The Mannich Reaction revisited

The Mannich Reaction (Carl Ulrich Franz Mannich, 1877-1947) is yet another one of those reactions that look brilliant on paper. However, I have on many occasions heard chemists attempting the reaction moan a fair bit to say the least. The major problem seems to be that the reaction is sluggish requiring heating/reflux to get anywhere and that the reagents (and desired product) start polymerising. You can find Mannich's original paper here: Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, p. 647. There is a detailed entry in Wikipedia on the reaction for those not familiar with it. A good alternative to the classic Mannich conditions is to use Eschenmoser's salt which I've seen used successfully in a number of total syntheses. Anyway, recently a PhD student in my lab was bitching about his Mannich Reaction. He left the lab, did some reading and came back with this nice JOC Note by A. Erkkila and P. M. Pihko, DOI: 10.1021/jo052529q. When he started using this stuff all his problems were solved. Fortunately, he sorted all this out right before I had to do my first Mannich Reaction. It also worked as a charm for me so I warmly recommend this simple, and efficient Mannich protocol.

Now Erkkila and Pihko are quite concerned about reaction times because they are thinking of industry applications. However, for the average chemist that does a lot of work overnight (whilst at home in bed) it isn't essential that it's done in 1 hour. We found that if you do these reactions overnight no heating is required and the products are of very high purity. Very clean reactions indeed. Here's four examples from the paper:

As it turns out the chemistry works really well for most systems using catalyst 1. However, some aldehydes require catalyst 2 to give a good result, eg. entries 3 and 4. The only compounds tested in this paper that failed completely were aldehydes that exist predominantly in a hemiacetal form, eg. 5-hydroxy-valeraldehyde. So there you have it. Maybe something you should consider giving a go next time it's alpha-methylenation time. D!

Chemistry Blogs

I've received some emails from people wanting me to link to their blogs and web sites and also had some people ask me why I don't provide links to certain chemistry blogs. The blogs on the lists are the ones I like and visit regularly. I have decided not to link to blogs were there is to much bitching and slander going on, in particular if the blogger is anonymous. And then there's obviously all the stuff that I still haven't had the time to check out. I've just added two new blogs this weekend that I would recommend. Organometallic Current is a great blog with detailed paper reviews and lots of mechanistic stuff. If you like your Palladium you should check it out. Also A Synthetic Environment is an excellent blog. This blog is looking at some more historic and equipment related topics which are quite entertaining. Check, check, cccheck it out man.... D!

Revenge of the NMR tube

Well I guess it had to happen to someone sooner or later. It appears that I applied slightly too much pressure when I was sticking the lid on my NMR tube the other night. As a result the tube snapped and proceeded to go straight through my glove and into my finger. Now that's obviously annoying but can be fixed with band aid. However, when the tube had finally embedded itself in my finger it decided to snap for the second time. In other words I had a piece of NMR tube thoroughly buried in my finger. This is not the sort shit you want to happen to you at 11 pm on a Monday. Trying to fish the glass out myself only resulted in pain and blood everywhere so off to the hospital. Fortunately, the hospital is only a short walk from the Chemistry Department. After waiting for an hour amongst screaming people on various drugs and/or totally shit faced with blood coming out of various openings I was attended by a very nice Doctor. She told me straight away that X-ray was no good for glass so she would have to dig around for the glass bits. At this point I would like to say thank you to whoever it was that came up with anesthetics. Anyway, after some serious digging and cutting a big chunk of NMR tube was extracted. This is what my finger looked like at 1.30 am when I was finally out of the Emergency room.
No my fingers weren't really blue. I have no idea why it keeps uploading the picture like this but it looks kind off cool and scientific. Anyway, it really wasn't particularly dramatic and if it wasn't for the glass I would never have gone to the Emergency Room. I have always heard that impaling yourself with an NMR tube is a particularly common accident amongst chemists. Nevertheless, I'm the first casualty that I know off. Does anyone else know of similar incidents? Finally, I have to say that there wasn't really anything I could have done to prevent this from happening. I used a brand new tube and applied a minimum amount of pressure when putting the lid on........just got unlucky I guess. And by the way what are people thinking off getting drunk and on drugs on a Monday. Save it for the weekend people. D!

