Methods that fizzle away and you wonder why….no microwave examples :(

It has been awhile since I looked this approach….many, many years. I once thought the Julia indole formation reaction was unique, and as it turns out that it is the case. Comeon, I dare you to find a citation with a microwave approach to indoles using this method…..so I will work with that premise today. Back in the mid-80s (Tett Lett 1986), Sylvestre Julia converted a sulfinamide into an indole with heat in toluene (I know this might be dating me a bit). See…

Aniline converted into sulfinamide rearrangment then ring closure Voila!

I see the delta so I know what I want to do. I got this from D. Taber’s Indole classification review in Tetrahedron 2011. I enjoyed the article but I bunched each of the “Type 1-9 ” classifications into heat — have to tell you there are a bunch. I jumbled the classifications and went looking for examples used in the literature — and this reaction didn’t have any follow-up to speak of….and I can’t figure out why. Anilines with SOCl2 the vinyl magnesium chloride then, for me, a microwave……zelch, nada. Anyway I am hopeful there is some utility to this reaction I am missing..maybe people aren’t that into making more indoles. Since this could be thought of as a [3,3] sigmatropic rearrangement, I think I can open up my search a bit and create a new category.

Delépine reaction, not a reaction used everyday

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.

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).

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.

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!

5th Installment of Indole Construction…Corey Chaykovsky Reaction

Alternative thinking…….one way to think of deconstructing a heterocycle is to sit down and break the bond forming steps into a spreadsheet of all the known reactions to form them. By now however I am hoping that intuition has crept into the toolbox of things to use…….ask yourself what chemists you know are more intuitive and who are more methodical?

moving on…..Corey Chaykovsky

Following Bill Johnson’s initial work on formation of three membered rings, Corey and Chaykovsky developed the reaction for what it is know today. The scheme below represents the approach: a sulfur ylide (comeon’ man….I love these) and a ketone, imine or an enone.

Corey Chaykovsky Reaction (CCr)

If you understand anything residual about Prof Corey, you will want to use this from/or for a disconnection. It just so happens that an epoxide attached to an aromatic ring is set up to undergo nucleophilic attack from an amine, and if alpha to that epoxide is a F group, we know that the amine can attack this as well — you see where I am driving at.

In a recent publication on the construction of N-subst indoles (Synthesis 2008), these 3 components were used in a clever way.

Corey Chayvosky constructed int with amine and elimination of H2O under microwave conditions: ketone, sulfur ylide then amine — indole

Enjoy the reaction!

just for giggles

In production….I will stop you

Even if your compound makes it….there are forces at work to stop it!

In the mood to celebrate some classic reactions…..Skraup reaction

Maybe it’s because I just finished Jobs…”the Iconic and Mysterious Steve Jobs” or perhaps I spent many years using different techniques and transformations to construct and substitute quinoline analog after analog. Yes, tis’ true I am an Apple devotee…from my days with the classic and Macintosh to my trusty MacBook Pro….and I also like to know the history of the heterocycle that I am going to bond with, call it the art in synthesis…I don’t know.

Attributed to Czech chemist, Zdenko Skraup, the formation of the quinoline ring system is a unique example of atom economy and also as an extremely aggressive or violent reaction…..love it. A number of variations of the scheme below have been used to place substitution patterns on the fused system.

Skraup Reaction

As affectionate as I am with the original scheme, the use of copious quantities of sulfuric acid generally makes most chemist frown….I too want to protect that new pair of jeans, ha! But seriously, metal catalysts and Lewis acids have replaced the traditional reaction conditions for all practical purposes. Although not terribly new, two improvements suggest we have gotten better at finding better ways to make this system and here’s the recipe: substituted anilines, vinyl ketone, SiO2-impregnated with InCl3 and some microwave irradition (no solvent and no H2SO4).

Skraup, mw 150C, no solvent

Since this is atypical to what people normally do, I wanted to add some of the notes from the paper (Tetrahedron 2003). The InCl3 is adsorbed in THF on SiO2 with heating for 3 hrs at 150C followed by stipping off the solvent. The remaining solid is mixed with the aniline and vinyl ketone and subjected to microwave heating at 600W for 2 intervals of 10 mins in a domestic oven (high yields across the board). Part of the table in the publication is shown below as well as a second scheme modifying starting materials to obtain dihydroquinolines. Certainly the concept would be useful in other ring constructions, eh?

Skraup Reaction under solvent-free mw conditions

dihydroquinolines under mw conditions

Although the process does help innovate I don’t suggest open flask domestic oven reactions. Many of these papers are difficult to repeat without more control. This particular publication may not suffer from this process, but many adsorbed catalysts of this nature don’t measure up to what we would want to do, partly because there is not reflection of the material absorbing the microwave power and if you don’t control the mixing, often hot-spots can be uncontrolled and provide a mess, or worse an unsafe environment. There are several reactors that address mixing issues with solids –of course, I would have probably done something modified after reading this because it begs to be looked at.

 

Chemjobber….a fun blog

Here is a cool blog Chemjobber on many topics in the industry and academic setting. Today’s post was particularly fun: When the Boss is Wrong About Chemistry. If you haven’t had a chance to catch the blog, I suggest you look at it from time to time — hilarious and some interesting facts in today’s climate of chemistry.

