Indole-like

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. 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

Indoles, like pyrroles, are very weak bases. The conjugate acid of indole has pATa — 3.5 that of pyrrole has pATa - 3.8. As in the case of pyrrole (see Section 11.3), nitrogen has already contributed its lone pair to the aromatic sextet, so A-protonation... 

A number of examples were shown to undergo amine addition to an adjacent carbon-carbon triple bond to give indole-like products. One such example shows pyrimidine 123 being converted to 124 in strong base (Equation 45) <2000AGE2488>. 

C) with an indole-like odor. It is prepared by a Prins reaction from indene and formaldehyde in the presence of dilute sulfuric acid [194]. It is used in perfumes for soap and detergents. 

Indolizine is an important ring system in view of its similarity to indole. Like indole, it has a delocalized 10ir-electron system that confers aromaticity, in contrast to its analogs, pyrrolizine and quinolizine. Consequently, it has a theoretical and practical interest. 

Indole, like benzothiophene, reacts with electrophiles to give preferentially -substituted products. Bromination241-243 in dioxane or pyridine, nitration by ethyl nitrate,244 chlorination by sulfuryl chloride,245 iodination in aqueous solution,246, 247 Vilsmeier and Reimer-Tiemann formylations,248-261 diazo coupling,252 thio-cyanation,263 and nitrosation254 all give the 3-substituted indoles, practically free from other isomers. 

Indole, like naphthalene, has ten it electrons in two rings and is aromatic. Two n electrons come from the nitrogen atom. 

Indol, like pyrrol, possesses slight basic properties, and also colours a strip of fir, moistened with acid, red. It forms colourless leaflets, M.P. 52°, which have a peculiax , unpleasant smell. It boils at 245° with partial decomposition. With nitrous acid it yields a nitroso-derivative. Of the salts, only the picrate is stable. With acetic anhydride it forms acetylindol. 

Indoles, like pyrroles, are very weak bases typical pA an values are indole, -3.5 3-methylindole,. 6 ... 

The odor threshold in water quoted by Maga (1978a) was 0.065 ppm. As reported by Kim Ha and Lindsay (1991), 2-methylphenol is phenol-like, indole-like, medicinal (neat) with odor thresholds varying from 65 to 260 ppb in water. 

The odor is dry-tarry, medicinal-leathery (Arctander, 1967). The flavor is described as phenolic, medicinal, barn-yard, dirty (Chemisis, 1999). Maga (1978a) reports a an odor threshold in water of 68 ppb. Kim Ha and Lindsay (1991) report phenol-like, fresh hot asphalt-like, wood preservative-like, indole-like (neat) characteristics with odor thresholds ranging from 68 to 200 ppb in water. 

The flavor description is smoky, sweet, earthy (Chemisis, 1994). The odor perception is phenolic at the sniffing port for Holscher et al. (1990). Kim Ha and Lindsay (1991) reported the odor as being chemical, phenolic, indole-like, animal-like (neat). 

Indoles, like pyrroles, are easily oxidized. During autoxidation, the 3-position is attacked by oxygen leading to a hydroperoxide which gives rise to indol-3(2//)-one (indoxyl) ... 

Indoles, like pyrroles, are very weak bases typical p a values are indole, -3.5 3-methylindole, -4.6 2-methylindole. -0.3. This means, for example, that in 6M sulfuric acid two molecules of indole are protonated for every one unprotonated, whereas 2-methylindole is almost completely protonated under the same conditions. By NMR and UV examination, only the 3-protonated cation (3//-indolium cation) is detectable it is the thermodynamically stablest cation, retaining full benzene aromaticity (in contrast to the 2-protonated cation) with delocalisation of charge over the nitrogen and o-carbon. The spectroscopically undetectable A -protonated cation must be formed, and formed very rapidly, for acid-catalysed deuterium exchange at nitrogen is 400 times faster than at C-3, indeed the A -hydrogen... 

Another strategy for annelation of pyrroles and indoles involves cycloaddition reactions. Because the heteroaromatic rings have substantial aromatic stabilization, the C2—C3 bond is not very reactive toward cycloaddition and there are only a few examples of the heterocycles acting as dienophiles. The carbocyclic ring of indole, like benzene, is unreactive toward cycloaddition. However, vinylpyrroles and indoles are quite reactive and react as electron-rich dienes because of the electron-donating nature of the ring. Other cycloaddition reactions involve the 2,3-dimethylene derivatives of pyrrole and indole, the so-called quinodimethanes, which are very reactive dienes. These intermediates, and more stable synthetic equivalents, are useful in cycloadditions with a variety of dienophiles. 27/-Isoindole, which itself can be thought of as a quinodimethane, is a very reactive diene. 

Other indole syntheses of this type include the preparation of 3-amino-lH-indole-2-carboxylates through aminobenzonitriles (14T8047), 3-aroylindoles via two metal-free sp C—H activations (14CC10445), and a Zn-mediated reductive ring closure which enables the synthesis of fused indole-like heteroacenes (14JOC11339). 

Matcha and Antonchick prepared a series of indoles, pyrazoles, and pyrid-azinones via the functionalization of alkenes in a cascade multicomponent process. An electrophilic trifluoromethyl radical added to the terminal position of olefin 119 to give radical intermediate 121. Then, in a Fischer indolization-like process, phenylhydrazone 122, through an ene-hydrazine, cyclized to aminoindoline 123. After elimination of ammonia, indole 120 was isolated in good yield (14AG(I)11960). 

The synthesis of 4,5,6,7-tetrahydroindoles from cyclohexanone oxime and 1,2-dihaloethanes has been disclosed [303], The best overall yields (52%-61%) of NH- and N-vinyl-4,5,6,7-tetrahydroindoles are reached when molar ratio of cyclohexanone oxime-dichloroethane-KOH-DMSO is 1 1-2 7 10. For the successful synthesis of 4,5,6,7-tetrahydroindoles, it is important to add the alkali and dihaloethane to the solution of the ketoxime in DMSO in portions. Otherwise, the reaction of diether formation becomes appreciable. At the sacrifice of decreasing the yield to -30%, one can attain 94%-95% selectivity relative to the major product, 4,5,6,7-tetrahydro-indole. Like in the reaction with free acetylene, this is achieved mainly due to the addition of small amounts of water (10%-20%) to the reaction mixture. In this case, the water can be conveniently fed into the mixture by dissolving alkali in it, which simultaneously also facilitates the dispensing of both components. Somewhat poorer results are obtained with 1,2-dibromoethane under comparable conditions [303]. 

CFE at 30°C for 1 hr. aCA isolated from the reaction mixture contained no or while jSCA contained no but 19% of the added It was clear that the CFE contained both an enzyme and a substrate which, along with dimethylallyl pyrophosphate (DMAPP), would produce ]8CA. This cosubstrate was a derivative of tryptophan (Trp), which was isolated and identified as a-acetyl-y-(j5-indolyl)methyltetramic acid (cycloacetoacetyl-L-tryptophanyl, cAATrp), 16. It was also established that this indole, like... 

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