Syringa aldehyde, 4-propoxy-3,5-dimethoxy-benzaldehyde preparation.

Quote: Originally posted by Fery

Welcome to the forum. Well done! Nice experiment! Do you intend to synthesize something further from the 4-propoxy-3,5-dimethoxy-benzaldehyde?

4-propoxy-3,5-dimethoxy-beta-nitrostyren

4-propoxy-3,5-dimethoxy-beta-nitrostyren
To obtain nitrostyrene, cyclohexylamine was chosen as a catalyst and a mixture of IPA and acetic acid as a solvent. These reaction conditions allow obtaining pure nitrostyrene in good yields.

Mix 4.3 gr 4-propoxy-35dimethoxy-benzaldehyde in 20 ml IPA , mix 1.5 gr cyclohehylamine in 10 ml acetic acid and add to IPA solution of aldehyde . Add nitromethane 3.5 ml stirred and heated at 70…75 3 hours . The mixture is poured into 30 ml of H2O, and the nitrostyrene solution crystallizes in the refrigerator within an hour. After filtering and washing with cold water twice 50 ml -3.6 g of bright yellow crystals are obtained. Recrystallization from 20 ml of IPA and 6 hours in the refrigerator yielded 3.4 g of nitrotyrene (65%).


syringaaldehyde


4-propoxy-35dimethoxy-BA


4-propoxy-35dimethoxy-betanitrostyren

Proscaline Preparation

Proscaline Preparation
Two methods for synthesizing proscaline have been described in the literature. The first was by the Czech chemist Leminger in 1972, followed by Shulgin and Nichols in 1977 using a nitrile. It was interesting to follow Leminger's route, obtaining syringaldehyde, then 4-propoxy-3,5-dimethoxy-aldehyde, and 4-propoxy-3,5-dimethoxy-beta-nitrostyrene. The aldehyde was obtained in DMSO in good yield and isolated as a white crystalline compound using the method of Trachsel (2002). Nitrostyrene was obtained by cyclohexylamine-catalyzed condensation in IPA-acetylic acid, yielding a pure, bright yellow crystalline product with a 65% yield. To obtain the amine, the method chosen was reduction with sodium borohydride and CuCl2, which I will describe below.

Reduction
3.2 g NaBH4 (0.087 M) was added to the IPA-H2O mixture (26 ml and 14 ml) with stirring, then, after dissolution, 3.14 g (0.0117 M) nitrostyrene was added in small portions. The flask was placed in a water bath at 20 degrees, and the temperature of the reaction mixture did not exceed 30 degrees. Each portion discolored fairly quickly, and the entire addition took 10 minutes (Note 1). Next, a solution of CuCl2 in water (0.7 ml of a 2 M solution) 0.18gr CuCl2 was added in a thin stream, causing the mixture to darken. The reaction mixture was heated to 80 degrees, and refluxing was continued for 30 minutes. Afterwards, the mixture was cooled to room temperature.

Note1
Initially, the reaction was run longer, for about 30 minutes before adding CuCl2 and 40-50 minutes of reflux at 80°C, but the yields were much lower. The original article (lit1) describes a reaction time of 10-30 minutes, after which a dimer and other byproducts form. Therefore, the first part of the reaction was completed in 10 minutes; copper chloride solution was added and refluxed for 30 minutes, after which the reaction stoped.

Lit1:
Attachment: Beilstein Jorg. 2025, 21, 39.pdf (524kB)
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first part - lose color


second part - refluxing



hydrofumarate presipitation


Workup
The reaction mixture is poured into a 150 ml beaker and the flask is rinsed with 10 ml of IPA. The layers are immediately separated, with the IPA-amine layer on top and the aqueous layer below. 25 ml (7 g NaOH + 20 ml H2O) are added. The upper layer is carefully separated to avoid dark copper flakes. The aqueous layer is then extracted with two 15 ml portions of IPA. A saturated solution of K2CCO3 (18 g + 20 ml H2O) is prepared. The IPA solution is shaken twice with 10 ml of K2CO3, then dried with MgSO4. The result is approximately 55 ml of a clear, slightly yellowish solution of amine in IPA. The alcohol is evaporated, and the resulting solution is dissolved in 10 ml of acetone. A solution of 0.8-0.9 gr fumarik acid is prepared in hot acetone and added to the amine solution until pH = 6. White crystals of hydrogen fumarate immediately precipitate; after washing with acetone and drying, 2.75 g (0.0077 M) was obtained.

