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    Protocatechualdehyde, Protocatechuic acid and Methylenation of the same
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Cleavage of Vanillin to Protocatechualdehyde - Posted on the Hive by Rhodium

Anhydrous AlCl3 (9.7 g, 0.0724 mol) was suspended in a solution of 10g 
(0.0658 mol) of vanillin in 100 ml of methylene chloride in an apparatus 
protected from atmospheric moisture. While stirring briskly and cooling to 
maintain the temperature at 30-35°C, 22.9g (0.290 mol) of pyridine was added 
slowly. The reaction was vigorous; the resulting clear light orange solution 
of the reaction complex was heated to reflux (45°C) and maintained at that 
temperature with stirring for 24 hours. The solution, which had darkened only 
slightly during the reflux period, was cooled to 25°C and the product was 
hydrolyzed, while stirring and maintaining the temperature at 25-30°C, by the 
addition of dilute (15-20%) HCl until the mixture was definitely acidic to 
congo red indicator. Of the two phases present at this time, the lower 
methylene chloride layer contained most of the small amount of the unchanged 
vanillin, and essentially no protocatechuic acid, the latter was dissolved in 
the aqueous phase. Evaporation of the methylene chloride yielded 0.8 g of 
vanillin. Extraction of the aqueous phase with ether followed by evaporation 
of the ether left 7.9 g (87%) of pale yellow crystals of protocatechualdehyde
melting at 153-154°C. 

Using the cheaper triethylamine in place of pyridine lowered the yield to 61.5%

The paper describes several aryl methyl ether cleavages, all with good yields, 
70-95%, and it would surprise me greatly if the above procedure wasn't 
applicable to eugenol. 

Ref: J. Org. Chem., Vol 27, 2037-2039 (1962)

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Protocatechuic Acid - posted on the Hive 980907 by Cherrie Baby


(3,4-dihydroxy-Benzoic acid)

Organic Syntheses Collective Volume 3, 745-6

Submitted by Irwin A. Pearl. (Checked by Allen and Wolf)

MeO(HO).C6H3.CHO + 4 KOH --> (KO)2.C6H3.CO2K + HCO2K + 3H2 + H2O

(KO)2.C6H3.CO2K + 3 HCl --> (HO)2.C6H3.CO2H + 3KCl

1. Procedure

In a stainless-steel beaker of approximately 3-L. volume (180 mm. by 150
mm.) (Note 1), equipped with an efficient mechanical stainless-steel
stirrer and heated by an electric hot plate, are placed 84 g. (2 moles) of
97% sodium hydroxide pellets, 332 g. (5 moles) of 85% potassium hydroxide
pellets (Note 2) and 50 mL of water. The mixture is stirred and heated.
When the temperature of the fluid mixture reaches 160° 152 g. (1 mole) of
vanillin is added in portions over a period of 2.5 - 3 minutes at a rate
sufficient to maintain the reaction

(Note 3). The temperature at this point is 190-195°. Stirring is
          continued, and heat is applied until the temperature reaches 240-245°
(Note 4). The temperature is maintained at 240-245° for 5 minutes.

The hot plate is removed, and the mixture is allowed to cool with stirring.
When the mixture has cooled to about 150-160° 1 L of water is added, and
the mixture is stirred until all the fusion mixture is dissolved. The
solution is transferred to a 4-L beaker, another 500 mL of water is added,
and sulfur dioxide gas is introduced for 2 minutes (Note 5); the mixture is
then completely acidified with 1.5 L of 6 N hydrochloric acid. The
acidified mixture is cooled in an ice bath (5°) for 2 hours, and the
crystalline precipitate is filtered, washed on the filter with two 100-mL
portions of ice water, and air dried. The tan crystals of protocatechuic
acid melting at 196-198° weigh 90-100 g. Extraction of the filtrate and
washings with two 1-L portions of ether yields an additional 45-55 g. of
protocatechuic acid melting at 190°. The total yield of crude
protocatechuic acid amounts to 135-153 g. (89-99%) (Note 6).

2. Notes

1. In the checkers' opinion a 2-L. beaker is sufficiently large, and the
   contents are easier to stir. Iron or nickel pots have also been used.

2. The exact proportion of sodium hydroxide to potassium hydroxide is not
   too critical as long as the total amount of alkali is more than 7 moles.
   Mixtures containing from 10% to 60% sodium hydroxide become fluid between
   120° and 130°. Increased percentages of sodium hydroxide in the mixture
   result in darker protocatechuic acid, but yields are not affected until
   70% sodium hydroxide is reached.

3. This reaction is the oxidation of vanillin to vanillic acid with the
   liberation of hydrogen.

4. The demethylation of vanillic acid to protocatechuic acid takes place to
   a slight degree between 210° and 235° but goes to completion only at
   temperatures above 240-245°.

