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.]
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 cyclize
s 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!
- Check out the International Society of Heterocyclic Chemistry’s New Website
- Regioselective synthesis of 3- and 5-aminopyrazoles
- Conditions-based regiocontrol in metal-catalyzed arylations of heteroaromatic C-H bonds
- “Glass Microbiology” sculptures are beautiful
- Pd(II)-Catalyzed Dehydrogenative Cyclizations of N-Allylimines
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