Any known bis-methylenedioxy compounds?

[Rhodium]

I have not been able to find any literature references on any benzene rings with two methylenedioxy groups on it. I believe that 4-bromo-[2,3],[5,6]-bis-methylendioxyamphetamine would be an interesting compound.

I have not been able to find pentamethoxybenzaldehyde in the chemical literature either. Is there such a critter out there?

[hest]

One off my friends and I have tryet to look into this too, wee could't find annye thing. The 'starting' material (1,2,4,5-tetrahydroxybenzene) is also imposible to find any thing abouth.

[foxy2]

Funny I was think about bis(methylenedioxy) compounds earlier today as a result of reading this new addition to Rhodiums site.  

https://www.thevespiary.org/rhodium/Rhodium/chemistry/pseudodillapiole.html

Wonder if this compound 4,5-Dihydroxy-2,3-Methylenedioxyallylbenzene is possible? Then turn that to 4,5-Methylenedioxy-2,3-Methylenedioxyallylbenzene.

"The 'starting' material (1,2,4,5-tetrahydroxybenzene) is also imposible to find any thing about.

Patent US3780114

lays out the synthesis starting from hydroquinone.

Abstract
1,2,4,5-C₆H₂(OH)₄ was prepd. in 70-90% yield by hydrogenation of 2,5-dihydroxy-p-benzoquinone (I) in THF over PtO₂ catalyst.  I was prepd. by H₂O₂ oxidn. of p-C₆H₄(OH)₂.
 
Do Your Part To Win The War

[hest]

I don't belive that oxidation off hyroquinone with H2O2 will give you 2,5-dihydroxy-p-benzoquinone , I think you will end up with quinon.

[foxy2]

Did you read the patent?
They say 84 to 100% yeilds on that step.
Finely divided hydroquinone(1 mol, 110g) in 800mL of 50% NaOH is heated to 50C and held at this temp with vigorous stirring 400mL of 30% H2O2 is dripped in over 6.5 hours.  Stir and additional 1.5 hours.  Then work up(look yourself).

Yeild 83.8%
Do Your Part To Win The War

[hest]

I'll give it a try this week.

[Rhodium]

Hest: You are wonderful! It will be interesting to see how this compound is methylenated in the best yields possible. I think dichloromethane is a too weak a nucleophile to not make polymers in this reaction. I'd use 4.5-5 moles base per tetrahydroxybenzene, and at least dibromomethane for the job, preferably bromoiodomethane or perhaps diiodomethane. Keep the phenol concentration high, and the dihalomethane low. I can't decide if the best way would be the PTC or the DMSO route though.

[boppesz]

Don't you think [2,3][4,5]bismethylenedioxyamphetamine would be very intersting? We can make that one after forming pseude dillapiole (isn't dillapiole the right name for this thing, what does pseudo mean?), break up all etheric bondages with AlCl3 or so, and than methylenate with DCM/DBM/BIM/DIM? Thought of this compound longago.

And, what about the methylversion?

[Rhodium]

Dillapiole is 2,3-Dimethoxy-4,5-Methylenedioxyallylbenzene and pseudo-Dillapiole is 4,5-Dimethoxy-2,3-Methylenedioxyallylbenzene.

The "pseudo" prefix denotes that the methoxies and methylenedioxy group has switched places.

[hest]

Fuck
I have tryet the synthesis from JACS twice. oxidation of hydroq. with H2O2 in 50%NaOH(aq).
First time I ended up with a lot off startingmaterial :-)
This try is right afther the book, but the isolation is a bitch. Don't think this is the way.

[Antibody2]

bopperes - dillapiole is what springs to mind as i read this thread also, its dirt cheap and unwatched. I think the problem there would be in the hydrogen bonding required to form the 2nd MD ring, i don't know if a good method exists for getting rid of the two carbons bonded to the benzene ring (decarboxylation?)

[hest]

Still no luck. The problem is not the synthesis but the workup. It is posible to filter off the Na salt when the synth. is done. But it is a very basic solution, it disolves my filterpaper in the büchner.
I think i quit for now.