5. The sulfur dioxide treatment prevents the formation of a very
   dark-colored product when the reaction mixture is acidified with a
   strong acid.

6. The first crop of acid is light tan and is suitable for most purposes.
   It can be improved slightly by recrystallising from hot water, with 3 mL
   per g. and 1 g. of Norit for every 10 g. of acid; the recovery is 75%,
   the remainder being retained by the charcoal. This recrystallized acid
   is a cream color and melts at 199-200°. If the Norit is omitted, the
   recovery is 90%, mp. 198-199°, and color unchanged.

The second crop is of decidedly inferior quality. It is easily purified as
follows: Fifteen grams of crude product is dissolved in 100 mL of 10%
sodium hydroxide solution at room temperature, 2 g. of Norit is added, and
the mixture is stirred for 10 minutes and filtered. Sulfur dioxide is then
passed in for 2 minutes, after which 60 mL of 6 N hydrochloric acid is
added. After chilling and standing, 10 g. (67%) of purified protocatechuic
acid, mp. 196-198°, is recovered.

3. Methods of Preparation

The only practical method for the preparation of protocatechuic acid is by
the alkaline fusion of vanillin. Refs below.

1. Pearl, J. Am. Chem. Soc., 68, 2180 (1946).
2. Tiemann and Haarman, Ber., 7, 617 (1874).
3. US. pat. 2,547,920 [CA 45, 8042 (1951)].

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1. That carboxyllic acid can't easily be turned into anything else. 
2. The di-hydroxoy needs to be closed to make the methylenedioxy bridge.
3. No one in their right mind would use this to make MDMA!

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Ramblings on pyrocatechuic acid

I'd have thought it would be impossible to protect the aldehyde. I can't 
see how any protecting group will resist strong alkali at 240C.

Your method of thionyl chloride, reduction and KF methylenation doesn't 
sound very OTC to me.

CH2Cl2 (4 mole) can be used to methylenate with tert-butylammonium 
Bromide (0.1 mole) + a little I2 promoter + alkali (KOH preferred) 
+ dihydroxy-compound (1 mole). This needs fast stirring under normal PTC 
conditions and will require enough pressure to get temperate to 70C or 
more (details in British & Japanese patents and Chinese Journal 
[These used to be on Rhodium's site - see details below]

I can't recall any studies of KF and CH2Cl2. I can recall KOH and CH2Br2 
as well (with a PTC)

Eugenol must be a better starting material than vanillin. I don't know 
what happens when Eugenol is heated with strong alkali (ala Organic 
Syntheses Collective Volume 3, 745-6). We might expect demethylation, we 
should also expect isomerisation of the allyl side chain to a propenyl 
side chain to get to get 1-(3,4-dihyroxy-phenyl)-propene - if we're 
lucky and careful. We could also get just a charred mess or a putty. 
This reaction looks like it would be tricky to control. Methylenation of
1-(3,4-dihyroxy-phenyl)-propene gives isosafrole - That would be heaven. 
97% eugenol is easily got from clove oil or cloves which are both OTC.

I would expect microwaves to help in the demethylation of vanillin or 
eugenol with solid KOH.

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Refs. to check from Merck:

Piperonal
US 2916499
JOC 26, 4814 (1961)

Piperine
Newman. Chem. Products 16, 379 (1953)
Compt. Rend. 258, 2864 (1964)

Piperonylic acid - 90-96 % yields by oxidation of isosafrole
Shriner. Org. Syn. 10, 82 (1930)

For more info. on piperonal you may want to read these:

Synthesis of Heliotropin; By Cervený, Kozel and Marhoul, 
Perfumer & Flavorist, 14, 13-18, 1989
S Arctander, Perfume and Flavour Chemicals, Arctander, New York, 
1969, pp 183-184 (not certain about this!)

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Methylenation Of Catechols


A Convenient, High-Yielding Method For The Methylenation Of Catechols; 
A. P. Bashall and J. F. Collins; Tet. Lett. No. 40, pp 5489-3490, 1975.

