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All 3 posts Subject: Concerning a sexy benzofuran... Please login to post Down

GC_MS
(Hive Addict)
12-11-03 19:55
No 476215
User Picture       Concerning a sexy benzofuran...
(Rated as: excellent)

Benzofurans have been explored in the past for their psychoactive properties. A recent article can be found in Post 185131 (hest: "New Amph. more potent than LSD", Serious Chemistry). Also, I consider this benzofuran (viz. 6,7-Dimethoxy-5-benzofurancarboxaldehyde) to be analogous to 2,3-dimethoxy-4,5-methylenedioxybenzaldehyde, which is derived from dillapiole (a precursor for one of the Essential Amphetamines). But aside all that, I think the article is a nice piece of chemistry: not too hard and it has a certain air of elegance. I would like to thank those Bees who have had a hand in providing me the article. Your help is most appreciated.

Benzofurans in PiHKAL:

#79, F-2: http://www.erowid.org/library/books_online/pihkal/pihkal079.shtml
#80, F-22: http://www.erowid.org/library/books_online/pihkal/pihkal080.shtml

A New Synthesis of Methoxalen
Pentti Nore and Erkki Honkanen
J. Heterocyclic Chem., 17, 985 (1980)

The key compound in this synthesis is 2-chloro-2'-hydroxy-3',4'-dimethoxyacetophenone (II). This is prepared in good yield from commercially available 1,2,3-trimethoxybenzene. On chloromethylation of II with paraformaldehyde and hydrogen chloride in acetic acid solution 2-chloro-2'-hydroxy-3',4'-dimethoxy-5'-chloromethylacetophenone (III) is obtained in 77% yield. Ring closure and substitution of chlorine with acetoxy group in position 5' occur on the treatment of III with sodium acetate in acetonitrile yielding 5-acetoxymethyl-6,7-dimethoxy-3-(2H)benzofuranone (IV) in almost quantitative yield. Reduction of IV with sodium borohydride and simultaneous loss of water and alcoholysis with methanol yields 6,7-dimethoxy-5-hydroxymethylbenzofuran (V) also in excellent yield. Oxidation of V with chromium trioxide-sulfuric acid in acetone, with chromium trioxide-pyridine complex in dichloromethane, with potassium permanganate in the presence of 18-crown-6 ether or with benzyltriethylammonium permanganate to 6,7-dimethoxy-5-benzofurancarboxaldehyde (VI).

2-Chloro-2'-hydroxy-3',4'-dimethoxyacetophenone (II)

This compound has been made by Price and Bogert [JACS 56, 2442, (1943)] in 16% yield. The synthesis was improved as follows:

To a mixture of 300g (2.25 moles) of aluminium chloride in 450 ml. of 1,2-dichloroethane was gradually added under cooling (0.10°) a solution of 168 g. (1 mole) of 1,2,3-trimethoxybenzene and 226 g. (2 moles) of chloroacetylchloride in 300 ml. of 1,2-dichloroethane. The solution was stirred for 2 hours at 0°C and for 3 hours at room temperature. Crushed ice (1.5 kg.) and concentrated hydrochloric acid (300 ml.) were added to the reaction mixture. The product was filtered, washed with acetone and dried. To increase the yield an additional amount of the desired product was obtained by separating the organic phase in the above filtrate, washing with water and evaporating to dryness in vacuo. The residue was triturated with ether and the crystallized product was filtered. The total yield of II was 162 g. (70%), m.p. 160-162° (from acetone). After evaporation of the ether 45 g. of 1,2,3-trimethoxyhenzene was recovered. Calculated from the reacted 1,2,3-trimethoxybenzene the total yield of II was 96%.

2-Chloro-2'-hydroxy-3',4'-dimethoxy-5'-chloromethylacetophenone (III)

A stirred mixture of 161.4 g. (0.7 mole) of II and 56.0 g. of paraformaldehyde in 1.4 1. of acetic acid was saturated at room temperature with hydrogen chloride gas. The temperature was increased to 60-70° during which time hydrogen chloride gas was bubbled through the mixture. After stirring for 24 hours at room temperature the crystallized product was filtered, washed with ether and dried. The yield of III was 151 g. (77%), m.p. 130-131°C (from acetone).

