Synthetic overviewConsider the tropinone molecule.
When the ketone reacts with aniline, an imine is formed. This tropananil compound can be reduced to give an anilino-tropane, which can be acylated with propionic anhydride to give a N-propananilido-tropane.
StereochemistryDon't worry: I will follow an intuitive approach on this in order to explain the rather complicated nomenclature.
When you look at the tropinone molecule, you see that there are in fact 2 ring systems. A 5 membered N-methyl pyrrolidine ring which is "fused" to a 6 membered N-methyl 4-piperidone ring. The 6 membered ring is like cyclohexane, in its chair conformation: at one end the N-CH
3 points upwards and at the other end the C=O points downwards. Concentrate now on the 6 membered ring. When the tropananil is reduced, 2 isomeres can be formed. The compound where the -NH-Ph points downwards is called 3
alpha-anilino-1
alphaH,5
alphaH-tropane
(1). And the product where the -NH-Ph points upwards is called 3
beta-anilino-1
alphaH,5
alphaH-tropane
(3).
Acylation of
(1) provides 3
alpha-(N-propananilido)-1
alphaH,5
alphaH-tropane
(2). And - guess what - when
(3) reacts with propionic anhydride, 3
beta-(N-propananilido)-1
alphaH,5
alphaH-tropane
(4) is obtained.
What the hell is the purpose of all this?The attentive reader will see a resemblence with fentanyl. Focus again on the 6 membered ring: at one end there is a N-methyl group instead of a N-phenethyl group. At the other end, there is the (for the fentanyl family of compounds caracteristic) N-propananilido group. There is no single hair on my head that doubts that these compounds will be powerfull narcotics (although not as powerfull as fentanyl). These compounds have like a combination of the meperidine, fentanyl and cocaine structural features.
SynthesisThe
alpha-compound:
(1)A solution of 30 g (0.215 mole) of tropinone and 40 g (0.52 mole) of aniline in 250 ml of toluene was refluxed with stirring over 90 g of 4A molecular sieves for 24 hours. The solution was cooled, filtered and concentrated in vacuo yielding a thick dark oil (the tropananil). A solution of tropananil in 100 ml of absolute EtOH was treated with 0.8 g of PtO
2 and the mixture was hydrogenated at 3 atm. until the calculated amount of hydrogen was consumed. The mixture was filtered and concentrated in vacuo and the resulting oil was distilled (132 - 141 °C / 0.6 mm Hg) to provide 14.4 g (31 %) of
(1). The distilled oil solidified upon standing and rectrystallized from petroleum ether, m.p.: 68 - 71 °C
This is an isomerically pure product.
(2)A solution of 1 g (0.0046 mole) of
(1) in 13 ml of propionic anhydride was refluxed for 24 hours. The reaction was cooled, diluted with 200 ml of ether and threated with 10 % NaOH for 15 minutes. The ether layer was separated, dried over MgSO
4, concentrated in vacuo and the residual oil distilled (170 - 175 °C / 0.10 mm Hg) providing 0.97 g (77 %) of
(2).
The HCl salt of
(2) is made from an EtOH -Et
2O mixture, m.p.: 196 - 197 °C.
The
beta-compound:
(3)A solution of tropananil, prepared as described above from 9.9 g (0.071 mole) tropinone and 18.0 g (0.194 mole) of aniline, was dissolved in 100 ml of absolute EtOH and 6.6 g (0.28 g-atom) of Na pieces were added over a 10 minute period. The reaction was then refluxed for 3.5 hours. The reaction was cooled and poured into 100 ml of ice water and extracted with 2 x 100 ml portions of ether. The etheral solution was dried over MgSO
4, concentrated in vacuo and the residual oil distilled (130 - 135 °C / 1 mm Hg). The distillate solidified upon standing yielding 3.2 g (21 %) of a mixture of isomers. Glc showed a 70:30 mixture of the
beta-isomer and the
alpha-isomer. Recrystallization of the isomer mixture from petroleum ether yielded 1.8 g (12 %) of pure
(3), m.p.: 105 - 107 °C
(4)Treatment of 1 g (0.0046 mole) of
(3) with 13 ml of propionic anhydride as described above provided 0.83 g (66
%) of
(4) (b.p.: 220 - 222 °C / 0.5 mm Hg)
The HCl salt of
(4) is made from an EtOH -Et
2O mixture, m.p.: 172 - 173 °C.
Ref.: J. Heterocyclic Chem. (1977) vol 14 p 599
It's a shame - although interesting - that the article is especially concerned with NMR analysis. Hence the desire to prepare isomerically pure compounds. They 'd better give the results of the pharmacological evaluation of this compound.
Synthetic improvements for bees* The acylation conditions they use are really a joke: propionic anhydride as a solvent
. Are those dudes nuts?
They 'd better use an equimolar amount (or a slight excess) of propionyl chloride and do the reaction in chloroform - like I said in
Post 342512 (missing)
(Cyrax: "If propionic anhydride is not reactive enough to ...", General Discourse). Another advantage of this approach is that the HCl salt will be generated in situ, since the N-CH
3 captures the during the reaction liberated HCl.
* The yields of the imine reduction would be considerably better if you use a procedure à la Labtop. Throw a 4A molecular sieves in the mixture of tropinone and aniline, so that the sieves absorb the H
2O that is liberated during the imine formation. And then add NaBH
4 to reduce the tropananil. I guess the reaction shall not be stereoselective, but who cares. This would be a one pot reaction.
Cfr.:
https://www.thevespiary.org/rhodium/Rhodium/chemistry/meth-nabh4.html
* A synthesis of tropinone can be formed at:
https://www.thevespiary.org/rhodium/Rhodium/pdf/2-carbomethoxytropinone.pdf
The original procedure used by Robinson is described in JACS (1917) vol 111 p 762 - 768.
Dreaming your narcotic dreams.
