Synthesis of 4-bromo-2,5-dimethoxy-(phenyl-2-aminopropan-1-ol)Starting material was 2,5-dimethoxybenzaldehyde.
Bromination:2,5-dimethoxybenzaldehyde, was dissolved in a minimal amount of GAA, and a solution of chilled bromine in GAA, was added in one portion. This beaker was stirred at room temperature for 24 hours. After this period it was poured into ice water and immediately formed brown/red crystals. These where filtered and recrystallized twice from acetonitrile, to yield 4-bromo-2,5-dimethoxybenzaldehyde(as slightly brownish crystals) in slightly less than 60% yield.
Bromo-2,5-dimethoxybenzaldehydeHenry rxn:7 g's of 4-bromo-2,5-dimethoxybenzaldehyde(245 g/moles) which is 0,0286 moles, was put in an beaker and 150 mL's ice cold methanol(-10 degrees) was added. 70% or so dissolved. In another RBF a 1,1 molar equalivent of nitroethane was mixed with a 1 molar equalivent of triethylamine. This was also cooled to -10 degrees and mixed with the contents of the other beaker. This was stirred in an ice/salt bath for two hours, while the temperature remained sub zero. No noticable change in color was noted. The solution was allowed to return to room temperature over one hour(this was probably a mistake as, according to
Indian Journal of Chemistry, Section B: Organic Chemistry (2001), 40B(1), 75-77., there will occur racemisation of the stereoisomers with increased temperature, when the catalyst isn't quenched with an acid). After this period, there was added a slow stream of GAA untill the solution was slightly acidic. The solvent was stripped under vacuum and the remaining red oil, was dissolved in 40 mL's of chloroform and washed twice with 50 mL's of water and once with brine. The choloform was stripped leaving a yellowish oil.
For the next trial of this reaction, it's probably a good idea just to use some excess nitroethane and skip on the alcoholic solvent, as it takes huge amounts to get everything in, and it seems that the reaction will run anyway.
4-bromo-2,5-dimethoxy-(phenylnitropropanol)Reduction:As it wasn't possible to crystallize the oil, it was used as it was. Theoretically there could be 9 grammes of the nitroalcohol(mw=306 g/mole), so this was used for the reduction. All of the nitroalcohol was dissolved in 30 mL's of methanol and placed in a RBF and fitted with a reflux condensor. The solution was quite reddish. 3 grammes of Zinc was stirred in 5% hydrochloric acid for two minutes, and then filtered, washed twice with water and once with acetone. This was put in the methanol/nitroalcohol solution and stirred. 16 mL's of 85% formic acid(the commercial version), was added in 1 mL's portions. The reaction was VERY vigorous, and required external cooling not to shoot up through the condensor. After the first 5 mL's was added, the reaction was more smooth, and more could be added. After 10 minutes the whole lot had been added. The mixture was stirred for 15 minutes, untill it returned to room temperature(without cooling). This was filtered to remove the remaining zinc and various salts. The mixture was now only slightly tinted yellow. The remaining solvent was removed under vacuum to give a yellowish oil.
Question for the people: Is formic acid a strong enough acid, to cause dehydration of the alcohol? If so, ammonium formate is probably a more wise choice!
4-bromo-2,5-dimethoxy-(phenyl-2-aminopropan-1-ol)WorkupThe workup will be performed soon, but nothing seems to indicate that anything went wrong. Hopefully the tertiary amine catalyst and the low reaction temperature used in the henry reaction will give a high yield of the desired stereoisomer, which can be used to make the aminorex analogue. Once complete, that will be written up aswell. The aminoalcohol is also usefull for preparing the Cat analogue of DOB, which also could be interesting to test.
More to come!
Have a nice weekend!
Regards
Bandil
