Author Topic: Benzodioxin MDA analogue?  (Read 8877 times)

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  • Guest
Interesting route to vinyl-dihydrobenzofurans..
« Reply #20 on: July 29, 2004, 09:36:00 PM »
2,3-bis(2-hydroxyethyl)phenol is converted to 4-(2-Chloroethyl)-2,3-dihydrobenzofuran utilizing the vilsmeier reagent, triethylamine and acetonitrile as the solvent.  The vilsmeier reagent is easily prepared from DMF or NMF and POCl3.

The product is then converted to the styrene using a PTC, NaOH and KI.

4-(2-Chloroethyl)-2,3-dihydrobenzofuran (6).

To a 500-mL, three-necked, round-bottomed flask equipped with a mechanical stirrer, thermocouple, and N2 was added Vilsmeier reagent (19.3 g, 151 mmol, 2.5 equiv). The flask was cooled to an internal temperature -15 °C to -20 °C and then charged with 76 mL of CH3CN. To the cooled yellow slurry was added 2,3-bis(2-hydroxyethyl)phenol (1) (10.97 g, 60 mmol, 1 equiv) in portions over 20 min. The reaction was exothermic, and careful control of the temperature to -15 °C was required. The reaction was stirred for 30 min until it was complete as judged by the disappearance of the triol by HPLC. A dilute solution of Et3N (24.39 g, 241 mmol, 4.0 equiv) in acetonitrile (1:1 by volume) was added slowly while the temperature was maintained between -15 °C and -20 °C. The reaction was heated to 50 °C for 3 h until the mono-imidate was completely converted to the chloroethyldihydrobenzofuran. The reaction mixture was cooled to room temperature and quenched with 25 mL of water; all the salts dissolved. The mixture was concentrated to one half the original volume and charged with 80 mL of MTBE and 35 mL of water. The organic phase was separated and washed twice with 55 mL of 10% w/v H3PO4 solution in 10% w/v brine. The MTBE phase was then assayed by GC and quantitated against a 4-(2-chloroethyl)-2,3-dihydrobenzofuran (6) standard and found to contain 10.1 g of 6 (92%). Samples for NMR assays were prepared by removing MTBE under reduced pressure. 1H NMR (300 MHz, CDCl3) ä 2.95 (t, 2 H), 3.15 (t, 2 H), 3.70 (t, 2 H), 4.45 (t, 2 H), 6.60 (d, 1H), 6.70 (d, 1H), 7.05 (t, 1 H); 13C NMR (CDCl3) ä 30, 37.5, 46, 72.5, 110, 122.5, 128, 130, 137.5, 162. HRMS [M + H] calcd for C10H11ClO, 182.05; found, 183.05.

4-Vinyl-2,3-dihydrobenzofuran (2).

To a 500-mL, three necked flask containing the MTBE solution of 4-(2-chloroethyl)-2,3-dihydrobenzofuran (6), 28 mL of water, 31.7 mL (600 mmol, 10 equiv) of 50% w/w NaOH, 13.8 mL (21 mmol, 0.35 equiv) of 40% w/v tetrabutylammonium hydroxide, and 1.0 g (6.0 mmol, 0.1 equiv) of solid KI were added. The reaction mixture was heated to 50 °C for 3 h until the reaction was found to be complete by HPLC (<1 relative area % of 6 remaining). On completion of the reaction, the phases were separated at 50 °C to minimize the loss of the product into the rag layer. The rag layer was discarded. The organic phase was cooled and washed once with 45 mL of 0.5 M sodium thiosulfate in 10% w/v brine followed by a wash with 45 mL of 1 N sodium hydroxide in 10% w/v brine. The MTBE solution contained 7.3 g (83%) of 4-vinyl-2,3-dihydrobenzofuran (2). Samples for NMR assays were prepared by removing MTBE under reduced pressure or by distilling crude oil as mentioned in the text. 1H NMR (300 MHz, CDCl3) ä 3.15 (m, 2 H), 4.45 (t, 2 H), 5.25 (d, 1 H), 5.65 (d, 1H), 6.6 (d, 1H), 6.7(d, 1H), 6.95 (d, 1H), 7.05 (t, 1H); 13C NMR (CDCl3) ä 28.84, 70.78, 108.25, 115.33, 117.48, 124.65, 127.87, 134.15, 134.52, 160.09. HRMS [M + H] calcd for C10H10O, 146.07; found, 147.07.

Ref:  Organic Process Research & Development 2003, 7, 547-550


  • Guest
2,3-dihydrobenzofuran from 2-chlorophenyl ethanol
« Reply #21 on: July 29, 2004, 11:45:00 PM »
Here is a nice simple route to 2,3-dihydrobenzofuran from 2-chlorophenyl ethanol..  The only drawback is the requirement of a very strong base (NaH) to achieve good yields.  In the article they get no yield using potassium carbonate, and only a 18.2% yield using NaOCH3.  Toluene can be used alone without the ethyl acetate causing only a slight drop in yield (81.4%).

