GC_MS (Hive Bee)
01-22-03 17:58
No 400454
      Ullmann and Wurtz reaction in methylenation     

I have a question regarding possible side reactions for a hypothetical synthesis of 5-bromopiperonal using 5-bromoprotocatechualdehyde as precursor.
Rh's site contains a page with sufficient examples on how to brominate/iodinate vanilline. There is also a page explaining how to demethylate the methoxy group of vanillin. One of the references on that page leads to "Cleavage of alkyl o-hydroxyphenyl ethers" by R G Lange. The article claims that it is possible to demethylate vanillin with 86.8% yield, and 5-bromovanillin with 95.1% yield. I was thinking about methylenating the 5-bromocatechualdehyde to obtain 5-bromopiperonal, which might be useful for several things.
However, if I use dibromomethane, would there be a chance that side-reactions occur? With side-reactions, I particulary have Ullmann and Wurtz-type reactions in mind. The Ullmann reaction uses Cu and Wurtz uses Na, but can these reaction types also occurr (on a lower scale) without these elements? Or are they absolutely necessary? Also, I have read a couple of texts where Cu or bronze turnings were  used to catalyze the methylenation. I guess that would not do good to the synthesis?
Any useful comment is welcome tongue

Ave Hive, synthetisandi te salutant!
(Chief Bee)
01-22-03 20:58
No 400496
      no problem     

Ullmann Coupling requires high temperatures to work, often about 200C. Wurz coupling requires a strong base (alkali metal) to rip off the halogen to form a carbocation, which in turn can couple with another alkyl halide. There is no risk that would happen in a simple methylenation, regardless if you use CH2Cl2 or CH2Br2. What reference do you have regarding Cu/bronze turnings as phenol alkylation catalysts?
(Hive Bee)
01-23-03 10:52
No 400750

From Meyer's Synthese der Kohlenstoffverbindungen (Springer Verlag, 1940), Vol IIa:

- p 396, #16: Brenzcatechinaethylenaether - Brenzcatechin, Aethylenbromid, K2CO3, etwas Cu-Pulver, Glycerin 190-200 C. Ausbeute: gut [3]

[3] GHOSH, Journ chem Soc London 107 (1915) 1591, 1597

- p 400, #40: 3,4-Methylendioxytoluol - 1 Mol Dioxytoluol, 1 Mol CH2Cl2, 1.4 Mol KOH, Bronzespaene, Alcohol in zu 9/10 gefuelltem Rohr 18 Stunden bei 100 C. Ausbeute: 63.7% [4].

[4] ASCHKINASI, RABINOWITSCH. Russ Journ allg Chem 10 (1937) 131.

Sorry, don't have the original articles frown

Ave Hive, synthetisandi te salutant!
(Hive Bee)
01-24-03 14:16
No 401099

Houben-Weyl: Methoden der organischen Chemie, 4. Auflage - Sauerstoffverbindungen I, Teil 3 (1965)

p 424. Benzo-1,3-dioxol (1,2-Methylendioxy-benzol) (5). Eine Loesung von 11 g (0.1 Mol) Brenzcatechin in 15 cm^3 Methanol, 3 g Kupferpulver und 10.2 g (0.12 Mol) Dichlormethan oder die aequivalente Menge Dibrommethan gibt man in ein dickwandiger Einschmelzrohr. Man fuegt, moeglichst ohne zu vermischen, 40 cm^3 Methanol hirzu, stellt das Rohr senkrecht in eind Eisbad und versetzt, wiederum ohne zu vermischen, mit einer Loesung von 11 g (0.2 Mol) KOH in 15 cm^3 H2O. Man schmilzt und erhitzt in einem Bombenschuettelofen 18 Stdn. auf 105 bis 110 C. Die aufarbeitung durch Wasserdampfdestillation und Rektifikation ergibt 51-53% Benzo-1,3-dioxol vom Kp: 172-175 C. Bei Verwendung von Dijodmethan erhoeht sich die Ausbeute auf 69% der Theorie.

(5) K N Campbell, J Org Chem 16 (1951) 1739

And yes, the reference is the original article in English...

Ave Hive, synthetisandi te salutant!
(Chief Bee)
01-24-03 23:40
No 401203
      Synthesis of Methylenedioxybenzene
(Rated as: good read)

Methylenation of catechol
J. Org. Chem. 16, 1739 (1951)

The most satisfactory results were obtained by the following procedure: A solution of 0.1 mole of catechol in 15 ml. of methanol was placed in a thick-walled Pyrex bomb tube, together with 3 g. of Tobin bronze shavings (Cu 6O%, Zn 38%, Sn 1.5%, Fe 0.2%, Pb 0.3%) and 10.2 g. (0.12 mole) of methylene chloride or the equivalent amount of the bromide. Methanol (40 ml.) was then added in such fashion that the minimum amount of mixing occurred. The bomb was clamped vertically in an ice-bath and a cold solution of 11.0 g (0.2 mole) of potassium hydroxide in 15 ml. of water was added quickly, so that very little mixing occurred. The bomb tube was now about 90% full; it was sealed immediately and heated in a shaking furnace for 18 hours at 105-115C. The product was isolated by steam-distillation and purified by distillation under reduced pressure. The methylenedioxybenzene obtained had bp 172-175C/755 mmHg. Numerous modifications of this method were tried. It was found that unless the bomb tube was carefully charged as described above, and unless it was at least 90% full before sealing, the yields of product mere lower, and more oxidative deconiposition occurred. It was also found that use of less than the stoichiometric aniount of potassium hydroxide (0.2 mole) led to lower yields in contrast t o the report of Rao (2). Methylene sulfate gave very poor results by this method; methylene iodide gave the highest yields, but since the pressure in the bomb tubes was much higher when the iodide was used, more of the tubes broke during the heating period, and so this reagent was not used in subsequent work. Methylene chloride and methylene bromide gave comparable results. Some of the results are given in Table I.

