dormouse (Member)
04-19-00 16:28
No 122789
      a novel route to the ketone - rev drone  Bookmark   


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rev drone
Member   posted 03-01-99 05:01 PM          
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A friend of mine and I were discussing this.
Epichlorohydrin is allowed to react with benzodioxole to produce 5-oxiranylmethyl-benzo<1,3>dioxole. Isomerize with LiI or LiBr, and you have the ketone.

I know this idea has been discussed, and I know it was discredited due to the reactivity of the intermediates, but maybe it isn't so bad.

Epichlorohydrin is nasty, but cheap and plentiful. Benzodioxole is expensive, but readily made from cheap catechol and extra-cheap DCM. Putting this all together, you have a method with a price that's low, no watched chemicals, doesn't use expensive catalysts, and leaves you nicely one step away from the final product. Whaddya say?

Also, what would be the best way of getting epichlorohydrin to add to the aromatic ring? I know some of you out there are experts in this field, so let's see what you got.

The only ref I could find related was Rev.Roum.Chim. 41; 3-4; 1996; 291-302. The problem is the use butyl lithium to get the reaction to work. Now I know such a strong base is not needed, so how would you do it?

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-the good reverend drone


 
Rhodium
Administrator   posted 03-01-99 06:46 PM          
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You might want to check out JACS 63, 602 (1941), they add oxirane to p-F-PhMgBr to give the phenethyl alcohol. Bromobenzodioxole is easily prepared, see TSII. I dunno if the Cl is more reactive than the oxirane though.
 
rev drone
Member   posted 03-01-99 07:31 PM          
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I've also seen a 1956 article from Yakugaku Zasshi (where-oh-where are our Japanese bees?) that reacted toluene with epichlorohydrin using AlCl3 as a Lewis acid.
The mechanism here is completely different. In the base-catalyzed reaction, a phenyllithium intermediate is formed, which quickly reacts with the carbon bonded to the chlorine. In this Lewis acid reaction, the AlCl3 pulls away electron density off the oxygen through partially binding with the lone pairs of electrons. This electron-depleated epoxide is more suseptible to nucleophilic attacks, which is where the aryl group steps in to take center stage. The result? The phenyl is in the 1-position of the propane chain, a hydroxy is in the 2-position, and a chlorine is in the 3-postion. Will a little strong base in the work-up, you generate the epoxide. This is theoretically distillable (may actually isomerize during distillation, but we'd want that anyways), then would be isomerized (if it weren't already) using SmI3, LiBr or LiI (um,...better yet, forget I ever mentioned SmI3.)

Examples abount of gringard reagents reacting, but that's at least two more synthetic steps, and I'd just as soon avoid all the byproducts I can forsee occuring from that mightmare.

This method looks like it has a lot of good things going for it, and would be good for producing 4-methoxyphenylacetone, 2,5-dimethoxyphenylacetone, 2,4,6-trimethoxyphenylacetone, as well as a number of other interesting phenylacetones, not to mention the potential usefulness in heterocyclic compounds.

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-the good reverend drone


 
Beagle
Member   posted 03-06-99 03:32 AM          
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In regards to the toluene/epichlorohydrin rxn, why would the phenyl ring end up attacking the oxirane? Unless there is some reagent missing here, seems more likely that the methyl group would end up attacking, giving a benzyl group in the 1 position, rather than 4-methyl-phenyl, as you are implying.
I think you are saying you don't like the idea of the substituted phenyl grignard reacting w/ propylene oxide? In this case you would get some amount of the unwanted hydroxy isomer, so I agree.

Maybe this route would not be so bad for PEA's though, by using ethylene oxide as Rho suggested. You then have several alternative routes for going from the phenethyl alcohol to the PEA.

And that Rev. Roum. Chim. (whatever the hell journal that is) ref does this reaction selectively?! I really would have thought that the epoxide would be attacked substantially, if not preferentially.


