Author Topic: Fisher Tryptamine Synthesis - is this right?  (Read 37570 times)

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4-Aminobutanal Acetals + 5-MeO-Tryptamine
« Reply #20 on: May 21, 2004, 07:05:00 PM »
More by the same author as in

Post 481048

(dioulasso: "Fisher w/ AcOH", Tryptamine Chemistry)

The Synthesis of 3,5-Disubstituted Indoles by Cyclization under Mild Conditions
D. Keglevic, N. Stojanac, and D. Desaty

Croatica Chemica Acta 33, 83-88 (1961)


3-Benzyloxy-6-formylaminotoluene (III) could not be converted by Madelung cyclization into the corresponding indole derivative. It was found, that 4-aminobutanal diethyl acetal and p-benzyloxyphenylhydrazine hydrochloride cyclize into 5-benzyloxytryptamine hydrochloride (V) in 25% acetic acid at 80°C in 68% yield. Under these mild conditions also other 3,5-substituted indoles were obtained: 3-methyl-5-benzyloxyindole (VI), 3-ethyl-5-benzyloxyindole (VII), 5-methoxytryptamine picrate (VIII) and N-acetyl-5-methoxytryptamine (Melatonin, IX).
____ ___ __ _

Aminoacetals. Syntheses of N,N-Disubstituted 4-Amino-2-butynal- and 4-Aminobutanal acetals
D. Keglevic and B. Leonhard

Croatica Chemica Acta 35, 175-180 (1963)


The synthesis of N,N-disubstituted 4-aminobutanal acetals (XV-XXII) was effected by the hydrogenation of the corresponding acetylenic analogues. N,N-Disubstituted 4-amino-2-butynal acetals (IV-XII) were prepared by the Mannich condensation of propargylaldehyde acetal, formaldehyde and the corresponding secondary amine. As an alternative route to N,N-disubstituted acetylenic aminoacetals. Bodroux-Tschitschibabin acetal synthesis was also applied in the preparation of 4-dibenzylamino-2-butynal acetal (VII).


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4-Dialkylaminobutyraldehyde acetals
« Reply #21 on: July 11, 2004, 10:05:00 AM »

Patent WO03101931

Abstract: The invention disclosed in this application relates to an improved process for the preparation of compounds of formula (I): R1R2NCH2CH2CH2CH(OR3)2; wherein, R1 = R2 = C1-C16 alkyl; C3-C7 cycloalkyl; R1 = C1-C16 alkyl; R2 = C3-C7 cycloalkyl; NR1R2 = pyrrolidino, piperidino, morpholino, thiomorpholino, R1 = C1-C6 alkyl; R2 = ArCH2; Ar =4-R4-C6H4-, R4 = MeO, EtO, Me, Et, NMe2, NEt2, SMe, SEt, etc; R3=C1-C6 alkyl; C3-C7 cycloalkyl which comprises: (i) Reacting 3-(N, N-disubstitutedamino)propyl halide of formula (XXI): R1R2NCH2CH2CH2X; wherein, R1, R2 = as defined above, X = Cl or Br, with magnesium in the presence of a solvent to get the Grignard reagent 3-(N, N-disubstitutedamino)-propylmagnesium halide; (ii) Reacting the resulting 3-(N, N-disubstitutedamino) propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula (XVII): HC(OR5)(OR3)2; wherein, R3 and R5 is same or different and represent C1 to C6 alkyl, C3 to C7 cycloalkyl OR R3 is as defined above and R5 represents phenyl radical; (iii) Filtering off the resultant reaction mixture and distilling the filtrate to isolate the compound of the formula (I). These substituted butyraldehyde derivatives of the formula (I) are very important building blocks for the synthesis of various tryptamine derivatives. In particular 4-(N, N-dimethylamino)butyraldehyde dimethyl or diethyl acetals are crucial intermediates for the synthesis of commercially available anti-migraine drugs, like sumatriptan, zolmitriptan, and rizatriptan.


N-(3-chloropropyl)-N,N-dimethylammoniumchloride ("C(CC[NH+](C)C)Cl")


triethylorthoformat ("C(OCC)(OCC)OCC")

Both compounds are commercially available and cheap.


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R2N(CH2)3MgCl + HC(OEt)3 : previous work
« Reply #22 on: September 22, 2004, 07:27:00 AM »
The following article was requested by Lego:

Oximes of ?-Dimethylaminoalkanals and derivatives thereof
I. N. Somin, S. G. Kuznetsov
Zh. Org. Khim.
, 1(11), 1973-1976 (1965).
(journal written in Russian)

   For the preparation of the oximes (Table 1), diethyl acetals of the corresponding aminoaldehydes were subjected to hydrolysis. The aminoaldehydes formed are unstable and polymerize readily [2,3], so we converted them to oximes without isolation.
?-Dimethylaminobutyraldehyde diethylacetal was obtained from 3-dimethylaminopropylmagnesium chloride and orthoformic ester in 30% yield following the procedure described for the analogous dibutylamino derivative [5], b. p. 73-75° (6 mm), n20D 1.4217. Literature data [2]: b. p. 94-95° (11 mm), n20.5D 1.4227.

