UnintentionalChaos
International Hazard
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Location: Mars
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Cinnamaldehyde synthesis (or DDQ synthesis)
Hello all, as some of you may be aware, I have a slight obsession with the receptors TRPV1 and TRPM8 which among other things register the sensations
of heat and cold from capsaicin/piperine/ginger and menthol/icilin respectively.
I have some intermediates for the prep of capsaicin on ice since I lack the ability to currently run an unstabilized wittig to assemble the fatty acid
tail.
Something else that has captured my interest however, is piperine. Most members of the TRPV1 agonist family bear a vanillyl moiety
((3-methoxy-4-hydroxyphenyl)methyl). Piperine however, bears a 3,4-methylenedioxyphenyl moiety.
I am interested in the synthesis of the the vanillyl version of piperine. To get there, I intend to proceed through 3-methoxy-4-hydroxycinnamaldehyde
(coniferyl aldehyde) with a protecting group on the phenol that can be easily removed (perhaps MOM ether).
It seems like the best strategy for making this intermediate is probably an allylic oxidation of protected iso-eugenol. I have found some literature
(attached) on the use of DDQ for this transformation and it seems relatively simple and clean.
The synthesis of DDQ, however, is not simple, and looks to usually use HCN addition to p-benzoquinone. Oxidation of 2,3-dicyanohydrquinone per http://pubs.acs.org/doi/abs/10.1021/jo01020a529 (full paper in preview) seems to be quite direct, but getting the hydroquinone is again, a
stumbling block.
One of the attached papers (I forget which) notes that chloranil doesn't react similarly and tends to make intractable tar instead of cinnamaldehyde.
The last item attached is a non-DDQ prep for allylic oxidation, but uses both PDC and tBuOOH for mostly modest yield. Also, there is no comparable
substrate they test it on for what I'd like to do.
Suggestions for alternate approaches or anything you might know about making DDQ would be appreciated.
EDIT: considering just using protected vanillin and 2-bromomethyl-1,3-dioxolane grignard (acetaldehyde enolate equivalent). If you've got any info on
that or similar reagents, that would work too.
[Edited on 7-14-14 by UnintentionalChaos]
Attachment: coniferaldehyde.pdf (295kB)
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Attachment: DDQ.pdf (235kB)
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Attachment: DDQthesis.pdf (4.7MB)
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Department of Redundancy Department - Now with paperwork!
'In organic synthesis, we call decomposition products "crap", however this is not a IUPAC approved nomenclature.' -Nicodem
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S.C. Wack
bibliomaster
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Location: Cornworld, Central USA
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Actual HCN or ? KCN solution added to the quinone + ~ ethylsulfuric acid is recommended.
There was a whole bunch of this, in packets IIRC, being sold by someone on ebay not long ago.
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Boffis
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Hi UC
What is wrong with the Walker & Waugh modification of the original Thiele synthesis? Admittedly it requires copious quantities of alkali cyanide
and benzoquinone but these can be prepared if required. The preparation is relatively simply to conduct. I have just acquired 1kg of benzoquinone for
this sole purpose.
Rather than looking at alternatives to DDQ or alternative routes to its preparation how about alternative routes to cinnamaldehyde/cinnamic acids.
According to Richter (vol III) cinnamaldehyde can be prepared by reaction benzaldehyde with acetaldehyde or by distilling calcium cinnamate with
calcium formate and so it might be possible to use these techniqies on substituted benzaldehydes. Substituted cinnamic acids may be available via the
haloform reaction on the condensation product of benzaldehyde and acetone; this reaction has been described for longer chain acid (eg Diehl, Berichte,
1885 p2331). The aldol route has been discussed elsewhere on this forum.
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