Niklas
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Posts: 155
Registered: 1-12-2023
Location: Germany
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Mood: Polymerized
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Synthesis of 3-Aminopropanal Diethylacetal
Greetings,
I‘m currently working on a larger project, I‘ll likely share the details if the first couple attempts end up being successful, and one of the
starting materials required for it is 3-Aminopropanal Diethylacetal. While it is a rather simple substance structurally, it’s prices are absolutely
outrageous (105€ for 25 g at BLD Phram), so it’s definitely not something I could have simply bought directly. Luckily the corresponding alkyl
chloride seemed to be much more affordable, so I ended up purchasing a small 25 g bottle for 34€.
The published procedure for converting one into the other consist of first generating the alkyl azide by Sn2 reaction with sodium azide followed by
catalytic hydrogenation to the amine in 63% yield [1].
Fig.1: Published synthesis of 3-aminopropanal diethylacetal
While this seems fine to perform, I‘d honestly prefer not to handle azides in a polar aprotic solvent that can easily penetrate gloves and skin, so
I decided on attempting the conversion by a Gabriel synthesis via the alkyl phthalimide instead.
Fig.2: Synthesis of 3-aminopropanal diethylacetal via the Gabriel synthesis
As this hasn’t been published before for this particular substrate I decided to base myself on Shulgin’s procedures for 3-T-TRIS (Sn2) and DOI
(hydrazinolysis), as those are usually quite nicely written [2][3].
One thing to quickly note out, there may be some inconsistency with the scale shown in the pictures, as I attempted this synthesis twice, first
attempt of which failed in the workup of the second step.
Potassium phthalimide:
29,4 g of Phthalimide (200 mmol) were suspended in 400 ml of methanol and brought to a reflux on a hotplate, causing a significant quantity of the
solid to dissolve. Meanwhile 14 g of potassium hydroxide pellets (250 mmol) were dissolved in 100 ml of methanol, and the resulting clear solution
added to the refluxing suspension in portions small enough to keep it boiling, quickly causing the solution to turn a slight yellow color and a white
granular precipitate to separate. Refluxing was continued for 10 min, and the white solids removed by vacuum filtration after cooling back down to
room temperature. After air drying the product was collected as white crystalline flakes. 34,36 g; 92,8%
Fig.3: Potassium phthalimide made by reaction of phthalimide with potassium hydroxide
N-(3,3-Diethoxypropyl)phthalimide:
A 100 ml round-bottom-flask was charged with 10 g of the potassium phthalimide (54 mmol) and 70 ml of DMF was added causing some of the solid to
dissolve. While stirring 8,95 g of commercial 3-chloropropanal diethylacetal (53,75 mmol) were added dropwise, an Allihin condenser was attached, and
the colorless mixture was heated to 90°C with the help of a heating block for 24 h. During this time most of the solids dissolved and the solution
gradually turned a cloudy orange color. It was added to 600 ml of dest. water to dilute things, and the resulting yellow solution with some sticky
orange oil separating was extracted three times using ethyl acetate. The yellow extracts were washed twice with diluted brine to remove remaining DMF,
once with saturated brine to remove remaining water, dried over sodium sulfate, and the solvent removed by rotary evaporation. The product was
collected as a viscous orange oil and used as such in the next step. 13,92 g; 93,5%
Fig.4: The progress of the Sn2 reaction
Fig.5: The crude alkyl phthalimide intermediate
3-Aminopropanal Diethylacetal:
The crude intermediate was dissolved into 150 ml of denatured ethanol and charged into a 250 ml round bottom flask. 9 ml of hydrazine hydrate (185
mmol) were added, an Allihin condenser was again attached, and the mixture was heated to a reflux with the help of a glycerol bath for 20 h. On
reaching reflux temperature a cottage-cheese like precipitate of phthalhydrazide started gradually appearing, making stirring impossible after the
first hour. After cooling back down to room temperature the solid was broken up with a stirrod, removed by vacuum filtration, and washed with a bunch
more denatured ethanol to make sure all product is dissolves. The filter cake should consist of fairly pure phthalhydrazide and could be collected if
desired. The yellowish filtrate was concentrated in the rotovap, and to remove remaining ethanol and probably excess hydrazine the orange liquid was
heated in a glycerol bath to 50°C while pulling a mild vacuum, until more phthalhydrazide started precipitating as a granular solid. The residue was
dissolved into 30 ml of 12-molar potassium hydroxide solution, and the resulting dark yellow solution extracted three times using diethylether. The
yellow extract were dried over sodium sulfate, the ether destilled off by regular destillation, and the remaining yellow liquid of crude product
purified by short-path destillation under an aspirator vacuum (55-70°C). The product was collected as a clear colorless liquid with a strong
amine-like smell. 6,78 g; 85,7% (from the alkyl chloride)
Fig.6: The progress if the hydrazinolysis
Fig.7: Destillation of the crude product
Fig.8: The destilled final product
Sources:
[1] Durrwachter, J. R., Wong, C. H. (1988). Fructose 1,6-diphosphate aldolase-catalyzed stereoselective synthesis of C-alkyl and N-containing sugars:
thermodynamically controlled C-C bond formations. J. Org. Chem. 53/18, 4175-4181
[2] Shulgin, A., Shulgin, A. (1991). #178 3-T-TRIS; 3-Thiothrescaline; 3-Thiotriescaline; 3,4-Diethoxy-5-ethylthiophenylethylamine. PiHKAL: A Chemical
Love Story. 918f
[3] Shulgin, A., Shulgin, A. (1991). #67 DOI; 2,5-Dimethoxy-4-iodoamphetamine. PiHKAL: A Chemical Love Story. 918f
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Niklas
Hazard to Others
Posts: 155
Registered: 1-12-2023
Location: Germany
Member Is Offline
Mood: Polymerized
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Forgot to mention, but by titration of a 618 and 642 mg sample with 1 molar hydrochloric acid against methyl orange an approximate purity of 95% could
be determined.
NMR will soon follow.
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