Kinetic (Newbee)
07-27-02 19:02
No 337745
      Pyridine carboxaldehyde + nitroethane?  Bookmark   

Due to certain restrictions in my country, I would like to attempt the synthesis of 1-pyridinyl-2-aminopropane (as oppose to amphetamine being 1-phenyl-2-aminopropane). Pyridine carboxaldehydes are available, so I was wondering;
Will pyridine-2 (or -3 or -4)-carboxaldehyde substitute for benzaldehyde in the condensation reaction with nitroethane, to form 1-(2-pyridinyl)-2-nitropropene, instead of the 1-phenyl-2-nitropropene? I was looking at an adaptation of Dreamer's procedure on ../rhodium/chemistry /phenyl-2-nitropropene.html.
Any help will be very gratefully recieved

Yours worriedly,
(Hive Bee)
07-27-02 20:06
No 337764
      Absolutely.  Bookmark   


Also, 3-carboxaldehyde pyridine can be had from the reduction of niacin plus DIBAL (reduction to the primary alcohol) followed by oxidation with PCC (pyridinium chloro chromate).
07-27-02 22:25
No 337800
      oh dear!  Bookmark   

Thankyou for your answer neuromodulater... I had hoped this would be the case, since the pyridine tertiary amine cannot interfere with the reaction in the same way a primary or secondary amine could, and cause for example polymerisation (which happens to amino benzaldehyde).

I must have done something wrong then, as I attempted this reaction this morning. I used 2/5 the quantity Dreamer used, and replaced benzaldehyde with 2-pyridinecarboxaldehyde. It was stirred at reflux at approx 1100C (it didn't boil at 1000C) for 5 hours, but after 2 hours or so, it went from a nice orange colour liquid to a nasty viscous dark oilblush. Can anyone see any obvious places I've gone wrong?

Another attempt, using the same starting materials as above, is underway. This has been adapted from ../rhodium/chemistry /meth.alles.html. Again it is a nice orange colour, and seems to be quite happy as there are two layers like it says in the procedure. This was started yesterday, and will therefore take two weeks from then for any results... I will report back on my results for this, and if anyone has any suggestions for my other synthesis, I will have a go and report back on this toolaugh.
(Hive Bee)
07-28-02 01:56
No 337860
      Use a different pyridine carboxaldehyde.  Bookmark   

Use 3-carboxaldehyde pyridine, not 2.  The 3 can be had from nicotinic acid, the 2 cannot.

If that proves to be problematic, scrap EtNO2 for the new 'Barium Reaction' to hopefully get your pyridinylacetone.
07-28-02 21:20
No 338119
      results already  Bookmark   

Already, contents of the second reaction flask have gone very dark. This is exactly what happened to the first attempt, but the second flask is taking longer as it wasn't being heated. These were both with 2-pyridinecarboxaldehyde as starting material. Tomorrow if possible, I will try using 3-pyridinecarboxaldehyde, with the same conditions as before. I'm wondering why the original reaction failed thoughfrown. Will 3-pyridinecarboxaldehyde have a different effect? Maybe in 2-pyridinecarboxaldehyde the nitrogen is too close to the carbonyl carbon, and interferes with the condensation. I'm clutching at straws here... I'll find out tomorrow.
(Hive Bee)
08-04-02 00:18
No 340766
      What's up with your analog?  Bookmark   

Although I doubt that your desired pyridinyl-analog would be centrally active, your synthetic efforts are interestingly. IIRC, the thienyl-analog has been synthesized and evaluated many years ago (JMC), without pleasant activity. I've synthesized the thienyl-analog of alpha-pyrrolidinopropiophenone, no central activity up to 500mgfrown.
08-04-02 18:24
No 341183
      still not right  Bookmark   