[Rhodium]

It's been a while since this thread had its heydays, but now it comes blazing back from the digital compost heap with a full synthesis of both bis-methylenedioxybenzaldehyde and its corresponding allylbenzene:

_{Derivate des Methylendioxybenzols. XXIII.}
Über das Benzo[1,2-d:4,5-d']bis[1,3]dioxol
Franz Dallacker, Wolfgang Edelmann und Anton Weiner

Liebigs Ann. Chem. 719, 112-118 (1968)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/dallacker.bis-methylenedioxybenzene.pdf)

Abstract
Zur Synthese des Benzo[1,2-d:4,5-d']bis[1,3]dioxols (5a) und seines 4-Methoxy- (5b) bzw. 4-Allyl-Derivates (5c) wurden 3,4-Methylendioxyphenol (3a), 2-Methoxy-3,4-methylendioxyphenol und 3,4-Methylendioxyphenol mit Kaliumnitrosodisulfonat in die 4,5-Methylendioxy-o-benzochinone 1a-c übergeführt. Die aus den o-Benzochinonen durch Behandlung mit Natriumdithionit erhältlichen Brenzkatechine 2a-c liessen sich zu den Benzo[1,2-d:4,5-d']bis[1,3]dioxol-Derivaten 5a-c methylenieren. Auch die Umsetzungen der Brenzkatechine 2a und 2b mit Dibromäthan zum 1,3-Dioxolo[4,5-_g][1,4]benzodioxan (4a) und seinem 5-Methoxy-Derivat 4b verliefen glatt. Mit N-Methyl-formanilid bzw. N,N-Dimethyl-formamid/POCl₃ liessen sich nur die Verbindungen 4b und 5b nach Vilsmeier zu den Aldehyden 4d und 5d umsetzen.

[Antibody2]

translation?

[ning]

In light of Nichol's group benzofuran psychedelic amphetamine, it does seem like a good idea to assay this material as well....

[GC_MS]

This is odd...

2-Hydroxy-4.5-methylenedioxybenzaldehyde (3b) - A solution of 19.6 g N-methylformanilidine in 100 mL chlorobenzene is added drop-wise to 22.2 g POCl3 at 0°C (anhydrous reaction conditions). One hour later, 9 g (3a - sesamol) is added and the reaction temperature allowed to rise to 20°C over six hours. The reaction mixture is subsequently heated at 60-70°C (bath temperature) for another 8 hours and poured over ice. The mixture is extracted with ether, the organic phase washed with 2 N NaOH and the alkaline phase acidified with 2 N HCl and reextracted. Vacuum distillation yields 60% 3b

I was under the impression that V-H formylations were not possible for substrates with a free phenolic functional group because of the formation of the O-formyl analogue. Have I been wrong all the time? Or are there exceptions?

[Saddam_Hussein]

Franz Dallacker, Wolfgang Edelmann, Anton Weiner. Derivate des Methylendioxybenzols, XXIII. Ueber das Benzo[1.2-d:4.5-d’]bis[1.3]dioxol. Liebigs Ann Chem 719 (1968) 112-118

[…]

3.4-Methylenedioxyphenol (sesamol) (3a) – Applying ice-cooling, 250 mL 85% HCOOH was added to 75 mL 30% hydrogen peroxide and the resulting mixture set aside at room temperature for 1 h. Subsequently, the performic acid solution was added portionwise and with stirring to a solution of 75 g 3.4-methylenedioxybenzaldehyde (piperonal) in 750 mL 85% HCOOH, cooled at –5°C. After 16 h, the resulting mixture was poured into 5 L ice/water (ca. –10°C) and filtered 30 min later. The precipitate was dissolved in slightly warmed 2 N NaOH, chilled, acidified with dilute HCl and the resulting mixture extracted with ether. The combined organic phases were washed with water and dried over magnesium sulfate, yielding a colorless oil, bp_.4 110-112°C, which solidifies rapidly giving colorless crystals, mp 65°C. Total yield: 35 g (51%).


