B.R.S.M. Pain is temporary, publications are eternal


Two Reactions of Hydrazones

I thought I'd quickly share with you a couple of useful transformations involving hydrazones that I read about recently. The first one I found yesterday, reading George Majetich's perovskone full paper in Gilbert Stork's special issue of Tetrahedron. Although it's not the most atom economic thing ever, it struck me as quite a neat, if somewhat oldschool, way to transfer chirality. The second reaction is from Rawal's recent total synthesis of the weltwitindolinones, which I blogged about in detail here, and which I actually saw Rawal himself talk about on Tuesday at Bristol. The reason I've brought it up again is that when I wrote my last post commenter MadForIt asked about the mechanism of this transformation, which at the time I didn't know and didn't get round to looking up. By chance I found out the mechanism a few weeks later (completely by accident) but never got round to posting it up. Rawal's talk reminded me of this, but it didn't seem worth burying the answer in the archives so I thought I'd make a new post out of it here.

So, before I give you some possible answers, have a think about how you might do these and then read on for more information.

When the group first published a racemic version of this synthesis back in 2004 they used this modified Wolff-Kishner reaction where the intermediate hydrazone was reduced by the cyanoborohydride. Following loss of tolylsulfinic acid, the reaction proceeds via the intermediate diazene shown below that undergoes a 1,5-rearrangement to lose nitrogen.

But how can one modify this to give a single enantiomer? Although you could think about just doing an asymmetric reduction of the intermediate hydrazone, Myers and coworkers came up with a clever alternative back in 1996. The decided to use a well known and reliable method for the enantioselective reduction of ketones - the CBS reduction - as the source of asymmetry. From here, a Mitsunobo-type reaction with 2-nitrobenzensulfonylhydrazine (NBSH) allowed them access to enantioenriched versions of the same intermediates as those in the reaction above .[1] Clever.

I should probably mention that, due to the fairly mediocre yield, the group actually used an alternative method developed by Tsuji in the final route, involving palladium mediated allylic reduction of the corresponding carbonate.[2]


As for Rawal's chlorination, the conditions that were used are shown below. The hydrazone was formed regioselectively and then treated with several equivalents of NCS in pyridine to give the vinyl chloride in quite good yield, considering the complexity of the system and the nearby double bond.

It turns out that these chlorination conditions are actually pretty old, developed by Mori and coworkers in 1962 for the preparation of 17-chlorosteroids.[3] On further reference chasing, it appears that Mori just adapted some conditions by (Chemistry Nobel Laureate) Derek H. R. Barton, published earlier in the year, for the synthesis of vinyl iodides.[4] Barton originally developed this reaction as a milder variant of the Wolff-Kishner reaction, when he need a method to reduce an aldehyde all the way to a methyl group in a complex steroid molecule. He reasoned, by analogy with the reaction of diazomethane with iodine, which was known to give diiodomethane, that it should be possible to intercept the diazo intermediates in the Wolf-Kishner reaction by addition of iodine to give gem-diiodides. He then planned to reduce these to the alkanes under mild conditions such as zinc and acetic acid. After a bit of optimisation it was found that the reaction could be carried out by simply warming hydrazones with iodine in triethylamine-THF under comparatively mild conditions. Interestingly, in the absence of base, the corresponding dimeric azines were isolated instead, probably formed via a radical mechanism. The product obtained was also found to depend on the nature of the starting carbonyl - aldehydes gave the expected gem-diiodides, but ketones tended to give the the corresponding vinyl iodides as the major products.

In the case of the weltwitindolinones, under Mori's conditions, the reaction mechanism probably looks something like the scheme below:

So, in slightly roundabout way, here's the answer to your question!


Bonus Information

1. A more complete mechanism for the reaction probably looks something like this:

For more information, the original Myers paper is Tetrahedron Lett., 1996, 37, 4841 . Although the Mitsunobo reaction is a bit nasty, this modification is quite useful, and can also be used to reduce primary alcohols to the corresponding alkanes (see J. Am. Chem. Soc., 1996, 118, 4492, with PhD student Movassaghi). There are a few examples in Myers' handout on reductions.

2. See the Majetich paper for full details, or the corresponding PhD thesis, free online here.

3. The original paper (Chem. Pharm. Bull., 1962, 684) is available online for free, although it doesn't contain much mechanistic information.

4. Definitely more useful than the previous paper, Barton does discuss the mechanism in some detail (J. Chem. Soc., 1962, 470)

Comments (9) Trackbacks (0)
  1. The hydrazone-ene reaction was actually a cume question I had in grad school. Some old school chemistry is always useful, specially in total synthesis. Also, great blog post. Would love to see more chemistry posts like this one on the internet.

  2. Great post! I am a big fan of hydrazone chemistry, and it is nice to see it come back once in a while. There is one small mistake near the end of your article: the scheme in the first bonus information features an arrow that eliminates Ar instead of going towards the oxygen during the sulfinate elimination.

    • Thanks! What I drew was deliberate as I thought that aryl sulfinate anions tended to fragment quite easily to give SO2 and Ar-. People definitely write that for thiolate based removal of nosyl groups, although I suppose the arrows go the other way there (losing RSC6H4NO2, SO2 and RNH-). I suppose you can buy the sodium salt of phenylsulfinic acid so it probably isn’t that unstable. I shall change it.

      • This is the first time I’ve see it written like that. I have used arylsulfinates a number of time to prepare sulfones and never observed decomposition to give off SO2. In fact, even the unstable arylsulfinic acids decompose via a pathway that preserves the C-S bond. I agree that the SNAr removal of nosyl groups should lead to the loss of SO2, but the leaving group (RNH2) is much better than Ar-.

  3. In note 1 the N-H bond should be behind the 7-membered ring.
    There are 2 note 4s.
    Totally off topic, but I thought of something weird. If you remove a hydrogen atom from each of the carbons of 1,3-diazacyclobutane you get what would appear to be an aromatic diradical (6 pi electrons). Has anyone heard of such a thing?

    • Good spot for the bonds, I’ve redrawn the C-N bond with the correct stereochem, and removed the fragmentation I had before. Thanks for the corrections!

      Regarding your off-topic question, unless I’m misunderstanding you I don’t think that would be aromatic – in that system aren’t both nitrogens sp3 hybridised, meaning there’s no flat pi-system to be aromatic? Also, unless the aromatic stabilisation energy is very large I think that deprotonation of CH in the presence of NH would be difficult.

      • Pyrole is rather aromatic – same idea. (I didn’t mean that you’d make it by removing H atoms (not protons) from diazacyclobutane; that’s just to explain the structure.)

  4. Great post! BTW: Mitsunobu 😉

  5. What can i say, many thanks man!!
    Really good blog, and plenty of useful chemistry!

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