Aromatic heterocycle synthesis indoles

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

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). 

S. Erase, C. Gil, and K. Knepper, The Recent Impact of Solid-Phase Synthesis on Medicinally Relevant Eenzoannelated Nitrogen Heterocycles, Bioorg. Med. Chem., 2002, 10, 2415-2437. A comprehensive review covering the solid-phase synthesis of not only indoles but also several other nitrogen-containing aromatic heterocycles. 

Monocyclic and Bicyclic aromatic heterocycles such as imidazoles, thiazoles, thiadiazoles, oxazoles, oxadiazoles quinazolines, indoles, benzimidazoles, purines pyrido[43-d]pyri-midines, thiazolo[5,4-d]pyrimidines, thiazolo[4,5-d]pyrimidines, oxazolo[5,4-d]pyrimi-dines and thieno[2,3-d]pyrimidines are renowned pharmacophores in drug discovery. These special structures are well explained and exemplified in chemical compound libraries. In this chapter, several types of thiazole based heterocyclic scaffolds such as mono-cyclic or bicyclic systems synthesis and their biological activities studies are presented, which are not frequently present in books and reviews. We mention the first importance of synthetic route of various thiazole based compounds and their applications in medicinal chemistry in this chapter. 

A variety of nitrogen nucleophiles have been utilized in Pd-catalyzed 77-alkenylation reactions. For example, Bolm has employed iV-alkenylation reactions for the preparation of iV-alkenyl sulfoximines (Eq. 18) [140], and Yudin has applied this method to the synthesis of W-alkenyl aziridines (Eq. 19) [141]. Analogous W-arylation reactions of sulfoximines and aziridines have also been developed [142, 143]. Movassaghi has effected W-alkenylation reactions between functionalized alkenyl triflates and several aromatic nitrogen heterocycles including indoles and pyrroles (Eq. 20) [144]. The use of p-chloroacrolein derivatives as substrates in iV-alkenylation reactions has also been illustrated [145, 146]. 

As noted previously, a wide variety of aromatic systems serve as nuclei for arylacetic acid antiinflammatory agents. It is thus to be expected that fused heterocycles can also serve the same function. Synthesis of one such agent (64) begins with condensation of indole-3-ethanol (60) with ethyl 3-oxo-caproate (61) in the presence of tosic acid, leading directly to the pyranoindole 63. The reaction may be rationalized by assuming formation of hemiketal 62, as the first step. Cyclization of the carbonium ion... 

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as useful starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, and pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromatics (mainly pyrroles and indoles) and saturated nitrogen heterocycles such as pyrrolidines and their derivatives. 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Wherever the heterocyclic ring is fused to an aromatic system the starting material must always be a preformed aromatic derivative. In this context the Fischer indole synthesis (Scheme 6.12) provides a good example ... 

The synthesis has been applied to a great variety of Mannich bases derived from aromatic compounds and from heterocycles, such as indole, pyridine, quinoline, coumar-in, etc.104 Compound 198, for instance, yields the pyranopyridine shown in equation 84104. 

Successful berbine synthesis summarized in Section IV,C prompted Nin-omiya s group (25,26,117,118) to extend enamide photocyclization to har-malane, therefore giving rise to a novel and facile synthesis of polycyclic heterocycles such as the yohimbine group of compounds. Before reductive photocyclization was introduced, the use of nonoxidative photocyclization with indole alkaloids was limited to simple systems and those possessing a large degree of aromaticity. 

Quintanilla-Licea R, Teuber HJ (2001) Review on reactions of acetylacetaldehyde with aromatic and biogenic amines and indoles-synthesis of heterocycles via hydroxymethylene ketones. Heterocycles 55 1365-1397... 

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