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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.

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The forward scheme into the intermediates is also captured below:

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

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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!

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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.

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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.

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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.

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

 

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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!

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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.

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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.

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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.

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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!

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With so many labs utilizing microwave chemistry for their drug discovery processes, the effective ability to monitor the temperature of a reaction (solvent) is critical. Since each commercial microwave vessel will have its’ own set of specifications will have limitations to the temperature that can be reached without generating a significant amount of pressure, and perhaps even more critical cause an unsafe reaction and damage equipment.

Examples of commonly used solvents and their temperature and vapor pressure set at 25 bar:

Hexane: 226C

CH2Cl2 172C

Toluene 281C

EtOH 191C

Dioxane 256C

Acetonitile 218C

I set the pressure at 25 bar to illustrate that depending on the solvent, very different conditions would be used in a chemical synthesis and while may here are above the temperature normally set, often the amount of pressure held within a microwave vessel is lower. I have often found these temperatures have been used and resulted in complications to a microwave and the chemistry.

While there have been a number of reports using IR or FO temperature monitoring, it depends on the reaction being used, how much agitation, and the type of vessel material — that’s a lot to keep track of in addition to the chemistry itself. Fortunately, there are set-ups which take into account each of these key features for our benefit. I am going to outline a portion of Oliver Kappe’s presentation at EUCHEM 2012, where he spoke on each of these. His concentration in the lecture was on ionic liquid chemistry and included both microwave and flow methodology for the synthesis and use of ILs.

Back to the question of effective monitoring: I will illustrate using the Anton Paar dual temperature control on the Monowave 300, because this system provides a number of options to control the temp/power of a reaction.

The first slide indicates that effective agitation using an IR sensor plays a key role in the temperature being measured in a reaction and that FO monitoring is somewhat less critical to stirring as it is in the reaction medium being measured. One thing to keep in mind throughout the slides is that these will be using ILs, and as a highly absorbing material the set temp can easily be overshot during the course of the reaction. As we see in the graph below, with the power delivered in this set-up, the actual temperature reached is 120C over the set temp (WOW!), and depending on what is being measured, a dramatic difference in temperature is measured (in this example, you can see both biotage  and CEM utilize different IR sensor engineering for their measurements.

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Simultaneous measurement can help improve the control of the chemistry being used. As shown in the slide below, measurements of the internal and external temperatures are be monitored and feedback to adjust the power — in this example the master slave control was set to each independently with an overshoot in the temperature internally when IR control is used…again notice the difference in the outcome for ILs. I should mention that the studies used here can be found in Org Biomol Chem 2011.

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ILs are still reasonably new and have been used sparingly compared with the solvents utilized in most synthetic transformations but the field is growing. Taking a look deltaTan values listed below, we can see that ILs are a bit off the normal functioning organic and aqueous environment with absorptivity that rivals metal catalysts (and often we see the increased reaction rates of organic reactions, but can’t measure the surface of the heterogeneous metal on the surface — perhaps this is why the inorganic chemists benefit from high reaction rates at higher temperatures on the surface of the nucleation and the aqueous or organic media temperature is being measured). It takes very little time for the temperature to go beyond the set point here (notice that no more power is being delivered). The good news is that ILs have very little vapor pressure associated with them, so an overpressure here will not be an issue — but depending on your chemistry, be aware of going to extreme temperatures if you don’t have the appropriate vessel materials. So where is the solution for using ILs and being comfortable with the temperature of the reaction?

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The answer is found in the same way we circumvent the ability of a microwave to be used with solvents that do not absorb microwave energy….by the appropriate choice of vessel material. You see when we use a hydrocarbon solvent or something like THF, the microwave simply delivers energy without getting the solvent up to temperature so we need to add a co-solvent (there are some tricks to this) or a susceptor so that there is something in the reaction absorbing the microwave energy and converting it into heat. Depending on the company, a version of Si-Carbide or Teflon impregnated with Carbon can be used to absorb microwave energy and not interfere with the reaction. Furthermore, their absorption properties outweigh that of the IL, so let’s take a look at the result. As we see here, pyrex shows the same issue of the lack of temperature control in the bmimBr synthesis, whereas the Si-Carbide vial absorbs the energy in a more controlled way, allowing for the reaction and temperature to stay on track with the reaction parameters.

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Hopefully this will help shed some light on temperature (and pressures generated) control in a single-mode microwave reaction. Certainly the ability to monitor both with control is something Anton Paar has built into their system for chemists to depend on their chemical environment and the use of Si-Carbide vials go along way in building in a way to help chemists move forward into different areas of research. Hope you enjoyed the slides (I thank Oliver Kappe for continued progress in the development of this field of research and development, and always looking for solutions to microwave development).

 

Microwave Flow Advancements

I have spoken about this area in the recent past, but some of the enhancements for flow chemistry has put some pressure on microwave engineers to push the envelope for large production scale chemistry. While batch has taken precedent, and there certainly is a place and need for that (med chem, kilo labs, scoping, etc), most will agree that microwave flow reactor development has been most discussed. With that, C-Tech industries has developed and put together some trials of their contribution to these developments. A quick look at their site will help you understand the thinking: 0.3 to 1l/hour flow with the capability of handling 250C and 30 bar of pressure and a production rate of >100 kg of product/day with an innovative way of delivering the required power to maintain a transfer over solvent and reactants moving through the piped system.

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Examples of their work are easily downloadable from the website and include an article from Specialty Chemicals magazine, a case study from lab to plant, and a collaborative poster illustrating improvements in production scale and impurity profiles in Pd-mediated coupling reactions and a supported project aimed at process scale-up while minimizes and chemical method development. Developments of this nature will help sustain the technology as a choice in today’s chemical research and development. C-Tech in addition to development, has set opportunities for collaborative partnerships.

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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.

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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).

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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).

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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)

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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).

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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.

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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!

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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.

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