Cross-Couple While the Iron is Hot

We are delighted to announce that our recent work on Fe-catalyzed cross-couplings of redox-active esters (RAEs) has recently been published in JACS! We'd like to share with you how we started out, developed this project, and how things evolved from the first discovery.

During the past year our group has been involved in using RAEs as coupling partners in cross-coupling. We have developed a variety of coupling reactions to make the route to C–C bonds easy and practical to anyone regardless of skill or level of funding. The reactions with RAEs allowed for the first time the use of any alkyl carboxylic acid as coupling partner. The acid is primed for reaction similar to the activation for amide coupling using simple phthalimide derivatives (NHPI or TCNHPI) or peptide coupling agents (HATU or HBTU). The use of a cheap and abundant Ni catalyst does the rest of the job. These reactions revealed very interesting features which were already described in previous blog posts here and here at Openflask.

We were very aware that our initial reports on Ni still presented some limitations which needed to be addressed. It's always fun to read the comments and concerns on Derek Lowe's blog :) The story with Fe started by trying to address those drawbacks and provide solutions to those chemists out there, which need molecules synthesized easily and in high yield during a coffee break.

Up until now, all RAE couplings we developed were restricted to the use of 10 or 20 mol% loading of Ni (sometimes as low as 5%). FDA considers Ni as class 2A toxic metal impurity, which makes its use in pharma industries less attractive (at least on process scale). In addition, these methodologies posed other issues: occasionally long reaction times for the cross-coupling, the use of isolated RAEs to obtain the very best yields, and in our Suzuki coupling, diluted conditions were also required.

All these issues were then considered in the lab and we decided to tackle these challenges by taking a closer look into the mechanistic aspects of the reaction. We knew this would not be an easy task but we were lucky to gather a team with different backgrounds and expertise to put together this nice story.

Everything started with a simple question, which would solve most of the drawbacks in our Ni-catalyzed reactions: What about Fe? Our lab has been playing around with Fe for quite some time now and we all know the advantages of using Fe over Ni.

What about Fe??

In the past decades chemists have been trying to identify what are the operating mechanisms in Fe-catalyzed cross-couplings. The literature is brimming with papers trying to catch the right intermediate… However, what it seems to emerge as a common theme is that oxidative addition of alkyl bromides and iodides proceeds via SET of a low-valent Fe complex. I believe you all know where I am going here… We simply wondered whether Fe could actually undergo SET to our RAEs, inducing radical fragmentation. If this was possible, a plethora of opportunities would open up by combining the RAEs and known reactivities for Fe catalysis.

Indeed, the answer to the question “What about Fe?” seemed to be “Why not!”. Jacob  tried this reaction using TMEDA and obtained around 30% yield. He graciously shared those results with us before moving to another exciting project (that you can read about in a few months). Fumi (a tremendously talented visiting scientist from Daiichi Sankyo) set up the first reaction using phosphine ligands and 60% yield of product was obtained!! But there is more… it not only afforded good yield of cross-coupling product, but it was extremely fast and proceeded in less than 1 hour! A little bit of tuning identified Bedford’ and Nakamura’s Fe system (Fe(acac)₃/dppBz) as optimal for these reactions.

However, it was clear since the very beginning of the project that we did not want to come up with “just the same but with Fe”. What we wanted is to improve our previous work by addressing all the issues we had until now with the Ni chemistry. To make this point very clear, we decided to directly compare Ni and Fe in every compound reported in the paper. In this manner we wanted the reader to contextualize the research and simplify the choice of the appropriate conditions. 

We were really thrilled to observe that a simple activation of the acid by HATU at rt afforded comparable yields as when using the isolated RAE. Unlike our experience with Ni-catalysis, HATU, TCNHPI, NHPI or HBTU all performed similarly. A very interesting feature of this reaction is that you can run the Negishi coupling with pretty much any solvent at reach in the lab. We used toluene, benzene, THF, 1,4-dioxane, DCM, DMF, hexanes, Et₂O… and all of them afforded the coupling product in good yields. The difficulty came to select the solvent to carry out the substrate scope. The source of Fe did not matter either… FeCl₃, FeCl₃ hydrated or Fe(acac)_3, valyrian steel_, they all performed equally. We bet the reaction would work as well with a piece of the iron throne.

Another interesting feature of this reaction is how fast these couplings are... even at –20 ºC. It is incredible to observe that once you add the zinc reagent into the Fe/ligand/substrate mixture you just have to wait only if you like waiting. The reaction is finished by the time you dispose of the syringe. Simple aqueous workup, evaporation and short chromatography will give you the pure cross-coupling product.

