Rhodium
(Chief Bee)
09-10-02 05:29
No 354784
      Tips & Tricks regarding dimethoxybenzene Grignards
(Rated as: excellent)
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I have heard a lot of people bitching about various dysfunctional dimethoxybenzene grignards, and I happened to find a solution to that problem while reading "Synthesis"...

Standard methods for preparing the grignard reagent of 2,5-dimethoxybromobenzene using ordinary magnesium turnings gave unsatisfactory and capricious results, but was readily generated by the MgCl2/K/KI system.

A mixture of freshly cut potassium (2.737g, 70 mmol), anhydrous magnesium chloride (3.427g, 36mmol) and potassium iodide (6g, 36 mmol) in 100ml dimethoxyethane is heated at reflux under nitrogen for 3h. 2,5-dimethoxybromobenzene (7.6g, 35 mmol) is then added and the mixture refluxed for another two hours. After cooling, the solution is ready for use.


Reference: Synthesis 585 (1981)
 
 
 
 
    hest
(Hive Adickt)
09-10-02 10:21
No 354852
      Grignard  Bookmark   

Usual you add the 2,5-dimethoxybrombenzene, disolved in ether, to the Mg. Iff you also ad 1% dibromoethan to this solution it works greath (done it in 100g scale) I think I have a writeup somwere at the hive. Just let the magnet stir around into the magnesium ower the night also make's the mg more potent (all done under nitrogen by the way).
Reducing MgCl2 wit kalium is a bit wiolent for mee laugh.
And ofcourse don't forget ultrasound. The Grignard's best friend.
 
 
 
 
    Rhodium
(Chief Bee)
09-10-02 12:58
No 354861
      Ultrasound would be the trick if you don't like ...  Bookmark   

Ultrasound would be the trick if you don't like potassium - the authors of the article considered 1,2-dibromoethane as well as iodine-activated magnesium "standard conditions".
 
 
 
 
    yellium
(Hive Addict)
09-10-02 18:40
No 354920
      Potassium is fun to work with :-).  Bookmark   

Potassium is fun to work with :-). Ultrasound does not always do the trick.
 
 
 
 
    Rhodium
(Chief Bee)
03-02-03 14:20
No 413041
      2,5-Dimethoxybromobenzene Grignards
(Rated as: excellent)
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2,5-Dimethoxybromobenzene1

To a stirred solution of potassium bromide (26.7g, 224 mmol) and 1,4-dimethoxybenzene (30.0g, 210 mmol) in a mixture of water (150ml) and ethanol (300ml) was added sulfuric acid (10 M, 38 mL). The solution was heated (gently) to reflux before hydrogen peroxide (90 mL, 30%) was added dropwise over 30 min. After a further 45 min at reflux, water (150 ml) was added to the hot mixture, which was then allowed to stand at room temp overnight. The solution was decanted and the solvent was evaporated. The residue was extracted with ethyl acetate (3x200mL) and the combined extracts were washed with dilute sodium thiosulfate (3x200ml), water (200ml), dried and evaporated. Flash pad chromatography3 of the residue using a gradient solvent system of ether/light petroleum followed by distillation gave 2,5-Dimethoxybromobenzene (30.1g, 62%) as a colorless oil, bp 107C/0.2mmHg (Lit.2 164-166C/55mmHg).

2,5-Dimethoxyphenylmagnesiumbromide1

A solution of 2,5-Dimethoxybromobenzene (3.19g, 14.7 mmol) in dry tetrahydrofuran (15 mL) was added gradually with stirring, to magnesium turnings (0.36g, 14.8 mmol) which had been activated by heating together with an iodine crystal, and the mixture was then heated at reflux for 4h and then cooled to room temperature.

Stereoselective ring-opening  of an epoxide with the Grignard reagent, catalyzed by Li2CuCl41

The above grignard reagent was added dropwise to a solution of 11.3 mmol of a terminal (R)-oxirane in tetrahydrofuran (15 ml) containing a catalytic amount of dilithium tetrachlorocuprate (0.1M, 1.0 mL, 0.10 mmol) at -78C. The mixture was allowed to slowly return to room temperature and then stirred for 18h. The reaction mixture was quenched with saturated ammonium chloride (30 ml) and the organic phase extracted into ether (3x70 mL). The combined extracts was washed with saturated sodium hydrogen carbonate (3x60 mL), brine (3x60 mL), water (80 mL), dried and concentrated under reduced pressure. Flash pad chromatography3 of the residue using a gradient solvent system of ether/light petroleum gave, after the evaporation of the solvent under reduced pressure, the optically pure alcohol in 92% yield.

