Abstract
Regiospecific syntheses of the three monomethylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane are described. The three isomeric amines were evaluated for potential psychotomimetic potency using the rabbit hyperthermia assay. Enantiomeric compositions and time-concentration curves in rat brains were determined following intraperitoneal administration of each compound. The biological data are contrasted with the corresponding results obtained with the potent human psychotogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM).
Extensive structure-activity relationship studies among the ring-substituted 1-phenyl-2-aminopropanes have established that compounds bearing methoxy groups at the 2 and 5 positions and an alkyl, alkoxy, or halo substituent at the 4 position are potent psychotomimetic agents in man.1 This ring-substitution pattern also is found in the sympatholytic agent 6-hydroxydopamine (1).2 We3 and other workers4 have examined the metabolic fate of the well-known psychotomimetic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (2, DOM). Our studies have established that bis-O-demethylation of DOM leads to the 6-hydroxydopamine analogue 3.
In order to further evaluate the structural significance of the 2,5-dimethoxy substitution pattern with regard to psychopharmacological activity, we have synthesized the three methylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane, compounds 6c, 9c, and 12c. The present paper describes the chemical characterization of these isomers together with a preliminary evaluation of their potential psychotomimetic activity.
Chemistry
The synthetic route to the three required methylthio analogues 6c, 9c, and 12c in each case started with the appropriately substituted dimethoxybenzene and involved two critical regiospecific aromatic substitution reactions (Scheme I). For example, 1,2-dimethoxybenzene (4) was converted to 3,4-dimethoxybenzenesulfonyl chloride (5a) by chlorosulfonation with chlorosulfonic acid.
Reduction of the sulfonyl chloride moiety with zinc and sulfuric acid provided the thiophenol derivative 5c which was readily methylated with methyl iodide to give 5d. Vilsmeier formylation of 5d gave 4,5-dimethoxy-2-methylthiobenzaldehyde (6a) in good yield.
Condensation of 6a with nitroethane gave the 1-phenyl-2-nitropropene 6b, which was smoothly reduced with LiAlH4 to the desired 1-phenyl-2-aminopropane 6c. The two positional isomers 9c and 12c were prepared in an analogous manner (Scheme I), except that direct chlorosulfonation of 7 failed. The desired intermediate 8b was obtained by treatment of 7 with sulfuric acid followed by phosphorus oxychloride. The 4-methylthio isomer 12c has been previously prepared by a different procedure.12
Compd | Dose µmol/kg |
Peak effect duration (min) | Potency Relative to DOM | |
Method A | Method B | |||
| 6c | 14.2 | 75-105 | 0.017 | 0.022 |
7.1 | 105-135 | |||
| 9c | 21.3 | 180-210 | 0.028 | 0.039 |
10.6 | 135-165 | |||
5.3 | 120-165 | |||
| 12c | 2.0 | 195-225 | 0.54 | 0.64 |
0.67 | 165-195 | |||
0.22 | 120-135 | |||
| 2 (DOM) | 1.00 | 165-210 | 1.0 | 1.0 |
0.50 | 195-225 | |||
0.25 | 135-165 | |||
| Mescaline | 0.0006a | |||
| LSD | 33a | |||
a: From Ref 7; normalized to DOM = 1.
Experimental
Chemistry
Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. The syntheses and properties of the nitropropene 12b and amine 12c have been described previously.12
3,4-Dimethoxybenzenesulfonyl Chloride (5a)
The procedure was based on the method of Huntress and Carten.16
Chlorosulfonic acid (50 g, 0.43 mol) was added portionwise, with stirring, to neat veratrole (4, 27.6 g, 0.20 mol) over a 20-min period. The reaction was exothermic and HCl was evolved. The viscous blue-green mixture was poured into 400 mL of crushed ice and after standing 1 h the mixture was extracted with methylene chloride (2x150 mL). The extract was concentrated in vacuo to give a colorless oil which solidified on standing. The yield of crude product was 37.1 g (79%): mp 63-66°C (lit.15 mp 72-73°C).
The sulfonamide 5b was recrystallized from ethanol as colorless needles: mp 132-133°C (lit.16 mp 135-136°C).
2,5-Dimethoxybenzenesulfonyl Chloride (11a)
This isomer was prepared from 10 as described for 5a, with the exception that the chlorosulfonation was carried out with methylene chloride as solvent. The yield of 11a was 42%: mp 109-112°C.
