Lithiation in flow chemistry

The thought in the post is simply to open discussion to areas where flow chemistry can be used in places where traditional batch and kinetic deprotonation and finally subsequent reaction has held pretty well over the course of organic synthetic chemistry. It is on our minds — certainly an area where medicinal chemists can start to think about utilizing flow methodologies for gain in their march to library development.

Firstly, and I won’t spend too much time on this, but considering the kinetics, it is hard to jump from a reaction that should be really fast into flow-thinking (but I can assure you the time in flow is very fast). I know it was hard for me at first — things crashing out, length of time arguments and such, but I have to say there are a number of publications suggesting that this is a very controlled and good chemical way of doing things. If you haven’t had enough reviews – there is an excellent book on Lithium Compounds in Organic Chemistry that I would like to point you to: Lithium Compounds in Organic Synthesis: From Fundamentals to Applications, Wiley, 2014. In Chapter 17, Aiichiro Nagaki and Jun-Ichi Yoshida illustrate Microreactor Technology in Lithium Chemistry, including unstable lithium species, switching reaction pathways, protective-group free synthesis to reaction integration — and areas of anionic controlled polymer chemistry.

There is even a report from Chemjobber illustrating Merck’s ability to perform a dianion formation in flow with process improvements over the traditional batch route. The citation and comments provide a nice account of the chemistry and easing the resistance to adopting to newer technologies.

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Another nice report can be found in Chemica Oggi (Chemistry Today July/Aug 2014) by JÖRG SEDELMEIER and  FRANCESCO VENTURONI from Novartis Pharma in Basel, Switzerland where they show the rapid generation of thermally unstable organolithium intermediates and their reactions. I thought this was a significant contribution in the operation window of temperature that can be used in flow methodology (for both research and manufacturing).

Lastly, because I want to move the thinking into areas of drug discovery research – a recent report (Org Biomol Chem 2010) on the synthesis of imidazopyridazines as casein kinase inhibitors, shows a key step in a library approach to these compounds with a flow lithiation method to form advanced intermediates which were then taken (again in a flow manner) to final compound libraries (great proof of concept med chem approach). For the lithiation, the continuous flow or feed of the organometallic solution could be easily controlled by simple valve and loop selection (temp and feed) for the lithium source and resultant reactive deprotonated nucleophile. I was particularly impressed with the usage of the intermediates in the SAR of the target compounds. If played well, a group of 2 could have final compounds for testing in a day — well, lol, at least that is how my group strategized our analog development. Enjoy the papers and references!

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Targets:

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The Need to have Flow Methods Operate at Low Temperature

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.

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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.

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Polar Bear Low Temp Reactor
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Low temp coil – Chip Temp Controlled

Concentration studies show the effective operable area for the the formation of the final boronic acids.

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Following the formation of the boronic acids, the system was set-up for the formation of a variety of boronates.

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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.

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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.

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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.

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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!

Flow ideas: Expanding the possibilities in Med Chem

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).

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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).

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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.

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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!

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