Synthèse de nouvelles tryptamines substituées Roland Stauffer Helvetica Chimica Acta 49(3)

1966 p 1199

This article is about N-methyl-N-ethyl analogs of tryptamines. (especially this true gem:MET, N-
methyl-N-ethyl-tryptamine)

The dude remarked than when quenching LAH solution of secondary amine with ethyl acetate,
some tertiary amine (with a new ethyl group) were synthetised. It is old news for most bees
than quenching those solution like this yield some ethylated amine, apparently because the
lithium salt of the secondary amine react with the acetyl of the ethyl acetate to yield an amide
which is further reduced with another LAH to the tertiary amine. I know the synthesis
described here is not suitable for us, but the experimental section has some interesting tricks.

He synthetise the esters of the indole-3-acetic acid with a sulfonic Dowex resin with good
yield and then synthetise the corresponding mono-methyl amide with aqueous methylamine.
The LiAlH4 reduction of this and the ethyl acetate quench afford the methyl ethyl amine and
the mono-methyl amine in variable yield: the more ethyl acetate used the more ethylated
amines.

If only we could find another reducing agent which could ethylate like this the amine it could
become a great road to MET:

IAA --Dowex, MeOH--> IAA ester --aq MeAm--> The Amide --hopefully another reducing
agent than LAH, ethylacetate--> MET

Another thing that is interesting is this pathway:

Tryptamine ---Ac2O, formic--> Formyl tryptamine --LAH, Ethyl acetate--> MET

If only I had some LAH

Here we go :

Experimental

Benzyloxy-5-N-formyltryptamine (VII)

82ml acetic anhydride and 35ml formic acid are stirred at 50-60°C for two hours. To this
solution is introduced dropwise 100g of benzyloxy-5-tryptamine in 250 mL of THF while the
reaction mixture is cooled at 30°C. After 12h at RT, the THF is removed in vacuo (12 Torr), on a
30°C waterbath. A oily residue is obtained, 100 mL H2O is added and after two hours the oil
crystallise. It is recrystallised in 700 mL of 50% EtOH to yield 99g (90%) of VII as white paillettes
mp 99-101°C.
(Benzyloxy-5-indolyl-3)-methyl acetate

220g of (Benzyloxy-5-indolyl-3)-acetic acid dissolved in 2L of absolute MeOH are refluxed for

6h with 20g of Dowex 50 x 8 sulfonic resin. The solution is filtered and decolorized with
activated charcoal, then concentrated under a 12 Torr vacuum till the start of cristallisation,
with waterbath temp not exceeding 35°C. After cooling and filtration, a yield of 200g (87%) of
the ester is obtained as light pink prisms, mp 72-74°C.

N-methyl-(benzyloxy-5-indolyl-3)-acetamide (V)

200g of (Benzyloxy-5-indolyl-3)-methyl acetate suspended in 600mL of 40% aqueous

methylamine are vigorously stirred for 12 h. After filtration, water wash and drying, 187g of
uncolored crude amide are obtained, with a mp of 140-142°C. After a two hours reflux in 500
mL of benzene the non-transformated ester is eliminated and 175g of pure amide are obtained
as white prisms, mp 142-143°C (ref [4] : 141-142°C).

Benzyloxy-5-N-methyltryptamine (III) by reduction of the amide V.

25g of the amide V is dissolved in 300 mL THF and introduced dropwise, at RT, in a suspension
of 10g LiAlH4 in 300 mL THF. After a 10h reflux, the excess hydride and the complex are
destroyed by the slow addition, with good stirring, of 10 mL water, 10 mL of 15% NaOH and 30
mL H2O. The formed hydroxydes are essorated and washed with THF. After the evaporation of
the filtrates under 12 Torr, a oily residue is obtained, which is dissolved in 100 mL MeOH. After
the addition of 10g of anhydrous oxalic acid, 17.5g of III oxalate are obtained, mp 203-205°C
(ref [4] : 201-203°C).

Benzyloxy-5-N,N-methylethyltryptamine (II) by reduction of the amide V.

A solution of 24g of the amide V dissolved in 300 mL THF is introduced dropwise, at RT, in a
suspension of 10g LiAlH4 in 300 mL THF. After a 10h reflux, the solution is cooled at 15°C and
50 ml ethyl acetate is added dropwise. The solution is then again refluxed for 2 hours. The
excess hydride and the complex are destroyed as above with 10mL water, 100 mL 15% NaOH
and 30 mL H2O. After concentration under 12 Torr until a oily residue is obtained, then
dissolution in 100 mL MeOH, the oxalate of II is obtained with the addition of 10g anhydrous
oxalic acid. Yield : 15 g (46%) as white needles, mp 165°C.

Benzyloxy-5-N-methyltryptamine (III) by reduction of the benzyloxy-5-N-formyltryptamine VII.

