Just a bit of sodium ethoxide does the trick …
The Knorr pyrazole synthesis, broadly defined, involves the condensation of hydrazines with 1,3-dielectrophiles, e.g., 1,3-diketones, beta-ketoesters, alpha-cyanoketones, beta-alkoxyacrylonitriles, alkoxymethylenemalonates, etc. When a nitrile electrophile is involved, an aminopyrazole typically results, producing compounds that are very useful in the pharmaceutical field. The first two equations in the general scheme below use hydrazine as the dinucleophile, but what happens when an unsymmetrically-substituted hydrazine is involved? Wouldn’t it be nice to be able to produce either the 3- or 5-aminopyrazole regioisomer in a selective fashion?
This problem has been kicking around the literature for a long time. The 5-aminopyrazole is generally the major product, leaving the 3-aminopyrazole as a useful-yet-expensive poor cousin. Much effort has been spent trying to rationalize and predict the outcome of these processes, so a recent paper from Fandrick, et al., from Boehringer Ingelheim is a most welcome arrival.
Heating the nitrile 3 with the alkyl-substituted hydrazine 4 in ethanol produces the 5-aminopyrazole 7, presumably through the adduct 5, a result that is consistent with the prior literature. At first glance, this should be rather surprising, since it is known that alkylhydrazines are more nucleophilic at the most substituted nitrogen, i.e., k1 should be larger than k2, thus producing adduct 6 and the 3-aminopyrazole 8. (Arylhydrazines are different; they are generally more nucleophilic on the unsubstituted nitrogen, though it depends on the nature of the arene.) Fandrick and co-workers proposed that 6 is indeed the kinetically-formed adduct, but its cyclization to 8 (under typical neutral conditions) is slower than isomerization to the more stable adduct 5, producing 7 instead.
In order to obtain the more rare and often desirable 3-aminopyrazole 8, Fandrick simply introduced sodium ethoxide to the mix with the idea that the kinetically favored 6 might be transformed to 8 before it can isomerize to 5. It worked, producing 3-aminopyrazoles with selectivities of up to 99:1 depending on the exact example.
Increasing the size of the alkyl group on the hydrazine should erode the selectivity for 8 in the kinetically-controlled ethoxide reaction, since the internal nitrogen of the hydrazine, while electronically more nucleophilic, is less accessible due to steric hindrance. Indeed, moving to cyclohexylhydrazine and then t-butylhydrazine leads to diminished and even reversed selectivities of 72:28 and 5:95 for 8:7. Under neutral thermodynamic conditions, cyclohexyl- and t-butylhydrazine gave >99:1 ratios of 7:8, as expected.
Arylhydrazines are known to highly favor 5-aminopyrazoles, which was supported by the current work when employing neutral (thermodynamic) conditions. Interestingly, reasonable quantities of 1-aryl-3-aminopyrazoles 8 were formed under kinetically-controlled (ethoxide) conditions. Hence, with phenylhydrazine, a 1:1 ratio of 8:7 was formed, indicating that a good deal of 6 was formed kinetically. Using the more electron-rich p-methoxyphenylhydrazine under kinetically controlled conditions produced even more of the 3-aminopyrazole, giving a 78:22 ratio of 8:7. This presumably reflects and increase in the nucleophilicity of the internal hydrazine nitrogen due to the resonance donating effect of the p-methoxy substituent.
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.
Off topic, but worth it: UK artist Luke Jerram, in consultation with U of Bristol scientists, has made some incredible 1,000,000x scale glass sculptures of viruses, bacteria, and other tiny critters. Check out a gallery of his Glass Microbiology sculptures, then take a look at his other work, which includes live arts projects, large-scale public engagement artwork, etc. This guy has range!