A mixture of water (20 mL), dibromomethane (0.15 mole) and Adogen 464[1] 
(1 mnole) was vigorously stirred and heated to reflux. The air in the 
system was displaced by nitrogen. A solution of the appropriate 
o-dihydroxy-benzene (0.1 mole) and sodium hydroxide (0.25 mole) in water 
(50 mL) was added at such a rate that the addition was complete after 
2 hours. After the addition was complete, the reaction mixture was 
stirred and refluxed for a further hour. The product was then isolated[2] 
and identified. Yields obtained are shown in the table. [76% to 86%]

It is, important to ensure (i) an adequate stirring rate [>400 rpm] and 
(ii) to add slowly the solution of catechoxide dianion to the reaction 
mixture, so as to avoid the possibility of intermolecular reaction

Notes:

[1] 	Adogen 464, is a methyl trialkylammonium chloride was supplied by 
	Aldrich Chemicals. The Alkyl groups are a mixture of C8-C10 
	Straight chains with an average of nine carbons. The molecular 
	weight, determined by titration, was found to be 457

[2] 	isolation [W. Bonthrone and J.W. Cornforth, JCS [c] 1202 (1969)] 
	The reflux condenser was replaced by a Vigreux column and a 
	constant-take-off distillation head. Water (50 ml.) was added and 
	the benzodioxole-water azeotrope was distilled off at 98-100°, 
	more water being added slowly as distillation proceeded. 
	Benzodioxole ceased to separate as a heavy oil from the distillate 
	after ca. 600 ml. of distillate had been collected. The aqueous 
	distillate was extracted with ether (3 x 60 ml.) and the combined 
	oil and extract was dried and distilled to yield benzo-1,3-dioxole 
	as a colourless oil; n[D]21 1·5377, b.p. 80°/9 mm., 173-176°/760 mm.
	[Bonthrone and Cornforth used a methylenation employing DCM in DMSO]

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British Patent 1518064, 1977

Example 4 ["Process For Preparing Aromatic Methylenedioxy Compounds"]

100 ml of methylene dichloride, 6.42 g of tetrabutylammnonium, bromide[1] 
and 200 ml of water were placed in an autoclave, and a total of 27.6 g 
(0.2 moles) of protocatechic aldehyde and 24 g (0.6 moles) of sodium 
hydroxide in 30 ml of water were added in stages at a temperature of 
70°C[2]. The pressure increased to a maximum of 2.4 atmospheres gauge, 
and the reaction was continued for 4 hours.

After this time the reaction mixture was cooled to ambient temperature, 
the organic phase was separated and the excess methylene dichloride was 
recovered by distillation. 21 g of high purity piperonal were isolated. 
Yield 70%.

Notes:

[1] 	other tetra alkyl ammonium salts may not work - if any of the alkyl 
	groups are lower than 4 carbons in length they are rapidly attacked 
	by strong alkali [Hoffman elimination of the quat] and the 
	quarternary ammonium salt destroyed.

[2] 	The patent reports temperatures between 30° C to 120° C. I would 
	expect microwave radiation to greatly improve this reaction. 

[3] 	As the reaction products form they are extracted by the methylene 
	dichloride, because of which at the end of reaction it is sufficient 
	to allow the organic layer to decant to obtain simple and rapid 
	separation of the reaction product from the starting compounds, 
	which remain in the aqueous layer. The methylene dichloride may 
	first be distilled from the organic phase and recycled, and then 
	the methylenedioxy product may be distilled off at high purity. The 
	catalyst remains as a residue, and may be recovered and recycled.
	The quantity of methylene dichloride may vary, but is preferably 
	between 1 and 5 moles per mole of the ortho-diphenol compound (i). 
	However it is always advantageous to operate with an excess of 
	methylene dichloride so as to work with a double phase and extract 
	the product in the organic phase.
	The catalysts are preferably used in quantities of from 1 to 10 
	mole % with respect to the ortho-diphenol compound (i), and may be 
	recycled. Sodium hydroxide is preferably present in an amount 
	between 30% and 150%, based on the mole equivalent of the diphenol 
	added. The concentration of the diphenol sodium salt in the aqueous 
	phase is advantageously maintained between 0.1% and 40% by weight.
	The reaction occurs between 30° C and 120° C, but maximum reaction 
	speed is obtained between 60° C and 90° C.

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Japan Patent 046949-B, 1984

The Preparation of methylenedioxy derivatives. Takasago perfumery KK, 
7 pages (Japanese). They improved on the British patent by employing 
iodine, an alkyl iodide or metal iodide as a promoter in an amount of 1/10 
to 1/100 molar times based on the diphenol compound.

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Methylenation of catechol at 95% yield (posted by Cherrie Baby)

US patent 5936103 describes the methylenation of catechols with methylene
chloride using K2CO3 as a base in N-methylpyrrolidone, as an aprotic solvent. A
yield of 95% is claimed. This method overcomes many drawbacks (described in the
patent) of the use of DMSO as a solvent.

The patent uses a continuous feed process and may require some conversion.

Note: DCM boils at 40°C.
      NMP boils at 202°C.

NMP can be prepared by the condensation of butyrolactone with methylamine (phew
what a waste!) Although looking at the structures I can't see how.

