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                      2CB for the LAH impaired - by Beaker
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The following is a synthesis of 2CB from 2,5-dimethoxybenzaldehyde that does not
require the use of the slightly hazardous and/or difficult to obtain reagents
normally associated with its synthesis, notably LAH, pressurized H2, and Br2. No
doubt some clandestine chemists have been discouraged from attempting the
synthesis of what is, IMHO, a pretty cool substance by the nature of these
reagents and the lack of a clearly written procedure for an alternate route that
does not use them. However, alternate routes do exist, and one of them is
detailed below. Note that this route does require one additional step to acheive
the nitrostrene reduction than with the use of H2 or LAH, but that the yield is
actually substantially higher than what others have reported with those reducing
systems. Also, the bromination procedure is somewhat unrefined at present and
does not result in the greatest of yields or the easiest of workups, so feel
free to use the classical procedure if you want to make or buy your own bromine.
As a final note, although this route will happily accomodate batch sizes of ~50g
in 2L glassware, it does not scale anywhere near as well as catalytic
hydrogenation, so if you're trying to go huge, it's probably not for you.

Step 1

Condensation of 2,5-dimethoxybenzaldehyde with nitromethane

In a 500mL RBF equipped with a relfux condensor and a stir bar, place 100g
2,5-dimethoxybenzaldehyde, 15g ammonium acetate, and 250mL of nitromethane. Heat
to a gentle reflux while magnetically stirring. Maintain reflux for ~45min, by
which time the color of the solution should progress from clear/yellow to a deep
reddish-black. Remove heat and carefully pour the hot rxn mixture into 1L of
ice-cold 70% IPA. Allow the IPA/rxn mixture to stand for a while. You should now
have a flask full of orange solids floating in red/black mother liquor.
Vacuum-filter the solids and wash them with additional portions of ice-cold 70%
IPA until the filtrate is no longer reddish. Thoroughly dry the collected orange
solids by pulling air through the filter for a while and then under vaccum. It
is very important that the nitrostyrene be completely dry before proceding to
the next step.

Yield - 106.1g (84%) of 2,5-dimethoxynitrostyrene

Purity - Single spot by TLC, NMR is clean


Step 2

Sodium borohydride reduction of 2,5-dimethoxynitrostyrene

Into a dry 2L RBF flask equipped with a stir bar was added 400mL of anhydrous
ethanol(If you can't get anhydrous ethanol, use anhydrous IPA. DO NOT USE
METHANOL!!!). The rxn was cooled to 0C in an ice/water bath and 36.2g of sodium
borohydride was added(slight H2 evolution). A pressure-equalized addition funnel
was charged with a pre-made saturated solution of 50g 2,5-dimethoxynitrostyrene
in THF(about 600mL) and attached to the flask. A piece of tubing was attached to
the top of the addition funnel and run outside to vent the hydrogen that is will
evolve during the course of the reaction. While maintaining the ice/water bath,
slowly(reaction is exothermic, so go slowly) all of the bright yellow
nitrostyrene solution(refill the addition funnel if necessary) was added to the
sodium borohydride solution over the course of ~90 min (Note: gas will evolve
over the course of the addition. It is H2. Be careful). After the addition is
complete, the rxn was allowed to stir for an additional 10 min and then poured
into a 4L erlenmeyer containing 1L of H2O and a 3" stir bar (H2 evolution).
While stirring, 250mL GAA (Heavy H2 evolution) was carefully added (one could
use 400 mL 31.45% HCl). The quenched reaction mixture was divided into three
portions. In a 2L sep funnel, each portion was combined with 500mL Et2O(or
toluene) and 500mL brine. The funnel was shaken and the aqueous(bottom) layer
was discarded. The organics were washed with 3 additional 500mL portions of
brine. This was repeated with the other two portions. The organics were
combined, dried over MgSO4, filtered and the solvent evaporated to give a clear
yellow oil.

Yield - 47.0g of crude 2,5-dimethoxynitroethane

Purity - Two spots by TLC. NMR analysis indicates a 50:1 molar ratio of the 
desired product to dimeric impurity (this is the only impurity present). 
Adjusted yield of 2,5-dimethoxynitroethane is 45.2g (89.5%).

