Archive for August, 2014


Just got a call from colleague looking at microwave pyrolysis — and like my first look into inorganic hydrothermal reactions — I thought, well we are going from something traditionally done at higher temperature to a lower temperature in the microwave — my horse is pushing the cart again. Anyway, I put my hook in the water too….and although this is not a well established area, it is certainly doable, and fascinating.

Let’s back up a bit — most of these reactions I am speaking of are centered around aromatic cyclizations and rearrangement reactions….lots of dancing and not enough N atoms for me, but I do appreciate ring construction. A recent publication (JOC 2009)has perked me up to a whole host of things that can be tried — and quick too.I have included the scheme below how to thing of moving from FVP to MFP:

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Azulene thermal rearrangement

Looking at the scheme is like taking in the development of Pd catalysts and ligand optimization for the first time– we all kind of get the idea that graphite and nanotubes might be effective, but who’s going to figure it out. Since there are a number of examples of graphite applications and modifications: exfloliation, intercalation and doping strategies — some fine tuning to fit the application. If you have ever used graphite in a synthetic reaction — as a “susceptor” then you have experienced how quickly it absorbs the microwave radiation and how quickly you can get to the desired temperature…so if we add to that CNTs and SiC there are a number of things that can be done. But for this exercise — this group performed these reactions in a solid form — or solventless.

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Cyclizations on graphite — very fast! 450C may be just a tad much

As I read through the article looking for signs on how I could use this — I noticed several critical points the group noted throughout their process: 1) open vs. closed-vessel, 2) nitrogen atmosphere 3) power applied at short intervals (not pulsing folks), 4) in open vessel glass wool plug applied to prevent “ejection of material,” (and sealed tubes to prevent sublimation or losing material) 4) the addition of a thermocouple to look closely at the temperature rather than relying on an outside IR measurement — for verification and because the IR sensor in their unit topped out at 300C and 5) the lack of a build-up of pressure — very good. What I also noticed was the lack of agitation in the mixture so there is a possibility of creating hot-spots. I can see thee chemists in the lab now.

I included a few of their successful schemes below to show the utility of the chemistry and to note that there is plenty of unexplored territory out there. Take a look at their improvements over taking these reactions to 900C.

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Thermal rearrangement of 2-ethynylbiphenyl on graphite

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Elbs Cyclizations and related reactions

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Continued

Nice development of some microwave pyrolysis reactions and a great starting point for further study. Kudos to this group and enjoy the paper.

 

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Have always had a fascination with compounds displaying chirality in the non-traditional sense….such as planar chirality present in many bi-aryl atropisomers or in some of the more recent work on helicenes or calixarenes to name a couple (some call this inherent chirality). Let’s stick to one for starters — and see where it leads.

Helicenes have been studied a fair bit in the last ten years — mainly due to the applications provided by their unique structure. A review of the current strategies can be found in Chemical Reviews 2012. A recent example of a cool cycloisomerization sequence provided an easy non-photochemical route to [6] helicenes (JOC 2009). To go along with the typical photochemical, Diels-Alder and cyclotrimerization work, RCM metathesis is joining the game for the formation of benzene rings in the helicene backbone.

Shawn Collins at the University of Montreal published a RCM approach (Angew. Chem. Ind. Ed. 2006) to [5,6,7] helicenes utilizing microwave irradiation. His group utilized two approaches these compounds — microwave with catalyst 3 and sealed tube with catalyst 4 depending on the functionality present (discoveries while doing research).

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RCM: Aptly put, metathesis with a twist!

Some interesting discussion in the article over functional groups, number or rings formed and their strain, time to form the desired products. Using the scheme above as the example — heating higher than 100C didn’t help the reaction along or provide a higher yield (for example, several reactions needed an hour to 140 min at 120C, but in general 25 min was the recipe of the day). Some of this is dependent on the vessel capability and the pressure generated — at 100C CH2Cl2 vapor pressure will be about 6 bar and at 120C 9 bar so I imagine some of these reactions could be improved. It should be noted that the reactions were performed by pulsing the reaction mixture at 100C — not quite sure what that means — perhaps they got the thing up to temp for a period and time then reapplied the power in pulses. What I enjoyed in the article is how the group provided some insight into what they felt would be problematic — so some general themes in this type of chemistry requires some prep work, or maybe some creative ways to get around problematic (e.g. 8,8′-positions as shown in example 11) substituent strain.

