Tag Archive | radical

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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Practical radical aminomethylation of electron-deficient heterocycles

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.

Heterocycles via alkyl-Heck-type reactions

How do you make saturated heterocycles via construction of the 3,4-C-C bond?

Erik Alexanian and co-workers at UNC have just published a nice report on the use of alkyl iodides in intramolecular Heck-type reactions, producing oxygen and nitrogen heterocycles by such a bond construction.  This is a significant result for several reasons, so let’s take a look.

A bit of background on this bond construction

You have a few basic choices as indicated in the electronic disconnection shown below, where ionic and radical chemistry are considered.

While there are examples of each, this general disconnection is usually not a first choice.  β-hetero anions are prone to β-elimination; β-hetero cations may cyclize onto the heteroatom, and β-hetero radicals… well, they involve radical chemistry.  Though having said that, β-hetero radicals are some of the best radical cyclizations out there, adding to tethered alkenes at rates higher than the benchmark 5-hexenyl radical.

The most powerful way to make this bond involves organometallic chemistry, generally involving two unsaturated sites (Heck chemistry, ring-closing metathesis, eneyne chemistry).  But what if we want one partner to be an sp3 carbon?  Specifically, what if we want to do a transition-metal-catalyzed reaction where a metal resides on the sp3 carbon?

Enter the Heck reaction

The classic Heck reaction comes to mind (hey, Nobel Prize and all), but primary organopalladium species tend to β-eliminate before they can cyclize (if there is a suitably-disposed β-hydrogen).

In 2007, Firmansjah and Fu reported intramolecular alkyl-Heck-type reactions in carbocyclic systems by tinkering with the palladium catalyst, finding that the rate of cyclization could beat out β-hydride elimination.  However, the reaction appears to be limited to primary halides and terminal alkenes.

The current work

Now, Alexanian and co-workers have shown that the alkyl-Heck reaction can be accomplished with good old tetrakis(triphenylphosphine)palladium.  Below you can see the use of a primary iodide with a tethered alkene, producing hexahydroindoles in good yield.  A variety of alkene types are tolerated. Note the use of 10 atm carbon monoxide; more on that later.

In contrast to Fu’s work, which was believed to involve a two-electron oxidative addition of the palladium(0) into the C-halogen bond, Alexanian has evidence that the UNC chemistry proceeds via one-electron chemistry.  Hence, single-electron transfer (SET) from the Pd(0) to the alkyl halide results in C-I bond cleavage to produce a β-hetero radical, which cyclizes and captures Pd(I)-iodide to give the organopalladium intermediate shown.  Normal β-hydride elimination, the last part of a classic Heck cyclization, then ensues.

It’s interesting to note that carbon monoxide is required for primary halides to work.  But secondary halides don’t need it, as shown below. [Edit – Second structure revised to correct missing oxygen.]

This is some promising work for sure, providing a nice alternative to known methods involving more classical radical conditions.  Let’s hope the Alexanian group will be able to tune the reaction a bit to make it as practical as possible; it would really fill a niche.

Happy holidays, everyone!