(Hive Bee)
11-30-03 15:35
No 473897
(Rated as: excellent)
Benzene or anisole is oxidized electrochemically to the bis-dimethyl acetal of benzoquinone 1 which can be further reduced to 1,4-dimethoxybenzene or any nucleophile can bee added to 2-position.
The patent (Patent US4046652) has already been mentioned:
Post 347768 (bottleneck: "1,4-Dimethoxy in two steps from benzene", Novel Discourse)
Post 273091 (PolytheneSam: "Electro hydroquinone method", Novel Discourse)
This opens new synthetic pathways for 2,5-dimethoxysubstituted-PEAs and -amphetamines. E.g. 2C-T-7 precursor can bee synthesized by the action of propanthiole on 1 or TMA-2 precursors from the action of acetic acid/acetanhydride on 1 and hydrolysis of the reaction product and of course the use of HCl or HBr leads to an ideal precursor of 2C-B or DOC.
Perhaps there is possibility to produce the bis-acetals from benzoquinoe (e.g. MeOH/H2SO4) or trimethylorthoformiat) without the need of electrochemical methods (electrochemistry is not one of Lego's strengths
).Only the interesting details of the articles have been translated.
Molecule: 1 ("C/1=C/C(\C=C/C\1(OC)OC)(OC)OC")
p-benzoquinone-bis-dimethylacetal 1
Molecule: 5 ("C\1=C\C(CCC/1(OC)OC)(OC)OC")
2-cyclohexen-1,4-dion-bis-dimethylacetal
Molecule: 6 ("C1CC(CCC1(OC)OC)(OC)OC")
1,4-cyclohexandion-bis-dimethylacetal 6
Here are two more articles:
Synthesis, 1979, 8, 603-605 (http://lego.chemistry.tripod.com/Journa
Reactions with p-benzoquinone-bis-dimethylacetal - hydrogenation products
[...]
3,3,6,6-Tetramethoxycyclohexen (2-cyclohexen-1,4-dion-bis-dimethylaceta
To a solution of p-benzoquinone-bis-dimethylacetal (11, 377.6 g, 1.866 mol) in methanol (1060 g) triethylamine (0.5 g) and palladium on charcoal (5%, 1g) are added. In an autoclave hydrogen is added up to a pressure of 50 bar at room temperature. 42.5 l hydrogen (standard conditions) are consumed in 20 min. After relieving the overpressure the catalyst is filtered off and the solvent removed under standard pressure. The residue distills at 110-150°/20 torr. According to a gas chromatographical analysis the distillate consists of 5 (92%), 4a (4%) and 6 (4%). 5 crystallizes almost completely at 20° and can be seperated as pure product. Yield: 343.2 g (90%).
[...]
Hydroquinone-dimethylether (4a)
Method A, starting from 5: 3,3,6,6-Tetramethoxycyclohexen (5, 250 g) is lead through a 50 cm pipe (diameter: 3,5 cm) heated to 250-280°C filled with boiling stones under standard pressure. The leaving vapor is condensed in a flask cooled with icewater. Yield: 167.7 g (>98%). GC-purity: 99,9%.
Method B, starting from 1: A 150-ml autoclave is charged with p-benzoquinone-bis-dimethylacetal (20.2 g, 0.1 mol), propionic acid (100 ml) and palladium on charcoal (5%, 0.5 g). The mixture is hydrogenated for 3 h at 20°C and 50 bar. The hydrogen uptake is 2.3 l (standard conditions). Fractionated distillation yielded pure 3. Yield 12.3 g (87%). GC-purity: 99.6%.
Method C, starting from 6: 1,4-cyclohexandion-bis-dimethylacetal (6, 40 g) is heated together with palladium on charcoal (5%, 1 g) for 4 h to reflux at 230° while bubbling a slow stream of nitrogen through the mixture. Then the mixture is distilled under vacuum. Yield: 21 g 5, 4 g of unchanged 6 are recovered. GC-purity: 99.4%.
1,4-Cyclohexandion-bis-dimethylacetal (6):
To a solution of p-benzoquinone-bis-dimethylacetal (1, 398 g, 1.99 mol) in methanol (1000 g) triethylamine (1 ml) and palladium on charcoal (5%, 1 g) are added. In an autoclave hydrogen is added up to a pressure of 50 bar. 46.8 l of hydrogen (standard conditions) are consumed in 30 min at 20-40°. After relieving the overpressure the catalyst is filtered off and the solvent is evaporated at standard pressure. 6 crystallizes from the residue on cooling of the residue. Yield: 345 g (85.0%). The mother liquor (46 g) consists of 30% 4a and 65% 6, total yield of 6: 92.5%.
