Tag Archive: microwave synthesis


I often wander how some chemists come up with their retrosynthetic approach or if it is simply that they have seen so many reactions that visually it all comes together. I spent most of my career in the Nitrogen non-aromatic and heteroaromatic world, so when I see a fused pyridine, quinoline, pyrrole, isoxazole I have a large library in my head on things done….condensations, Pd-mediated events….but I have to admit I never see these in my head, and that is a way to extrude N2 in the formation of a pyridine ring.

The reaction scheme below (Beilstein JOC 2014) utilizes a 1,2,4-triazine in a thermal DA(INV) reaction in the construction of a 3,4-dihydronaphthyridone system. This not only serves as a masked construction of the the fused pyridine (naphthyidone), but also serves as a way to substitute depending on the group on the alkyne or something in place of the Ph group on the triazine. The microwave conditions: 1 h, chlorobenzene, 220C to provide a route into a library of 1,5,7-substitution patterns around the ring.

Screen Shot 2014-11-20 at 7.47.37 AM

 

 

The forward scheme into the intermediates is also captured below:

Screen Shot 2014-11-20 at 7.57.19 AM

A table of examples illustrates the use of the triazine in the DA process — clearly open to a number of changes for this transformation.

Screen Shot 2014-11-20 at 8.02.04 AM

As I mentioned — it impresses me that some chemists can think backwards in these structures — I get it, because this strategy is not new, but it just seems like when I look at a pyridine ring, I can’t visualize the triazine prior — For additional examples of inverse-electron demand hetero diels-alder reactions see the following paper in the construction of N-heteroaromatics (Chem Sci Rev 2013). Happy Reading!

Advertisements

The preparation of nanoparticles with microwave energy has developed extensively over the last 5 years and I have posted examples of this development in the recent past (Review of Inorganic Microwave Approaches and Microwaves in Nanoparticle Synthesis: Fundamentals and Applications). But a recent publication (Sustainable Chemical Processes 2014) utilizing specific properties of nanoparticles with a magnetic core (MNPs) was particularly intriguing. In addition to the ability to adjust or tune different structures, compositions and morphologies, these structures offer an opportunity to run cleaner reactions with easy separation from reaction media in additional to reaction media to be used in place of typical organic solvents –so they satisfy some of the core fundamental ideas in a “Green Process” and lend themselves to enabling technologies as Ultrasound, Microwave and Mechanochemical mixing. I will show a couple of examples, but this is something everyone should take a look at as an alternative to existing strategies. The article discusses several areas where these core structures can be changed depending on the transformation needed.

In the example below, we see a hydration of a cyanobenzene to the corresponding amide with a nano-ferrite magnetic core with an Ru-OH exterior. At the end of the reaction, the catalyst is simply removed with a magnet on the exterior of the reaction vessel and the amide crystallizes on cooling.

Screen Shot 2014-11-11 at 3.10.06 PM

 

With many ways to modify the central core, the catalyst shown below was used in a C-S coupling reaction with aryl halides and thiophenols under microwave heating in high yields in 25-45 min.

Screen Shot 2014-11-11 at 3.17.17 PM

Screen Shot 2014-11-11 at 3.17.28 PM

 

As you can see I view this as an opportunistic publication — one where it is merely putting a small positioning out there and chemists can mold the shape of the technology. Happy reading!

 

I came across an interesting article on alpha arylation of a 3-benzazepin-2-one, which is a particularly sluggish reaction (TL 2013). First thing is first, the formation of a traditional amide enolate with n-BuLi doesn’t effectively alkylate with simple substrates and the use of NaH was needed as the base to obtain the desired reaction (this was back in 1979), which was not going to be a good starting point for arylation. Unfortunately, the addition of Pd into the cycle did not produce any of the desired product so the base strength was a consideration as an issue. The addition of Cu2I2 from Li and Na amide enolates provided the first successful formation of the desired material with heat helping the reaction along (and effectively forming a Cu-amide enolate that can transmetallate). A switch from Li to Na improved the process, but examining solvent and the best Pd source (Pd2dba3) for the combination improved the process. Once the addition of microwave heating with NaH (DMF:Dioxane 1:5) with stoichiometric Cu2I2 effectively entered the Pd Cycle to provide high yields in short reaction times (10-20 minutes from 12 hours)…..and the dependency on EWG, electron-neutral or EDG was negligible.

Screen Shot 2014-11-10 at 6.53.42 PM

 

The table shows the improvement in moving from n-BuLi, Cu2I2 to NaH, Cu2I2 to microwave heating with method E.

