Boffis
International Hazard
Posts: 1843
Registered: 1-5-2011
Member Is Offline
Mood: No Mood
|
|
1,2-oxazolones and 3,3'-bi-oxazolone
Oxazolones
I am interested in ligands with the N=C-C=N motif such as 2,2’-dipyridyl and 1,10-phenanthroline, however, there are many more theoretical
possibilities particularly amongst the heterocyclic compounds. One particular heterocyclic moiety that is of interest to me is the 1,2-oxazole-5-one
group. Simple 3-substituted examples are prepared by condensing beta-ketoesters with hydroxylamine (1). So for example:
(Chemsketch likes the more convoluted IUPAC names!)
is prepared by condensing ethyl acetoacetate with hydroxylamine and this compound:
from the ethyl benzoylacetate ester.
My target compound is 3,3’-bi-(1,2-oxazol-5(4H)-one):
By analogy with the reactions above the obvious starting material is therefore 3,4-dioxo-hexanedioic acid:
This compound is known as ketipic acid or oxalodiacetic acid but very little information is available on its preparation though the latter name
suggests that it may be available via a double Claisen condensation (2 moles of ethyl acetate with one of ethyl oxalate. Is this possible?). An
internet search turned up a few papers of which the most useful is a Russian paper from the University proceedings- Volga Region which describes two
different Claisen type syntheses of various dialkyl ester (2).
So then I decided to look at building it from two oxazolone rings. My initial idea was from say a 3 halo-oxazolone and copper powder but while looking
at the preparation of such starting compounds I came up with a better idea. How about reducing the diazonium compound prepared from the
3-amino-oxazolone in a fashion analogous to the classical biaryl synthesis. The starting material should be available from cyanoacetic acid and
hydroxylamine to give an amidoximopropanoic acid followed by cyclitization to 3-amino-1,2-oxazol-5(4H)-one (in theory, by extension of other related
reactions). There are several possible issues with this route:
a) the amino group may not form a diazonium compounds with nitrous acid, this is not uncommon in heterocyclic amines.
b) cyanoacetic acid may condense with hydroxylamine to give a hydroxamic acid, however, generally hydroxamic acid are prepared from the acid chloride
or ester and hydroxylamine, free carboxylic acids generally do not react but the reaction between some nitriles and hydroxylamine is slow.
c) even if the amine forms a diazonium compound there is no guarantee that it will be reducible to a bi-heterocyclic.
So my questions are:
1) can anyone see a better route to either the 3,3’-bi-(1,2-oxazol-5-(4H)-one, 3,4-dioxohexanedioic acid or the 3-amino-1,2-oxazol-5-one?
2) do you think that the 3-amino-oxazolone will be capable of forming a diazonium compound?
3) will cyanoacetic acid react with hydroxylamine to form an amidoxime compound (I have a paper by C. Ulpiani in which he describes a similar reaction
within the fulminuric acid series [the reactions of isonitroso-cyanoacetic acid with hydroxylamine, can’t find reference just now])?
References
1. Hantzsch; Chemische Berichte, v24, p502 [1891].
2. Mukovoz & Kozminykh, University Proceedings; Volga region; No. 2 (2) pp88-101 [2013]
|
|
|
clearly_not_atara
International Hazard
Posts: 2722
Registered: 3-11-2013
Member Is Offline
Mood: Big
|
|
Pinacol coupling on ethyl 3-oxopropionate might be a little cleaner than the Claisen -- no side reactions. Oxidizing the diol can probably be done
easily enough.
3-oxopropionic acid might be made by oxidizing hydracrylic acid or beta-alanine, or reducing cyanoacetate with SnCl2, or dehydrating glyceric acid or
its esters, or by oxidative decarboxylation of malic acid, or the Strecker degradation of aspartate.
[Edited on 27-2-2016 by clearly_not_atara]
|
|
|
PHILOU Zrealone
International Hazard
Posts: 2893
Registered: 20-5-2002
Location: Brussel
Member Is Offline
Mood: Bis-diazo-dinitro-hydroquinonic
|
|
1)I would start from 2,3-butandione (CH3-CO-CO-CH3).
2)Then halogenation in mild acidic media (for monohalogenation, otherwise haloform splitting) --> X-CH2-CO-CO-CH2-X
3)Then reaction with Na-C#N --> N#C-CH2-CO-CO-CH2-C#N
4)Then hydrolysis in mild acidic media (basic media is forbidden because of condensation-crotonisation of keto groups with activated methylen groups
between keto-cyano or keto-acyl.
--> HO2C-CH2-CO-CO-CH2-CO2H
Now about 3,3’-bi-(1,2-oxazol-5(4H)-one), following retro-synthetic pathway you come from:
RO2C-CH2-C(=N-OH)-C(=N-OH)-CH2-CO2R expecting bicyclization and evolution of R-OH...
