The benzofuran analogues of classical indolic hallucinogens (eg. DMT) have been shown to be effective serotonin agonists, albeit with lower the potency at 5-HT2A (1.). (Incidentally, I wonder why the benzofuran analogue of LSD hasn't been synthesized?) In any case, while these may be prepared from the easily made benzofuran itself instead of indole by analogous methods, another possibility has occurred to me, which starts with catechol. In short, my idea is this: 1,2-benzoquinone to the ethynylcarbinol derivative. This is then reacted with the proper R-X in the presence of palladium (my reasoning may be terribly wrong, but nickel, or a nickel salt, being similar to palladium, may also suffice - which would be far more practical; other catalytic metals may be of use as well, see (3.) ). This rearranges so that there is a hydroxyl on the 4 position (a la psilocin) secondary to tertiary carbocation, then aromatisation. (2-ethynylphenol would yield a product unsubstituted on the four, but it's preparation it somewhat less accessible - via suzuki coupling perhaps). If the RX is chloro/bromoacetone, the resulting ketone can be reductively aminated with ammonia, or with the alkylamine of choice (I assume no P-S cyclisation would occur). This gives the 4-OH-alpha-methyltryptamine analogue, and note Shulgin's description:
The 4-hydroxy analogue of ?MT has been looked at in human subjects. It is reported to be markedly visual in its effects, with some subjects reporting dizziness and a depressed feeling. There were, however, several toxic signs at doses of 15 to 20 milligrams orally, including abdominal pain, tachycardia, increased blood pressure and, with several people, headache and diarrhea.
If ethylene glycol (and possibly solvent in that case), chloroethanol (from ethylene and hypochlorous acid), or other such substance is used as the RX , than a simple route to 4-OH-dialkyl substances can readily be seen, analogous to the known preparation of dialkyltryptamines from tryptophol. Other variations, such as substitutions on the catechol are apparent.
It is well known that acetylene can condense with ketones to form the ethynylcarbinols under proper conditions (ie. base, often with copper salts, in which the acetylene is deprotonated). If the addition occurs twice, 1,4-dihydroxynaphthalene, which is useless could easily form. However, 4-ethynyl-4-hydroxycyclohexa-2,5-dienone is a known substance, which suggests that addition to both ketone groups can be circumvented by proper conditions, if it is inclined to occur at all. Also, 2-ethynylphenols and similar substances are known to condense to benzofurans; p.71 of (2.) notes such a reaction to form a 3-substituted indole, catalysed by palladium - an interesting chapter over all in fact.
It also occurs to me that I'm just being silly, being rather a novice when it comes to chemistry. Nonetheless; my humble offering.
Some relevant materials:
1. Tomaszewski Z; Johnson MP; Huang X; Nichols DE
Benzofuran bioisosteres of hallucinogenic tryptamines.
J Med Chem. 1992 May 29. 35(11). P 2061-4.
"The benzofuran analogues of the hallucinogens 5-methoxy-N,N-dimethyltryptamine and 5-methoxy-alpha-methyltryptamine were synthesized and evaluated for affinity at the serotonin 5-HT2 and 5-HT1A receptors in rat brain homogenate, labeled with [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) and [3H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([3H]-8-OH-DPAT), respectively. At the 5-HT2 receptor, the benzofurans had slightly decreased affinities, approximately one-third and one-sixth those of the indoles, for the primary amines and the tertiary amines, respectively. The benzofurans also had lower affinity at the 5-HT1A receptor, but decreased only about 20-30% from that of the indole isosteres. Thus, the 5-HT1A receptor is less discriminating with respect to preference for an indole versus a benzofuran, although all of the compounds did have higher affinities for the 5-HT2 receptor than for the 5-HT1A receptor. It is suggested that benzofurans may be useful in design of serotonin receptor ligands."