A solution of 35g benzyloxy-5-N-formyltryptamine in 150 mL of THF is introduced dropwise in

a suspension of 10g LiAlH4 in 400 mL THF. After a 10h reflux the decomposition is effectued as
above with water and 15% NaOH. The oxalate is formed in MeOH with anhydrous oxalic acid.
32g (73%) of the oxalate of III is such obtained, mp 205°C.

Indole-3-methyl acetate

50g of acid indolyl-3-acetic in 500 mL of MeOH is refluxed for 4 h with 10g of Dowex 50 x 8
(dried in oven at 120°C until constant weight). After cooling and filtration of the resin, the
solution is concentrated under 12 Torr at 35°C, then the residual oil is distilled at bp 180-
185°C/0.2 Torr. 49g (91%) of the ester is obtained, it crystallise in benzene, mp 49°C (ref [11] :
49-50°C).

beta-(Indolyl-3)methyl propionate

50g of acid beta-(indolyl-3)-propionic in 500 mL of anhydrous MeOH is refluxed for 4 h with

10g of Dowex 50 x 8 (dried at 120°C). After cooling and filtration of the resin, the solution is
concentrated under 12 Torr, the residual oil is distilled at bp 180°C/0.2 Torr. The ester
obtained is crystallised in benzene to yield 45g (84%) of product as white needles, mp 81-83°C.

N-methyl-indolyl-3-glyoxylamide (VI)

In a solution of 100g of indol in 2.5L of anhydrous Et2O dried on CaH2, is introducted dropwise
in one hour, with strong stirring 100 mL of oxalyl chloride, the temperature maintened below
20°C. The indolyl-3-glyoxylic acyl chloride begin to crystallise after the introduction of 1/3 of
the oxalyl chloride. After the end of the addition, stirring is continued for one hour, then the
chloride is filtered (145g, air dried). It is added by small quantity in 500 ml of aqueous
methylamine between 0 and 10°C. The chloride yield 125g (73%) of the amide VI, mp 222-
223°C, white needles from EtOH.

N-methyltryptamine (IV)

30g of the amide VI are placed in a Soxhlet apparatus and are extracted for 6 days with 2.5 L of
anhydrous Et2O containing 30g of LiAlH4 suspended. The decomposition is effectued in the
cold with 100mL of THF containing 20% water, then with 1300mL H2O. After filtration of the
hydroxydes and concentration of the filtrate under 12 Torr, 25g of a yellow oil is obtained. It is
distilled in vacuum (bp 150-155/0.2 Torr). The distillate is dissolved in 75 mL of benzene to
yield 18g (71%) of IV as white prism, mp 89°C (ref [8] : mp 89-90°C ; cfr [9] and [10] too).

Benzyloxy-5-N,N-methylethyltryptamine (II) by alkylating reduction of the benzyloxy-5-N-

formyltryptamine VII .

A solution of 35g of VII in 150 mL THF is introducted dropwise to a suspension of 20g LiAlH4 in
400 mL of THF. After a 12h reflux, 35 mL ethyl acetate is slowly added, the reflux is continued
for 2 h more and then the reaction mixture is decomposed with water and 15% NaOH like
above. The yield is 20g (42%) of II, isolated as its oxalate, mp 165°C.

N-methyltryptamine and N,N-methylethyltryptamine (I)

45g of the amide VI are extracted in a Soxhlet apparatus with 2.5 L anhydrous Et2O, containing
45g of LiAlH4 in suspension. The extraction is done for 6 days. After cooling to 15°C 100 mL of
ethyl acetate is added slowly, then the reflux is continued for 2 hours more. The reaction
mixture is decomposed with water and 15% NaOH as above, the hydroxydes are filtered and
the filtrates concentrated in vacuo (12 Torr). An oil is such obtained, which shown a violet
fluorescence and distill between 160 and 168°C at 0.2 Torr. It is dissolved in 100 mL of MeOH
and 15 g of anhydrous oxalic acid is added. A first oxalate fraction (13g) correspond to the
oxalate of N-methyltryptamine (IV), as uncolored prisms, mp 178-180°C.
To the filtrate is added 50 mL Et2O and then it is cooled at -10°C. A second crop of oxalate
crystallise. It is recrystallised in MeOH to yield 15g of the oxalate of N,N-
methylethyltryptamine as white needles, mp 120°C.

References:

[4] A. Stoll, F. Troxler, J. Peyer and A. Hoffman, Helv. 38, 1466 (1955).
[8] A. Fiser, JACS 78, 3670 (1956).
[9] M. E. Speeter and W. C. Anthony, J. Pharmacol. 14,99 (1959).
[10] T. Hoshino, Liebigs Ann. Chem. 520, 13 (1934).
[11] R. W. Jackson, J. Biol. Chemistry 88, 659 (1930).