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anton_berg (Stranger) 06-05-02 01:54 No 317662 |
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a novel route to tryptamines (Rated as: excellent) |
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Hello All, Now stop me if you've already heard this one... ![]() I think I've found yet another way of using N,N,N-trimethyltryptamine salts to preparing novel biologically-active compounds. In fact, quaternized tryptamines look like a very desirable starting material for a number of reasons. As it turns out, quaternary amines (trimethylated in particular) make great leaving groups. Allowing quaternary trimethylated amines, which are good electrophiles, to react with secondary amines, which are good nucleophiles, gives tertiary amines, along with trimethylamine and an acid equivalent as byproducts. Suggested reaction example 1: N,N,N-trimethyltryptamine iodide + dipropylamine + (alkali base)-> N,N-dipropyltryptamine (DPT) + trimethylamine + iodide salt, H2O. Suggested reaction example 2: N,N,N-trimethyltryptamine iodide + N-methyl-2-propanamine + (alkali base) -> N-methyl-N-isopropyltryptamine (MIPT) + trimethylamine + (iodide salt, H2O). This route looks like it may have some great advantages over other routes to common dialkylated tryptamines. The reaction is extremely selective, offering only the desired tertiary amine - there is no possibility of secondary amines forming, thus eliminating byproducts that are difficult to separate from the target compound. The starting materials and the final products are all very chemically distinct from each other, making the separation and work-up procedures relatively facile. In addition, the chemist has a choice of any secondary aliphatic amine they wish, include secondary amines with dissimilar alkyl groups (e.g. methyethylamine), making it an extremely efficient route for N,N-diakylated tryptamines, where the two alkyl groups are not the same. By using trimethyltryptamine as a reagent, the chemist can quickly and efficiently synthesize an entire "library" of tryptamine analogs with minimum effort. Moreover, the reaction conditions seem to be quite forgiving as well - often done in protic media, and under easily managed temperatures. For examples and experimental details for the preparation of tertiary amines using quaternized trimethylammonium compounds and secondary amines, please read the following: Bioorg.Med.Chem.Lett. (2001) 11(20), 2735-2740. Chem.Ber. (1980) 113(3), 970-8. Chem.Lett. (1997) 9, 893-894. Eur.J.Med.Chem.--Chim. Ther. (1985) 20 (3), 228-34. J.Med.Chem. (1989) 32(6), 1157-63. J.Org.Chem. (2001) 66(1), 41-52. J.Org.Chem. (1996) 61(10), 3228-9. Organometallics (1985) 4(7), 1275-83. Synlett (1993) 5, 353-4. Tetrahedron Lett. (1992) 33(3), 357-60. Tetrahedron Lett. (1995) 36(40), 7267-70. Tetrahedron (1987) 43(13), 3021-30. Zh.Org.Khim. (1990) 26(3), 631-4. That's all for now. Any comments? Any thoughts about this method? Oh well. I thought it was clever, at least. -anton berg |
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obia (Stranger) 06-06-02 00:05 No 317963 |
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excellent! the next question is do you know of a ... | Bookmark | |||||
excellent! the next question is do you know of a better methylating agent than MeI or Me2SO4? neither is particularily appealing... |
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anton_berg (Stranger) 06-18-02 04:38 No 322610 |
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some experimental details... (Rated as: excellent) |
