Indoles annulations

A similar synthetic transformation has been reported for a variety of substituted indole annulated rings (2005JA13148, 20060L3601). 

Stoltz has reported the first oxidative indole annulations that are catalytic in palladium,... 

A tandem strategy for indole annulation has been developed from indolylborates. Initial b-annulation was effected by the following sequence hydroboration of a terminally imsaturated allylic acetate with 9-BBN, reaction with 2-lithio-l-methylindole to nerate the borate palladium-induced cyclization at C-3, migration from boron to carbon and aromatization (Scheme 49) <91CC1219>. A development of this uses the hydroboration derivative (156) of a 1-alkenylindole, followed by... 

As indole-annulated sulfur heterocycles continue to gain popularity as synthetic targets, Majumdar s approach to trihydrothieno[2,3- ]indole [118] and benzo[c] thiopyrano[2,3-6]indole derivatives [119] is well placed as a viable route. As seen with sulfide 226 and sulfoxide 228, 5-endo- and 6-endo-trig cyclizations onto the C-3 position of the ring occurred in fair yields. 

Majumdar KC, Debnath P, Alam S, Maji PK (2007) Thiol-mediated radical cyclization regioselective formation of indole-annulated sulfur heterocycles by tandem cyclization. Tetrahedron Lett 48 7031-7033... 

This reaction was first reported by Fischer and Jourdan in 1883. It is a synthesis of indole derivatives by the treatment of aryl hydrazones coupled from aromatic hydrazines and ketones or aldehydes with either a mineral or Lewis acid. Therefore, it is generally known as the Fischer indole synthesis. In addition, it is also referred to as Fischer cyclization, Fischer indole cyclization, Fischer indole reaction, Fischer indolization, Fischer reaction, and Fischer indole annulation. Although the mechanism has been extensively studied, the one formulated by Robinson and Robinson is now generally accepted. It involves the following steps (a) initial acid-catalyzed tautomerization of an aromatic hydrazone to an ene-hydrazine, b) a [3,3]-sigmatropic rearrangement of ene-hydrazine to a M-imine intermediate, (c) re-aromatization to aniline, d) intramolecular nucleophilic attack to form aminal, and (e) extrusion of an ammonia to afford the indole. 

The regioselectivity of Larock indole annulation with 2-alkynylpyridines and o-iodoaniline to give 3-substituted-2-pyridin-2-ylindoles has also been rationalized by a combination of steric and electronic coordinative effects (2008TL363 Scheme 3). A coordination of the pyridine nitrogen during the catalytic cycle was postulated to justify the different regioisomeric ratios 94 6, 68 32, and 72 28 of the Larock reaction obtained with cyclopentyl 2-, 3- and 4-pyridyl acetylenes, respectively. 

Table 9.1 Ligand electronic effects in oxidative indole annulations.

The choice of solvent also proved to be important in these indole annulations. In standard solvents and in the absence of catalyst, the annulated indole products were susceptible to oxidative decomposition. After a thorough analysis of solvent and catalyst effects, it was found that the products were stabilized in the presence of the Pd(OAc)2/ethyl nicotinate catalyst in a 4 1 mixture of tert-amyl alcohol/AcOH as the solvent. Since the oxidative decomposition of indoles is generally initiated by addition at C(3), it was hypothesized that the catalyst and/or AcOH can act as a competitive inhibitor. With this carefully optimized system, the oxidatively annulated indoles could be accessed in good to excellent yields. 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

As in the palladium(II)-catalysed indole annulation, a diastereomerically pure substrate was designed to help elucidate the mechanism of the benzofuran and dihydrobenzo-furan syntheses (Scheme 9.21). When aryl allyl ether 163 was treated with the palladium oxidation catalyst, dihydrobenzofuran 164 was produced as an exclusive di-astereomer in 60% yield. This observation confirmed that an oxidative Heck reaction pathway, featuring arene palladation, alkene insertion and /3-hydride elimination, was operative. 

In 2006, Lu and coworkers [53] described a method for the synthesis of carbazoles using the palladium(ll)-catalysed oxidative Heck reaction (Scheme 9.25). Indole 177 was subjected to catalytic Pd(OAc)2 and 2.1equiv of benzoquinone to afford carbazole 178 in 88% yield. Because the alkene is 1,1-disubstituted, a 5-exo cyclization mode (as seen in Ferreira and Stoltz s [48] indole annulation) is unproductive, and a 6-endo cyclization ultimately occurs. The putative intermediate is then believed to be oxidized to the aromatic carbazole by the excess benzoquinone. When indole 179, featuring a terminal alkene, was treated with these oxidative conditions, a mixture of products from 6-endo cyclization (180) and 5-exo cyclization (and subsequent isomerization and [3+2] cycloaddition, 181) was observed. A variety of substituted carbazoles were obtained by this palladium(n)-catalysed oxidative cyclization. 

A formal [4h-2] cycloaddition between arylidenoxin-doles and ethyl allenoate afforded dihydropyran-fused indoles, as shown by Wang and colleagues (Scheme 10, equation 1) [67]. Density functional theory (DFT) implicates a stepwise mechanism. A not-unrelated synthesis of indole-annulated dihydropyrano[3,4-c]chromenes via a hetero-Diels-Alder reaction was discovered by Jha and colleagues (equation 2) [68]. The requisite precursors 26... 

A similar aqueous domino Knoevenagel/lietero-DA reaction of o-propargylated salicylaldeliyde with l-methylindoline-2-thione in the absence of any Lewis acid has been developed by Majumdar and coworkers [78]. Seven examples of new indole-annulated pentacyclic heterocycles 138 were obtained in 72-80% yields (Scheme 12.54). 

Scheme 12.54 Domino synthesis of indole-annulated heterocycles.

Kiamehr, M. and Moghaddam, F. M. 2009. An efficient ZnO-catalyzed synthesis of novel indole-annulated thiopyrano-chromene derivatives via Domino Knoevenagel-hetero-Diels-Alder reaction. Tetrahedron Lett. 50(48) 6723-6727. 

Cyclohepta[ ]indole 107 was prepared by a one-pot indole annulation/ [4 + 3] cycloaddition of acetylene 105 with diene 106 under either... 

A tandem indole annulation-[4 + 3] cycloaddition of propargylic ethers with furans gave rise to cyclohepta[l>]indoles (13AGE3237). 

A range of pentacyclic thiopyran indole-annulated benzo-6-sultone deriratives are obtained through a domino Knoevenagel-hDA reaction of 2-formylphenyl (B)-2-phenylethenyl sulfonates with indohne-2-thiones in water (Scheme 99) (13TL2685). 

K. Majumdar, S. Ponra, R. K. Nandi, Tetrahedron Lett. 2012, 53, 1732-1737. One-pot efficient green synthesis of spiroox-indole-annulated thiopyran derivatives via Knoevenagel condensation followed by Michael addition. 

Scheme 37 Brpnsted acid-catalyzed redox-neutral indole annulation cascades...

---