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7th July 2014 @ 12:55

UPDATE 24/7/14

After blogging my first proposal for the synthesis of a fluoroalkene (below), Mat Todd suggested this review (doi: 10.1021/cr200165q) might contain answers to a shorter synthetic route. This indeed was the case, and I have presented a quick revised synthetic route below.

 

Things to note:

  1. The paper for the first step is doi: 10.1021/jo962373h, the paper for the second step is doi: 10.1016/s0022-1139(99)00172-4.
  2. This paper (doi: 10.1016/S0040-4039(00)79700-0), suggests that Pd(PPh3)4 doesn’t work with heterocycles. The authors used Pd(dppb)Cl2 (dppb = diphenylphosphinebutane) instead which worked very well although the paper is brief and contains no procedures.
  3. I have not yet found a method for synthesising the heterocyclic boronic acid. An alternative could be to substitute it for the bromine on the alkene and couple it directly with the chloro group on the pyrazine or triazolopyrazine. UPDATE: Paper for this using pyridines is here 

    http://dx.doi.org/10.1016/j.tet.2003.10.020, which I would like to try on pyrizines. 

  4. This synthesis is not stereoselective like the previously proposed synthetic route. However, it would be interesting to test both E and Z isomers so this isn’t too much of a problem (assuming the isomers can be resolved).
  5. The fluoroalkene could potentially be coupled both before and after the formation of the triazolopyrazine core. I will attempt both.
  6. The fluoroalkene is one carbon shorter than in the previous synthesis. This matches up better with the amides and by changing the aldehyde used in the first step I can make fluoroalkenes with 3-carbon chains. 

 

7/7/14

As part of my coursework for honours I was required to give a short presentation on the Shapiro reaction. During my research I happened across this paper (DOI: 10.1021/ol401637n), which describes the synthesis of fluoroalkenes using the Shapiro reaction. It also mentions that they are isopolar and isoteric mimics of amides, often used in peptidomimetics.  Fluoroalkenes were first introduced as a possible replacement for amines in synthetic peptides in 1986 (DOI: 10.1016/s0040-4020(01)87627-4). Since then they have been well studied in peptides and suggested as an amide replacement in other pharmaceuticals (DOI: 10.1039/b701559c). They are thought to participate in hydrogen bonding (although weaker than an amide) and are dipolar similar to an amide, making it a close mimic.

This had me thinking about how to include them in my triazolopyrazines as amide replacements, not only as an interesting group to test for antimalarial activity, but also for some interesting chemistry to try for my honours project. A representative amide from Series 4 and the replacement fluoroalkene can be seen below, along with an ether from the series for comparison. 

Below is a proposed scheme for the synthesis of a fluoroalkene. This functionality could theoretically be introduced either before or after the triazolopyrazine is synthesised. I will try introducing it first, onto dichloropyrazine for simplicities sake. If this is successful I will also try to introduce it after the formation of the triazolopyrazine core, similar to the synthesis of the ether series.

 

Feedback on this synthetic route is most welcome. Suggestions for aldehydes that I could incorporate into step 4, and also into the triazolopyrazine core would also be very useful. A downside for our molecules is that the fluroalkene is more lipophilic than an amide, however this could be counteracted by introducing more hydrophilic aldehydes such as pyridine carboxaldehyde or even formylbenzonitrile as shown above.

Papers from Scheme:

1. doi: 10.1021/jo01103a013

2. doi: 10.1021/ja00252a029

3. doi: 10.1016/S0040-4020(01)00076-X

4/5. doi: 10.1021/ic400851w

6/7. doi: 10.1021/ol401637n

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