A typical procedure:

To a dry, 100 mL, three-necked, round-bottomed flask equipped with condenser, thermocouple, and stir bar was added 2-chlorophenyl ethanol (1.0 g, 5.23 mmol) with toluene (12 mL). To the flask was then added NaH (0.165 g, 6.54 mmol, 1.25 equiv.) with toluene (4 mL). The reaction mixture was heated at 40°C for 15 min before cooling to room temperature. Then CuCl (0.026 g, 0.26 mmol, 0.05 equiv.) was added with toluene (4 mL) and EtOAc (0.03 g, 0.26 mmol, 0.05 equiv.). The reaction mixture was again heated at reflux for 24 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), filtered over Celite and the cake was washed with MTBE. The aqueous layer was separated and extracted with 2x25 ml MTBE. The combined organic layers were then washed with 100 mL 1N HCl followed by 2x100 mL portions of saturated NaHCO3 solution and 100 mL saturated NaCl solution. The final solution was dried with anhydrous sodium sulfate before being concentrated under reduced pressure to give ~0.7 g product, yield 88%.

Ref:  Tetrahedron Letters 41 (2000) 4011-4014


  • Guest
As you all know, substituted ...
« Reply #22 on: July 30, 2004, 12:45:00 AM »
As you all know, substituted dihydrobenzofurans can be easily converted into the aromatic benzofurans by treatment with DDQ or Pd/C at higher temperatures.


  • Guest
More benzofuran possibilities
« Reply #23 on: July 30, 2004, 09:25:00 AM »
Thanks for the input everyone! This is getting interesting. ;)

My initial idea was to try to make 5-(2-aminopropyl)-2,3-dihydrobenzofuran which can - as Lili said - be dehydrogenated to the aromatic benzofuranyl analogue. If the one-pot cyclisation and formylation of 2-(2,4-dibromophenoxy)ethyl chloride works as hoped, I think this will still be the easiest way to get both products to test without performing two full syntheses. I still have other plans should the cyclialkylation fail.

phenethyl_man: That is a very nice method using 2-chlorophenylethanol; it's a real shame the precursor alcohol is so expensive. I researched into a simliar method last year, and have a paper detailing the synthesis of 2,3-dihydrobenzofurans from 2-aminophenylethanol via a diazo intermediate. The yield isn't great but the procedure is very easy, if you can get the 2-aminophenylethanol. Here is the paper:

Synthesis of 2,3-dihydrobenzofuran
Jan M. Bakke and Hæge M. Rohdolt
Acta Chem. Scand. Ser. B
, 34(1), 1980, 73-74

Rhodium: I also did some research on a similar method to the one you posted. I would add a slight modification to your method, however. If one were to start with 4-bromophenol, then the end product would of course be 5-bromobenzofuran, greatly assisting formylation in the desired 5-position. Phenol can be selectively brominated in the para-position using a number of reagents. The Bull Chem Soc Jpn paper I referenced in my first post in this thread had a regioselective para-bromination of phenol in 93% yield. Here is the full paper:

Halogenation Using Quaternary Ammonium Polyhalides. IV. Selective Bromination of Phenols by Use of Tetraalkylammonium Tribromides
Shoji Kajigaeshi, Takaaki Kakinami, Tsuyoshi Okamoto, Hiroko Nakamura and Masahiro Fujikawa
Bull. Chem. Soc. Jpn.
, 60, 4187-4189 (1987)

Reaction of phenols with calculated amounts of benzyltrimethylammonium tribromide or tetrabutylammonium tribromide in dichloromethane-methanol for 0.5-1h under mild conditions gave, selectively, the objective mono-, di-, or tribromophenols in good yields.

I also came across some other interesting references for the same para-bromination of phenol. In J. Chem. Soc. Chem. Commun., 23, 1996, 2679-2680, the authors para-brominate phenol in 89% yield using nothing but aqueous HBr in DMSO; I will retrieve this as soon as possible. The same transformation is carried out using elemental bromine in J. Org. Chem., 23, 1958, 280; likewise, bromine is also used in a fantastically ancient Compt Rend article. I can't find reference to any 4-bromophenol in this article, but then again I don't speak French. Here it is anyway:

Synthèse de la résorcine
M. W. Korner
Compt Rend
, 63, 564-566 (1866)

There are a lot more references, but I will finish with this patent, assigned to Dow in 1957:

Halogenation of phenols with cupric halides

Patent US2805263

It should be possible to formylate the thus formed 5-bromobenzofuran by forming the Grignard reagent and adding DMF followed by acidic workup. This works for the formation of benzaldehyde from bromobenzene in 88% yield (see

Post 512847

(Kinetic: "Grignard formylation article", Novel Discourse)
, above). The formylation certainly works if 5-bromobenzofuran is first treated with tert-butyllithium followed by DMF; for this, the article below (which may be interestig for several other reasons too):

Potent and Selective Non-Benzodioxole-Containing Endothelin-A Receptor Antagonists
Andrew S. Tasker et. al.
J. Med. Chem.
, 40(3), 1997, 322-330.