Near-simultaneous reports of an interesting new pyrrole (and dihydropyrrole) synthesis have appeared recently from the labs of Frank Glorius (Westfälische Wilhelms-Universität Münster) and Naohiko Yoshikai (Nanyang Technologial University, Singapore). Optimization of the additives, solvent, and temperature led to essentially the same conditions from each laboratory. A balloon of oxygen is preferred: yields are much lower when air is used. A Heck-type mechanism is shown, but a Wacker-type mechanism involving nucleophilic attack of an enamine onto a Pd-complexed alkene could not be ruled out.
The scope of the reaction is decent, as indicated below. Failures include R3 = CF3 or cyclopropyl and R2 = Ph. N-Homoallylic and N-cinnamyl imines were also unsuccessful.
Specific examples are shown below:
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.
Sometimes you just have to step back and marvel at the structures that are found in nature. Check out zamamiphidin A, a new manzamine alkaloid isolated from an Okinawan sponge by J. Kobayashi and co-workers (Organic Letters). Heptacyclic. Quaternary ammonium. Massively bridged. Well done, sponges!
Here’s a process that I think needs continued attention from the synthetic community: Making saturated nitrogen heterocycles from simple N-alkylamines by intramolecular CH amination reactions. There’s a lot of great chemistry out there for related process where there is an electron-withdrawing group attached to the nitrogen within the tether (vide infra), but let’s focus on N-alkyl groups. With all the activity on CH functionalization chemistry in general, I hope this reaction will become routine at some point. Let’s take a look at some recent work in this area.
The Hoffmann-Löffler-Freytag reaction – An medicinal chemistry application
To exemplify the need for such a reaction, consider the compounds shown below, appearing in a recent J. Med. Chem. paper by McClure and coworkers at Pfizer. The diazatricyclodecane (or diazaadamantane) heterocycles in the dotted boxes were proposed as conformationally restricted piperidines that might make good agonists of G-protein-coupled receptor 119.
The Pfizer group settled on a Hoffmann-Löffler-Freytag (HLF) reaction to form the heterocycle. In their initial work, they were unable to reproduce Rassat’s route to such diazatricyclodecanes (JACS 1974), which involved heating the N-bromoamine in acid. Switching to the N-chloroamine led to only 14% of the desired compound accompanied by 40% of an elimination product involving the N-benzyl group.
Ultimately, forgoing the protecting group was fruitful. N-Chlorination of the primary amine shown below was followed by photolysis with a 450 W mercury lamp to provide multigram quantities of the crude cyclization product. Acylation followed by demethylation of the other amino group provided the key diazatricyclodecane for their studies.
One curious bit is the chlorination reaction: The authors do not state how many equivalents of t-butylhypochlorite are used. This seems rather important, since primary amines are well-known to form dichloroamines. I’ve contacted to authors, so hopefully we’ll know soon whether they were dealing with the monochloroamine or the dichloroamine. [Update: Dr. McClure responded that 1.2 equivalents of t-BuOCl were used.]
The Pfizer compounds did not pan out, so we’ll never know if their process research wizards would be able to employ the HLF route in a scaleup setting, but I imagine it would be an uphill battle. If photochemistry is ruled out, I imagine the “acid and heat” HLF would have to be sorted out somehow.
Now it’s easy to see why a more modern CH functionalization reaction with a catalytic transition metal would be useful, right?
Toward a practical intramolecular CH functionalization reaction
This seems like an excellent strategy, and I look forward to seeing where this research will go. How about metal-free, light-free, halogen-free versions? There’s a worthy goal!
Finally, I’d be remiss if I didn’t mention the extensive work in the literature on intramolecular aminations using nitrenoids that are substituted by strong electron-withdrawing groups (DuBois, Sanford, Davies, White, Lebel, Panek, and others, leading reference here). It’s a bit different from what we’re talking about here, since the electron-withdrawing group ends up in the tether, making cyclic sulfamates, carbamates, and the like.
By the way, if you’re interested in this topic, you might also look at some nice recent work by Tom Driver at UIC, who is using aryl azides as the nitrogen source for metal-catalyzed intramolecular CH aminations. His paper is also a good entry to the literature of CH aminations in general.