There is a new short course on flow chemistry being offered by Scientific Update in Nice France (June 2-3 2015) with Oliver Kappe and Will Watson as instructors…..should be a great course with Oliver as a leader in the field of new flow chemistry information and current state-of-the-art techniques. I have included the information on the side – In the News (can also be found on the Kappe Group site). Anyone in the field should plan to visit and join the group in France for the latest education in flow chemistry….looks good to me!
OK it was an extended time away from posting — I totally blame the Turkey, Ham, Beer, Stuffing, Pie — at least I have tapered off over the years.
So what’s sitting on my desk — after several pontifications, I have gotten back to thinking about how chemists think about their chemistry and where it can go in flow processes — so, OK, retrosynthesis — but I often think in classes of fragments and what they can do (think of it as a review on enaminone transformations so to speak). In this case, Ian Baxendale got me thinking about ynones or alpha, beta-acteylenic ketones — used quite a bit right? furans, flavones, pyrazoles, pyrimidines and heck back at Bayer I used them in a number of dipolarcycloadditions and intramolecular cyclizations to isoxazoles and pyrroles……you get the point……if interested in a nice article on using a flow approach to ynones and their divergent reaction with different nucleophiles then (Chem Eur Journal 2010) is the ticket.
In the three schemes below we see the utility of using several clean-up and scavenging steps to develop an outnumbering process to libraries of heterocycles with a single ynone. By starting with a simple acid chloride under Sonogashira coupling conditions (Pd(OAc)2, Hunig’s Base) with an acetylene at 100C over a 30 min period, the ynone is formed and used with several reagents (hydrazines, guanidines, etc) to form libraries. To take this to the crux, 4 columns were used to clean up the ynone or post nucleophilic reaction: polyol for the acid chloride, CaCO3 for the HCl and knock the ammonium salts, sulfonic acid for the tertiary amines and finally an immobilized thiourea for the Pd catalyst prior to diverting the product to additional steps. On a personal level, this really shows the power of combining purification techniques (many which have fallen through the educational cracks of developing a thought process around what’s going on in a reaction — I was lucky enough to learn most of this because I had too many nitrogens around my compounds of interest) with the power of flow methodology.
Happy Reading! Good to be back!
Electrochemistry falls into one of those categories of expansion, where the chemists who perform these reactions are more similar to their specialties — as is the case with photochemistry. These simply don’t fall into the area of study, education or applied retrosynthetic strategies. However, flow chemistry allows us to level the playing field a bit, and asks us to include new reaction space which we would otherwise never draw on the chalkboard.
In a recent example (OL 2014), we are treated with a modification on a throwback Shono oxidation of cyclic amines (protected as a carbamate or amide in the generation of an acyl iminium species with a nucleophilic attack of MeOH). I particularly like this since I have used this reactions in the past, but it requires some care into the appropriate choice of anode and salt bridge — in this case electrolyte in flow).
The scheme to Nazlinine is shown below with a flow oxidation reaction followed by a microwave accelerated Pictet-Spangler to several additional non-natural Nazlinine analogs:
The table below illustrates the use of a microreactor with choice of anode, electrolyte, flow rate and current (Carbon, 20% Et4NBF4, 43mA, flow,100-120 microliters/min).
Expanding beyond pyrrolidine expands the utility and the chemical space for libraries around Nazlinine, but also into areas of related systems beyond the scope of the paper:
Although not the focus of my post, the second reaction, which would otherwise take 15 hours to complete, was shortened to 30 min using microwave irradiation as a final step into Nazlinine and related compounds. You will notice a big effect in the acid choice — they found optimized results with CSA in H2O, but with a deprotection, imiminium formation, and more than one amine, screening additional acids will add additional opportunities here (med chemists — you know that I am talking to you).
Enjoy the rest of the paper in looking at additional substitutions on the indole and extension of the exo-alkylamine. This should help you think of additional electrochemical reactions that are out there to be used — I can think of a few that I would want to incorporate (please note that references 1-2 in the paper include examples of electrochemical and photochemical reviews as excellent starting points when considering flow approaches). Happy Reading!
Ah, back to my old thiolactam days, when I would utilize and Rapaport protocol to extend a pyrrolidine or piperidine out. So I thought this has to be a reaction that has been reduced in a continuous flow manner — low and behold, someone has used this sequence in functionalizing pyrimidines (Beilstein JOC 2011)……..are my med chem colleagues in the house?
As a starting point if you haven’t ever performed these reactions, a scheme for the secondary lactam transformation is shown below and the subst version just below that.
Using this concept, the transformation was applied to some substituted sulfur-pyrimidines.
As part of the reaction intensification process, this group found the kinetic profile quickly to go along with the concentration for the residence time and made a small library of compounds (see paper for how the kinetic studies were performed). The tables below indicate the materials to start and corresponding final compounds and their yields.
The coiled capillary reactor design is shown for the control of temperature and flow. Happy Reading!
The latest addition of Specialty Chemicals Magazine (November 2014 pp 26-28) features a perspective on flow photochemistry today and tomorrow- both, the process and available tools or light sources needed to operate at the gound state, but also at an excited state (single and triplet state). If interested, I have posted my thoughts on expanding capabilities in flow chemistry. Before highlighting a couple of reactions, I wanted to point out the Duncan Guthrie does an excellent job of setting the mindset that one should enter with for thinking about photochemisty. He talks about the fact that 1% of the total reaction availability is accessed through photochemistry over the years, but that a number of these can be utilized and expanded through use of the appropriate light source and the sustainability of flow techniques — I agree. Duncan then goes on to express that these processes should be embraced by the non-photochemical expert and can be easily performed as a skill developed by performing an extension of normal ground state flow methods…..again, I agree with this sentiment. It can be viewed no different from adding hydrogenations to your arsenal having not done one before…as easy as that, not to mention that re-educating the number of chemical transformations that can be added by opening up this capability.
The article is reasonably short and if you are a synthetic organic chemist, you should dig into the article — a few examples are shown from the article to illustrate the point:
Pericyclizations of the benzamide under flow conditions.
Publication out of the Seeberger group shows divergent continuous-flow photochemical methods toward Arteminisin-derived targets as an example of broadening application of flow and photochemistry in natural product synthesis:
One last point, the filtering of light sources is well defined when application and technique is detailed….as well as the utility of the cooling process for the type of flow technology. Enjoy the article, because the implications provide a broadening of several industries and research. Happy Reading!
Just recently had the opportunity for some interaction with Duncan Browne at Cardiff University. You will want to keep track of the work Duncan is doing — having recently left collaborative work with Steven Ley and Ian Baxendale, Duncan is exploring several enabling technology ideas in the area of organic and materials synthesis in his own labs. If you have looked at the area of flow chemistry for any length of time you will have come across his work — and I am told to expect some really creative work from Cardiff. One of the key things I enjoy from my contact is Duncan’s interest on the educational side of enabling technologies, he has a strong commitment to evangelizing the movement or casting a wider group of people joining the changing landscape of synthetic processes.
So no doubt that I was familiar with HEL and their automated chemistry systems, but I am happy to see that not only are they involved in reactor development, but have added tubular reactor designs for a wide range of temp and pressure, different reactor material options — extending the range of heterogenous and homogeneous catalysis and gas additions (hydrogenations and carbonylations). Take a look through their site for a better idea of what the group is doing in flow chemistry.