Proscaline-HCL
2.75 g of fumarate are dissolved in 27 ml of H2O with heating. 7 g of NaOH in 7 ml of water is added. The released amine base is extracted with three portions 10ml of DCM, the DCM is dried with magnesium sulfate, and evaporated. The amine is dissolved in 10 ml of IPA and carefully neutralized with approximately 0.6 ml of 35% HCl acid to a pH of 6. The IPA is slowly evaporated in a water bath, yielding a brownish crystalline solid. After washing with acetone and drying, white crystals of Proscaline hydrochloride (1.6 g) (0.0058 M or 50% based on nitrostyrene) were obtained.

Thank you all for reading , and I am personally grateful to everyone who posted their work online, for example, Benignium, the preparation of nitrostyrene 345trimethoxyBA, and its reduction. All these experiments help avoid mistakes and achieve good results.

Thanks The appendix to the article posted above contains various
conditions for this reaction, primarily increasing the reaction time for
25-dimethoxystyrene. As the reaction time increases to an hour or more,
the yields drop significantly and the amount of dimer increases.
For different styrenes, several reactions can be performed with small quantities, varying the reaction time—for example, 20 minutes,
then 40 minutes—and the yields can be compared.

Attachment: Beilstein-5397-21-4-S1 _suplmnt.pdf (2.5MB)
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Good job, it is an interesting class of compounds. The 4-cyclopropylmethoxy derivative made some stunning crystals as the hydrochloride, see attached picture. If you want to go for the secondary analogues, say the 4-isopropoxy isomer, time for the alkylation is significantly longer and monitoring via TLC to replenish the 2-bromopropane may be helpful.

Two questions: I assume you used anhydrous CuCl2 for the reaction, was this reagent purchased or prepared? If prepared, how? I preferred making CuBr or CuI as it is easier to get anhydrous starting from hydrated Cu(II) salts. Additionally, did you ever TLC the syringaldehyde? I attempted methoxylation of 5-bromobourbonal some time ago in a botched attempt (conditions not kept entirely anhydrous) and ended up with a complex mixture of starting material, bourbonal (which was not present in the precursor, so must have dehalogenated) and what I assume to be the product 5-methoxybourbonal. Did you TLC your syringaldehyde to ensure homogenous product?

PS: Depending on the substrate, higher catalyst loading and NaBH4 can be beneficial in the NaBH4/Cu. It seems like molecular oxygen coming into contact with the Cu particles can be particularly detrimental, even up to the filtering step. Excess NaBH4 and inert atmosphere can be helpful. Some substrates seem to benefit from significantly longer reflux periods than outlined in the publication, but it is probably best to keep the reaction under inert gas then. Against the findings of the publication, depending on substrate and exact conditions, partial to full dehalogenation of brominated substrates has been observed by various connoisseurs of nitrostyrene reduction.



[Edited on 7-2-2026 by pihkameleon]

Good afternoon!
Thank you for your feedback and congratulations on your result

About your questions -
1. Regarding the preparation of syringaldehyde.
I'll cite three articles on various methods of halogenated vanillin methoxylation, with preparation examples.
The article in Tetrahedron vol. 45 is particularly interesting, as it covers a large number of reaction conditions
with different copper salts, reaction times, and reagent concentrations.

Attachment: Terrahedron Vol. 45. No. 17_5565.pdf (958kB)
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Attachment: pepper-macdonald-2011-the-synthesis-of-syringaldehyde-from-vanillin.pdf (390kB)
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Attachment: US4218567.pdf (637kB)
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I used anhydrous CuCl2, purchased and of good quality.
CuCl2 dissolves much better in a DMF-methanol system.
I also used freshly prepared NaOMe in methanol, since the reaction conditions require anhydrous reagents.
The following additional conditions can also be used for a successful reaction: methylate concentration of 5.4 M
and a molar excess of 5x or higher.
Under these conditions and a reaction temperature of approximately
110°C, the reaction is complete in two hours maximum for bromovanillin.
I didn't perform TLC, but I was guided by the considerations above.
The resulting syringaldehyde dissolves in a very small amount of methanol upon recrystallization, unlike bromovanillin.

For each new substrate, such as bourbonal, separate studies are needed. For example,
if methoxylation proceeds well under these conditions, ethoxylation is much worse or does not occur at all
. Also, different substituents in the ortho position to the halogen
affect the reaction course.

2. Regarding the 4-isopropoxy-substituted aldehyde, it would be interesting to try it.
I would like to know the reaction time and evaluate the results.
Your 4-Cycloproploxy variant could be quite interesting, as would 4-Methallyloxy.

3. Regarding reduction, I think an inert atmosphere is definitely welcome, and the reaction time and catalyst concentration should be tested for each styrene.
In the case of propoxy, increasing the time resulted in a decrease in yield. If there are successful experiments with other substrates,
I'd be happy to read about them



[Edited on 9-2-2026 by Valery]