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All 25 posts   Subject: 3-Meo-4-Me-BA Proposal.   Please login to post   Down

(Hive Bee)
09-01-04 17:04
No 528883
      3-Meo-4-Me-BA Proposal.     

As you know 3-methoxy,4-methylbenzaldahyde is a use precursor or making MMA and MMAI.

There have been a lot of posts about creating the 3-hydroxy-4-methyl-BA compound using toulaldahyde. Post 429604 (GC_MS: "translation", Chemistry Discourse)
According to the post this is accomplished via nitration of the the precursor followed by reaction with Sn(II)Cl2*2H20.

The reaction seems high yielding unfortunately to make the methyl ester on the 3rd position a methylation agent is used, in the example Dimethyl Sulfate is used, although I assume both Methyl Iodide and Trimethyl phosphate can be used. 

Most chemist including myself would prefer to avoid usage of these cancerous methylating agents so here is my proposal. More so a question to whether this proposal will work.

1.) The touladahyde is mono-brominated at the 3/5th position.

2.) This then undergoes a substitution reaction using a Sodium Methoxide as the base. The 3/5 position is meta towards the aldahyde group.

* In 5-bromovanillin the bromo group is also meta towards the aldahyde and the substitution seems to work well. The aldahyde is deactivating towards the meta position which favors the nucliophillic substituion

Any comments would be greatly appreciated.
(Hive Bee)
09-01-04 18:16
No 528896
(Rated as: good read)

There is only a single method in the literature for the bromination of para-tolualdehyde, using bromine and AlCl3. The two articles dealing with this are J. Org. Chem., 23, 1412-1416 (1958) and Org. Synth. Coll. Vol. V, 117-120 (1973) ( The yield of 3-bromo-4-methylbenzaldehyde in the Org Syn article is a little low and I'm sure there are better ways for bromination to be carried out; AlCl3 as catalyst seems overkill. Unfortunately you may be limited somewhat with the neater methods (such as oxidant/bromide source) as the aldehyde is susceptible to oxidation.

I haven't seen any Cu-catalysed methoxylations in the presence of aldehydes. The literature has examples of alkoxylation in the presence of aryl ketones, carboxylic acids, amides and esters. Unfortunately this may be because the reaction cannot be performed in the presence of aldehydes: copper (II) salts (the sulfate is generally used in Benedict's reagent) are well known as analytical reagents for oxidising aldehydes to carboxylic acids. During the Cu (I) catalysed methoxylation the salt will disproportionate to copper metal and Cu (II), the latter of which may destroy your product.

I assume you've seen both of the related methoxylation articles archived at Rhodium's site? I have the latter as a pdf if you would like it (I know some people have trouble with viewing DejaVu files):

Tet Lett 46(6) 1007-1010 (1993) (
Tetrahedron 45(17) 5565-5578 (1989) (

Edit: According to, as well as several other online sources, Benedict's reagent will not react with aromatic Hopefully your idea will work after all.
(Hive Bee)
09-01-04 21:31
No 528940
      Bromination via Oxone.     

Thanks for the info kinetic, I've found a few posts of people brominating vanillin using the oxone method, the aldahyde group seems to not be oxidized during the reaction.

Maybe, this product would be a somewhat substitute for mdma.
(Chief Bee)
09-02-04 06:53
No 529056
User Picture 
      p-Tolualdehyde -> 3-Bromo-4-Methylbenzaldehyde
(Rated as: good read)

The article mentioned above in Post 528896 (Kinetic: "Bromination", Methods Discourse)

The Swamping Catalyst Effect. II. Nuclear Halogenation of Aromatic Aldehydes and Ketones
D. E. Pearson, H. W. Pope, W. W. Hargrove, and W. E. Stamper
J. Org. Chem. 23, 1412-1419 (1958) (

Sufficient aluminum chloride to complex with aromatic carbonyl compounds completely has been found to deactivate the aliphatic side chain toward substitution and to permit nuclear substitution. In this manner, good yields of 3-bromo-, 3-bromo-4-methyl-, 3,4-dibromo-, 3-bromo-4-tert-butyl-, 3-bromo-4-ethyl-, and 3,5-dibromo-4-methylacetophenones and of 3-bromobenaaldehyde, 3-bromo-4-tolualdehyde, 3-bromopropiophenone, and 3,3'-dibromobenzophenone have been obtained. Good yields of chloroaldehydes and ketones, including tetrachloroacetophenones, and fair yields of iodoketones have also been obtained by this method using the reagents chlorine and iodine monochloride, respectively. No other catalyst has been found to function in the same manner as aluminum chloride or bromide.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
09-06-04 13:08
No 529886
User Picture 
      Cu(I) catalysed aromatic nucleophilic substitution
(Rated as: good read)

Besides the ones mentioned in Post 528896 (Kinetic: "Bromination", Methods Discourse) there are a few other articles on the copper-catalyzed alkoxylation of alkyl halides available, of which two can be found on the Hive:

Post 475380 (Rhodium: "Cu-Catalyzed Aryl Halide Heteroatom Coupling", Novel Discourse)
Post 529885 (Rhodium: "Cu-Mediated Arene-Heteroatom Bond Formation", Novel Discourse)

Below are three articles not available in the Hive database. The first two are of definite interest to us, while the last review might deal with other nucleophiles (such as amines and nitrogen heterocycles) instead of alkoxides, and thus are outside our sphere of interest.

