Chimimanie
(Stranger)
10-28-02 20:50
No 373715
      Synthesis of 2-Chloromethyl-5-alkyl-DMB
(Rated as: excellent)
    

5-chloromethyltoluhydroquinone dimethyl ether (Ia)
Gaseous hydrogen chloride was bubbled into a well-stirred  mixture of 200ml of 35% formaldehyde, 100 ml of concd. hydrochloric acid and 400 ml of dioxane for 15 min at such a rate that the temperature of the mixture remained between 55-60 with no external heating. To this mixture 152g (1.0 mole) of 2,5 dimethoxytoluene was added, dropwise, over a period of 20 min, while the temperature was maintened between 55-60. When the addition was completed, the passage of hydrogen chloride was stopped. The mixture was cooled and poured into 2 L of ice water and 300 ml of ethyl ether. The aqueous layer was extracted twice more with 250 ml portions of ether. The combined ether extracts were washed with cold water until the washings were neutral to litmus, then dried with anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was distilled through a 4-in Vigreux column to give 110-130g (55-65%) of colorless liquid, bp 144-153/14-16 mm, which solidified on cooling. Recrystallization from CH3CN gave white crystals, mp 61.5-62.5


2-chloromethyl-5-n-octylhydroquinone dimethyl ether (Ib)
The reaction was performed exactly as described for the preparation of Ia. From 100g (0.4 mole) of n-octylhydroquinone dimethyl ether there was obtained, after distillation, 75g (62%) of colorless liquid, bp 170-173/0.4 mm which solidified on cooling. Recrystallization from acetonitrile gave white crystals, mp 51-52


The authors do this reverse addition of reagent because the others reaction conditions yielded only 5,5'-methylenebis(toluhydroquinone dimethyl ether):

'When 2,5-dimethoxytoluene was slowly added to a chloromethylation mixture at 55-60C, yields of Ia from 55-65% were obtained. This mode of addition of reagent differs from those generally applied in which either all reactants are mixed at once or formalin is added slowly to the reaction mixture.'

'This technique of chloromethylation, when applied to n-octylhydroquinone dimethyl ether gave Ib in comparably good yield, and it is reasonable to assume that other alkyl or aryl substituted hydroquinone dimethyl ethers can be chloromethylated with similar ease.'


ref: The Synthesis of 2-Chloromethyl-5-alkylhydroquinone Dimethyl Ethers by a Controlled Chloromethylation, Gregory J. Lestina and Homer W.J. Cressman, august 1960, 1453-4, journal unknown
 
 
 
 
    Rhodium
(Chief Bee)
10-29-02 13:27
No 374023
      Ref     

The correct reference is Journal of Organic Chemistry Vol 25, 1453-54 (1960).
 
 
 
 
    Bandil
(Hive Bee)
10-30-02 09:43
No 374446
      Could dioxane be subst.     

Could dioxane be subst. with another ether like diethylether og THF?
 
 
 
 
    Rhodium
(Chief Bee)
11-30-02 14:49
No 384897
      Chloromethylation of p-dimethoxybenzene - 61%!
(Rated as: excellent)
    

Finally! A procedure for chloromethylating para-Dimethoxybenzene without extensive dimerization!

2,5-Dimethoxybenzyl Chloride [4]

This compound has been prepared previously [1] from the benzyl alcohol and by chloromethylation [2]. Since details of the latter preparation are not available, and the usual procedures [3] lead to extensive disubstitution, the method is described.

A stirred solution of 55g of p-dimethoxybenzene in 100 mL of benzene and 200 ml. of concentrated HCl was saturated with hydrogen chloride. With a slow stream of HCl, 30 g. of formalin solution (37%) was added dropwise during 1 h with intermittent cooling in an ice bath. The HCl stream was then increased and the mixture was stirred for 1 h; the temperature rose to 55C. The mixture was then extracted with benzene and the benzene layer was washed with water and NaHCO3, dried, and evaporated. Recrystallization of the solid residue from heptane gave 45g (61%) of colorless crystals, mp 69-70C (lit.[1] m.p. 70-72C). Note: One of us experienced a very severe allergic-type reaction to this compound, with extensive dermatitis and edema.