I think I'd better stop there for now.


  • Guest
Benzofurans from Isovanillin
« Reply #24 on: July 30, 2004, 09:55:00 AM »
Synthesis of Benzofurans from Isovanillin via C-Propenylation-O-Vinylation and Ring-Closing Metathesis
Tzu-Wei Tsai,ab Eng-Chi Wang, Keng-Shiang Huang, Sie-Rong Li, You-Feng Wang, Yu-Li Lin, and Yung-Hua Chena
Heterocycles 63(8), 1771 - 1781 (2004)

Substituted benzofurans derived from isovanillin were synthesized. 2-Allyl-3-alkoxy-4-methoxyphenol, prepared from isovanillin via the Claisen rearrangement, O-alkylation and Baeyer-Villiger oxidation, were chloroethylated by two-phase reaction to furnish 1-allyl-3-alkoxy-(2-chloroethoxy)-4-methoxybenzenes. The given compounds were treated with potassium tert-butoxide to undergo the isomerization of O-allyl group and dehydrochlorination of 2-chloroethoxy group to efficiently construct the precursors with C-propenyl-O-vinyl function for the ring-closing metathesis (RCM) in one pot. Then, then precursors were subjected to RCM to furnish 4,5-O difunctionalized benzofurans in good over-all yield, respectively.

General procedure for the preparation of 1-allyl-2-(2-chloroethoxy)benzene (6a-d).

To the solution of allyl phenol (5a-d) (10 mmol) in dichloroethane (15 mL) was added NaOH solution (2.4 M, 15 mL), and TBAB (10% mol) at rt. The reaction mixture was stirred, and heated to the reflux for 8 h. Then, the organic layer was separated, dried under anhydrous MgSO4, and filtered. The filtrate was concentrated to remove the excess dichloroethane in vacuo, and the resulting residue was purified by column chromatography on silical gel (ethyl acetate: n-hexane = 1:12) to give pale yellow to colorless liquids (6a-d) in good yields.

General Procedure for the Preparation of Propenyl vinyloxybenzenes (7a-d)

To a stirred solution of 1-(1-propenyl)-2-chloroethoxybenzenes (6a-d) (5 mmol) in anhydrous THF (30 mL) was added potassium tert-butoxide (0.62 g, 5.5 mmol) at rt, and the reaction mixture was under reflux for 30 min. THF was removed from the reaction mixture in vacuo, and the residue was extracted with ethyl acetate (5×20 mL). The extracted solution was dried from anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo, and the resulting residue was purified by column chromatography on silica gel (ethyl acetate: n-hexane = 1:20) to give 7a-d, respectively.

General Procedure for the Preparation of Benzofurans (8a-d)

To a stirred solution of 1-(1-propenyl)-2-vinyloxybenzenes (7a-d) (1.15 mmol) in dichloromethane (23 mL) was added Grubbs’ catalyst (50 mg, 5% mmol) at rt, and the reaction mixture was stirred for 8 h. Excess dichloromethane was removed from the reaction mixture in vacuo, and the resulting residue was purified by column chromatography on silica gel (ethyl acetate: n-hexane = 1:50) to give 8a-d.


  • Guest
2,3-dihydrobenzofurans from phenethyl alcohols
« Reply #25 on: July 30, 2004, 03:32:00 PM »

I'm not sure what you mean; phenethyl alcohol is easily and inexpensively obtained or synthesized.  It is used abundantly in the cosmetics industry and I believe it is even present in respectable amounts in many essential oils.

It can be synthesized by the reduction of ethyl phenylacetate, or a friedel-crafts alkylation with ethylene oxide and your desired aromatic.

Once you have your phenethyl alcohol, just dihalogenate it, cyclize the 2,4-dihalophenethyl alcohol using the procedure above; then form the grignard and away you go..

As I said, the drawback here is finding a suitable base to obtain a decent yield.  I think at some point I will attempt this synth using potassium tert-butoxide.

However, depending on what base you use, it may fuck w/the second halogen.  I would only use 1.0 eq of base instead of the recommended 1.25 eq if you plan on keeping the halogen intact.  It's too bad sodium methoxide doesn't cut it as a base; then you could form a precursor to an MMDA-type 2,3-dihydrobenzofuran analogue in one step.

Of course there is a million ways to go about this; basically just halogenate a phenethyl alcohol that has the para position occupied with something you can manipulate later.


  • Guest
Brominations and benzofuranyl DOM analogues
« Reply #26 on: July 31, 2004, 08:06:00 AM »
After seeing the cyclisation of 2-(2-chlorophenyl)ethanol I too thought of dibromination of 2-phenylethanol. I even included it in my post, then deleted it. My idea was essentially the same as yours: selectively dibrominate 2-phenylethanol, cyclise as in your post above (obtaining NaH shouldn't be a problem for me), then form the Grignard to formylate the ring. Dichlorination isn't a viable option here as aryl chlorides are notoriously difficult to prepare Grignard reagents from.