Copper(I) halide catalysed synthesis of alkyl aryl and alkyl heteroaryl ethers
M. A. Keegstra, T. H. A. Peters and L. Brandsma, Tetrahedron 48(17), 3633-3652 (1992)

A number of alkyl aryl and alkyl heteroaryl ethers have been prepared from (hetero) aryl halides (mainly bromides) and sodium alkoxides, using copper(I)bromide as a catalyst. The influence of the main solvent, the halogen atom, reaction temperature and the presence of oxygen upon the rate and selectivity has been studied. Furthermore the decomposition of the catalyst and the reduction of the aryl halide are studied.
____ ___ __ _

Copper(I) catalysed aromatic nucleophilic substitution: A mechanistic and synthetic comparison with the SRN1 reaction
W. Russell Bowman, Harry Heaney, and Philip H. G. Smith, Tetrahedron Letters, 25(50), 5821-5824 (1984)

Evidence is provided to support a mechanism for Cu(I) catalysed aromatic nucleophilic substitution via inner-sphere electron-transfer and a Cu(III) intermediate, and to show the synthetic potential for Cu(I) catalysis relative to the SRN1 reaction.
____ ___ __ _   

Tetrahedron Report #163
Copper assisted nucleophilic substitution of aryl halogen

James Lindley, Tetrahedron 40(9), 1433-1456 (1984)

The Hive - Clandestine Chemists Without Borders
(Hive Bee)
09-06-04 20:33
No 529947
      Less toxic methylations
(Rated as: good read)

The first Tetrahedron article (Brandsma et. al.) is very interesting. It is a detailed study much like the previous one by Aalten et. al. Aryl fluorides can be selectively displaced in the presence of bromide substituents, and vice-versa. There is also an interesting trifluoroethoxylation of an aryl chloride. I have two pages missing from my copy (that is the last time I visit the library under the influence of IAP), so I will post the article tomorrow when I go back to the library.


I made a stupid mistake in my previous post when I said I hadn't seen any Cu-catalysed methoxylations in the presence of aldehydes. Somehow I had forgotten Post 514141 (psyloxy: "3,4,5 precursors revisited", Chemistry Discourse) and Post 189401 (hest: "Re: 3,4,5 Trimethoxybenzaldehyde Synth", Chemistry Discourse). Your proposal looks to be a pretty good I'm certain the bromination can be done in better yield. The AlCl3 is only necessary to stop the alpha-bromination of the acetophenones the original procedure was designed for. This isn't a problem with the aldehyde, of course.

As your reason for not wanting to follow the nitration/reduction/diazotization/hydroxylation/methylation route was the toxicity of the methylating agents, I did a search for some less toxic methods. I retrieved the one I have online access to and which doesn't appear to have been posted.

J. Chem. Soc. 1939, 1168 uses dimethyl phthalate to methylate phenols (as potassium phenoxide); and J. Chem. Soc. Perkin Trans. 2, 4, 1992, 519-522 uses methyl acetate to methylate phenol in 70% yield using potassium carbonate as the base. I will take a look at these articles tomorrow. The patent in Post 529571 (Kinetic: "Methylations with trimethyl phosphate", Chemistry Discourse) my also be of use; trimethyl phosphate is relatively benign. The use of a stoichiometric amount of the methylating agent also means none is left over at the end of the reaction.

You could use dimethyl carbonate with potassium carbonate as base; see Post 426189 (Vitus_Verdegast: "Methylation of phenols using DMC and a PTC", Novel Discourse) and Post 432395 (Lego: "Methylation of phenol w/ DMC-derivates w/o PTC Pt1", Novel Discourse).

Although dimethyl sulfate is used in the following paper it is only used as stoichiometric amounts, so there are no 'toxic' byproducts. It should be possible to replace dimethyl sulfate with methyl tosylate. The yield is 97% for the alkylation of phenol:

Reactions in Slightly Hydrated Solid/Liquid Heterogeneous Media: The Methylation Reaction with Dimethyl Sulfoxide
D. Achet, D. Rocrelle, I. Murengezi, M. Delmas, A. Gaset
1986, 642-643

The O-methylation of alcohols and phenols with stoichiometric amounts of dimethyl sulfate in 1,4-dioxan or triglyme in the presence of solid potassium hydroxide and small amounts of water represents a useful method for the synthesis of methyl ethers in high yields and with high selectivity. The complete consumption of dimethyl sulfate in this reaction avoids the problems connected with the work-up of reaction mixtures still containing excess amounts of this toxic reagent.

Methyl Ethers from Alcohols, Diols, or Phenols; General Procedure:
To a stirred solution of the alcohol, diol, or phenol (0.07 mol) in 1,4-dioxan (70ml) or triglyme (70ml) at 65oC (oil bath temperature) (40oC for 2-hydroxymethylfuran) is added crushed commercial potassium hydroxide (14g for alcohols and phenols, 28g for diols) containing ~ 15 weight % water. Then, dimethyl sulfate (0.07 mol for alcohols and phenols, 0.14 mol for diols) is added at a rate of 3 drops in 5 min. The progress of the reaction is followed by G.L.C. After completion of the reaction (1.5 h), the mixture is filtered to remove the solid material and the filtrate is distilled to give the pure methyl ether.
(Hive Bee)
09-07-04 16:43
No 530127
      Methyl Acetate Alkylation
(Rated as: good read)

Esters and orthoesters as alkylating agents at high temperature. Applications to continuous-flow processes
Maurizio Selva, Francesco Trotta and Pietro Tundo.
Chemical Society, Perkin Transactions 2, 1992 (519-522)

At high temperature (180–200 °C) esters, orthoesters, carbonates and orthocarbonates have been found to alkylate acidic compounds via a BAl2, mechanism. Phenol gives anisole with methyl acetate in the presence of potassium carbonate. Thiols and other CH-acidic compounds are also alkylated under such conditions.The results obtained under batch conditions can be repeated under continuous-flow conditions, if the base which promotes the reaction can be used in catalytic amount. Continuous-flow alkylation of thiophenol by methyl acetate on a sodium acetate-type fixed bed, and other alkylations by orthoesters or orthocarbonates on a potassium carbonate catalytic bed, have been achieved.

