Week 10 Mega Chemist Challenge Solution

We had a few entries this week, all of which were correct.  The man in question was Armido Studer who is currently a Full Professor of Organic Chemistry at the Westfälische Wilhelms-Universität Münster.  As many of you know I will soon be working at the Westfälische Wilhelms-Universität Münster in the group of Professor Glorius, so hopefully I will get the chance to meet Professor Studer in person.

After Studer completed his undergraduate and postgraduate studies under the supervision of Prof. D. Seebach at ETH Zurich, he completed only a single year as a post-doc (with Prof. Dennis Curran) before beginning his independent research career. Very impressive. After his post-doc Studer returned to ETH Zurich to complete his habilitation (1996-2000), and then via the Philipps-Universität Marburg, became a full professor in Münster in 2004. Studer has won numerous awards throughout his career including the Solvias Ligand Contest and the Novartis Young Investigator Award in 2006.

Angewandte, as regular followers of this blog, agreed to interview Studer just in time for his feature in the Mega Chemist Challenge (this may be stretching the truth somewhat/completely), and you can find this here:  Armido Studer.

Studer’s research interests are of course varied, and his five top papers at the bottom of his interview linked above demonstrate this. The one that hit the top of my reading list is The Persistent Radical Effect in Organic Synthesis.

Studer made this weeks Mega Chemist Challenge as I wanted to learn a bit about the oxidative Heck reaction, and this paper synthesising tetrasubstituted olefins using consecutive oxidative Heck reactions hit the ASAP at just the right time. DOI: 10.1002/anie.201108211.

The traditional Heck reaction is prolific in organic chemistry, and is used to couple olefins (alkenes) with halides, or pseudo halides (triflates, tosylates and diazo compounds) using palladium catalysis. A typical mechanistic cycle starting with Pd(0) proceeds through oxidative addition of the organohalide/pseudo halide, insertion of the the olefin, syn beta-hydride elimination to generate the coupled product, and reductive elimination of the catalyst to regenerate the active catalytic Pd species (scheme 1). You can find a nice-ish picture here (it is too late for me to draw one). In contrast, the oxidative Heck reaction (or arylation) uses an external oxidant to regenerate the active palladium (0) species.

In Studer’s paper he reports the challenging synthesis of tetra-substituted olefins through iterative oxidative Heck coupling reactions. As many of you will expect, Studer utilises his favourite oxidant TEMPO 1 (scheme 1) to regenerate the active catalyst. Reactions are undertaken primarily in environmentally benign low molecular weight carboxylic acids as solvents, and proceed at ambient temperature.

Starting with methyl acrylate, selective formation of trans-olefins proceeds rapidly in 2 h and in very good yield (scheme 1, A). The second coupling reaction is where the real challenge begins as selectivity and steric congestion begin to play there part. Best results were achieved using Pd(OAc)2 and HO-TEMPO in propionic acid, and complete regioselectivity was observed (scheme 1, B). Following this success, stilbene derived substrates were investigated, though slightly modified conditions were reported [1]. All reactions proceeded, though yields (35-99%) and selectivity (E/Z, 9:1-99:1) varied immensely depending on a number of steric and electronic considerations.

With tri-substituted olefins in the bag it was time for the big one – the introduction of a third aryl group. The geminal bis-aryl  acrylates proved to be too electron poor to undergo reaction, so reduction to the allyl alcohol was undertaken. Initial results gave looked good in the regard that tetra-substituted olefins were synthesised, but rather poor E/Z selectivities (2.3-9:1) were observed (scheme 3). Studer proposed that reduced nitroxides were chelating the Pd metal and influencing the stereochemical outcome of the beta-elimination step, and thus tried more sterically hindered nitroxides. x proved to be the winning oxidant, though it was also shown that O2 could do the job. 14 tetra-substituted olefins were synthesised using either O2 or x with ranging yields and selectivity, though considering the challenge of synthesising such tough targets, this is more that acceptable.

When I started reading this paper I was a little stuck as to why people first investigated oxidative Heck reactions beyond an academic interest. Avoiding aryl-halides is all well and good, but replacing them with boronic acids didn’t really seem to be a gain to me.  There are a lot more commercial arylhalides, and they are generally a lot easier to make and handle than the boronic acid analogues. Also, the need for stoichiometric oxidants is something modern organic chemists typically work to avoid, so the using them here does not seem like a natural step forward, but more of a regression. This paper though has demonstrated the power of oxidative Heck reaction in generating very challenging substrates, and that these reactions proceed under mild conditions and use (mostly) environmentally benign solvents is excellent. What really sold me on this paper in the end though was the last big hurrah – the use of O2 as the oxidant. Although Studer is a big fan of nitroxides, the fact you could leave them out altogether removing so much of the waste from the reaction was a brilliant end to a challenging endeavour.

 [1] TEMPO instead of HO-TEMPO and a mixture of tBuCO2H/THF (5:1) – presumably to facilitate solubility of reactants – were utilised.


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