Tag Archive | CH functionalization

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.

Advertisements

On the regioselectivity of metal-catalyzed functionalizations of heteroaromatic C-H bonds

The direct functionalization of aromatic heterocycles at ring C-H bonds via transition metal-catalyzed processes has become a powerful alternative to electrophilic aromatic substitution.  Arylation, benzylation, alkenylation, and amination of aromatic heterocycles are possible, largely via palladium or copper catalysis.  There are hundreds of papers describing the functionalization of both five- and six-membered ring heteroaromatics, but here’s the rub:  How can one predict the regioselectivity of these reactions?  A recent paper by Daniel Ess and co-workers at BYU (Organic Letters) moves us closer to that goal.

Let’s say you’re in the drug discovery business and would like to snap a bunch of different arenes onto a core structure.  Where will they go?  Regioselectivity is often high (c.f. the example from Lapointe, Fagnou, and co-workers below), but how can we rationalize and predict the regioselectivity, especially in cases where there is no directing group present?

Ess and co-workers summarized the work that has been done so far on rationalizing the regioselectivity of these reactions.  I would also suggest looking at the Lapointe/Fagnou paper cited above, which focuses on the same issue.  C-H bond acidity, carbon center nucleophilicity, steric and stereoelectronic effects, activation-strain analysis, etc., have all been posited.  If you have the software, know-how, and patience to calculate the geometries and energies of all of the relevant transition states, go for it.  In that vein, I’ve shown an exemplary transition state from Ess’s (that’s a lot of esses!) paper below, which features the widely accepted six-membered ring CMD (concerted metalation-deprotonation) mechanism.  Shown is the transition state for the reaction of pyrazine-N-oxide with PhPd(PMe3)OAc.

But who wants to calculate transition states?  Well, Ess has uncovered an attractive shortcut:  He and his co-workers, upon noting that the CMD step is inherently endothermic and thus has a late transition state, postulated that all you really need to know are the relative thermodynamic stabilities of the palladium aryl intermediates.  After all, in a late transition state, the C-Pd bond is well along the way to being formed, so a higher C-Pd bond strength should be correspond to a lower TS energy.  Indeed, after adjusting for some hydrogen bonding effects in certain substrates, they found that the regioselectivity of fourteen out of fourteen examples were correctly rationalized by estimating the thermodynamic stability of the palladium aryl intermediates, a much easier task than TS calculation.

Ess and co-workers also proposed another way to get at this problem:

…the strongest C-H bond (in the substrate) will be preferentially activated since it will lead to the most stable Pd-C bond.  Indeed, for arenes and heteroarenes 1 – 14 the strongest C-H bond generally has the lowest activation energy.

Now the task becomes a “comprehensive thermodynamic analysis of palladium aryl bonding,” which “will be the subject of a future detailed study.”  Add in an understanding of C-H bond strength in heteroaromatics and these reactions will be even more attractive.

A final note.  Focusing on the substrate alone is only part of the picture.  In the Lapointe/Fagnou work, conditions-based site-selectivity was also found to be important:

 

 

[EDIT: A follow-up to this post was published July 7, 2015, focusing on conditions-based regioselectivity.]