2-Hydroxy-4.5-methylenedioxybenzaldehyde (3b) – A solution of 19.6 g N-methylformanilidine in 100 mL chlorobenzene was added drop-wise to 22.2 g POCl₃ (temperature: 0°C; anhydrous reaction conditions). After 1 h, 9 g 3a was added and the temperature allowed to rise to 20°C in the course of 6 h. Subsequently, the mixture is heated for 8 h to 60-70° (bath) and poured over ice. The reaction mixture is extracted with ether and the organic phase washed with 2 N NaOH. The alkaline phase is acidified with 2 N HCl and extracted with ether once again. By distillation under reduced pressure, colorless crystals (mp 128°C, bp_.1 103-104°C) are obtained. Total yield: 6.5 g (60%).


2-Methoxy-4.5-methylenedioxybenzaldehyde (3c) – Analogous to 3b, a VH-complex was prepared by adding 115 g POCl₃ to 111.5 g N-methylformanilidine in 100 mL chlorobenzene. Subsequentlym a solution of 76 g 1-methoxy-3.4-methylenedioxybenzene in 150 mL chlorobenzene was added to the complex at 0-70°C, but now the mixture was filtered with suction, the precipitate washed with water and recrystallized from aqueous methanol (1:1). This yielded colorless needles, mp 111°C. Total yield: 73 g (81%).


2-Methoxy-4.5-methylenedioxyphenol (3d) – Analogous to 3a, a solution of 60 g 3c in 500 mL 85% HCOOH was added to a mixture of 165 mL 85% HCOOH and 50 g 30% hydrogen peroxide. After 16 h at 0°C, the mixture was diluted with water and filtered. The precipitate was washed with water, dissolved in 300 mL 3 N NaOH by gentle heating, the cold alkaline solution filtered and acidified. The resulting product was extracted with ether, washed with water and dried over magnesium sulfate, giving colorless needles with mp 84°C (from cyclohexane). Total yield: 51.5 g (92%).


4.5-Methylenedioxy-o-benzoquinone (1a)

a) An 8 L stainless steel funnel was charged with a slurry of 530 g potassium nitrosodisulfonate in 6 L water containing 22 g KH₂PO₄ and a saturated solution of 100 g 3a in acetone. Vigorous shaking causes an immediate dark red discoloration, from which the yellow o-benzoquinone 1a precipitates. The latter is isolated via filtration (Buechner), the filtrate extracted trice with 1 L CHCl₃ and the combined organic phases dried over magnesium sulfate. The residue was further processed.

b) As described in a) using 16.6 g 3b and 70 g potassium nitrosodisulfonate. Yield: 10.5 g (69%).

c) Analogous to a) using 16.8 g 3d and 70 g potassium nitrosodisulfonate. The residue contains 2.5-dimethoxy-1.4-benzoquinone: yellow crystals with mp 219°C (from GAA). Total yield: 5 g (33%). 1a crystallizes from the filtrate as lemon crystals, mp 206°C. Total yield: 1.9 g (12%).


1.2-Dihydroxy-4.5-methylenedioxybenzene (2a)

a) A solution of 15.2 g 1a in 35 mL acetone and 300 mL water was warmed up to 70°C (bath). For 10 min, a vigorous beam of SO₂ was introduced into the mixture. The latter was allowed to reach ambient temperature, extracted twice with 200 mL ether and the organic phases washed with a saturated NaHCO₃ solution and water. Drying and removal of the mixture yielded 12.5 g (81%) of product.

b) The crude 1a obtained as described in a) was suspended in water and joined by 3 L ether in a 5 L stainless steel funnel. After addition of saturated aqueous Na₂S₂O₄, decoloration is noted when the mixture is shaken. Extraction with ether and drying over magnesium sulfate yields colorless crystals, mp 159°C (from cyclohexane). Total yield: 74.3 g (66%, relative to 2a).


