Sciencemadness Discussion Board

methylenedioxybenzyl chloride + sommelet?

Douchermann - 25-9-2008 at 06:53

In this link:

http://www.erowid.org/archive/rhodium/chemistry/piperonal.ni...

a method is given to produce piperonal from methylenedioxy benzene, with the substituted benzyl chloride being an intermediate. My question is, can the sommelet reaction work to produce an aldehyde from this? Why or why not? (I'm more interested in the theory than practicality)

Thanks

ScienceSquirrel - 25-9-2008 at 07:12

I don't see why not.

If you search on 'piperonal sommelet' you will find that several patents refer to the preparation of this compound by this method.

Douchermann - 25-9-2008 at 07:25

Haha whoops, forgot to search other places than just sciencemadness. Well thank you.

Klute - 25-9-2008 at 08:18

Refluxing in somewhat conc. HCl might damage the methylendioxy bridge though... So better use more dilute acid and lower temps.

smuv - 25-9-2008 at 09:35

GB1538214: What is refrenced in the rhodium article (its always best to track down the primary source)

Journal of Asian Natural Products Research, Vol. 9, No. 1, January–February 2007, 23–28.
Similar procedure; 82% yield on a 50mmol scale.

[Edited on 9-25-2008 by smuv]

Douchermann - 25-9-2008 at 13:51

Excellent, thank you all.

Klute: In the sommelets I have performed, the HCl is quite dilute in the final mixture, not to mention the concentration would decrease rapidly due to the formation of the methylamine hydrochloride

Klute - 26-9-2008 at 02:31

Good point.

The yields of piperonyl chloride from chloromethylations are very impressive. PainKilla had it right all along :)

Nicodem - 29-9-2008 at 00:31

The Kornblum oxidation using NaHCO3/DMSO at 100°C works very well on benzyl chlorides. You might consider this as an alternative depending on the substrate nature. The Sommelet reaction is fine but it suffers from poor yield on ortho-substituted benzyl chlorides while the Kornblum oxidation does not have this limitation.

Klute - 30-9-2008 at 15:04

Has anyone have the mp for piperonyl chloride and bromide? I don't have a handbook, and quite surprisingly haven't found anything (bo or mp) by searching the net.

I suppose both are solids?

BTW, I'm considering using them to prepare Cassione, or 4-(3',4'-methylendioxyphenyl)butan-2-one, a derivative of Raspberry ketone that smells like blackcurrant, by alkylating acetoacetate anion. Less trouble than going through the aldehdye IMHO.

smuv - 30-9-2008 at 17:21

I ran a quick beilstein search...

For the bromide: mp range 45-50 the average being about 48c

Bp: 101-103c @ .1 torr; 110c @ 5 torr

For the chloride: mp range 20-23; most being 23

Bp: 78-80C @ .05torr; 89-91 @ 1torr; 134-135 @15 torr

I have not checked primary literature so keep that in mind; these are just straight from a database.

EDIT: Just to clarify the MP range is the min and max melting point recorded in the literature search among all the data collected.

[Edited on 9-30-2008 by smuv]

Klute - 30-9-2008 at 22:06

Thank you very much Smuv. I guess the bromide is more practical to work with (recrystallization), less volatil and (possibly?) irratating?

smuv - 1-10-2008 at 07:39

The conditions required to make the bromide might compromise the dioxol ring. Maybe look into it. After all HBr used to be used to cleave phenol ethers (albeit under harsher conditions).

If it were me...I would make the chloride; even if I could never practically recrystallize it. After distillation I am sure it would be pure enough to move onto the next step (all the side products I can fathom would have much higher bp's and also could be readily detected by TLC).

Whichever route you choose, good luck.

