Introduction:
Phenylephrine is structurally very similar to Pseudoephedrine and is also used as a nasal decongestant.
Pharmaceutical companies favour using Phenylephrine over Pseudoephedrine to prevent the direct conversion to Methamphetamine.
Pseudoephedrine can also be converted indirectly directly via P2P/BMK/Phenylacetone.
Since Phenylephrine cannot be used to make meth, it has therefore received little attention to date.
Theoretically, Phenylephrine can also be converted in the same manner as Pseudoephedrine, yielding a highly desirable precursor (3-hydroxyphenyl)acetaldehyde.
The benefit of this process is that Phenylephrine is relatively inexpensive and easy to find compared to 2,5-dimethoxybenzaldehyde.
2,5-dimethoxybenzaldehyde also relies on you having access to nitromethane for the Henry condensation which might not be the case.
RXN 1:
Phenylephrine, (an alpha-hydroxy amine), is first converted to the aldehyde; (3-hydroxyphenyl)acetaldehyde using an acid catalyst.
The mechanism is fairly complex and proceeds via numerous intermediates which exist in equilibrium.
The reaction begins with protonation of the benzyl alcohol, water is eliminated forming an enamine which then isomerizes to form the imine.
The imine is then attacked by water, forming the hemi aminal which eliminates methylamine/methylammonium ion forming the desired aldehyde.
The methylamine byproduct can be separated and saved for other reactions! It doesn't make sense to waste it and helps to improve the atom economy of the process if
you are doing this at scale.
Note! Leaving the reaction going for too long or too low of a pH will likely cause problems. Once formed the aldehyde might start to undergo
aldol polymerization since it partially exists as its enol form. Aldehydes (and also phenols) are somewhat unstable in air so the reaction might have to be performed under nitrogen.
Avoiding side reactions is the main concern!
Once the aldehyde is formed may routes are possible. The reaction scheme was designed to avoid 2 main side reactions that can
occur when using dichromate to oxidize the phenol to the benzoquinone.
Route 1 forms the amine first and then protects it as the phthalimide to prevent an intramolecular cyclization with the benzoquinone
which aims to restore the aromaticity of the system.
Route 2 forms the amine last and starts by protecting the aldehyde as the acetal to prevent oxidation to the carboxylic acid.
Proposed (Hypothetical) Reaction Scheme:
The overall process might not be economically viable at scale however it definitely seems plausible for the amateur.
The required reagents don't seem overly toxic, expensive or hard to find.
Although I will admit that Methyl Iodide, Dichromate and Hydrazine are quite nasty without proper safety precautions in place.
Hydrazine can probably also be replaced with a safer alternative for the de-protection step of the phthalimide.
If you think Hydrazine is too dangerous or hard to find, the acetal route could be a better alternative.
I wouldn't be surprised if someone else figures out a better way to do this reaction in fewer steps or with improved reagents.
If you have any suggestions/constructive criticism/feedback make sure to leave it in the comments.
Like with all chemistry this is just speculation on my part, there could be numerous unforeseen issues or reasons why this reaction doesn't work.
Until someone tries it and gives feedback we won't known for certain.
SWIM dreams of a version where atmospheric oxygen is used to form the benzoquinone although this might not be possible.
Phenylephrine is structurally very similar to Pseudoephedrine and is also used as a nasal decongestant.
Pharmaceutical companies favour using Phenylephrine over Pseudoephedrine to prevent the direct conversion to Methamphetamine.
Pseudoephedrine can also be converted indirectly directly via P2P/BMK/Phenylacetone.
Since Phenylephrine cannot be used to make meth, it has therefore received little attention to date.
Theoretically, Phenylephrine can also be converted in the same manner as Pseudoephedrine, yielding a highly desirable precursor (3-hydroxyphenyl)acetaldehyde.
The benefit of this process is that Phenylephrine is relatively inexpensive and easy to find compared to 2,5-dimethoxybenzaldehyde.
2,5-dimethoxybenzaldehyde also relies on you having access to nitromethane for the Henry condensation which might not be the case.
RXN 1:
Phenylephrine, (an alpha-hydroxy amine), is first converted to the aldehyde; (3-hydroxyphenyl)acetaldehyde using an acid catalyst.
The mechanism is fairly complex and proceeds via numerous intermediates which exist in equilibrium.
The reaction begins with protonation of the benzyl alcohol, water is eliminated forming an enamine which then isomerizes to form the imine.
The imine is then attacked by water, forming the hemi aminal which eliminates methylamine/methylammonium ion forming the desired aldehyde.
The methylamine byproduct can be separated and saved for other reactions! It doesn't make sense to waste it and helps to improve the atom economy of the process if
you are doing this at scale.
Note! Leaving the reaction going for too long or too low of a pH will likely cause problems. Once formed the aldehyde might start to undergo
aldol polymerization since it partially exists as its enol form. Aldehydes (and also phenols) are somewhat unstable in air so the reaction might have to be performed under nitrogen.
Avoiding side reactions is the main concern!
Once the aldehyde is formed may routes are possible. The reaction scheme was designed to avoid 2 main side reactions that can
occur when using dichromate to oxidize the phenol to the benzoquinone.
Route 1 forms the amine first and then protects it as the phthalimide to prevent an intramolecular cyclization with the benzoquinone
which aims to restore the aromaticity of the system.
Route 2 forms the amine last and starts by protecting the aldehyde as the acetal to prevent oxidation to the carboxylic acid.
Proposed (Hypothetical) Reaction Scheme:
The overall process might not be economically viable at scale however it definitely seems plausible for the amateur.
The required reagents don't seem overly toxic, expensive or hard to find.
Although I will admit that Methyl Iodide, Dichromate and Hydrazine are quite nasty without proper safety precautions in place.
Hydrazine can probably also be replaced with a safer alternative for the de-protection step of the phthalimide.
If you think Hydrazine is too dangerous or hard to find, the acetal route could be a better alternative.
I wouldn't be surprised if someone else figures out a better way to do this reaction in fewer steps or with improved reagents.
If you have any suggestions/constructive criticism/feedback make sure to leave it in the comments.
Like with all chemistry this is just speculation on my part, there could be numerous unforeseen issues or reasons why this reaction doesn't work.
Until someone tries it and gives feedback we won't known for certain.
SWIM dreams of a version where atmospheric oxygen is used to form the benzoquinone although this might not be possible.