I am trying to plan a reaction in which I incorporate a sulfonamide in the last step of the reaction. I need the conditions to be mild and the yields to be good. I found a paper by Mayer et al. in which the reaction conditions I want may be used:

Sulfonamide/aniline, KOt-Bu, NMP, allylchloro{1,3-bis(2,6-di-propylphenyl)imidazol-2- yilidine]
palladium(II) (IPr•HCl•Pd), Pd(dppf)Cl2•CHCl2,

What I see as a problem is the imidazol Pd(II) salt that is used. Is actually the first time I see it and they use it in 20% amounts along with Pd(dppf)Cl2•CHCl2 and I have a hard time understanding why. I have to find something more general or an explanation for this...

On the other hand, there are many other methods to go. Wang et al recently (2012) published a paper were mild reaction conditions were used. This method is very similar to an older paper by Wei et al (2005) in which they use an aminoacid as a ligand stabilizing the copper reagent.

Of course, the group of Buchwald et al. have Pd-methods that can be used, and in an earlier paper, they stress the importance of using a bulky P-ligand for the reaction to work (here are some examples with amides, and one example with sulfonamide working with chlorides).


An update. Tried out all these reactions, but the one that worked best was an old protocol using Pd(OAc)2 and the ligand Xantphos and Cs2CO3 (s) as the base in THF:Toluene (1:1) at 120 °C. Got almost 80 % product after a very easy purification procedure.

Synthesis of Cyanthiwigin U

Cyanthiwigin U is a challenging molecule to synthesize, and is the topic of tomorrow's synthesis seminar. Cyanthiwigin U is a diterpenoid which is isolated from both fungal and marine sources. It contains a cyclohepta[e]indene ring system, and has no less than 5 stereocenters, a real synthetic challenge.

In this paper, Phillips and Pfeiffer shows a very beautiful approach to synthesize Cyanthiwigin U. It all begins with the synthesis of an endo-acrylisoborneol. The authors used a synthetic strategy presented by Palomo et al. Lithiated methoxyallene is reacted with (1R)-(+)-camphor (1) using THF as solvent at -30 °C and TMEDA as metal ligand. The intermediate (2) is then hydrolyzed in 1M HCl, yielding the desired enones (3, 4 or 5 in the scheme 1 below).

Scheme 1. Taken from Palomo's publication

Through

In  Phillips and Pfeiffer's paper, the endo-acrylisoborneol is then reacted with alkene 6 via a metathesis using Grubb's catalyst (7). The product is a substrate (8) which is next used as a Diels-Alder precursor.

Conditions: (1) 5 mol % Grubbs catalyst (7), 93%

The precursor 8 was then reacted with 1,4-dimethylcyclohexadiene in acidic media (2 equiv TfOH) at -78 °C provided the Diels-Alder product (9, a bicyclo[2.2.2]octene).

Conditions: (2) 1,4-dimethylcyclohexadiene, TfOH (2 equiv), -78 °C, 70%

The cyclization between 8 and 1,4-dimethylcyclohexadiene occurs through a Diels-Alder cyclization. 

Reacting product 9 with CAN (Cerium Ammonium Nitrate), removes the borneol group through a radical reaction. This procedure is also described by Palomo et al. in an earlier publication.

Conditions: (3) CAN, aqueous MeCN, 82%.

The carboxylic acid and pivalic ester are thereafter reduced to the alcohols using LiAlH4. The product is then  subjected to a Swern oxidation to yield the corresponding aldehydes.

Conditions: (4) a) LiAlH4, THF, reflux, 16h, 99%. b) (COCl)2, DMSO, Et3N, 84% 

The dialdehyde 11 is trated with vinylmagnesium bromide. The formed alcohols were re-oxidized
using Dess-Martin periodinane, providing the bis-enone 12. The bis-enone 12 was then exposed to Grubb's catalyst 7, under an atmosphere of ethylene, providing 13.

Conditions: (5) a) Vinylmagnesium bromide, CeCl3. b) Dess-Martin Periodinane. (6) 20 mol% 7, ethylene, Toluene

So, I did not quite get it at the beginning what was going on between 12 and 13, but I tried to make a drawing to understand it better. Here it is:

So the Grubbs catalyst open up the ring's alkene, and from there, it could either make the 7-membered ring first and then the 5-membered ring right after. It could also be the other way around. The important thing is that the alkene in the ring is opened first.

And it is very late right now so I will pause here and continue tomorrow or when I have some more time to write.

Peace & Luv

BJJ, Monday 20101008

Today Åke went through two techniques that can be used when your opponent is turtling.

The first one, an important detail: when you are putting your foot underneath his armpit, make sure your heel is underneath or tightly pushed to your opponent's chin. This will allow the lock-down to be easily set-up.