Klute - 1-10-2008 at 07:57

I have stumble don several prearation forming the bromide form the alcohol with aq. HBr at RT or under in good yields:

WO 98/22417:

and J. CHEM. SOC. PERKIN TRANS. 1; 1235-8 (1993)
Quote:

Piperonyl Bromide- Piperonyl alcohol (101.44g, 0.067 mol) was added portionwise to HBr (49% aq. 100 mL), and the resultant suspension was allaowed to stand at room temp for 2h. DCM (1L) was then added, and the organic layer seperated. The aq layer was extracted with DCM (3x 800mL), and the combined organic extract was washed with water (2x500mL) and saturated aq NaHCO3 (3x500mL), dried and concentrated to yield the crude bromide (123.63g, ca. 85%), which was sued without further purification. An analytical sample was prepared by recrystallisation from light petroleum, mp 46-48°C (lit. mp 48°C) [NMR].


Or where you talking about bromomethylation? I think it is done in basicly the same conditions, with even more dilute acid at RT, so the HBr won't be such a problem for the ether bridge I suppose. But the very activated ring might cause di-halomethylation to some extent? Well, again it doesn't seem that problematic considering the high yields obtained in the refs you kindly provided.


EDIT: Considering that I want to use the benzyl halides for AcAcoEt alkylations in acetone and a weak base (carbonate), I prefer betting on the bromide which might be more reactive in these conditions, considering the preparation of the chloride or the bromide are very simialr and I suppose pretty much as efficent. But, if I had to go via halomethylation, I would do a first try with chloromethylation accoridng to the article you posted, and eventually try bromomethylation as the conditions are more practical and the bromomethyl methyl ether less volatil that it's counterpart (not like I was going to prepare before hand, be reassured :) ).

I will report back when i get time to start this.


[Edited on 1-10-2008 by Klute]

smuv - 1-10-2008 at 09:34

I was worried about ether cleavage during bromomethylation. Of course the procedure you posted shows that my concerns were not warranted.

With these reactions there is always some dihalomethylation additionally the formation of derivatives where the halomethylated product is attacked by some uncreated substrate (like a Friedel-Crafts between product and substrate).

I have seen a few examples of bromomethylation of activated substrates in literature, they all seem to use HBr in AcOH along with paraformaldehyde. I am not sure why these conditions were used instead of aqueous HBr, then again this is just what I have stumbled upon, I have never extensively researched this subject.

PS I never knew acetoacetic ester synthesis could be preformed under such mild conditions.

Klute - 1-10-2008 at 12:36

See patent US 1 094 417 for an example, where AcAcOEt is alkylated with p-MeOBnCl in ~50% isolated yield. I guess conventional RONa/ROH conditions would be prefered.

Do you still ahve the bromomethylation refs at hand? I remeber reading one or two myself, the reaction looked very practical and pretty high yielding.

smuv - 1-10-2008 at 18:34

So here is what I have on the subject:

Eur. J. Org. Chem. 2002, 3162-3170
Bis-bromomethylation of p-dimethoxybenzene

J. Org. Chem. 1993,58, 1262-1263
General bromomethylation procedure for activated aromatics; every modern bromomethylation paper seems to reference this one.

Fuson, R. C.; McKeever, C. H. Org. React. 1942, 1, 63.
Review of chloromethylation; covers some bromomethylation and chloroethylation, propylation etc...

Organic Process Research & Development 2005, 9, 1013-1014.
Observation of Bromomethyl Ethers during the Bromomethylation of Aromatic Compounds.

P.S. its a GB patent no US; interesting though.

Klute - 1-10-2008 at 22:22

Thank you very much!

What's the problem with british patent, heh? :mad: :P

PainKilla - 2-10-2008 at 02:17

Attached.

Attachment: Aqueous bromomethylation utilizing PTC.pdf (96kB)
This file has been downloaded 1800 times

PainKilla - 2-10-2008 at 02:18

Attached.

Attachment: Chloromethylation of Alkoxybenzenes and conversion to benzaldehyde via sommelet.pdf (205kB)
This file has been downloaded 1322 times

PainKilla - 2-10-2008 at 02:21

Attached.