1 (a) Gas-phase Ion Chemistry, ed. M. T. Bowers, Academic Press, New York, 1979–1984, vols. 1–3;; (b) J. E. Bartmess and R. T. J. McIver, The Gas-phase Acidity Scale in, Gas-phase Ion Chemistry, 1979, vol. 2.
2 (a) M. Comisarov, Can. J. Chem., 1977, 55, 171; (b) C. Reichardt, Pure Appl. Chem., 1982, 55, 1867; (c) E. K. Fukuda and R. T. J. McIver, J. Am. Chem. Soc., 1979, 101, 2498.
3 (a) P. A. Bartlett and W. S. Johnson, Tetrahedron Lett., 1970, 46, 4459; (b) P. Muller and B. Siegfried, Helv. Chim. Acta, 1974, 57, 107.
4 P. Tundo, Continuous-Flow Methods in Organic Synthesis, E. Horwoord, Chichester, 1991.
5 P. Tundo, G. Moraglio and F. Trotta, Ind. Eng. Chem. Res., 1989, 28, 881.
6 P. Tundo, F. Trotta, G. Moraglio and F. Ligorati, Ind. Eng. Chem. Res., 1988, 27, 1565.
7 P. Tundo, F. Trotta and G. Moraglio, J. Chem. Soc., Perkin Trans. 1, 1989, 1070.
8 See ref. 4; ch. 4.

Article which kinetic mentioned in the post above.
(Hive Bee)
09-07-04 18:41
No 530142
      Phenol methylation with dimethyl phthalate
(Rated as: good read)

This is the second of the methylation papers mentioned above in Post 529947 (Kinetic: "Less toxic methylations", Methods Discourse). It should be possible to use pre-made potassium methoxide instead of preparing it in-situ as the authors did in 1939.

Phthalic Esters as Alkylating Agents
Harold King and E. V. Wright
Journal of the Chemical Society
1939, 1168-1170

A new method is described for the alkylation of phenols in good yield. It consists in heating, to 190-200o, a salt of the phenol, preferably the potassium salt, with a molecular proportion of an alkyl phthalate.

Preparation of anisole
Potassium (3.91 g.) was allowed to react with ice-cold methyl alcohol (30 c.c.) and then phenol (9.4 g.) and methyl phthalate (19.4 g.) were added. The excess of methyl alcohol was removed by warming under diminished pressure and the syrupy residue was heated, in a flask fitted with an air-condenser, in an oil-bath at 190—200° for 3 hours. When cold, the partly solid mass was dissolved in water and ether and the ether-soluble portion was washed with 2N-sodium hydroxide and fractionally distilled. The fraction, b. p. 150—200°, was redistilled, the anisole then boiling between 152° and 156°; yield, 8.1 g. (75%).
(Hive Bee)
09-07-04 19:29
No 530151
      Cu catalysed nucleophilic aromatic substitutions
(Rated as: excellent)

Copper(I) Halide Catalysed Synthesis of Alkyl Aryl and Alkyl Heteroaryl Ethers
Menno A. Keegstra, Theo H. A. Peters and Lambert Brandsma
48(17), 3633-3652 (1992)

A number of alkyl aryl and alkyl heteroaryl ethers have been prepared from (hetero) aryl halides (mainly bromides) and sodium alkoxides, using copper(I)bromide as a catalyst. The influence of the main solvent, the halogen atom, reaction temperature and the presence of oxygen upon the rate and selectivity has been studied. Furthermore the decomposition of the catalyst and the reduction of the aryl halide are studied.

Copper(I) Catalysed Aromatic Nucleophilic Substitution: A Mechanistic and Synthetic Comparison with the SRN1 Reaction
W. Russell Bowman, Harry Heaney, and Philip H. G. Smith
Tetrahedron Letters
, 25(50), 5821-5824 (1984)

Evidence is provided to support a mechanism for Cu(I) catalysed aromatic nucleophilic substitution via inner-sphere electron-transfer and a Cu(III) intermediate, and to show the synthetic potential for Cu(I) catalysis relative to the SRN1 reaction.

Tetrahedron Report Number 163:
Copper Assisted Nucleophilic Substitution of Aryl Halogen

James Lindley
40(9), 1433-1456 (1984)


Scope of Copper Assisted Nucleophilic Displacement of Aryl Halogen
Reaction With Nitrogen Nucleophiles
  With ammonia
  With amines
  With imides and amides
  With azide
Reaction With Oxygen Nucleophiles
  With phenols and phenoxide
  With alcohols and alkoxides
  With carboxylic acids and carboxylates
Reaction With Sulphur Nucleophiles
  With arene thiolates
  With alkyl thiolates
  With other sulphur nucleophiles
Reaction With Halide
Reaction With Phosphorus Nucleophiles
  With phosphite esters
  With tertiary phosphines
Reaction with Carbon Nucleophiles
  With active methylene carbanions
  With cyanide
  With alkynide
  With alkyl and aryl copper compounds
Mechanistic Considerations
  Nature of catalyst and solvents effects
  Kinetics and mechanism
Other Metal Assisted Nucleophilic Substitutions
(Hive Bee)
09-07-04 21:51
No 530183
      Bromination of an Acetophenone via Oxone
(Rated as: excellent)

Bromination of Activated Arenes by Oxone® and Sodium Bromide
Kee-Jung Lee,* Hye Kyung Cho, and Choong-Eui Song.
Bull. Korean Chem. Soc. 2002, Vol. 23, No. 5 (773-775)

General Procedure for the Preparation of Bromoarenes.
Sodium bromide (5 mmol, 0.51 g) was added to a stirred solution of arenes (5 mmol) in 30 mL of CH3CN-H2O (2 : 1 v/v), and then followed by the dropwise addition of Oxone® (5 mmol, 3.07 g) in 10 mL of H2O. Reactions were  ontinuously monitored by thin-layer chromatography and stirred at r.t. for generally 0.5 h to 24 h.

The reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with Et2O (3 ´ 30 mL). The combined organic layers were washed with water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was crystallized with petroleum ether or chromatographed on a silica gel column and eluted with hexane-ethyl acetate 15 : 1 to give the products.

It should be worth noting that the acetophenone, in the example, (edit) 4-amino-acetophenone is brominated with a 93% yield. The reaction time is 0.5h.
(Hive Addict)
09-07-04 22:00
No 530186
      That's 4-aminoacetophenone.     

That's 4-aminoacetophenone.

fear fear hate hate
(Hive Bee)
09-08-04 16:46
No 530321
      Bromination of deactivated arenes
(Rated as: excellent)

Unfortunately there is a vast difference between 4-aminoacetophenone and 4-methyacetophenone (or 4-methylbenzaldehyde).

The NaBr/oxone method is a nice procedure for the bromination of activated arenes, and activated arenes only. I'm pretty certain it won't work on something as deactivated as a methyl substituted benzaldehyde, having a roughly comparable electronic environment to methyl benzoate (entry 13 in the paper) which does not react under the conditions. The slightly activating methyl group does not make up for the deactivating aldehyde function. The similar method in Syn Comm 32(15) 2313-2318 (2002) ( agees with this as other non-activated arenes do not react under the conditions.

Fortunately, there are plenty of other options. If I were to try this I would add a slight excess of bromine, dropwise, to the arene dissolved in glacial acetic acid containing 10-100mol% ZnCl2. It will be very easy to see whether the reaction is working as the bromine colour should disappear on addition to the solution of arene. You may need to heat the solution to get the reaction going at a decent rate.

If that were to fail, there are several other methods for brominating deactivated arenes. A literature search for the ortho-bromination of benzaldehyde gives the following references. The second is probably the most interesting as it simply uses bromine in CCl4 at 50oC:

Bromination by means of sodium monobromoisocyanurate (SMBI)
Organic and Biomolecular Chemistry, 1(14), 2506-2511 (2003)


A variety of aromatic compounds with both activating and deactivating substituents were brominated with sodium monobromoisocyanurate (SMBI)1, diethyl ether, diethyl ether–methanesulfonic acid, trifluoroacetic acid, or sulfuric acid were employed as solvents. Thus nitrobenzene was conveniently brominated in sulfuric acid, benzene was readily monobrominated in diethyl ether–methanesulfonic acid, and phenol was selectively brominated at the ortho position under mild conditions in refluxing diethyl ether. With substituents that are easily protonated, trifluoroacetic acid may be employed as solvent in the reaction with 1, in contrast NBS was ineffective in trifluoroacetic acid. This renders 1 a superior reagent relative to NBS. In addition to aromatics, alkenes, ketones and esters were also brominated with 1. Diethyl malonate was brominated with 1 and then subjected to a Bingel reaction with NaH to afford the desired methanofullerene in reasonable yield.

Change of orientation in electrophilic substitution of benzaldehydes by O-alkyloximation derivatives
Hiroshi Goda,* Hirotaka Ihara and Chuichi Hirayama
Tetrahedron Letters
35(10), 1565-1568 (1994)


By the introduction of O-alkyloxyimino group, orientation in electrophilic substitution of benzaldehyde can be selectively controlled.

A Convenient New Method for the Bromination of Deactivated Aromatic Compounds
Jianxin Duan, Lian Hao Zhang, William R. Dolbier, Jr.*
1999, No. 8, 1245–1246

Treatment of deactivated aromatic compounds with N-bromosuccinimide in trifluoroacetic acid solvent in the presence of sulfuric acid gave the corresponding monobromoaromatic compounds in good to excellent yields.

In my opinion the most promising route would be to adapt the method from Chemistry Letters 32(10), 932-933 (2003), which gives a 99% yield of 3-bromo methyl benzoate from methyl benzoate and NBS, using FeCl3 catalyst. The system is so powerful it can even brominate nitrobenzene. The article is available online for free, and has been posted by demorol in Post 459979 (demorol: "High-Yielding Halogenations using Halosuccinimides", Chemistry Discourse).
(Hive Bee)
09-10-04 13:55
No 530638
User Picture 
      4-methyl-3-methoxy-P2P from isothymole proposal
(Rated as: excellent)

As you know 3-methoxy,4-methylbenzaldahyde is a use precursor or making MMA and MMAI.

This post might sound a little off topic after the original goal of this thread diverted to a quite interesting halogenation and nucleophylic aromatic substitution discussion. Nevertheless, I thought to share this idea of getting to the above mentioned amphetamines from certain more or less easily obtainable terpene,  carvacrol (1):


O-methyl-carvacrol  (2):
The idea was to methylate carvacrol (1, alias isothymol) with any of the numerous methods available. The easier, less troublesome and relatively safe might be the methylation with Na(MeO)SO3 as in Post 256342 (Antoncho: "Methylation of hydroquinone w/NaMeSO4: good news!", Novel Discourse) but that is just a personal preference while many other alternatives are available: Post 452497 (Aurelius: "Methylating", Methods Discourse).

