Reaction of the week: 3-component domino synthesis of indolodiazepinotriazoles

Went looking for something current that I thought would provide some reflection on the part of the reader. A nice report from a group looking into annulated (is it annelated or annulated — I think I know but the topic has come up when to use which term, lol, as funny as the infinitive to column) indole-based polyheterocycles.

Lots of action around azide-alkyne inter/intramolecular 1,3-dipolar cycloadditions in the current literature. In most cases, we now accept that these process can stand a little steam room (heat, that is) cranked up to satisfy ring closure. Ah, a soft spot for say, a microwave.

In this particular report (2013), this group is interested in a domino process where 3 distinct reactions can be combined for the final construction of the indolodiazepinotriazoles, alkylation of indole, epoxide opening with azide and finally an intramolecular 1,3-cycloaddition of the pending azide and alkyne.

Strategy to set-up the 3-component domino reaction

I have included the table to illustrate the amount of work that went into finding best conditions from conventional heating, solvent study to choosing the best base for the sequence.

Optimization

Summarizing the table: #3 provided NR at 110C of the alkylation, #4 solvent switch to CH3CN provided alkylation, 5-9 DMF provided alkylation at an interim time followed extending time to eventually give the desired material in 18 h. 11-13 provided a similar profile in DMSO, 14-19 while maintaining Cs2CO3 in DMSO at 120C the procedure was switched to microwave 10 to reduce the time to 1.5 h, lastly switching base to KOt-Bu resulted in similar results to Cs2CO3 in DMSO.

There was a lot of work that went into the procedure and a clear advantage for the microwave conditions. Certainly I think there might be some addition modification of the temperature, but if the microwave is used to screen bases and solvents this would take more advantage of the technology. That said, I enjoyed the process to coming up with these compounds. Although not mentioned above, they did take the time to illustrate the stepwise process by indicating the transformation of each of the steps to the final compound through the intermediates.

product through a)epoxide with N3 and b) azide

Happy Reading!