B.R.S.M. When all you have is a hammer everything looks like a nail


Eaton’s other reagents

On Friday, I found myself discussing the use of Eaton's reagent with a coworker. Many people know it as a handy alternative to polyphosphoric acid (PPA) for acylations, Friedel-Crafts reactions and the like. It's even endorsed by Milkshake. A simple 7.7 wt% solution of phosphorus pentoxide in methanesulfonic acid, it's not as viscid, viscous or  unpleasant to work up as PPA.[1] And it's commercially available. But neither my coworker, nor many other people I know, are aware of Eaton's other contributions to the synthetic world. He's still an emeritus professor at the University of Chicago, and you can read about his interests on his website, but what he's most famous for, unbeknownst to many younger chemists, is his synthesis of the cubanes.

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(+)-Loline Alkaloids

2330 - update: Just noticed the Tot. Syn. writeup. Check it out for an alternative discussion! Funny that this work's two weeks old, yet we both write about it today!

An Efficient Synthesis of (+)-Loline Alkaloids

D. Trauner et al., Nature Chemistry, 2011, 3, 543 [PDF][SI][GROUP]

DOI: 10.1038/nchem.1072

I just noticed this very efficient enantioselective synthesis of a trio of the loline pyrrolizidine alkaloids reported by Trauner and coworkers back in June. Although loline has been known for more than a century, prior to this work only one enantioselective synthesis had been reported, and at 20 steps in length - that's well over two synthetic operations per carbon atom - it's as good an example as any to illustrate the point that size isn't always what makes a target challenging. Trauner, with characteristic German efficiency, took only 9 steps to reach loline through clever use of some simple and largely well established chemistry. Reading this paper reminds me of one of the most important axioms for designing anything (syntheses, websites, software, machinery...): that a thing should only be as complicated as it needs to be - and no more.

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Named Reactions: The Hugershoff Reaction

Now over a hundred years old,[1] the venerable Hugershoff reaction is a great way to convert aryl thioureas to 2-aminobenzothiazoles.[2] Classically, an aryl thiourea in chloroform is treated with an equivalent of bromine at around room temperature then the product is just filtered off. The first step is believed to be bromination on sulfur, followed by electrophilic aromatic substition in the usual manner. Yields are generally good (in my experience), but it's important to get the electronics of the ring right - some activation is usually required, but if it's too electron rich then bromination on the aromatic ring can compete with bromination of the thiourea.

There's actually very little information on the reaction available through casual googling - it has no wikipedia page and I don't believe it's even been reviewed.[3] You're not limited to elemental bromine, with NBS and other halogenating reagents reported to work. A similar transformation (via a different mechanism) can be accomplished by treating aryl thioureas with iodine(III) reagents, or even DDQ.

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