I deleted that part of my post because - to my amazement - the only reference I could find for a regioselective 2,4-dibromination of the similar toluene involved the use of bromine monofluoride ::)  at -78oC. The reference is J. Org. Chem., 53(23), 1988, 5545-5547. All other references appear to give an ugly mix of products.

In Chem. Lett., 32(10), 2003, 932-933, 2,4-dibromotoluene is produced in 6% yield, but appears to be a byproduct from the monobromination with NBS and FeCl3. Maybe using more NBS could produce the desired dibromo compound as the major product. But I don't have access to the journal so I can't comment further.

The authors of J. Indian Chem. Soc., 14, 1937, 157 brominate ethylbenzene with bromine in a mixture of GAA, fuming nitric acid and SO2 to give a mixture of 1-ethyl-4-brombenzene and 1-ethyl-2,4-dibromobenzene. But I don't have any more information on the selectivity.

A final paper which may actually be of use involves the (apparently) selective 2,4-diiodination of ethylbenzene with aqueous iodic acid, iodine, and sulfuric acid. The reference is J. Prakt. Chem., 14, 1961, 24-33. If you have any more references, or ideas, I would very much like to see/hear them. Two heads are better than one.

If you want to try a MMDA type benzofuran analogue, you might like to read the related articles below. I had the idea of a cyclic DOM or 2C-D analogue (dibromination of 4-methoxyphenol, O-alkylation with ethylene chloride, one-pot cyclisation and formylation with Mg followed by DMF to give the benzaldehyde) but according to the papers it has a 10-fold decrease in potency compared to DOM [Edit: Oops - this proposal will not give the desired benzaldehyde but an isomer, 7-formyl-5-methoxy-2,3-dihydrobenzofuran, whose corresponding amphetamine or PEA has not been made. Maybe they will be of interest; dehydrogenation to the benzofuran will give a hemi bis-benzofuranyl analogue]. Anyway, here are the articles:

Synthesis and Evaluation of 2,3-Dihydrobenzofuran Analogues of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane: Drug Discrimination Studies in Rats
David E. Nichols,* Andrew J. Hoffman, Robert A. Oberlender, and Robert M. Riggs
Journal of Medicial Chemistry
, 29, 302-304, (1986)

Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate saline from LSD tartrate (0.08 mg/kg), stimulus generalization occurred to both of the 2,3-dihydrobenzofuran analogues but at doses more than 10-fold higher than for DOM. A possible explanation for this dramatic attenuation of LSD-like activity could involve a highly directional electrophilic binding site on the receptor that cannot accept the orientation of the unshared electron pairs on the heterocyclic oxygen atom in the benzofurans.

2,3-Dihydrobenzofuran Analogues of Hallucinogenic Phenethylamines
David E. Nichols,* Scott E. Snyder, Robert Oberlender, Michael P. Johnson, and Xuemei Huang
Journal of Medicinal Chemistry
, 34, 276-281 (1991)

Two 2,3-dihydrobenzofuran analogues of hallucinogenic amphetamines were prepared and evaluated for activity in the two-lever drug-discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/ kg) and for the ability to displace [125I]-(R)-DOI ([125I]-(R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) from rat cortical homogenate 5-HT2 receptors. The compounds, 1-(5-methoxy-2,3-dihydrobenzofuran-4-yl)-2-aminopropane (6a) and its 7-brominated analogue 6b, possessed activity comparable to their conformationally flexible counterparts 1-(2,5-dimethoxypheny1)-2-aminopropane (3) and, its 4-bromo derivative DOB (5), respectively. The results suggest that the dihydrofuran ring in 6a and 6b models the active conformation of the 5-methoxy groups in 3 and 5. Free energy of binding, derived from radioligand displacement KA values, indicated that addition of the bromine in either series contributes 2.4-3.2 kcal/mol of binding energy. On the basis of surface area of the bromine atom, this value is 2-3 times higher than would be expected on the basis of hydrophobic binding. Thus, hydrophobicity of the para substituent alone cannot account for the dramatic enhancement of hallucinogenic activity. Although this substituent may play a minor role in orienting the conformation of the 5-methoxy group in derivatives such as 4 and 5, there appears to be some other, as yet unknown, critical receptor interaction.


  • Guest
"super-potent" compound from eugenol?
« Reply #27 on: August 02, 2004, 02:23:00 AM »
It's funny, when Nichols published that article about the "super-potent" bis-dihydrofuran analogues of the 2,5-dimethoxy-substituted series of hallucinogenic amphetamines, I got this crazy idea for a novel compound of this sort which might be able to be synthesized from eugenol.  The scheme goes something like this..

It's all very basic chem, but if you want a ref on any of the reactions just say so.  Basically, it goes:  alkylation of eugenol w/an allyl halide, claisen rearrangement, cyclization w/GAA to the mono-2-methyldihydrobenzofuran, elbs persulfate oxidation, and finally, another cyclization to form a 5-methoxy-bis(2-methyldihydrobenzofuran).

