Effective use of an inverse demand Diels-Alder: the microwave way

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.

 

 

The forward scheme into the intermediates is also captured below:

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

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!

Combination of MW and Nanocatalysts with Magnetic Core: Greener Approach to Synthesis

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.

 

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.

 

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!

 

Alpha-arylation of 3-benzazepin-2-ones with microwave heating

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.

 

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

 

 

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!

Domino 3 Component Microwave: Mannich, Indole formation, N-Arylation

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.

 

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!

Aristolactams: One-pot Miyaura-Suzuki/Aldol cascade microwave method

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.

Lithiation, SNAR in a microwave: method expansion

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.

 

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!