Microwave extraction….what applications are useful

Microwave extraction is oddly newer then its’ synthetic brethren. Not really sure why — digestion and synthesis had the jump — maybe, it was application or research driven. At any rate, this has quickly changed……and at the end of the day, may have a broader spectrum of usefulness. It probably seems obvious to the folks reading this blog that microwave solvent extraction of natural products is an area where work has been done ( a nice review has been published specifically on natural products 2010)…..that is true, although not as much as one would think. I believe this partly since the art and science of natural product extraction itself has been an arduous journey…..picking the right solvent, finding the right temperatures, purification of the concentrates, etc…..that paints a pictures. This picture has changed dramatically over the last ten years……The EPA approved microwave extraction for semivolatiles and non-volatiles in soil and solids…such as PCBs, PAHs, pesticides. Microwave extraction has also found its way into the extraction of API in simple and difficult formulations — more control, multiple samples, easy…..minimal solvent. And some of the more recent developments include — biomass, sedimentary rock and essential oil extraction in the flavor and fragrance industry…….I am sure you see the payoff and also why it makes sense.

Rather than an exhaustive account of a thousand references, I have highlighted a few areas where there has been some advancement in both, microwave-assisted solvent and solventless extraction.

1) EPA 3546 — microwave extraction of contaminants in soils, solids and sediments. This is a fairly benign application validated using hex, hex:acetone, CH2Cl2 and CH2Cl2 variations to extraction known analytes of interest 100-110 for 30-30 min. The acetone is used to drive through the matrix and absorb microwave power so that the mixture can be heated above its’ boiling point. You remember — for every ten degrees it cuts the rate in half. Very powerful application and nearly every environmental contract lab is using this for sample testing.

2) API extraction – There are several reports on the utility of microwave extraction of API in raw and formulated forms. Most of the activity is done on the development end of things so the number of journal articles has been limited. Having said that, a research group at Pfizer, in the middle as a transition to development published a couple of papers evaluating several techniques used in the pharma industry. A more in depth look can be found in a recent book by Beverly Nickerson on sample preparation of pharmaceutical dosage forms. To simplify, microwave heating is simply a heat source so solvent and temperature studies are developed to maximize extraction without degradation. As formulations become more challenging — and they are — this technology is adding promise to helping keep the process efficient. The benefit in the end is that multiple batches can be performed simultaneously – allowing for a reproducible method with a simple process (now hours and days turn into minutes).

3) Solventless (solvent-free) microwave extraction — this is the current state-of-the art technology, both in concept and practice. Championed primarily by Farid Chemat and Giancarlo Cravotto, essential-oil, biomass and natural products have been isolated in a much more efficient way. The primary advantage of this process comes from the advantage of using a plant’s water content as a microwave absorbing source — water is internally heated and the cells within a material burst with a release of product as part of the process. For a microwave configuration to work in this manner, volatile components are condensed into a trap over the microwave as you would set up a distillation, and heavier or higher molecular weight compounds are isolated below the microwave — which can be cooled or isolated under reduced pressure….actually the process is quite cool and extremely effective. A few resources are shown below but there have been a number of books and journal articles to both processes:

Solvent Free Microwave Extraction: An Innovative Tool for Rapid Extraction of Essential Oil from Aromatic Herbs and Spices 2004 The Journal of Microwave Power and Electromagetic Energy.

Microwave Assisted Extraction for Bioactive Compounds 2013. This is a comprehensive book with several chapters dedicated to basic microwave processing and applications.

Green Extraction of Natural Products: Concepts and Principles 2012 (International Journal of Molecular Sciences)

Solvent-free microwave extraction of essential oil from aromatic herbs: From laboratory to pilot and industrial scale: Food Chemistry

Go ahead and give some of these a read — it is an expanding area of research and application. As we start to move into more enabling technologies, the research is starting to stretch into utilizing natural resources to provide more efficient processes.

Small ring formation….metathesis in a bag

That turkey is still keeping me a bit droopy-eyed. Time to shake it off and see what looks interesting. Since some of the theme last week involved asymmetry or chiral processes under thermal control (well ok, under thermal conditions), I thought I would go in a different direction and have a little fun this morning with metathesis processes. Just read the current state of affairs in the catalyst showdown to see what is grabbing the highlights. One of the recent interests involves a ring-opening metathesis followed by a ring-closing metathesis (ROM-RCM). Pretty cool process and one that will continue to get play.

ROM/RCM

I think at this point we have seen some elegant examples of the relief of strain in 3/4-membered rings as a thermodynamically favorable process — a bit surprised that more methods haven’t shown up using a microwave ( and even more surprised that more reactions haven’t shown some stability of the chirality in these processes, perfect opportunity — and ethylene gas can be used in the microwave as well with some positive effects). Nevertheless, what if we are looking to form a 4-membered ring? Not so much, huh. Well at least one report (Debleds, 2008) not only illustrates that it is possible in a 1,5-enyne RCM, but with much better yields under microwave radiation and the right catalyst (in fact, this doesn’t show up on our literature radar without it). This is a good read!

1,5-enyne RCM under mw conditions

To further illustrate the possibilities, Mori’s review (Materials 2010) provides examples of how the reaction has been applied in natural product synthesis. What caught my eye in the general reading (JOC 2010) however was a report on the process in the total synthesis of (±)-grandisol with a 1,5-enyne metathesis as the key transformation (83% yield) in the sequence. Not only did this group utilize the microwave to figure out the transformation, they also were able to screen catalyst and parlay the results into going back to a purely thermal sealed tube once the chemistry was a bit better understood. It was interesting to note that the yields in the thermal process were not as good as performing the transformation in the microwave….seems reasonable to assume there is some superheating in the catalyst. The other thing that sticks out is in their description of the catalysts has to do with thermal stability and it seems the most stable was also the best catalyst (for me this would lead me to conduct additional research on the process).

Total Synthesis

mw 1,5-enyne RCM 70C, 30 min

Enjoy the 4-membered ring formations!