The sulfonamide 11b, from ethanol, had mp 147.5-148.5°C (lit.16 mp 148°C).
2,4-Dimethoxybenzenesulfonyl Chloride 8b
The chlorosulfonic acid procedure described above for the sulfonation of the o- and p-dimethoxybenzenes 4 and 10, respectively, was not effective for the sulfonation of 7. The procedure employed was essentially that of Suter and Hansen.17 Concentrated sulfuric acid (29 g, 0.30 mol) was added to neat 1,3-dimethoxybenzene (7.27 g, 0.20 mol), with stirring, over a 15-min period. The mixture was stirred 1 h at ambient temperature and then poured slowly into 250 mL of saturated aqueous potassium carbonate. The resulting precipitate was collected by filtration and dried (air oven, 125°C) to give 59.6 g of crude potassium 2,4-dimethoxybenzenesulfonate (8a). Phosphorus oxychloride (35 g) was added to the pulverized salt 8a (30 g) and the mixture was heated on a steam bath with occasional swirling (2 h). After cooling to room temperature the mixture was poured onto 300 mL of crushed ice, stirred until the ice had melted, and extracted with ether (2x150 mL). The combined extracts were washed with saturated aqueous NaCl (50 mL) and evaporated under reduced pressure to give 14.2 g (62% based on 7) of a white solid: mp 69-72°C (lit.17 mp 70.5°C).
A small portion was converted to the amide 8c by heating with concentrated ammonium hydroxide. Recrystallization from ethanol provided white needles, mp 165.5-166.5°C (lit.16 mp 166-167°C).
2,4-Dimethoxythiophenol (8d)
The procedure was based on the method of Field and Grunwald.18
A solution of 8b (13.2 g, 0.056 mol) in ether was added dropwise to a stirred, refluxing suspension of 11.0 g of lithium aluminum hydride in 750 mL of ether. The mixture was heated under reflux with stirring for 48 h, cooled externally with ice, and treated dropwise with 600 mL of 10% H2SO4 (w/v). The resulting two-phase system was separated, and the aqueous phase was extracted with ether (2x200 mL). The ether extracts were pooled, washed once with water (200 mL), and flash evaporated to yield a pale amber oil with a slight sulfide smell. This was dried by the azeotropic removal of added methylene chloride and distilled through a short-path still. The final product was a colorless oil: bp 89-92°C (0.5 mm) (8.0 g, 84% yield).
3,4-Dimethoxythiophenol (5c)
The method of Adams and Marvel19 was employed.
The sulfonyl chloride 5a (33 g, 0.14 mol) was pulverized in a mortar and added to a mixture of 55 mL of concentrated H2SO4 and 900 cm3 of crushed ice contained in a 2-L flask. Zinc dust (50 g, 0.77 mol) was added portionwise with vigorous stirring over a 10-min period. A condenser was attached, and the mixture was held at reflux for 1.5 h with vigorous stirring. The mixture was cooled to room temperature, decanted from unreacted zinc, and extracted with ether (3x150 mL). The combined extracts were washed with 40 mL of saturated aqueous NaCl, concentrated under reduced pressure, and distilled through a short-path distillation head to give 20.8 g (87%) of a colorless liquid: bp 86-88°C (0.4 mm) [lit.20 bp 138°C (14 mm)].
2,5-Dimethoxythiophenol (11c)
This isomer was prepared from 11a as described for 5c. It was obtained as a colorless liquid in 59% yield: bp 95-97°C (0.6 mm); n20D 1.5829 [lit.21 bp 138-140°C (14 mm); n20D 1.5848].
3,4-Dimethoxythioanisole (5d)22
To a nitrogen-flushed 250-mL flask was added 3,4-dimethoxythiophenol (5c, 10 g, 59 mmol), absolute ethanol (50 mL), and KOH (5 g, 85%, ~75 mmol) in 80 mL of ethanol. A reflux condenser was attached to the flask and methyl iodide (6 mL, ~90 mmol) was added. The reaction was exothermic, and a white precipitate formed. The solution was heated under reflux for 30 min, cooled, and poured into 200 mL of water. The mixture was extracted with ether (3x50 mL) and the combined extracts were washed with saturated aqueous sodium hydrosulfite. The ether was removed under reduced pressure and the residue distilled to provide 10.3 g (90%) of a colorless liquid, bp 94-95°C (0.4 mm), that solidified on standing: mp 31-32°C.