Selected scope of >40 examples

We were very pleased to see that these conditions were very general across a wide range of substrates. Primary and secondary acids performed extremely well. Natural products and drugs were all arylated easily. As in any Baran lab project, pyridines are mandatory :)

During the exploratory scope of the reaction, our “human molecular machine synthesizer” Tie-Gen, also managed to obtain secondary-primary couplings with alkyl zincates. However, we want to warn practitioners that the primary alkyl-alkyl coupling is still beyond the scope of these conditions and more screening is needed. The main byproducts observed when attempting the primary alkyl-alkyl coupling were beta-hydride elimination of both partners in addition to the decarboxylated Barton-type product from the acid. If one wants to perform such coupling, we recommend having a look at our previous method using Ni. It is extremely efficient.

Another important feature of these particular Fe conditions is the possibility of arylating tertiary carboxylic acids. Previously, arylation of such acids was attempted for long time albeit unsuccessfully… We were really happy in the lab when we managed to arylate a [1.1.1] bicyclic system bearing a carboxylic acid in 35% yield. Notably, this is a bond formation that our collaborators at Bristol-Myers Squibb have been eying for years now.

We were thrilled to find that these conditions now allow another type of nucleophile to be introduced in our repertoire: welcome aryl Grignards. We had the idea of using Grignards for the cross-coupling for quite some time now but using Ni, ketone formation with the RAE was always problematic. And we kept failing dramatically… With Fe however, the extremely fast reaction rates observed allow for the integration of aryl Grignards without any ketone formation. It is interesting to mention that Grignards react at faster rates with the Fe catalyst than with the starting RAE. This result is consistent with Fürstner’s cross-coupling with low-valent Fe species where even isocyanates are tolerated.

Grignards work!

At this point, our Austrian postdoc Laurin took a step forward and decide to explore the limits of this system. He decided to subject the terrible beast of cubane to our arylation conditions; cubane is known to be an extremely sensitive material in the presence of transition metals. We were extremely delighted when we saw the GCMS of that reaction… a peak for phenylated product was there! Indeed, Laurin managed to put a phenyl ring into a cubane!!!!

To contextualize this result, a deep search in the literature revealed seldom methods for the synthesis of arylated cubanes. They seem to be restricted to rather bizarre reactions, such as Pb-promoted oxidative Minisci, where the regioselectivity is not controlled. 

Remarkable cubane examples

This modular protocol now allows the introduction of a wide variety of aromatic rings as we demonstrated in a 3-step double arylation of cubane scaffolds. These structures were obtained in reasonable yields and they turned out to be crystalline. We are so proud of these bis-arylated bioisosteres that the X-ray pictures are hanging on the walls in our offices as one of our best achievements :) (Proof of it just below).

Beautiful X-rays

Methods at the Baran lab are conceived with the ultimate goal of being applied at the industrial level. For this reason, the Fe team tackled a question that has been around since we started developing the chemistry of RAEs: can we apply this method in the context of process chemistry (it's already used in medicinal chemistry)?

One of the Figures in the manuscript resumes the work involved in the development of both a medicinal and a process chemistry approach. Since this protocol is easily scalable, no problem was found for the medical chemistry approach when using 1.4 g of starting carboxylic acid. Simple aqueous work-up followed by quick chromatography afforded pure cross-coupling material.

Real scalability

A critique we heard over and over again from process chemists associated with this chemistry was the high catalyst loading of toxic Ni salts, difficulties associated to its removal and dilute conditions for the Ni-catalyzed Suzuki. Our visiting process chemist Fumi gathered the team and said: “I think we can do better”.

Fumi ran the Fe cross-coupling reaction with just 1 mol% Fe and after a series of solvent exchanges and washes, followed by a crystallization, gave us a 61% yield of product. To our excitement, the purity of the compound was 99%. And since we are in the realm of non-toxic Fe, there is no regulatory limit for Fe impurities according to the FDA.

For those process chemistry readers, another feature of this chemistry is that a very small exotherm was obtained when running the reaction at 1.4 g. The internal temperature only rose from 1.5 to 19 ºC (note that most of the temperature increase came from addition of room temperature solution)! So we hope such small temperature change will pose no problem for scaling up cross-couplings with Fe and RAEs in the near future.  We also got the seal of approval from our process chemistry collaborators at BMS (thanks Gardner and Darryl!) who performed several examples in the table.

We hope people will find immediate applications for this interesting cross coupling. We hope you enjoy reading the manuscript and as always, if you have any comments/suggestions/criticism/questions feel free to contact us here directly (anonymous posts are welcome).

Pep and the Fe team

p.s. Check out the SI with photos, FAQ, and even some flow-charts to help practitioners :)