Well the adaptaion of Dreamer's procedure was again tried, this time using pyridine-4-carboxaldehyde etc. This time it was added to 500mL dH2O, and washed with 3x50mL DCM. The DCM was boiled off (and saved!), leaving a dark oil, which still refuses to crystallise, even in the freezer. I may try some of the solutions MaDMAx has been given in his thread Post 340758 (MaDMAx: "Beta-nitrostyrene cleanup (for making PEA)", Chemistry Discourse), as he has a very similar problem. If anyone can think of a solution more specific to my problem, I'd love to hear it!
Whether I can get crystals or not, I am going to try the same procedure with 2-trifluoromethylbenzaldehyde + nitroethane sometime this week... I'll post the results of this (if it's successful) for anyone who's interested.
(Hive Bee)
08-05-02 00:31
No 341360
      Nemo_Tenetur, you wouldn't happened to have any ...  Bookmark   

Nemo_Tenetur, you wouldn't happened to have any experience with alpha-pyrrolidinopropiophenone?

I too was wondering about heterocyclic amphetamine derivatives and am planning to do a literature search on them, but it's on my low-priority list and will take some time. Here is my list:

Molecule: c7 ("NC(C)CC1=CC=CC=N1.NC(C)CC2=CC=CN=C2.NC(C)CC3=CC=NC=C3.NC(C)CC4=NC=CC=N4.NC(C)CC5=CN=CN=C5.NC(C)CC6=NC=NC=C6.NC(C)CC7=NC=CN=C7")

Happiness, health and wealth through chemistry...
(Hive Bee)
08-05-02 11:43
No 341582
      Three years experience ...  Bookmark   

with alpha-pyrrolidinopropiophenone until it was scheduled here in Germany (emergency scheduling followed by regular scheduling, effective date: october 10th, 1998). Then I moved to para-methyl-alpha-pyrrolidinopropiophenone, which was exactly one year later scheduled. One effort to synthesize 1-(thien-2-yl)-2-(pyrrolidin-1-yl)propan-1-one was successful, but no central activity of the target compound up to several hundred mg intranasallyfrown. Thats the reason (and the fact that 1-(thien-2-yl)-2-aminopropane is according to JMC inactive) why I guess that pyridino-amphetamines are probably inactive as CNS agents.

But I have to emphasize this is just my guess. There are always unexpected exceptions... Shulgin brought it to the point "mak'em and tast'em", no further comment necessary!

I personally, however, would start with the more promising ring-trifuoromethylated amphetamine analogs. Good luck, Kineticwink.
(Chief Bee)
08-05-02 12:05
No 341590
      Something to consider  Bookmark   

The nitrogen heterocycle is basic, and can be protonated and all, wouldn't that in some fashion influence the reactions involved here - the base-catalyzed knoevenagel condensation for example?

Also, when purifying the final amphetamine analog, all the impurities as well as the product amine will be basic, and will go right through an acid/base extraction to varying degrees. Vacuum distillation of the freebase is absolutely necessary, as well as recrystallization of the salt made from it. Simple gassing will perhaps not be optimal, as several HCl molecules can add to it, you will probably have to add exactly 1 molar equivalent of conc 37% HCl to a solution of the amine in IPA, followed by crashing out the HCl salt with the addition of ether.

08-05-02 13:49
No 341622
      thinking  Bookmark   

Dr_Heckyll; As you can see, the first three of your amphetamine derivatives are the ones I am trying to synthesise! Do you have any experience/references for these compounds?

Nemo_Tenetur; I'm sure you know almost every amphetamine derivative imaginable is scheduled in the UKfrown. This synthesis is a legitamate way to test whether I can do such a condensation, and the activity of the final compound is not the main concern (although it would be fantastic if it was active!). I'm still waiting for my 2-trifluoromethylbenzaldehyde to arrive...

