Hello All,
I have to say I'm surprised that nobody had anything to say about this proposed synthetic route -- though at least it was given an "excellent" rating (thanks, btw.) Perhaps what is needed is some experimental detail to get people to look into this more closely.
Med. Chem. Res. (1999) 50-60.
Molecule:
{2-(1,3-Dimethyl-5-methylcarbamoyloxy-2,3-dihydro-1H-indol-3-yl)-ethyl}-trimethyl-ammonium methyl sulfonate ("CNC(=O)[OH+]c1ccc3c(c1)[C@]2(C)CC[N+](C)(C)C2N3C>>CNC(=O)Oc1ccc2c(c1)[C@](C)(CCN(C)C)CN2C")
(3S)-3-[2'-(Dimethylamino)ethyl]-1,3-dihydro-1,3-dimethyl-2H-indol-5-yl (10)
Compound 7 (220 mg, 0.53 mmol) [(-)-Physostigmine methiodide] was dissolved in MeOH (5 ml), and NaBH4 (62 mg) was added. The mixture was stirred at rt under N2 overnight. The solvent was evaporated under reduced pressure, the reside then was dissolved in H2O (5 mL), and extracted with CH2Cl2 (5 x 10 ml). After the removal of solvent under reduced pressure, the residue was flash chromatographed (CH2Cl2/MeOH/Et2NH=9/1/0.1) to give 10 (129 mg, 84%)...
Well, it's not a tryptamine in the strictest definition of the term, but it definately has a lot in common with tryptamines structurally. What's important here is the demonstration of the reduction of the quaternary nitrogen, substituted (essentially) by 4 aliphatic alkyl groups. In this instance, the C-N bond being broken does not belong to a methyl group as we are hoping for, but rather a bond in the pyrrolidine ring. The energy released from relieving 5-membered ring strain makes the ring opening far more favorable than that of removing the methyl group (with a hydride moiety as the nucleophile, sterics don't play as significant of a role as in other SN2 reactions.) Again, the point is to demonstrate the efficacy of NaBH4 in reducing quaternary aliphatic amines under facile conditions, which I think it does well.
J. Org. Chem. (1985) 50(25) 5440-5441.
J. Org. Chem. (1978) 43, 2259.
Molecule:
(3-Cyano-bicyclo{2.2.1}hept-5-en-2-yl)-trimethyl-ammonium iodide ("C[N+](C)(C)[C@H]1[C@@H](C#N)[C@@H]2C=C[C@H]1C2>>CN(C)[C@H]1[C@@H](C#N)[C@@H]2C=C[C@H]1C2")
There is no experimental section offered in the '85, though do state that the reaction took place in DMSO, the temperature was kept at 65 ºC, which afforded 90-100% yields. In the '78 article, in which several examples of the removal of methyl groups via NaBH
4 is discussed, the authors indicate that for aliphatic quaternary amines, the initial concentration of starting material they used was 0.4 M, the hydride:amine ratio was 3:1, and the reaction time was 9.0 h.
The '78 article is really worth getting. Not only does it have some useful experimental details, but it also has a good discussion on the mechanism for this reaction (S
N2), and even a study on solvent effect. In the '85 article, we see here an even closer example to what we're hoping for: demethylation of an N,N,N-trimethylated quaternary aliphatic amine, and with excellent-to-quantitative yields!
J. Org. Chem. (1985) 50(20) 3760-3767.
Molecule:
("CC[C@]35CCC[N+]4(CCc1c([nH]c2ccccc12)[C@]34C)C5>>CC[C@]14CCCN(CCc2c(C1)[nH]c3ccccc23)C4")
...To a solution of 6 (X=CH3SO3-; 0.50g, 1.38 mmol) in EtOH (10 mL) was added NaBH4 (0.50g, 13.2 mmol) in small portions. The reacion mixture was stirred at room temperature for 20 min and then refluxed for additional 30 min. The solution was diluted with water (45 mL), and the precipitate was collected by filtration and washed with water and EtOH to afford 10 (0.30g, 81.0%) as a white powder...
The authors are dequaternizing a rigid tryptamine, and in very good yields!
J. Am. Chem. Soc. (2000) 122 10561-10572.
J. Am. Chem. Soc. (1990) 112 8604.
Molecule:
3a,8a-Dimethyl-decahydro-5a,8a,10a-diaza-3a,8a-diazonia-pyrene diiodide ("[H][C@@]14N2CCC[N+]1(C)CCN3CCC[N+](C)(CC2)[C@@]34[H]>>CN1CCCN2CCN(C)CCCN(CC1)CC2")
4,11-Dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4b). Scale-up and optimization of the previously reported prepn.: NaBH4 (4.00 g, 105 mmol) was slowly added in small portions to a stirred solution of 3b monohydrate (5.71 g, 10.9 mmol) in 95% EtOH (200 mL). The reaction mixture was stirred at room temperature for 72 h. Excess NaBH4 was then decomposed by slow additino of 10% aq HCl (50 mL) (final pH ~ 1).Absolute EtOH (400 mL) was added and the mixture was reduced to dryness by rotary evaporation. The white residue was dissolved in H2O (60 mL), the solution was made strongly basic (pH=14) by slow addition of NaOH pellets with cooling, and the basic solution was extracted with benzene (4 x 100 mL). The combined extracts were dried and the solvent was removed to give the crude product, which was kugelrohr-distilled from KOH pellets (0.02 mmHg, air bath temp 70-75 ºC) to yield 2.49 g (9.80 mmol; 90%) of pure 4b as a viscous, colorless liquid...
Heterocycles (1986) 24(6) 1687-1698.
Molecule:
2-Benzyl-1,1-dimethyl-pyrrolidinium iodide ("C[N+]1(C)CCCC1Cc2cccnc2>>CN1CCCC1Cc2cccnc2")
(R,S)-1-Methyl-2-benzylpyrrolidine (12c)
A stirred solution of CH3CN (15 mL) containing 8c (1.0 g, 6.28 mmol) [(R,S)-2-benzylpyrrolidine] was treated with CH3I (1.0 mL) and let stand for 5 days at room temperature. The solution was cncentrated on a rotary evaporator and the residue triturated with hot ethyl acetate. The slightly off-colored hygroscopic quaternary salt was collected and directly dissolved in MeOH (25 mL). The solution was cooled (0-10 ºC), treated with NaBH4 (0.75 g, 19.8 mmol), stirred for 2 h in the cold and then allowed to sit overnight at room temperature. The solution was concentrated and the residue solubilized with dilute HCl. The aqueous phase was basified (50% KOH) and extracted with ether. The dried (Na2SO4) ethereal phase was filtered, concentrated, and bulb-to-bulb distilled [oven temperature 68 ºC (0.025 torr)] to give 12c (0.62 g; 56.3%) as a colorless oil...
In spite of the low yields, I think this one I still find interesting and full of potential. The yields are low for a reason: competing with the desired demethylation reaction is the pyrrolidine ring opening, which is kinetically favorable - but the tryptamines that we're interested in mostly don't have this problem, so this shouldn't be an issue. The part I find most encouraging here is the fact that we have a quaternized arylethylamine being demethylated.
Well, that's all for now. Hopefully this is enough to gain some people's interest in this topic, and hopefully some good work will come out of all the effort I went through here. Unfortunately, I'm not in a position where I can do any practical work with this, so I'm hoping for a group effort to bring this to fruition.
Success,
-anton_berg
