Indole scaffold

More recently, the utility of the indole group as a scaffold for cannabinoid agonists has been demonstrated by a number of new patent applications appearing in the literature (286)-(290) [187-190]. Of particular note is compound (286) that is reported to have 18-fold selectivity for the CBi receptor (CBp Ki — 0.08 nM CB2 Ki — 1.44nM). In addition to the indole scaffold, a number of patent applications by AstraZeneca claim indole-like scaffolds such as benzimidazoles (289) [191-193] and azaindoles (290) [194]. Although these compounds bind to both CBi and CB2 receptors, the inventors claim that they may be useful in treating diseases without the associated CNS side effects. 

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

Reaction of melatonin with various aryldiazonium chlorides in ethanolic sodium acetate solution afforded arylazo-melatonin derivatives. Reactions of these products with either malonitrile or ethyl cyanoacetate formed the corresponding ary lam inotriazino[4,3-/z indole scaffolds 60-63 <2005BMC1847>. 

The utility of the privileged structure concept is illustrated by compound library synthesis based on the indole scaffold and the biologically active compounds resulting from that. The indole scaffold is found in natural products, like for example, the neurotransmitter serotonin (5-hydoxytriptamine, 5-HT) and in well-know drugs, like for example, the... 

Kalinski C, Umkehrer M, Schmidt J, Ross G, Kolb J, Buidack C, Hiller W, Hoffmann SD (2006) A novel one-pot synthesis of highly diverse indole scaffolds by the Ugi/Heck reaction. Tetrahedron Lett 47 4683 686... 

Fig. 18. Mannich reaction on a resin-bound indole scaffold, (a) Amine (1.5 equiv.), HCHO (1.5 equiv.), HOAc/l,4-dioxane (1 4), 1.5 h RT (b) 30% TFA, CH2C12, 1 h, RT.

Mannich Reaction on a Resin-Bound Indole Scaffold (89) (Fig. 18).50 Commercially available indole 5- or 6-carboxylic acid supported on Rink amide resin is suspended in HOAc/l,4-dioxane (1 4). A secondary amine (1.5 equiv.) and formaldehyde (1.5 equiv.) are added. The suspension is shaken for 1.5 h at RT. The resin is then filtered, washed with appropriate solvents, and dried under vacuum to obtain (90). 

The indole scaffold as seen in the antipyetic or anti-inflammatory indomethaci and etodolac. (R3 and R4 also form a ring)... 

More recently a study on sulphonamide drugs binding to the colchicines site of tubulin has been reported [38]. A series of diarylsulfonamides containing an indole scaffold was also found to have antimitotic properties, and to bind to the colchicine site of tubulin in a reversible manner. 

The synthesis of indoles on soHd supports has been driven by the wide range of indole derivatives that occur in Nature [142-144], and by the biological activity of many indole derivatives of both natural and synthetic origin [145]. The indole scaffold appears in the amino acid tryptophan, the metabolites of which are important in the biochemistry of both plants and animals. In addition, the indole ring appears in many compounds that have found use as drugs, e.g., indomethacin [146], sumatriptan [147], and pindolol [148]. Synthetic approaches towards indoles on solid phases have also been reviewed elsewhere [149]. 

The core skeleton of geissoschizine, an important biosynthetic precursor to numerous polycyclic indole scaffolds, was the target of a nickel-catalyzed alkylative coupling strategy. Cyclization precursor 13 was prepared by ozonolysis and double reductive amination of cyclopentene 12 (Scheme 8.13) [35]. Nickeldeprotection/oxidation sequence followed, and chromatography led to complete inversion of the C3 stereocenter. A Fisher indole synthesis followed to afford ( )-deformyl-isogeissoschizine, the core skeleton of geissoschizine. 

This team pursued a strategy similar to Dolby by first constructing a hexa-hydro-l,5-methanoazocino[3,4-l)]indole scaffold and then attempting to... 

They initially discovered several synthetically efficient routes to obtain the hexahydro-l,5-methanoazocino[3,4-f)]indole scaffold. For example, they found that treatment of the pyridine 222 with methyl iodide furnished the pyridinium salt 223, which could be hydrogenated using platinum oxide in ethanol to yield the piperidine 224 (Scheme 26). Oxidative cycHzation was then employed with mercury(II) acetate in a buffered aqueous medium to form iminium ion 225, which underwent subsequent cycHzation at the 2-position of the indole to furnish tetrahydrocarbazole 226. ... 

The group next expanded upon this tactic of using an iminium ion cycHzation with an indole to construct the more fuUy elaborated hexahy-dro-lH-l,5-methanoazocino[3,4-fc]indole scaffold 234, an intermediate that contained all of the functionahty required for strictamine (6), except... 

Kanai and colleagues developed an enantioselective synthesis of various 2-(2-hydroxyethyl)indole scaffolds via the amido-cupration of allenes followed by the asymmetric addition of carbonyl compounds. Treatment of allene 88 with a copper catalyst forms a stable and highly nucleophilic allyl-copper species, which then adds into benzaldehyde (89) to furnish indole 90. A range of carbonyl compounds are competent in the sequence, including aryl- and heteroaryl aldehydes, alkyl aldehydes, and aryl ketones. This is reported to be the first example of a combined catalytic indole generation and subsequent enantioselective addition of carbonyl compormds (14CS1585). 

A review described azaindoles as a scaffold in the design of kinase inhibitors (14MOL19935).Triazoloindoles 296 can be used as valuable carbene precursors and allowed to react with azaindoles 297 to form a 3,3 -biindole-type product 298. The reaction manifold can be used to synthesize other valuable molecules with the indole scaffold such as pyrroloindoles, spirocy-clopropyliminoindoles, 2,3-dihydropyrroloindoles, and 2,3 -biindoles (140L1244). 

The reaction proved to be remarkably tolerant of substitution on the indole scaffold. Further exploration of indole substituents will not be shown in the scheme but will be discussed. Comparison of the coupling of a 5-OMe analogue versus the unsubstituted analogue of indole 128 with unsubstituted imine 133a (R = H) afforded similar results as the 5-OMe analogue of 133a was obtained in 92% yield (94% ee). Introduction of a 5-Br substituent into... 

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]. 

Inspired in the combination of the Ugi-Smiles reaction with other transformations, the same group envisaged a new route for the construction of indole scaffolds 121 based on an extension of this novel Ugi-Smiles protocol with a subsequent Heck cyclization in an one-pot procedure (Scheme 7.50) [107]. 

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