Sciencemadness Discussion Board

Substituted Benzoic acid to primary 2ndry tertiary Benzylamine?

glen - 18-5-2023 at 17:48

I’m trying to figure out a way to a 1st,2nd,3rd benzylamine from benzoic acids or benzoyl chlorides. The obvious method and most common being benzoic acid to benzoyl chloride/halide then amidate it with the desired amine then reduce the ketone with LAH or red-Al or a silane combination, which I don’t have. I was thinking ( if applicable) a similar route as that from phenylacetic acid to the amine or is that not applicable in a benzylamine? I can chlorinate it and amidate it but the issue is the removal of the ketone. I imagine NaBH would reduce it to the alcohol but is there a way outside of LAH or Red Al (silanes) that is feasible. I saw in the search engines alternative to LAH Gallium aluminium amalgam was suggested in IprOH though probably useable in ETOH I’d assume. If that’s possible could gallium aluminium amalgam be used with nitromethane to N methylate the benzylamine while reducing the amide?
Others suggested LiBH or maybe Lithium Na BH? Would this work on benzamides?
The other suggestion was Ni NaBH? Would this reduce benzamides?
I have basically most common reagents but lack LiAlH or red Al, Nobel catalyst. I could alloy Raney Ni but I lack H2 in significant quantities,
I was also wondering about Mg gallium amalgam. Mg has a large reduction potential obviously.
Any suggestions of reagents or pathways would be appreciated.

Lionel Spanner - 19-5-2023 at 01:59

You can decarbonylate acids and amides with sodium borohydride and iodine, forming borane as a transient intermediate. The attached paper (DOI 10.1021/jo00020a052) has the details.
Interestingly, unlike the normal usage of borane, the wording of the paper suggests it doesn't require air-free techniques.

[Edited on 19-5-2023 by Lionel Spanner]

Attachment: borohydride-iodine reduction of carboxylic acids.pdf (207kB)
This file has been downloaded 180 times

glen - 19-5-2023 at 20:31

Interesting! Thanks! Though I did think borane as a reagent requires inert gas.

Lionel Spanner - 20-5-2023 at 03:41

Quote: Originally posted by glen  
Interesting! Thanks! Though I did think borane as a reagent requires inert gas.

Normally it does, but in this case I would guess it's only present as an active species in traces for very short periods of time.

Loptr - 20-5-2023 at 07:06

I don't think you can call a reduction of a carboxylic acid to an alcohol a decarbonylation reaction, there is usually an expectation of CO production. You won't be losing a C in that reduction.

Lionel Spanner - 20-5-2023 at 10:22

Quote: Originally posted by Loptr  
I don't think you can call a reduction of a carboxylic acid to an alcohol a decarbonylation reaction, there is usually an expectation of CO production. You won't be losing a C in that reduction.

That's true, but you are losing a carbonyl group. It was just lazy wording on my part.

glen - 20-5-2023 at 18:57

I checked the paper you provided, does it in practice apply to benzamides? I didn’t see any mention in the paper of such. If it does apply to benzamides is this primary, secondary and tertiary or are you aware of it only applying in particular cases?
Or were you suggesting to go from a benzoic acid to alcohol via the cited reduction and then benzyl alcohol to a benzyl chloride/halide, then aminate the chloride/halide? If so, I know working with the benzyl chloride and bromide would not be pleasant but would at least would form extremely easily, I found benzyl bromide and iodide to actually be less problematic as it didn’t seem as volatile but then I was working in a fairly cold outbuilding in NY in winter so maybe it wasn’t volatilizing as much.
It would be fairly doable if so, but I’d definitely prefer to avoid the THF mainly due to cost but also other issues. Any idea if Ethyl Acetate would be a viable THF alternative in this reaction?. Would it just depend on solubility of the substrate?

SplendidAcylation - 21-5-2023 at 04:57

Out of curiosity, what are you planning?