Tethered aminohydroxylations Donohoe stylie

Back in 2002 I started on a project where we considered using the Sharpless asymmetric aminohydroxylation (AA) as a key step. However, the anticipation of major regioselectivity issues and the success we experienced using the Sharpless asymmetric dihydroxylation meant we abandoned this approach entirely. However, I clearly remember sitting at my desk drawing a tethered version of the AA reaction where the amine was attached to an allylic alcohol as a carbamate. I'm sure that hundreds of other guys where drawing similar stuff and scratching their heads, however, Timothy Donohoe, from Oxford University decided to put the pencil down and get some students to get on with it. I completely missed the first paper that came out in 2001 in Chem. Commun. (DOI: 10.1039/b107253f) and only picked up on what they were doing when they published a paper on their TA work in JACS in 2002 (DOI: 10.1021/ja0276117). Ever since I have been following the Donohoe groups progress closely. The reason that I'm posting this now is because they finally nailed the reaction down in a recent Org. Lett. paper (DOI:10.1021/ol070430v). Anyway, let's get down to business. Firstly, it's important to realise that the TA reaction isn't asymmetric. It is however, a stereospecific, stereo-, regio- and chemoselective process. In other words if you start with optically active substrates you are laughing. Here's the condensed version of the story so far:

(1) Donohoe et al., Chem Comm, 2001, pp 2078-2079 (DOI: 10.1039/b107253f)
TA of acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 41 to 61%. Here's a really nice example with a diene:

(2) Donohoe et al., JACS, 2002, pp 12934-12935 (DOI: 10.1021/ja0276117)
TA of cyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 50 to 83%. Works for 6,7 and 8-membered rings but only 5-membered rings with exocyclic double bonds undergo aminohydroxylation. Here's another nice example making a protected amino-sugar:

(3) Donohoe et al., Org. Lett., 2004, pp 2583-2585 (DOI: 10.1021/ol049136i)
TA of chiral acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 57 to 74% with excellent syn-selectivity. Some very impressive examples of TA reactions in this paper, for example:

(4) Donohoe et al., JACS, 2006, pp 2514-2515 (DOI: 10.1021/ja057389g)

Finally, they manage to get rid of hypochlorite and NaOH by attaching a mesitylsulfonyl substituent to the carbamate nitrogen. As a consequence catalyst loading can go down to 1%, yields have improved (69-83%) and homo-allylic carbamates have become viable systems. Check this homo-allylic TA out:Nice stuff innit and it gets better.

(5) Donohoe et al., Org. Lett., 2007, pp. 1725-1728 (DOI: : 10.1021/ol070430v)

And finally the climax. This is the final, and very recent paper, from the Oxford lab. Previously some of the TAs just didn't work (with the mesitylsulfonyl N-substituent) for no apparent reason. So they screen a bunch of different N-leaving groups and discover that things take off big time when pentafluorobenzoyl is attached to the carbamate. Catalyst loading is now permanently down to 1 mol%, yields are up (71-98%) also for difficult homo-allylic substrates, and it works for both cyclic and acyclic systems. Here's a nice homo-allyic example:

So it took about 6 years to develop this methodology to the point where I believe it will start finding wide spread use in synthesis. I'm itching to try one of these for myself and I'm desperately looking for an excuse. If anyone has tried running some of these Donohoe TAs I would very much like to hear any comments - is it really as good as it looks on paper? D!

Monkeys

Yes, yes, yes I know Curly Arrow hasn't exactly been a hive of activity lately. Trust me it isn't because I spend my evenings sipping red wine and watching the sun set. There's a post in the making on tethered amino-hydroxylations so come back tomorrow and check it out. Until then have a look at this most interesting Monkey Distribution Map.

You'll notice that neither Europe nor North America has any monkeys. Where I used to work we saw many similarities between PhD students and monkeys (except monkeys have better lives). However, this is clearly not reflected on this map. Anyway, serious stuff tomorrow. D!