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Author: Subject: Novel route to Methylone?
Dextrose
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smile.gif posted on 12-1-2007 at 21:37
Novel route to Methylone?


Hi there...

I've really set my mind on a Methylone synthesis, since all reagents and precursors are widely available.

I know that the first, third and fourth step gives near quantitive yields, but i don't know if it's possible to condensate propanal like that in second step.
- That's why i'm asking here. ;)
AFAIK the oxygen should be a good electrondonor, thus making the nearest hydrogen most willing to leave.

Am i totally wrong about this? Maybe with the help of another catalyst, could this be possible in good yields?

I know that propionyl chloride can be used in the first step, but i would really like to avoid that one.

Thanks in advance
Dex

[Edited on 13-1-2007 by Dextrose]

methylone.gif - 6kB
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Sauron
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[*] posted on 12-1-2007 at 22:05


Yet another flavor & fragrance chemist.

The step you propose is a Friedel-Crafts. This ought to be in the literature, at least for chlorobenzene.

See if the 3,5 methylenedioxy group will affect the F-C one way or the other.



[Edited on 13-1-2007 by Sauron]
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Nicodem
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[*] posted on 13-1-2007 at 01:51


That step is not a Friedel-Crafts reaction. Actually it has no name since it is complete nonsense. A Friedel-Crafts reaction is an electrophilic substitution of a hydrogen atom on an nucleophilic aromatic compound * by a strong enough electrophile generated by the complexation of a Lewis acid catalyst with an otherwise too weak electrophile. The main (and perhaps the only) difference between a Friedel-Crafts reaction and the numerous other electrophilic aromatic substitutions is that the electrophile is a carbocation.
Dextrose you might start by reading some books on basic organic chemistry first (before planning syntheses) and preparative chemistry (before actual experimentation). But first read about the Friedel-Crafts reaction as well as it seems you have lots of confusion regarding it and also a complete lack of insight in its mechanism:
http://en.wikipedia.org/wiki/Friedel-Crafts_reaction
http://www.chemguide.co.uk/organicprops/arenes/fc.html
http://www.organic-chemistry.org/namedreactions/friedel-craf...
http://www.organic-chemistry.org/namedreactions/friedel-craf...

* Which is not the case in your proposal.




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Sauron
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[*] posted on 13-1-2007 at 02:27


My suggestion in sending him to study the F-C rxn was for him to discover on his own that the -Cl was not needed.

Better pedagogically for him to learn on his own. And he had his heart set on using AlCl3.

But anyway now that is short circuited. Oh well.

I do believe the appropriate F-C acylating agent to be propionyl chloride not propanal. And the target aromatic the methylenedioxy benzene not the corresponding chlorobenzene.

That might be feasible. Cf. the well known prep of chloroacetophenone from benzene and chloroacetyl chloride over AlCl3.

I have not looked up F-C acylation yet so I can only speculate about what effect the presence of the phenolic ether functionaility might have. That's a mildly activating group insofar as Hammett is concerned, rather like anisole. To go beyond that comment I would have to crack a book.

[Edited on 13-1-2007 by Sauron]
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leu
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[*] posted on 13-1-2007 at 05:59


Aluminum chloride is incompatible with methylenedioxy bridges, since the result will be polymerization :( See Khim.Farm.Zh.; RU; 21; 5; 569-573 (1987) for a feasible procedure :P



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Sauron
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[*] posted on 13-1-2007 at 06:20


Thanks, leu. I think I'll let someone else dance with this one, it really does not interest me much.

A quick look at an old review of F-C suggested that phenols were a complex substrate because of possible coordination between the oxygen (or oxygens) and the Lewis acid.

Still there were some examples of succesful alkylations of anisole.

Perhaps not with AlCl3.

I don't read Russian anyway, although I suppose they have drawn some rxn schemes.

But thanks again.

[Edited on 13-1-2007 by Sauron]
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Dextrose
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[*] posted on 13-1-2007 at 08:57


Quote:
I know that propionyl chloride can be used in the first step, but i would really like to avoid that one.


As i wrote, i would like to avoid F/C, since i don't like acyl-/alkyl-halides.

The question was, is this condensation possible with any catalyst at all?

Thanks.

I've read heavily up on my McMurry, Carey, etc. in the past months, so please don't ask me to plow more books.
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Nicodem
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[*] posted on 13-1-2007 at 09:03


Quote:
Originally posted by Dextrose
The question was, is this condensation possible with any catalyst at all?

I thought it was obvious the answer was "No"?
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Sauron
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[*] posted on 13-1-2007 at 09:07


I believe Nicodem called that "condensation" complete nonsense.

There's your answer. I won't quarrel with him.

I think you had best plan on ploughing through a lot more books. A few undergrad tests for a few months? I've been at this for 40 years and I still plough through a lot of books. We call that using the chemical literature, and a chemist regards it as home and hearth and mother's milk.
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[*] posted on 13-1-2007 at 09:10


Quote:
Originally posted by Nicodem
Quote:
Originally posted by Dextrose
The question was, is this condensation possible with any catalyst at all?

