(Hive Bee)
01-14-03 22:30
No 398206
      Electrosynthesis of gamma-asarone
(Rated as: excellent)

The article has been mentioned by LR: Post 108370 (dormouse: "Synthesis of asarone from eugenol methyl ether  -Labrat", Novel Discourse) - Here follows the actual article (I heard of ppl with too much clove oil to handle wink)

Tetrahedron Letters 30(31) (1989) 4037-4040
Electrosynthesis of gamma-asarone
R R Vargas et al.

Abstract: g-asarone is synthesised in high yield, and conveniently, by anodic methoxylation of methyl eugenol, at constant current. The method is extremely simple and inexpensive.

2,4,5-trimethoxyallylbenzene (1) is one of the rarer natural allylbenzenes. It was isolated for the first time from Caesulia axillaries and named g-asarone.1 The back and wood of Aniba hostmanniana, an arboreous species of Lauraceae contain essential oils composed of ca 95% of (1).2 The only reported3 synthesis of (1) is based on the geneneral sequence of reactions: dimethoxyphenol -> allyl dimethoxyphenyl ether -> allyldimethoxyphenol -> trimethoxyallylbenzene, and the overall yield is less than 30%.
Here we report a new synthesis of g-asarone, via the anodic oxidation of methyl eugenol (2) at a platinum electrode in alkaline methanol solution and under controlled current conditions. The average yield, from several experiments, is 80% and the simplicity and low cost clearly show the advantage of this method as compared with the one previously described.3 This synthesis is another application of anodic methoxylation, a well established method which has been widely used.4
General procedure: The electrolyses were performed in an undivided cell using a Pt foil anode (2.5 x 3.5 cm) and a W wire as cathode. A solution of methyl eugenol (2.8 mmoles) in MeOH (60 mL) containing NaClO4 (6.0 mmoles) and NaOH (30.0 mmoles) was electrolyzed at room temperature (50 mA, 0.0057 Acm-2 3F/mol). After completion, MeOH was removed under reduced pressure [because of the possible formation of explosive perchlorates the mixture should never be taken completely to dryness]. Water added to the residue, the mixture acidulated with hydrochloric acid until pH 4 and extracted with ether. After concentrating under vacuum, g-asarone was isolated by column chromatography (SiO2, hex-EtOAc 3:2) and fully characterised; spectral data were according to the litterature.2 When 5.6 moles of (2) were used, under otherwise similar conditions, g-asarone was obtained in lower yields (55%).
The reaction probably proceeds through an intermediate (3) which during acid work-up originates product (1). This type of intermediate was observed during the anodic oxidation of dimethoxybenzenes.5

      CH--CH==CH2                         CH--CH==CH2                    CH--CH==CH2
      |                                   |                              |
      C                           MeO     C                              C
    /   \                             \ /   \                          /   \
   C     C                          H--C     C                   MeO--C     C
   |     |         -2e, 2 MeOH         |     |             H+         |     |
   C     C--OMe   ------------->       C     C--OMe    ---------->    C     C--OMe
    \   /              -2H+             \   / \          - MeOH        \   /
      C                                   C     OMe                      C
      |                                   |                              |
      OMe                                 OMe                            OMe
      (2)                                 (3)                            (1)

