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.
The aminomethylation of arenes and electron-rich aromatic heterocycles typically involves iminium ion chemistry, i.e., Mannich-type reactions. But when the heterocycle is electron-poor, what then? Recent work offers an attractive approach involving nucleophilic α-amino radicals.
David Mitchell and co-workers at Lilly recently published the scaleup of LY2784544, a JAK2 inhibitor. Their paper is chock-full of interesting chemistry and is highly recommended for a read, but let’s look at just one slice: the installation of the morpholinomethyl group using a radical addition reaction.
In a first-generation approach, the intermediate shown below was subjected to Minisci’s method for radical alkylation. Phthalimide-protected glycine was used as a source of pthalimidomethyl radicals. Around 3.5 kg of the CH substitution product was obtained, but the route was abandoned due to reproducibility problems, relatively low regioselectivity, insoluble by-products, and the need for large amounts of silver nitrate.
In a second-generation route, iminium ion chemistry was explored, but none of the desired material was formed. In their survey of iminium ion techniques, however, the Lilly group found one outlier: Hwang and Uang’s method using N-methylmorpholine-N-oxide and VO(acac)2. In the Uang work, electron-rich arenes such as phenols and naphthols were aminomethylated; there were no examples of electron-deficient heterocycles. Nonetheless, after some optimization, the Lilly group was able use the Uang method to produce the desired aminomethylated material shown above in good yield on a 44 kg scale.
Mechanistically, Mitchell and co-workers believe the Uang chemistry is substrate-dependent. For electrophilic substrates such as the current imidazopyridazine, the reaction proceeds by a radical mechanism involving the addition of a relatively nucleophilic α-amino radical to the pyridazine ring. With electron-rich systems such as those found in Uang’s work, an iminium ion mechanism is probably operational. Further mechanistic work is underway.
For those of you in drug discovery, do you think it would be interesting to carrying out such radical aminomethylations on existing drugs or related compounds? I’m reminded of the recent bevy of direct trifluoromethylation reactions by Baran, MacMillan, and Qing, featured at C&EN and In The Pipeline. Yes, aminomethyl groups and trifluoromethyl groups serve greatly different ends, but direct introduction of the former at rather unreactive sites would seem to be a nice option.