Methylindole reduction

Methylindole has also been prepared by lithium aluminum hydride reduction of 1-methylindoxyl. Compounds giving rise to NH absorption in the infrared (indole, skatole) can be completely removed by refluxing the crude 1-methylindole over sodium for 2 days and then distilling the unreacted 1-methylindole from the sodio derivatives and tarry decomposition products. 

The dimerization of skatole proceeds in an entirely analogous manner, cation (44) now being the electrophilic reagent. This is sufficiently reactive to effect substitution at the a-position of a neutral skatole molecule. Attack by the less hindered side of cation (44) will be favored, leading to the stereochemistry shown in structure (30). The failure of 2-methylindole to dimerize is paralleled by the failure of 2-methylpyrrole dimer to react with a further molecule of 2-methylpyrrole. The main reason is almost certainly again the reduction in the electrophilic character of the immonium carbon by... 

The product that 2-methylindole would form if it dimerized, base (46), has been synthesized by the LiAlH4 reduction of the 2-methyl-... 

With the use of this methodology, 2,4-dimethylindole, 4-rhydroxymethyl -2-methylindole, and 4-fmethoxymethyl -2-methylindole are readily obtained, as shown in Eq. 10.63. These indoles have been recently isolated from European Basidmycetes. Watanabe and coworkers have used a catalytic amount of PdCTfPPh-vi -SnCT under carbon monoxide for reductive iV-heterocyclizadon of o-nitrostyrenes. ... 

The results presented above indicate that the previously unknown head-to-tail polymerization is the major reaction product of the iminium methide species. To investigate the generality of this reaction, we next studied a neutral ene-imine species shown in Scheme 7.9.48 As illustrated in this scheme, the generation of this reactive species requires quinone reduction followed by elimination of acetic acid. The ene-imine is structurally related to the methyleneindolenine reactive species that is a metabolic oxidation product of 3-methylindole (Scheme 7.9).57 59... 

The toxicity of 3-methylindole has been attributed to methyleneindolenine trapping of nitrogen and sulfur nucleophiles.57 60-62 Likewise, the ene-imine shown in Scheme 7.9 readily reacted with hydroquinone nucleophiles, resulting in head-to-tail products. Shown in Fig. 7.6 is the 13C-NMR spectrum of a 13C-labeled ene-imine generated by reductive activation. The presence of the methylene center of the ene-imine is apparent at 98 ppm, along with starting material at 58 ppm and an internal redox reaction product at 18 ppm. Thus, the reactive ene-imine actually builds up in solution and can be used as a synthetic reagent. 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

Selenium has now been added to the growing list of transition metals shown capable of catalyzing the reductive A/-heterocyclization of 2-nitrostyrenes to indoles with carbon monoxide <99TL5717>. Utilizing the palladium-phosphine catalyzed methodology, Soderberg achieved the synthesis of several 4-substituted 2-methylindole natural products isolated from TricMoma... 

One of the main products in each case was the expected 5,6-dihy-droxy-7-iodoindole,70,109,119, 1B1,166 which was invariably accompanied by some of the corresponding deiodinated product.1BB (The elimination of the halogen atom in reactions of this type has been referred to previously.109) Reduction of 7-iodoadrenochrome (12) with Na2S204 gives, besides 5,6-dihydroxy-7-iodo-V-methylindole (55) and 5,6-dihydroxy-iV-methylindole (28), the sodium bisulfite... 

Reduction of the 7-iodoaminochromes70 with zinc and dilute acid was usually accompanied by virtually complete elimination of the iodine atom,109,155 except in the case of 7-iodonoradrenochrome (42), where, although the main product was 5,6-dihydroxyindole (29), traces of 5,6-dihydroxy-7-iodoindole (56) were also detected.156 Only partial debromination was observed when 7-bromoadrenochrome (57) was reduced with this system 7-bromo-5,6-dihydroxy-.V-methylindole (58) and 5,6-dihydroxy-iV-methylindole (28) were both obtained in significant quantities.155... 

The reduction of adrenochrome (1) with ascorbic acid (59) was first reported in 1948,158 although the nature of the reaction products (which may be of physiological importance, cf. ref. 159) was not determined until several years later. It was shown by Heacock and Laidlaw in 1958 that reduction mixtures of this type contained at least three indolic products,147 one of which was isolated and shown to be 5,6-dihydroxy- -methylindole (28).147 The major component of aqueous adrenochrome-ascorbic acid reaction mixtures has recently been shown to be a secondary product (60) (which was isolated as its di- and tetra-acetyl derivatives) produced by the interaction of the o-dihydroxy group of 28 with the a-dicarbonyl function of dehydro-... 

Reduction of 7-iodoadrenochrome (12) with glutathione gave a complex mixture of products.155 The main product appeared to be chromatographically similar to the glutathione-5,6-dihydroxy- -methylindole complex obtained from adrenochrome (cf. 64B or 65B). However, both the expected 5,6-dihydroxy-7-iodo-lV-methylindole (55) and the corresponding deiodinated product (28) were also detected in the reaction mixture,155 together with a compound which is possibly... 

A number of /i-oxo-osmium(IV) porphyrin complexes have been prepared by the reaction of [Osn(OEP)(CO)(MeOH)] with air and 2,3-di-methylindole in dichloromethane (80). Cyclic voltammetric studies show that [0s20(0EP)2(0Me)2] can undergo reduction to give an Os,v—Os111 dimer. The X-ray crystal structure of [0s(0EP)(0Me)]20 revealed a linear Os—O—Os backbone with OsIV—O and OsIV—OCH3 distances of 1.808(3) and 1.997(29) A, respectively (81). 

Reductive cyclization of nitrostyrene precursors has also proven to be a useful route to 5,6-dihydroxyindole and its derivatives, as illustrated by the efficient preparation of the system 32 (Scheme 18) <1999S793>. A general synthetic approach to indoles involves a palladium-catalyzed reductive cyclization of 2-nitrostyrenes <1997JOC5838>. This procedure was used in the synthesis of several natural products, e.g., 4-(methoxymethyl)-2-methylindole 33 (Scheme 19), a constituent of a tricholoma species <1999JOC9731, CHEC-III(3.03.2)282>. 

---