1.2-Dimethoxy-4.5-methylenedioxybenzene (3e) – A mixture of 15.5 g 2a, 125 mL anhydrous acetone, 26 g DMS and 28 g anhydrous potassium carbonate is stirred and heated to reflux for 12 h. Subsequently, the mixture is diluted with water and extracted with ether. Washing the combined ether extracts with water and drying the organic phase over magnesium sulfate yield colorless crystals, mp 111°C (from cyclohexan or ligroin). Total yield: 13.3 g (73%).


1.3-Dioxolo[4.5-g][1.4]benzodioxan (4a) – A mixture of 16 g 2a, 40 g 1.2-dibromoethane, 40 g anhydrous potassium carbonate and 300 mL anhydrous acetone are stirred at 125° (bath). After 42 h, the mixture is reduced in volume, diluted with water and extracted trice with 200 mL ether. The combined ether phases were washed with diluted aqueous NaOH and water, and subsequently dried over magnesium sulfate, giving colorless crystals, mp 89°C (from cyclohexane). Total yield: 4.35 g (23%).


Benzo[1.2-d:4.5-d’]bis[1.3]dioxol (5a) – 74.3 g 2a in 250 mL DMF is mixed with 76 g potassium carbonate and 72.5 CH₂BrCl, and the mixture stirred 42 h at 100°C (bath). The mixture is chilled and the precipitate filtered, washed with a little DMF and poured into 3 L ether. The latter is combined with 1 L water, decanted from resinous material and the ether phase washed twice with 1 L water, once with 0.5 N NaOH and anew with water. Drying the ether phase over magnesium sulfate and removal of the solvent yields 20.1 g (25%) of colorless crystals (recrystallized from cyclohexane), mp 141°C.


3-Methoxy-4.5-methylenedioxy-o-benzoquinone (1b) – Synthesis analogous to 1a, using 16.8 g 2-methoxy-3.4-methylenedioxyphenol (mp 61.5°C). Deep red crystals, mp 160°C (from ethanol). Total yield: 15.9 g (69%).


1.2-Dihydroxy-3-methoxy-4.5-methylenedioxybenzene (2b) – Synthesis analogous to 2a from 18.2 g 1b. Colorless needles, mp 130° (ligroin). Total yield: 12 g (65%).


1.2.3-Trimethoxy-4.5-methylenedioxybenzene – A mixture of 9.2 g 2b, 14.2 g MeI, 13.8 g potassium carbonate and 250 mL acetone is heated at 50°C for 10 h, and the resulting mixture reduced in volume and diluted with water. The mixture is subsequently extracted with ether and washed with 1 N NaOH and water. This yields a colorless oil, bp_.2 113°C, which solidifies after standing for several hours. Colorless crystals, mp 46°C. Total yield: 8 g (76%).


5-Methoxy-1.3-dioxolo[4.5-g][1.4]benzodioxane (4b)] – A mixture containing 25 g 2b, 40 g 1.2-dibromoethane, 60 g potassium carbonate and 200 mL acetone was heated for 25 h at 130°C (bath). The mixture was reduced in volume, diluted with water and extracted with ether. The extract was washed with 1 N NaOH and water, yielding colorless crystals, mp 66° (from cyclohexane). Total yield: 17.5 g (61%).


4-Methoxy-benzo[1.2-d:5.4-d’]bis[1.3]dioxol (5b) – In analogy to 5a, 18.5 g 2b gave colorless crude and fine needles, mp 83°C, after 36 h at 120°C (bath). Total yield: 8.8 g (45%).


2.5-Dimethoxy-3-hydroxy-p-benzoquinone – Prepared in analogy to 1a from 1.8 g 2.5-dimethoxy-3.4-methylenedioxyphenol (mp 85.5°C), 24 g potassium nitrosodisulfonate and 13.6 g KH₂PO₄ in acetone/water with addition of 0.01 g 4.5-methylenedioxy-o-benzoquinone (1a). This yields violet red crystals, mp 207°C. Total yield: 0.9 g (53%).


