Always looking for reaction types which fit a thermal process, or the type which needs cooling to say -78C (gosh not everything I would do is a thermal process). We should have chart of reactions defined in categories by how often they are used and what kind of process is at work. I also tend to think there are starting materials that seem to fit a list where one can use them in a wide diversity of reactions or schemes to form multiple core molecules or advanced structures…..now, that’s my kind of combichem! Benzoylacetonitrile is just that, one of those materials which can be used in so many ways, condensation, anion formation, addition to ketone and more….and you would imagine is ready for the part in many thermal processes

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Benzoylacetonitrile

Using the following review article (Turk J Chem 2013) on this substrate for the formation of 5-membered heterocycles there are a number of products formed (as well as intermediates) which were made using microwave heating  and compared with conventional. Two nice things about the review — you can see the utility of the starting material, but also that several schemes show where a microwave can be used — and if you pay attention, there are many more examples where one probably would have provided a substantial benefit over the described process (that is a take home message reading any of the journal articles, not all reactions are thermally driven, but many can be performed much quicker in the microwave and with a better yield in most cases.

In the scheme below, substrate 44 has been shown to be fully aromatized under microwave conditions with MnO2 in toluene in minutes at 120C compared to long times conventionally (BMCL 2006).

2-aminothiophenes/amino subst thieno[2,3-c]pyridines

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benzoylacetonitrile condensations for amino thiophenes: Substrate 44 is aromatized under mw irradiation

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thieno[2,3-c]pyridine derivative

Aminopyrazoles

a-d are different conditions for the hydrazine addition and ring-closure: for the mw conditions see citation

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pTsOH, MW <1 hr

If you like to look at patents, here is an example — little surprised they didn’t go higher in temperature an cut the reaction time (For patents ESPACENET and USPTO patent pair sites are great for dissecting patent synthetic schemes)

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MeOH, 120C, MW 1 h vs. 2 step 13 h reflux

2 additional sources of mw conditions for aminopyrazoles: OBMC 2006 and Patent 2012 

Keep in mind reading the microwave conditions in patents that most have not been optimized and fewer reported in journal format — no reason why most of these wouldn’t be done in minutes.

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For MW conditions: MeOH 110C, 1h

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Nice formation of tricycle in 5 min

In the kinase arena, a number of amino pyrazoles were used to form advanced clinical candidates for Raf and p38 kinases from both Bayer and BI in the 1990s (example Future Medicinal Chemistry 2010). Here is an example of a two step process using microwave irradiation.

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2 steps: microwave assisted Knoevenagel condensation and ring closure

Benzothiazoles

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1:1 mix of benzoylacetonitrile and o-aminothiophenol

OK that is just the glimpse into what I was thinking here. See if you can come up with few reagents or starting materials that would provide a wheel of reactions — and where would be the thermal reactions and the reactions which are not thermally driven…let me know what you are thinking…would be great to get some different perspectives on the site. Happy Reading!

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