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


(–)-N-Methylwelwitindolinone C Isothiocyanate

Update: 13/09/11. I have reworded the introduction considerably as the original version of this paragraph described work by Rawal and coworkers in this area unfairly. Having reread the papers and what I'd written I couldn't leave things as they were. The original text can be found in [5] at the end of the article.

Sorry things have been so quiet around here lately - moving out of the flat I've lived in for the past three years, having no internet and applying for conferences have made blogging tricky. I was a bit worried that someone'd beat me to this as it's such a nice bit of work, and Tot. Syn. did on Sunday, but I'd mostly finished this by then, so here's my take anyway.

Total Synthesis of (–)-N-Methylwelwitindolinone C Isothiocyanate

Garg et al., J. Am. Chem. Soc., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ja206538k

There's been a lot of interest in these unusual looking natural products in the past decade with publications from Wood, Trost, Baran, Simpkins, Martin and Rawal all appearing in the literature. Credit for the first total synthesis of a member of this family goes to Rawal and coworkers, who reported a neat route to racemic N-methylwelwitindolinone D isonitrile back in March of this year, unfortunately before I'd started this blog.[1,2] This paper by Garg describes the first synthesis of N-methylwelwitindolinone C isothiocyanate to date, using a chiral pool based approach from (S)-carvone, and also contains lots of interesting chemistry.

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I’m sure glad I don’t use thiophosgene anymore

I doubt many people have used thiophosgene. Especially not as much as I have. For those that haven't experienced its penetrating odour and beautiful red colour, on balance I wouldn't recommend it. I used to use it for the second step in an (as yet unfinished) total synthesis of a natural product, to make an arylisothiocyanate, which meant using lots of it. I starting to bring more material through the route a few weeks ago and, performing the same step on 50 grams, was glad that I'd changed to using thiocarbonyl diimidazole (TCDI) the last time I had to do this. It's a pretty, bright yellow solid and far less malodorous; you can even weight it on a bench top balance (in the evenings and at weekends). It costs a bit more and isn't as reactive (my reaction takes 24 hours refluxing 1,2-DCE as opposed to a few hours at room temperature with thiophosgene), but on the upside it's not a war gas. TCDI is to thiophosgene what the ever popular carbonyl diimidazole (CDI) is to phosgene (also a war gas, but slightly better smelling).

So why bring this up? Well, today I needed to dry some carbon disulfide,[1] so I dug out the trusty lab copy of Amarego and Chai (or as most call it, and note the definite article here, 'The purifications book'). After finding the information I needed (distill it from CaH2 - who'd've guessed?) I glanced at the opposite page (always do this - you can learn a lot) and noticed that the entry for carbon tetrachloride listed the major impurity as CS2. That's a bit odd, right? I mean, they're quite different compounds. One's good for dry cleaning and global warming and the other's good mostly for eroding the inside of your face.[2]

Well, it turns out that back in the day a lot of carbon tetrachloride was produced from the reaction between CS2 and chlorine gas, via thiophosgene and trichloromethanesulfenyl chloride. In fact if you ever wanted to fall out badly with your coworkers you could even make your own thiophosgene from good old CS2 by stopping the reaction part way, and reducing down the CSCl4 intermediate with a bit of tin or sodium sulfide. You're having a bad day with Na2S is the least hazardous component in your reaction mixture. There's even an organic syntheses proceedure for the tin reduction, which somewhat redundantly points out 'the vapors formed in the experiment are very objectionable'. Don't do it. They don't pay you enough.

For a review on things you can do with thiophosgene,[3] see S. Sharma, Synthesis, 1978, 803 - 820.

[1] To quote from my supervisor's textbook on practical organic chemistry 'the use of this solvent should be avoided at all costs'. I share a lab with an inorganic group into nanotubes and fullerenes, and a postdoc of theirs used to run all his columns in carbon disulfide, claiming nothing else worked. They literally got though litres of it each day.

[2] According to the Merck index, pure carbon disulfide has a pleasant odour redolent of diethyl ether. A shame that you can't buy it pure enough to ever experience this. Even the stuff I distilled stinks. Apparently the culprits are OCS and thiols, which can be removed by washing with aq KMnO4 solution, followed by mercury. Or not.

[3] There are a few gems in here. For example, were you ever curious as to what happens when you mix thiophosgene with sodium azide and quench with dimethylamine? Me neither, but apparently 'the preparation is generally accompanied by violent detonations'.

Filed under: Lab, Serious | 29,797 views | 7 comments 6 Comments