v16
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Eugenol Demethylation, revisted.
I know this has been discussed numerous times over the years on this board. I have investigated it periodically from time to time, and recently came
a crossed a new (to me at least) procedure. It seems most of the procedures that have been discussed in the past have had the disadvantage of using
somewhat toxic and/or expensive reagents (pyridine), or are difficult to reproduce (LiCl in DMF).
I recently came across this paper
Cleavage of aromatic methyl ethers with 1-dodecanethiol (C12H25-SH) and sodium methoxide (NaOMe)
Practical synthesis of a highly functionalized thiazole ketone
Lisa F. Frey, Karen M. Marcantonio, Cheng-yi Chen, Debra J. Wallace, Jerry A. Murry, Lushi Tan, Weirong Chen, Ulf H. Dolling and Edward J. J.
Grabowski
Tetrahedron, 2003, 59(33), 6363-6373
and of the paper
Many standard demethylation conditions were screened for the transformation of 6 to 8 (Scheme 4). In several cases (i.e. boron tribromide), competing
cleavage of the cyclopropyl ether was a problem. Fortunately, the use of a slight excess of sodium ethanethiolate in N,N-dimethylformamide
(1-Methyl-2-pyrrolidinone and dimethylacetamide were also acceptable solvents for this reaction) at 100°C effected clean demethylation of 6 with no
detected cleavage of the cyclopropyl ether.
Scheme 4: EtSNa or CH3(CH2)11SH and NaOMe, DMF, 100°C, 1 h
Because the stench of sodium ethanethiolate and the reaction byproduct, ethyl methyl sulfide, made this reaction unpleasant to run on a large scale,
we were interested in carrying out the same transformation under non-odorous conditions. Recent papers discuss the use of long chain thiols to
minimize odor so we used this work as a basis for choosing a long chain thiol for our demethylation reaction. Following a literature result, the use
of mixtures of a thiol and various lewis acids was explored.19 Unfortunately, these reactions were not successful on our substrate; however, employing
the sodium salt of a thiol afforded clean demethylation. Hence, the use of 1.7 equiv. of dodecanethiol and 1.7 equiv. of sodium methoxide in
N,N-dimethylformamide at 100°C gave an almost quantitative yield of phenol 8. Work up involved extraction of the product into aqueous base with thiol
byproducts left behind in the organic phase. The product was extracted from the aqueous layer simply by adjusting to acidic pH. This work up provided
an odor free solution of compound 8 that was used in the next reaction without further purification. Due to our success with demethylation using a
non-odorous long chain thiol, we explored the generality of the method with a few model compounds. Using the procedure described above for the
conversion of 6 to 8, the compounds shown in Table 1 were readily demethylated by heating each substrate with sodium methoxide and dodecanethiol in
N,N-dimethylformamide at 100°C. Demethylation of 4-methoxybenzonitrile and methyl 2-methoxybenzoate (Table 1, entries 1 and 2) proceeded in high
yield. Demethylation of hindered 2,6-dimethylanisole (Table 1, entry 3) was sluggish and did not go to completion. Interestingly, selective (4.9:1)
demethylation of 3,4-dimethyoxybenzonitrile (Table 1, entry 4) was observed, with preference for demethylation para to the electron withdrawing
nitrile substituent. Clearly, these results demonstrated that demethylation using a non-odorous long chain thiol and sodium methoxide was a viable
alternative to sodium ethanethiolate for a range of anisole related substrates.
Table 1: Demethylation using sodium methoxide and 1-dodecanethiol in N,N-dimethylformamide at 100°C
Entry Starting material Product(s) Yield
1  
4-Methoxybenzonitrile
4-Hydroxybenzonitrile 97%
2  
4-Methoxy benzoic acid methyl ester
4-Methoxy benzoic acid 89%
3  
3,4-Dimethoxy benzonitrile
3-Hydroxy-4-methoxy benzonitrile 17%
4-Hydroxy-3-methoxy benzonitrile 83%
4  
2,6-Dimethylanisole
>2,6-Dimethylphenol 75%a
a 21% starting material recovered
3-(Cyclopropyloxy)-4-hydroxybenzonitrile 8
To a solution of 6 (47.7 g, 0.252 mol) in DMF (450 mL) was added 1-dodecanethiol (104 mL, 0.432 mol) followed by NaOMe (23.4 g, 0.432 mol). The
mixture was heated to 100°C and aged for 1 h (monitoring by HPLC). After cooling to RT, iPAc (404 mL), water (518 mL), and 5N NaOH (45 mL) were added
and the layers mixed well. The aqueous layer was washed with iPAc (350 mL) to remove more thiol byproducts. The aqueous layer was neutralized to pH 6
by addition of conc HCl (45 mL), and the product was extracted into iPAc (518 mL). The aqueous layer was extracted with iPAc (278 mL then 150 mL). The
organic layers were concentrated and flushed with 160 mL DMF (43.7 g, 99% yield of 8 as compared to a chromatographed standard) before being used
directly in the difluoromethylation.
I was wondering if anyone had any experience with this system. Or if I could get some thoughts on attempting it with eugenol trying to produce
4-allylcatechol.
thanks
V16
[Edited on 8-8-2008 by v16]
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12AX7
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Embedded images hosted by Tripod? Ha.
Tim
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Ritter
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Isn't 4-allylcatechol one starting point for MDMA? Hmmm... There's lots of stuff on this over at Erowid.
Ritter
=============================
\"The production of too many useful things results in too many useless people.\"
Karl Marx
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Klute
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I don't think we should dismiss this kind of discussion simply because it cna be used to form a precursor to MDMA, which doesn't seem like a practical
way in any case. Demethylation, or dealkylations in general, are very usefull to obtain various products from more accesable compounds.
In any case, I guess most "receipe cooks" won't go looking out for dodecanthiol... So this procedure can be more usefull for people with chemistry
background, affording better yeilds in delicate reactions. I don't see any reason to close this discussion on the absics that it can be applied to
drug manufacture. Without wanting to start the debate again, any discussion on alkylations, condensation, reductions could fall under the sama
amalgam.
V16, could you kindly attach the papers so that we could see the tables and diagrammes? Thanks in advance.
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
-Alice Parr
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v16
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I am planing to go down to the library to grab it Monday. I read the abstract online, and was able to find the section i posted from another web
site, but the whole paper wasn't posted there, hence the less the perfect images. If anyone has journal access from home and can post a link to the
paper, let me know.
V16
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v16
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Here is the paper link.
Cleavage of aromatic methyl ethers with 1-dodecanethiol (C12H25-SH) and sodium methoxide (NaOMe)
link
http://rapidshare.com/files/136936029/paper1.pdf.html
also came across this paper
Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine
link
http://rapidshare.com/files/136936703/demethyl.pdf.html
it is interesting because it shows a demethylation of a somewhat similar molecule to eugenol that contains a methyl ether and a alkene. It is
performed using NaH/ 2-propane thiol in DMF. Yield is 38%, sadly they also found that a pyridine based system ultimately gave the best yields (68%)
I do not totally understand the chemistry of the thiol reaction. If someone could point me to a good chapter to read I would be grateful. But so far
it seems that a thiol system might yield a new approach to this tough demethylation.
V16
V16
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Klute
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Well, the thiolate anion, formed by reaction between the methoxide and thiol, simply acts like a nucleophile, as I- would, producing a methyl thiol
ether and the phenoxide.
I think some proceudres also use a Lewis acid to make the oxygen more "nucleophobic".
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
-Alice Parr
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