2. http://books.google.com/books?id=WzhLRR-we-AC&pg=PA51&lpg=PA51&dq=cyclisation+of+alkynes+heterocycle&source=bl&ots=8fd1CoRPUz&sig=T1AfEq13VosAljcOushZPOyraTY&hl=en&ei=BdKsS9LgDIO78gbt_oHcCw&sa=X&oi=book_result&ct=result&resnum=8&ved=0CC0Q6AEwBw#v=onepage&q&f=false
3. http://pubs.acs.org/doi/abs/10.1021/ol060896y "2,3-Disubstituted Benzofuran and Indole by Copper-Mediated C?C Bond Extension Reaction of 3-Zinciobenzoheterole"
4. http://pubs.acs.org/doi/abs/10.1021/ja01194a018 "Condensation of Acetylene with Acetone and Other Ketones"
5. "Derivatives of 2-ethynylphenol are known to form benzofurans by rapid intramolecular addition of the hydroxyl group to the adjacent triple bond"
6. Also interesting: http://www.ics-ir.org/jics/archive/v5/S1/article/pdf/JICS-5-S1-Article-16.pdf
The 4-hydroxy analogue of ?MT has been looked at in human subjects. It is reported to be markedly visual in its effects, with some subjects reporting dizziness and a depressed feeling. There were, however, several toxic signs at doses of 15 to 20 milligrams orally, including abdominal pain, tachycardia, increased blood pressure and, with several people, headache and diarrhea.
If ethylene glycol (and possibly solvent in that case), chloroethanol (from ethylene and hypochlorous acid), or other such substance is used as the RX , than a simple route to 4-OH-dialkyl substances can readily be seen, analogous to the known preparation of dialkyltryptamines from tryptophol. Other variations, such as substitutions on the catechol are apparent.
It is well known that acetylene can condense with ketones to form the ethynylcarbinols under proper conditions (ie. base, often with copper salts, in which the acetylene is deprotonated). If the addition occurs twice, 1,4-dihydroxynaphthalene, which is useless could easily form. However, 4-ethynyl-4-hydroxycyclohexa-2,5-dienone is a known substance, which suggests that addition to both ketone groups can be circumvented by proper conditions, if it is inclined to occur at all. Also, 2-ethynylphenols and similar substances are known to condense to benzofurans; p.71 of (2.) notes such a reaction to form a 3-substituted indole, catalysed by palladium - an interesting chapter over all in fact.
It also occurs to me that I'm just being silly, being rather a novice when it comes to chemistry. Nonetheless; my humble offering.
Some relevant materials:
1. Tomaszewski Z; Johnson MP; Huang X; Nichols DE
Benzofuran bioisosteres of hallucinogenic tryptamines.
J Med Chem. 1992 May 29. 35(11). P 2061-4.
"The benzofuran analogues of the hallucinogens 5-methoxy-N,N-dimethyltryptamine and 5-methoxy-alpha-methyltryptamine were synthesized and evaluated for affinity at the serotonin 5-HT2 and 5-HT1A receptors in rat brain homogenate, labeled with [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) and [3H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([3H]-8-OH-DPAT), respectively. At the 5-HT2 receptor, the benzofurans had slightly decreased affinities, approximately one-third and one-sixth those of the indoles, for the primary amines and the tertiary amines, respectively. The benzofurans also had lower affinity at the 5-HT1A receptor, but decreased only about 20-30% from that of the indole isosteres. Thus, the 5-HT1A receptor is less discriminating with respect to preference for an indole versus a benzofuran, although all of the compounds did have higher affinities for the 5-HT2 receptor than for the 5-HT1A receptor. It is suggested that benzofurans may be useful in design of serotonin receptor ligands."
2. http://books.google.com/books?id=WzhLRR-we-AC&pg=PA51&lpg=PA51&dq=cyclisation+of+alkynes+heterocycle&source=bl&ots=8fd1CoRPUz&sig=T1AfEq13VosAljcOushZPOyraTY&hl=en&ei=BdKsS9LgDIO78gbt_oHcCw&sa=X&oi=book_result&ct=result&resnum=8&ved=0CC0Q6AEwBw#v=onepage&q&f=false
3. http://pubs.acs.org/doi/abs/10.1021/ol060896y "2,3-Disubstituted Benzofuran and Indole by Copper-Mediated C?C Bond Extension Reaction of 3-Zinciobenzoheterole"
4. http://pubs.acs.org/doi/abs/10.1021/ja01194a018 "Condensation of Acetylene with Acetone and Other Ketones"
5. "Derivatives of 2-ethynylphenol are known to form benzofurans by rapid intramolecular addition of the hydroxyl group to the adjacent triple bond"
6. Also interesting: http://www.ics-ir.org/jics/archive/v5/S1/article/pdf/JICS-5-S1-Article-16.pdf