This is a follow-up to a previous post on the regioselectivity of C-H arylation reactions of heteroaromatic compounds.
The direct C-H functionalization of aromatic compounds (including heterocycles) via transition metal catalysis has emerged as a powerful alternative to electrophilic (or nucleophilic) aromatic substitution and transition metal-catalyzed cross coupling reactions. If you’re looking for an overview, Jie Jack Li has edited an excellent book on the general subject of C-H bond functionalization entitled C-H Bond Activation in Organic Synthesis. Heterocyclist readers are directed to Chapter 10 by Donna A. A. Wilton for a treatment of C-H activation in heteroaromatic compounds.
In a previous post, we considered the regioselectivity of C-H arylation reactions of heteroaromatic compounds, focusing on substrate-based regiocontrol, i.e., factors in the heteroaromatic compound that influence the site of C-H functionalization.
In this post, we consider emerging examples of conditions-based regiocontrol, i.e., modifying the reaction conditions, including the catalyst itself, to direct the regioselectivity of heteroaromatic C-H arylation reactions. While there is little in the way of a satisfying mechanistic rationale for these results, it’s a promising synthetic approach. For entry into the relevant literature on this strategy, take a look at Engle and Yu’s JOC Perspective and Neufeldt and Sanford’s review in Accounts.
First up is an early report of conditions-based regiocontrol by Lapointe, Fagnou, and coworkers. Conditions for selecting electron-rich (indole) or electron-poor (pyridine N-oxide) sites were explored using chemistry from various labs:
Next up, in very recent work by Bedford, Durrant, and Montgomery (U Bristol and Vertex), regiocontrol in the palladium-catalyzed arylation of pyrazolo[1,5-a]pyrimidine was achieved by tuning the catalyst. The presence of a phosphine ligand directed arylation to C-7, the most acidic C-H as determined by NaOD exchange. In contrast, phosphine-free conditions favored arylation at C-3, the most electron-rich carbon as determined by calculations. The two processes are believed to involve different mechanisms, though the details are not yet known. The SPhos ligand system was homogeneous. Deuterium labeling studies showed that coordination to palladium was followed by a slower deprotonation that was still not the rate-determining step. The phosphine-free system was heterogeneous and proceeded with a protracted induction period via two discrete catalytically-active species.
Finally, consider the promising work of Yu and co-workers on the arylation of pyridines. Six-membered-ring heteroaromatics are still relatively rare substrates for C-H functionalization because of the basic nitrogen, which tends to bind to the metal. Most examples rely on making the N-oxide to circumvent this problem (e.g., the Fagnou example above), but Yu has been able to arylate simple pyridines by adding 1,10-phenanthroline, which competes well for the palladium, allowing the pyridine substrate to enter into the activation cycle.
Further advances in the understanding of substrate-control of regioselectivity combined with efforts at conditions-based control will surely elevate C-H functionalization to a new level of predictability and utility.
Update: Hong, et al. (KAIST), have recently published a nice paper on catalyst-controlled divergent C4/C8 regioselective C-H acylation of isoquinolones. Aryliodoinium salts were used as the aryl donors. C4 selectivity was achieved via an electrophilic palladation pathway; C-8 arylation was performed using an Ir(III) catalyst.
Interested in having a short course on Heterocyclic Chemistry at your company?
In late 2011, I put together a new two-day short course entitled “Heterocyclic Chemistry – A Drug-Oriented Approach” to present at companies. In a nutshell, it’s an intensive, preparatively-oriented course on the synthesis of the types of molecules encountered in the pharma and agricultural endeavors. There is a heavy focus on practical, proven methodology that people actually use. I keep it updated with lots of current chemistry.
Beyond the two days of instruction at your company, participants are left with a great resource: A book of over 500 slides of information, nicely organized, well-referenced, and containing many specifics on the best ways to make heterocycles.
I’m booking courses for 2013 and early 2014. Learn more by checking out the course web site, where you’ll find more on what the course covers. You can also download a two-page summary of the course to pass around to your colleagues. If you know of other chemists who might be interested in the course, I’d appreciate passing this along. You can reach me at will at pearsonchemsolutions dot com.
A recent paper by Xingwei Li and co-workers in Angewandte Chemie International Edition has some nice chemistry in it, but take a look at the title, “Rhodium(III)-catalyzed oxidative C-H functionalization of azomethine ylides.” One might expect to see some azomethine ylides, right? No, they are azomethine imines:
I suppose one could make the case that azomethine imines are a subset of azomethine ylides, but I’ve never seen it done. What am I missing here?
[Edit: Correspondence with Professor Li reveals his point of view: “the structure can be called both azomethine ylides and azomethine imines,” (sic) and there “is not much difference,” (I strongly disagree on both counts) and “we simply want to emphasize the ylidic character of our substrate.” Okay, I can understand wanting to emphasize that something is an ylide, but there’s no need to choose an incorrect name to do so. Learning organic nomenclature is hard enough. Enough said. I’m now going to retire my Professor Pearson hat on this issue.]
[Edit: Here’s another paper from the same lab, still referring to azomethine imines as azomethine ylides. Apparently the referees at Advanced Synthesis and Catalysis aren’t minding the store either.]