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!
As a continuation in theme perhaps made me think of additional reactions where an enolate is used in the formation of a useful or studied heterocycle. Although furans are not at the top of the list as medicinal chemistry frameworks (simply take a look at how CYP enzymes rid themselves of this backbone), they do represent an area of interest on the materials side of things. A recent publication from Mark York (TL 2011) shows an efficient modification of a low temperature batch enolate formation followed the addition of an alpha-bromoketone to form di-/tri-substituted as well as annulated furans in moderate to very good yield without the need for traditional cooling. So in this particular case, a simple solution of a ketone was mixed with LiHMDS at room temp (starting with a flow of 0.76 ml/min and the base at 1.54 ml/min) while flowing through a 10 ml loop…as the enolate is formed it is reacted with an alpha-bromoketone pumped in from a separate line — the mixture is allowed to flow through 2 10 ml loops and quenched at the end of the sequence — so based on the flow the total time for the reaction sequence is about 9 minutes. The scheme (shown: the appropriate substitution which postulated to form from an initial enolate, addition to the haloketone, elimination of LiBr with concurrent epoxide formation and internal attack with the elimination of water) and a section of the table is included to show some of the compounds made (yields were improved moving from low temp to room temperature — indicating that additional work would be of interest in evaluating reactions at higher temperatures than traditionally reported — with flow the kinetics may serve to eliminate a need to cool the reaction as we have done in the past. Happy Reading!
For all of the work done utilizing stereoselective chemistry, we have certainly struggled with this concept in med chem from the standpoint of building chiral centers in an advanced drug candidate. With all of the synthetic knowledge, we knew that if something wasn’t naturally built in, we were going to be adding steps on the cost end of the development. I was lucky enough to be part of a number of these types of targets, and it made you think….but with continuous flow developments, this process has been streamlined. Part of the effort here is to bring it back on the table in your thought process. A reasonably recent review from Peter Seeberger et al. (Beilstein JOC 2009) provides a nice review of many of the current methods used in flow chemistry — and this particular review is on applications of homogeneous and heterogeneous asymmetric catalysis, as a sustainable cost effective way generating chiral materials from achiral starting materials.
The number of homogeneous enantioselective reactions reported using a continuous flow technique is low – with hydrogenations and silyl-cyanations reported. From the Seeberger group (Angew Chem Int Ed 2009), aldol condensations catalyzed with 5-(pyrrolidine-2-yl)tetrazole was compared with batch and microwave procedures to provide shorter reaction times and lower catalyst loadings as shown below. Clearly the benefit of these microreactor processes is the ability to screen catalysts, flow and temperature quickly.
Moving over to the use of heterogeneous chiral catalysts, we have to way the expense of using expensive catalysts and leaching the material through the transformation….however, since we discussed the use of supported reagents, the use of a supported catalysts provides an opportunity to recover catalysts and the format is easy to develop. The downside is that these catalysts need to be put on a supported media, so screening has the potential to take longer. Below are several examples of some of the work done using this concept:
The first example (Adv Synth Catal 2008) is using a Meerifield amino-alcohol resin with the addition of Et2Zn to an aromatic aldehyde to provide good conversions with high ee%s with a flow rate of 0.24 ml/min and a residence time of 9.8 min to provide mutligram quantities of the desired compound in 98% conversion with 93%ee within 3 hr. The catalyst activity remained provided identical recoveries with different aldehydes over a 6 hr time period.
A similar process for an ene reaction of ethyl glyoxylate and alpha-methylstyrene and a stainless steel column packed with a PyBox-Cu complex (and good for over 80 hours – 5 runs) following the load with Cu(OTf)2 to the PyBox resin (Tetrahedron: Asymmetry 2004).
Cinchona alkaloid derivatives has been utilized in solution and solid supported reactions for a number of years. The scheme below shows a reaction of ketene (generated from an acid chloride) and imino esters for the formation of beta-lactams (JACS 2001)…so we see the ketene generation on passing through a BEMP support (so no isolation) which was then reacted with a flow of the imino ester in the presence of the supported cinchona resin, and a clean up of excess reagent and by-product and a benzyl amine scavenger. While this was elegant, the process was driven through glass columns and gravity driven, so improvements would increase the utility of the concept.
