Came across some interesting observations in a recent publication (Akivoc, 2009) on the synthesis of some pyridyl-benzimidazoles through 2 Sonogashira coupling reactions. The scheme is shown below: cyclocondensation of an aromatic acid in PPA with  phenylenediamine to give the benzimidazole. While unprotected, the pyridyl halide was treated with bis(triphenylphosphine)palladium(II)dichloride and CuI and the requisite terminal acetylene under microwave conditions: key to note, only 100C in DMSO (5-10 minute reactions).

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Full scheme for advanced benzimidazoles utilizing 2 Sonogashira coupling

Taking a look at the table — it is clear that the microwave conditions accelerated the reaction in a huge way….and postulated that the yields go up because the homocoupling of the terminal alkyne is reduced by the quick reaction time — I tend to agree — funny how it isn’t apparent in many cases why a yield is improved…this one helps clear both couplings. In addition, I am always struck by the use of DMSO in a microwave reaction, but particularly with a coupling reaction such as this. It is know that a number of Pd reagents decompose in DMSO with heat at an accelerated rate. It seems like there is a balance here between reactivity and the possibility of decomposition or the possibility of homocoupling with heat and time…..well I know I am hand waving, but after 1000s of my own reactions like this, I speculate a bit.

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3 MW methods (cyclocondensation, 2 Sonogashiras — comparison to conventional heating)

Although not the crux of the article — the benzimidazole doesn’t need protection during the chemistry — and EDGs and EWGs on the aryl are acceptable partners in the final coupling so it should be easy to expand if needed. Happy Reading!

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