 

Screen Shot 2014-11-10 at 6.58.06 PM

 

The entire cycle where the group finally worked out the entire process is shown below. Interesting backbone that shows potential for extending what can be performed if the Me on the nitrogen is replaced and the lactam further functionalized as a handle. Happy Reading!

Screen Shot 2014-11-10 at 7.00.04 PM

I have been reading through cyclocondensations and multi-step routes to fused ring systems and came across a highlight from Doris Dallinger’s post on the Organic Chemistry Portal. Although a bit older I have always found domino multi-component reactions have a penchant for the dramatic and this example (OL 2008) is no exception. This group, out of Kyoto, utilized a Cu(I) catalyzed 3-component microwave reaction sequence, starting with a Mannich, followed with an indole ring formation at 170C for 20 min. Addition of NaOMe and re-heating in the microwave for an additional 20 min at 170C deprotected and N-Arylated the Indole nitrogen for a short route to mixed-1,4 diazepines. Solvent studies and catalyst loadings were optimized to show dioxane and 2.5%CuI for the protocol. In addition to the benzene ring on the lower portion of the scaffold, additional heterocycles were used to broaden the availability of fused rings….which would tell me that the amine, left-hand or indole substitution and the lower ring system can be varied to include a number of different features as well as additional space to consider from a med chem point of view.

Screen Shot 2014-11-07 at 9.17.14 AM

 

If the ring system looks slightly familiar or the subject matter, I have posted an indole based domino sequence in the past and if it just happens to be that day, have a look. Happy Reading!

An elegant approach to a variety of Aristolactams was reported in Org Lett 2008, taking advantage of alpha-formylaromatic boronic acids and an appropriately substituted lactam. As illustrated below, initial coupling with the bromide on the advanced lactam with a variety of aryl and heteroaryl boronic acids provides a the bis-aryl coupled product which undergoes a simple aldol condensation to close the ring in a one-pot format under microwave heating at 150C in 10 minutes…..providing a route to natural aristolactams as well as an opportunity to study substitution patterns around the phenanthrene or heteraromatic fused rings.

Screen Shot 2014-11-06 at 12.18.39 PM

This is an area that you don’t typically read about when thinking about microwave technology — a lithiation followed the reaction of a subsequent electrophile with heat, and that it usually because the initial deprotonation is performed at low temperature….in fact these techniques are not adequately discussed in the heavy hitting books that we have come to rely on in the last 5-10 years…some due to the technology and some because the percentage of reactions hasn’t taken its’ place in the column, sitting way down the list from couplings, condensations, cycloadditions, etc. If one thinks about it intuitively, typical deprotonations are performed in non-polar non-protic solvents that are not generally used in microwave heating — but give it some more thought……anions formed, higher-ionic content following the deprotonation is an excellent way to spice up your non-absorbing solvent media.

Well I am simply going to point to a couple of examples so that it at least is a potential strategy to consider.

The first report comes from Ley and Baxendale — and their paper (Molecules 2014) is on the topic of flow chemistry to form different pharmacophore scaffolds….and in the process, they needed to deprotonate an aniline to react with a fluoroarene with subsequent heating for the SNAR to be a useful process. Although, this was an excellent way to make an advanced intermediate, it helped the group transfer the technology over to a flow method — back to the microwave. As mentioned earlier, most chemists don’t do their microwave chemistry this way, but it should be food for thought — do you know enough about the stability of the lithiated species — is it stable at 0C, can the electrophile be present during the lithiation and once the anion or lithiated species is formed, can it be heated?

The scheme below shows that in fact the process to form the desired nitro diaryl amine could be made efficiently in a microwave with the lithiation step at RT in the presence of a 1:1 mixture of aniline:fluoroarene and subsequently heated in a microwave for 30 min at 100C…….there are plenty of ways to use this strategy, but it’s just underutilized.

Screen Shot 2014-11-05 at 10.38.27 AM

 

The next example (TL 2012) is the typical grueling process of decision making that one undertakes when moving from a reaction where you would traditionally deprotonate, and in this case, there is more than one lithiation…..let me make it more complicated — they had already done this in prior publications with LDA and multiple hours and multiple temperatures to provide compound 5 (Full disclosure — I wasn’t looking for a lithiation — this group was making BRAF inhibitors, and were comparing sorafenib (fondness of my former Bayer days). So in this example, the lithiation was changes over to LHDMS at 0C for 30 min, followed by the addition of the formyl-morpholine and heated to 100C in the microwave to produce the desired advanced intermediate 5, which was split into two divergent pathways to final compounds. The scheme below shows the final process for the synthesis of one of the final compounds. Notice the additional microwave steps to the final compound. 🙂 Happy Reading!