5-Acetoxymethyl-6,7-dimethoxy-3-(2H)benzofuranone (IV)

A mixture of 136.6 g. (0.5 mole) of III and 102.5 g. (1.25 moles) of anhydrous sodium acetate in 2.5 L of acetonitrile was stirred and refluxed for 1.5 hours. Acetonitrile was distilled off and the residue was treated with 1 L of water. After extraction with dichloromethane (3 x 500 ml.) the extract was washed with water and the solvent was removed in vacuo. The oily product was used without purification to the next step. The yield of IV was 132 g. (99%)

6,7-Dimethoxy-5-hydroxymethylbenzofuran (V)

To a solution of 79.8 g. (0.3 mole) of IV in 1.81. of methanol was added gradually with cooling (below 20°) a solution of 17 g. (0.45 mole) of sodium borohydride in 45 ml. of water. After stirring for 1.5 hours at room temperature 600 ml. of water was added. The solution was made acid with 350 ml. of 20% hydrochloric acid and extracted three times with dichloromethane. The solvent was removed from the extract in vacuo. The oily residue of V, which was used without purification in the next step, weighed 62 g (99%).

6,7-Dimethoxy-5-benzofurancarboxaldehyde (VI)

a) By Oxidation with Chromic Oxide-Sulfuric Acid in Acetone

To a cooled (0°) solution of 20.8 g. (0.1 mole) of V in 350 ml. of acetone was added with stirring a solution of 6.7 g. of chromic oxide (0.067 mole) and 5.8 ml. of sulfuric acid in 14 ml. of water. The mixture was diluted with 700 ml. of water and then was extracted with dichloromethane (3 x 100 ml). The extract was washed with water, sodium bicarbonate solution and once more with water. After evaporation of the solvent in vacuo the residue crystallized on standing. The yield of VI was 12.6g (61 %), m.p. 32-34°C.

b) By Oxidation with Chromic Oxide-Pyridine Complex in Dichloromethane

To a solution of 31.7 g. (0.4 mole) of pyridine in 750 ml. of dichloromethane was added gradually with cooling (0-10°) 20.6 g. (0.2 mole) of chromic oxide. After stirring for 15 minutes a solution of 10.4 g. (0.05 mole) of V in 50 ml. of dichloromethane was added. The mixture was stirred for 1.75 hours at room temperature. The reaction mixture was filtered and the precipitate washed with dichloromethane. To the filtrate 100 ml. of water was added and the organic phase was separated, washed first with 2 N sodium hydroxide solution, then with 2 N hydrochloric acid and lastly with water. The solvent was evaporated in vacuo and the yield of VI was 6.3 g. (61%).

c) By Oxidation with Potassium Permanganate in the Presence of 18-Crown-6 Ether in Dichloromethane

A solution of 10.4 g. (0.05 mole) of V in 50 ml. of dichloromethane was added during 25 minutes to a stirred mixture of 9.1 g. (0.058 mole) of potassium permanganate, 0.75 g. of 18-crown-6 ether and 200 ml. of dichloromethane at room temperature. After stirring for 6 hours at room temperature charcoal and Celite were added and the mixture was filtered. The precipitate was washed several times with dichloromethane. The filtrate was washed with water and the solvent removed in vacuo. The yield of VI was 6.5 g. (63%).

d) By Oxidation with Benzyltriethylammonium Permanganate in Dichloromethane

To a solution of 16.0 g. (0.05 mole) of benzyltriethylammonium permanganate [Angew. Chem. 91, 77 (1979)] in 250 ml. of dichloromethane was added gradually with stirring at room temperature 10.4 g. (0.05 mole) of V in 30 ml. of dichloromethane. The solution was stirred for 5 hours at 20°. The isolation of the product was performed as described in example c). The yield of VI was 7.5 g. (73%).

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".

Nicodem
(Newbee)
12-12-03 18:43
No 476440
      It is nice this benzofuran-benzaldehide of...