2,4-Dimethoxythioanisole (8e)
This isomer was prepared from 8d as described for 5d: yield 83%; bp 100-103°C (0.6 mm); mp 35-37°C [lit.17 bp 115-118°C (4 mm); mp 38-39°C].
2,5-Dimethoxythioanisole (11d)
This isomer was prepared from 11c as described for 5d. The product was a colorless oil, obtained in 83% yield by bulb-to-bulb distillation: bp 150°C (0.6 mm) [lit.20 bp 86-88°C (0.4 mm)].
4,5-Dimethoxy-2-methylthiobenzaldehyde (6a)
Phosphorus oxychloride (15 g, 0.10 mol) was mixed with N-methylformanilide (14 g, 0.10 mol) and warmed gently on the steam bath. 3,4-Dimethoxythioanisole (5d, 8.2 g, 42 mmol) was added portionwise over 5 min. The reaction was exothermic, and the color changed from orange to dark red. The mixture was heated on the steam bath for 20 min and then poured into 200 mL of water. After stirring 15 min the precipitated product was collected by filtration and recrystallized from ethanol (100 mL) to give 8.05 g (85%) of off-white needles: mp 112-113°C.
2,4-Dimethoxy-5-methylthiobenzaldehyde (9a)
This isomer was prepared from 8e as described for 6a. Recrystallization from methanol provided a 96% yield of fine white crystals, mp 124.5-125.5°C. This compound exhibits dimorphism. ln one experiment, the product melted at 109-110°C and displayed an infrared spectrum (Nujol mull) with major peaks at 691, 734, 819, and 994 cm-1. These were lost and an infrared spectrum of the more stable higher melting form (694, 731, 839, and 897 cm-1) was obtained following intense grinding prior to mull preparation or by recrystallization from a more concentrated methanolic solution.
2,5-Dimethoxy-4-methylthiobenzaldehyde (12a)
This isomer was prepared in 53% yield from 11d as described for 6a. Off-white crystals from methanol were obtained: mp 97.5-98.5°C. The mixture melting point with an authentic sample (lit.12 mp 95-96.5°C) was 96-96.5°C.
1-(4,5-Dimethoxy-2-methylthiophenyl)-2-nitropropene (6b)
A mixture of aldehyde 6a (2.0 g, 9.4 mmol) and ammonium acetate (0.45 g) in 8 mL of nitroethane was heated on a steam bath for 4.5 h. Removal of the excess nitroethane in vacuo gave a red oil, which upon addition of methanol (5 mL) spontaneously crystallized. The crude product (mp 98-101°C) was recrystallized from 25 mL of boiling methanol and provided 1.85 g (73%) of bright orange crystals: mp 104-105°C.
1-(2,4-Dimethoxy-5-methylthiophenyl)-2-nitropropene (9b)
This isomer was prepared in 80% yield from 9a with nitroethane as described for 6b: mp 112-113°C (ethanol).
1-(4,5-Dimethoxy-2-methylthiophenyl)-2-aminopropane Hydrochloride (6c)
A 200-mL three-neck flask was flushed with nitrogen and then charged with THF (50 mL) and lithium aluminum hydride (1.3 g, 34 mmol). The mixture was heated to reflux with stirring, and a solution of 6b (1.65 g, 6.1 mmol) in THF (20 mL) was added dropwise over a 30-min period. Heating at reflux was continued overnight, while maintaining a static pressure of nitrogen. The mixture was cooled externally with ice water and the excess hydride destroyed by careful addition of a solution of 1.3 mL of water in 10 mL of THF. Aqueous NaOH (1.3 mL of 4 N) was added, followed by 3.9 mL of water. The mixture was filtered to remove the precipitated salts, and the filter cake was washed with 20 mL of THF. Concentration of the filtrate in vacuo gave a light yellow oil which was taken up in 20 mL of 2-propanol and converted to the hydrochloride by the addition of 0.9 mL of concentrated HCl. The solution was diluted with 200 mL of anhydrous ether, which resulted in the formation of pale yellow crystals (1.20 g, 71%): mp 218-219.5°C. An analytical sample was obtained from methanol: mp 222-223°C.
1-(2,4-Dimethoxy-5-methylthiophenyl)-2-aminopropane Hydrochloride (9c)
This isomer was prepared from 9b as described for 6c. The free base was isolated (71% yield) by short-path distillation as a colorless oil, bp 125-128°C (0.1 mm), that solidified on standing, mp 47-48.5°C. The hydrochloride salt was prepared as described for 6c: mp 140.5-142°C.