2-(3-methoxy-4-methylphenyl)propan-2-ol  (3):
There is a paper in the Wanted references that I so eagerly awaited. It is the review of “Dioxirane epoxidation of alkenes” requested by Rhodium and delivered by Lugh (Post 530567 (lugh: "Organic Reactions Articles Sans Tables", Novel Discourse)). Besides the information that I waited for, I also noted that dimethyldioxirane (DMDO), the infamous shock sensitive OTC explosive easily prepared from acetone and H2O2, is capable of oxidizing the tertiary benzylic position to the appropriate alcohol. Such benzylic compounds are also otherwise quite easily oxidized by oxygen radicals by other methods (see Post 513325 (Nicodem: "Phenylcyclohexane as starting material for PCA", Novel Discourse) under point 1). However, I’m sure that the yields are higher and the preparation easier by using DMDO. Anyway, we should read more about it*. (Working with DMDO is dangerous due to its detonation potential and special care should be taken to avoid handling dry DMDO crystals!)
* a review on tertiary benzylic oxidations with DMDO: Adam, Smerz, Zhao. J. Pract. Chem. 339 (1997) 298.

4-methyl-3-methoxy-alpha-methyl-styrene  (4):
The tertiary alcohols, especially benzylic alcohols, are easily dehydrated into the corresponding styrenes. This can be done by refluxing in an appropriate solvent together with a catalytic amount of p-toluenesulphonic acid or simply by dehydrating with sulphuric acid. There are numerous examples of this elimination reaction described in the literature.

4-methyl-3-methoxy-phenylacetone  (5) :
The alpha-methyl-styrene can be transformed into the appropriate phenylacetone in one step as described in Post 530316 (Rhodium: "Novel route to P2P from alpha-methylstyrene", Novel Discourse) with a not so good yield.
As an alternative the 3-MeO-4-Me-alpha-methyl-styrene can be first epoxidazed, with DMDO for example*, and then rearranged with oxalic acid like in Post 512034 (Rhodium: "Both phenyl-1,2-propanediols will do!", Novel Discourse) (point II) where the glycol is used but it should work just the same (or better) with the epoxide since it gets hydrolyzed in situ. See also other posts in the thread Post 411744 (Rhodium: "New P2P syntheses from industrial chemicals", Novel Discourse), Post 43910 (CheshireHouse: "alpha-methyl styrene", Serious Chemistry) and in .
* DMDO is mentioned just to keep on the subject but of course many other methods exist and also the performic acid method to get the glycol directly instead should be kept in mind.

This should be applicable also to certain other “thymoles”. By using thymole itself which is an OTC photography chemical you should get 4-methyl-2-methoxy-phenylacetone, but I don’t know if the parent 5-desmethoxy-DOM compound posses any activity. I also think carvacrol could bee prepared by refluxing carvone in a strong acid. Any critique is welcome.

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Addict)
09-10-04 19:20
No 530677
      Nice thinking Nicodem, very nice!     

Nice thinking Nicodem, very nice!smile

The only criticism I can come up with is that the aromatic methyl group can be oxidized too, but I believe that the tertiary carbon could be oxidized selectively as the bond dissociation energy is lower for that C-H bond (considering hydrogen abstraction). Other possibilities for effecting the transformation could be the method from Post 468077 (moo: "Oxidations and brominations w/ H2O2/Br2/HBr", Methods Discourse) leading straight to the alpha-methylstyrene, or the Fe(II)/Cu(II)/peroxydisulfate radical oxidation from Patent US4146582. The latter is a bit uncertain one because the reaction mechanism is quite odd, not proceeding through hydrogen abstraction for example. I'll have to return to the subject of that reaction in general once more in another thread - interesting stuff has been laying around for too long (lazy me). Etard reaction (chromyl chloride) might be a possibility too, but then one would have to change the rest of the route a bit as the product would be 3-methoxy-4-methylhydratropic aldehyde.

fear fear hate hate
(Hive Bee)
09-11-04 08:06
No 530816
User Picture 

...for your thoughts Moo.

I don't think there is the slightless chance of the methyl group geting oxidized. Like you said the H abstraction energy is much lower for the 2-propyl group. I'm quite sure the DMDO oxidation is completely selective to the tertiary benzylic possitions. However, I will see if I can get that review. Probably not, so I might ask in the Wanted ref.

The idea of using the method described in Post 468077 (moo: "Oxidations and brominations w/ H2O2/Br2/HBr", Methods Discourse) to get to the alpha-methyl-styrene in one step is good. My only concern would bee that you might end also with a bromine on the ring due to its activation by the methoxy. Actually, I think this is unavoidable, but who knows what kind of activity would the resulting amphetamine have?

The idea was to use DMDO since it is so available and the reactions can be done in acetone and/or CH2Cl2. The side product of DMDO is only acetone so all you have to do to get the crude product is evaporate the acetone after you make sure all the DMDO has been consumed. There is no need for non OTC solvents and reagents.

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Addict)
09-11-04 09:38
No 530828
      My pleasure     

I don't think there is the slightless chance of the methyl group geting oxidized. Like you said the H abstraction energy is much lower for the 2-propyl group. I'm quite sure the DMDO oxidation is completely selective to the tertiary benzylic possitions. However, I will see if I can get that review. Probably not, so I might ask in the Wanted ref.

I should be able to get that ref and you bet I'm interested in it too.