I thought it was obvious the answer was "No"?


No it wasn't obvious to me, but if the answer is a no, i would like to hear your argumentation why, so i can increase my knowledge.
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[*] posted on 13-1-2007 at 09:13


@leu was kind enough to point out why AlCl3 is not the way to go and to cite a reference that gives a feasible procedure.

Khim.Farm.Zh.; RU; 21; 5; 569-573 (1987)

Go to the Wanted References and Translations thread in References forum, obtaining a PW if you don't have one. Ask politely for help in obtaining that article and if it in Russian language as seems probable, ask for a translation.
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[*] posted on 13-1-2007 at 09:23


Thank you.

I must admit that AlCl3 as catalyst was just a wild guess, but i had no other ideas.

Will aquire the reference, ask politely (:P) and study some more.
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Sauron
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[*] posted on 13-1-2007 at 09:38


A wise plan of action.
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Nicodem
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[*] posted on 13-1-2007 at 10:07


Quote:
Originally posted by Dextrose
No it wasn't obvious to me, but if the answer is a no, i would like to hear your argumentation why, so i can increase my knowledge.

Because there is no viable mechanistic explanation for such a condensation. And besides, propanal in the presence of AlCl3 immediately creates tar due to the alpha-hydrogens condensing with the aldehyde group. Even if an aldehyde without alpha-hydrogens would be used, for example benzaldehyde, one would utmost obtain only the Friedel-Crafts reaction product, namely the SMILE code Clc1cc5OCOc5cc1C(c2cc3OCOc3cc2Cl)c4ccccc4
in the case of 6-chloro-1,3-benzodioxole and benzaldehyde.
Quote:
Originally posted by leu
Aluminum chloride is incompatible with methylenedioxy bridges, since the result will be polymerization

Actually, according to Kinetic, AlCl3 can be used in the Friedel-Crafts reaction of benzodioxole with Et-COCl if nitromethane is used as a solvent at 0°C. The yield was a bit on the low side (40%), which is however still very much better than the complete cleavage that happens in CH2Cl2, for example. In my personal opinion the same yield might be obtainable by using propanoic acid in polyphosphoric acid, but such Friedel-Crafts acylation is a bit tricky and a good strength polyphosphoric acid must be used (pyrophosphoric acid made from H3PO4 only gives a terribly low yield on a substrate similarly reactive as benzodioxole).




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[*] posted on 13-1-2007 at 16:14


There is a nice paper about FC reaction using the free acid and carbon/p-toluenesuphonic acid as catalyst and reactant... it is quite new and published in thieme synthesis... there is no need for the acyl chloride nor for polyphosphoric acid in this paper...
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[*] posted on 13-1-2007 at 22:07


Citation please for the sake of those who want to look this up.
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[*] posted on 14-1-2007 at 01:44


I think Ullmann is refering to Helvetica Chimica Acta, 88(8 ), (2005), 2282 - 2287. If there is really a similar paper in Synthesis, I'm unaware of it. The referred paper can be found in the old Wanted References and Needed Translations (about in the middle of the thread, requested by Vitus and uploaded by Mephisto). However, the authors have not included any examples using benzodioxole. Nevertheless it just might survive the conditions of 17mol% TsOH at 90°C that they use.
Seems like benzodioxole can survive even the toughest protic acids as long as they are in catalytic amounts only. For example, in US6342613 they condense propionic anhydride with benzodioxole with perchloric acid as Friedel-Crafts catalyst at room temperature. That is only 2.6mol% of catalyst and at a lower temperature, but nevertheless the acid is added to plain benzodioxole at 0°C before the addition of the anhydride. The yield is only 36%, but the unreacted benzodioxole gets recovered.

Edit:
I checked Synthesis for any papers using graphite and a protic acid for the Friedel-Crafts acylation and could only come out with two papers from the same Iranian authors as for the Helv. Chim. Acta paper. In both papers they use the less accessible and more expensive methanesulfonic acid in a much higher mol%. One from 2005 is about the acylation of phenols, but an older one from 2004 (attached bellow) is about phenol ethers acylation. The paper must have never seen any peer reviewer as it is full of terrible errors (just look the last two entries in Table 2!). Just another blatant example of how the peer reviewing system slowly decays dragging the academic science with it. Now I have serious doubts about their method especially since they use way more methanesulfonic than they later use tosylic acid on same substrates at the same conditions. But most annoying is the presence of the entry 8 in Table 2 with the 2-pyridinecarboxylic acid which would definitively neutralize/quench the 50mol% MeSO3H used as catalyst! Looks like Synthesis is getting as shitty as Tetrahedron Letters!

[Edited on 14-1-2007 by Nicodem]

Attachment: s-2004-831162.pdf (588kB)
This file has been downloaded 3134 times

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[*] posted on 14-1-2007 at 12:21


To go back to the first post: it may be possible to react the organomagnesium compound derived from 1-halo-3,4-methylenedioxybenzene with propionitrile. Hydrolysis of the thus formed iminium salt yields the corresponding propiophenone.