I have not even attempted this synth; I am concerned the claisen rearragement or the persulfate oxidation will not work as advertised..

However, if this compound were to somehow be synthesized, or for that matter, the benzofuran or dihydrobenzofuran analogues (minus the 2-methyl group), what would make them even more interesting is the orientation of the ring-oxygen atoms.

They are oriented in the notoriously difficult to synthesize and largely unexplored 2,3,5 configuration (see Shulgin's commentary in PiHKAL under the TMA-4 entry.)  Since MMDA-4 hasn't even been synthesized, who would know what kind of activity to suspect, however, I'd certainly be willing to bet on the fact that it won't be inactive   ;)


  • Guest
On chlorinations and brominations
« Reply #28 on: August 03, 2004, 02:23:00 PM »
Now that'd be something fun to make from eugenol. ;)

But I fear that the isolated alkene may react with persulfate more favourably than the aromatic ring. The same conditions (persulfate and OH-) required to add a hydroxyl group to the ring can also oxidise an aromatic methyl group to an aldehyde. Maybe you'd end up with a glycol as byproduct, I don't know. I should stress that I have no experience with the reaction, and this worry is only based on the information from the Merck Index entry:

Elbs Persulfate Oxidation

( If you have any references for this reaction (especially in the presence of an isolated alkene) I would like to see them. :)  For the ring closing steps I have similar refs as Shulgin uses them in his synthesis of the F-series.

Back to the original topic for now: after making the 2-phenoxyethyl chloride I tried the dibromination, but unfortunately my product didn't crystallise, nor did it appear to have taken up the full two equivalents of bromine. Since I need to be sure I have pure 2-phenoxyethyl chloride I have decided to make this by the chlorination of 2-phenoxyethanol. Until I get a crystalline substance in both steps I don't want to proceed with the Grignard. My first idea was to use concentrated HCl under PTC conditions, using the following procedure which has been referenced here several times:

Organic Synthesis in Micellar Media. Oxidation of Alcohols and Their Conversion into Alkyl Chlorides
Branko Jursic
, 1988, 868-871

The use of micelles was investigated for various organic reactions: oxidation of alcohols with sodium hypochlorite in micelles, oxidation of alcohols with hexadecyltrimethylammonium chromate as micelle, and conversion of primary alcohols to 1-chloroalkanes by aqueous hydrogen chloride in the presence of micelles. In all cases, product isolation was simple and satisfactory yields were obtained.

However, as the reaction conditions could cleave the ether, I think I will instead try the following. This procedure also happens to give superior yields:

An Efficient Route to Alkyl Chlorides from Alcohols Using the Complex TCT/DMF
Lidia De Luca, Giampaolo Giacomelli,* and Andrea Porcheddu
Organic Letters
, 2002, 4(4), 553-555

Efficient conversion of alcohols and beta-amino alcohols to the corresponding chlorides (and bromides) can be carried out at room temperature in methylene chloride, using 2,4,6-trichloro[1,3,5]triazine and N,N-dimethyl formamide. This procedure can also be applied to optically active carbinols.

Finally, here is the paper I mentioned earlier: the bromination of arenes using nothing but aqueous HBr in DMSO. I may well try this on benzodioxole; hopefully the dioxole ring will survive:

Novel site-specific one-step bromination of substituted benzenes
Sanjay K. Srivastava, Prem Man Singh Chauhan* and Amiya P Bhaduri
Chem Commun
, 1996, 2679-2680

Regiospecific bromination of benzene derivatives has been carried out with Me2SO-HBr; this method gives excellent yields of 2-bromobenzaldehyde and 2-bromonitrobenzene; strong ortho- and para- directing monosubstituted benzenes give para-bromo derivatives; a general discussion of the mechanism of these reactions is given.


  • Guest
hmm.. I wonder if this procedure could be...
« Reply #29 on: August 05, 2004, 04:01:00 AM »
hmm.. I wonder if this procedure could be applied to bromo phenols with a formyl group already in place; for ex. from the easily acquired 5-bromo-vanillin.. would be much easier then the MMDA synth from the same, and prob near as potent.

kinetic;  did you synth dichloroethane?  if so, could you give the procedure you used?

why don't you describe your dibromination as well, maybe we can figure out where it failed..


  • Guest
drug design and its difficulties
« Reply #30 on: August 08, 2004, 10:16:00 AM »
 it`s nice to see that someones brain is working. But sometimes another person should help the first one showing him/her his/her mistakes. It`s called criticism and it`s very essential for our work at The Hive.

 What I`m talking about is the compound you suggested in

Post 523206

(phenethyl_man: ""super-potent" compound from eugenol?", Novel Discourse)
. We all know that the potency of that compound - 2-(5-methoxy-2,7-dimethyl-2,3,7,8-tetrahydrobenzo[1,2-b;3,4-b']difuran-4-yl)-1-methylethylamine - depends on its interaction with the 5-HTRs. And the ligand-receptor interaction is relevant to some of the compound properties. One of them is the lone pairs orientation.