Screen Shot 2014-11-05 at 12.12.02 PM

 

Screen Shot 2014-11-05 at 12.13.02 PM

The words microwave heating and carbohydrates are usually used together to roll of the tongue when talking about microwave technology. There have been a number of times, I have worked with carbohydrate researchers who insist that microwaves destroy and don’t have a good place with their chemistry — but give it some thought, this doesn’t mean we are going to heat things to 100-200C, moving from room temp to 50C is a major change in the energy of the system. OK- enough on that: a contemporary review on microwave heating in turning carbohydrates in heterocycles (is this like going from wine to water, lol!) has just been published by Venerdando Pistara at the Dept of Pharmacy – University of Catania, Italy (Current Organic Chemistry 2014, covering the major work accomplished in the last 4-5 years…..it’s a good review and opened my eyes to some interesting ways to use carbohydrates as part of the synthetic arsenal.

Let’s start off easy with some simple methodology in the formation of optically active cis-b-lactams. In using an acid chloride and TEA, a mixture of cis/trans b-lactams with a low level of microwave heating — and higher temperature didn’t help. Moving over to a Schiff base of the carboydrate substrate provided the cis-b-lactams and could be performed on a reasonably large scale in a commercial microwave at 800W of power for 3 minutes.

Screen Shot 2014-10-30 at 9.59.55 AM

Now moving over to the formation of heterocycles. Generation of optically active pyrazoles has been in the literature a fair bit lately. Utilizing a 2-formyl glycol and hydrazines, several optically active advanced pyrazoles were provided under microwave heating (TL 2004).

Screen Shot 2014-10-30 at 10.15.47 AM

If we take this approach as a comparison to conventional heating – and exchange the pyrazole with a pyrimidine (from 2-formyl glycals and amidines, you will notice the reaction optimization illustrates the shortened reaction time utilizing microwave heating (TL 2008).

Screen Shot 2014-10-30 at 10.23.35 AM Screen Shot 2014-10-30 at 10.23.12 AM

Pd-mediated microwave couplings can also be performed on carbohydrate substrates as shown in the example of an acetylene with a b-amino glycoside substrate in a Sonogashira coupling (Carbohyd. Res. 2010)

Screen Shot 2014-10-30 at 11.09.38 AM

Additional examples of transformations highlighted in the literature (Click  chemistry) can be found with the formation of a linked carbohydrate triazoles from galactose azides in the presence of a variety of acetylenes under microwave heating, and opening the ability to substitute at the C-1 and C-6 position (Biorg Med Chem  2010).

Screen Shot 2014-10-30 at 11.18.39 AM

Stepping away from from having the sugar backbone in place, a  mulitcomponent RCM-HDAR with 2nd generation Grubb’s catalyst was an excellent entry into the construction of the pyran ring without the need for protecting group chemistry (Carbohyd Res 2009) in toluene at 80C under microwave heating.

Screen Shot 2014-10-30 at 11.39.22 AM

Several additional examples of linking, ring construction and annulated ring systems are covered throughout the remainder of the review, and if you have any interest in sugar chemistry or the possibility of using the backbone as a handle then you need to understand some of the strategies laid out in this review — and see that microwave technology is been used extensively. So my last example is the formation of a spiro substituted sugar from a nitrone-sugar olefin cycloaddition. Using exo-glycal and a variety of nitrones, the spiro-isoxazolidines could be formed under microwave heating (Lett Org Chem 2005) — of course this has been applied to the 6-membered ring variation as well. Enjoy the rest of the review — Happy Reading!

Screen Shot 2014-10-30 at 11.50.34 AM

 

 

 

Although I found an example in the literature in moving from a microwave method to a micro-reactor method – and placed it in my synthflow resource blog, it should also be placed here — there are advantages born out in each technology depending on the application. To give yourself something to think about, and there are going to be several more publications using this theme, follow the paper described.

Screen Shot 2014-10-27 at 4.44.28 PM

The field of cycloadditions under microwave control is vast and has been represented in a fair number of books and review articles. What is noteworthy is the array of important advanced intermediates that can be used as handles or core heterocycles and complex carbocyles for future chemistry. Without a lecture I will highlight a few examples from a review article from Erik Van der Eycken (a well known microwave strategists) in Chem Soc Reviews 2010 (can be found as a pdf with a quick google search).