Intermediate (3) was isolated by work-up under alkaline conditions and characterised by 1H NMR. When analysed by GC/MS (3) gave a peak the at highest mass m/z 194 instead of the expected 240. This is probably due to a fragmentation, in which a molecule of dimethyl ether is lost, and (3) yields (4). [note: fragmentation and molecule (4) not shown].
The g-asarone obtained was isomerized in alkaline solution quantitatively3 into a 5:1 mixture of (E)- and (Z)-2,4,5-trimethoxypropenylbenzenes; the (E) isomer is important as a precursor in a synthesis of magnosalicin.6
As the alkaline isomerization of g-asarone showed to be very time consuming, attempts to prepare (E)-2,4,5-trimethoxybenzene via anodic oxidation directly from methyl isoeugenol (5) were made. However no nuclear methoxylation product could be isolated. In a typical experiment, the electrolysis of a solution of (5) (5.7 mmoles) in MeOH (60 mL) containing NaClO4 (6 mmoles) and NaOH (26.0 mmoles) at room temperature (80 mA, 00.91 Acm-2, 2F/mol), after work-up as described for methyl-eugenol (2), afforded two products derived from the side-chain methoxylation of (5): 1,2-dimethoxy-1-(3,4-dimethoxyphenyl) propane (6) (2.85 mmoles, 50%, erythro/threo, 2.5:1) and 1-(3,4-dimethoxyphenyl)-2-methoxy-propanol (7) (1.14 mmoles, 20%, erythro/threo, 2:1). Both structures were assigned based on GC/MS, IR and 1H/13C NMR measurements.

                                          OMe OMe             OH  OMe
                                          |   |               |   |
      CH==CH--CH3                         CH--CH--CH3         CH--CH--CH2
      |                                   |                   |
      C                                   C                   C
    /   \                               /   \               /   \
   C     C                             C     C             C     C
   |     |         -2e, 2 MeOH         |     |       +     |     |
   C     C--OMe   ------------->       C     C--OMe        C     C--OMe
    \   /                               \   /               \   /
      C                                   C                   C
      |                                   |                   |
      OMe                                 OMe                 OMe
      (5)                                 (6)                 (7)

Eugenol (8) when oxidized under similar conditions as for (2), but to 1F/mol afforded dehydrodieugenol (9)7 in almost quanitative yield. This electrochemical dimerization has been reported8 but substituting NaClO4 for LiClO4 enabled us to use solutions with eugenol concentrations of up to 0.1 M which is ten times the one originally employed. With LiClO4 and 0.1 M of eugenol the lithium salt of (9) is formed on the electrode impeding the passage of current.

      CH--CH==CH3                H2C==CH--CH       CH--CH==CH2
      |                                   |        |
      C                                   C        C
    /   \                               /   \    /   \
   C     C                             C     C  C     C
   |     |         -2e, -2 H+          |     |  |     |
   C     C--OMe   ------------->  MeO--C     C--C     C--OMe
    \   /                               \   /    \   /
      C                                   C        C
      |                                   |        |
      OH                                  OH       OH
      (8)                                     (9)

Acknowledgements: We are grateful to the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) for a scholarship (RRV) and to Programa de Apoio as Desenvolvimento Cientifico e Tecnologico (PADCT) for financial support.


1. ON Devgan, MM Bokadia, Aust J Chem 21 (1968) 3001
2. OR Gottlieb, AI de Rocha, Phytochem 11 (1972) 1861
3. AT Shulgin, Can J Chem 43 (1965) 3437
4. For leading references see S Torii, "Electroorganic synthesis: methods and applications" Part 1: Oxidations, monographs in modern chemistry, Vol 15, Kodansha, Tokyo and VCH, Weinheim, 1985.
5. NL Weinberg, B Belleau, Tetrahedron 29 (1973) 279
6. K Mori, M Komatsu, M Kido, K Nakagawa, Tetrahedron 42 (1986) 523
7. AF Dias, Phytochem 27 (1988) 3008
8. A Nishiyama, H Eto, Y Terada, M Iguchi, S Yamamura, Chem Pharm Bull 31 (1983) 2820

.: THE END :.

I'm not a specialist in electrochemistry, but I'm sure there are bees who are. This article is intended for them. Enjoy.
Also note that The only reported synthesis of (1) is based on the general... is not completely true, not even for 1989. I've seen several alfa/beta and gamma-asarone synthesis procedures. There even is a procedure involving Elbs persulfate oxidation, but the yields are less then 10%.

