Maybe you can think of this as a fondness for indoles or if you have read a number of my posts, that I tend to dabble a bit in the construction of heteroaromatic rings…but just a bit, lol! So I decided that next to the reaction of the week I will give an installment of some indole and azaindole construction and perhaps some substitutions to relive my old days.One of the cool things about this ring is that it has been made in so many different ways and with so many patterns it has a place on the top shelf of the heterocycle hall of fame…..we should do the stats and see which ring or fused system has been made the most. OK OK I better get to it. The Hemetsberger indole synthesis is not the most popular of the brands out there but it is an elegantly simple process to use if you can make variations of the starting 3-aryl( or heteroaryl)-2-azido-propenoic ester because upon heating you should generate the 2-carboxylate on the indole nucleus. LOVE IT! what, heat from starting material to product — I can’t think of anything but a microwave. And for those of you who like arrows like I do — watch the energy give off during the reaction. As a side note the vinyl azide is made with an aromatic aldehdye and ethyl azidoacetate condensation. Since it is a thermal process with N2 release most of these have been made with refluxing toluene or xylene.

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Hemetsberger Indole Method

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Reaction mechanism

Application of the process (TL 2009) in the microwave provided the indoles in 10 minutes under microwave conditions. Several substrates indicated the utility of the process but what was most interesting end up being the method screening. Several different solvents were examined for conversion. Note in these cases the best reactions were performed in poor microwave absorbing solvent systems.

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Solvent screening

Another method study involved the temperatures used and pressures developed from the release of N2 during the reaction along with the vapor pressures generated for each solvent. (this is something many chemists don’t keep track of moving from conventional methods over to the microwave — consider the solvent choices and the vapor pressure they can generate at high temperatures — the vessel choice based on that is critical for success).

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A) 200 °C, 15 min, 13.5 bar. (B) 200 °C, 10 min, 13.5 bar. (C) 200 °C (only 136 °C reached), 5 min, 6.2 bar. (D) 150 °C, 10 min, 6.9 bar. (E) 100 °C, 10 min, 4.2 bar

So in the end — 200C in hexanes for 10 min provided the compounds with no side reactions during the process.