The ability to utilize gaseous reagents and expand microwave capabilities has been underappreciated in many regards. The amount of research in this area pales compared to the need to perform these transformations and understand what can and can’t be done. The focus for this will be carbonylative insertions on aromatic halides to prepare carboxylates or amides.

The apprehension and lack of microwave capability for performing reactions under what I would call reasonable pressure is evident in the literature. Because of this, several researchers have used reagents that can generate CO in situ. An intriguing report from Mats Larhed helped shed some light on some of what can be accomplished. Mo(CO)6 has been used to generate CO in situ for a number of reactions over the years (Pauson-Khand reaction comes to mind).

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Competition between two pathways

The initial design, with Mo(CO)6, used excess allyl amine with iodobenzene under a variety of microwave time and temperature studies to show that the fast CO insert step followed addition of the nucleophile was the dominant pathway over the Heck reaction. Taking these results a number of aryl and heteroaryl iodides were used to exemplify the idea (scheme 1).

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Scheme 1: In situ microwave CO insertion – amidation

Expanding the scope to include less reactive aryl halides and aryl triflates and tosylates offers several opportunities to functionalize rings systems.

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Aryl halides CO amidation under microwave conditions

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Aryl and HetAr-triflates/tosylates CO amidation under microwave conditions

Dr. Larhed’s work has recently expanded this to additional areas of functionalization. One thing they were able to show was a larger scale reaction of scheme 1 to 25 mmole scale in a large scale Biotage Advancer system. I know that doesn’t impress the process chemists — I am sure they are sneering at me now. Stay tuned — I will turn this to advances on the microwave side next — with much larger scale possibilities.