B.R.S.M. To strive, to seek, to find and not to give a yield

2Jul/1212

A New Coupling Agent, And Sandmeyer’s Other Reaction

I wrote this post a couple of weeks back, but wasn't happy with how rambling it was. Anyway, it's only getting more out of date, so I'm putting it up now. Someone might learn something.

 

I’ve always had a soft spot for hypervalent iodine reagents, especially iodine(III). In fact, they were the cornerstone of a methodology project that I worked on last year. You can imagine, then, that the rather usual looking iodosobenzene derivative above, which was published in Org. Lett. a couple of weeks back (DOI: 10.1021/ol301085v), immediately caught my eye. Such compounds tend to be very useful oxidants, and you can check out a few recent applications on the relevant organic-chemistry.com page. Surprisingly, though, this wonderful new reagent wasn’t being touted as an oxidant (although I’m sure it is)… apparently, it’s a great new coupling agent!

You’ll have to read the paper for the specifics, but needless to say good results were obtained for couplings between acids and alcohols, and even the rather more oxidisable amines and acids. Racemisation was low, conditions were mild, and in fact, if your substrate wasn’t too redox active, you might even consider trying out this wonderful sounding reagent. But that’s where things get a little tricky. Of course, you can’t simply just buy this particular magic powder from Aldrich yet, so you’ll have to make it yourself. If you know a little iodine chemistry, you won’t be surprised to hear that you can just make it from the corresponding iodoisophthalic acid by oxidation, and this step has been reported using bleach. Easy. Except you can’t buy the iodide (at least not from any of the common suppliers in the UK). I’m sure you can outsource production of it, but no-one’s going to do that to just to add another line to a table of conditions tried. Better put that iodide into Scifinder!

Perhaps not too surprisingly, it’s made from the corresponding aniline by the very useful Sandmeyer reaction. The aniline itself, though, is still not commercial, although there are a couple of options available for its synthesis. The most recently reported is by the oxidation of acetyl protected toluidine with permanganate, but although that’s a reaction that sometimes doesn’t give total crap, as with many journals whose titles are 60% vowels, I sadly don’t have access to Gaodeng Huexiao Huaxue Xuebao to see what the procedure is. The other option to get the required aniline is via the oxidation of the isatin shown below. Fortunately, it turns out that this actually is commercially available, although for the princely sum of almost £200/10 g. So, unfortunately anyone in the UK wanted to try this new reagent has quite a bit of work to do! At least it’s recyclable.

One thing I did learn from chasing down these references was a new named reaction, the Sandmeyer isatin synthesis.[1] I’d never really given much thought to where isatins actually come from, so let’s quickly look at how you might make the commercial isatin if you had to. Turns out it’s as easy as heating methyl anthranilate with some chloral hydrate and hydroxylamine in sulphuric acid, followed by hydrolysis.

On the downside, the reaction does require chloral hydrate, but on the upside, it’s a good excuse to own chloral hydrate.[2] Not an easy reaction to draw a mechanism for!

 

Etc.

1. Traugott Sandmeyer did particularly well to get two important reactions named after himself, considering he didn’t even have a degree in Chemistry.

2. Interestingly, although chloral hydrate is a controlled substance in the US and Canada, it isn’t in the UK.

 

Comments (12) Trackbacks (0)
  1. I wonder if there could be a simple route from very cheap (~$20/100 g) 2,6-dimethylaniline – although I’m guessing two permanganate oxidations might be problematic.

    • I did wonder about that. Obviously, if the first one works then you get to the same substrate that was reported above, so the second one ought to as well. I am a little skeptical as I’ve always found it to be an awful reaction, but it would be cheap to try!

  2. I _love_ hypervalent iodines! My personal favorite is the sulfonic acid variation, from this JACS paper. This is good stuff…:

    http://dx.doi.org/10.1021/ja807110n

  3. A more modern/more elegant route would be to start with a diester or diamide of isophthalic acid and do ortho lithiation with LDA + iodine quench

  4. It might be more convenient to do the Sandmeyer reaction before the permanganate oxidation. I’ve done xylene-to-isophthalic acid oxidations before, they work quite nicely in aqueous t-BuOH. They do have a tendency to erupt if you run them in pyridine.

  5. Sandmeyer sucks on scale IMHO. If I REALLY wanted to make several grams of 2-iodoisophthalic acid, I would take dirt cheap 1,3-dicyanobenzene, ortho-lithiate with LDA (or LiTMP) — good lit precedence — and use elemental iodine as the electrophile. Then double nitrile hydrolysis, acidic or basic, to give desired in two simple steps. Cheap and fast.

  6. JACS Select (pubs.acs.org/JACSbeta/jvi/issue15.html) has a series of articles on cross-coupling reactions available free.

  7. Dr Freddy:

    We did a lot of large scale Sandmeyer syntheses and there were two tricks we came to find that were key for good yields:

    The first step to make involves heating the reagents at reflux for about 2 minutes. The key to getting it right on large scale is to get it to reflux as soon as possible. If you have a large flask and cold oil bath/heatng mantle it takes too long to heat up. So you need to get your oil bath smoking first and get the flask hot asap. We never tried getting it boiling and then adding some combination of reagents whilst hot. I have not studied chemical engineering but there may be something nasty around the corner if you get an exotherm whilst at reflux so don’t try this at home kids…

    Secondly at the end of the cyclisation step you need to add the mix to ice-water and allow to precipitate. We found in many cases that you needed to leave this for 24hs or more to get decent yields – we were working with isatins derived from toluidines so quite small, but presumably more fatty isatins would precipitate quicker. Filter too quickky and yields are poor.

    Advantages to the Sandmeyer are the reagents are dirt cheap, don’t use air / moisture sensitive reagents and water as solvent.

  8. I guess that journal should be Gaodeng Xuexiao Huaxue Xuebao since it means Chemical Journal for Chinese Universities or something like that. But contents from such journals are not that trustworthy.

  9. When faced with finding a greener oxidant, hypervalent iodine compounds are always one of the first things I look at. So often they can replace lead compounds which is a boon.


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