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Synthesis of Methylenedioxybenzene Derivatives

Claude Feugas
Bull. Soc. Chim. France 1892-1895 (1964)

Translated by Hypo, HTML by Rhodium

Reacting 4-bromo-1,2-methylenedioxy-benzene or its higher homologue 2,2-bis-ethyl-5-bromo-benzodioxole with magnesium in tetrahydrofurane gives organo-magnesium compounds. These new compounds allow to introduce the methylenedioxy-benzene heterocycle into numerous compounds in a single step. The piperine derivates safrole, isosafrole, piperonal, piperonylic acid and alcohol, 3,4-methylenedioxytoluene, alpha-ethyl-piperonylic alcohol, piperonylacroleine, piperic acid and finally piperine have thus been synthesised.

Many natural or biological active compounds contain in their structure the 1,2-methylenedioxybenzene (1,3-benzodioxole) group. These alkaloids and flavones have been extensively researched and some of them have interesting pharmacodynamic applications. Right now there is a renewed interest in these compounds due to the recent discovery of their insecticide and fungicide properties1-9, and especially their antimitotic properties in certain forms of cancer10-17. A big number of structural derivates were prepared and systematically explored3,10,15,16,17. One limiting factor in these studies has been the difficulty in synthesis, because the acetalisation of a substituted diphenol already in place is nearly impossible18.

The importance of an organo-metallic derivate of 1,2-methylenedioxybenzene became quickly apparent; it would allow the addition of the heterocycle during any part of the synthesis by various reactions with reaction conditions favourable for the stability of complex molecules. Nevertheless, until now all attempts at the synthesis of organo-magnesium compounds were failures10-19a. The same was true for attempts to prepare organo-lithium compounds by direct action of 3,4-methylenedioxy-bromobenzene on lithium, exchange reagents under common temperature and dilution conditions, or reaction between butyl lithium and 3,4-methylenedioxy-bromobenzene10. Lithium reagents destroy the dioxole cycle10,20,21,22. Concerning 3,4-methylenedioxy-bromobenzene we have now discovered a solvent effect analogous to the one already noted during the study of the reaction of halogenated ketals with magnesium24-26. Contrary to the situation in ether, in which most of the mentioned experiments took place, in tetrahydrofurane, the reaction between 3,4-methylenedioxy-bromobenzene and magnesium proceeds "normally", giving the organo-magnesium compound with good yields. The utilisation of this new Grignard reagent permitted new syntheses of a certain amount of natural piperine derivates.

Safrole was obtained by condensation of 3,4-methylenedioxy-phenylmagnesium bromide with allyl bromide:

Piperonal (heliotropin) by condensation with N-methylformanilide:

Piperonylic acid by carbonation of 3,4-methylenedioxy-phenylmagnesium bromide:

Piperonylic alcohol by condensation of 3,4-methylenedioxy-phenylmagnesium bromide with trioxane:

alpha-ethylpiperonylic alcohol by condensation of the organo-magnesium compound with propanal:

The simple dehydration of alpha-ethylpiperonylic alcohol gives isosafrole:

3,4-Methylenedioxytoluene was prepared by condensation of 3,4-methylenedioxy-phenylmagnesium bromide with dimethyl sulfate:

Piperonylacroleine by condensation of the organo-magnesium compound with 1-(N-phenylmethylamino)-prop-1-ene-3-al:

The yield of the condensation with the higher vinyl-derivate [French: vinyloge] 1-(N-phenylmethylamino)-penta-1,3-diene-5-al was very low.

Piperic acid is synthesised by Doebner reaction with piperonylacroleine followed by decarboxylation:

Piperine, the alkaloid of black pepper, by reaction of piperic acid chloride with piperidine:

It is equally possible to prepare an organo-magnesium compound using 2,2-bis-ethyl-5-bromo-1,3-benzodioxole. Like in the previous case, this reaction behaves "normally" only in THF. The condensation with dimethylsulfate gives the expected product:

The structure of 2,2-bis-ethyl-5-methyl-1,3-benzodioxole was verified by acid hydrolysis, which gave 4-methyl-pyrocatechol.

Experimental

The melting points were determined using a Kofler apparatus. The pure products were analysed and infrared (Perkin-Elmer "Infracord" spectrophotometer) and UV (Perkin-Elmer 137 U.V. spectrophotometer) spectra were recorded. The analyses and the absorption spectra were in accordance with the structures; being already published in most cases, they are only detailed in some cases. All encountered 1,2-methylenedioxy-benzenes derivates had IR-absorption peaks at v=1480 cm-1, 1250 cm-1, 1040 cm-1, 920 cm-1. The micro-analyses were done by the Microanalysis Service of the "Faculté des Sciences de Paris".

