Indoles annulated

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

Bis-indolylmaleimide 30 was transformed into the aza-l,7-annulated indole 31 by an oxidation procedure, followed by the /-butoxycarbonyl (BOC) deprotection in one pot (Equation 6) <2004BML3925>. 

Ring-closing metathesis has been applied to the preparation of annulated indoles including indolo[2,3-a]carbazoles <05JOC10474> and azepino[4,3-h]indoles <05TL7881>. 

From nitroarenes hydrogenation in the presence of aldehydes leads to A-monoalkyl arylamines. Hydrogenation of 2-(o-nitroaryl)-2-cycloalkenones gives annulated indoles (e.g., tetrahydrocarbazoles). ... 

Scheme 9 Annulated indoles via a tandem alkylation/direct arylation reaction.

Scheme 10 Proposed reaction mechanism for the formation of annulated indoles.

Tautens and co-workers subsequently extended this methodology to the functionalization of other heteroarenes and to eight-membered ring-annulated indoles, even though with lower yields than their six- and seven-membered counterparts (08JOC1888). 

Scheme 6.45 Asymmetric synthesis of 3,4-annulated indole derivatives 114 reported by Fochi and Bernardi.

A similar transformation was described later by the Lautens group [84], With a modification of the sequence, annulated indoles 150 were obtained by using iV-bromoalkyl indoles of type 148 and aryl iodides 149 [85], 2,3-Disubstituted indoles and thiophenes can also be prepared in the same way [86] (Scheme 8.39). 

Bressy, C., Alberico, D. and Lautens, M. (2005) A route to annulated indoles via a paUadium-catalyzed tandem alkylation/direct arylation reaction. J. Am. Chem. Soc., 127,13148-9. 

In 2003, Ferreira and Stoltz [48] described an aerobic palladium(II)-catalysed intramolecular oxidative Heck reaction to form annulated indoles. The core annulated indole smicture is prevalent in a number of biologically active natural products, including pax-illine, penitrem A, and yuehchukene (Figure 9.5). Because indoles are susceptible to oxidative decomposition, carefully optimized conditions had to be developed that were compatible with the substrate and product indole species. 

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. 

A variety of annulated indoles were obtained via this mild palladium oxidation system (Figure 9.6). Five- and six-membered rings were constructed by this method. Indoles with electron-withdrawing and electron-donating groups on the arene were oxidatively cyclized in good yields (131 and 132). When a substituent was placed on the tether between the alkene and the indole, diastereoselective cyclization occurred to form 133. The cyclization can occur not only from C(3) to C(2), but also from N(l) to C(2) (indole 138) and C(2) to C(3) (indoles 135 and 139). 

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. 

Lin and colleagues expanded the Nenitzescu indole synthesis to include a wide variety of 1,3-diazaheterocycle-fused [l,2-fl]indoles (Scheme 13, equation 1 and 55-57) [51], Parr and Reiss employed the Nenitzescu indole synthesis to prepare several benz[ ]indoles and 1,2-annulated indoles (equations 2, 3) [52]. 

In this domino process, first, the nitro group gets reduced to give an amine moiety, which then undergoes a Michael addition to afford an unsaturated ester the final step is the elimination of water to yield 117 [69]. Recently, Banwell et al. applied a domino nitroarene reduction protocol for the total synthesis of 1,5-methanoazocino[4,3-f)]indole 118 framework of the uleine and strychnos alkaloids (Scheme 9.24). Pd/C reduction of nitroarene 119 in methanolic solution afforded annulated indole 120, which presumably arose from the reduction of both nitro and the carbon-carbon double bond. Raney-nickel reduction produced the amine analog 121. However, Raney-cobalt reduction resulted in the tetracyclic compound... 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

In particular, 1,7-annulated indole derivatives, such as the prototypical Cilansetron A, display high activity as 5-HT3 receptor antagonists and are being clinically tested for the treatment of symptoms in the gastrointestinal system such as the irritable bowel syndrome (IBS) [26]. To extend our previous synthetic strategy based on the reactivity of hydrazinediido zirconium complexes to annulated polycyclic indole derivatives, we aimed to prepare such hydrazides derived from cyclic hydrazines (B). 

The amidozirconium complex [Zr(N2 Npy)(NMe2)2] was tested as catalyst for the formation of 1,7-annulated indoles, starting from the... 

A norbornene-mediated, palladium-catalyzed sequence was described to form annulated indoles (eq 155). Furans or thiophenes can undergo a similar cycUzation to provide annulated... 

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