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Sauron
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[*] posted on 14-1-2007 at 17:49


Calling Dr Grignard!
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[*] posted on 15-1-2007 at 00:32


what about ketonization of piperylic acid with propionic acid?
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[*] posted on 15-1-2007 at 17:23


I once posted the paper mentioned above by Nicodem and Ullman to the russian HyperLab forum, below follows experimental procedure:

---------------------------------------------------------

Speaking of arylketones...

Solvent-Free Catalytic Friedel-Crafts Acylation of Aromatic Compounds with Carboxylic Acids by Using a Novel Heterogeneous Catalyst System: p-Toluenesulfonic Acid/Graphite

Sarvari, Mona Hosseini; Sharghi, Hashem. Chemistry Department, College of Sciences, Shiraz University, Shiraz, Iran. Helvetica Chimica Acta (2005), 88(8), 2282-2287.

Abstract

TsOH/graphite was found to be an effective catalyst system for the Friedel-Crafts acylation of aromatic compounds with carboxylic acids. Both aliphatic and aromatic carboxylic acids reacted smoothly under TsOH/graphite catalysis to afford the corresponding aromatic ketones in high yields. The graphite was easily recovered by simple extraction and could be reused without decrease of activity in the presence of fresh TsOH.

Acylation of Aromatic Compounds, General Procedure: To a mixture of graphite (CAS No.7782-4 2-5; fine powder extra pure, from Merck; 0.3 g, 25 mmol) and anh. TsOH (0.03 g, 0.17 mmol) at 90 C in an oil bath the aromatic compound (1 mmol) and carboxylic acid (1 mmol) were added. The mixture was kept at 90 C while stirring with a mechanical stirrer for the time required to complete the reaction (see Table 2; TLC or GC monitoring). The solid mass (graphite) was then extracted with AcOEt (20 ml) and the AcOEt extract washed with aq.NaHCO3 soln., dried (Na2SO4) and evaporated: practically pure product. Yields are excellent.

What a lazy referee at Synthesis missing such obvious errors... :o :P

Quote:
Originally posted by Sergei_Eisenstein
To go back to the first post: it may be possible to react the organomagnesium compound derived from 1-halo-3,4-methylenedioxybenzene with propionitrile. Hydrolysis of the thus formed iminium salt yields the corresponding propiophenone.


I have posted a paper (Org. Lett IIRC) in which a method is presented that involves the preparation of arylzinc reagents from elemental Zn (dust) in dimethylacetamide (I2 catalyzed), these reagents react with acylhalides (I guess anhydrides would also work) to give corresponding phenones (one-pot)... Relevant thread can be found using tfse (Sandmeyer Knochel).

[Edited on 16-1-2007 by Sandmeyer]




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stoichiometric_steve
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[*] posted on 29-9-2007 at 04:42


Quote:
Originally posted by Sandmeyer
Solvent-Free Catalytic Friedel-Crafts Acylation of Aromatic Compounds with Carboxylic Acids by Using a Novel Heterogeneous Catalyst System: p-Toluenesulfonic Acid/Graphite


bump! just one thought...reacting benzodioxole with a carboxylic acid the way they propose it in the above mentioned paper, i wonder if there is ever any ortho-acylated product formed?

what about acylation of benzofuran, would it be acylated next to the oxygen?

this method looks very good on paper, if you have Pd/C, DMF and POCl3, you're set for yet another easy route to the 2C-X series.
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Sergei_Eisenstein
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[*] posted on 29-9-2007 at 05:23


Quote:
this method looks very good on paper, if you have Pd/C, DMF and POCl3, you're set for yet another easy route to the 2C-X series.


If you have access to Pd/C, DMF and POCl3, all routes to 2C-X are easy.

Quote:
reacting benzodioxole with a carboxylic acid the way they propose it in the above mentioned paper, i wonder if there is ever any ortho-acylated product formed?


It may be possible that some o-acylated product is formed, but this is not the main route. If you desire to synthesize o-acylated methylenedioxyarenes, you can use organolithium chemistry.




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Epopteia
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[*] posted on 29-9-2007 at 05:39
nitromethane co-ordination of AlCl3


Quote:
Actually, according to Kinetic, AlCl3 can be used in the Friedel-Crafts reaction of benzodioxole with Et-COCl if nitromethane is used as a solvent at 0°C. The yield was a bit on the low side (40%), which is however still very much better than the complete cleavage that happens in CH2Cl2, for example.


His procedure did indeed work, but the workup is a nightmare, and I think a lot of losses happen there.

If a better workup was found it could be possible to do much better.
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stoichiometric_steve
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[*] posted on 29-9-2007 at 07:30


Quote:
Originally posted by Sergei_Eisenstein
If you desire to synthesize o-acylated methylenedioxyarenes, you can use organolithium chemistry.


actually, i'd prefer the para-acylated product, so this procedure might be worth a try.

about organolithium chemistry...i don't feel to comfortable with BuLi, it scares me just as high pressure cat.hyd. does. are my fears justified?
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