I think there are easier routes to benzylamines, especially primary ones! :P

Lionel Spanner - 21-5-2023 at 09:33

Quote: Originally posted by glen  
I checked the paper you provided, does it in practice apply to benzamides? I didn’t see any mention in the paper of such. If it does apply to benzamides is this primary, secondary and tertiary or are you aware of it only applying in particular cases?
Or were you suggesting to go from a benzoic acid to alcohol via the cited reduction and then benzyl alcohol to a benzyl chloride/halide, then aminate the chloride/halide? If so, I know working with the benzyl chloride and bromide would not be pleasant but would at least would form extremely easily, I found benzyl bromide and iodide to actually be less problematic as it didn’t seem as volatile but then I was working in a fairly cold outbuilding in NY in winter so maybe it wasn’t volatilizing as much.
It would be fairly doable if so, but I’d definitely prefer to avoid the THF mainly due to cost but also other issues. Any idea if Ethyl Acetate would be a viable THF alternative in this reaction?. Would it just depend on solubility of the substrate?

Given that borane reduces amides to amines, I should think this method would do the same. I've not actually tried it myself.
Borane forms a coordination complex with ethers, which helps to stabilise it in solution. If you don't have THF, the best substitute would be another ether.

glen - 21-5-2023 at 19:00

Yes I realized what I was suggesting with the ethyl acetate shortly after posting. Apparently it seems THF has gone down drastically in price and up in availability…. Seems if you look enough you can get a lot of previously unobtainable lab supplies. Sort of shocking in comparison to my required university contracts that lock us into prices ten times higher then you can buy elsewhere, through Fisher. The same aluminium MityVac hand pump I have for working on engines at home that cost me 60$ ( after shipping) is 750$ ( for 2 units on contract. I’m sure someone is making a fortune
But I saw that gallium apparently produces Gallane or digallane at temps below -10 or -20c depending on the source. Allegedly it’s very similar to borane and diborane. Maybe there is something to the gallium/Aluminium alloy or amalgam? Some things seem to suggest it needs a LiAlH or LiH to form it but seems a bit unknown. The NaBH +I2 seems useful but are there any more details on the Gallium/Aluminium amalgam? Ethanol would remain fluid at even -80 so a -25c reaction might not be a big ask.

glen - 3-6-2023 at 17:52

I’ve looked into this reaction. It seems there is still debate over the exact reduction pathways. Some think it’s borane others diborane doing the job. I did find a few other papers on it which seem to indicate a need for a 1.25% or higher rate of NaBH4. I plan to test it tomorrow on a tertiary benzamide. I’ll be Inerting with N2 the setup of a: 2 neck 250ml RB flask, a 125ml pressure equilized addition funnel with2 stopcocks, and 2 (2) nipple gas adapters ( for lack of single nipple gas adapters or at least I can’t find any), but I’m linking the 2ndry nipples together to allow for equilized pressure and flushing the system. I’d prefer a smaller flask but don’t have a2 neck 100ml or similar and my adapters are all Chineseium glass which sag before they flow in so reagents pool in the sagging area. I can set up so it drains in but I’m running nitrogen so the extra volume won’t hurt and I find it helps maintain a better temperature as the excess glass acts as a heat sink as well as increased surface area. Im modifying the amount of NaBH4 to at least 12.5mmoles but more likely 13-15 mmole to give some extra. I’m also going to distill off a lot of the solvent as in the erowid document as I don’t feel like screwing around with emulsions and THF miscible issues and I dont feel like making diethyl ether from 200p anhydrous ethanol right now as I’m lacking BHT at the moment and it would take longer etc. But I will update with any relevant information tomorrow or soon after if the NaBH4/I2/THF reduction works (or doesn’t) on teriary benzamides.

https://totallymechanistic.wordpress.com/2006/12/11/sodium-b...

https://www.erowid.org/archive/rhodium/pdf/borohydride_iodin...

Lionel Spanner - 4-6-2023 at 08:55

Nice one - hope it goes well!