 The second one is a bit different and in my opinion somewhat easier to execute than the first one (the first one feels a bit riskier, especially when the foot is going underneath the armpit).

We also warmed up with some take-down techniques, but I did not captured them on film ://. I am planning to go on Wednesday again if nothing unplanned happens at home :))

Peace and luv

Photoshoot on a beautiful autumnday

Yesterday Sunday  I went with Julia and Miranda to Botaniska trädgården in Uppsala. It was a very beautiful  day perfect for photography, so we decided to take some pictures. What I most like about the autumn are the colorfulness of the leafs. They are still a little bit too green but we managed to find some spots  where they went from green to yellow and red. Here are some of the picts:

Miranda is quite good at taking pictures. I gave her my very very old camera. A Minolta Z1, which was one of the first digital cameras I ever had. She loves to experiment with it

And here is Julia in front of the "Orangeriet" 

Miranda, of course, wanted to have some pictures of her own. The tree which Julia is standing in front of was had really fantastic colors. I do not think I really nailed it on that picture though ://; its still a good one... 

 And last, both playing with the leafs...

Well, that is it for today... now I have to write about the BJJ training :). Tomorrow, I'll try to write about a very interesting synthesis. Peace and luv...

BJJ Training Sunday 20101007

Today, Kristofer substituted Henke as instructor and the warm up was quite tuff... so, after an exhausting warm-up, we practiced some techniques from the guard (two). The first one is aimed to take control of your opponent's upper-body and set-up triangles or omoplatas. I guess it is possible to set-up sweeps whit a little bit more of practice from this position. Well, here it comes:

The second technique was a sweep from guard. I use it a lot after failing an armbar, but it is also very good as a technique of its own.

Well, planning to go tomorrow to practice some more. Will put those techniques here as well :)

BJJ Training, 20121003

Today Nils went through some De la Riva techniques. The language, as usual is Swedish.

The first video below just shows a set-up for De la Riva guard:

Next, this is one sweep from De la Riva guard. It is quite important to really hold the foot to make the sweep work properly, but please correct me if I am wrong...

And last, another "sweep" you can use from De la Riva to take your opponents back. I could not make it work but I know there people there who makes it work pretty well. 

Hell... I am tired. Enough for today.

Chemistry Problem Set #1

At work, every Wednesday we have a problem set to solve. I will try to solve them and write down the solution here (I will loose my papers if I write them down on a paper-block, here I can always go back and look).

So, the target molecule for this week is (1)

(1)

It did not look like something difficult, especially if you think about the parent scaffold (2)

(2)

So, I started to think how to make the parent scaffold (2) and then go back to the target. So, retro-synthetically I was thinking that you would need to have 2-(aminomethyl)aniline and react it with some kind of carbonyl with good leaving groups (like L1-CO-L2). Some brainstorming and google search gives me CDI (carbonyldimidazole)

Anyway. They usually are not happy with one-step answers, but want you to go further back. So, how to make the 2-(aminomethyl)aniline? Well. I guess you could do something like having a bromide where the aminomethylgroup is (i.e. having a bromomethyl instead of amino, and yea, the aniline should be a nitro group which can be reduced with iron dust). Well, they say one image says more than 1000 words and it is very truth in chemistry. This is the route I would choose:

a) AIBN, NBS in CHCl3. b) NH3 in... something aprotic. Maybe neat NH3 (?). c) Reduce the NO2, Fe-dust in ethanol and NH4Cl is quite normal to use here. Or  Zn(Hg) in HCl

Well, I guess there are other routes. I found this papers (here and here) in which other routes are conducted (and the molecule looks a bit different).

Do not have much more time now so I will have to do the rest later :).

And here is the rest of the exercise. So, the target molecule can be synthesized in a different way. Here is a short retrosynthetic analysis

And the mechanism for this is a one-pot reaction (click on the image to see it clearly), but you can also isolate the imidine and then react it with the nitromethane

One thing I was wondering for my self... why does the methoxi do not attack the imidine carbon? I have to check the paper and see what they say about it (do not have the paper with me at the moment)

BJJ training

So, today's BJJ was quite fun. A lot of people are coming to practice and it seems like Hilti Uppsala is growing :).

We did some techniques from butterfly guard. Got only two of them on video. The first one is a armlock/armbar from butterfly.

The one we did looks like this:

And here is another variant I found on youtube (I guess you can find as many different variants as there are grain of sand in the sea):

Last technique was a triangle from butterfly. I would personally never go for this one as a first option, but I think is good to know.

Hell, I am to tired to write anything about these techniques but I just want to go back and remember the details in a near future. Time for me to sleep, have to work tomorrow :))