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All 2 posts Subject: 2-Alkoxy-4,5-methylenedioxybenzaldehyde Synthesis Please login to post Down

imp
(Stranger)
10-13-03 05:11
No 464339
      2-Alkoxy-4,5-methylenedioxybenzaldehyde Synthesis
(Rated as: excellent)

Piperonal can be nitrated to 6-nitropiperonal, reduced to the aminoaldehyde, and diazotized to 2-hydroxy-4,5-methylenedioxybenzaldehyde. This can be methylated to 2-methoxy-4,5-methylenedioxybenzaldehyde all in good yields.

Searching through many articles, the entire process has been refined, all the tricks have been discovered and the issues have been hashed out and solved. Lets begin with the nitration of piperonal...

6-nitropiperonal
refs: JACS, vol. 51, pp.534 (1929)
JACS, vol. 50, pp.2712 (1928)
Ber., vol. 24, pp.625 (1891)

To 500 cc. of concentrated nitric acid (sp. gr. 1.42) cooled to 0 C, there was added 50 g. of finely pulverized piperonal slowly and with constant stirring, the temperature being maintained below 0 C during this addition and for two to three hours thereafter. If some of the piperonal still remained undissolved, the freezing mixture was removed and the mixture allowed to warm gradually, until all was dissolved. The solution was poured immediately into ice water, the yellow precipitate collected, washed free from nitric acid and stirred with sufficient 40% sodium bisulfite solution to make a thick paste. Two volumes of water were added and the mixture filtered. The residue was subjected to the same treatment and this was repeated with the two or three succeeding residues. The combined filtrates were made alkaline with sodium hydroxide, the precipitate collected, washed thoroughly and crystallized from a 1:1 mixture of ethyl acetate and alcohol. The nitropiperonal so obtained formed long, pale yellow needles, m.p. 97-98 C; yield 46 g., or 70%. There was recovered also 14 g. of 4-nitro-1,2-methylenedioxybenzene which, taken together with the nitropiperonal, accounts for 96% of the piperonal used.

Using a nitric acid of sp. gr. 1.38 gave 51.7g nitropiperonal. Also, the sodium bisulphite purification can be omitted as described in a very similar procedure by Shulgin in TihKaL #32. 5,6-MDO-MIPT.

6-aminopiperonal
refs: JOC, vol. 16, pp.1736 (1951)
JACS, vol. 51, pp.536 (1929)
JACS, vol. 39, pp.1435 (1917)

The synthesis looks straightforward, but unexpected complications were found. Reduction of 6-nitropiperonal to 6-aminopiperonal in satisfactory yield is very difficult to accomplish. Catalytic hydrogenation, and reduction with iron or tin and acid were unsatisfactory. The reaction was best carried out using ferrous sulphate. The quality of the ferrous sulphate was very important, as the reagent grade material gave poor results, but the USP quality was satisfactory; this points to a promoting or catalytic effect of some impurity present in the USP material.

Ten grams of 6-nitropiperonal in 500 ml. of boiling 50% ethanol was added to a boiling solution of 100 g. of USP ferrous sulphate in 500 ml. of water. The solution was boiled for one minute, and then 130 ml. of concentrated ammonium hydroxide was added with rapid stirring in 5-10 ml. portions. An interval of 30-40 seconds was allowed between each addition, and the mixture was kept at the boiling point for 5-10 minutes after addition was complete. It was then centrifuged while hot, and the residue washed with 500 ml. of boiling water. The filtrate and washings were cooled in an ice-bath, and the precipitated 6-aminopiperonal was collected and recrystallized from hot water. The product was obtained in 70-75% yield as yellow needles, m.p. 107-108 C.

A similar procedure omits this centrifugation...

...After boiling the mixture for five minutes, it was filtered, the precipitate washed thoroughly with boiling water and the filtrate and washings were combined and cooled. The crude amino-aldehyde which separated was recrystallized from water and then formed long yellow needles, m.p. 107-108 C; yield 5 g., or 60%.

6-hydroxypiperonal
refs: JOC, vol. 16, pp.1736 (1951)

The diazotization and replacement of the amino group by hydroxyl was likewise more difficult and more subject to experimental variations than had been anticipated, but a satisfactory procedure was finally developed. Previous to this procedure, diazotization of 6-aminopiperonal had failed altogether and was considered 'futile'.