But there is a big chance the two viccinal C=N-OH react together to form a furazan ring
--> 3,4-Di(methylenecarboxy)furazan
PH Z (PHILOU Zrealone)
"Physic is all what never works; Chemistry is all what stinks and explodes!"-"Life that deadly disease, sexually transmitted."(W.Allen)
|
|
|
Boffis
International Hazard
Posts: 1843
Registered: 1-5-2011
Member Is Offline
Mood: No Mood
|
|
@clearly_not_atara. Thank you for your suggestions, I like the possible routes via beta-alanine or ethyl cyanoacetate to the 3-oxopropionate ester and
then the pinacol coupling. Any ideas on how to oxidized the glycol to a diketone? I did some research and the only option I could find was
2-iodoxybenzoic acid which is rather difficult to prepare (though I see its preparation is covered by an SM thread). I'll keep looking into this as it
looks possible.
@Philou, I had thought about various routes to the 3,4-dioxo-adipic acid including one from butandione, bromination in the presence of chalk to
(hopefully 1,4-dibromo-2,3-butadione and not 1,1-dibromo derivative) and then react this with cuprous cyanide. The problem I see then (and the reason
I dismissed this route) is that the CH2 bridge is going to be very reactive and even under mildly acid conditions will react with another carbonyl
group rather faster that the nitrile groups hydrolyse. Are then any milder techniques of hydrolysing nitrile? Might it be better to carry out the
hydrolysis in an alcohol to obtain an easter directly (as in diethyl malonate from cyanoacetic acid in ethanol)?
I have also come up with another possible route that results from the multi-step deconstruction of the target. Basically reacting diethyl oxaloacetate
with hydroxylamine to give the oxazalone-3-carboxy ester; Claisen condensation with ethyl acetate in the presence of sodium hydride to give the
oxazolone-ketoacetate and finally hydroxylamine again to give the desired product. One thing I have discovered in my reading around is that the
1,2-oxazolone ring is prone to cleavage and rearrangement so mild conditions are required.
|
|
|
PHILOU Zrealone
International Hazard
Posts: 2893
Registered: 20-5-2002
Location: Brussel
Member Is Offline
Mood: Bis-diazo-dinitro-hydroquinonic
|
|
Your idea of ester formation during nitrile hydrolysis is a good one!
Maybe the N#C-CH2-CO-CO-CH2-C#N could be protected by urea (such structures easily form glucoluryl related bicyclic compounds...those survive strong
HNO3 and H2SO4 to make dinitroglucoluryl and tetranitroglucoluryl compounds)
Or protection by glycol like for conventionnal ketons?
Another OTC-ish start could be erythritol (HOCH2-CHOH-CHOH-CH2OH)
The reaction with HCl and ZnCl2 will favourise the terminal OH substitution --> ClCH2-CHOH-CHOH-CH2Cl
Then substitution of the halides by cyanide... --> N#C-CH2-CHOH-CHOH-CH2-C#N
Then reaction with diluted HOCl (hypochlorite solution in acetic acid) will oxydise the alcools into ketons (hypochlorous esters form aldehyd or
ketons by expelling HCl)...hypochlorite will also turn the cyano into carboxylates...
PH Z (PHILOU Zrealone)
"Physic is all what never works; Chemistry is all what stinks and explodes!"-"Life that deadly disease, sexually transmitted."(W.Allen)
|
|
|
clearly_not_atara
International Hazard
Posts: 2722
Registered: 3-11-2013
Member Is Offline
Mood: Big
|
|
| Quote: | | Any ideas on how to oxidized the glycol to a diketone? I did some research and the only option I could find was 2-iodoxybenzoic acid which is rather
difficult to prepare (though I see its preparation is covered by an SM thread). I'll keep looking into this as it looks possible.
|
If you believe the claimed mechanism in this article, TEMPO can do it:
http://www.organic-chemistry.org/abstracts/lit1/603.shtm
Using PhICl2 as co-oxidant is one of those things that you wonder if they did just to fuck with our heads. Recent papers about TEMPO focus on its
pH-dependent chemoselectivity: it will oxidize primary and secondary alcohols under acidic conditions, but it will only oxidize primary alcohols under
alkaline conditions. Under some conditions it can selectively oxidize primary alcohols in presence of secondary alcohols, or convert diols to
lactones, or terminal glycols into alpha-hydroxyacids. However it will also oxidize secondary alcohols under the right conditions:
https://www.researchgate.net/profile/Francesca_Fontana3/publ...
Attached is a reaction using TEMPO with bromine as co-oxidant to make a 1,2-diketone.
Attachment: inokuchi1990.pdf (111kB)
This file has been downloaded 347 times
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
