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                              New 2C-B synth idea?
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Rhodium:

1,4-diMeO-benzene + chloroacetyl chloride => 2,5-di-MeO-beta-chloro-acetophenone

a) Wolff-Kishner or Clemmensen on the ketone
b) Swap the Cl with NaN3 in DMSO
c) Reduce the azide to the amine
d) Monobrominate the phenyl
e) Make the freebase, distill it and precipitate 2C-B HCl from ether

Maybe step b should be carried out first, and step a and c could be carried
out simultaneously?

(Of course the alpha halo acid halide can be bromo instead of chloro, as
well as propionyl instead of acetyl if one wish to obtain DOB.)

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Osmium:

I think the problem here is the demethylation of the methoxies by the lewis
catalyst needed in this reaction, making it necessary to remethylate the formed
phenol.

Tar formation by reaction of this phenolic by-product with the omega-chlorine is
another possible problem. For the same reason Clemmensen reduction of the
acetophenone is no option (phenol formation). Wolff-Kishner reduction will
probably producethe omega-hydrazine derivative, meaning one should do the azide
first. The Friedel-Crafts-alkylation (reaction of the "wrong end of the acid
chloride) is reversible, so probably no problem here. Do you have a ref. for
this kind of Friedel-Crafts acylation?

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Fudd:

Well, here's a few ideas on that.

1) Starting from hydroquinone is cheaper and less suspicious than 1,4-dimethoxy
   benzene, so while adding on a methylation step will be required, it isn't
   such a bad thing.

2) Would the Wolff-Kischner be able to reduce an azide? I mean, its been a long
   time since I took basic organic chemistry, and I honestly don't remember half
   the reactions they made us learn. If I remember right, azides are pretty
   weak, but what do I know?

3) Where are you going to purchase your chloroacetylchloride? Is there a way to
   make this? Obviously bromoacetylbromide would work better, but where would
   you get that either?

4) I like the acetophenone detail of this synthesis. Making use of that adjacent
   carbonyl to deactivate the benzene ring after substitution is a nice touch.
   However, how will the Lewis acid interact with the carbonyl? Won't that
   impede the mechanism?

5) How stable is sodium azide? I don't know much about it, but it sounds
   dangerous.

6) Also, hydrazine is a little dangerous too. Where would you get it, and how
   would you handle it without killing yourself?

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David:

You can buy hydrazine sulfate. It's not illegal. You can make it a number of
different ways also.

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Rhodium:

Osmium: Then make the diester of chloroacetic acid with hydroquinone, and
        subject it to friedel-crafts rxn conditions. No matter how you do it,
        you'll end up with the chloroacetophenone. Reduce this Wolff-Kischner
        style to give 2,5-dihydroxy-phenethylchloride. Now methylate the phenol
        groups with CH3I or Me2SO4 (hopefully, the methyls will add faster than
        everything will polymerize), followed by a delepine reaction on the
        terminal chlorine to give 2C-H (thanks Drone!).

OR - Chloroacetylate 1,4-dibromobenzene, reduce the ketone, delepine of the
     terminal chlorine, and finally methanolysis of the 2,5-dibromophenethyl-
     amine with NaOMe/EtOAc/CuBr.

Fudd: Sodium azide is relatively stable, the only thing it doesn't like is
      acids. the carbonyl will indeed interact with the lewis acid, forming a
      complex, so you'll need at least a full equivalent of it. Chloroacetyl
      chloride can be made by just chlorinating acetic acid if you have no
      other source for it.

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Fan of shulgin:

Just wanted to point out that hydrazine hydrate is seriously fucking nasty
stuff. Its just about as carcinogenic as you can get and you have to be really
careful when using it. Fume hood! Not just a room with a draught! Apart from
that, it aint illegal anywhere I know of!

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Rhodium:

Nasty stuff: HCN, HCl(g), BBr3, Cl2SO4 etc, anything lachrymatory or instantane-
ously toxic. Theoretically nasty stuff: Hydrazine, mercury compounds, benz[a]-
pyrene etc. Things that have no acute noxiousness or toxicity, but gives you
cancer or chronic poisoning.

I suffer from the inability to realize that I should sniff from a hydrazine
bottle just as little as I would sniff from a bottle of chlorosulfonic acid, or
that I should wash my hands as thoroughly after handling 100mg HgCl2, as after
spilling 10 ml of ethylmercaptane on them.

Well, I probably notice when I start to grow arms all over my back...

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Rhodium:

Oh, I discovered another new method when reading some old patents...

2,5-dimetoxybenzaldehyde is reacted with methyl chloroacetate and sodium
methoxide in methanol to form sodium alpha,beta-epoxy 1-(2,5-dimethoxyphenyl)-
propionate (Darzen condensation). This is decarboxylated with potassium
phosphate to yield 2,5-dimethoxyphenylacetaldehyde, which is condensed with
ammonia and reduced with NaBH4 to yield 2C-H.