3-Allyl-4.5-methylenedioxy-o-benzoquinone (1c) – Analogous to 1a from 9 g 2-allyl-3.4-methylenedioxyphenol. Orange crystals, mp 104° (from ligroin). Total yield: 5.6 g (58%).


1.2-Dihydroxy-3-allyl-4.5-methylenedioxybenzene (2c) – The crude quinone 1c was dissolved in ether and mixed with a cold saturated aqueous NaS₂O₄ solution. The mixture decolorizes and is washed with water. The ether phase is dried over magnesium sulfate and the solvent in vacuo removed. The residue is subjected to methylenation as soon as possible due to instability of the intermediary product.


4-Allyl-benzo-[1.2-d:4.5-d’]bis[1.3]dioxol (5c) and dimere 6 – A mixture of 19.4 g crude 2c, 19.4 g CH₂BrCl, 27.6 g potassium carbonate and 250 mL acetone is heated (150°C, bath) and stirred for 56 h. The mixture is reduced in volume at 100°C and the residue extracted with ether. The organic phase is washed with 1 N NaOH and water. The residue is crystallized from acetone at –5°C.
6 – The precipitate is filtered (with suction) and washed with little acetone. This yields a colorless substance, mp 152°C. Total yield: 2.9 g (21%).
5c - The filtrate obtained from 6 is reduced in volume and the oily residue subjected to distillation under reduced pressure. A colorless oil, bp_.2 108-112°C, is obtained. It crystallizes from n-hexane (colorless needles, mp 53.5°C). Total yield: 3 g (44%).


8-Formyl-5-methoxy-1.3-benzodioxolo[4.5-g][1.4]benzodioxane (4d) – Analogous to 3b from 15.3 g POCl₃ and 13.5 g N-methylformanilidine dissolved in 200 mL o-dichlorobenzene, and 16 g 4b in 40 mL o-dichlorobenzene at 0-50°C. For this procedure, the precipitate is washed with water and dried over magnesium sulfate, yielding yellow crystals, mp 160°C (from ethanol). Total yield: 12.5 g (68%).
Thiosemicarbazone: from GAA with addition of decolorizing C, colorless crystals decomposing at 233°C.


1-Formyl-4-methoxy-benzo[1.2d:4.5-d’]bis[1.3]dioxol (5d) – Analogous to 3b using 8 g POCl₃ and 16 g DMF with 8 g 5b at 0-100°C. Isolation of the product as described for 4d yields colorless crystals, mp 164°C (from GAA). Total yield: 4.4 g (48%).
Thiosemicarbazone: colorless crystals, decomposition at 242°C (from GAA).

[descent]

I am a newcomer in The Hive, but I will share my experience on the synthesis of  bis-methylenedioxy-benzene.

1. 2,5-hydroxy-benzoquinone
I used the method, described in Acta Chim. Hung., v. 20, p. 239 (1959) in 1/2 scale. The most important thing is that you need a GOOOOD MECHANICAL STIRRER. The minimum required for success is a 30 Watt stirrer, but it is almost dying of tiredness at the end of the reaction. The best option is to use a drill with stirrer attached. It works great, and I made an improvised stirring loop from 5mm Al wire, clothed in PVC to avoid contact with the strongly alkaline RM. After you have a stirrer you can begin.
230 g NaOH are dissolved in 150-200 ml water. The idea is to have 50% NaOH, but the yield is better with 70%, which is quite liquid if the temp. is high enough. The viscous solution is very hot so you must wait till the temp. drops to 60-70 deg. Add 32g hydroquinone (I used photographic grade).  The thick solution/mixture turns slightly blue. Now you began to drop 115 ml 30% H2O2 – or add it in small portions, keeping the temp. in the range 60 to 80 deg. The reaction is very slow below 40 deg., and you shall not exceed 80 deg. The addition may take 1-2 hours in which time the color of the RM is becoming shit-like and, in the end, dirty-red. Its viscosity is gradually increasing and it is becoming like mud – that’s why you need powerful stirrer. Add a little more H2O2 if needed to obtain the final reddish color, because at 80 deg. part of the peroxide is decomposed before reacting. At this point you may safely leave the RM overnight.
The so obtained red shit is added to 1 kg of crushed ice and appr. 0.5 l conc. HCl. When dilutind with water you will see the bright red color of the sodium salt of the quinone, which in contact with HCl is turning to the bright yellow quinone. Add enough HCl to convert all red sodium-quinone salt into yellow quinone. Filter the beautiful yellow precipitate and wash with a little conc. HCl and cold water. I made this synthesis twice with excellent results. Yield in the order of 50-60%.
A problem emerges with drying. The crystals of the DRY quinone fly in all directions and precipitate on all surrounding objects because of some kind of static electricity and operating with them is a dulling work. May be it is worth, when they are almost dry, but not very dry, to recrystallize them from EtOH. Or they can be used for the next step without much drying.