My only concern would bee that you might end also with a bromine on the ring due to its activation by the methoxy. Actually, I think this is unavoidable, but who knows what kind of activity would the resulting amphetamine have?

Of course!laugh It is funny I should overlook now something I didn't overlook when writing the post on that method. Somehow I'm very sceptical of those phenethylamines where the "usual" methoxy has been replaced by a halogen... but there is only one way to know.

The product of ring bromination should be 2-bromo-4-methyl-5-methoxy-alpha-methylstyrene. If this was to be methanolysed with NaOMe/Cu the result should be 4-methyl-2,5-dimethoxy-alpha-methylstyrene, a DOM But that's off-topic...

fear fear hate hate
(Hive Bee)
09-11-04 21:43
No 530920
User Picture 
      The best spices for DOM
(Rated as: good read)

Moo, unfortunately a simple nucleophylic aromatic substitution on the resulting bromo compound is not feasible since there is no electronwithdrawing group present. Even with a catalyst it would be a bad choice. However, there are simpler and much more kitchen friendly methods to get around this problem, but first…

I just found out that getting carvacrol is a joke. Apparently the oil of many Origanum species contains it as the major component. I have seen sellers on the net offering Origanum oil with a content of carvacrol of 90%! Besides, if that is not pure enough you can use its phenol properties to purify it further, since carvacrol can be “extracted from Origanum oil by means of a 50% potash solution. It is a thick oil which sets at 20°C to a mass of crystals of melting point 0°C, and boiling point 236-237°C”. (
“It may be prepared from carvone by treatment with acids, and also by heating camphor with iodine.” (

But that is not all. As I hopped, carvacrol can be oxidized to thymoquinone which upon a simple reduction (Zn/AcOH, Al/acid, SnCl2/HCl etc.) should yield the perfect hydroquinone that could bee used in the sequence proposed above to get DOM instead of 3-methoxy-4-methyl-amphetamine.
"By oxidation with chromic acid mixture, thymoquinone results. This compound forms crystalline tables melting at 45° to 46°."  But of course the same product you get also from thymol which can even be bought OTC in its already pure form. “By oxidation it yields thymoquinone, C6H2(O2)(CH3)(C3H7), melting at 48°C.” (both citations are from The chemistry of essential oils and artificial perfumes, Vol. 2. Parry, 1921)

So, let’s consider this:

#1 Oxidize carvacrol or thymol to thymoquinone with K2Cr2O7/H2SO4 (a literature example must be out there somewhere).

#2 Reduce the thymoquinone to 2-isopropyl-5-methyl-hydroquinone with any of the numerous standard methods for reducing benzoquinones. For example, with Zn in acetic acid. Some care should be taken to avoid oxygen exposure of the product while wet as I suspect it would be even more oxidation sensitive than the plain hydroquinone.

#3 Methylate the 2-isopropyl-5-methyl-hydroquinone to 4-isopropyl-2,5-dimethoxy-toluene.
…and then continue as sketched for the carvacrol.
One concern might rise here due to the highly activated 4-isopropyl-2,5-dimethoxy-toluene, but I think that DMDO should not cause any ring hydroxylation since it is not very electrophylic and it acts trough a mechanism involving radicals. However, I’m not 100% sure about this not being a problem.

Actually the steps 2 and 3 might be possible in one-pot to avoid the reoxidation and make it easier. Vogel’s book states that the dithionite reduces quinones in the aqueous NaOH solution: “Dissolve, or suspend, 0.5g of the quinone in 5 ml. of ether or benzene and shake vigorously with a solution of 1.0g of sodium hydrosulphite? (Na2S2O4) in 10 ml of N sodium hydroxide until the colour of the quinone has disappeared.” Ether might not be necessary as the product dissolves in the aqueous phase. Then just add 2 equivalents of dimethylsulphate and proceed as the general methylation of hydroquinones described in the Organikum book. I think the side product of the sodium dithionite oxidation should not interfere, but it should not bee in excess.

OK, enough of this (semi)theoretical speculations, I think it is time for preparative literature now.

DOM from Origanum or Thyme oil? Damn, I would like to see how the law would regulate such ubiquitous precursors. There must be at least tens of plant species containing these two compounds in useful amounts. If I’m just dreaming someone please wake me up!

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Addict)
09-12-04 08:18
No 530988
      More thoughts     

That is much better. My second option would've been NaOH/Cu on the ring-brominated compound followed by methylation but that's not as good.

Those with no K2CrO7 should be able to pull off that oxidation to the quinone with H2O2 and catalytic I2, Patent EP0249289

It is told in Merck index that Carvacrol can be prepared from α-pinene by chlorination with tert-butyl hypochlorite (JACS 72, 2381)... sheesh, there are shitloads of that stuff in turpentine and it comes cheap from the hardware store by the litre. Maybe something else could be used instead of the t-BuOCl.

Looks good!smile

fear fear hate hate
09-13-04 01:12
No 531089
      Free radical chlorination     

Since the point of the benzylic oxidation is to produce an alpha-methyl styrene, couldn't a free-radical halogenation with bleach or TCCA or NBS be used, followed by dehydrohalogenation be used? This would be much more OTC.