References
[1] Aust. J. Chem. 53, 245-256 (2000) [Kudos to Chimimanie for finding this ref, and to ChemisTris for retrieving it]
[2] Aust. J. Sci. Res. Ser. A, 2, 595 (1949)
[3] Leonard & Lygo & Procter, "Advanced Practical Organic Chemistry" 2nd Ed, Stanley Thornes (1998), pp 215-216; Aldrichimica Acta 18, 25 (1985)

Edit: Ref 1 came from ChemisTris' Bee Library (http://www.crosswinds.net/~blibrary/chemistry/index.html)
 
 
 
 
    hest
(Hive Adickt)
03-02-03 18:38
No 413093
      Grignard  Bookmark   

Notes to the ' young chemist's ' dont use all your brominated prduct at once, the grignard on 2,5-dimethoxybomobenzene is notorius har to start.
 
 
 
 
    yellium
(I'm Yust a Typo)
03-02-03 18:55
No 413096
      Yeah, but if it doesn't work, you can usually...  Bookmark   

Yeah, but if it doesn't work, you can usually filter off the Mg turnings, evaporate the THF, and try something else. Like BuLi.
 
 
 
 
    Chimimanie
(Hive Bee)
03-06-03 18:58
No 414337
      This describe a grignard on ...
(Rated as: excellent)
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This describe a grignard on 1,4-dibromo-2,5-dimethoxybenzene, it is reacted with CO2 after the formation. To get the 4-bromo-2,5-dimethoxybenzaldehyde a reactant like DMF must be used instead. This aldehdye can be used for instance to make the 2C-T compounds ../rhodium/chemistry /4-alkylthio-25-dmb.html.

There is a gatterman formylation to the same compound also.


Experimental [2]:

4-Bromo-2,5-dimethoxybenzaldehyde (I):

A mixture of 70 g of bromohydroquinone dimethyl ether and 350 ml of anhydrous chlorobenzene was cooled to 0C in a thin-walled glass vessel. Then 50g of aluminium chloride and 14g of anhydrous hydrocyanic acid were added. With cooling to -30 to -35C (bath temperature), the mixture was saturated with dry hydrogen chloride until the increase in weight was 20g and then the vessel was tightly closed and was shaken at room temperature for 15 h. The contents of the reactor were transferred to a flask and boiled with a mixture of 80 ml of concentrated hydrochloric acid and 280 ml of water under reflux for 1 h. Then the mixture was cooled and extracted with chlorobenzene (3 x 100 ml), the combined organic extracts were washed with 140 ml of 10% NaOH solution and then with water and were dried with MgSO4, the solvent was driven off in vacuum, and the residue was recrystallized from methanol Mp 132C. Yield 56g (75%).

(Oxidation of the resulting aldehyde with potassium permanganate as described by Rubenstein [1] yielded 4-bromo-2,5-dimethoxybenzoic acid. Mp 168-169C, yield 88%)

4-Bromo-2,5-dimethoxybenzoic Acid (II):

 A solution of 20g of the dimethyl ether of 2,5-dibromohydroquinone in 100 ml of absolute tetrahydrofuran was added dropwise to a mixture of 1.6 g of magnesium and 15 ml of hot absolute tetrahydrofuran with stirring at such a rate that the mixture boiled gently. Then it was boiled under reflux for another 1 h, after which it was cooled with water and, with stirring, 4.5-5g of solid carbon dioxide was added to the reactor in small portions. The mixture was stirred for another 15 min, evaporated in vacuum to approximately 1/5 of its original volume, and, with cooling ice-water, treated with an excess of hydrochloric acid; the mixture was extracted with ether, the extract was washed with water and 10% NaOH solution, and the alkaline solution was separated off and acidified with hydrochloric acid. The crystals that deposited were washed with water and recrystallized from acetic acid. Mp 168-169C. Yield 8.3g (48%).

References:

[1] Rubenstein, J Chem soc 127 1999 (1925)
[2] Methods of obtaining 4-bromo-2,5-dimethoxybenzoic acid, J.Org.Chem.USSR (Engl.Transl.); 8; 1972