Quinolines and Isoquinolines…..priviledged frameworks

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).

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.

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.

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.

It’s all about the branding….we have always had a way to make our approach important

Just sitting back trying to decide if microwave synthesis has really made it. Maybe my coffee was a little too strong — with all the compare and contrast looking back at the shifts in organic and medicinal chemistry it would seem the obvious answer is yes, but I have to think if you drill down into what we all do as chemists, maybe not as much as I would like to believe.

You see I started today thinking of a small cliff notes on specific cycloadditions under mw irradiation – then I thought well, where is the real impact here. When I think of branding or remissioning a shift in message as “combinatorial chemistry” I pause and see that some of the big names on our field grabbed it and did a few papers and left it up to the masses to drive the product — and for all practical purposes, unless you are answering a key scientific question, libraries have been an afterthought in recent years. Next – microwave as well as many other technology movements enhanced or changed some of the strategies applied – and to be honest there are so many who just don’t jump in – or their chemistry hasn’t provided a heating component to lend itself. Or how about some of the recent big hitters – metathesis, Pd-mediated couplings C-C, C-N. In some ways the vastness of their application has dumbed down some of your applications — fortunately for these transformations, there are some highend chemists applying their ingenuity to new problems. So then I come back to something like microwave synthesis – -where is it making strides? more complex systems, macrocycles, inorganic material synthesis, med chem — wide net but no giant steps transfering this technology to new heights.

Ha,ha! enough of that — I will get back to looking at ways people want to dig into their mw sitting at the end of the bench.

Continued progress towards macrocyles…..what’s the upside?

Just this morning after listening to Nick Terrett on the C&EN’s virtual symposium, I was intrigued by his statements on macrocyle available space and added protein interaction potential — it provided a glimpse on how complex and how one would differentiate added interactions when we are so used to directed targeted small binding sites using traditional approaches. Drug designers are starting to wrap their heads around these approaches as we move away from the small chemical space available – considering this, there is going to have to be a needed relationship built between synthetic chemistry and macrocylic targeted design to take advantage of the potential of the availability of the good protein-compound interaction over the bad…something challenging for today’s crop of medicinal chemists.

Moving into some chemistry

Although the research done toward the synthesis of complex macrocyles using microwave irradiation is a small percentage of overall strategies, there are examples when needed where improvements have been made. Clearly C-C forming reactions dominate the effective transformations, some out of the box thinking has resulted in progress (search the blog for examples).

One of the recent examples (Org Lett 2014) involves an unexpected subsstitution pattern in the synthesis of oligophenyl systems with a diyne-ethylene glycol macrocyles. In performing their research, some surprising results provided a change in the mechanism for the cycloadditions providing a different relief of induced-strain to provide products from a [2+1+2+1] over a [2+2+2] cycloadduct. A schematic of the forward approach is shown below:

Design of reaction process

So rather than the expected para-terphenylene systems the ortho-substitution pattern resulted in all cases. From catalyst to solvent experimentation provided the same result….classical heating compared with microwave heating also gave the same result. Fortunately, the microwave process reduced decomposition and reaction times from 40 hrs to 6 hrs without refreshing catalyst or high loading. The table below illustrates the applicability of the process:

And while this is a worthwhile transformation, it does provide a look into the possibilities of going after the desired products through a different approach. For all of you mechanistic chemists, I have included the thought process around this transformation. Happy reading — hope this gives you some thought for additional approaches.

[2+1+2+1] process

Tricky little Smiles Rearrangements — put the right pieces where they belong

Totally Microwave

Got my mind on rearrangements lately. Thought this recent article (ChemInform 2013) served both to help remind us of appropriately positioned functionality can provide the right recipe…..and chiral to boot (I’m telling you that we have only scratched the surface of enantioselective microwave work — just who is going to do it.

First thing — Smiles rearrangment:

Smiles Rearrangements

Mechanistic: The arrows at work

The group was interesting in testing substituted benzoxazinones and benzothiazinones and needed an efficient method for obtaining a chiral substituent alpha to the carbonyl, but also something easily accessible from cheap starting materials. By starting with (S)-2-chloroproprionic acid, it was easy to form the desired N-Benzyl-(S)-2-chloroproprianamide by direct coupling from DCC activation. Following this, any appropriately substituted phenol or thiophenol could be added to the starting material to provide the desired final compounds following — chloro displacement and rearrangement from internal attack of the impending N…

View original post 105 more words

Tricky little Smiles Rearrangements — put the right pieces where they belong

Got my mind on rearrangements lately. Thought this recent article (ChemInform 2013) served both to help remind us of appropriately positioned functionality can provide the right recipe…..and chiral to boot (I’m telling you that we have only scratched the surface of enantioselective microwave work — just who is going to do it.

First thing — Smiles rearrangment:

Smiles Rearrangements

Mechanistic: The arrows at work

The group was interesting in testing substituted benzoxazinones and benzothiazinones and needed an efficient method for obtaining a chiral substituent alpha to the carbonyl, but also something easily accessible from cheap starting materials. By starting with (S)-2-chloroproprionic acid, it was easy to form the desired N-Benzyl-(S)-2-chloroproprianamide by direct coupling from DCC activation. Following this, any appropriately substituted phenol or thiophenol could be added to the starting material to provide the desired final compounds following — chloro displacement and rearrangement from internal attack of the impending N forming the requisite spirocycle and finishing with the loss of HCl to complete the aromatization.

Displacement and a Smile

Checking over the reaction benefits — this was either performed conventionally at 130C — overnight (sounds like someone had to be at the bar ;)). Using microwave irradiation, the reactions were finished within 20 min at 130C. The Table indicates several examples in a small library. For me, because the reaction sequence contains so few steps — would be nice to see some additional substitutions. With the activity this is preliminary or a subsequent paper will flash out the SAR. Enjoy the article.

Conventional v. MW

Selective homogeneous microwave absorption

As a continuation from previous posts on selective microwave absorption from “solutes” in a non-polar or non-absorbing medium, Chemistry World has updated their information on the works out of FSU (Stiegman and Dudley). The experimental design is getting better and better — and still bears additional work. For me, it has been exiting to see approaches designed to go after an explanation of the hand-waving in rate of reaction acceleration. While I have spent a number of years looking at inorganic synthesis using microwave energy — there is still a question mark that goes off on hot-spot absorption in these nucleation events, where the temperature is clearly above the bulk temperature of the reaction media — and opens possibilities to create new morphologies over conventional heating.

 

Take a look through the links and read through papers on experimental design…..a bit more detailed than the next set of reaction libraries.