06-05-02 01:54
No 317662
      a novel route to tryptamines
(Rated as: excellent)

Hello All,

Now stop me if you've already heard this one... wink

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
06-06-02 00:05
No 317963
      excellent! the next question is do you know of a ...  Bookmark   

the next question is do you know of a better methylating agent than MeI or Me2SO4? neither is particularily appealing...
06-18-02 04:38
No 322610
      some experimental details...
(Rated as: excellent)


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>>CC(C)N(CCc1c[nH]c2ccccc12)C(C)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(CCN(C)C)n1")

yield: 85%

Molecule: RXN2 (" Cc1noc(CC[N+](C)(C)C)n1>>Cc2noc(CCN1CCC(O)C1)n2")

yield: 97%

Molecule: RXN3 (" Cc1noc(CC[N+](C)(C)C)n1>>Cc1noc(CCN)n1")

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")

To a stirred mixture of 4 (2.0 mmol) in methylene chloride/methanol (10:1, 11 mL) was added the appropriate base (DIEA and DBU were used catalytically (10% mol %), NaH was used in Excess) as shown in scheme 1, followed by the appropriate nucleophile (amines were used in 3-fold excess, methanol was used as the solvent, and only 0.5 equiv of malonitrile was used.) [note: malonitrile was used as a nucleophile in another reaction listed. The same goes for DBU, obviously.] The resulting solution was stirred for the time and temperature shown in Scheme 1. The resulting reaction solution was then evaporated under reduced pressure. Purification of the residue could be accomplished via removal of insoluble solids through trituration using diethyl ether (or methylene chloride)/hexanes followed by evaporation of the filtrate or via chromatography using silica gel and an appropriate solvent system.

Okay, this one may need a little explaining, since what’s going on is not intuitive. This one involves the addition of a base catalyst to remove the trimethylammonium group, yielding a vinyl arane intermediate (they claim this was demonstrated using TLC.) This intermediate acts as a Michael acceptor for a nucleophile to attack, yielding the final product. The nucleophile is the amine you want to add, and the base used depends on the reaction conditions: in the first example listed here, dimethylamine acts as both the base and the nucleophile. In the second example, ammonia acted as both the base and the nucleophile. However, in the last example, diisopropylamine (DIEA) was used as the base, and 3-hydroxypyrrolidine was the nucleophile. I imagine that diethyl- and diisopropylamine would probably work well as both base and nucleophile.

This reaction involves the nucleophilic addition to a Michael receptor. The Michael reaction refers to base-promoted addition of carbon nucleophiles to activated olefins, which are the acceptors. In fact, they propose a mechanism that involves, at one point in the reaction, the trimethyl moiety splits off, yielding 3-methyl-5-vinyl-[1,2,4]-oxadizole as an intermediate. It’s quite reasonable to expect the [1,2,4]-oxadiazole system to act as an electron-withdrawing group in protic media (hint: start with protonating the nitrogen in the 2-position), so this the mechanism seems plausible. Whether this can be extended to indole remains to be seen. Considering the electron-donating nature of the pyrrole nitrogen, I am a little pessimistic. I tried to think of an equivalent mechanism that would make this work, but I couldn’t. Maybe someone else can.

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])CCN(C[Fc])CCN(C[Fc])CCN(C[Fc])CC1")

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.

1,4,7,10,13-Penta-(ferrocenylmethyl)-1,4,7,10,13-pentaaza-cyclopentadecane, L4. 1,4,7,10,13pentaazacyclopentadecane (0.4 g, 1.86 mmol) and 4.29 g (11.16 mmol) of (ferrocenylmethyl)trimethylammonium iodide… were heated to reflux in acetonitrile (300 mL) for 4 days in the presence of sodium carbonate (6 g). The warm reaction mixture was filtered and the yellow solution evaporated to dryness. The resulting solid was dissolved in dichloromethane-methanol (99:1) as eluent. Further recrystallization in dichloromethane-hexane gave L4 as an organic solid (700 mg, 30%)

What can I say? There were other examples given in the article with higher yields, but there is no way to draw their structures here. Typical yields were in the 70% range.

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>>c4ccc(CN3CCC(CCN(c1ccccc1)c2ccccc2)CC3)cc4")

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.

Ring Opening: General Procedure.