Furthermore, if KMnO4 was used under gentle conditions, it could bee possible to make 2,5-dimethoxy p2p in a few steps--

First, a careful KMnO4 oxidation. It's very likely the acid will decarboxylate spontaneously. Otherwise, heat to remove it.:

Molecule: oxidize ("Cc1c(O)cc(C(C)C)cc1>>OC(=O)C1C(=O)C=C(C(C)(C)O)C(=O)C=1")

Molecule: decarboxylate ("OC(=O)C1C(=O)C=C(C(C)(C)O)C(=O)C=1>>C1C(=O)C=C(C(C)(C)O)C(=O)C=1")

If this doesn't work, then oxidation to yield a quinone, followed by reduction, methylation, then finally KMnO4 benzylic oxidation could yield the desired compound -- precursor for DOM and DOI. Also, KMnO4 might add to the double bond of a-methylstyrene to give the desired diol, reducing the quantity of reagents necessary.

This pill is my spacecraft
(Hive Bee)
09-13-04 17:09
No 531156
User Picture 
      The Methyl and a DMDO correction     

Yei, thanks for your input, but the point was that we need and want that methyl group to stay there. Maybe in all this excitation I failed to express myself clearly. That methyl is one of the crucial reasons why carvacrol and thymol look so promising. The goal is to prepare either 4-methyl-3-methoxy-phenylacetone or 4-methyl-2,5-dimethoxy-phenylacetone since these two yield psychedelics that are otherwise synthesized from difficult to obtain precursors. This proposal is in my opinion the most OTC and kitchen chemist friendly that I ever saw (if it works!). As you can see the chemicals needed on the way to the two P2P’s are all OTC except maybe for Oxone which is needed for the in situ generation of DMDO (well, at least in my country Oxone is not OTC, but I heard that elsewhere it can be obtained and if not, maybe ammonium persulphate might substitute it). However, now we first have to hold down the wishful thinking and examine that benzylic DMDO oxidation review to see its applicability in the reaction in question as well as its kitchen chemistry potential. If it turns out as theoretically possible we will have the opportunity to add DOM and MMA to the list of “essential amphetamines” but unlike the others on that list the essential oils needed would bee literally uncontrollable as they are everywhere around (oregano, thyme, camphor, carvone, turpentine and who know how many other ubiquitous essential oils can bee a potential source).

Yei, BTW, the oxidation of thymole/carvacrol would unlikely go the route you described. The methyl group would not be oxidized that easily. It would probably be left intact and the quinone would break into a maleic acid and other degradation products. Also the isopropyl groups tend to be quite easily oxidatively cleaved. However, if you are interested in the benzylic vs. ring oxidations you can check this review: DOI:10.1016/S0040-4020(02)01492-8. But if you would still want to use this method for 2,5-dimethoxy-phenylacetone you can already start with 2- or 3-isopropyl-phenol though I have not check their availability. Or furthermore it might be possible to “isopropylate” p-dimethoxybenzene or 2,5-dimethoxy-halobenzene as can be done for benzene in Post 517569 (Organikum: "Cumene by H2SO4 catalyzed Friedel-Crafts reaction", Chemistry Discourse) (thanks to Moo for reminding me about it).

Your question about benzylic halogenation has already been discussed and it was said that ring halogenation was unavoidable. See Post 530677 (moo: "Nice thinking Nicodem, very nice!", Methods Discourse) and the replies. Though DMDO is somewhat electrophylic and we still have to see if it leaves the highly activated benzene ring intact, we already know that the halogens and halogantion reagents are all too electrophylic to not cause ring halogenation. There are other methods, off course, to make a double bond on that isopropyl and other oxidants like KMnO4 or air in the presence of Co(AcO)2 might also be useful. It’s just that this DMDO thing caught my attention as it seams so easy, available and selective.

I must also apologize for a misinformation in one of my posts above. I confused DMDO with the “acetone peroxide”. Apparently the later is the cyclic trimer of DMDO. While acetone peroxide ([-Me2C-O2-]3) forms easily from acetone and hydrogen peroxide in the presence of an acid as a catalyst the acetone solution of DMDO (Me2C=O2) is prepared with Oxone. Acetone peroxide* is also a shock sensitive explosive while DMDO doesn’t have to be isolated. For those with access to Oxone it seams to be the best choice for peroxidations, certainly superior to the performic or other similar methods which require more chemicals and work.

* those of us who were fascinated with dangerous stuff in the early years already know what acetone peroxide is (see while the structure and some typical reactions with DMDO are depicted in

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Addict)
09-14-04 00:21
No 531199
      Dimethyldioxirane articles
(Rated as: good read)

Dioxiranes - Highly Reactive Oxidants for Stereoselective Oxyfunctionalizations
Waldemar Adam, Alexander K. Smerz, Cong-Gui Zhao
J. prakt. Chem. 339, 298-300 (1997)

The following is reference number 9 from the article above.

Epoxidations and Oxygen Insertion into Alkane CH Bonds by Dioxirane Do Not Involve Radical Pathways
Waldemar Adam, Ruggero Curci, Lucia D'Accolti, Anna Dinoi, Caterina Fusco, Francesco Gasparrini, Ralph Kluge, Rodrigo Paredres, Manfred Schulz, Alexander K. Smerz, L. Angela Veloza, Stephan Weinkötz, Roland Winde
Chem. Eur. J. 3(1), 105-109 (1997)

There's more but it remains to be scanned or digged up later. What I found interesting is the fact told in the title of the second reference. They seem to have quite a solid support for their statement. It is still obvious radical pathways aren't excluded if the reaction isn't free of eg. ferrous ions.

fear fear hate hate
(Hive Bee)
09-14-04 05:27
No 531231
      Toluene to Tolualdehyde (OTC)     

The proccedure is pretty simple and can be done with fairly good yields.


