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Topic: one-pot transformation of an alkene to bromomethylketone  (Read 859 times)

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Offline Babcock_Hall

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one-pot transformation of an alkene to bromomethylketone
« on: May 16, 2022, 08:30:19 PM »
Chandra A et al., Tetrahedron 73 (2017) 5827e5832. http://dx.doi.org/10.1016/j.tet.2017.08.019
I worked out a route to a synthetic intermediate, a protected amino acid bearing a bromomethylketone (I can use it to make a couple of potential inhibitors).  My first route required the use of reagents that are too toxic for my circumstances, and I am researching alternatives before starting.  One possibility is to convert a commercially available alkene into a bromomethylketone.  I found a one-pot method that employs, OxoneR, NBS, and modified IBX.  The method uses "in situ-generated 3,4,5,6-tetramethyl-2-iodoxybenzoic acid."  This method tolerates methyl esters.

My preferred protecting groups are BOC and tertiary-butyl ester on the nitrogen and carboxylic acid respectively.  To use this transformation, I suspect would have to buffer the OxoneR or find a different protecting scheme.  An alternative is to form a bromohydrin from the alkene, then find a suitable oxidant in the subsequent step.  Thoughts?

Offline rolnor

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Re: one-pot transformation of an alkene to bromomethylketone
« Reply #1 on: May 17, 2022, 01:46:55 AM »
Dissolve a little oxone in water and check the pH. I dont know how acidic it is but some peroxo-acids are weak acids, much weaker than its parent acid.

Offline Babcock_Hall

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Re: one-pot transformation of an alkene to bromomethylketone
« Reply #2 on: June 04, 2022, 01:03:56 PM »
https://doi.org/10.1021/ol990140h
This paper gives the pH of Oxone as 2.8, but I am not sure whether it was measured in water or 50% aqueous methanol.  I'll try measuring it myself next week.  The paper itself shows that primary TBDMS ethers are labile to Oxone, but TBDPS ethers are not.

Offline rolnor

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Re: one-pot transformation of an alkene to bromomethylketone
« Reply #3 on: June 04, 2022, 04:53:53 PM »
Its a close call, 2.8 is not really acidic but TBDMS can be very labile. It probably is a matter of if time untill it is cleaved. TBDPS is much more stable.

Offline Babcock_Hall

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Re: one-pot transformation of an alkene to bromomethylketone
« Reply #4 on: June 06, 2022, 08:39:10 AM »
"On the other hand, the TBDMS ethers of the secondary and tertiary alcholos were unaffected by treatment with Oxone. When the reaction was carried out in the absence of oxidant with 1% dilute HCl and HF adjusted to the same pH as the Oxone (pH 2.8), the cleavage of TBDMS group had not occurred after 2.5-3 h."

It sounds as if the Oxone, rather than the pH itself, is responsible for the cleavage.  I am a little surprised that the degree of substitution on the alcohol has as much effect as it does.  TBDPS ethers are much less labile, according to the authors of the 1999 paper.

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