Attachment: WO2005042512 - Piperonal - chloromethylation benzyl acetate alcohol oxidation to aldehyde.pdf (620kB)
This file has been downloaded 1427 times

PainKilla - 2-10-2008 at 02:23

One more, can post more on chloro/bromomethylation if it's needed, but this covers a lot.

Attachment: Bromomethylation with paraformaldehyde and HBr.pdf (249kB)
This file has been downloaded 1078 times

Klute - 2-10-2008 at 05:52

Wonderfull! thanks alot PainKilla!

Ephoton - 2-10-2008 at 20:01

klute I tried that us patent at espace and got a patent on folding gocarts any chance on some more info on this condensation as I would love to know about it.

thanx

Klute - 2-10-2008 at 22:49

Sorry, I thought you were refering to the WIPO patent at first..

I was pretty stunned, as I had the paper version in front of my eyes, and fell onto the bloody folding go-cart at espacent or pat2pdf.org!

I've just realized that it's a british aptent actually! Sorry for the mistake! (see, british patents kick ass :P
:D )

Here is the link:

Method of producing 1-(4-methoxyphenyl)butanone and 1-(4-methoxyphenyl)butanone

and the WIPO patent:

[Edited on 3-10-2008 by Klute]

Attachment: 98022417.pdf (893kB)
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Klute - 2-10-2008 at 22:52

And the quoted J. Chem. Soc., Perkin Trans. article

I haev found more info on the acetoacetate condensation, and will post the article as soon as i gather them. I have found a patent where a michael addition very similar to a claisen, except that a Mannich base is used instead of a alkyl halide (forming the alkene in-situ), using sodium isopropoxide in IPA.
There also a seemingly very interesting article on Claisen via ptc in aprotic solvents. I will post all this in a related thread, as I'm deviating from the thread subject here..


[Edited on 3-10-2008 by Klute]

Attachment: Perkin1_1993p1235.pdf (520kB)
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Ephoton - 3-10-2008 at 04:11

thanx ill give that one a go ;)
sorry for the short replies im on pda at the moment
im sure some here would like this as it checks my spelling better than my nix box

[Edited on 3-10-2008 by Ephoton]

Klute - 3-10-2008 at 07:47

With what benzyl halide? Piperonyl?

Did you make i by halomethylation or from the alcohol?

I'm planning on trying this reaction this weekend. Hopefully i will have some black currant to add to the ginger, raspberry and coconut. Should try adding them to tea one day :)

Ephoton - 3-10-2008 at 11:57

hehe yep I think its well time I made some more inocent compounds too ;) ill just use the product from a loomins for now.

what about putting the product through a beayer villager. this way you can get the alcohol after hydrolisis with an extra carbon.

ie phenethyl alcohol.

Klute - 3-10-2008 at 12:09

Well, there would be more simple ways of doing this, like aldol with formaldehyde and reduction of the vinyl ketone, or even grignard from the benzyl halide with paraformaldehyde. I guess it depends on how well the BV proceeds (oxidation of the alcohol?)

[Edited on 3-10-2008 by Klute]

Ephoton - 4-10-2008 at 02:21

I am interested in the flavor as well its just nice to find new ways to compounds I can make already.

bv ends in an ester you don't get the alcohol till the hydrolisis to my knowlage and experience. yes formaldehyde aldol another nice idea.
thanx.

anyway this is getting way off topic ;)

smuv - 4-10-2008 at 07:02

Quote:
Originally posted by Klute
Well, there would be more simple ways of doing this, like aldol with formaldehyde and reduction of the vinyl ketone, or even grignard from the benzyl halide with paraformaldehyde. I guess it depends on how well the BV proceeds (oxidation of the alcohol?)

[Edited on 3-10-2008 by Klute]


I hope I am not mistaken but, do you mean an aldol between the benzaldehyde and formaldehyde? They are both non enolizable.

