We have a project in my group on bitopic ligands targeting the adrenergic receptors. We recently published a perspective paper on the topic that you can check out here. Anyway, today we had a project meeting regarding the synthesis of bitopic salbutamol analogues.
To this end, one of the guys wanted to synthesise an epoxide as outlined above. However, to his (and everyone else surprise) even under mild conditions he managed to loose both of his benzylic alcohols in the process. The crude product is of excellent purity and he isolated the over-reduced phenol in >90% yield.
This is a common problem but it really is trial and error. I would say that the case above is the most extreme example I have seen considering that it was run at atmospheric pressure and room temperature. It brought memories back from when I was a PhD student. The very last reaction I did in the lab was an attempt to reduce an alkene, however, as you can probably guess what I got out as the major product was the deoxygentaed molecule. However, this reaction was somewhat more messy than that above and the desired molecule may have been hiding in the mixture as well. D!
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Please explain... why would one start with hydrogenation conditions? That would be the at the bottom of my list of conditions to try first.
Yes I agree. I also would not have considered these conditions at first. In fact our attempt at the reaction was a NaBH4 reduction in MeOH. However, this gave a complex mixture so we tried the hydrogenation procedure that was described for a similar substrate in a Synthesis paper: A Short Synthesis of Albuterol, Babad et al., Synthesis, 1988, 966-968. D!
Interesting, thanks. It always seems like some of the simplest reactions on the simplest substrates give the strangest results.
This happens with acid present in the system. The alpha-chloroketone is a tricky substrate because obviously the reaction product is prone to losing HCl and off you go...
I believe the HCl generated by hydrogenolytic cleavage was responsible for the activation of primary benzylic hydroxyl as well.
Once I was dealing with reduction of chloroacetone with NaBH4 to the corresponding chlorohydrine. The best conditions were to suspend chloroacetone in water and slowly add borohydride to it until the initial exotherm subsided.
You might as well add a phosphate buffer to maintain the pH at neutral although it increases the rate of NaBH4 decomposition.
Then convert the chlorohydrin to epoxide under basic conditions but here I do not have any procedure that I tried.
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