Aryl Glycols from Aryl Vinyls Oxidation

Here are the reaction schemes. The first is the Edgewood patentfor 3-quinuclinol from 4-vinylpyridine. Conversion to the glycol by aq KMnO4 or an improvement as suggested by Ritter, peracetic acid; conversion to HCl salt (not shown) and catalytic hydrogenation, then cyclodehydration over basic alumina in vapor phase.

My modification is to chlorinate the glycol alpha-hydroxyl selectively via Org.Syn., then proceed as above to obtain the unscheduled compound 3-chloroquinuclidine.

Ritter says he prefer hypochlorite addition to the vunylic pi bond but that leaves the Cl in the beta position always. Thus far he has not elaborated how he would cyclize that compound (not shown) to the 3-hydroxyquinuclidine.

My desire is to elaborate a reaction path that explicitly avoids intermediates and product that are CWC scheduled, and which can be used to prepare quaternized esters of unscheduled glycollic acids potentially useful as smasmolytics and devoid of the delerium-inducing properties of BZ etc.

3-hydroxyquinuclidine is scheduled in Schedule III of CWC and so is benzilic acid. But a number of quaternized esters have been patented and meet the criteria I desire.

3-chloroquinuclidine can be prepared from the alcohol of course but that means having the alcohol as an intermediate, which is legal quicksand.

[Edited on 18-7-2008 by Sauron]

The world might condemn it but it's love!

I am not married to that Org Syn method, it is just first one I found. If you don't like it, complain to the authors, or the editors of Org.Syn., or to Wiley. But don't posture about it not being a valid method.

Here's my modified xcheme which removes any and all concerns about lability of Cl in reduction step.

[Edited on 19-7-2008 by Sauron]

Really, read it again carefully and check the yields with primary alcohols -0%.

There are 13 examples in Table 1.

Yes it works on tertiary alcohols but there are none such ligands present in the piperidyl glycol, are there?

It does not touch primary alcohols.

Is it expensive? Yes.

Is it practical beyong a bench scale? Probably not.

But it IS selective viz. this glycol.

I just need to go find a similarly selective reagent that is not so exotic and dear.

The example of a primary alcohol they used was 2-phenylethanol and 0% yield.

Another example was a compound containing both tertiary and primary hydroxyls and only the tertiary was chlorinated.

Quote: followed by jpg of Table 1

"The generality of this chlorination method is summarized in Table 1. Various secondary and tertiary alcohols are converted into the corresponding chlorides in high yields (entries 1-6). A primary alcohol (2-phenylethanol) does not give the desired product (entry 7). However, effective transformation proceeds in the reaction with benzylic alcohols which bear electron-withdrawing or donating substituents (entries 8-10). Nitro and ester groups tolerate these reaction conditions to furnish the corresponding chlorides (entries 11 and 12). The enantiomerically pure alcohol (1-phenylethanol) gives racemic 1-phenylethyl chloride (entry 13)."



[Edited on 19-7-2008 by Sauron]

I think you're beating that proverbial dead horse with that approach.

I don't have access to any quinuclidine chemistry review articles at the moment but both 4-chloro- & 4-hydroxyquinuclidine are known compounds. Just blue-skying it from either of those starting points, you could imagine either a dehydration or a dehydrochlorination to give the 1-azabicyclo[2.2.2]oct-4(8)-ene, then add HCl under anti-Markovnikov conditions to get your 3-chloro compound. (I could find no reference to the 1-azabicyclo[2.2.2]oct-4(8)-ene so this method is either a) not technically possible or b) has not been described). The N-oxide derivatives may be needed here. Access to the starting materials is another question.




[Edited on 20-7-2008 by Ritter]

Here's a variation on my earlier suggestion. I found one reference to 2-chloroquinuclidine, so it is a known compound. But I found no reference to 1-azabicyclo[2.2.2]oct-7-ene though FMC prepared some 3-methanol derivatives of it.

The idea is to add HCl to the alkene, then separate the isomers & recycle the 2-chloro.

Here is some thoughts on the model piperidine system. The most direct approach to the terahydropyridine system seems to be via an aza-Diels-Alder between isoprene & N-methylformidine, but then you have 2 positional isomers to contend with. I also have no references on the aldimine synthesis.