The review is broken down into the types of cycloadditions starting with the familiar [3+2] triazole forming reactions (click, click) then proceeds to other [3+2], [4+2] and ends with [2+2] reactions. At the risk of labeling these tranformations as percyclic reactions, we will hand wave and and end that some are very quick step transformations (and often concerted) and their selectivity patterns are well documented. I certainly have a fondness for these reactions with my background in isoxazole, diels-alder and isomunchnone cascade studies — so I have to like these, right? Well below, I have used a couple of examples from the review to give you a flavor, but left the triazole chemistry for you:

[3+2] Polycyclic pyrrolidines 1,3-dipolar process

Condensation of diaminoarene to form an N-allylhydrobendimidazole intermediate provided the requisite backbone to react with a variety of amino esters. The s-ylide could be then be react with the 1,3-dipole under microwave heating in toluene at 130C for 20-30 minutes to provide the fused system in high yields – much faster, cleaner and higher yields when compared with conventional heating.

Screen Shot 2014-10-17 at 10.03.38 AM

 

Isoxazole formation via nitrile oxide intermediate

This was a rather slick method when you can use it. The group started with an aldoxime — generated the corresponding nitrile oxide alumina-NCS under microwave heating at 110-150C with a 3 min pulse of microwave power and the advanced acetylene was added for a 2 step-one pot solid phase formation of a library of isoxazoles — sure beats the classical ways of the formation of nitrile oxides and when you can get a terminal alkyne — take it. It is mentioned that the yields were much higher and less time consuming than the traditional solution phase heating of up to 5 hours.

Screen Shot 2014-10-17 at 10.18.01 AM

[4+2] Pendant furan cycloaddition-rearrangement a plus cascade reaction to Strychnine

Al Padwa seemed to always have an elegant approach to complex structures – I was lucky enough to have a number of interactions with him and a number of his students who had passed through Emory University (of course I got the smelly Pummerer reactions, LOL!). Rather than looking into his volumes of straight-up DA reactions we will go to a COOL example. The example highlighted involved the use of a pendant amido-furan under a Mg-I2 catalysed [4+2] cycloaddition reaction followed by rearrangement to form an advanced tetracycle on the way to Strychnine (this is a great example for anyone drawing the arrows to push the formation of the intermediate cycloadduct then rearrangement — I think I still have it on a napkin someplace).

Screen Shot 2014-10-17 at 10.25.30 AM

And lastly because the formation of 4,5,6 and 7 positions of an indole can be difficult to build substitution patterns the use of cycloaddition strategies can prove highly useful. The [4+2] cycloaddition of a representative set of 2H-pyran-2-ones and a suitable alkyne to form the requisite amido-arene with the double bond positioned for ring closure to the indole system, which was also performed under microwave heating. Although this group used a two-step 2-pot approach, it is likely that conditions could be used to add reagents for this transformation to be done in one-pot — I know the process chemists would find a way. Great example of the use of this strategy.

Screen Shot 2014-10-17 at 10.32.20 AM

Many more examples are available to read — and too many for a single post so enjoy the article.

The organic chemistry undergraduate curriculum has evolved over the last 20 years into half name reaction and theory with a fair amount of instrument introduction for what students will see if they enter the workforce or go to graduate school in this area. I remember microscale chemistry was a push in my time simply to reduce the internal costs of solvents and reagents per student if you will — and we spent time on the NMR, TLC and IR analysis. Today much of this has changed. Having helped a number of universities incorporate microwave synthesis into their core teaching strategies has been a fun process, but it has also enabled teachers to spend their time aligning the material with technologies that a real once they move forward — but it doesn’t have to start from zero. There are a number of resources to build 4-5 lab days into microwave technology with the information at hand. Whether the university or mid-level teaching college using a small microwave footprint or a larger multimode system to cover up to 32-40 students in a single lab – it is out there. One of the newest and quickest resources I have come across is a Laboratory Experiments using Microwave Heating (Nicholas Leadbeater @ University of Connecticut and Cynthia McGowan @ Merrimack College): a step-by-step guide to understanding microwaves and a load of defined experiments — a real plug and play way for any institution to grab hold of new technology and provide a great positive growth to our organic chemistry community. Take a look into the book for a low price point as an avenue into microwave chemistry.

flowchemistryblog

a new blog to keep all updated with flow chemistry articles

GreenChemBlog

Green Chemistry Awesomeness.

The Organic Solution

Random musings about chemistry from the real world

SynthFlow

Bringing the world of flow synthesis under one roof!

Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal - http://PharmaceuticalIntelligence.com