References
1) J. Chem. Soc. 1165 (1954)
2) K. Hejno and Z. Arnold, Chem. Lisy, 47, 601 (1953).
3) Organic Reactions 1, 63 (1942)
4) J. Org. Chem. 29, 2860 (1964)
 
 
 
 
    moo
(Hive Bee)
11-30-02 17:10
No 384925
      Marvelous! I thought that was next to impossible.     

Marvelous! I thought that was next to impossible.
 
 
 
 
    Chimimanie
(Stranger)
11-30-02 19:43
No 384966
      Good find Rhodium!     

That is really good, thank you!
 
 
 
 
    Antoncho
(Official Hive Translator)
12-04-02 09:40
No 386114
      OHHHHHHHHHHH!!!     

Rhodi - let me second what Moo said!

Gooooood.

You've once again bested all of us with this findsmile




Antoncho

P.S. I'm out of Nirvana already but won't bee fully fuctioning for some time yetsmile
 
 
 
 
    Vibrating_Lights
(Hive Addict)
03-12-03 08:22
No 416044
      Benzene     

COuld anything be substituted for the benzene as the solvent in RHodiums post?

Start thinking more like a chemist and less like a criminal
 
 
 
 
    Bandil
(Hive Bee)
03-12-03 10:48
No 416086
      Take a look here     

In this patent the use some differerent solvents for the reaction with paraformaldehyde(should be about the same).

Patent GB986040

The mention acetic acid as a suitable solvent... Perhaps its worth a try instead of the dioxan/benzene...

edit: actually a lot of patents suggest acetic acid as a solvent...

 
 
 
 
    Chimimanie
(Hive Bee)
04-01-03 23:29
No 423119
      Synthesis of 2-Chloromethyl-5-alkylthio-DMB
(Rated as: excellent)
    

Synthesis of 4-(alkylthio)-2,5-dimethoxyphenethylamine derivatives

This is a repost of Post 210276 (Sonson: "Re: New route to PEAs?", Novel Discourse) with a little more experimental detail but since Rhodium asked it in the Wanted References sticky thread and since I had already OCRed it month ago I repost it.

They synthetise these phenethylamines to do THC analogs from the skeleton of 2-CT-# analogs. It always shock me when I see the similarities between the structure of different entheogens: lysergides, tryptamines, benzofuranamines, phenethylamines, THC.

Well enough rambling, now place to the fun part:

Experimental:

1,4-dimethoxy-2-(pentylthio) benzene (IVa)

A solution of sodium ethoxide (from 9.75g Na and 200 ml ethanol) was treated with 63.6g 2,5-dimethoxythiophenol and 67.4g pentyl bromide and the mixture was stirred and refluxed for 5h. Ethanol was distilled off, the residue was diluted with 250ml water and the mixture was extracted with benzene. The dried extract was processed by distillation; 86.8g (97%) bp 139-142C/0.1 kPa, mp 38-39C (MeOH)

2-(Heptylthio)-1,4-dimethoxybenzene (IVb)

Similar reaction of sodium ethoxide (from 6.30g Na and 130 ml ethanol) with 46.7g 2,5-dimethoxythiophenol and 50.3g heptyl bromide gave 73.5g (theoretical) of homogeneous IVb melting at 46-47C. The melting point remained unchanged after crystallisation from methanol.