Attempts to repeat the procedure of Rao and Seshardi (2) were unsuccessful. This method involves treating the ortho-dihydroxybenzene with methylene sulfate in acetone-potassium hydroxide solution at atmospheric pressure, in a stream of illuminating gas, at 60C for several hours. Despite many attempts, no appreciable amount of methylenedioxybenzene could be obtained, and extensive oxidation occurred with the formation of large amounts of tarry by-products.

Attempts to use methylene sulfate under pressure in acetone solution were abandoned because of the highly exothermic reaction which frequently led to destruction of the bomb tube.

(2) Rao and Seshardri, Proc. Indian Acad. Sci., 23A, 147 (1946)
(Hive Bee)
01-30-03 11:58
No 402636
      methylenation with CuO     

Here is another example of methylenation using Cu catalyst: J Med Chem 33 (1990) 703-710, Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA). From the Nichols lab...

p 709 - 5,6-(methylenedioxy)-2-phthalimido-1,2,3,4-tetrahydronaphtalene (15). Dihydroxy compound 14 (0.249 g, 0.8 mmol) was dissolved in 2 mL of dry DMF. After addition of 0.42 g (2.41 mmol) of CH2Br2, 0.334 g (2.41 mmol) K2CO3, and 4 mo of CuO22, the mixture was stirred and heated at reflux under N2. An additional 0.42 g of CH2Br2 was added after 4 h, and heating was continued for 20 h. The reaction was cooled, and the volume was reduced by rotary evaporation. The the residue was added 25 mL of water, and the product was extracted into CH2Cl2 (5 x 10 mL). The organic extract was washed with 5% KOH and brine and dried (MgSO4). The solution was filtered and concentrated under vacuum, and the residue was purified by radial chromatography on a silica gel rotor, and elution with dichloromethane. The product was recrystallized from 2-propanol to provide 0.101 g (39%) of material: mp 207-208.

Abusus non tollit usum
(Chief Bee)
05-14-04 19:24
No 507151
      Synthesis of 5-Bromopiperonal
(Rated as: excellent)

Synthesis of 5-Bromopiperonal & 2-Bromo-6-Methoxypiperonal
Hisashi Ishii, et. al.
Chem. Pharm. Bull. 26, 864-873 (1978) (../rhodium/chemistry /5-bromopiperonal.html)

5-Bromoprotocatechualdehyde (11) was obtained from 5-bromovanillin quantitatively by applying the method which Lange reported for the cleavage of various alkyl o-hydroxyphenyl ethers. This bromoaldehyde (11) was treated with methylene iodide in dimethylsulfoxide (DMSO) in the presence of anhydrous potassium carbonate to give 5-bromopiperonal (12) in 38.8% yield. The Baeyer-Villiger oxidation of 5-bromopiperonal (12) with performic acid gave 5-bromosesamol (13), mp 102-104C, in 78.8% yield, accompanied by a small amount (0.6%) of 5-bromopiperonylic acid (14). Methylation of 5-bromosesamol (13) in the usual way gave 1-bromo-5-methoxy-2,3-methylenedioxybenzene (15), mp 49-51C, in 96.5% yield. Treatment of this methoxybenzene (15) with phosphorus oxychloride and dimethylformamide (DMF) gave 2-bromo-6-methoxy-3,4-methylenedioxybenzaldehyde (16), mp 208-209C, as the sole product in 91.5% yield.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
05-18-04 02:43
No 507808
      Copper(II) Oxide Catalyzed Methylenation
(Rated as: good read)

This is Ref #22 from Post 402636 (GC_MS: "methylenation with CuO", Methods Discourse)

Eine einfache Darstellung von 2,3-Methylendioxybenzaldehyd
Jan Smidrkal & Jan Tronnek
Zeitscrift fr Chemie 13(6), 214 (1973) (../rhodium/pdf /methylenation.cuo.pdf)

2,3-Methylenedioxybenzaldehyd (o-Piperonal)

A mixture of 2,3-dihydroxybenzaldehyde (69g, 0.5 mol), anhydrous potassium carbonate (208g, 1.5 mol), copper(II)oxide (2.3g, 29 mmol) and dibromomethane (261g, 1.5 mol) in 1110 mL freshly distilled DMF is stirred vigorously and allowed to boil under reflux for 7 hrs. The solvent is then evaporated in vacuo, and 700ml ice-water added to the residue and the mixture extracted with 5x200mL ether. The etheral extracts are pooled and washed with 5% aqueous KOH followed by water, and the solution then dried over anhydrous sodium sulfate. The ether is distilled, and the residue vacuum distilled to give a colorless oil (bp 129-129.5C/11mmHg) which later crystallized (mp 32-33C) to give 61.1g (81.5%) of o-piperonal.

The Hive - Clandestine Chemists Without Borders