A suspension of 10.6 g. of 6-aminopiperonal in 300 ml. of water was cooled to 5 C and acidified with 10 ml. of concentrated sulphuric acid in 60 ml. of water. The cold mixture was diazotized by the addition of 4.5 g. of sodium nitrite in 50 ml. of water at 0-5 C. The diazonium solution was gradually warmed to room temperature, diluted with an equal volume of water, and added slowly to a boiling solution of 125 g. of copper sulphate in 125 ml. of water. The solution was steam-distilled for eight hours, and the product was recovered from the steam-distillate by extraction with ether. The yield of product of m.p. 125-126 C was 60%.

[Notice the weak acid concentration and large solvent volume during the diazotization]

2-methoxy-4,5-methylenedioxybenzaldehyde
refs: JOC, vol. 16, pp.1736 (1951)

To a mixture of 4 g. of 3,4-methylenedioxy-6-hydroxybenzaldehyde, 14 g. of anhydrous potassium carbonate, and 100 ml. of dry benzene there was added 9 g. of methyl sulphate slowly, with stirring. The mixture was refluxed for 48 hours and filtered while hot. The solvent was removed from the filtrate, and the residue was recrystallized from hot water. The yield of 3,4-methylenedioxy-6-methoxybenzaldehyde was 92-95%, and the material had m.p. 111.5-112 C.

Now of course from the aldehyde you can go the usual path to the amphetamine.

GC_MS
(Hive Addict)
10-13-03 13:44
No 464403
User Picture       nitration

There was recovered also 14 g. of 4-nitro-1,2-methylenedioxybenzene which, taken together with the nitropiperonal, accounts for 96% of the piperonal used.

Loss of the formyl group indeed is not uncommon when nitrating a benzaldehyde derivative - in this case piperonal. What you might want to consider - at least if you plan to start from scratch - is to nitrate 1,2-methylenedioxybenzene to yield 1,2-methylenedioxy-4-nitrobenzene. I have performed this reaction in the past and yield easily exceeds 90%. The nitrated product forms typical yellow needles. You can convert the nitrated substance to 1-alkoxy-3,4-methylenedioxybenzene via the routes you have described, followed by formylation with POCl3/DMF. My personal experience stops at the diazotation reaction though...

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".

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	All 2 posts		Subject: 2-Alkoxy-4,5-methylenedioxybenzaldehyde Synthesis		Please login to post		Down