Acta Pharmaceutica Suecia Suppl. 1985:2


...Perhaps most interesting was the finding by Shulgin (personal communication) that the compound where R=H 2-(5-methoxy-2,3-dihydrobenzofuran-6-yl)-1-methylethylamine - l., as hydrochloride, produced no effects in humans when administered in an acute oral dose up to 20 mg.

...if arguments about oxygen lone pair directionality are valid, this would indicate that a potential electrophilic site on the serotonin receptor may have strict requirements for electron pair directionality in substituted phenethylamines. As has been noted by Glennon et al. [

J. Med. Chem. 1980, 23, 294-299

(] - l., a similar situation applies to phenethylamines with a 2-methoxy group, that have been also substituted at the 3-position.

 And now lets look at the model of phenethylamine binding to the human 5-HT2A receptor suggested in

Journal of Computer-Aided Molecular Desing, 16: 511-520, 2002


or more schematic:

 And after all a comparison between the oxygen lone pair directionality in Nichol`s "super-potent" and your compound (without the "2-methyl"s):

 Different, don`t you think so?
 Possibly lack of interaction with 3.36 and possible interaction with 5.46; possibly lower affinity than DOM or even maybe different pharmacological profile.
 What I`m trying to say is that that compound is not likely to be a very potent 5-HT2A agonist.
 Keep digging.


  • Guest
further speculation..
« Reply #31 on: August 09, 2004, 02:31:00 AM »
longimanus:  I appreciate all the information, however, I never stated that this theoretical compound would have a similar pharmacological profile as DOM, nor that it would be as potent; only that it would be something interesting to explore, and for precisely that reason; it is different.

The two compounds I did compare it to, TMA-4 and MMDA-4, one is unexplored and the other Shulgin states to have activity around 80mg.  So it is still more potent than the traditional 3,4,5 orientation of TMA and mescaline.  TMA-2, which has the orientation which Nichol's "super-potent" compound is based upon, is active around 20-40mg.  It would be logical then to assume that the compound I proposed would at least be quite significantly more potent than TMA-4.  After all, every amphetamine with three-MeO groupings is active at some level, except for TMA-3 I believe.

I believe Nichol's point in that paper is that the oxygen lone pair directionality of DOM is what contributes to it's extraordinary potency.  However, if potency was all that mattered, compounds like MDA wouldn't even be worth exploring..


  • Guest
"greater than 80 mg"
« Reply #32 on: August 09, 2004, 07:15:00 AM »
Greater than 80 mg doesn`t mean it`s active at this range - it`s the bottom threshold, so TMA-4 should be twice as potent as mescaline. On the other side lets compare TMA-4 with G-3 - it`s dose is 12-18 mg!!! So, we even don`t need that 3- or 4-positioned oxygen, actually it seems to be lowering the activity.

 And now the numbers - if your compound (have you already named it after sth?) binds to the 5-HTR in a manner similar to that of DOM its active dose ahould be (just some scientific quessing ;) ) around 25-100 mg or more. But I`m almost sure that its binding and pharmacological profile will be rather different. That`s why I`d be very interested in the exploring of that cmpd when it`s synthesized. Hope you`ll be the one to do this :) .


  • Guest
I doubt I will be the one to do it, at least...
« Reply #33 on: August 09, 2004, 09:36:00 PM »
I doubt I will be the one to do it, at least not in the near future, simply don't have the time..

If I were to try thou.. a good place to start would be to stop after the third step in that synth I proposed.  Right there you have an allylbenzene that would be good for a MMDA analogue.  I would probably use oxymercuration on that, demercuration to the phenyl-2-propanol, oxidation to the 2-propanone and finally reduction to the amine.  I recently used this process for safrole to MDP2P and it was by far the easiest synth from an allylbenzene I have ever performed.  If this compound was inactive, I wouldn't even bother with the latter.

Kinetic is right about the step following that thou, a persulfate oxidation right there would also oxidize the allyl side chain.  Instead, the compound would have to be brominated or iodinated right there, the halogen would go para to the MeO group, and then the halogen could be stripped to a hydroxy using a copper catalyst and NaOH using well known methods (even thou I hate this reaction).  Then the second cyclization could be performed and the benzene could then be formulated or whatever is desired.  Anyone see any pitfalls there?

Of course the good thing about the synth would be the cheap and unlimited supply of the starting material (eugenol).

It's interesting you bring up G-3, an indane.  It is true that the analogue of MDA with no oxygens on the ring (IAP) is more potent in the binding studies I have seen than any with oxygens on there.  I know of no good synthesis for indane though, can anyone chime in here?  The only one I know of is converting phenylpropanoic acid to an acid chloride, cyclization only gives you the indanone, which still needs to be reduced to indane.  A real PITA.  I guess that's why most all the synths for indanyl-phenethylamines I have seen start with the indane already formed.


