Hard to imagine if you have had a career in med chem or ag chem that you have not run up against the need to make a quinoline, isoquinoline or their non-aromatic brethren ( I know I have had my fair share — haha, you can look me up). I must have missed and end of the year special on microwave approaches in Current Organic Chemistry….slipping? For those of you interested, the issue dedicated to mw approaches can be found at COC 2013. For me there is some really interesting stuff there but I enjoyed the work on monoazanapthalene scaffolds — man that brings me to when I had to get the numbering and IUPAC naming down on fused heteroaromatic and partial heteroaromatic structures — now I guess the software will simply name it for you……I must have been the middle child.

Anyway — it wasnt simply the compound discussion but the emphasis the authors placed on what is important in the mw and the progress against it. For example, the difficulty in keeping a homogenous microwave field with a single or multiple reactions — agitation, hot spots, heat sinks, temperature measurements — conditions exacerbated in moving from single mode to multimode cavities. There is even some thought given to moving to solid phase as a possible solution — nope!, no more control than solution phase — and in many cases less. They some up all the challenges with an invitation to look at developments in mw toward these systems — I will mention a couple and then leave the rest in your capable hands to enjoy.

Let’s just take quinoline: Here are the typical synthetic approaches to the scaffold (so many words for this — framework, advanced building block).

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Some of the traditional approaches have been replaced — the Skraup approach is a bit messy and often difficult to tone down once the reaction gets moving. Some early examples of acid/solid catalyst on clay or silica show what the thinking was in moving to more mild methods.

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Approaches to Quinolines

Normally I would dig into the chemistry a bit more — but it seemed better to cast a net and let the reader have the fun. The next examples involve Shiff bases and cyclocondensation strategies to desired substitution patterns. It is important to note that these are cases where you can tune the time and temperature much more using a microwave approach to the overall strategy — with a number of the clay examples the literature provides high variability — conditions and source of catalyst with a dash of each chemist is different leaves this a bit more experimental than one would like. Love the handles that are left — acids, amines, halogen, nitro functionality — such an easy approach to converting and advanced intermediate into the desired targets with handles like these.

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Newer Approaches

The remainder of the review moves into Isoquinolines — Nitrogen musical chairs – an excellent learning tool for those new to heterocyclic construction strategies. And leave with some of the fused systems carrying non-aromatic features.

Enjoy the link and if you are pretty good on the searching side there are pdf versions of this article as well.