ToN-Benzylquinuclidinium bromide (2[/b] (1.00 g., 3.54 mmoles)were added the appropriate nucleophile (3.54 mmoles) and cesium carbonate (1.15 g. 3.54 mmoles). The flask was flushed with nitrogen and the mixture was stirred at 170° (bath temperature) for 15 hours. After cooling to room temperature, the solid was dissolved in a mixture of ethyl acetate (50 ml) and aqueous sodium hydroxide (50 ml of a 1 M solution. The phases were separated and the aqueous layer was extracted with another 50 ml portion of ethyl acetate. The combined organic phases were dried over magnesium sulfate. Generally the compounds were purified by column chromatography on silica gel using appropriate mixtures of dichloromethane and methanol. The compounds were in most cases precipitated as their oxalates by treatment with 50 ml of a saturated solution of oxalic acid in ether. Analytical samples were recrystallized from water/ethanol (1:1)…

J. Org. Chem., (1992), 57(25), 6966-9.
Tetrahedron Lett., (2000), 41(33), 6527-6530.

Molecule: binapthyl1 ("C[N+]5(C)Cc2ccc1ccccc1c2c3c(ccc4ccccc34)C5>>C[C@H]([C@H](O)c1ccccc1)N(C)Cc3ccc2ccccc2c3c4c(CN(C)C)ccc5ccccc45")

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.

(S,1S,2R)-2-Azido-2’-{{N-(-2-hydroxy-1-methyl-2-phenylethyl)-N-methylamino]methyl]-1,1’binaphthyl[(S,1S,2R)-11]. A procedure similar to that described for the preparation of 8b was followed.[a mixture of 100 mg ((0.225 mmol) of quaternary salt 3 and 22 mg (0.338 mmol, 1.5 equiv) of sodium azide in 2 mL of DMF was stirred under heating at 110 °C for 25 h. The reaction mixture was then treated with water (20 mL) and extracted with ether (3 x 20 mL). The ethereal layer was washed with water (10 mL) and dried over anhydrous Na2. The removal of solvent under reduced pressure left the residue which was purified by flash chromatography…] Starting from 1 g (1.75 mmol) of quaternary salt11 (S,1S,2R)-6 (crystallized with 1 EtOH), 810 mg (95%, oil) of (S,1S,2R)-11 was separated by flash chromatography.(

J. Med. Chem., (1989), 32, 1157-1163.

Molecule: diazepine1 ("C[N+](C)(C)CC(c1ccccc1)c5nnc4CN=C(c2ccccc2)c3cc(Cl)ccc3n45>>Clc1ccc6c(c1)C(c2ccccc2)=NCc5nnc(C(CN3CC[R]CC3)c4ccccc4)n56")

where R= -, O, CH3N, PhN

Molecule: diazepine2 ("C[N+](C)(C)CC(c1ccccc1)c5nnc4CN=C(c2ccccc2)c3cc(Cl)ccc3n45>>CN(C)CC(c1ccccc1)c5nnc4CN=C(c2ccccc2)c3cc(Cl)ccc3n45")

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.

Procedure B.
A stirred mixture of 9 (2.0 g, 0.0034 mol) and morpholine (10 mL) was warmed, under N2, at 110 °C for 3h, cooled, and mixed with ice-cold saturated NaHCO3 (30 mL). The resulting precipitate was collected by filtration, washed with water, dried in vacuo, and chromatographe on silica gel (100 g) with 3.75% MeOH-CH2Cl2. The first compound eluted from the column was the elimination product (10), which amounted to 0.09 g (6.6%). The second compound eluted from the column amounted to 1.24 g. This was recrystallized from MeOH-H2 to give 0.91 g of 15

Bioorg. Med. Chem. Lett., (2001), 11, 2735-2740.

Molecule: opioid1 ("[H][C@@]12CCCC[C@@]14CCN[C@@H]2Cc3ccc(O)cc34")

 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)c2cccs2)[C@@H]3Cc4ccc(O)cc45")

2nd attempt:

Molecule: opioid1 ("[H][C@@]12CCCC[C@@]14CCN[C@@H]2Cc3ccc(O)cc34.C[N+](C)(C)CCC(=O)c1cccs1>>[H][C@@]13CCCC[C@@]15CCN(CCC(=O)c2cccs2)[C@@H]3Cc4ccc(O)cc45")

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.