  • Guest
On indane
« Reply #34 on: August 10, 2004, 07:13:00 AM »
Maybe we should start a new thread for a discussion on indanyl analogues; it's something I'm also very interested in. I actually made some IAP for the first time last week, and have tried it twice. It is most definitely active at 30mg; a distinct mood elevation, but nothing much else. Starting from indane is 'safe' for me as there's essentially no way I can end up with a controlled substance.

I had a similar idea about a MMDA indanyl analogue, which would be the analogue of MMDA-2. I would synthesise it by the 5-bromination of indane (72% yield), methoxylation of this to 5-methoxyindane and formylation to 6-methoxyindan-5-carboxaldehyde, probably using a modified Duff as I don't have any POCl3 handy. Of course, I have no idea if the final product will be active or interesting. If you start a thread on the synthesis of indane or analogues containing the indanyl skeleton I'll add whatever relevant information I can find. I have a couple of references for the synthesis of indane, but at first glance there doesn't seem to be any simple way. A PITA is probably a good description, if it stands for what I think it does.

In response to your earlier questions: I bought my 1,2-dichloroethane as it is so cheap; and the problems with the bromination are at least in part due to the impure starting 2-phenoxyethyl chloride. Once I get this pure (hopefully soon) I should have no trouble with the subsequent bromination following the procedure I used for the bromination of 2-phenoxyethyl bromide. I need to make sure there is as little monobrominated product as possible as the cyclisation won't take place without a bromine atom ortho- to the 2-chloroethoxy group, and - as you will know - the best way to ensure complete dibromination is to start with as pure a product as possible. The result of incomplete bromination would be the contamination of my end product with the illegal 4-ethoxyamphetamine or the probably toxic 4-(2-chloroethoxy)amphetamine, depending on the method I used for the reduction of the nitrostyrene.


  • Guest
MMDA analogue; benzodifuran paper..
« Reply #35 on: August 10, 2004, 08:19:00 AM »
kinetic;  ya, unfortunetly I don't even have an account with a chem supplier anymore (they keep asking for a business license, go figure), so buying indane is not a possibility.  Did you use a modified Duff formylation on indane?  What acid did you use?

Right now I'm working on a dihydrobenzofuran MMDA analogue from vanillin.  I happenend to have some 2-butoxyethanol lying around, so I cleaved the ether with HBr and hopefully some dibromoethane is crystallizing out right now.  I plan to react that with vanillin and NaOH to produce vanillin bromoethyl ether; and that should be easily cyclized to 7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde-- precisely the same molecule as myristicinaldehyde except only one lone oxygen on the furan ring (ortho to the methoxy group.)  Should be quite an interesting compound and so easily synthesized..  maybe I'll name it MDBAP: 1-(7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-aminopropane. ;)

I also have something else very interesting to add to this thread.  I actually found a synthesis for the symmetrical version of tetrahydro-benzo-difuran from the year 1920!  They use resorcinol, form the di-beta-hydroxyethyl ether, and then perform a cyclic dehydration with P2O5 to form the difuran.

I would venture to guess, that using hydroquinone here instead of resorcinol would form the assymetrical version; which would be a precursor for the potent compounds in the Nichol's paper.  Here is the ref: J. Am. Chem. Soc.; 1920; 42(1); 157-165.


  • Guest
« Reply #36 on: August 10, 2004, 09:39:00 AM »
Did you use a modified Duff formylation on indane?  What acid did you use?

Indeed, and the acid was TFA. See

The 5-bromination of indane is also covered. ;)

That is a nice idea for the synthesis of MDBAP but are some things you should be aware of, assuming you are planning on a Parham-type cyclialkylation:

Unlike with the less reactive dichloroethane, etherification with dibromoethane may lead to dphenoxyethane formation as well as the desired monoalkylation. From the Synthesis article in

Post 512847

(Kinetic: "Grignard formylation article", Novel Discourse)

Bromoethyl ethers 1a and 1b were obtained from phenols 2 in only moderate yields,11 due to formation of diphenoxyethanes.

Further, the bromoethyl ether when treated with Mg is more likely to lead to elimination than the chloroethyl ether:

The ease of halogen-metal exchange has been found to be ArBr> ArOCH2CH2Br> ArOCH2CH2Cl and it is essential that conditions are used, which favour the formation of the organometal derivatives 4 leading to cyclisation and 6, rather than the alkyl-metal derivatives 5, which result in dealkylation and generation of the phenoxides 8. In order to minimise this side-reaction, we reasoned that utilisation of the chloroethyl ethers would allow selective arylbromide-lithium exchange to occur at temperatures higher than -100oC and render the reaction more suitable for large scale plant [as well as most bees].

Finally, of course, the aldehyde function will need protecting, but this could be almost to your advantage, if you were to dry it thoroughly using a Dean-Stark trap and ethylene glycol. The necessary acidic workup would regenerate the carbonyl from the acetal.