Preparation of methylenedioxy benzene. This is the exact text from the patent:

650 g of NMP (6.5 moles) and 173 g K2CO3 (1.25 moles) are charged into a 1000 cc
reactor equipped with a stirrer, condenser and a phase separator, thermometer
and two distributors, one of which with a plunged pipe immersed in the reaction
mixture. The suspension obtained is then heated to 130°C.

At this temperature, the feeding is initiated over a period of 4.5 hours of
110.11 (1 mole) of catechol in the molten state.

The methylene chloride is fed in continuous contemporaneously, by means of the
distributor with a plunged pipe immersed in the reaction mixture, and this
feeding is continued for a further two hours after the feeding of the catechol
has finished and in such quantity as to maintain an abundant reflux at the
reaction temperature.

The methylene chloride, after condensation and separation of the water, is
recycled in the same reaction mixture.

The total reaction time at a temperature of 130°C is about 6.5 hours.

The reaction mixture is cooled to room temperature for filtration and
elimination of the filtered solid.

The solution, after filtration, is evaporated from the methylene chloride
present and then distilled at reduced pressure in a rectifying column obtaining
a pure fraction of MDB of 116.62 g (boiling point 110°C at 100 torr).

Catechol conversion 100%.
Selectivity to MDB: 95.5%.

- - - -

Not bad. The yield is great. But what's the vapour pressure of DCM at 130°C?
That reactor and the feed systems will be very expensive. How much DCM do they
add? Excess? Probably, but how much?

NMP can be bought without suspicion. Maybe it can be hydrolysed to produce two
good precursors? Or even one precursor and a drug? Don't know if it works, but
sounds good!

- - - -

I think that DCM and water which escape are condensed, separted, and DCM
recylcled into the reaction. I would use an xs of DCM (4 moles) to minimise
production of catechol-dimer.

Ah I was lazy and forgot to read the rest of the patent. We nearly missed:

Example 6: Piperonal

The same procedure was carried out as in Example 1 (above) charging
3,4-dihydroxybenzaldehyde in a solution of NMP instead of catechol. At the end
of the reaction after separation by distillation under vacuum (10mm Hg) 141.6 g
of pure 3,4-methylenedioxybenzaldehyde [piperonal] was obtained.

Conversion of 3,4-dihydroxybenzaldehyde: 100%
Selectivity to piperonal: 93.5%

Compared with other solvents: They claimed only 80% selectivity with either
sulpholane or DMF as the solvent. DMSO has serious drawbacks eg. it may
decompose explosively when heated much above 50C with strong alkali.

They give references to older processes:

1) Franz Dallacker, et al., Zeitschrift Fur Naturforschung, Teil B: Anorganische
Chemie, Organische Chemie, vol. 34b, No. 10, pp. 1434 to 1442, "Darstellung und
Eigenschaften von Naphtho [1.2-d]-und Naphtho [2.3-d]-1,3-dioxolen", Oct. 1979.

2) Robert E. Zelle, et al., Tet. Lett, vol. 32, No. 22, pp. 2461 to 2464, "A
Simple, High-Yielding Method for the Methylenation of Catechols", May 27, 1991.

- - - -

The reaction takes place at atmospheric pressure.
The only mention they made of the quantity of DCM was that an excess was used.
Other N-Alkylpyrrolidones are acceptable solvents, Na2CO3 is also suitable base.

- - - -

How about this for a conversion:

1L 3-Necked flask, fitted with thermometer, dropping funnel and a central
two-way adaptor (fitted with a stirrer & reflux condensor). [Or a 4-Necked
reactor or flask if you have one!] The reflux adaptor has a condensor, followed
by a tube leading back to the top of the dropping funnel. DCM is added through
the dropping funnel. Perhaps a funnel with phase separation paper could be
fitted between the condensor and the dropping funnel.

The quantities used as in the patent. Sufficient DCM added to maintain a reflux
temperature of 130C during the reaction.

Sorry that's two condensors. After the reflux condensor is a conventional one to
condense DCM and water that escape the reflux.



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PTC methylenation of catechols 

Tet Lett 40, 3489-3490 (1975)

A mixture of water (20 ml), dibromomethane[1] (0.15 mole) and adogen 464 [2]
(1 mmole) was vigorously stirred and heated to reflux. A solution of the 
appropriate catechol (0.1 mole) and sodium hydroxide (0.25 mole) in 50 ml 
water was added at such a rate that the addition was complete after two hours. 
After the addition was complete, the reaction mixture was stirred and refluxed 
for a further hour. The product was then extracted with DCM, the extracts 
dried over MgSO4 and distilled to isolate the product. Yield 76-86%.

[1] Dichloromethane can probably be used with slightly diminished yield. 
    If you use that, increase the reaction time with one hour.
[2] Or Aliquat 336.

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