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!

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One response to “Heterocycles via alkyl-Heck-type reactions”

  1. Patrick Stoy (GlaxoSmithKline R&D) says :

    That’s a neat cyclization — “Pd as radical initiator”. I wonder why the CO atm is necessary? Is it to deactivate the palladium toward oxidative insertion, and thus avoid beta-elimination side products? I wonder if a “solid CO equivalent” like Mn(CO)6 can be used instead if one wants to avoid messing around with a CO lecture bottle….

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