Beiträge zur Chemie des Indols, XI. Synthesen und Eigenschaften vor 2‐(2‐Indolyl)‐1,3‐dicarbonyl‐verbindungen, I (Entaromatisierungseffekte in der Indolreihe)

Abstract

2-Nitrophenylacetylchlorid reagiert mit den Na-Salzen CH-acider Verbindungen zu den 2-Nitrobenzylketonen 7, die zu den 2-lndolylderivaten 10 katalytisch reduziert wrrden. Contributions to the Chemistry of Indole, XI')Syntheses and Properties of 2-(2lndolyl)-l,~icerbonyl Compounds, 1" (Dearomatisation Effects in the Indole Series) 2-Nitrophenylacetyl chloride reacts with the Na salts of CH-acidic compounds to give the 2-nitrobenzyl ketones 7 which are catalytically reduced to the 2-indolyl derivatives LO.Wir erhielten friiher4) aus den 2-Nitrophenylacetylketonen 1 (R' und R" = Kohlenwasserstoffreste) in guten Ausbeuten die entsprechenden Indolketone 2, begleitet von geringen Mengen der isomeren Benzazepinone 3, die infolge ihrer pharmakologischen Eigenschaften eigenes lnteresse beanspruchen. Anstelle der zur Synthese von 1 verwendeten Enamine lassen sich auch die Na-Salze von CH-aciden Verbindungen (mit mindestens gleich gutem Erfolg wie die Alkoxy-Mg-Derivate) mit 2-Nitrophenylacetyichlorid umsetzen. Man gelangt auf diese Weise zu den 2-Nitrobenzyl-tricarbonyl-bzw. analogen Verbindungen 7, die wir darstellten, um zu priifen, o b 1. die statistische Chance einer erhohten Benzazepinonbildung genutzt wird, 2. gegebenenfalls entstehende Indole 10 mit P-Dicarbonylfunkticin in ,-Stellung Eigen-3. derartige Verbindungen 10 zu weiteren Synthesen herangezogen werden konnen.

Environmentally Friendly Synthesis of Indoline Derivatives using Flow‐Chemistry Techniques

“…The most promising results were achieved by Kulkarni et al, [50] who used an acid catalyst to protonate the indoles at the C3 position to disrupt the aromaticity and to generate an iminium ion, which could be hydrogenated under less harsh conditions. Nevertheless, the use of an acid as a catalyst [37,[51][52][53][54][55][56][57] raises further difficulties, such as polymerization caused by even weak electrophiles, as it is known that indoles are highly activated aromatic compounds. [58,59] Unfortunately, overhydrogenation also remained an issue in acidic media, and this resulted in the formation of significant amounts of byproducts (mainly octahydroindoles).…”

“…This correlates with previous findings [50] that the selectivity towards 4 is increased upon increasing the nucleophilicity of the solvent. Consequently, a less polymerized byproduct is formed along with a lower amount of the N-hydroxy derivative [37] of 3. This is because in more apolar solvents, aniline and N-hydroxyaniline compounds are more nucleophilic.…”

“…In the latter case, the ring-closing reaction followed by the loss of water in the geminal dialcohol intermediate is faster than hydrogenation (see Table S2 in the Supporting Information). As the reduction of the N-hydroxyindole derivative requires a longer reaction time, or harsher conditions, the use of EtOAc as the solvent results in a main product with m/z = 220, which is ethyl 2-(1-hydroxy-1H-indol-2-yl)acetate, and this is the Nhydroxy derivative of indole 3 (based on the literature [37] and LC-MS).…”

“…The syntheses of ethyl 2-(1H-indol-2-yl) acetate (3) could also be divided into two main groups, excluding those reactions for which functional-group addition, [19,20] conversion, [21][22][23] and ring-contraction [24] reactions occurred or 3 was formed as a side product. [25,26] Several authors used 2-aminobenzyl alcohol as a starting material, from which a Wittig precursor could be obtained by the formation of the corresponding triphenylphosphonium salt followed by an N-acylation reaction.…”

“…Intermediate 2 could be obtained from 2-nitrophenylacetic acid (7), which was used in the acylation of malonic ester [30,31,35,36] or ethyl acetoacetate [35,[37][38][39] in the presence of a strong base, and the resulting intermediate was then transformed into 2 in low to good yields. The most promising route involved the preparation of 5-[1-hydroxy-2-(2-nitrophenyl)-ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (11) as an intermediate from 2-(2-nitrophenyl)acetic acid (8).…”