1,2,4,5-tetrahydroxybenzene
I lost the reference for this step; I suspect it’s again from the Hungarians.
75 g SnCl2.2H2O are dissolved in 250 ml conc. HCl and 20 g 2,5-hydroxy-benzoquinone are added. The flask is equipped with a reflux condenser, placed in a water bath, and heated till all solids dissolve. According to the original publication the reaction time is 90 min, but in my case 2 hours were needed to dissolve the quinone. Add another half-hour heating and leave it overnight. In the morning a gray crystalline precipitate is deposed, which I supposed was the desired tetrahydroxy. It was filtered and washed twice with conc. HCl. If you drop few crystals in water it will become yellow-green and, upon staying for few hours, the color will change to the orange-red color of the diluted quinone/water solution – a good lesson that the tetrahydroxy is air sensitive. I dryed it on CaCl2 and a little CaCO3 as HCl acceptor, but it was considerably oxidized during drying. Yield 18 g of almost black crystals.
The next time I will use for drying NaOH pellets and an inert atmosphere or vacuum.
A similar procedure for hexahydroxybenzene is described in Organic Synthesis. Recrystallization first from conc. HCl with a few grams of SnCl2 and act. carbon, then from HCl.
Conclusion: crude 1,2,4,5-tetrahydroxybenzene can be made without difficulties, but you must pay attention to the work up and drying and use an inert atmosphere to obtain product with acceptable purity.

bis-methylenedioxy-benzene
It’s the most problematic part. The German paper says that the 1,2,4,5-tetrahydroxybenzene cannot be methylenated. But, despite of the lack of a sensible success in my methylenation experiment, I am still optimistic.
I tried to methylenate the said black dirty 18 grams according to the standard procedure: DMSO with CH2Cl2 and 50% NaOH. The idea was to heat the DMSO/DCM mixture, and add with syringe calculated portions of 50% NaOH and 1,2,4,5-tetrahydroxybenzene solution in DMSO. It was a disaster, because I used the same syringe and, after the first addition the sodium salt of the terahydroxy precipitated in the needle. (I found the other glass syringe accidentally at home the next day.) I panicked and added through the open neck all the remaining tetrahydroxy solution and NaOH at once. I suspect I lost much DCM from the hot flask and I added a little more DCM. There was a nasty slurry in the flask and I lost the temp. control; the temp. raised in a moment to 160 deg, when 130 deg are recommended. After a few hours I made a steam distillation and obtained less than 200 mg of white crystals. Yield less than 1%.
In this moment I am making recrystallization from EtOH – just to liberate the beautiful crystals from the devilish sulfur smell ? May be I will make an NMR, if I can afford this, of I will just see the melting point to be completely sure that it’s the bis-methylenedioxybenzene.
The yield is symbolic but, giving my total loss of control over the reaction – and my total lack of experience in methylenations – there is a hope for the future. May be the Germans are right that the methylenation cannot be done with K2CO3 as a base. But I still believe that it can be done with NaOH in DMSO with some improvements:
Use separate syringes with maximally wide needles and wash the needles with water after each use. Use CH2Br2 or better CH2I2 to decrease the needed reaction temp. to not more than 100 deg. Above 130 deg. DMSO becomes an oxidizer and there is much thing to oxydize in the RM. If you are rich enough you can use HMPA instead of DMSO. An inert atmosphere is highly desirable. There are other possibilities which can be explored: dry KF, of better CsF, as a base, etc.. I do not believe PTC will help, because, even with 4 moles of ammonium salt, the tetra-anion of the phenol will not be soluble in non-polar solvent. But who knows?

