Methoxyindole

A mixture of 3-methoxy-2-nitro-P-pyrrolidinostyrene (lOg, 40 mmol) and Raney nickel (25 g) in methanol-THF (40 ml of each) was heated to 60 C and, 

Printed with FinePnnt 2000 - register at http //wwwfmepnnt c( 

With Stirring, hydrazine hydrate (4 ml in 30 ml of THh ) was added over 60 min. The reaction mixture was then cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo and the residue purified by chromatography through silica gel using 10% ether in hexane for elution. The fractions containing product were combined and evaporated to give the product as a clear oil (2.94g, 50%). 

Dulenko and V. A. Nikolyukin, Chem. Heterocycl. Cmpds. English Tram . 22, 36 (1986). 

---

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

The isomeric 7-MeO-MIPT was synthesized by the exact same five-step reaction sequence starting with 7-methoxyindole, in an overall yield of 24%. The actual reaction conditions for this conversion are detailed in the recipe for 4-MeO-MIPT. The mp of 7-MeO-MIPT was 72-73 °C and its MS (in m/z) C5H12N+ 86 (100%) indolemethylene+ 160 (5%) parent ion 246 (4%). 

The annelation of indoles to produce carbazoles is also frequently a satisfactory synthetic process. Reaction of 5-, 6- or 7-methoxyindole with 2,5-hexanedione, for example, gives... 

A new synthesis of ethyl 7-methoxyindole-3-acetate was accomplished by reductive cyclization of the o-nitrobenzyl cyanide 22a. The indole was then elaboarated to the tetracycle 22d by an intramolecular Pummerer reaction. <95JHC947> ch2co2c2h5... 

Gelsemicine, C20H26N2O4, mp 171°-172°, [a]D-142°, is a monoacidic base, which contains one C -methyl and two methoxyl groups (14,16,18) the presence of a methylimino group, reported earlier, has since been shown to be erroneous. The UV-spectrum of gelsemicine has a comparatively unfamiliar appearance and it is difficult to deduce the nature of the chromophore present. The spectrum shows some resemblance to those of 7-methoxyindole derivatives, although it does not possess a pronounced minimum at 250-260 mp. in neutral solution (18, 100). In alkaline solution, the curve is more like that expected for a substituted indole derivative. 

Catalytic hydrogenation of the molecule 137, which is available by exposure of l-methoxy-4-nitro-2-(trifluoro-methyl)benzene to 4-chlorophenoxyacetonitrile in the presence of potassium /-butoxide, provided a practical approach to the indole 138 (Equation 38) <1998JME1598>. A related strategy has also been used in preparation of pyrroloquinolines <2002H(57)129> and ethyl (7-methoxyindol-3-yl)acetate <1995JHC947>. 

The synthesis of 7-methoxyindole was accomplished starting from 1-acetylindoline (34). Regioselec-tive introduction of iodine was achieved using thallium trifluoroacetate, then potassium iodide. Deacetylation and oxidation to the indole (35), followed by reaction with sodium methoxide in DMF, gave the... 

The synthesis of 7-methoxyindole was accomplished starting from 1-acetylindoline (34). Regioselec-tive intr uction of iodine was achieved using thallium trifluoroacetate, then potassium iodide. Deacetylation and oxidation to the indole (35), followed by reaction with sodium methoxide in DMF, gave the 7-methoxyindole (36) in 48% overall yield (Scheme 13). More recently, Somei et al have reported that treating the intermediate thallium species with copper(II) sulfate pentahydrate gives directly the l-acetyl-2,3-dihydro-7-hydroxyindole (37) in 42% yield (Scheme 14). It remains to be seen whether this is a general process. 

Oxidation of l-amino-4-methoxybenzenes with CAN is expected to afford p-iminoqninones. Thns, batzellines, makalnvamines and discorhabdins, isolated from marine organisms, possess a pyrroloiminoqninone moiety and can be synthesized by CAN-mediated oxidation of the corresponding 4-amino-7-methoxyindole derivative. 

When the Fischer synthesis is applied to an unsymmetrical ketone, either one of two isomers or a mixture of them may be produced. (+)-3-MethylcycIopen-tanone gives a mixture of I- and 2-methylcyclopent[0]indoles, and the relative amounts of these formed under various conditions are analysed [3222]. Further work has recently been published on the Fischer indolization of -methoxy-phenyl- -phenylhydrazones of an unsymmetrical ketone (ethyl pyruvate). Cyclization in acid occurs mostly on to the more electron-rich benzene ring whereas under nonacidic (for example, thermal) conditions there is less regio-selectivity [3539]. 2-Methoxyphenylhydrazine sometimes behaves anomalously and does not yield the expected 7-methoxyindole, but when o-4-toluenesuIphonyl-or o-4-trifluoromethylsulphonyI-phenylhydrazine is used to prepare the hydra-zone, the main product is the 7-sulphonyloxyindole which may be hydrolysed to the 7-hydroxyindole with alkali [3629]. 

Alstophylline showed an UV-spectrum consistent with isolated 7-methoxyindole and j8-methoxy-a,)3 unsaturated ketonic chromophores. The NMR-spectrum was informative and identified the methoxyl, the two A-methyls in different environments, the terminal methyl, the... 

Murakami et al. were able to confirm this process by demonstrating bromine transfer from ethyl 3-bromoindole-2-carboxylate to form 4-bromo-7-methoxyindole-2-carboxylate. 

---