Step 3

Catalytic Transfer Hydrogenation of Crude 2,5-dimethoxynitroethane

The crude product of the previous step was dissolved in 400mL MeOH and placed in
a 1L RBF equipped with a stir bar. In a separate beaker away from all
combustible materials, 1g of 10% Pd/C was carefully wetted down with MeOH and
the resulting slurry transferred to the rxn flask. To the rxn flask was added
62g ammonium formate. The flask was equipped with a reflux condensor, a piece of
tubing was attached to the top of the condensor, and the end of the tubing was
submenged in a container of water (this works to exclude O2 from the rxn while
allowing the evolving CO2 to escape). The rxn was gently refluxed for 24 hr.(CO2
evolution), cooled, filtered through celite to remove the Pd/C, and the solvent
evaporated. The residue was taken up in 150 mL of Et2O (or toluene) and 300 mL
of H2O and the pH adjusted to >12 with 20% NaOH. The mixture was transfered to a
sep funnel, shaken, and separated. The aqueous layer was extracted with 2 x 100
mL portions of Et2O (or toluene). The combined organics were dried over MgSO4,
filtered, and gassed with HCl (2CH x HCl is partially soluble in DCM, so don't
gas in that solvent). The resulting white crystalline solids were filtered,
washed with Et2O, and allowed to air dry to give 2CH Hydrochloride.

Yield - 43.8g (94%) of 2CH Hydrochloride

Purity - Single spot by TLC. NMR is clean.


Step 4

Bromination of 2CH Freebase

The 2CH x HCl was dissolved in a 300 mL H20. The pH was adjusted to >12 with 20%
NaOH and the aqueous layer was extracted with 4 x 100 mL DCM. The DCM was
evaporated to give 2CH freebase, which was dissolved in 500 mL of 3:1 AcOH/H2O.
The rxn was cooled to 0C in an ice/water bath. 37.3g of 48% aq. HBr was added,
followed immediately by 23.8g of 30% H2O2. The rxn was stirred for 6 hr,
allowing the ice bath to melt. The majority of the AcOH was removed under vacuum
and the nasty reddish-black rxn mixture was partitioned between 1L H20 and 500
mL EtOAc(EtOAc was found to be much better for dissolving the impurities in this
rxn than Et2O or toluene. This is messy at first, but everything should go into
solution after much agitation). The layers were separated and the aqueous
extracted with an additional 500 mL EtOAc. The aqueous was basified to pH >12
with 20% NaOH and extracted with 3 x 200 mL portions of Et2O. The combined
organics were washed with 400 mL brine, dried over MgSO4, filtered and gassed
with HCl. The resulting tan crystalline solids were filtered and recrystalized
from boiling 1:1 IPA/Toluene to give pure 2CB x HCl as a white crystaline solid.

Yield - 34.0g (57%) of 2CB Hydrochloride

Purity - Single spot by TLC. NMR is clean.


I have references for the two reduction steps and the bromination, but can't
seem to find them. If someone asks really nicely I might be persuaded to find
and post them.

Also, before some jackass reads this procedure and asks me why 4 eq.of sodium
borohydride is used for the reduction, here is a interesting little table for
your reading pleasure.

(Eq. NaBH4) -> Molar ratio of 2,5-dimethoxynitroethane to dimer
(2.5) -> 6.25 : 1
(3.5) -> 44 : 1
(4.0) -> 50 : 1

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Sunlight:

After several failures, we finally got an interesting success using Beaker's 2CH 
synth. We post it due me and others had problems with it. The rxn was carried out
exactly as Beaker posted, no problems, everything goes fine. We made the sulfate 
salt instead of the hydrochloride by adding a 1:10 H2SO4:IPA v/v to the toluene 
extracts until the pH was slightly acidic. Yield was 65% from the nitrostyrene, 
not the >80% of Beaker, but anyway really interesting. By the way, we have never 
got a 84% of the nitro in step one, only 65-75% and reacting 2.5 hours, not 45 
minutes, at 45 minutes the rxn seemed to be incomplete.

The reason of the success is the catalyst, all attempts with homemade catalyst 
gave miniscule yields, so we decided to buy it from Aldrich, 10% Pd/C on 
activated carbon, and now rxn finally works. In the reduction with Pd/C and 
ammonium formate, solid crystals are formed in the condenser (we guess they are 
ammonium carbonate) and they can clog the condenser. We had a little hazard in a 
previous test, so you need to control it and remove the crystals. We doubled the 
catalyst in order to finish rxn in 12 hours instead of 24, but rxn finish in 
about 5 hours, but we let it 12 hours. Other thing, the catalyst was washed with 
methanol, and when it was drying, it catched fire, next time we'll make a final 
wash with water before letting it dry, so we could reuse it.

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