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                     Another route to 2C-[BDE] - by Yellium
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2,5-Dimethoxytoluene [1]

A solution of 100 mmol (13.8 gr) 1,4 dimethoxybenzene in dry THF (80 ml) was
added dropwise to a solution of 1.6 M BuLi (69 mL, 110 mmol) in dry THF (30ml)
at rt under argon and stirred for 1h. Reaction was brought to approx. -80'C
using a bath of ethylacetate, cooled with liquid nitrogen.  MeI (25 ml, 400
mmol) was added via syringe at -78'C to the above solution and after 1 h at rt
the mixture was quenched with saturated aqeous NH4Cl solution. Separation of the
organic layer, and extraction of the water layer with CH2Cl2, drying of the
combined organic fractions over Na2SO4, and removal of the solvent under vacuum
afforded 18,4 gr 2,5-dimethoxytoluene as an oil, which was used in the next
step without further purification.

Reaction of this compound with BuLi at 0'C for 10 minutes, followed by addition
of 1 equivalent DMF, 10 minutes stirring, and workup with dilute HCl yielded
only a small amount of impure aldehyde. This was most likely due to a too short
reaction time, and wet DMF. Destillation of the reaction mixture yielded 13.4 gr
2,5-dimethoxytoluene, followed by 3 gr of an unknown yellow/greenish liquid.

2,5-dimethoxytoluene -> 4-bromo-2,5-dimethoxytoluene (after [2])

13.4 gr 2,5-dimethoxytoluene was dissolved in 200 ml DCM, to which 15.5 gr nbs
was added.  After 39h stirring at room temperature, followed by the classical
workup (washing with sodium sulfite, drying over Na2SO4, and evaporation of the
solvent), 18.9 gr of slightly brown-colored 4-bromo-2,5-dimethoxytoluene was
obtained. Impurities could be removed by washing with a little ether, yielding
almost colorless crystals.

Attempts to prepare the grignard reagent from the above bromide were futile.

4-bromo-2,5-dimethoxytoluene -> 2,5-dimethoxy-4-methylbenzaldehyde

17.1 gr of the above bromide was dissolved in 200 mL dry ether, cooled to -80
using ethylacetate/LN2, was added 55 ml of 1.6M BuLi, letting the mixture return
to room temperature in the course of one hour, followed by the addition of 5.9
gr dry DMF in 20 ml ether over a 2 minute period. After stirring at room
temperature for another hour, a few hundred mL of aqeous HCl was added, the
organic layer was separated, and the aqeous phase was extracted with 3x100ml
DCM. The organic extracts were combined, and the solvent was removed under
vacuum yielding 8.2 gr brown-colored aldehyde (61%), which crystalized upon
standing.

2,5-dimethoxy-4-methylbenzaldehyde ->
2,5-dimethoxy-4-methyl-beta-nitrostyrene [3]

8.2 gr impure aldehyde was dissolved in 40 ml IPA, followed by addition of 3.4
gr nitromethane and 0.55 gr ethylenediammonium diacetate. After 24h stirring at
room temperature the solid chunk of orange stuff was filtered and washed with a
little cold IPA. After drying, 9.0 gr nitrostyrene was obtained. Reduction of
this nitrostyrene using 8.2 gr LAH gave about 6 gr 2-CD hydrochloride. [4]

This reaction was also succesfully employed using ethyl iodide in the first
step, giving 2C-E.  Yields are comparable, at some points slightly higher.
(FYI:12.8 gr 2.5-dimethoxyethylbenzene was obtained from 10.3 gr
1,4-dimethoxytoluene, 51.5 ml 1.6 M BuLi and 24 ml EtI; which gave 18.1 gr
4-bromo-2,5-dimethoxyethylbenzene from the reaction with NBS. 18.1 gr 2.5dmebr,
53 mL 1.6M BuLI and 5.7 ml dry DMF in 20 ml dry Et2O gave 9.0 gr aldehyde, which
finally resulted in 10.2 gr nitrostyrene.)

Care must be taken that the DCM layer in the bromination step is thoroughly
washed with sodium sulfite, removing all color. If not, a nasty brown
contamination will follow you through the formylation, hindering
crystallization. It does not affect nitrostyrene formation, however. Another
point: 4-bromo-2,5-dimethoxyethylbenzene is a lot more soluble in Et2O than its
methyl counterpart.

And regarding BuLi: 1.6M solutions in hexane can be handled with syringes &
septums.  As long as you flush your environment with N2 or Ar, nothing
spectacularly explosive happens. Drying solvents ghetto style was done by
dumping a lot of NaH in Et2O/THF, letting it stand for a few hours and then
taking the required amount of solvent by syringe. Sure, not as good as refluxing
with benzoquinone & distillling, but a hell of a lot easier :-)

Another bedtime story:

1,4-dimethoxybenzene-> 1-bromo-2,5-dimethoxybenzene. [2]

14.1 gr 1,4-dimethoxybenzene was dissolved in 190 ml ch2cl2, and 18.2 gr nbs was
added. After 36h stirring at room temperature, the mixture was washed with
sodium sulfite, dried over Na2SO4, and the solvent evaporated. In contradiction
with the results of the original authors, there was still an appreciable amount
of 1,4-dimethoxybenzene present, which was removed by filtering the liquid
1-bromo-2,5-dimethoxybenzene through a pasteur pipette with a small amount of
glass wool in it. Final yield: 14.7 gr 1-br-2.5dmb.

Reaction of this bromide in a similar way as described above with BuLi and DMF
gave about 8 gr 2,5-dimethoxybenzaldehyde.

(For those who don't want to use BuLi, it could be useful to try to form the
grignard reagent with Mg, and reacting that with DMF as in [5]. Experiences in
this lab has shown that formation of the grignard reagent of
1-bromo-2,5-dimethoxybenzene is quite difficult to get started.)

Excerpt from [5]:

A solution of 20 mmol N,N, dimethylformamide in Et2O or THF (3oml) is slowly
added to the corresponding freshly prepared grignard reagent (21mmol) in Et2O or
THF (50 ml) at 0'C under nitrogen over a period of 5 minutes. An instant
exothermic reaction takes place with the formation of a sticky white
precipitate. The mixture is then brought to room temperature and stirred for one
hour. Subsequently, the reaction mixture is carefully quenched with 3 N HCl
until the solution becomes acidic. The product is extracted with ether (3x50ml),
the ether layer washed with water (150ml), aqeous sodium hydrogen carbonate
solution  (100ml) and saturated sodium chloride solution (150 ml). After drying
of the ether layer with anhydrous magnesium sulfate, the solvent is evaporated
to provide the carbonyl product. The carbonyl product is further purified by
recristallization or distillation.

Yield for benzaldehyde, from bromobenzene: 88%.

[1] Tetrahedron Asymmetry, 1997, 913
[2] Syn. Comm. 28, 1998, 2087-2095
[3] http://rhodium.lycaeum.org/chemistry/henryrxn.txt
[4] PIHKAL, #23
[5] Synthesis 1984, 228

