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Author: Subject: how to oxidize ring chain with KMnO4
pbmineral
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[*] posted on 22-7-2008 at 05:29
how to oxidize ring chain with KMnO4


Hello,

I'm working on the synthesis of benzocain (ethyl p-aminobenzoate) which is a local anesthetic.

/
O-CH2
/
O=C
\---
// \\
\ _ /
---\
NH2

A friend gave me some p toluidine and I would like to obtain the carboxylic acid.

\---
// \\ ?
\ _ /
---\
NH2

I protected amino group using acetic anhydride and got 10.8 g of pure p-methyl acetanilide.

\---
// \\
\ _ /
---
\
NH
/
O=C
\

I would like now to oxidize the methyl chain to have an acid.


OH
/
O=C
\---
// \\
\ _ /
---\
NH
/
O=C
\

I think I could use some KMnO4 but I wonder about conditions to use it.

I've just created an amide R-C=O
|
NH2

and it may ben sensitive t dilute acid or bases.
First I thought I culd oxidise with a 30% H2SO4 permanganate solution. this way I could get no MnO2 BUT acid !!!

Also I could use some soda and KMnO4, this way I would get large amuntsof MnO2 but the acid would be a base, and I would only have to make the filtrate acid for it to precipitate !


What do u think of ?
What's the most suitable method ?

PS another route would be to fully oxydise p-toluidine and get p-nitrobenzoïc acid but it costs more snce I destroy an already existing function (R-NH2)
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[*] posted on 22-7-2008 at 05:35


I would not start from there!

Rationally;

4-nitrotoulene -> 4-nitrobenzoic acid -> 4-aminobenzoic acid - > Benzocaine
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[*] posted on 22-7-2008 at 05:57


Have a look a this thread:

http://www.sciencemadness.org/talk/viewthread.php?tid=8268&p...

I don't know if the basic conditions provoked by using neutral KMnO4 would affect the amide, you might want to heat at a lower temp and for shorter periods of time, or doing it a RT for longer reaction times...

IIRC, you said you obtaine dbad yeilds from p-nitrotoluene? It's true de oxidation would be better with the nitro- than the amine.

On the other hand, I'm sure I have already nitrated an anilide with con. HNO3 and H2SO4, followed by deprotection by refluxing with KOH, so I guess such an amide will survive conc. HNO3. You could try oxidizing the methyl group with ~50% HNO3, I will dig up the ref I had on this.


Here we are: Nitration of anilide Sorry, in French, if anyone but pbmineral wants detaisl on things I can translate it.

US4302599: Nitration of sub. anilides

So this would mean an anilide would survive harsh acidic conditions. Oxidation with HNO3 and ac. chroamte should be ok then, but ac. KMnO4 wouldn't be practical as the acid would gradually crisatillze out, forming a thick sludge.


[Edited on 22-7-2008 by Klute]




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[*] posted on 22-7-2008 at 07:15


You could try halogenation of the side chain to produce the benzyl halide.
This could then be oxidised under milder conditions.
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Stramonium
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[*] posted on 22-7-2008 at 08:32


Here is link to a multistep synthesis you might find useful
Revised Procedure: Expt. 21.1 Multistep Synthesis of Benzocaine Analogs

I personally wouldn't use the aqueous acetylation, opting for the fool-proof addition of a decent excess of Ac2O to the substituted aniline in glacial acetic acid, followed by 1hr or so reflux but you have the acetylation covered anyway.

The oxidation of N-acetyl-p-toluidine with the KMnO4 (aq)/MgSO4 system in this link works well. Adding the permanganate in a single addition (as described in other procedures) seems to reduce yields significantly IIRC. The big pain is the manganese dioxide sludge - definitely get Celite before you tackle the oxidation as hot filtering the mud through paper or sintered glass alone is useless. Maintain strong stirring if you are chasing high yields.

This oxidation reaction was effective when scaled to use ~25g toluidines but even at this scale, magnetic stirring is hindered by the MnO2 and a good overhead stirrer was employed.

I once tried to avoid the messy filtration work-up by addition of saturated sodium bisulfite to the post reaction mixture. Everything went smoothly to afford (on acidification of clear aqueous solution) what visually appeared to be the desired acid (which doesn't mean much) - the ID/purity of the product was never investigated any further. Also, you have to put up with some sulfur dioxide emissions using this technique.

[Edited on 22-7-2008 by Stramonium]
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