2-(Chloromethyl)-1,4-dimethoxy-5-(pentylthio)benzene(Va)
see Post 210276 (Sonson: "Re: New route to PEAs?", Novel Discourse)

2-(Chloromethyl)-5-(heptylthio)-1,4-dimethoxy-benzene(Vb)

A mixture of 20 ml 38% aqueous formaldehyde, 10 ml HCl and 40 ml dioxane was saturated for 10 min with HCl and the mixture was similarly reacted (cfr Sonson's post) with 26.8g IVb in 20 ml dioxane and similarly processed. Crystallization of the inhomogeneous residue (31.3g) from 100 ml acetone gave 26.7g of the diphenyl compound. Processing of the mother liquor gave 19.05g (60%) of Vb mp 66-69C (light petroleum)

4-(pentylthio)-2,5-dimethoxyphenyl)acetonitrile(Vb)
see Sonson's post

4-(heptylthio)-2,5-dimethoxyphenyl)acetonitrile(Vb)

A similar reaction (see Sonson's post) of 25.3g Vb with 12.65 NaCN in 80ml DMF gave 26g of an inhomogeneous solid which was crystallised first from 50ml MeOH and then from 50ml cyclohexane affording 17.3g (71%) of VIb, mp 69-71C (light petroleum)

2-(2,5-dimethoxy-4-(pentylthio)phenyl)ethylamine(XIIIa)

A solution of 15.7g AlCl3 in 110 ml ether was slowly added to a stirred solution of 5.7g LiAlH4 in 110ml ether under nitrogen and the mixture was treated dropwise over 30 min with a solution of 22.4g VIIa in100 ml THF. The mixture was stirred and refluxed for 6h, after cooling decomposed with water and 20% NaOH, and extracted with benzene. Processing of the extract gave 22.7g (theoretical) of oily XIIIa.

2-(4-(heptylthio)-2,5-dimethoxy-phenyl)ethylamine(XIIIa)

The reagent was prepared from 11.0g AlCl3 and 4.0g LiAlH4 in 160ml ether under nitrogen and was used to reduce similarly (like XIIIa) 17.3g VIIb; 14.9g (85%) of oily XIIIb was obtained.   


Also they synthetised their dimethoxy-thiophenol from potassium ethyl xanthate in a process similar to this:

p-Methoxythiophenol (ref unknown)

This was first prepared by Gatterman by reduction of the corresponding sulfinic acid. In the present work it was prepared from p-anisidine by the Leuckart reaction. The following conditions were found to be the most satisfactory. In a 5-liter 3-necked flask equipped with a mechanical stirrer, dropping funnel and outlet tube to the hood, was placed a solution of 300g (1.9 moles) of potassium ethyl xanthate dissolved in 700 cc of water. To this solution, kept at 70 to 80, was added slowly with vigorous stirrring a cold solution containing 123g (1 mole) of diazotized p-anisidine to which had been added enough sodium acetate to neutralise the free acid. Stirring and heating were continued for about an hour after the addition of the diazonium solution to complete the decomposition of the intermediate diazonium ethyl xanthate. The dark oil was removed from the cooled solution and the aqueous layer extracted with ether, the product obtained being combined with that first removed; this material was then refluxed for three hours with a solution of 115g of potassium hydroxide in 2 liters of 95% ethyl alcohol to which had been added 20g glucose. The alcohol was removed by distillation until the residual volume was about 300cc. This was acidified with cold dilute sulfuric acid, a few grams of zinc dust added, and the oily thiol removed by distillation with steam. The distillate was extracted with ether, the ether dried over calcium chloride, and the oil remaining after distillation of the ether was distilled under reduced pressure. The yield was 100 to 110g or 71 to 79%

This was a reference they cited but i dont have it at hand. Take care that here it is not the 1-methoxy-4-thiophenol but the 1,4-dimethoxy-2-thiophenol that is wanted. The procedure is similar but the yield is more like 50% (I dont remember exactly).

See also Patent CS271850

ref:
Collection of Czechoslovak Chemical Communications  (1990),  55(3),  782-96.
 
 
 
 
    Rhodium
(Chief Bee)
11-24-03 10:39
No 472838
      Bromomethylation of 1,4-Dimethoxybenzene
(Rated as: excellent)
    

This one is related to the procedure in Post 384897 (Rhodium: "Chloromethylation of p-dimethoxybenzene - 61%!", Methods Discourse) I'm sure that this procedure can be tweaked with the aid of the other one (i.e. adding the formaldehyde equivalent slowly) to create a synthesis of 1-Bromomethyl-2,5-dimethoxybenzene from 1,4-dimethoxybenzene in at least moderate yield without this extensive dimerization. Using 33% HBr in HOAc also seems to side-step the cumbersome common practice of gassing the reaction solution with anhydrous HX.