The above is based on the assumption you are performing the reaction I suspect: bromination of vanillin ortho- to the OH followed by alkylation with a 1,2-dihaloethane, then cyclisation with Mg. All of these problems should be surmountable with a little work. Maybe you could try and make some 1-bromo-2-chloroethane from your 2-butoxyethanol: it should assist the desired etherification, and the chloroethoxy compound will perform better in the subsequent cyclisation. I look forward to hearing how you get on.

Some references:

For the formation of 4-(2-bromoethoxy)-3-methoxy-benzaldehyde from ethylene bromide and vanillin, see Monatsh. Chem., 88, 1957, 1064-1067, and J. Org. Chem., 19, 1954, 1029-1031. The product melts at 69-70oC from aqueous IPA, and 66-67oC from water.

For the formation of 4-(2-chloroethoxy)-3-methoxy-benzaldehyde from ethylene chloride and vanillin in 85% yield, see  J. Med. Chem., 42(4), 1999, 649-658. The product melts at 60-61oC from ether.


  • Guest
kinetic; check out the paper in the edit to my
« Reply #37 on: August 10, 2004, 10:04:00 AM »
kinetic;  check out the paper in the edit to my previous posting; also take a look at this one:  J. Am. Chem. Soc.; 1919; 41(4); 665-670.  I think you will find them quite interesting..

My synthesis of 4-(2-bromoethoxy)-3-methoxy-benzaldehyde from vanillin and DBE seems to have worked well.  I slowly added the DBE to the vanillin dissolved in a stoichiometric methanolic NaOH soln and then I heated it under reflux for one hour.  Judging by the large precipitation of NaBr, something got alkylated.


  • Guest
JACS 1919
« Reply #38 on: August 10, 2004, 02:07:00 PM »
Thanks for the refs; as it happens, I have the earlier article as a PDF already. In fact my carpet still smells of partially polymerised 2-phenoxyethanol from an attempt at the direct cyclisation to dihydrobenzofuran last summer. Unfortunately, nothing was isolated from the carpet the product was spilled on. Fortunately, I still have some 2-phenoxyethanol for my proposed chlorination to 2-phenoxyethyl chloride, using trichloroisocyanuric acid and DMF.

I will get the JACS 1920 article asap.

I almost mentioned the Friedel-Crafts alkylation in my earlier post; is this the method you're using? It certainly is a lot easier. Fingers crossed the O-alkylation has worked as planned, and good luck for the cyclisation, whichever route you're using. Maybe the more activated ring of 4-(2-bromoethoxy)-3-methoxybenzaldehyde will lead to a higher yield than the 30-40% for plain 2,3-dihydrobenzofuran from 2-phenoxyethyl bromide.

Here is the article from JACS 1919 for those who are interested. Although the yield of dihydrobenzofuran is relatively low, the procedure is extremely easy:

Synthesis of Chromanes and Coumarans
R. E. Rindfusz
Journal of the Americal Chemical Society
, 41(4), 665-670, 1919


Coumarane [2,3-dihydrobenzofuran] from beta-Hydroxyethylphenyl ether C6H5O.CH2CH2OH [2-phenoxyethanol]

This ether is prepared in 50% yields from sodium phenolate and ethylene chlorohydrine as described by Bentley, Haworth and Perkin.4 It is a colourless liquid boiling at 134-135o at 18mm. [n]D20 1.534, d22 1.102. 50g of this ether is heated for 5 hours with 5g of zinc chloride. The temperature goes at first to 225o and then slowly drops to 190o. The product may be distilled directly and boils at 88-90o at 18mm. Yield 25%, d24 1.0576,[n]D20 1.543.

Coumarane from p-Bromo-ethyl-phenyl Ether [2-phenoxyethyl bromide]

The beta-bromoethyl phenyl ether is prepared by treating sodium phenolate with an excess of ethylene bromide, following the method of Weddige.1 On treating this with 1/10 of its weight of zinc chloride, the reaction is not so vigorous as in the analogous formation of chromane and two hours' heating is necessary. The product may then be distilled directly in 30-40% yields.


  • Guest
yea.. the JACS 1920 article is part II of the...
« Reply #39 on: August 10, 2004, 02:50:00 PM »
yea.. the JACS 1920 article is part II of the 1919 article.  In this one he realizes that the cyclization takes place merely due to dehydration instead of his halogenation hypothesis stated in the first article.  Thus, he uses phosphorus pentoxide as a dehydrating agent instead of zinc chloride and obtains around 50-80% yields as opposed to only a 10-15% yield with ZnCl2.

Here is the general procedure:


Preparation from y-hydroxypropyl-o-tolyl ether and phosphorus
pentoxide. Forty g. of phosphorus pentoxide was suspended in 200 cc.
of dry benzene and 100 g. of the hydroxy ether slowly added with shaking.
After refluxing for a short time, the mixture was poured from the
phosphorus compounds and distilled. The product may be washed with
alkali and with water and redistilled with very little loss. An excellent
grade of material practically all boiling at 114-115 deg at 20 mm. was obtained
in 76% yield.

For coumaranes, just use the hydroxyethyl ether instead.