Ave Hive, synthetisandi te salutant!
(Hive Bee)
01-16-03 07:23
No 398635
      Methyl Eugenol synth references  Bookmark   

Possibly useful Chem Abstracts for the synthesis of Methyl Eugenol (Eugenol Methyl Ether):

94: 121019n Synthesis of Eugenol derivatives with biological activity
Oliveira, Alaide B.; Shaat, Vanilda T.; Oliveira, Geovane G. (Inst. Cienc. Exatas, Univ. Fed. Minas Gerais, Belo Horizonte, Brazil). Cienc. Cult. (Sao Paulo) 1980, 32(Suppl., Simp. Plant. Med. Bras., 5th, 1978), 130-4 (Port).
Methyl Eugenol prepd. 54-95% yields by treating Eugenol with Me2SO4-K2CO3-Me2CO or Me2SO4-K2CO3-KOH-Me2CO.

97: 215884e Substitute methylating agent for the production of methyleugenol
Nguyen Quang Huynh; Le Thanh Cam; Nguyen Trinh Kiein (Vietnam). Cong Nghiep Hoa Chat 1981,(2), 1-3 (Vietnamese).
Methyleugenol is prepd. by methylating eugenol with NaMeSO4, obtained by reacting MeOH and H2SO4 and neutralizing with NaOH. The optimal reaction conditions were given.

Mountain Boy
(Master Searcher)
03-13-03 04:18
No 416369
      See also Post 218257  Bookmark   

See also Post 218257 (PolytheneSam: "ArOR, Alternatives to dimethyl sulfate", Novel Discourse)

The hardest thing to explain is the obvious
(Hive Bee)
03-13-03 12:47
No 416528
      Anodic methoxylation is a well-known reaction.  Bookmark   

Anodic methoxylation is a well-known reaction. See for example Post 347768 (bottleneck: "1,4-Dimethoxy in two steps from benzene", Novel Discourse)

It sounds good in theory, but it is, oh, about 100 times more difficult to effect than anodic hydroxylation.

I have attempted to methoxylate anisol many times, but the choice of anodic material is absolutely crucial, and I have not been successful.

Lead should work, but doesn't. It begins to dissolve pretty quickly, ultimately short-circuiting the cell. I have tried both anodized lead (dil. H2SO4) and pure lead.

Graphite works, but graphite-electrodes are so expensive you'd need 500 dollars just to make an anode of about 100 cm2.

Platinum also works, but is even less pracitical. A small (5cm2?) platinum sheet is not going to be of any preparative use.

What we are left with is trial-and-error using home-made lead dioxide anodes or something, or hoping some "real" electrochemist will find a better material for anodic methoxylation than graphite.

I say, go for hydroxylation instead. It can be done with cheap lead in dilute suluric acid. It is much more practical, and is a time-honored way of producing hydroquinone from benzene, phenol or aniline. The reactions are almost analogous.

Besides, with the advent of non-toxic methylating agents like trimethylphosphate and methyl esters of sulfonic acids, not a lot is gained by expending a lot of effort trying to make methoxylation practical.
(Master Searcher)
03-30-03 23:44
No 422586
      Here's an interesting way of making ethers...
(Rated as: excellent)

Here's an interesting way of making ethers.
Patent US4657700

Example 1

100 g of ethylvanillyl alcohol (4-hydroxy-3-ethoxybenzyl alcohol) are dissolved in 200 ml of methanol. The solution is treated with 10 g of sodium hydrogen sulphate and a knife tip of hydroquinone. The mixture is firstly heated to 50.degree. C. for 2 minutes and left to cool again to room temperature. The methanolic solution is now poured into 85 ml of a saturated sodium hydrogen carbonate solution. The methyl alcohol is distilled off in vacuo, the residue is taken up in toluene, the organic solution is washed neutral with water and evaporated. The residue (95.5 g) is fractionally distilled. There are obtained 61.1 g of chemically and olfactorily pure 4-hydroxy-3-ethoxybenzyl methyl ether; b.p.=77.degree. C./0.03 mmHg; d.sub.4.sup.20
=1.1084; n.sub.D.sup.20 =1.529.

Yield: 56.3%.

(Note that it is a benzyl methyl ether here (above) and not a phenol ether, but it may suggest possibilities.)

