Unstablypersistent
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Mild alkylation via excess AgNO3 and alkyl halide
Hello everyone,
I need some feedback for a reaction I want to try for a side project. I'm working with a cyclopentadiene pentaester anion as a catalyst platform and
have been alkylating the ring by forming the silver salt of the cyclopentadienide, then adding a bit of excess alkyl halide. This has been working
well and getting me yields in the 20-60% range depending on the alkyl halide. For my project, I'm convinced that a more withdrawn cyclopentadiene
system will be highly beneficial and may even give access to more difficult substrates. My PI doesn't think its worth putting the synthesis time into
but I can't let it go until I at least try.
Now here's the rub: while making the more withdrawn catalyst as an alkali metal salt is easy enough, I can't use the standard method of converting it
to the silver salt. Typically I make the potassium salt of the cyclopentadienide pentamethyl ester, then protonate it with HCl. Mix the resulting acid
with some silver oxide or carbonate and it directly forms the silver salt that is easily dried. The more withdrawn salts are only partially protonated
at best, and decompose at worst. So I'm wondering if I can simply forgo swapping out the sodium or potassium with silver by simply adding two
equivalents of AgNO3 before adding the alkyl halide.
Typical reaction conditions are dissolving the cyclopentadienide silver salt in anhydrous acetonitrile, then adding in 1.5 equivalents of a phenethyl
chloride or bromide, letting stir for ~30-60 mins or until precipitation has stopped, filtering, rotovapping, and running a column. My modification is
just using the cyclopentadienide sodium salt and adding 2 equivalents of AgNO3, then adding in 1.5 equivalents of the phenethyl halide. I can't see
any reason why this shouldn't still result in alkylation and I am planning on doing some test reactions of the pentamethyl ester beforehand. My main
concern is figuring out if the nitrate is going to lead to any side reactivity. Can't find anything that indicates the nitrate would capture the
carbocation, but my substrate anion is pretty stable. While I doubt I'd somehow form a phenethyl nitrate ester, confirmation would be appreciated. I
also don't trust any of the old bottles of silver sulfate or triflate we have lying around the lab and acetate would have separation difficulty so
nitrate it is. I've also already considered just making a concentrated AgNO3 solution and doing a biphasic cation exchange, but due to similar
solubilities I'd definitely end up with a lot of silver nitrate mixed with my substrate anyways.
Any input from those with experience using silver salt - alkyl halide metathesis for alkylation will be appreciated. I am intimately familiar with the
literature surrounding the synthesis and reactivity of the cyclopentadienide pentaester already.
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Dr.Bob
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That sounds like an interesting way to alkylate a tough substrate. I am not real familiar with that part of the chemistry, but am familiar with
phenethyl halides, and they are a challenge, as they easily dehydrohalogenate to form styrene, so you often need a large excess of them. Another
possible alternative it to use the mesylate instead of the chloride or bromide. Not sure why, but these form easily from the alcohol, MsCl, and TEA,
and seem to not eliminate as much. Sometimes adding a trace of KI will also help swap the halogen for I if the reaction is sluggish. Good luck.
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Unstablypersistent
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Quote: Originally posted by Dr.Bob  | | That sounds like an interesting way to alkylate a tough substrate. I am not real familiar with that part of the chemistry, but am familiar with
phenethyl halides, and they are a challenge, as they easily dehydrohalogenate to form styrene, so you often need a large excess of them. Another
possible alternative it to use the mesylate instead of the chloride or bromide. Not sure why, but these form easily from the alcohol, MsCl, and TEA,
and seem to not eliminate as much. Sometimes adding a trace of KI will also help swap the halogen for I if the reaction is sluggish. Good luck.
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I haven't looked at phenethyl mesylates at all, thank you for the suggestion. I've definitely had some issues with trying to make electron rich
phenethyl chlorides that don't just fall apart. Does the mesylate abstract on its own with some gentle heating, or just a better leaving group for
SN2? I'm trying to form a quarternary carbon on the cyclopentadiene ring connected to the benzylic carbon, and the substrate is a terrible
nucleophile.
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