It is nice this benzofuran-benzaldehide of yours, GC_MS, but I just must remind you that the resulting amphetamine does not seem really promising (while the F-2 and F-22 are something else). If you compare its substitution pattern (2,3,4) to their relative PEAs (IM) and amphetamines (TMA-3, TA) you see that they are quite inactive. I’m not claiming that the resulting amphetamine would be inactive. I’m very curious about it. What i think, is that this is interesting chemistry for the target benzodifuranes. There are maybe some other routes to these “only one wing” analogs. Those who might be up to these compounds might find it interesting to research a similar ciclisation, but from the other end of the -CH2-CO- moiety. Here is what I mean (with the 2,4,5-substitution pattern):

Molecule: part of a route to the second sexiest benzofuran ever ("c1c(c(cc(c1OCC(=O)O)Br)OC)COC(=O)C>>c12c(c(cc(c1OCC2=O)Br)OC)COC(=O)C")

I’m quite confident that this condensation should go smoothly in polyphosphoric acid (PPA) at 90 to 120°C or some other dehydrating Lewis or protic acid (maybe even conc. H2SO4 would work). These kinds of ciclizations are quite known in organic chemistry. The thing is, that the phenoxyacetic acids are easy to synthesise from the phenols and sodium chloroacetate. Though I have no idea how the chloromethylation step would work, but the reduction to the benzofurane shouldn’t be a problem. But the 2-bromo-4-methoxy-phenol is right the correct product from the bromination of the hydroquinone monomethyl eter, while the chloro compound should be obtainable with the chlorination with NaOCl that proceeds readily with phenols.
Just meditating on some new chemistry...

“The real drug-problem is that we need more and better drugs.” – J. Ott

Rhodium
(Chief Bee)
12-12-03 19:22
No 476448
User Picture       5-(2-aminopropyl)-benzofuran

I'd be really interested in what the effects would be of 5-(2-aminopropyl)-benzofuran, as it is halfway between IAP and MDA...

The Hive - Clandestine Chemists Without Borders

	https://the-hive.archive.erowid.org	the-hive@erowid.org



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	All 3 posts		Subject: Concerning a sexy benzofuran...		Please login to post		Down