Macroporous monolithic materials are becoming popular as strategies for a number of transformations, owing their increased surface area, improves mass-transfer between the supported reagent and liquid phase – and the advantage of not clogging or pressure fluctuation often found in gel-type resins. The ability to adjust the porosity, composition and shape provides a broader range of experimentation (we owe a shout out to our inorganic brethren for giving us insights into this strategy).
A nice example of this process can be found in (Angew Chem Int Ed 2001) from Kirschning et al. with a functionalized chiral Co(salen) complex monolith reactor used in the dynamic kinetic resolution of epibromohydrin (continuous circulated over 20 hr). This example shown could be operated continuously over a 6 day period without the loss of activity of the catalyst, and thus the corresponding ee%s.
Several additional examples are present in the review, and this topic is receiving attention throughout the field – I imagine you have seen several examples of your own. It is pretty wide open – the wild west. Happy Reading!
It may have been placed at an earlier date but it was just simply an issue with getting to the topic: Cold Flow — perhaps the strongest in flow developments since a high percentage of reactions are performed from RT to -70C (maybe even -78C). Nice thing is that many of these low temperature reactions will need techniques discussed early on in-line removal of a reactive or species which might clog a flow line or need an in-line work up. For today, I will highlight 2 examples to illustrate the importance of these developments and you can venture into this arena with periodic updates on my side from time to time…..I will stick to Cold Flow since the term Cryo leaves me with the feeling that I am an Asimov book (besides it means icy cold anyway).
The first example (OL 2011) should stick out a particularly valuable: the preparation of aromatic and hetroaromatic boronic acids (and boronates) following a lithium halogen exchange. Two things should jump out prior to performing these sorts of reactions: solubility (concentration of reactants and products) and how to cool effectively without in-line quenching or cooling reactor operation. In each of these cases, a team from the University of Cambridge and Cambridge Reactor Design (Ley, Browne, Baxendale, Baumann and Harji) walk us through an effective reactor design and implementation. For starters, picking the formation of an aryl and heteroaryl boronate with low-temperature lithium-halogen exchange is particularly pleasing with the abundance of starting materials available.
In the figures below, a low-temperature reactor with a flow coil and a pre-cooled coil for the introduction of reagents into the entire block of temperature controlled region is used — along with that is an in situ IR to monitor the flow of reagents and product formation (have to say that this is key when checking for a buildup of a material at any phase of the flow of materials.
Concentration studies show the effective operable area for the the formation of the final boronic acids.
Following the formation of the boronic acids, the system was set-up for the formation of a variety of boronates.
Although an number of questions come to mind doing this sort of chemistry, this group detailed the ability to operate the cooling reactor for long periods of operation to ensure durability, taking nBuLi straight from a reagent bottle avoids the need to generate reactants prior to flow, and in these cases optimal flow of solvent ratios were studied to ensure successful processing.
The second example stayed true to the control of low temperature reaction zones as well as an in-line FlowIR to monitor and correlate batch to flow method design. In this report out of ThalesNano, the group illustrates the value of the IceCube reactor (uses a two-zone cooling and heating zone areas to either cool or heat when needed to complete a multi-step process). In the report, they performed a Swern Oxidation under flow conditions and studied the temps needed for the conversation without the formation of reactive by-products often associated with the reaction from a batch process.
For the sequence of reactant flow, they have 3 areas of input for the flow: a solution of the alcohol in DMSO, Oxalyl choride in DCM and TEA at the end of the reaction. Optimized for concentration and flow, the group monitored the reaction for the formation of the desired aldehyde as well as potential side-reactions during the course of the reaction — in that, they were able to show the temperature ranges that were effective and when undesired formations were taking place.
Although the IceCube has an extended range of of -70C to 80C and -30 to 80C, they were able to show a full conversion from -30 to -10C without any deleterious effects in the reaction — a choice of temperature range control in the reaction zones coupled with with FlowIR monitoring makes this an easy operation in reaction feasibility.
