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 -78
oC. 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 FeCl
3. 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 SO
2 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 RatsDavid E. Nichols,* Andrew J. Hoffman, Robert A. Oberlender, and Robert M. Riggs
Journal of Medicial Chemistry,
29, 302-304, (1986)
AbstractTwo 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 PhenethylaminesDavid E. Nichols,* Scott E. Snyder, Robert Oberlender, Michael P. Johnson, and Xuemei Huang
Journal of Medicinal Chemistry,
34, 276-281 (1991)
AbstractTwo 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-HT
2 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 K
A 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.