Tag Archive | palladium

Conditions-based regiocontrol in metal-catalyzed arylations of heteroaromatic C-H bonds

This is a follow-up to a previous post on the regioselectivity of C-H arylation reactions of heteroaromatic compounds.  

The direct C-H functionalization of aromatic compounds (including heterocycles) via transition metal catalysis has emerged as a powerful alternative to electrophilic (or nucleophilic) aromatic substitution and transition metal-catalyzed cross coupling reactions.  If you’re looking for an overview, Jie Jack Li has edited an excellent book on the general subject of C-H bond functionalization entitled C-H Bond Activation in Organic Synthesis. Heterocyclist readers are directed to Chapter 10 by Donna A. A. Wilton for a treatment of C-H activation in heteroaromatic compounds.

In a previous post, we considered the regioselectivity of C-H arylation reactions of heteroaromatic compounds, focusing on substrate-based regiocontrol, i.e., factors in the heteroaromatic compound that influence the site of C-H functionalization.

In this post, we consider emerging examples of conditions-based regiocontrol, i.e., modifying the reaction conditions, including the catalyst itself, to direct the regioselectivity of heteroaromatic C-H arylation reactions.  While there is little in the way of a satisfying mechanistic rationale for these results, it’s a promising synthetic approach. For entry into the relevant literature on this strategy, take a look at Engle and Yu’s JOC Perspective and Neufeldt and Sanford’s review in Accounts.

First up is an early report of conditions-based regiocontrol by Lapointe, Fagnou, and coworkers.  Conditions for selecting electron-rich (indole) or electron-poor (pyridine N-oxide) sites were explored using chemistry from various labs:

Conditions-based control

Next up, in very recent work by Bedford, Durrant, and Montgomery (U Bristol and Vertex), regiocontrol in the palladium-catalyzed arylation of pyrazolo[1,5-a]pyrimidine was achieved by tuning the catalyst.  The presence of a phosphine ligand directed arylation to C-7, the most acidic C-H as determined by NaOD exchange. In contrast, phosphine-free conditions favored arylation at C-3, the most electron-rich carbon as determined by calculations.  The two processes are believed to involve different mechanisms, though the details are not yet known.  The SPhos ligand system was homogeneous. Deuterium labeling studies showed that coordination to palladium was followed by a slower deprotonation that was still not the rate-determining step.  The phosphine-free system was heterogeneous and proceeded with a protracted induction period via two discrete catalytically-active species.



Bedford 2

Finally, consider the promising work of Yu and co-workers on the arylation of pyridines.  Six-membered-ring heteroaromatics are still relatively rare substrates for C-H functionalization because of the basic nitrogen, which tends to bind to the metal.  Most examples rely on making the N-oxide to circumvent this problem (e.g., the Fagnou example above), but Yu has been able to arylate simple pyridines by adding 1,10-phenanthroline, which competes well for the palladium, allowing the pyridine substrate to enter into the activation cycle.


Further advances in the understanding of substrate-control of regioselectivity combined with efforts at conditions-based control will surely elevate C-H functionalization to a new level of predictability and utility.

Update: Hong, et al. (KAIST), have recently published a nice paper on catalyst-controlled divergent C4/C8 regioselective C-H acylation of isoquinolones. Aryliodoinium salts were used as the aryl donors. C4 selectivity was achieved via an electrophilic palladation pathway; C-8 arylation was performed using an Ir(III) catalyst.

Pd(II)-Catalyzed Dehydrogenative Cyclizations of N-Allylimines

Near-simultaneous reports of an interesting new pyrrole (and dihydropyrrole) synthesis have appeared recently from the labs of Frank Glorius (Westfälische Wilhelms-Universität Münster) and Naohiko Yoshikai (Nanyang Technologial University, Singapore).  Optimization of the additives, solvent, and temperature led to essentially the same conditions from each laboratory.  A balloon of oxygen is preferred: yields are much lower when air is used.  A Heck-type mechanism is shown, but a Wacker-type mechanism involving nucleophilic attack of an enamine onto a Pd-complexed alkene could not be ruled out.


The scope of the reaction is decent, as indicated below.  Failures include R3 = CF3 or cyclopropyl and R2 = Ph.  N-Homoallylic and N-cinnamyl imines were also unsuccessful.


Specific examples are shown below:


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.]

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!