Take a look through the table to give yourself some perspective on the reactions, time and functionalities — something that can be improved upon with the compatibility of the Ru catalysts being developed. I was impressed with the work presented since there is a clear direction from easily available 1,1′-binaphthyls.

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[5,6,7] Helicenes: Catalyst 3 mw, Catalyst 4 sealed tube

Enjoy the read!

After coming across the phase separation strategy for preparing medium to large macrocycles with  a 1,3-diyne moiety, I thought about the holes in my background in this area — which is a bit strange considering I started my career at Abbott and with all the Erythromycin or macrolide chemistry performed there in general one would think I would have been up on it…alas, about as much as not finding Clarithromycin internally (not really a parting shot, but if the resident experts miss a billion dollar drug how am I expected to keep up — knowing the stories it is easy to miss). 😉

Usually the intro for this topic starts with clinically relevant and natural macrocyclic antibiotics — lots of them, but there is so much more from branching polycyclic peptides to the antifungal and antiparastics adding to the structural diversity. I certainly remember when the epothilone synthetic strategies came out initially — still a hot topic with all the relavance for cancer targets.

If you want a good current review of synthetic methodologies toward macrocycles — and their relevance to drug discovery — turn to Molecules 2013. Dianqing Sun does an excellent job of breaking down each of the classes of macrocyles, strategies in their synthetic pathway and their relevance in drug discovery and natural product research. For me — haha, I am so selfish…I found some examples where the microwave has gone unexplored in the “macrocycle” world. I have touched on ring closing metathesis (RCM) in the microwave for all of the obvious benefits and at the risk of turning on that broken record — nearly all of the ring-closing steps INCLUDE a heating as a critical component. However as you can imagine — there was some time dedicated to metal-mediated C-C and C-O couplings OR, hmmm, maybe a Buchwald-Hartwig cyclic amination.

I have included a few of the relevant references below:

Lépine, R.; Zhu, J. Microwave-Assisted Intramolecular Suzuki-Miyaura Reaction to Macrocycle, a Concise Asymmetric Total Synthesis of Biphenomycin B. Org. Lett. 2005, 7, 2981–2984.

Su, Q.; Beeler, A.B.; Lobkovsky, E.; Porco, J.A.; Panek, J.S. Stereochemical Diversity through 
Cyclodimerization: Synthesis of Polyketide-like Macrodiolides. Org. Lett. 2003, 5, 2149–2152.

Pérez-Balado, C.; Nebbioso, A.; Rodríguez-Graña, P.; Minichiello, A.; Miceli, M.; Altucci, L.; de Lera, Á.R. Bispyridinium Dienes: Histone Deacetylase Inhibitors with Selective Activities. J. Med. Chem. 2007, 50, 2497–2505.

Afonso, A.; Feliu, L.; Planas, M. Solid-phase synthesis of biaryl cyclic peptides by borylation and microwave-assisted intramolecular Suzuki-Miyaura reaction. Tetrahedron 2011, 67, 2238–2245.

Nnanabu, E.; Burgess, K. Cyclic Semipeptoids: Peptoid-Organic Hybrid Macrocycles. Org. Lett. 2006, 8, 1259–1262.

Bedard, A.-C.; Collins, S.K. Microwave accelerated Glaser-Hay macrocyclizations at high concentrations. Chem. Commun. 2012, 48, 6420–6422.

Dong, H.; Limberakis, C.; Liras, S.; Price, D.; James, K. Peptidic macrocyclization via palladium-catalyzed chemoselective indole C-2 arylation. Chem. Commun. 2012, 48, 11644–11646.

For those of us who enjoy the visual schemes:

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Intramolecular Suzuki-Miyaura ring closure: Biphenomycin

I particularly like the next reaction — an intramolecular Ullmann approach (plenty of these in my nightmares — I think I probably ran a thousand of these reactions). Go ahead and look through SciFinder for a macrocycle with phenoxy-alkyl or aryl and you are set up nicely for this type of ring closure (e.g. Hisutellone B)

For a detailed account of this approach compared to much more traditional sealed tube and conventional thermal heating check out Tett. Lett. 2011, 52, 4570-4574.

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Intramolecular Ullmann: MW, 35 min, 85%

Enjoy the article. Hopefully it makes you think about additional ways to improve this area of research.

 

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