Powers indole synthesis

The reductive cyclization of o-nitrophenylacetaldehyde dialkyl acetals is a powerful indole synthesis as shown by many investigators (Table 1). The reaction presented in... 

Similar to the Fisher indole synthesis, reductive cyclization of nitro aromatics offers a powerful means of forming indoles. Reductive cyclization of ortho, 2 -dinitrostyrenes has occurred in many ways, by TiCl3, NaBH4-Pd/C, H2-Pcl/C, and other reductive methods.89 Corey and coworkers have used the Borchardt modification (Fe-AcOFI, sihca gel, toluene at reflux for the reductive cyclization of o-ji-dinitrostyrenes) to prepare 6,7-dimethoxyindole (Eq. 10.65) in a total synthesis of aspidophytine (see Schemes 3.3 and 3.4 in Section 3.2.l).89d... 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Finally, although a practical total synthesis of a naturally occurring indole alkaloid using a tandem radical cyclization strategy has yet to be demonstrated this strategy has shown great potential as a powerful tool in indole synthesis. 

However, the Fischer indole synthesis met with failure under classical heating conditions, using a variety of solvents and catalysts. The authors then explored ZnCl2-mediated microwave-assisted cyclization in a domestic microwave oven using the full irradiation power of c.a. 1500 W. The cyclization was found to proceed smoothly in DMF in a mere 9 min and the iso-Meridianins were isolated in good yields. 

The Fischer indole synthesis. The Fischer acid-catalyzed conversion of an 7V-arylhydrazone 42 into an indole is one of the most powerful and versatile methods for the preparation of indoles . The mechanism involves a [3,3] sigmatropic Claisen-type rearrangement of a protonated enehydrazine tautomer 43 to give intermediate 44, which spontaneously cyclizes by loss of ammonia, probably via indoline 45, to an indole 46 (Scheme 27). For unsymmetrical ketones, two isomeric indoles are possible and the general result is that the indole derived from the more stable (usually the more highly substituted) enehydrazine is formed. 

The Fischer indole synthesis is commonly recognized as one of the most powerful and versatile tools for construction of indoles, as reflected by the amount of recent publications in which it has been used successfully. The usual approach involves initial preparation of a phenylhydrazone 323 from a suitable phenylhydrazine and an enolizable carbonyl compound, followed by an acid-induced cyclization to the target indole 324, featuring a [3,3]-sigmatropic rearrangement as the key step (Scheme 38). Some selected new examples of indoles prepared using standard Fischer conditions are collected in Table 2. 

The current popularity and undisputed power of the Larock indole synthesis [371] is... 

An important variation of the Jones-Schmid indole synthesis is the base-mediated cyclization onto esters, which affords 3-hydroxyindoles (indoxyl tautomers) under mild conditions. Three case studies are shown in Scheme 2 (equations 1-3) [18-20]. This chemistry, like that in Table 1 (Entries 4-11), represents a powerful route to C-3 functionalized indoles. Kraus and coworkers use the steri-cally hindered phosphazine base, P -t-Bu, to prepare the 5,6-dihydroindolo[2,l-a]isoquinoline ring system (equation 4) [21]. Several derivatives display immunosuppressive activity. 

The Engler-Kita indole synthesis, combined with the Nenitzescu indohzation, represent powerful and versatile syntheses of 5-hydroxyindoles. 

The first example of an indole-2,3-quinodimethane (IQM) undergoing a Diels-Alder cycloaddition to furnish a carbazole was reported by Plieninger and coworkers in 1964 [9], Thus, indole-3-acetic acid was readily converted to pyrano[3,4-fe]indol-3-ones upon treatment with carboxylic acid anhydrides (Scheme 1, equation 1). These stable synthetic equivalents of IQMs undergo Diels-Alder reactions with electron-deficient dienophiles (A-phenytma-leimide,maleicanhydride,dimethylacetylenedicarboxylate) (equation 2). Plieninger s discovery notwithstanding, it was Moody and coworkers who parlayed this chemistry into a powerful carbazole synthesis (equations 3,4) [10-18],... 

In summary, the original discovery by Mori and Ban of a new Pd-catalyzed indole synthesis involving an intramolecular Heck cyclization has been refined by many investigators to become a powerful method for the synthesis of diverse indoles. 

In a relatively short time span, gold-catalyzed reactions have blossomed into a powerful new methodology in organic synthesis. Given several reviews in the period 2011 throngh 2014 on gold-catalyzed indole synthesis [1-4], this chapter focuses on a few seminal papers and then very recent work. 

Mori and Sato [17], Rasmussen [18], and Shuto and Arisawa [19, 20] have each exploited the synthetic power of these ruthenium catalysts in indole synthesis (Scheme 3,... 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

The incredibly powerful and versatile Heck coupling reaction has found enormous utility in indole ring synthesis and in the elaboration of this important heterocycle. Due to the enormity... 

The intramolecular reaction between carbenoids and amides is clearly emerging as a powerful tool for the synthesis of saturated oxazolo[3,2-tf]pyridine derivatives as shown by the cyclization of simple to extremely functionalized substrates 379 <2003CC440> and 381 <20050L47> (Scheme 100) trapping the intermediate isomtinchnone 1,3-dipoles by external (MeOH) or internal (indole) nucleophiles results in new heterocyclic fused systems with especially high efficiency. 

ABSTRACT The acid-catalysed epimerization reaction of bioactive indole alkaloids and their derivatives is reviewed. The three mechanisms, which have been proposed for the (J-carboline-type indole alkaloids, are discussed. Through recent developments, evidence for all three mechanisms has been obtained, which shows the complexity of the epimerization reaction. The epimerization seems to depend on structural features and reaction conditions making it difficult to define one universal mechanism. On the other hand, the isomerization mechanism of oxindole alkaloids has been widely accepted. The acid-catalysed epimerization reaction provides a powerful tool in selectively manipulating the stereochemistry at the epimeric centre and it can also have a marked effect on the pharmacology of any epimerizable compound. Therefore, examples of this reaction in die total synthesis of indole alkaloids are given and pharmacological activities of some C-3 epimeric diastereomers are compared. Finally, literature examples of acid-catalysed epimerization reactions are presented. 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

Reductive intramolecular cyclizations constitute a powerful tool for the synthesis of various indoles. The tricyclic indole derivative 118, a key intermediate in a previous synthesis of the alkaloid r//-physostigmine, was prepared by reductive cyclization of the precursor 119, for which an interesting synthetic route was developed <03JOC6133>. 

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