Tricky cross coupling

[democanarchis]

Hi all, having a bit of a headache trying to work out what cross coupling to use. This is the basic reaction scheme, with the main headache being the carboxylic ester.

 

Was originally planning a suzuki, heard that you could use base free conditions with KF if you had base labile groups eg the ester, but couldn't find a paper on it.
Kumada/Negeshi/Grignard would require me to protect the carbonyl, anyone know if there is some kind of way of "bulking up" the grignard?

So it looks like stille coupling is the only feasible route. Not familiar with stannane chemistry, can anyone see any potential issues with this molecule? Or if someone has a link to a base free/ester tolerant suzuki, it'd be a huge help, as obv would like to avoid tin compounds.

[stewie griffin]

The Stille's I've done have always worked well with just plain old tetrakis. The only real pain is getting rid of the tin byproducts when the reaction is complete, though there are a few tricks (wash with sat. KF solution, or do a hexane/acetonitrile extraction if your stuff isn't soluble in hexanes).
If you'd prefer to do a Suzuki, why not make the tert-butyl ester instead of the ethyl ester? Tert-butyl esters are much less sensitive to basic hydrolysis.

[democanarchis]

The Stille's I've done have always worked well with just plain old tetrakis. The only real pain is getting rid of the tin byproducts when the reaction is complete, though there are a few tricks (wash with sat. KF solution, or do a hexane/acetonitrile extraction if your stuff isn't soluble in hexanes).
If you'd prefer to do a Suzuki, why not make the tert-butyl ester instead of the ethyl ester? Tert-butyl esters are much less sensitive to basic hydrolysis.

The ethyl ester was installed via diethyl oxalate, the upper aryl is actually a pyrimidine ring with the ester at the C between the two N, thought i drew them in. Using a bulkier oxalate eg tBu doesn't work very well, however if its poor yield vs extending the synthesis, I might give it a shot. As the target molecule has an allyl ester at that position, I'm going to have to do a transesterification anyway. Anyone know if there is a "one pot" condition to do an esterification/transesterification simultaneously? That way if 50% of my product is hydrolysed to the carboxylic acid, it shouldn't matter.

[movies]

Are the Suzuki conditions really that problematic for esters?  I have seen examples with acetates & benzoates surviving the cross-coupling.  Is the bigger problem with just preparing the organoboron compound?

For the esterification you may want to look into Otera's catalyst.  I don't know for sure if it will do exactly what you want, but it works wonders in some cases.

[democanarchis]

Are the Suzuki conditions really that problematic for esters?  I have seen examples with acetates & benzoates surviving the cross-coupling.  Is the bigger problem with just preparing the organoboron compound?

For the esterification you may want to look into Otera's catalyst.  I don't know for sure if it will do exactly what you want, but it works wonders in some cases.

To be honest, I'm not sure. I have a really nice selective procedure for preparing the boronic acid http://pubs.acs.org/doi/abs/10.1021/jo025792p so that isn't an issue here. I had completely overlooked the base hydrolysis issue until just the other day. I dont know *how* labile the ester is, just that it is to an extent. I may just make up a solution of the suzuki base and leave a small amount of the compound stirring for however long the cross coupling should take and then estimate degradation. Even if there is some cleavage, if its less than product loss of an additional step it may be worth it.

[dunno260]

I would think you can find a condition you can do a suzuki without worrying about base hydrolysis of the ester.   I don't know of any examples of the top of my head.  Just looking at Kurti and Czako section on, 3 of the 4 highlighted uses of Suzuki coupling have esters in them (methy, acetate, and a large functionalized ester and all used basic conditions (one using potassium carbonate and the other two cesium carbonate and two of the three were heated.  I have only run a couple of suzuki couplings and we used 9:1 DME/H20 with sodium bicarbonate as the base and ran it at 40C overnight with decent yields.

I have run a number of Stille couplings, though only with commercial tin reagents.  They tended to work pretty well and I removed the tin byproducts on a column by just liberally flushing with hexanes.  I don't believe the tin reagents are any trickier to prepare than the suzuki reagents.

I think you can get the suzuki to work.  For the use of KF see http://pubs.acs.org.libdata.lib.ua.edu/doi/pdf/10.1021/ja992130h as one paper I found using google scholar (its becoming one of my favorite quick literature search methods).

[408]

Microwave assisted Yamomoto coupling!  Ni(COD)2, bipy in dry DMF and toluene.
I have done it with two bromo cpds, the chloro may affect kinetics favoring dimerization of individual components.  Only one way to find out though. 
Can you prepare the bromo instead of the chloro ester?

[democanarchis]

dunno260, I had a look at the Kurti book (Awesome book btw, will definately get a copy), and the methyl ester coupling seems to survive 80C with K2CO3. Now whether the molecule will couple under those conditions is another story

408, I found a procedure for iodinating the chloro position selectively, so it should be easier to brominate it, and as it looks like i'll probably have to do that for the suzuki anyway, I'll definately give that yamamoto coupling a look. My only concern would be dimerisation, but if i could couple without having to make a boronic acid/stannane that would be ideal so definately worth investigating.  

[g-bones]

you should check out the work of Paul Knochel at the Ludwig-Maximilians-universitat.  He has done a lot of work with coupling reactions in the presence of sensitive groups, including esters.  his work focuses on the use of main group metals and some transition metals in the presence of LiCl and he reports good yields for palladium coupling reactions.  hope this helps

http://www.knochel.cup.uni-muenchen.de/index.php

[democanarchis]

you should check out the work of Paul Knochel at the Ludwig-Maximilians-universitat.  He has done a lot of work with coupling reactions in the presence of sensitive groups, including esters.  his work focuses on the use of main group metals and some transition metals in the presence of LiCl and he reports good yields for palladium coupling reactions.  hope this helps

http://www.knochel.cup.uni-muenchen.de/index.php

Heh, I'm planning to use a procedure by knochel for this actually now funnily enough. Basically instead of brominating the lower aryl, i'm planning to do a directed magnesiation, then a transmetallation to zinc then do a negishi, if it works it'll cut out a lot of steps.

[g-bones]

awesome! let us know how it works!