[ DN24PH = 2,4-Dinitrophenylhydrazone derivative ]

1,2-Methylenedioxy-benzene (1,3-Benzodioxole)

Different methods27,28,29,30 were tried for the synthesis of this compound. None gave very satisfactory results. The same is true for many other attempts, either by direct acetalisation in benzene or chloroform, with or without catalyst (tosic acid, ferric chloride), or by exchange between pyrocatechol and bispropoxymethane, or by condensation of the disodium derivate of pyrocatechol (by sodium hydride) with dibromomethane in THF or dimethylformamide. The yields were below 20%.

bp17=68°C; nD21=1.5390

3,4-Methylenedioxy-bromobenzene

This compound is prepared by direct action of bromine vapours on 1,2-methylenedioxybenzene in acetic acid31. Yield = 89%

bp17=114°C; nD21=1,5838

Reaction with magnesium

I. In tetrahydrofuran

The Gilman test was performed using the following procedure: 0.5ml organo-magnesium compound solution, obtained by reaction of the halogen derivate with some magnesium turnings, cleaned by a drop of dibromoethane, are added to 1ml of 0.5% Mischler ketone solution in benzene. The mixture is brought to boil, cooled and hydrolysed (2 ml H2O), shaken, and some drops of 0.5% iodine solution in acetic acid are added. A deep blue colour appears, corresponding to a positive test.

The organo-magnesium compound was prepared in a 250ml flask with multiple necks equipped with a stirrer, a cooler, a thermometer, a vinylchloride bulb and possibly a nitrogen connection. The reaction was moisture protected with calcium chloride drying tubes. The magnesium turnings (1.2g) were covered with 20ml anhydrous THF (the commercial THF, after long standing on potassium, is distilled twice over potassium, then over sodium and finally stored over sodium wires). The reaction is started by adding two drops of 1,2-dibromoethane, then 3,4-Methylenedioxy-bromobenzene (0.05 mol in an equal volume of solvent) is added drop wise to the flask such that the temperature is kept below 55°C. The reaction becomes more or less yellow-green. After the addition is finished, the same temperature is maintained for 45m.

Hydrolysis in alkali conditions is done by pouring the organo-magnesium solution in a mixture of ice (100g), ammonium chloride (10g) and ammonia (5 ml of 10N solution) while stirring; the organic phase is decanted, the aqueous phase extracted with ether (3x50ml), the combined organic phases are washed with water (20ml), dried over potassium carbonate or sodium sulfate; the solvents are evaporated, the residue is distilled then fractionated on oil bath. One thus obtains 1,2-methylenedioxybenzene identical (constants, spectrography) to the previous compound. Yield = 77%

II. In Diethyl ether

The Gilman test gives various results, more often than not positive.

If one attempts to prepare the organo-magnesium compound, one notes the apparition of a persistent whitish cloudiness and the reaction stops despite long heating (7 h). After hydrolysis one obtains basically the unchanged starting product, 3,4-methylenedioxy-bromobenzene.

4-Allyl-1,2-methylenedioxy-benzene (safrole)

The organo-magnesium solution obtained using the previously given method is added to refluxing allyl bromide. After alkaline hydrolysis, one isolates safrole. Yield = 87%

bp0.2 = 62-63°C nD = 1.538932a

3,4-Methylenedioxybenzaldehyde (piperonal)

The organo-magnesium solution is added at low temperature (-20°C) to N-methylformanilide. After return to room temperature (12 h), one observes formation of 2 phases, the lower one being brown. After hydrolysis under acidic conditions (5N H2SO4 + 200g ice) and usual work up, one obtains piperonal: Yield = 65%.

bp0.5 = 88°C; DN24PH mp(acetic acid) = 269°C32b; Semicarbazone mp (75% ethanol) = 241°C.

3,4-Methylenedioxy-benzoic acid (piperonylic acid)

The carbonation of the magnesium compound is done by adding the latter to crushed dry ice in ether (Dewar). After return to room temperature (12 h), the mixture is poured on hydrochloric acid + ice (1:5). After usual work up, the solvents are evaporated and the residue recrystallised in ethanol to give piperonylic acid. Yield = 85%.

mp(ethanol) = 229°C32c

3,4-methylenedioxy-benzyl alcohol (piperonylic alcohol)

The condensation of the magnesium reagent with trioxymethylene is performed by addition at 40°C. The mixture, kept 2h at this temperature is then heated to reflux and then half of the solvent evaporated. After hydrolysis in alkali conditions and usual work up, piperonylic alcohol32d is distilled under nitrogen atmosphere. Yield = 70%

bp0.5 = 98°C; mp (pet. ether) = 55°C

1-(3',4'-Methylenedioxy-phenyl)-propan-1-ol (alpha-ethylpiperonylic alcohol)

Prepared by condensation of the magnesium reactant with propanal at 15°C. After return to room temperature the solution is refluxed (30min). After hydrolysis under alkali conditions and usual work up, one obtains alpha-ethylpiperonylic acid32e. Yield = 81%.

bp0.07 = 114°C; nD18 = 1.5413.

1-(3',4'-Methylenedioxy-phenyl)-prop-1-ene (Isosafrole).