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obia, What is it that you don't like about methyl iodide and dimethyl sulfate? Any other methylating agent is going to be carcinogenic as well, and undoubtedly more expensive and exotic. Use accepted GLP in a proper workspace, and you should be alright. Now, back to nucleophilic cleavage. Molecule: diptrxn ("C[N+](C)(C)CCc1c[nH]c2ccccc12>>C Now, since my last big posting seemed to be received favorably, I will try something similar with this subject. Hopefully, the accessibility of this information will encourage some discussions and some experimentation. This reaction scheme is a little less certain, in my opinion, and I would appreciate people’s help in refining the details. J. Org. Chem., (1996), 61(10), 3228-3229. Molecule: RXN1 (" Cc1noc(CC[N+](C)(C)C)n1>>Cc1noc(CC yield: 85% Molecule: RXN2 (" Cc1noc(CC[N+](C)(C)C)n1>>Cc2noc(CC yield: 97% Molecule: RXN3 (" Cc1noc(CC[N+](C)(C)C)n1>>Cc1noc(CC yield: 61% DIEA, diisopropylethylamine, Hünig’s Base: Molecule: DIEA ("CCN(C(C)C)C(C)C") DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene Molecule: DBU ("C2CCC1=NCCCN1CC2")
J. Chem. Soc. Chem. Comm., (1993), 1046-1047. J. Chem. Soc., Dalton, (2000), 9, 1403-1409. J. Chem. Soc., Dalton, (2000), 9, 1411-1417. J. Chem. Soc., Dalton, (2000), 11, 1805-1812. Molecule: ferrocene1 ("C[N+](C)(C)C[Fc]>>[Fc]CN1CCN([Fc Where Fc = ferrocene complex This one is difficult, since SMILES can't handle this sort of compound (metallocences.) I will do my best. The reason these four are grouped together is that they all deal with the synthesis of tertiary aminomethylene-substituted ferrocenes whole group of articles use the same technique of nucleophilic cleavage of 1-trimethylammoniumferrocenes with secondary amines.
J. Heterocyclic Chem., (1997), 34, 461-463. Org. Prep. Proc. Int., (1995), 27, 271. Neuropharmacol. (1993), 32, 1249. Molecule: quinucrxn1 ("CCCCC[N+]12CCC(CC1)CC2>> CCCCCN2CCC(CCOc1ccc(Cl)c(Cl)c1)CC2") Molecule: quinucrxn2 ("c3ccc(C[N+]12CCC(CC1)CC2)cc3>>c4 I really enjoy sharing quinuclidinyl chemistry; something about that symetry is just so cool… So, what do we got here? Nucleophilic additions to quinuclidinium salts. Most of the nucleophiles they chose were phenols, but there were a couple amines, and dialkylamines are fine nucleophiles in their own right.
J. Org. Chem., (1992), 57(25), 6966-9. Tetrahedron Lett., (2000), 41(33), 6527-6530. Molecule: binapthyl1 ("C[N+]5(C)Cc2ccc1ccccc1c2c3c(ccc4ccccc3 This one is fun for several reasons. Of course, it’s an example of nucleophilic cleavage, but on top of that, they use ephedrine (among others) as the nucleophilic amine to do it. Note: sodium azide is to be replaced with the freebase amine as the nucleophile.
J. Med. Chem., (1989), 32, 1157-1163. Molecule: diazepine1 ("C[N+](C)(C)CC(c1ccccc1)c5nnc4CN=C(c2cc where R= -, O, CH3N, PhN Molecule: diazepine2 ("C[N+](C)(C)CC(c1ccccc1)c5nnc4CN=C(c2cc There are too many variations of this reaction in the article to list here. Yields aren’t especially great (~51%), but not all that bad either.
Bioorg. Med. Chem. Lett., (2001), 11, 2735-2740. Molecule: opioid1 ("[H][C@@]12CCCC[C@@]14CCN[C@@H]2Cc3ccc( is allowed to react with Molecule: michael acceptor ("C[N+](C)(C)CCC(=O)c1cccs1") to yield this Molecule: final opioid ("[H][C@@]13CCCC[C@@]15CCN(CCC(=O)c2cccs 2nd attempt: Molecule: opioid1 ("[H][C@@]12CCCC[C@@]14CCN[C@@H]2Cc3ccc( This one is very interesting looking, but unfortunately the authors did not offer complete experimental details. What they do say, however, is certainly promising: norlevorphanol + quaternary amine, with Na2CO3, in DMF, at rt, -- 82% yields. I think the most important details missing are concentrations of reagents and the reaction time, but I'd imagine it would probobly be similar to the other examples listed here. Well that’s all for now. Wow, that took a long time to type! I hope people appreciate this. |
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