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Assholium:

> 1,4-diMeO-benzene + chloroacetyl chloride => 2,5-di-MeO-beta-chloro-acetophenone

This is stupid idea. Use chloroacetic acid and PPA (oh, well, polyphosphoric
acid) as FC catalyst. See PIHKAL for common procedure. Acylation with
chloroacetic acid described in OS'es in synth of adrenalone.

> a) Wolff-Kishner or Clemmensen on the ketone

Why do you like this kind of chemical masturbation? Exchange terminal chlorine
to amine group with urotropine (Delepine rxn), and then reduce aminoketone to
amine with Rh/C* and borohydride Na. Or this too simply for you?

If chloroacetic acid unavailable, use acetic acid instead, - react 1,4-diMeO-
benzene with AcOH in presence polyphosphoric acid (always got 85-90 yields), and
make nitrosation of this acetophenone, and then reduce isonitrosoacetophenone
directly to amine (using Os' lovely 4 bar catalytic hydrogenation or (my
favorite) NaBH4 and 5%Pd-5%Rh/C*).

Needless to say - you can use propionic acid instead of AcOH - and obtain
2,5-diMeO-phenyl-isopropylamine.

> b) Swap the Cl with NaN3 in DMSO
> c) Reduce the azide to the amine
> d) Monobrominate the phenyl

Monobrominate, you say. What about thiocyanate? - just add in soln 1.2 eqv of
KSCN and then dropping bromine. This will be very fun product. BTW, the
rodano-derivative can be reduced to Shulgin's dream - bare thio group :)

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Rhodium:

What are you talking about?

The reason I wanted to use chloroacetylchloride was that otherwise I have
nothing to stick my azide ion or hexaiminium salt to, right?

And I DON'T think benzylic ketones will fall of especially easy, or anyone would
be using meth instead of cat...

And nitrosation? Would you convert the ketone to an oxime, which you later will
recuce? Sorry, but I do not like alpha-phenethylamines.

And using propionic acid would look nice, until you discover that there is NO
way you could add an amine at the beta carbon.

As for 4-substituents, what about cyano, methylenemethoxy (-CH2OCH3),
trifluoromethyl, cyklopropoxy, cyclobutoxy, or why not Hg(I) ;)

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Assholium:

> And nitrosation? Would you convert the ketone to an oxime, which you later
> will recuce? Sorry, but I do not like alpha-phenethylamines.

Wondered, but I'm too :))

> And using propionic acid would look nice, until you discover that
> there is NO way you could add an amine at the beta carbon.

Beautiful words, Rhod! Possibly you mean alpha-carbon, not beta? If you like
beta (end of side chain for propiophenone) - Mannich condensation do the work.
But about alpha. For you information:

Benzylketones have acid carbon in alpha position, and nitrosation (treatment
with NaNO2/HCl(aq)) always goes on alpha-carbon, and f.e. for propiophenone we
will have alpha-oximinopropiophenone (troubles? this is Ph-C(=O)-C(=NOH)-CH3 :)
This is well-known widely-implemented bulk plant process, f.e. for preparation
lovely PPA (DL-phenylpropanolamine, erythro-isomer in this case, mp 103-105C).

Well. Refs:

nitrosation methoxy, dimethoxy, hydroxy-propiophenones:

Org. Synth. coll vol 2, 363 (1943)
Ber, 30, 1515 (1897)
Ber, 22, 526 (1889)
JACS, 51, 2262 (1928)

Result - alpha-oximino-propiophenones with yields 65-70%.
         Can be readily reduced to phenyl-isopropylamines.

Nitrosation 2,5-di-ethoxy-propiophenone:

JACS, 70, 1084 (1948).

PS. And I'm serious about thiocyano in 4-position. Very fun compound.
    But frankly speaking, trifluoroethyl better :))

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Fudd:

Assholium,

That's some wacky chemistry you got there; if it's 1/2 as slick as it looks,
you're my hero. Do you have journal articles for all of this?

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Rhodium:

Assholium: Oh, I thought your nitrosation reaction was something you did ON the
carbonyl...

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Osmium:

Do the nitrosation of the propiophenone with organic nitrite ester (isoamyl-
nitrite) as in J. Med. Chem. 1991, 34, 1662-1668 (97% yield in that step, they
used an indanone, not propiophenone). Reduction of this intermediate to the
amphetamine with Pd/C at 60psi/4 bar 77% after recrystallization.

Tell us more about thiocyanate, assholium. Dosage, duration, all the juicy
details.

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JOC 1987, 52, 2945-2947.
                            
(E)-1-(2,5-Dimethoxyphenyl)-2-nitroethene

A mixture of 2,5-dimethoxybenzaldehyde (1.97 g, 11.8 mmol) and nitromethane 
(0.72 g, 11.8 mmol) in methanol (200 mL) was stirred at room temperature until 
the solids dissolved. The solution was cooled to 0 deg C and a 10.5 M NaOH 
solution (2 mL) was added dropwise over 20 min. The alkaline solution was added 
slowly to a 4% HCl solution (200 mL) maintained at 60 deg C. The pale yellow 
amorphous solid that formed was filtered and washed with water (200 mL). The 
crude product was recrystallized from absolute ethanol to give yellow needles 
(2.11 g, 85%)

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