A solution of alpha-ethylpiperonylic alcohol in benzene is heated to reflux with tosic acid (100mg). The water formed is azeotropically removed. After washing with diluted soda solution (5%), followed by usual work up, one obtains isosafrole32f. Yield = 79%.

bp17=131°C; nD20 = 1.5784

3,4-Methylenedioxytoluene

The organo-magnesium solution is added to boiling dimethyl sulfate. Alkaline hydrolysis and usual treatment gives 3,4-methylenedioxytoluene32k (Yield = 78%):

bp15 = 85°C; nD20 = 1.5314

1-(3'-4'-methylenedioxy-phenyl)-prop-1-ene-3-al (piperonylacroleine)

The organo-magnesium solution is added at -20°C to 1-(N-methylphenylamino)-prop-1-ene-3-al33. A white precipitate forms which quickly turns brown. The mixture is left standing for 1h then heated to 45°C (15min). After alkaline hydrolysis, washing the red organic phases with diluted hydrochloric acid and usual work up, one distills and fractionates under nitrogen to obtain piperonylacroleinic acid32g. Yield = 52%.

bp0.05 = 148°C; mp (pet. ether) = 87°C; DN24PH mp (ethanol) = 238°C Rf (DMF/Decaline) = 0.21

1-(3',4'-Methylenedioxy-phenyl)-5-carboxy-penta-1,3-diene (piperic acid).

Recrystallised and vacuum dried malonic acid (0.048 mol) is added to piperonylacroleine (0.025mol) in dry pyridine (20ml) with a few drops of piperidine; the mixture is heated (1h) on boiling water bath then to reflux. A big amount of yellow precipitate forms which turns red after being poured on a hydrochloric acid/ice mixture (1:8). The precipitate is filtered, sucked dry and recrystallised from alcohol (mp = 248°C) then dissolved in acetic anhydride (40ml) and heated to reflux for 30min. Treatment with cold dilute hydrochloric acid gives a brown precipitate. The latter is redissolved in concentrated ammonia, the solution filtered and piperic acid32h precipitated as voluminous yellow precipitate by addition of hydrochloric acid.

Yield = 55%, mp(ethanol) = 218°C;

Piperine

Piperic acid (2g) is added under cooling to thionyl chloride (8.5g). It rapidly dissolves, giving a deep red solution. After 45min, the excess thionyl chloride is removed under vacuum (Temp. < 40°C). A small fraction (0.5g) of the red crystals such obtained is recrystallised from benzene and gives piperic acid chloride32j

mp (benzene) = 180°C.

Piperidine (6ml in 20ml anhydrous benzene) is added to the rest of the crystals dissolved in anhydrous benzene (40ml). The temperature climbs to about 50°C; the solution is left standing for 48h, the formed precipitate filtered off, the solution washed with dilute hydrochloric acid, water, a 10% sodium bicarbonate solution, and finally water. After drying (Na2SO4) the benzene is removed under vacuum, the obtained piperine32i crystals recrystallised in alcohol then ether. Yield = 64%.

mp (ether) = 129°C

The piperine hydrobromide precipitates quantitatively after addition of benzene saturated with dry hydrobromic acid to a solution of piperine in benzene.

mp (benzene) = 170°C (34)

2,2-bis-ethyl-1,3-benzodioxole

Prepared by heating pentan-3-one (0.2mol) in benzene and pyrocatechol (0.2mol) in presence of tosic acid (0.5g) for 24h. The formed water is azeotropically removed. The cooled solution is poured into cold dilute soda solution then extracted using the usual method. Yield = 92%

bp0.1 = 50°C; nD19 = 1.5050. DN24PH; mp (ethanol) = 156°C; Rf (DMF/Decaline) = 0.8

2,2-bis-ethyl-5-bromo-1,3-benzodioxole

Prepared by reacting N-bromosuccinimide (0.12 mol) with 2,2-bis-ethyl-1,3-benzodioxole (0.1mol) in tetrachloromethane at reflux (18h) under UV irradiation in presence of perbenzoic acid. The dark red solution is washed with dilute soda (10%) and after extraction with ether and the usual work up gives 2,2-bis-ethyl-5-bromo-1,3-benzodioxole. Yield = 52%.

bp0.07 = 79°C; nD20 = 1.5358

Reaction with magnesium:

Gilman test: in ether the reaction is violent, but the test turns out negative.
In THF: test positive (violet coloration).

The formation of the organo-magnesium compound is performed in THF using the procedure mentioned before. The reaction proceeds quickly and completely.

2,2-bis-ethyl-5-methyl-1,3-dioxole

The organo-magnesium solution formed using 2,2-bis-ethyl-5-bromo-1,3-benzodioxole in THF is condensed with diethylsulfate with heat. After alkaline hydrolysis and extraction with ether one obtains 2,2-bis-ethyl-5-methyl-1,3-dioxole with a yield of 85%:

bp0.5 = 70°C; nD22 = 1.5010. DN24PH; mp (ethanol) = 156°C Rf (DMF/Decaline) = 0.8

The hydrolysis, performed by refluxing in an equal amount of 20% sulfuric acid for 5h, gives, after extraction with ether 4-methyl-1,2-pyrocatechol. Yield=65%.

bp0.7 = 95°C; mp = 64°C32l

Distillation of the residue at atmospheric pressure allows the isolation of pentan-2-one32m.

bp760 = 102°C; nD20 = 1.3920; DN24PH mp (ethanol) = 156°C.

References

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