Wizard X
Moderator   posted 03-06-99 07:32 PM          
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Firstly,convert the Epichlorohydrin to chloroacetone via LiBr or LiI.
Then react with benzene or benzodioxole + AlCl3. This will eliminate any side reactions with the epoxide.
 
Rhodium
Administrator   posted 03-06-99 09:32 PM          
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Yes, but the MD ring wouldn't like the idea of being refluxed with AlCl3...
 
rev drone
Member   posted 03-08-99 01:09 PM          
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All the reagents are listed. I don't see any problems mechanisticly (did you take into account the lithiated intermediate -- i.e. the strong base that would deprotonate the phenyl ring?) Why do you think epichlorohydrin would attack the methyl group rather than the ring? In any case, they reportred it adding ortho and para to the methyl, not on it.
Still, this is beside the point. The plan is with benzodioxole, which has no methyl group.

Wizard X,

Chloroacetone is nasty, nasty stuff, used as a chemical weapon; I wouldn't ever want work with it. Period. Also, Rhodium is absolutely right; Lewis acids like AlCl3 don't mix well with methylenedioxy rings.


Wizard X
Moderator   posted 03-08-99 05:48 PM          
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Benzodioxole is 1,2 methylenedioxybenzene, Ok, so where did this methyl group come from ?
Sure the methylenedioxy ring is suscepiable to ring cleaverage with AlCl3 at reflux temperatures. I'm not talking refluxing with benzene or benzodioxole. I'm talking 5 - 45 deg C with AlCl3 partial deactivation with longer reaction time.
I see your product is Ph-CH2-CH2(OH)-CH2Cl, Ok, but forming the chloroacetone first eliminates one reaction step and side reactions. Also, epichlorohydrin is a class 1 carcinogen.


rev drone
Member   posted 03-08-99 10:56 PM          
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Chloroacetone is used as a weapon of mass destruction, fercrissakes; how much more of a detraction do you need? If you're playing with this stuff, please do it as far away from me, or my family as you can.
Yes, epichlorohydrin is carcinogenic; I have a copy of the MSDS, and yes its nasty. But its still safer than chloroacetone (not exactly one of the four basic food groups.)

There was no methyl group. The methyl came in the context of reaction epicholrohydrin in a similar reaction with toluene. However, there is no methyl group to discuss in the reaction mentioned, since we're talking about reacting epichlorohydrin with benzodioxole, not toluene. What step does the use of chloroacetone alleviate anyways?

The temp isn't the problem with the AlCl3. It forms a salt, regardless of temperature, that, when worked up, results in the cleavage of the methylenedioxy bridge. That's the problem; its in the work-up that things get messy (actually, things can get kinda messy before then too.)

Forming chloroacetone adds another step (specifically, the formation of chlorocacetone). Its an isomerization one way or another, and I'd rather not take my chances with chloroacetone.

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-the good reverend drone


 
Wizard X
Moderator   posted 03-09-99 03:05 AM          
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Drone ! If you think chloroacetone is far too dangerous, then I'm sure you will be absolutely shocked out of your skin if you know of the synthesis " I've played with ".
God help me !
Ok, so be it ! AlCl3 cleaverage of the methylenedioxy bonds ?

Good talking with you Drone. I'll be posting something soon on my Webpage that might interest you.


rev drone
Member   posted 03-09-99 05:21 AM          
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You've been messing with chloroacetone? Admittedly, a lot of times the nastiness of a chemical is overrated, but this is one I've heard nothing but bad about. I mean, I've worked with cyanogen gases and never had a problem, but for whatever reason, I was told that the lachrymatory properties, not to mention everything else about chloroacetone, made it exceptionally dangerous to handle. Please, do tell us more. I have to admit, I *am* shocked.
As for the AlCl3 cleaving the methylenedioxy ring, I'm pretty confidant it does. I'd be utterly delighted if you could show that it doesn't, but I've seen example after example in the literature where it does just that, at all sort of different temperatures. Please feel free, no, feel obligated to surprise me about this one. I'd be happy to be wrong.

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-the good reverend drone


 
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