The synthesis, reactions, and spectra of 1-acetoxy-, 1-hydroxy-, and 1-methoxy-indoles

Abstract

Reduction of 2-nitrophenylacetaldehyde gave the unstable 1hydroxyindole, trapped as 1 -acetoxyindole. Concurrent alkaline hydrolysis with methyl iodide present yielded 1 -methoxyindole which was substituted by electrophiles a t position 3. The 3-carbaldehyde, from a Vilsmeier reaction, was converted into 1 -methoxy-NN-dimethyltryptamine. 1.5-Dirnethoxyindole underwent the Mannich reaction forming the 3-dimethylaminomethyl derivative. 1 -Acetoxyindole with dimethylforrnamide and phosphoryl chloride yielded 2-chloroindole-3-carbaldehyde and 1 -hydroxyindole-3-carbaldehyde, while (1 -hydroxyindol-3-y1)glyoxylic acid with hydroxylarnine gave 3-cyano-1 -hydroxyindole or indole-3-nitrile oxide. The u.v., i.r., n.m.r.. and mass spectra of the 1 -hydroxyindole derivatives are discussed.RECENT interest in 1-hydroxyindole derivatives has been stimulated by the isolation from plants of five l-methoxyindole derivatives, 1,5-dimethoxygrarnine [5-Me0-( 8)] ,l 1 -met hox y-NN-dime t h yl t ryp t amine (28), 1 -met hoxyindole-3-acetonitrile (10) ,3 a derivative of l-methoxyindole-3-acetic acid called neoglu~obrassicin,~ and oxaline, the major alkaloid of PeniciZZium oxalicum, which is a complex 2,3-dihydro-l-metho~yindole.~ As secondary aliphatic amines can be oxidised to hydroxylamines by peroxy-acids and in mammals,' the possibility that Nhydroxylation of indoles could occur in vivo needs to be explored, and the biological properties of l-hydroxyand similar analogues of tryptophan, serotonin, etc. can hardly fail to be of interest. An investigation of the synthesis of compounds of these types has therefore been started, syntheses of l-acetoxy-and l-methoxy-indoles have been developed, and the first syntheses of 1,5dimethoxygramine, briefly reported,8 and l-methoxy-NN-dimet hox y trypt amine are described. RESULTS AND DISCUSSIONl-Hydroxyindole (3) was first obtained by Mousseron-Canet and Bocas by the hydrolysis with sulphuric acid2) (a hydrolysis which has been described as ' tres difficile ' and which we have failed to reproduce), followed by a reliable, carefully controlled reduction with zinc-ammonium chloride. Although

The Chemistry of Indoles. CIII. Simple Syntheses of Serotonin, N-Methylserotonin, Bufotenine, 5-Methoxy-N-methyltryptamine, Bufobutanoic Acid, N-(Indol-3-yl)methyl-5-methoxy-N-methyltryptamine, and Lespedamine Based on 1-Hydroxyindole Chemistry.

“…The first one is the simplest among the thus far reported syntheses. 10,25) Methylation of 8e, obtained from 6c in three steps, as described above, with CH 2 N 2 resulted in 5 in 57% yield. Thus, 5 is now available in four steps from 6c in 29% overall yield with 40% originality rate.…”

“…The first total synthesis of 5 by Acheson and co-workers 10) was carried out in thirteen steps from 2-nitroaniline (21) via such intermediates as 22 and 23 in 2.6% overall yield. We needed a simpler synthesis of 5 in order to Chart 1 Chart 2 begin a study of its derivatives and their biological activity.…”

“…In the case of 5, the unique 1-methoxyindole structure required chemists to devise an ingenious synthesis. 10) Generally speaking, the above syntheses are complex compared to the simple structures of the target compounds. How to prepare a simple target in a simple way is the most challenging ongoing subject in our group.…”

Synthesis and antiproliferative activity of 1-methoxy-, 1-(α-D-ribofuranosyl)- and 1-(β-D-ribofuranosyl)brassenin B

“…Consequently, we decided to verify the information that the reaction of peracetylated ribofuranose 13 with indoline (7) produces only 1-acetylindoline. 11 It was found that condensation of protected ribose 13 with 3 equivalents of indoline under reflux during 6 hours afforded the desired 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)indoline (14) in 63% yield after column chromatography in addition to the 1-acetylindoline (Scheme 2). We presented this result in 2003 on the 10 th Blue Danube Symposium on Heterocyclic Chemistry in Vienna.…”

Nucleophilic Substitution Reaction of 1-Methoxyindole-3-carbaldehyde

“…1-Methoxyindole-3-carbaldehyde 5 (1, Scheme 2) is one of the simplest 1-methoxyindoles and a natural product, isolated from radish as a phytoalexin by Takasugi 6 and co-workers. They also isolated another phytoalexin, brassicanal A (2), from Chinese cabbage.…”