Hope you enjoyed the 2 examples — there will be several upcoming posts with this theme in mind since it is a reasonably new area of capability in the last few years — so we will want to see a variety of applied synthetic transformations and combined cooling/heating multi-step methods in a full flow manner as a way to encompass flow chemisty’s full potential as a research and development technology. 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.
Just read an article (Molecules 2014) on flow through hydrogenations through the eyes of a medicinal chemist….sort of. A combination out of Baxendale and Ley is a contribution in the area of heterocyclic construction using an appropriately placed hydrogenation of an aromatic nitro group, strategically located to take place in a subsequent reaction to form advanced riboflavins, quinoxalinones and benzodiazepines…..each important in their place as strong pharmacophores.
Two things that stick out to me as important: how do they arrive at a final working method and what were the issues….when you read an article by these authors it will inevitably have this information present and that is the type of discussion that will help push the area of flow chemistry forward. For instance, in the first scheme below, the group needs a diamine functionality and over-reduction of an aromatic halogen took place with Pd/C but not with PtO2 (ha, how many times have you read a BIOMCL — the things that don’t work are not discussed)— and this is likely made more challenging by the fact that they had to heat the reaction to 45C for the reaction to work well and use MeOH to keep the materials in solution for the duration of the reaction. The nice thing about the reaction is that it was easily be performed and optimized for catalyst using the H-Cube by ThalesNano. Another piece of anecdotal information — the diamine is typically not stable for any appreciable length of time — but can be used in the subsequent step. The scheme below indicates the two possibilities for the reaction — and note that the condensation here was done in batch fashion for 10 hrs at room (must decompose the diamine with heat because 10 hours is a long time).
Although they applied the same methodology to a quinoxalinone series, I am going turn our attention to the work done on benzodiazepines. Work on the scaffold is traditionally considered older — with new developments as a rarity — I know my early research included an aza-version of this and it felt like a total synthesis. For the storyline, some conditions needed some attention in order to move to a complete flow system. For example to build the amino-nitro diarene, they chose a microwave mediated SNAR reaction of a fluoro-nitro arene and the requisite aniline. Fortunately, I have discussed this type of reaction in a past post so there is some development utilizing this approach — in this case, however, the aniline is deprotonated with LHDMS and irradiated in the presence of the fluoroarene to produce the diaryl scaffold in high yields in a short amount of time. The product was redissolved and hydrogenated and cyclo-dehydrated to provide the benzodiazepine in high yield. To adequately handle the dehydration, an in-line MgSO4 filled glass Omnifit column was placed subsequent to the flow hydrogenation (again – H-Cube with in-line MgSO4).
The great thing about the microwave method is that it provided a good reaction starting point for a medicinal chemist planning a library for some initial screening hits. The bad news is that scale-up in this fashion would require a different microwave or a continuous flow method if additional testing or to get the compound through an entire cascade an on its’ way to animal studies….this group recognizes this as a key criteria in developing the technology and therefore worked out a method for the first step in a continuous format. Prior to jumping into the flow conditions, the 2-step process provided a nice route into the desired compounds with microwave (1) and flow (2) method.
In moving over to the flow conditions, the base and mixing were critical for the execution. Although the scheme helps you follow the format, three separate lines were used to form a good process with n-BuLi in channel A, the amino-benzophenone in channel B and the fluoroarene waiting in channel C, with the appropriate mixing chambers and T or Y-lines adjusted to provide the mixing and timestamps for delivery of reactants/reagents. The initial solutions for deprotonation were cooled to 0C, mixed for a quick reaction and flowed into a flow stream of the electrophile. Once this last mixing is started, the flow went into a heated coil loop (52 ml) at 115C for the cyclization to proceed. Once the product was formed, the group added a process to quench and work-up the reaction so that the desired solution of organic product (plus the addition of MeOH if needed) would flow into the H-Cube midi under similar conditions indicated above (5 bar, 45C, 2.2 ml/min, coil loop, PtO2) provide up to 120 mmol or 38.1 g. The in-line work-up process is certainly worth a detailed read — this is an area of discussion that chemists will eventually develop innovative ways of handling reactions that include lithiations mid-stream (and other transformations)…although we would like to make everything plug-and-play, we need to make sure to understand what’s in the line to have a successful flow method in the lab. Happy Reading!