Also, I believe that the 2,5-bis-(bromomethyl)-1,4-Dimethoxybenzene formed in the procedure below could be selectively reduced to 1-Bromomethyl-4-Methyl-2,5-dimethoxybenzene somehow, this product being a precursor to 2C-D/DOM.

Bromomethylation of 1,4-Dimethoxybenzene
Eur. J. Org. Chem. 3162-3170 (2002)

A 33% solution of HBr in glacial acetic acid (14 mL, 0.08 mol) was added dropwise to a suspension of 1,4-dimethoxybenzene (5.0 g, 0.04 mol) and paraformaldehyde (2.37 g, 0.08 mol) in glacial acetic acid (25 mL). The mixture was stirred for 1 h at 50C. The doubly bromomethylated product precipitated and was isolated by filtration, dissolved in chloroform (80 mL) and the solution dried with anhydrous sodium sulfate. After filtration, partial evaporation of the solvent under vacuum (100 Pa) enabled precipitation of colorless crystals (yield 10.14 g, 87%), mp 198C. The remaining reaction mixture was added to water (100 mL) and the precipitate isolated by filtration and purified by column chromatography over silica gel (70-230 mesh, 310 cm) using toluene as eluent. The monobromomethyl compound thus obtained formed almost colorless crystals (yield 1.11g, 12%), mp 73C.

1-Bromomethyl-2,5-dimethoxybenzene
1H NMR (CDCl3): δ 3.75(s, 3 H, OCH3 ), 3.84 (s, 3 H, OCH3), 4.52 (s, 2 H, CH2Br), 6.80 (m, 2 H, arom. H), 6.88 (m, 1 H, arom. H) ppm.
13C NMR (CDCl3): δ 28.9 (CH2), 55.8, 56.2 (OCH3), 112.2, 115.0, 116.4 (arom. CH), 127.0 (C-1), 151.7, 153.4 (C-2, C-5) ppm.
 
 
 
 
    Rhodium
(Chief Bee)
01-11-04 00:28
No 481663
      Another Bromomethylation Reaction     

Patent US6620941

Example 10

4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole

A 500-ml 4-necked jacketed reactor equipped with a mechanical stirrer, a thermometer, a 50-ml dropping funnel, an argon inlet, a PT100 temperature sensor and a thermostat was charged with 33.54 g of 4-[2-(Benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole (0.100 mol) and 400 ml of dichloromethane. After cooling the solution to 0C., 30.3 ml of hydrobromic acid 62% (0.400 mol) were added dropwise within 9 min at a temperature of 0-4C. To the yellow biphasic mixture a solution of 3.30 g of trioxane (0.110 mol) in 40 ml of dichloromethane was added at 0-1C. After 3 h 15.1 ml of hydrobromic acid 62% (0.200 mol) were added within 7 min at 0-1C. After 4 h additional 15.1 ml of hydrobromic acid 62% (0.200 mol) were added and the mixture was stirred over night at 0C. After a total of 24 h the colorless bottom HBr-phase was removed through the bottom valve and extracted with 100 ml of dichloromethane. To the combined organic phases in the reactor 300 ml of sat. aqueous sodium bicarbonate solution were added at ca. 0.degree. within 30 min. The resulting biphasic mixture was stirred for 5 min and the aqueous phase was extracted twice with 100 ml, a total of 200 ml of dichloromethane. The combined organic phases were dried (Na2SO4), rotary evaporated (45C, 600 mbar) and shortly dried (45C, 20 mbar, 15 min). The resulting light brown residue was suspended in 200 ml of acetone and the suspension stirred for 1 h at reflux, 1 h at rt and 1 h in an ice bath. The crystals were filtered off with suction, washed with 50 ml of cold (-20C) acetone and dried to constant weight at 55C. and 10 mbar for 4 h, affording 24.88 g of 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole as off-white crystals with mp of 143-144C.

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