		GC_MS (Hive Addict) 12-11-03 19:55 No 476215				Concerning a sexy benzofuran... (Rated as: excellent)
						Benzofurans have been explored in the past for their psychoactive properties. A recent article can be found in Post 185131 (hest: "New Amph. more potent than LSD", Serious Chemistry). Also, I consider this benzofuran (viz. 6,7-Dimethoxy-5-benzofurancarboxaldehyde) to be analogous to 2,3-dimethoxy-4,5-methylenedioxybenzaldehyde, which is derived from dillapiole (a precursor for one of the Essential Amphetamines). But aside all that, I think the article is a nice piece of chemistry: not too hard and it has a certain air of elegance. I would like to thank those Bees who have had a hand in providing me the article. Your help is most appreciated. Benzofurans in PiHKAL: #79, F-2: http://www.erowid.org/library/books_online/pihkal/pihkal079.shtml #80, F-22: http://www.erowid.org/library/books_online/pihkal/pihkal080.shtml A New Synthesis of Methoxalen Pentti Nore and Erkki Honkanen J. Heterocyclic Chem., 17, 985 (1980) The key compound in this synthesis is 2-chloro-2'-hydroxy-3',4'-dimethoxyacetophenone (II). This is prepared in good yield from commercially available 1,2,3-trimethoxybenzene. On chloromethylation of II with paraformaldehyde and hydrogen chloride in acetic acid solution 2-chloro-2'-hydroxy-3',4'-dimethoxy-5'-chloromethylacetophenone (III) is obtained in 77% yield. Ring closure and substitution of chlorine with acetoxy group in position 5' occur on the treatment of III with sodium acetate in acetonitrile yielding 5-acetoxymethyl-6,7-dimethoxy-3-(2H)benzofuranone (IV) in almost quantitative yield. Reduction of IV with sodium borohydride and simultaneous loss of water and alcoholysis with methanol yields 6,7-dimethoxy-5-hydroxymethylbenzofuran (V) also in excellent yield. Oxidation of V with chromium trioxide-sulfuric acid in acetone, with chromium trioxide-pyridine complex in dichloromethane, with potassium permanganate in the presence of 18-crown-6 ether or with benzyltriethylammonium permanganate to 6,7-dimethoxy-5-benzofurancarboxaldehyde (VI). 2-Chloro-2'-hydroxy-3',4'-dimethoxyacetophenone (II) This compound has been made by Price and Bogert [JACS 56, 2442, (1943)] in 16% yield. The synthesis was improved as follows: To a mixture of 300g (2.25 moles) of aluminium chloride in 450 ml. of 1,2-dichloroethane was gradually added under cooling (0.10°) a solution of 168 g. (1 mole) of 1,2,3-trimethoxybenzene and 226 g. (2 moles) of chloroacetylchloride in 300 ml. of 1,2-dichloroethane. The solution was stirred for 2 hours at 0°C and for 3 hours at room temperature. Crushed ice (1.5 kg.) and concentrated hydrochloric acid (300 ml.) were added to the reaction mixture. The product was filtered, washed with acetone and dried. To increase the yield an additional amount of the desired product was obtained by separating the organic phase in the above filtrate, washing with water and evaporating to dryness in vacuo. The residue was triturated with ether and the crystallized product was filtered. The total yield of II was 162 g. (70%), m.p. 160-162° (from acetone). After evaporation of the ether 45 g. of 1,2,3-trimethoxyhenzene was recovered. Calculated from the reacted 1,2,3-trimethoxybenzene the total yield of II was 96%. 2-Chloro-2'-hydroxy-3',4'-dimethoxy-5'-chloromethylacetophenone (III) A stirred mixture of 161.4 g. (0.7 mole) of II and 56.0 g. of paraformaldehyde in 1.4 1. of acetic acid was saturated at room temperature with hydrogen chloride gas. The temperature was increased to 60-70° during which time hydrogen chloride gas was bubbled through the mixture. After stirring for 24 hours at room temperature the crystallized product was filtered, washed with ether and dried. The yield of III was 151 g. (77%), m.p. 130-131°C (from acetone). 5-Acetoxymethyl-6,7-dimethoxy-3-(2H)benzofuranone (IV) A mixture of 136.6 g. (0.5 mole) of III and 102.5 g. (1.25 moles) of anhydrous sodium acetate in 2.5 L of acetonitrile was stirred and refluxed for 1.5 hours. Acetonitrile was distilled off and the residue was treated with 1 L of water. After extraction with dichloromethane (3 x 500 ml.) the extract was washed with water and the solvent was removed in vacuo. The oily product was used without purification to the next step. The yield of IV was 132 g. (99%) 6,7-Dimethoxy-5-hydroxymethylbenzofuran (V) To a solution of 79.8 g. (0.3 mole) of IV in 1.81. of methanol was added gradually with cooling (below 20°) a solution of 17 g. (0.45 mole) of sodium borohydride in 45 ml. of water. After stirring for 1.5 hours at room temperature 600 ml. of water was added. The solution was made acid with 350 ml. of 20% hydrochloric acid and extracted three times with dichloromethane. The solvent was removed from the extract in vacuo. The oily residue of V, which was used without purification in the next step, weighed 62 g (99%). 6,7-Dimethoxy-5-benzofurancarboxaldehyde (VI) a) By Oxidation with Chromic Oxide-Sulfuric Acid in Acetone To a cooled (0°) solution of 20.8 g. (0.1 mole) of V in 350 ml. of acetone was added with stirring a solution of 6.7 g. of chromic oxide (0.067 mole) and 5.8 ml. of sulfuric acid in 14 ml. of water. The mixture was diluted with 700 ml. of water and then was extracted with dichloromethane (3 x 100 ml). The extract was washed with water, sodium bicarbonate solution and once more with water. After evaporation of the solvent in vacuo the residue crystallized on standing. The yield of VI was 12.6g (61 %), m.p. 32-34°C. b) By Oxidation with Chromic Oxide-Pyridine Complex in Dichloromethane To a solution of 31.7 g. (0.4 mole) of pyridine in 750 ml. of dichloromethane was added gradually with cooling (0-10°) 20.6 g. (0.2 mole) of chromic oxide. After stirring for 15 minutes a solution of 10.4 g. (0.05 mole) of V in 50 ml. of dichloromethane was added. The mixture was stirred for 1.75 hours at room temperature. The reaction mixture was filtered and the precipitate washed with dichloromethane. To the filtrate 100 ml. of water was added and the organic phase was separated, washed first with 2 N sodium hydroxide solution, then with 2 N hydrochloric acid and lastly with water. The solvent was evaporated in vacuo and the yield of VI was 6.3 g. (61%). c) By Oxidation with Potassium Permanganate in the Presence of 18-Crown-6 Ether in Dichloromethane A solution of 10.4 g. (0.05 mole) of V in 50 ml. of dichloromethane was added during 25 minutes to a stirred mixture of 9.1 g. (0.058 mole) of potassium permanganate, 0.75 g. of 18-crown-6 ether and 200 ml. of dichloromethane at room temperature. After stirring for 6 hours at room temperature charcoal and Celite were added and the mixture was filtered. The precipitate was washed several times with dichloromethane. The filtrate was washed with water and the solvent removed in vacuo. The yield of VI was 6.5 g. (63%). d) By Oxidation with Benzyltriethylammonium Permanganate in Dichloromethane To a solution of 16.0 g. (0.05 mole) of benzyltriethylammonium permanganate [Angew. Chem. 91, 77 (1979)] in 250 ml. of dichloromethane was added gradually with stirring at room temperature 10.4 g. (0.05 mole) of V in 30 ml. of dichloromethane. The solution was stirred for 5 hours at 20°. The isolation of the product was performed as described in example c). The yield of VI was 7.5 g. (73%). Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".



