Transition metal catalyzed reductive N-heteroannulation heterocyclization of 1-(2-nitroaryl)-1-alkenes, using carbon monoxide as the ultimate reducing agent, is emerging as a powerful methodology for the synthesis of a wide variety of functionalized indoles.^{2,3,4,5,6,7,8} Palladium complexes have mainly been used as the catalyst of choice but other transition metals including ruthenium (Ru₃(CO)₁₂,⁸ RuCl₂(PPh₃)₂⁶), rhodium (Rh₆(CO)₁₆,⁸ RhCl(PPh₃)₃⁶), iron (Fe(CO)₅),⁸ nickel (NiCl₂(PPh₃)₂),⁶ and and platinum (PtCl₂(PPh₃)₂)⁶ also catalyze this transformation. A molybdenum (MoO₂Cl₂(dmf)₂) catalyzed reaction in the absence of carbon monoxide has also been described.⁹ In addition to transition metals, a catalytic amount of elemental selenium in the presence of carbon monoxide can be used.¹⁰ A direct comparison between all of the different catalysts cannot be made, however in general the palladium diacetate - triphenylphosphine catalyst system usually afford superior yield of product at lower temperature and pressure.

For most substrates, the exclusion of oxygen and water is not required and reagent grade chemicals and solvent can be used with excellent results. The palladium-catalyzed annulations cyclizations are usually free from byproducts derived from the starting material. If observed, byproducts include N-hydroxyindoles, indole dimerization products, and reduction of the nitro-group to an amine. T he former impurity can be eliminated or minimized by extending the reaction time or increasing the CO pressure. A potential purification problem is triphenylphosphine and the small amounts of triphenylphosphine oxide formed when using Pd(OAc)₂-PPh₃. This can be particularly problematic on a larger reaction scale. Replacing triphenylphosphine with 1,10-phenanthroline or a related bidentate ligand is a convenient solution to this problem although, these ligands are significantly more expensive.

Davies and Smitrovich et al. have more recently found, after extensive optimization using a Parallel Pressure Reactor (PPR^®), conditions wherein indoles are formed at a low catalyst loading (1 mol% Pd(OAc)₂, 2 mol% 1,10-phenanthroline) under 1 atm of CO at 80 ^oC in DMF (Scheme 1).¹¹ To our knowledge, this reaction represents the largest scale used to date for this type of annulationcyclization. An even lower catalyst loading was realized for a specific target substrate employing 0.1 mol% of palladium ditrifluoroacetate, 0.7 mol% of 3,4,7,8-tetramethyl-1,10-phenanthroline under the same CO pressure, solvent, and reaction temperature. Rigorous exclusion of oxygen is necessary for reproducibility using the latter conditions.

A wide range of functional groups are compatible with the reaction conditions. Recent applications of the palladium-catalyzed N-heteroannlulation heterocyclization include the synthesis of tryptophane derivatives,¹² bicyclic pyrrolo-fused heteroaromatic compounds,¹³ a synthesis and revision of the structure of fistulosin,¹⁴ koniamborine,¹⁵ tjipanazoles,¹⁶ 1H-indole-2-yl-1H-quinolin-2-ones,¹⁷ murrayaquinone,¹⁸ bauerine A (Scheme 2),¹⁹ carbazole

alkaloids (Scheme 3),²⁰ and mushroom metabolites (Scheme 4).²¹ Enhanced reactivity is observed in some cases when two bidentate ligands, bis(diphenylphosphino)propane and 1,10-phenanthroline, are employed. The reason for this is presently unknown.

The reductive N-heteroannulation heterocyclization of 1-(2-nitroaryl)-1-alkenes to give indoles is relatively insensitive to the catalyst system used. In contrast, annulation cyclization onto an aromatic ring forming carbazoles and related compounds from 1-aryl-2-nitroaryls is not universal. For example, the Pd(OAc)₂-PPh₃ catalyst system and reaction conditions used to prepare methyl indole-4-carboxylate do not affect the cyclization of 2-nitrobiphenyl to give carbazole. Both Ru₃(CO)₁₂,²² and Fe(CO)₅,²³and MoO₂Cl₂(dmf)₂⁹ have been used to prepare carbazoles and related compounds but to date the best results are obtained using Pd(OAc)₂-1,10-phenanthroline in DMF at 140 ^oC and 5 atm of CO (Scheme 5).²⁴ 1-(2-Nitroaryl)-1-alkenes can also be cyclized to form 3-arylindoles via a cyclization onto an aromatic ring (Scheme 6).²⁵

The transition-metal catalyzed reductive N-heteroannulation heterocyclization reaction forming indoles is mechanistically related to reductive annulations cyclizations of nitroaryls using trivalent phosphorous compounds, usually triethylphosphite, at elevated temperatures. However, the palladium-catalyzed reaction offers advantages such as lower reaction temperatures, wide functional group compatibility, and few if any byproducts.