Step 1. Bromomethylation of toluene.
        This can be done using Paraformaldahyde***, HBr      (produced in-stu via NaBr and H2SO4 and GAA as the solvent.) (87% yield)
        Reference:Post 475109 (Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse)

Step 2. Coversion of Toluene to Alcohol (may not be needed).
       I can't seem to find any data, but I'm sure a base-catalysed hydrolysis would remove the bromine group and leave you with a hydroxyl group. NaBr is regenerated (but NaBr is dirt cheap anyway).

Step 3. Oxidation of Benzyl Alcohol via Oxone, NaBr.*
      Proceedure uses NaBr, Oxone and CH3CN for the solvent.
      I assume that NMP** could be used in place (NMP can be distilled out of several paint strippers) It is a polar solvent. (correct me if I'm wrong) (Yield 96%)

The advantages are that this proceedure is cheap, much cheaper than buying the tolualdahyde.  And toluene ain't that hard to come by. 1 Gallon = $10 dollars?

Does anyone have a reference proceedure for Step 2. I know it should be a relatively easy proceedure.

* There are many other ways to do this Oxidation, DMSO and catalytic HBr could be used. In which case the hydrolysis (Step 2) becomes uncess. It seems though, that yields are higher when oxidation is done w/ the alcohol.
** NMP is found in a 70-85% concentration in some paint strippers.
*** The paraformaldahyde can be replaced by trioxane which are sold as fuel bars. Post 442563 (Rhodium: "Trioxane as (para)formaldehyde substitute", Methods Discourse)90g for ~$0.95. Keep in mind the bars must be cleaned. The outside layer needs to be scaped off, and the rest of the bar crushed up and washed with acetone to remove the color.


(Hive Addict)
09-14-04 06:11
No 531234
      You could make the last two steps one by using     

You could make the last two steps one by using the Sommelet reaction (hexamethylenetetramine), but with the first reaction one has to be very careful -- bis(bromomethyl)ether is going to form and I assume it is as bad as if not worse than bis(chloromethyl)ether, a violent carcinogen. The latter is formed in mixtures of HCl and formaldehyde. If only it wasn't so...

fear fear hate hate
(Hive Bee)
09-14-04 17:39
No 531304
User Picture 
      Cool, benzylic hydroxylation in >90% yield!
(Rated as: good read)

Thanks for the papers, Moo. Too bad they (the 2nd paper) didn't use the in situ method of preparing DMDO, but I think it was only because they were interested in the reaction mechanism and did not use the method for preparative methods. Well, at least the references point to other C-H hydroxylation papers worth checking. The funny thing is that in the same paper we can also find the study of alpha-methyl-styrene epoxidation (two steps in one papersmile).

I found some other papers on DMDO oxidations and only in one of them there is a case of ring hydroxylation of a reactive aromatic but under special conditions. I still have to read on this potential problem, but even if it turns out that these potential DOM precursors are too sensitive for DMDO, this method would still bee good for preparing P2P from cumene by avoiding the use of Cl2 or Br2 (for those interested in stimulantsfrown).

Here is the ref. 9 of the first review in Moo's post. It is a good source on ideas of alternative oxidants useful for benzylic hydroxylation but it is also a thorough selectivity, reactivity and mechanistic study. Apparently there is quite a wide choice of reagents for this oxygen insertion in the tertiary C-H bond.

Tertiary : secondary : primary C-H bond relative reactivity in the one-electron oxidation of alkylbenzenes. A tool to distinguish electron transfer from hydrogen atom transfer mechanisms
Enrico Baciocchi, Francesca D'Acunzo, Carlo Galli and Osvaldo Lanzalunga
J. Chem. Soc., Perkin Trans. 2 (1996) 133

Abstract: Data of tertiary: secondary: primary C-H bond relative reactivity (TSP selectivity) for a number of electron transfer (ET) and hydrogen atom transfer (HAT) reactions of alkylbenzenes have been critically reviewed and in a few cases supplemented by additional experiments. The resulting picture indicates that there are significant differences in TSP selectivity between ET and HAT reactions. When the HAT mechanism is operating the reactivity order tertiary > secondary > primary C-H bond is always observed. This order never holds in reactions occurring by an ET mechanism where, generally, the secondary C-H bond is the most reactive one and the tertiary centre can be either more or even less reactive than the primary one. Whatever the possible reasons for these differences, it turns out that TSP C-H bond selectivity determinations can afford useful information with respect to the distinction between ET and HAT mechanisms in the oxidations of alkylbenzenes. To check this conclusion a study of TSP selectivity in the oxidation of alkylbenzenes promoted by metalloporphyrins and by microsomal cytochrome P-450 has been carried out, which has allowed us to assign a HAT mechanism to these reactions, in full accord with previous attributions.

…and meanwhile novel methods for direct alpha-methyl-styrenes to P2P’s methods continue to pop up: Post 531247 (psychokitty: "New synthesis of phenylacetones", Novel Discourse)

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
11-03-04 22:49
No 539517
      Oxidation of thymol and carvacrol to thymoquinone
(Rated as: good read)

Two points:

Firstly, amine: I strongly recommend you buy your 4-methylbenzaldehye, if at all possible. It is more expensive than toluene, but it cuts two or three steps of work out and guarantees a high purity of aldehyde. I would be surprised if the bromomethylation you propose gave more than 70% of the desired isomer, and the resulting 2- and 3-methylbenzaldehydes will be essentially impossible to remove, remaining in your mixture to give isomeric impurities all the way to your final product.

Secondly, here is a paper which details a simple oxidation of both thymol and carvacrol to thymoquinone using hydrogen peroxide:

CLV. The Oxidation of Monohydric Phenols with Hydrogen Peroxide
George Gerald Henderson and Robert Boyd, B.Sc.
Journal of the Chemical Society
, 1910, 1659-1669


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