Rhodium; Yes, I have thought of the problem of the basic nitrogen interfering in the Knoevenagel condensation, but was hoping that because;
a) an aromatic amine is less basic than an aliphatic one (cyclohexylamine in this case), and
b) the tertiary amine in the pyridine ring cannot be deprotonated, therefore cannot react with the aldehyde as such,
it would not interfere in the condensation. Of course something may have gone wrong, because I don't have crystals. However, I may have the correct product, as I don't know of anyone else synthesising 1-(4-pyridinyl)-2-nitropropene, and it's melting point may be well below room temperature.

Also (please forgive my ignorance), what is the structure of alpha-pyrrolidinopropiophenone? Is it just propiophenone with pyrrolidine bound via the nitrogen to the alpha carbon (the same place the nitrogen is bound in all PEA's)?

And finally, can anyone think of a reason why forming pyridine-2-propanone wouldn't work via Barium's new method, in Post 333551 (Barium: "benzaldehydes to phenylacetones", Novel Discourse)? I would love to get this to work somehow!
(Chief Bee)
08-05-02 15:11
No 341639
      Darzen reaction on heteroaromatic substrates  Bookmark   

Kinetic: You are correct in your assumption regarding the structure of alpha-pyrrolidinopropiophenone.

The Darzen condensation of pyridinecarboxaldehyde to form the phenylacetone would work all right in my eyes, if there isn't a general incompability between pyridines and carbanions, but I don't recall reading about any such problem.
(Hive Bee)
08-05-02 21:42
No 341768
      Nemo_Tenetur - I was mainly curious about the ...  Bookmark   

Nemo_Tenetur - I was mainly curious about the effect of alpha-pyrrolidinopropiophenone. How's the high?

Kinetic - sorry, no refs. These are just molecules I "designed" in an idle hour, and one day hope to have the time to check them out via Beilstein. I guess someone made them before...

Btw, Kinetic, to legitimately try the condensation you could use 2-naphthaldehyde, although it's not cheap. 1-Naphthaldehyde is cheaper.

Happiness, health and wealth through chemistry...
(Hive Bee)
08-06-02 15:32
No 342096
      APP high ...  Bookmark somewhat shorter and weaker than plain amphetamine, but generally accepted as a speed substitute. It can always compete with the usual cutted "street quality speed". APP was explored together with diethylpropion/amfepramone, the latter has better therapeutic qualities (less stimulation/more anorexic), the former is more pleasant under the clandestine chemist's view (pleasant kick, desire to repeat the experience). Unfortunately, schedule I in Germanyfrown
(Stoni's sexual toy)
08-06-02 22:09
No 342194
      Diethylpropion is 1-phenyl-2-diethylamino-1-propan...  Bookmark   

Diethylpropion is 1-phenyl-2-diethylamino-1-propanone, right?
Anyone got a synth starting from propiophenone?

I'm not fat just horizontally disproportionate.
(Chief Bee)
08-06-02 22:41
No 342203
      basement diethylpropion  Bookmark   

Use ../rhodium/chemistry /dimethylcathinone.html , substituting dimethylamine for diethylamine.

For propiophenone to alpha-bromopropiophenone, see ../rhodium/chemistry /ppa.html
(Stoni's sexual toy)
08-06-02 23:01
No 342212
      How embarassing. :-o I guess I have to do more ...  Bookmark   

How embarassing. blush
I guess I have to do more reading at your site. Sorry.

I'm not fat just horizontally disproportionate.
(Hive Bee)
08-07-02 06:02
No 342360
      Two more questions, Nemo_Tenetur: how is the dose ...  Bookmark   

Two more questions, Nemo_Tenetur: how is the dose for APP, and is there any tolerance developing? Just in case you was able to enjoy it long enough smile.

Happiness, health and wealth through chemistry...
(Hive Bee)
08-07-02 20:03
No 342568
      Dosage etc.  Bookmark   

An unexperienced bee should start with abt. 50 mg intranasally. After approx. 30 minutes you can estimate the strenght of its effects (depending on body weight etc.) and take some supplements, if desired. Unfortunately, tolerance developed rather quickly. After several consumptions, quantities up to a half gram were used.