Also the grignard of benzyl halides with formaldehyde can be irregular for some substrates. For example the major products of the reaction of formaldehyde and benzyl magnesium chloride are o-Methylbenzyl alcohol and 2-hydroxymethylphenylethanol. I think this occurs because the charge of the 'benzyl anion' gets conjugated with the ring making it super electron rich, allowing it to undergo electrophilic aromatic substitution under these conditions. This is just my theory I could be dead wrong on why but I know it happens, Less so with acetaldehyde.

Klute - 4-10-2008 at 18:01

My bad on the aldol, I don't know know what I was thinking :)

That unconventional grignard seems pretty interesting. How is that o-methyl group formed? Dehalogeantion? I can understand the nucleophilic substitution with formaldehyde to the benzylic alcohol, but how can there be two reactions with the anion (Aromatic nucleophilic substituion, and addition on formaldehyde) to 2-hydroxyphenethylethanol? Or is this considering excess Mg?

Is the yield of these products high enough to be a preparative procedure, or is this only a complex mixture in low yields?


Well, terribly sorry for the bad suggestions, even though I would have placed my bets on the grignard.. Too bad then.

I guess Ephoton idea stands then. Although a smooth peracid would be needed to avoid any hydrolysis (using caro acid or even performic usually causes aprtial or total hydrolysis of the ester during the oxidation). Hopefully peracetic should be kind enough with the ester?

smuv - 4-10-2008 at 23:11

Quote:
Well, terribly sorry for the bad suggestions, even though I would have placed my bets on the grignard.. Too bad then.


Completely understandable. I have come to discover the grignard reaction is more complex than it seems on the surface. I find its reactivity with unconventional substrates extremely interesting (non carbonyl compounds). Who knows though, maybe for methylenedioxybenzene things work out.

Are these alcohols supposed to smell nice?

Mechanism of the Reaction between Benzylmagnesium Chloride and
Carbonyl Compounds. A Detailed Study with Formaldehyde

Journal of Organic Chemistry, 47(7), 1243-9; 1982

[Edited on 10-5-2008 by smuv]

[Edited on 10-5-2008 by smuv]

Attachment: Irregular_grignard.pdf (897kB)
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Ephoton - 5-10-2008 at 03:32

ammonium persulfate is the go for hydrolisis I would think.

butan - 2 - ones can then be made after nitric oxidation too PAA then any p2p synth from this compound if modified for the extra carbon will work.

Klute - 5-10-2008 at 05:50

Yes, I beleive the corresponding 2-phenyethanols posses pleasants smells too.

I think you must have attached the wrong article: this one is on the Hofman decomposition of N-bromo amides...

Ephoton, do you mean basic/neutral ammonium persulfate would be ok for the BV? I think this would majorily SEM, and oxidation to the acid and other complex reactions.... Peroxodisulfates are suually used with H2SO4 (optionally in AcOH) for BV oxidations, and would surely cause at leasts ome hydrolysis, although in 75% AcOH and stoechiometric amount of H2SO4 at 0-10°C it seems the ester is largely present.

I would go with a traditional peracetic, or perborate in GAA. Possibly the ester itself will smell very nice!

smuv - 5-10-2008 at 08:35

I fixed the link...woops!

If I were in your situation, I would seriously consider friedel crafts with ethylene oxide or grignard with ethylene oxide (starting from methylenedioxybenzene or the para halide). I am fairly sure the friedel crafts can be done at low temperatures, so ether clevage should be minimal; of note grignards on this substrate conceivably and to some extent do react with the methylenedioxy ring.

I guess ethylene oxide isn't the nicest stuff to work with though.


[Edited on 10-5-2008 by smuv]

Klute - 5-10-2008 at 09:48

Good point, but making ethylen and ethylen oxyde isn't evry practical, well not quite the chemistry I like. The BV oxidation does sound like a good option now. I might give a try on microscale with some of the butanones.

stoichiometric_steve - 27-10-2008 at 05:22

Just to bring this up: in chloromethylations, usually bis(chloromethyl)ether is formed, a pretty potent carcinogen.

I hope all of you that want to follow this route keep that in mind...