		Nicodem (Newbee) 12-12-03 18:43 No 476440				It is nice this benzofuran-benzaldehide of...
						It is nice this benzofuran-benzaldehide of yours, GC_MS, but I just must remind you that the resulting amphetamine does not seem really promising (while the F-2 and F-22 are something else). If you compare its substitution pattern (2,3,4) to their relative PEAs (IM) and amphetamines (TMA-3, TA) you see that they are quite inactive. I’m not claiming that the resulting amphetamine would be inactive. I’m very curious about it. What i think, is that this is interesting chemistry for the target benzodifuranes. There are maybe some other routes to these “only one wing” analogs. Those who might be up to these compounds might find it interesting to research a similar ciclisation, but from the other end of the -CH2-CO- moiety. Here is what I mean (with the 2,4,5-substitution pattern): Molecule: part of a route to the second sexiest benzofuran ever ("c1c(c(cc(c1OCC(=O)O)Br)OC)COC(=O)C>>c12c(c(cc(c1OCC2=O)Br)OC)COC(=O)C") I’m quite confident that this condensation should go smoothly in polyphosphoric acid (PPA) at 90 to 120°C or some other dehydrating Lewis or protic acid (maybe even conc. H2SO4 would work). These kinds of ciclizations are quite known in organic chemistry. The thing is, that the phenoxyacetic acids are easy to synthesise from the phenols and sodium chloroacetate. Though I have no idea how the chloromethylation step would work, but the reduction to the benzofurane shouldn’t be a problem. But the 2-bromo-4-methoxy-phenol is right the correct product from the bromination of the hydroquinone monomethyl eter, while the chloro compound should be obtainable with the chlorination with NaOCl that proceeds readily with phenols. Just meditating on some new chemistry... “The real drug-problem is that we need more and better drugs.” – J. Ott



		Rhodium (Chief Bee) 12-12-03 19:22 No 476448				5-(2-aminopropyl)-benzofuran
						I'd be really interested in what the effects would be of 5-(2-aminopropyl)-benzofuran, as it is halfway between IAP and MDA... The Hive - Clandestine Chemists Without Borders

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