Synthesis, 1979, 8, 605-607 (http://lego.chemistry.tripod.com/Journa
Reactions of p-benzoquinone-bis-dimethylacetal - reaction with nucleophiles to substituted hydroquinone dimethylethers
[...]
| 3 | H-Nu | Yield [%] |
| a | H3C-OH | 90 |
| b | HCl | 93 |
| c | H3C-COOH | 92 |
| d | HN3 | Reduction with NaBH4, isolation of the amine, total yield: 87% |
| e | C2H5-SH | 69 |
| f | i-C4H9-SH | 51 |
| g | HS-CH2-COOC2H5 | 61 |
| h | 5-H-1,2,4-Trimethoxybenzene | 61 |
| i | 4-H-1,3,5-Trimethoxybenzene | 50 |
| j | 4-H-1,3-Dimethoxybenzene | 20 |
| k | 2-H-Pyrrole | 51 |
| l | 4-H-Dimethylaniline | 48 |
| m | 2-H or 4-H-Phenol | 72 (mixture of the isomers) |
[...]
The reaction of 1 with nucleophiles of weak acidity (e.g. methanol or thiols) has to be catalysed through the addition of acids with weakly nucleophilic anions (e.g. sulfuric acid, p-toluenesulfonic acid, perchloric acid, ...). At the necessary proton concentration hydrogen cyanide is undissociated and amines are protonated and do not react.
Possible solvents are the either the products (e.g. chloro or bromo-hydroquinone dimethylether), the nucleophile or other inert solvents. In strong acid media the reaction occurs so fast due to the exothermic character of the aromatization that the bis-acetal 1 can only be added slowly and cooling the mixture heavily.
During the reaction methanol is set free which can react as a nucleophile with 4, therefore a sideproduct is 1,2,4-trimethoxybenzene (2a) which can react to 2,2',4,5,5'-pentamethoxybiphenyl (2h) as a further sideproduct. The yield depends on the nucleophilic character of the reaction partner HNu. Very good nucleophiles like thiols can bee used in equimolar amounts, weaker nucleophiles have to be used in excess to prevent the formation of 1,2,4-trimethoxybenzene (2a) and 2,2',4,5,5'-pentamethoxybiphenyl (2h).
1,2,4-Trimethoxybenzene (2a):
To a stirred solution of p-Benzoquinone-bis-dimethylacetal (1; 94.7%, 80.4 g) in methanol (625 ml) a solution of concentrated sulfuric acid (0.05 ml) and trimethylorthoformiat (2.5 ml) in methanol (125 ml) is added dropwise at 20° C while cooling the solution. After 16 h the mixture is neutralized with solid sodium hydroxide, the excess of methanol is evaporated in vacuo and the residue is distilled fractionally. Yield: 57.5 g (90%)
Chlorohydroquinone dimethylether (2b):
A solution of p-benzoquinone-bis-dimethylacetal (1, 10 g, 50 mmmol) in ether (20 ml) is added dropwise to a cooled and stirred solution of hydrogen chloride (18.2 g, 0.5 mol) in ether (80 ml) at 10° over a period of 10 min. The mixture is stirred for 1 h at 10-15°, washed with water (2 x 100 ml) und 5% sodium hydrogencarbonate solution (100 ml). The organic phase is dried over sodium sulfate and the ether is evaporated with aspirator vacuum. 96% of the residual oil are 2b. Yield: 7.5 (88%). The neglible impurity is 2a which can hardly be seperated by distillation.
Acetoxyhydrochinon-dimethylether 2c):
p-benzoquinone-bis-dimethylacetal (1, 98.6%, 104 g) is dissolved in glacial acetic acid (3000 ml) in the cold. To this stirred solution over a period of 3 h at mixture of acetic anhydride (50 ml) and concentrated sulfuric acid (2 ml) is added dropwise at 55°. Afterwards the acetic acid is evaporated in vacuo the oily residue is distilled fractionally. Yield: 92.2 g (92%). GC-purity: 99.2%. For total purification the product can be recrystallized from hexan/tetrachloromethane.
Ethyl-(2,5-dimethoxyphenylthio)-acetate (2g):
To a stirred solution of p-benzoquinone-bis-dimethylacetal (1, 10 g) and ethyl mercaptoacetate (9 g) in ether (50 ml) glacial acetic acid (1 ml) is added dropwise at 20°. After 15 h 10% sodium carbonate solution (250 ml) is added and the mixture is extracted with dichloromethane (2 x 50 ml). The organic phase were pooled, washed with water (2 x 100 ml) and dried over sodium sulfate. The solvent is evaporated and residue distilled in vacuo. Yield: 7.8 g (61%).
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