Saturated nitrogen heterocycles by intramolecular CH amination reactions

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 basic CH amination reaction

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.

Pfizer diazatricyclodecanes

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.

Initial HLF route

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.

Final HLF route

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

In recent work, Chen (Penn State) and Daugulis (U. Houston) and their coworkers have independently described palladium-catalyzed picolinamide-directed intramolecular CH amination reactions:

Chen + Daugulis insertions

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!

[Edit: More Chen goodness covered by See Arr Oh at Just Like Cooking: Remote alkylation directed by PA groups.]

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.

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7 responses to “Saturated nitrogen heterocycles by intramolecular CH amination reactions”

  1. DrFreddy says :

    Nice challenge! Much to be won if a general method is found.

    I once attempted something similar, treating an exocyclic primary amine (sitting on a ring with several other nitrogens) with NBS in hope for C-H activation magic to occur.

    The pure and isolated product, however, came to give me a serious headache. It was not the desired compound, but it had survived a silica column. Curiously, Both MS and H-NMR (also compared with the predicted spectrum using a state-of-the-art software) were consistent with a N-Br species. Is that even possible – a bench stable =NBr?

    According to LCMS taken couple of months later, no change in purity, mass or retention time.

    Man, I dunno….

    • Will says :

      Interesting. I wonder what the deal is with primary amines and X(+) sources? For doing aminyl radical chemistry (HLF, alkene additions), I thought the lore was to stick with secondary amines, since primary amines can make N,N-dihaloamines that aren’t well-behaved. The Pfizer paper and maybe your work seem to point in a different direction. I imagine it comes down to “it depends.” On the structure, for example. Perhaps you can chime in with more on your particular compound.

      • DrFreddy says :

        Not to mention TRI-haloamines! Ammonium hydroxide with elemental iodine…. unpleasant memories.

        I wish nitrogen was as well-behaved as sulfur. I like umpolung reactions! Thiols give sulfenyl chlorides nicely upon treatment with SO2Cl2, and add to arenes or double bonds in predictable and useful ways, often in good isolated yields.

        Oxygen (alcohols), another bastard element, almost never do what you want it to, i.e. addition of the corresponding hypochlorite to an activated arene or double bond. I wish that someone comes up with a solution for that one too!

        Oh, and regarding the details of the aforementioned chemistry. I could tell you, but… I think my NDA expires in 2021 or so – remind me to hit you back then!

  2. milkshake says :

    these diaza adamantanes could be useful for making TEMPO analogs used as catalysts for alcohol oxidation with bleach. I remember the mono aza adamantane derived nitroxide radica was more useful than TEMPO for some substrates but the reagent was hard to make. So using diaza analog could be a good solution. Aminohomotropanes are easily accesible from glutardialdehyde by Robinson tropanone synthesis followed by reductive amination

    • Will says :

      Agreed! Now we just need a robust synthesis of the diazaadamantanes. Regarding the Robinson chemistry, the Pfizer group tried it to no avail. They got the bridged bicycle snapped together as you suggest, but could not install the second amine using an intramolecular reductive amination.

  3. Sir Derek Barton says :

    maybe I`m an ignorant chemist….but….it seems that a simple reductive amination wit a ketone in the apical position would be straightforward…..anyway the tretiary amine won`t interferes…….no problem if I´m wrong

  4. Anonymous says :

    Just FYI, your first link is the same as your second link.

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