I am always intrigued when someone uses a piece of equipment or a synthetic design for some other reason than its intended design….maybe they see it differently. It’s not like a disconnection or a strategy for a total synthesis of an alkaloid — it’s like when you look at something and notice something only important to you, but it isn’t really a key feature in the product. The Delepine reaction is a perfect example of that idea….a very elegant way to make selective primary amines with little to no side reactions all starting from hexamethylenetetramine.

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Delepine Reaction

But I don’t know too many of you making primary amines….only using them. If we look at the first step, the alkylation of a pretty exposed lone pair of electrons on one of the amines is open to a whole host of possibilities. Then  instead of hydrolysis, we can decompose, wait that’s not really the word, focus the breakdown of the extra stuff selectively…there that’s better. A recent publication (2010) caught my eye as rather unusual. This group used a Delepine reaction to set up an intermediate to breakdown into a diazepine, which I thought was a clever way to form the ring. Really, check it out.

Starting from an isatin to make the requisite alkylating agent, followed by the reaction with hexamine (sounds like a street name for the reagent– like Molly, we are really good at this sort of thing). In the paper, the key component in the discussion: really long reaction times and low yields for most of the approaches (hope we are still making these compounds).

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Benzodiazepines from Delepine approach in microwave

For both reaction sequences, details of both solid and solution phase microwave reactions were used and compared with conventional reflux. I am sure you here me rant over the use of a domestic microwave oven, so let me be clear — it is 2013, let’s use the technology folks. Anyway, good yields for the addition of the acid chloride to the isatin as well as for the Delipine reaction. Description of the microwave Delepine — microwave 180C for 8 min, but a note was made that in intervals MeOH had to be added to avoid evaporation of solvent (boy there’s something I don’t want to do — monitor a technology designed to let you go do something different while it’s going). That’s ok, because they pointed out that the reaction can be performed on a basic alumina support in good yield (I still about the mixing concerns I have…uniform heating is a critical component when reactions are done on scale). Take a look at the proposed reaction mechanism — I still applaud whoever got up at the white board and presented this idea — clever and it makes sense, after you see it, lol.

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Proposed mechanism for the Delepine microwave approach

All in all, my thanks to Derek Lowe (In the Pipeline) for pointing out that he had done one of these reactions and this group for innovating the concept. Enjoy the reading!

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