		imp (Stranger) 10-13-03 05:11 No 464339				2-Alkoxy-4,5-methylenedioxybenzaldehyde Synthesis (Rated as: excellent)
						Piperonal can be nitrated to 6-nitropiperonal, reduced to the aminoaldehyde, and diazotized to 2-hydroxy-4,5-methylenedioxybenzaldehyde. This can be methylated to 2-methoxy-4,5-methylenedioxybenzaldehyde all in good yields. Searching through many articles, the entire process has been refined, all the tricks have been discovered and the issues have been hashed out and solved. Lets begin with the nitration of piperonal... 6-nitropiperonal refs: JACS, vol. 51, pp.534 (1929) JACS, vol. 50, pp.2712 (1928) Ber., vol. 24, pp.625 (1891) To 500 cc. of concentrated nitric acid (sp. gr. 1.42) cooled to 0 C, there was added 50 g. of finely pulverized piperonal slowly and with constant stirring, the temperature being maintained below 0 C during this addition and for two to three hours thereafter. If some of the piperonal still remained undissolved, the freezing mixture was removed and the mixture allowed to warm gradually, until all was dissolved. The solution was poured immediately into ice water, the yellow precipitate collected, washed free from nitric acid and stirred with sufficient 40% sodium bisulfite solution to make a thick paste. Two volumes of water were added and the mixture filtered. The residue was subjected to the same treatment and this was repeated with the two or three succeeding residues. The combined filtrates were made alkaline with sodium hydroxide, the precipitate collected, washed thoroughly and crystallized from a 1:1 mixture of ethyl acetate and alcohol. The nitropiperonal so obtained formed long, pale yellow needles, m.p. 97-98 C; yield 46 g., or 70%. There was recovered also 14 g. of 4-nitro-1,2-methylenedioxybenzene which, taken together with the nitropiperonal, accounts for 96% of the piperonal used. Using a nitric acid of sp. gr. 1.38 gave 51.7g nitropiperonal. Also, the sodium bisulphite purification can be omitted as described in a very similar procedure by Shulgin in TihKaL #32. 5,6-MDO-MIPT. 6-aminopiperonal refs: JOC, vol. 16, pp.1736 (1951) JACS, vol. 51, pp.536 (1929) JACS, vol. 39, pp.1435 (1917) The synthesis looks straightforward, but unexpected complications were found. Reduction of 6-nitropiperonal to 6-aminopiperonal in satisfactory yield is very difficult to accomplish. Catalytic hydrogenation, and reduction with iron or tin and acid were unsatisfactory. The reaction was best carried out using ferrous sulphate. The quality of the ferrous sulphate was very important, as the reagent grade material gave poor results, but the USP quality was satisfactory; this points to a promoting or catalytic effect of some impurity present in the USP material. Ten grams of 6-nitropiperonal in 500 ml. of boiling 50% ethanol was added to a boiling solution of 100 g. of USP ferrous sulphate in 500 ml. of water. The solution was boiled for one minute, and then 130 ml. of concentrated ammonium hydroxide was added with rapid stirring in 5-10 ml. portions. An interval of 30-40 seconds was allowed between each addition, and the mixture was kept at the boiling point for 5-10 minutes after addition was complete. It was then centrifuged while hot, and the residue washed with 500 ml. of boiling water. The filtrate and washings were cooled in an ice-bath, and the precipitated 6-aminopiperonal was collected and recrystallized from hot water. The product was obtained in 70-75% yield as yellow needles, m.p. 107-108 C. A similar procedure omits this centrifugation... ...After boiling the mixture for five minutes, it was filtered, the precipitate washed thoroughly with boiling water and the filtrate and washings were combined and cooled. The crude amino-aldehyde which separated was recrystallized from water and then formed long yellow needles, m.p. 107-108 C; yield 5 g., or 60%. 6-hydroxypiperonal refs: JOC, vol. 16, pp.1736 (1951) The diazotization and replacement of the amino group by hydroxyl was likewise more difficult and more subject to experimental variations than had been anticipated, but a satisfactory procedure was finally developed. Previous to this procedure, diazotization of 6-aminopiperonal had failed altogether and was considered 'futile'. A suspension of 10.6 g. of 6-aminopiperonal in 300 ml. of water was cooled to 5 C and acidified with 10 ml. of concentrated sulphuric acid in 60 ml. of water. The cold mixture was diazotized by the addition of 4.5 g. of sodium nitrite in 50 ml. of water at 0-5 C. The diazonium solution was gradually warmed to room temperature, diluted with an equal volume of water, and added slowly to a boiling solution of 125 g. of copper sulphate in 125 ml. of water. The solution was steam-distilled for eight hours, and the product was recovered from the steam-distillate by extraction with ether. The yield of product of m.p. 125-126 C was 60%. [Notice the weak acid concentration and large solvent volume during the diazotization] 2-methoxy-4,5-methylenedioxybenzaldehyde refs: JOC, vol. 16, pp.1736 (1951) To a mixture of 4 g. of 3,4-methylenedioxy-6-hydroxybenzaldehyde, 14 g. of anhydrous potassium carbonate, and 100 ml. of dry benzene there was added 9 g. of methyl sulphate slowly, with stirring. The mixture was refluxed for 48 hours and filtered while hot. The solvent was removed from the filtrate, and the residue was recrystallized from hot water. The yield of 3,4-methylenedioxy-6-methoxybenzaldehyde was 92-95%, and the material had m.p. 111.5-112 C. Now of course from the aldehyde you can go the usual path to the amphetamine.



		GC_MS (Hive Addict) 10-13-03 13:44 No 464403				nitration
						There was recovered also 14 g. of 4-nitro-1,2-methylenedioxybenzene which, taken together with the nitropiperonal, accounts for 96% of the piperonal used. Loss of the formyl group indeed is not uncommon when nitrating a benzaldehyde derivative - in this case piperonal. What you might want to consider - at least if you plan to start from scratch - is to nitrate 1,2-methylenedioxybenzene to yield 1,2-methylenedioxy-4-nitrobenzene. I have performed this reaction in the past and yield easily exceeds 90%. The nitrated product forms typical yellow needles. You can convert the nitrated substance to 1-alkoxy-3,4-methylenedioxybenzene via the routes you have described, followed by formylation with POCl3/DMF. My personal experience stops at the diazotation reaction though... Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".

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