[2] V. Harries, F. Düvel, Liebigs Ann. Chem., 410, 54 (1915).

[3] R. Voet, Bull. Soc. Chim. France, 45, 61 (1929);
    F. E. King, J. R. Marshall, P. Smith, J. Chem. Soc., 1951, 239. 

[5] is the article below:

Attempts to Find New Antimalarials. Phenanthryl- and Quinolyl-alkamines of the Type RCHOH(CH2)3-11N(C4H9)2
T. D. Perrine
J. Org. Chem.
, 18, 1356-1367 (1953).

   The best approach found for the synthesis of ?-dibutylaminobutyraldehyde... involved the reaction of IV (Bu2N(CH2)3MgCl) with ethyl orthoformate [4] which yielded the diethyl acetal of ?-dibutylaminobutyraldehyde in about 60% yield. Mild acid hydrolysis afforded the free aldehyde in 86% yield. It is remarkably stable and can be distilled at atmospheric pressure.
   3-Dibutylamino-1-chloropropane was prepared as described by Marxer [2].
   Grignard reagents from dibutylamino halides. By observing certain precautions, the above halides may easily be converted to Grignard reagents. The chief factors affecting the conversion can be enumerated as follows:

   1. Moisture must be rigorously excluded. We used an apparatus in which ether from ethereal methylmagnesium iodide was directly distilled into the reaction flask. This ether was used both to help in drying the apparatus, and as a reaction solvent.

   2. The magnesium should be activated with methyl iodide or ethyl bromide. We used a reaction flask with a stopcock sealed to the bottom for removing the activating solution  prior to the introduction of the amino chloride.

   3. The minimal amount of ether should be used in the initial phase of the reaction.

   4. Stirring should be employed sparingly, if at all, until the reaction is well under way.

   5. Once started, the reaction should be continued unabated until complete.

   After activating the magnesium (a large excess is advantageous) with about 5 ml. of methyl iodide, employing vigorous stirring, and removal of the activating solution, a small amount of ether was distilled into the reaction flask and about 5 ml. of the amino halide added. The reaction usually started promptly, warming being rarely necessary. The reaction was kept going steadily by the addition of the amino chloride, diluted if desired with one or two volumes of ordinary anhydrous ether. The desired concentration was maintained in the reaction flask by distilling in ether from the methylmagnesium iodide flask. Moderate stirring was usually employed. The reaction was completed by heating at reflux for 0.5 hour. The yields were usually 80-85%.

   These Grignard reagents are fairly insoluble in ether, and crystallize either at once, or on long standing. They are easily soluble in benzene. A normal color test (Gilman's color test I) is obtained with Michler's ketone and iodine in acetic acid. We were unable to prepare the Grignard reagents in which the halogen and nitrogen atoms were separated by 4 and 5 carbon atoms respectively.

   ?-Dibutylaminobutyraldehyde*. Ethyl orthoformate (100 g.) and 320 ml. of 0.85 N 3-dibutylaminopropylmagnesium chloride in benzene were kept at 65° for 15 hours to give 47 g. (60%) of ?-dibutylaminobutyraldehyde diethylacetal, b. p. 90-110°/2 mm., and on redistillation, b. p. 149.5°/9 mm., n29D 1.4330.
   On mild acid hydrolysis this gave the aldehyde (86% yield) of b. p. 235°; 71.0°/0.08 mm., n30D 1.4398 (1.4460 after 16 hours).
   The 2,4-dinitrophenylhydrazone melted at 65-67°.

   *The Stephen reaction [13] on ?-dibutylaminobutyronitrile gave none of this aldehyde; ?-chlorobutyronitrile (6.6 g.), 17 g. of anhydrous SnCl2, and 80 ml. of dry ether gave, after 18 hours at 0°, a 10% yield of ?-chlorobutyraldehyde as the 2,4-dinitrophenylhydrazone, m. p. 132° (from alcohol).

[2] Marxer, Helv. Chim. Acta, 24, 209E (1941).

[4] Smith and Bayliss, J. Org. Chem., 6, 437 (1941).

[13] Stephen, J. Chem. Soc., 127, 1875 (1925).

As I can see, these articles are not mentioned in the patent posted by Lego  :)