(Hive Bee)
07-31-03 11:32
No 450928
      2,5-DMBA directly from 1,4-DMB
(Rated as: excellent)

dear bees,

ne the major routes to 2-CXes, 2,5-DMBA is the key intermediate. Most 2-CB syntheses on Rhodiums site start from 2,5-DMBA. Quite some research on its synthesis has been done so far, especially from Antoncho. An easy acces to this aldehyde remains a difficult problem.
In principle, the lithiation of 1,4-DMB and subsequent reaction with DMF looks straightforward, however no example in the hive could be found (../rhodium/chemistry /2cbde.html uses brominated aromatics for aldehyde preparation, one trial to go directly failed). In the literature examples surprisingly are rare too. To lithiate 1,4-DMB either an alternative approach via the 2-bromo-1,4-dimethoybenzene or more drastic conditions like the use of tert-BuLi or 1 equivalent of TMEDA (Tetrametylethylenediamine Me2NCH2CH2NMe2) were applied. Only one example otto could find, deals with direct lithiation of 1,4-DMB, its from our beloved Shulgin (../rhodium/chemistry /doef.html).

So otto tried:

1,4-Dimethoxybenzene (13.7 g, 99.3 mmol, grey color) [1] were dissolved in 50 mL THF in a 100 mL erlenmeyer flask. Some MgSO4 was added to ensure dryness of both 1,4-DMB and THF. The solution was suction filtered into a two necked 250 mL RBF containing a stirrer bar. The erlenmeyer and MgSO4 were washed three times using 10 mL of THF each. The washings went directly in the RBF, too [2]. The RBF was purged with Argon and the stirrer set to ~500 rpm. Then, a solution of BuLi in toluene (55 mL, 2.5 n, 138 mmol) [3] was added slowly via syringe within about 10 min. The mixture became warm to the touch during this operation. the setup was then immersed into an oil bath maintained at 55°C overnight (20 h) [4].
The next day, dry DMF (10 mL, 132 mmol) was added to the mixture via syringe within 2 min and the mixture was kept for another 4 hours at 55°C. After quenching with 100 mL water, the phases were separated, the aqueous layer extracted twice using 50 mL ethyl acetate [5] each time and the combined organic phases washed with 50 mL brine, dried (MgSO4) and finally evaporated.
A TLC (silica gel, CHCl3) shows two major spots at RF ~ 0.6 - 0.7, the lower one being propably the aldehyde, a GC shows a 2:1 mixture of 1,4-DMB and 2,5-DMBA.

To isolate the aldehyde, otto tried the good old bisulfite method. As indicated in literature, a 40% NaHSO3 solution will give the crystalline adduct whereas a 15% solution only extracts aldehydes into the aqueous layer. otto found, the 15% solution forms the adduct in crystals almost quantitatively indeed.

The crude product mixture was shaken in a sep. funnel with 40 mL NaHSO3 solution (NaSO3 12.6 g, 100 mmol dissolved in water 75 mL, added 8.3 mL HCl 37%, 100 mmol carefully, then well mixed) [6]. Within one minute the mixture became sticky from crystals. This was given 5 more minutes and then all was suction filtered. The filtrate was separated into phases and the organic phase shook again with the remaining 40 mL NaHSO3 solution. Only few more crystals appeared. All was sucked through the same funnel. The filter cake was washed three times with diethyl ether and dried in vacuo to yield 9.63 g (35.6 % of theory) of yellowish 2,5-DMBA as the bisulfite adduct. [7]

The aqueous phase was washed twice using 30 mL diethyl ether each time to remove rest of unreacted 1,4-DMB, acidified and extracted twice using the same amounts of ether. The etheral extracts gave another 180 mg of 2,5 DMB upon evaporation (1% more yield). The organic phase plus ether washings (3 from filter cake, 2 from aqueous phase workup) were evaporated to give 1,4-DMB (8.4 g, 61,3% of starting material, now black, not grey).

[1] The 1,4-DMB was prepared from hydroquinon, K2CO3, DMSO4 and water in only 74% yield. After column chromatography
the product was obtained in white crystals which gradually turned grey.
[2] This drying procedure can be omitted, if one has dry ingredients at hand.
[3] This was a leftover from a charge one year old.
[4] Shulgin (../rhodium/chemistry /doef.html) did the lithiation by refluxing for 4 hours. Otto didnt have a suitable setup and traded reaction time for temperature.
[5] Other solvents like CHCl3, DCM, benzene will work equally well.
[6] No NaHSO3 was to get.
[7] The adduct is water soluble.
(Hive Adickt)
07-31-03 11:37
No 450930
      2,5-DMBA  Bookmark   

It's posible to do it in one hit, as you describe here.
But the yeald is much higer when you brominate the dimethoxybenzene first. The bromination in cold chloroform is over 90%, the aldehydeformation as well.
(Hive Bee)
08-01-03 15:09
No 451121
      Otto, this is write-up is great!  Bookmark   

Otto, this is write-up is great! cool

Few bees like you are trying new synthetic methods. Although the yield is not great it is enough for further synthesis wink
For some bees 2,5-DMBA is far away from being commercially available and synthetic methods are few. The methylation of 2,5-dihydroxybenzaldehyde (from salicyl aldehyde) needs DMS or other nasty methylating agents, the direct methylation with TFA and HMTA is not high yielding and so on. So this methods offers an alternative.......

You did a great job!

Hm, if you do not mind working with DMS you could try the oxididation of 2-hydroxybenzaldehyde to 2,5-dihydroxybenzaldehyde and methylation to 2,5-DMBA. Just a suggestion...........

It would bee great to read more write-ups like this!

Note: BuLi (n-butyl lithium) is moisture sensitive, pyrophoric and very flammable. Bee careful!

The candle that burns twice as bright burns half as long
(Hive Bee)
08-02-03 03:14
No 451214
      Hello Hest, thank you for that remark.  Bookmark   

Hello Hest,

thank you for that remark. Otto didnt think, that selective monobromination was possible in 90%+ yield. This two step procedure is of course more reasonable. Otto just has been impatient and wanted to skip one step. By the way, did you ever hear of a trial of that iodination procedure (nitrate, iodine in HOAc) mentioned on Rhodiums site on 1,4-DMB?
(Hive Adickt)
08-02-03 05:41
No 451237
      2,5-DMBA  Bookmark   

My luck with iodination is limitid. Usual it's much more easy to stay with the bromine. (and for the bee's without buli an grignard and some DMF will do the work)
(Chief Bee)
08-03-03 16:42
No 451516
      2-Cl, 2-Br, 2-I, 2-CH2F, 2-CF3-1,4-MeO-Benzene
(Rated as: excellent)

2,5-Disubstituted N,N-Dicyanoquinone Diimines (DCNQIs)
Siegfried Hünig, Robert Bau, Martina Kemmer, Hubert Meixner, Tobias Metzenthin, Karl Peters, Klaus Sinzger, Juris Gulbis
European Journal of Organic Chemistry, 335-348 (1998) (../rhodium/pdf /2-halo-1.4-dimethoxybenzene.pdf)

Very interesting article, with syntheses of 2-Chloro, 2-Bromo, 2-Iodo, 2-Fluoromethyl and 2-Trifluoromethyl-1,4-Dimethoxybenzene, among others.