Why IMHO bis-methylenedioxy (4-bromo, etc.) is important to be synthesized and tested?
If you check the classic works of our dear Drs Shulgin and Nichols, you will see that the 2,6-O pattern is working well. Not as well as the 2,5-O but still well. Nichols thinks – and I have long ago come to this conclusion too – that the 6-oxygen probably forms additional H-bond with the receptor. The existing models of the 5-HT2a/c receptor are far from being perfect, but in all detailed pictures I have seen, there is an amide NH2 group close to the 6-position of the phenethylamine ring. The bis-methylenedioxy is a good candidate for a compd. which will form three H-bonds with its 2, 5, and 6-oxygens and a considerable potency can be expected. The 3-oxygen seems useless and only decreasing the hydrophobicity of the molecule, but this nucleus is not so hydrophilic as it seems at first glance, because vicinal oxygens have dramatically decreased affinity to water. I found no data on the octanol/water partition coefficient of benzodioxole but the simple 1,3-dioxole is an order of magnitude more hydrophobic than the predicted value!
And – last but not least – My molecular mechanics software says that the 2,6-O pattern is the best in view of conformational flexibility of the aminoethyl which is considered very important for 5-HT2 agonists. The rotation barrier of the aminoethyl chain in bis-methylenedioxy is considerably wider than the 2,5-O-furano analog, not to speak about the 2,5-O-tetrahydrofyrano which is the most restricted among all tricyclics in question; I think this rotational restriction can explain the lowest potency of the hydrated analog in comparison with the furano. At least, I do not see other explanation since furan is the worst e-pair donor for H-bonding, and both cycles are almost equally flat.
So, I think, we can swallow the useless 3-oxygen and hope that the high symmetry and beauty of the molecule will compensate for this.

I don’t know when I will be able to start again with this work but I hope that my experience will help the curious bees to explore the unknown.

[GC_MS]

bis-methylenedioxy-benzene
It’s the most problematic part. The German paper says that the 1,2,4,5-tetrahydroxybenzene cannot be methylenated. But, despite of the lack of a sensible success in my methylenation experiment, I am still optimistic.

I suspect polymerization to be the cause that this tetrahydroxybenzene cannot be methylenated, or at least will give very low yields. Compare with pyrogallol:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methylenation.cuo.html

Although 3,4-dihydroxy-5-methoxybenzaldehyde (III) and pyrogallol 1-methyl ether were shown to be readily methylenated into corresponding 1,3-benzodioxoles, any uccessful example of methylenation of pyrogallol has not yet been reported. From this point of view, it appeared of interest to investigate the product of the same reaction using cupric oxide as catalyst in DMF. A neutral crystalline product which showed positive Labat test was obtained in 41% yield by the reaction, though any phenolic product was not isolated. Characterization of this product was effected by NMR spectrometry and elemental analysis. These data were in accord with the structure VIII.

[descent]

I am dissapointed by the pyrrogallol case. It convinced me that real yield methylenation of the tetrahydroxybenzene is more than doubtful. But I began to think on other possibilities. Like, for example, starting from sesamol and making an additional dihydrofuran (furan) ring a la Nichols. It means that the useless 3-O is replaced with a well established structure, and the promising 5,6-O pattern can be tested. Formylation will proceed again between the 2- and 6-0 - or at least I hope so. Making bis-methylenedioxy from sesamol seems more difficult.