chemrox
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reduction of aryl halides using Cuprous ion & NaBH4
Selective reduction of aryl halides using Cuprous ion and NaBH4 (J. Org. Chem. 1989,54, 5308-5313). The substrate I want to apply the method to is a
heterocyclic amide HCl salt. My question is: would it be necessary to yield the amide as the free base before starting the reduction? I don't see why
but please explain if you find it necessary to convert the salt to the base before running he reduction. Thanks!
[Edited on 20-11-2015 by chemrox]
Attachment: Selective reduction of aryl halides and .alpha.,.beta.-unsaturated esters with sodium borohydride-cuprous chloride in me (1.5MB)
This file has been downloaded 595 times
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User123
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If you don't you will waste some borohydride. Whether or not you are prepared to waste some by reacting it with hydrogen chloride is up to you. It
rather depends upon the scale of the reaction, I suppose.
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CharlieA
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chemrox: I downloaded your attachment, but I can't open it up. Any suggestions?
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chemrox
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use you pdf reader.. it's a pdf
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AvBaeyer
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I'd be a bit suspicious of the yields reported as it appears nearly every reaction was followed only by some analytical method rather than isolated
product yields. (If I had been a reviewer on this paper I would have sent it back for more useful experimental detail and utility.) Also, note the
large excess of borohydride required which is partly due to the use of methanol as solvent. Sodium borohydride is very unstable in methanol.
Here is a suggestion. Release your compound from its HCl salt. Dissolve the free-base in THF, add about 2xtheory NaBH4 and the Cu2Cl2. Slowly add
methanol over a period of time, say 30 minutes. Dilute the methanol with THF if necessary. Follow the reaction by TLC to determine if you need more
borohydride or methanol. This protocol, sans Cu2Cl2, is an efficient way to reduce esters at the boiling point of THF. Heck, I might even try this
myself.
Have you checked Google Scholar to see how many times this paper has been cited?
AvB
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Dr.Bob
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For most borohydride reactions, HCl is contraindicated, so free basing before the reaction is best. You can add more NaBH4, but the nutralization of
the acid will create excess heat and side reactions will be more likely.
For cyanoborohydride type reductive aminations, it is more reasonable to use a salt, although acetates would be better.
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chemrox
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@AvBaeyer- thanks very much for the google scholar suggestion. If you have a moment the cmp I'm trying to reduce is soluble in DCM and methanol. Would
you please suggest an efficient protocol for knocking the HCl off? I was thinking of washing the solution with 6M NH4OH/water. I really don't want to
use a PTC if avoidable.
[Edited on 10-12-2015 by chemrox]
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AvBaeyer
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chemrox,
What is soluble in DCM or methanol - the free base or the HCl salt? If you are refering to the salt, what is the free base soluble in?
There are obviously many ways to release an amine from a salt. Inmy experience, one of the most efficient is to partition the salt between
concentrated K2CO3 solution (eg 50% saturated) and a suitable solvent like ether or DCM or whatever the free base is soluble in.
Could you provide more information about the heterocyclic compound that you want to operate on? The type of heterocycle could make the reduction more
complex or there may be a better alternative. For example, many halides attached to a heterocyclic ring can be efficiently removed with a catalytic
reduction. Alternatively, the heterocyclic ring may itself be subject to reduction under the conditions you want to use. Heterocylic chemistry is
interesting because of its "mysteries."
AvB
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chemrox
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New data. 6M NH4OH gets through the DCM barrier and the base is not soluble in DCM. Now I can dry it remove the DCM and collect it in MeOH for the
reduction. @Av: u2u me and I'll be more specific. However the amount I hope to yield is more than I want to work up in the Parr. The reduction can
also be done by hydrogenation at STP but still would require more Pd than I wanted to use. The Pd is recyclable of course but still I only have enough
for a few grams at a time. I want to process 25 g. So Cu/NaBH4 seemed the most economical approach. I am going to post the resulting optimized
procedure on another forum where there's a lot less chemistry and the members there will have to get their borohydrides on ebay. @Av: yes you're right
about the yields in the article; they are questionable. I'd much prefer weight percents based on starting material weights.
Av: I believe the procedure you suggested would have been better. A 50% carbonate solution would probably get through as well and would have the
advantage of showing the disconnection with evolution of CO2 and would leave a neutral aqueous layer over the DCM. The base would be completely or
nearly so insoluble in the upper layer. Good call. I'll try it next time around. I suspect that out of 25 g of salt I will only obtain 10-12 g of
base. Getting the rest would cost more in extraction materials than the stuff is worth. Flash chromatography would cost even more. Here again are the
parameters of scale so to speak that one has to consider.
[Edited on 12-12-2015 by chemrox]
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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