Preparation of 2C-CN

[yellium]

Looks like somebody needed an excuse to waste a lot of 2C-B  

J. Med. Chem. 27(4), 513-520 (1984)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/2c-c.2c-cn.synthesis.pdf)

2,5-dimethoxy-4-bromophenyl-2-(phthalimidoamino)-ethane (11d)

To a solution of 11c (2CB freebase) (7.24 g, 27.8 mmol) and phthalic
anhydride (4.5 g, 30 mmol) in 100 mL of DMF (disilled) was added molecular
sieves. The reaction mixture was heated under reflux overnight and, after
cooling, was suction filtered to remove the molecular sieves. Treatement
with CH2Cl2 resulted in the formation of yellow needles. Recrystallization
from EtOH provided 7.57 g (69%) of 11d: mp 141.5-142'C.

2,5-dimethoxy-4-cyanophenyl-2-(phthalimidoamino)-ethane (12d)

Compound 11d (7.57 g, 19.4 mmol) and cuprous cyanide (2.0 g , 22.3 mmol) in
150 mL of DMF were heated under reflux for 5 h. The mixture was poured into
a solution containing hydrated ferric chloride (6g), 1.48 mL of concentrated
HCl, and 9 mL of water. The solution was maintained at a temperature of
60-70'C for 20 min. to decompose the complex and then extracted with
CH2CL2. The orgranic phase was washed with diluted aqeuous HCl (100mL),
dried (MgSO4) and evaporated to give a white solid. Recrystallization from
EtOH provided 5.96 g (91%) of 12d as white needles. mp 194-195'C.

1-(2,5-dimethoxy-4-cyanophenyl)-2-aminoethane (12c)
 

Phthalimide 12d (9.2 g, 27.38 mmol) and hydrazine (2.2 mL, 68.55 mmol, 98%)
in 50 mL of anhydrous EtOH were heated under reflux for 15 min. After the
mixture was cooled, the phthalazinedione was filtered off, and the filtrate
was evaporated to give a solid residue. The solid was dissolved in H2O and
extracted with CHCl3. The organic extract was washed with aqeous Na2CO3
(10%, 3x100mL), dried (Na2SO4) and evoparated to give 3.6 g (64%) of 12c.
The HCl salt (precipitated from ether) was recrystallized from EtOH, mp
220-222'C.

[Greensnake]

>Looks like somebody needed an excuse to waste a lot of 2C-B

Not necessarily waste, maybe they even improved it... a little.    Are human bioassay data available?

[yellium]

In the article, the authors present a study of neurotoxic effects of 6-OHDA analogues (where 6-OHDA is 2,4,5-trihydroxyphenyl-2-aminoethane, or 6-hydroxydopamine).
Basically, they are looking at quinone derivatives of phenethylamines. Some interesting tidbits:

1) Using cyclic voltommagrammy, they show that a quinone can cyclize to a 6-substituted-5-hydroxyindole (yum!). Dunno if  you could use this for synthetic purposes.


They try to assert neurotoxic properties by giving lab rats an IV shot of the quinone they want to study. Neurotoxicity is measured by measuring the percentage inhibition of tritiated norepinephrine (NE) uptake by heart atria; This technique is based on the observation that once noradrenergic neurons are destroyed, they lose their ability to take up NE.

2) C4-methoxy and C4-methyl derivatives of 6-OHDA also show some neurotoxic properties (4-5 times less than 6-OHDA) upon IV adminstration to rats.

3) C4-chloro, C4-bromo, C4-cyano, C4-nitro derivatives show no neurotoxic effects.


Is there any evidence that phenethylamines are reduced to quinones?

[Rhodium]

Thank you! I uploaded it here:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/2c-cn.html

[yellium]

In that same article they also prepare 2C-COOH and 2C-C.
I've included them here, and also included the 1H NMR spectrum describtion for 2C-C/

Preparation of 2C-COOH:


1-(2,5-dimethoxy-4-carboxyphenyl)-2-aminoethane (13c)

To a solution of 1-(2,5-dimethoxy-4-cyanophenyl)-2-aminoethane (12c; 12 g,
58 mmol) in 50 mL of EtOH was added 100 mL of 25% aqeous NaOH. The
resulting solution was held under reflux for 5h. After cooling, the
mixtures was treated with Dowex 50x8 cationic resin until the pH reached
1. The resin was collected and washed with water, and then the product was
eluted with concentrated NaOH. The filtrate was concentrated in vacuo to a
solid residue, which was triturated with acetone and crystallized from
EtOH to yield 2.3 g (17%) of 1-(2,5-dimethoxy-4-carboxyphenyl)-2-aminoethane.
mp 135-137c.




Preparation of 2C-C:

2,5-dimethoxy-4-chlorophenyl-2-(phthalimidoamino)-ethane (14d)

Compound 11d (2C-B freebase; 14.94 g, 38.3 mmol) and cuprous chloride were
allowed to react in a way similar to that described for the synthesis of
12d. Recrystallization from hot EtOH provided 12.18g (92%) of 14d as yellow
needles, mp. 138-140'C.


1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (14c)

Phthalimide 14d (12.18 g, 35 mmol) and hydrazine (2.86 mL, 87.5 mmol, 98%)
in 60 mL of anhydrous EtOH were heated under reflux for 15 min. After the
mixture was cooled, the phthalazinedione was filtered off, and the filtrate
was evaporated to give a solid residue. The solid was dissolved in H2O and
extracted with CHCl3. The organic extract was washed with aqeous Na2CO3
(10%, 3x100mL), dried (Na2SO4) and evaporated. Bulb to bulb distillation
[oven temperature 145-155'C (0.05 mm Hg)] afforded 5.16 g (67.8%) of 14c as
a clear, colorless oil.

1H NMR (80 MHz, CDCL3):
6.87 (s, 1H, Ar-H),
6.76 (s, 1H, Ar-H),
3.84 (s, 3H, OCH3),
3.76 (s, 3H, OCH3),
2.77 (m, 4H, CH2),
1.37 (br, s exchanges with D2O, 2H, NH2).

The HCl salt (precipitated from ether) was crystallized from EtOH, mp
220-221'C.

[Rhodium]

Good. I believe this is one of the two procedures quoted by Shulgin in Pihkal for the synthesis of 2C-C, as he in the commentary section mentions that 2C-CN and 2C-COOH is not tested in man.

However, I believe that there are many more superior methods available for synthesizing 2C-C today, so I won't add this to the document at my page.