Wednesday, 10 July 2013

#chemclub Reviews: The Pummerer Reaction

This month’s review looks at the Pummerer rearrangement. I first met this reaction as an undergraduate and liked it for a few reasons: for one thing, it worked well! It has a simple mechanism that can lead to diverse behaviour and is always nice in group problem sessions. This brief discussion will cover the basic details of the reaction and a few interesting variants.

The Pummerer rearrangement was discovered in the early 20th century, although probably not by Rudolph Pummerer (a recurring theme with named reactions). Closely-related reactions were reported by Fromm & Achert and by Smythe before Pummerer’s first papers on the subject were published in 1909 and 1910, but it languished in obscurity until the 60s. It was only then that Pummerer’s name was attached to the reaction (for a nice discussion of the history of this chemistry see the review by Feldman). Pummerer's career included a great deal of sulfur chemistry but this class of reactions was not a great focus of his work; perhaps more important than his chemical legacy is his involvement in the relaunch of Angew. Chem. in 1947.

The classic Pummerer rearrangement involves acylation of a sulfoxide by an anhydride, followed by elimination to a thionium cation. This is then trapped by a nucleophile; in early reports this was often acetate from the anhydride, but in principle any nucleophile can be used. Activation by anhydrides remains common, but milder methods exist, such as direct oxidation of sulfides and the use of silyl chlorides.

The mechanism of the classic reaction isn't much more complicated than you might expect. Elimination of the carboxylate group proceeds via an intermediate ylide, which can either be acylated directly or go on to eliminate the carboxylate from sulfur. In the latter case, the nucleophile then simply adds at carbon. If the ylide is acylated directly there is the possibility of intramolecular delivery of the carboxylate from sulfur to oxygen.

This core mechanism leads to a great number of variations. In fact, there have been at least six reviews of Pummerer-type reactions since 2000. The most obvious modification is trapping of the thionium ion by useful nucleophiles, which as you might imagine has frequently been exploited to form C-C bonds. If anhydrides are used to activate the sulfoxide, the residual carboxylate can compete with the desired nucleophile; a number of tricks exist to get around this, such as using particularly non-nucleophilic anions such as triflate, or by quenching the anion with acid. Other variations naturally include vinylogous, asymmetric, and selenium-based reactions.

Some variants are particularly clever. For example, the Procter group in Manchester (my alma mater) use a connective Pummerer reaction in which the sulfoxide is bypassed entirely: the addition of a thiol to an aldehyde followed by elimination is used to generate the thionium ion. This allows for a great deal of versatility, and offers an attractive option for convergent syntheses. More recent work from this group (and others) uses a variation in which the Pummerer reaction is interrupted before the thionium ion can be generated. The activated sulfoxide is intercepted by a nucleophile, allowing for some quite interesting reactivity. In the most recent paper from the Procter group, for example, a triflic anhydride-activated aryl sulfoxide is intercepted by propargyl silane. The allene this produces is converted to an ylide by the addition of a nucleophile, possibly triflate, which then undergoes a thio-Claisen rearrangement. This sequence ultimately gives propargylation ortho to sulfur.

More elaborate cascade reactions involving Pummerer-type processes have been reported (and provide great fodder for problem sessions). For example, Padwa’s synthesis oferysotramidine uses a classic Pummerer reaction initiated by TFAA to kick-start a series of cyclisations, producing three rings and a quaternary centre in 83% yield. The thionium ion is trapped intramolecularly by the amide oxygen to form a furan, which undergoes an intramolecular [4+2] addition to the neighbouring alkene. Fragmentation and rearrangement then gives an iminium ion, which the aromatic ring adds to.

Feldman et al. used Pummerer-type reactions in the synthesis of palau’amine analogues. Here a Pummerer reaction initiates an oxidative bicyclisation sequence: activation of a sulfide bonded to an imidazole ring activates the ring to cyclisation by a neighbouring amide – effectively a vinylogous Pummerer reaction. In this case the activating agent is Stang’s reagent, but in earlier work on model systems the authors report using various methods such as H2O2/TFA, mCPBA, Tf2O, and others.

This quick overview draws heavily on reviews by Smith et al. and Feldman, both of which are engaging reads. I strongly recommend both if you want to get into the details of this chemistry for pleasure or profit... or simply for problem session fodder. For biographical information about Rudolph Pummerer, see this article by Oesper.


  1. Phil Magnus' work on strychnine alkaloids in which the indole traps the sulfenium ion deserves mention

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  3. Padwa loved giving problems based on his research, and the example above is the exact same one he gave in our synthesis course for the Pummerer reaction. Naturally, he also threw a lot of rhodium(II) problems at us :)