Notice the part in column 7 of
Patent US5214034
which says under "IV. Catechol derivative having the formula (F) "

Examples of the acid catalyst which may be used in this method include mineral acids such as sulfuric acid, phosphoric acid, hydrogen halide etc., Lewis acids such as anhydrous aluminium chloride, zinc chloride, iron chloride, titanium tetrachloride, tin tetrachloride, boron fluoride etc., organic sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, dodecylsulfonic acid etc., organotin compounds such as dibutyltin oxide, dibutyltin dilaurate, dimethyltin dichloride etc., metal alkoxides such as titanium isopropoxide, cation exchange resin and the like.

and example 10


Preparation of 5,2,2-trimethyl-1,3-benzodioxol

A mixture of 6.21 g (50 mM) of homocatechol (commercially available special grade reagent), 15 ml of acetone, 30 mg of
p-toluenesulfonic acid monohydrate and 15 ml of benzene was heated under reflux for 48 hours with stirring. During the
reaction, a three-component azeotropic mixture composed of acetone, benzene and water as a by-product was passed through a molecular sieve packed column to remove only the by-product water. Acetone and benzene were returned to the reaction system.

After completing the reaction, the reaction mixture was distilled in vacuum to obtain 7.88 g (48 mM) of
5,2,2-trimethyl-1,3-benzodioxol as light brown liquid having a boiling point of 79.degree.-80.degree. C./9 mmHg.

IR Spectrum .nu..sub.max.sup.neat cm.sup.-1 : 2990, 2920, 2870, 1500, 1440, 1380, 1350, 1255, 1230, 1155, 1120, 1070,
1040, 980, 930, 880, 840, 825, 795, 745.

NMR Spectrum [C.sub.10 H.sub.12 O.sub.2 ]:

                    C    H
    Calculated, (%)   73.15  7.37
    Found (%)         72.87  7.13

see also
Post 227445 (Antoncho: "Re: ArOR, Alternatives to dimethyl sulfate", Novel Discourse)

which refers to Russian patent 197613 which was found with the following English abstract:

PHENOL METHYL ETHERS are conventionally prepd, by acid esterification
In the proposed method the process is improved by using a cation-exchange resin as catalyst.  In an example, 0.5 mole phenol, 0.5 -2.0 mole methanol and 23 g. resin are heated for 10 hrs. at 110 C.  The product is filtered and fractionated, yield of anisole. 98% theoretical. 

The hardest thing to explain is the obvious
(Master Searcher)
03-31-03 01:00
No 422599
      acid and CuSO4  Bookmark   

I wonder how acid, anhydrous CuSO4 (or other drying agent) and MeOH would work for making phenol methyl ethers (ie. reflux 48 hours) and/or let stand a long time (2-3 weeks?).  The drying agent might increase yields.
see also Post 422597 (PolytheneSam: "CA4:905", Chemistry Discourse)

The hardest thing to explain is the obvious
(Hive Bee)
03-31-03 11:52
No 422690
      toxicity of trimethyl phosphate  Bookmark   


do you have any experience / information on the toxicity of trimethyl phosphate?

Although it is reputed to be less toxic than say Dimethyl Sulfate, it is still pretty toxic I think.

By virtue of being a strong alkylating agent it is potentially carcinogenic.

It is also a mutagen and animal teratogen. It also has effects on animal sperm morphology.

The vapor pressure of TMP is double that of DMS.

I really don't know whether you would want to use this without a good fume hood or not....
(Hive Bee)
03-31-03 12:27
No 422698
      > do you have any experience / information...  Bookmark   

> do you have any experience / information on the toxicity of trimethyl phosphate?

No, I don't. Took a good whiff of it though.

> It is also a mutagen and animal teratogen. It also has effects on animal sperm morphology.

Oh... thanks!

I guess dimethylcarbonate or even that methylation with methanol and catalytic arenesulfonic acids is looking better and better all the time Post 418138 (bottleneck: "Etherification by cat. amounts of a tosylate?", Novel Discourse)