yield.

Palladium-Catalyzed Synthesis of Indoles by Reductive N-Heteroannulation of 2-Nitrostyrenes

A palladium−phosphine catalyzed reductive N-heteroannulation of 2-nitrostyrenes, in the presence of carbon monoxide, producing indoles has been developed. Indoles were obtained, in moderate to exce...