Author Topic: 4-Hydroxyindole Synthesis  (Read 2124 times)

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4-Hydroxyindole Synthesis
« on: December 29, 2002, 04:52:00 AM »
I moved this discussion from the "Wanted References" thread in Novel Discourse, as that thread is for requests only, and below the posts made by Antoncho and hest has been reiterated, as well as all the mentioned articles I had access to has been linked to inline. /Rhodium

Posted by Antoncho:

Here's a humble request from two of our Hyperlab bees: Fomalhaut and Dionket. They are going to try synthesizing psylocybine in the upcoming weeks. Both having an extensive lab experience and an access to all the fancy reagents and equipment, i dare say they have a decent chance of succeeding at this - if they don't get too lazy to purify their intermediates, that issmile

However, they lack one crusial detail - 4-hydroxyindole or, to put it more precisely, a synthesis of such from more or less available reagents (on the pic beelow you'll see what they mean by 'more or less available'smile). They dug up a route to their precursor on the Chemical Abstracts, but the journal to which the abstract references isn't available to them.

Please, if somebee can find this article for them, do so! In case of either outcome the results of their experimentation promise to bee interesting.

J.M. Bobbit, Dutta, Journal of the Chemical Society, Chemical Communications 1968, 22, 1429.

Posted by hest

It should bee straightforward, start with some analogue of salisylaldehyde (the benzyloxy?) Make the synth, deprotect and make the acetate.
I think we could use a psilocybin synth here, growing mussies is too slow

Some refs:
Synth. Comm. 2077-2102 (1992) AND 186-188 (1995) (the indole synth)

Synthesis 935-938 (1999)


J.Med.Chem. 4701-4710 (2000)


Organic Syntheses, CV 7, 34

( (Found by Terbium)

JCS Chem Comm 22, 1429 (1968)
By J. M. Boitt and C. P. Dutta

Condensation of a 1,3-cyclohexanedion with an aminoacetaldehyde in benzene and in the preseceof p-toluen-sulphon acid yealded after azeotropic destil of wather an oxo-amine.
treatment of this with cold 3M HCl gave the 4,5,6,7-tetrahydro4-oxo-indole. (app.50%). More concentrated acid gave a dimer.
Convertion to the indole has been done (W.A. Remers and M.J.Weiss

JACS 87, 5262 (1965)

(There is no experimental in this article)


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4-Hydroxyindole synthesis references
« Reply #1 on: January 08, 2003, 01:50:00 AM »
Repost from my harddrive:
One of the most interesting (i.e. cheap and easy) routes to 4-OH-indole is the ammonolysis of 4-oxo-4,5,6,7-tetrahydrobenzofurane (4-OTHB) to 4-oxo-4,5,6,7-tetrahydroindole (4-OTHI) and subsequent dehydrogenation. Here's a list of papers:

4-OTHI from 4-OTHB:

Heterocycles 22, 2313 1984 M. Matsumoto e.a.: one of the most interesting papers, 4-OTHB from 1,3-cyclohexanedione and chloroacetaldehyde.
CA 101, 23319d 1984 (EP 101,003) M. Matsumoto e.a.: the corresponding patent for 4-OTHB preparation(download the patent).
CA 101, 23331b 1984 (EP 101,004) M. Matsumoto e.a.: the corresponding patent for 4-OTHI preparation (download the patent).
CA 104: 148736f (JP 60,228,457) + 148737g (JP 60,228,456) +148738h (JP 60,228,455) 1986 K. Goto e.a.: ammonolysis in H2O, purification.
CA 106, 67111n (JP 61,180,768) + 67112p (JP 61,180,767) 1987 S. Matsuno e.a.:
4-OTHB ammonolysis in polyol partial ethers, dehydrogenation, purification.

4-OTHI from different routes:

Ann. Chem. 655, 20 1962 H. Stetter e.a.: 4-OTHI from 2-acetonyl-1,3-cyclohexanedione.
Tet. Lett. 37, 9203 1996 Y. Aoyagi e.a.: 4-OTHI from 1,3-cyclohexanedione, 2-amino-ethanol, and catalyst.
CA 102, 62078q 1985 (JP 59,144,758) Ube Industries: 4-OTHI from 1,3-cyclohexanedione, 2-amino-ethanol, and catalyst.
Recl. Trav. Chim. Pays-Bas 109, 287 1990 E. M. M. van den Berg e.a.: 4-OH-indole from 4-OTHI from 4-OTHB-3-carboxylic acid (with ammonium carbonate) from 1,3-cyclohexanedione and ethyl bromo pyruvate.
CA 101, 7022w 1984 (JP 59 05,159): 4-OTHI from 4-OTHB-3-carboxylic acid with ammonium salts.
Synth.Commun. 16, 1635 1986 Kneen e.a.: 4-OTHB-3-carboxylic acid from 1,3-cyclohexanedione and bromo pyruvate or bromoacetaldehyde diethylacetal.
Chem. Lett. 1603 1980 S. Torii: 4-OTHI from cyclohexanedione and ethyl vinyl ether via electrolysis and ammonolysis with ammonium carbonate.
CA 108, 94379d 1988 (JP 62,138,469) K. Nagao e.a.: 4-OTHI from 1,3-cyclohexandione + NH3 / H2O + acetic acid 1,2-dibromoethyl ester.
CA 71, 81163w 1969 M. Julia: 4-OTHI from 4-(2-pyrrolyl)-butyric acid.
J. Chem. Soc. Perk. I 1237 1974 A. G. Sánchez: 4-OTHI from 1,3-cyclohexanedione and aminosugars.
Chem. Commun. 1429 1968 J. M. Bobbitt e.a.: 4-OTHI from 1,3-cyclohexanedione and aminoacetaldehyde dimethylacetal.
J. Org. Chem 43, 3541 1978 M. Bobbitt: 4-OTHB from 1,3-cyclohexanedione and aminoacetaldehyde dimethyl acetal.
Chim.Ther. 5; 279 1970 Julia e.a.: 4-OTHI preparation.
Dokl. Chem.(Engl.Transl.) 171, 1191 1966 Yurchenko e.a.: 4-OTHI preparation.

4-OH-indole from 4-OTHI dehydrogenation:

J. Het. Chem. 14, 71 1977 D. B. Repke: dehydrogenation, synthesis of 4-OH-tryptamines.
J. Org. Chem. 36, 1232 1971 W. A. Remers e.a.: dehydrogenation + some references.
CA 103, 215269t 1985 (JP 60,152,462) H. Fukumitsu e.a.: dehydrogenation.
CA 107, 236506y 1987 (JP 62 63,563) Nagao e.a.: dehydrogenation.
Chem. Ber. 101, 2605 1968 H. Plieninger e.a.: dehydrogenation.
Heterocycles 23, 165 1985 M. Matsumoto e.a.: aromatization via halogenation with CuX2 and dehydrohalogenation with Li2CO3 + LiX in DMF.

Here are some other interesting articles for alternative 4-OH-indole syntheses:

J. Het. Chem. 19, 845 1982 D. B. Repke e.a.: 4-AcO-indole to many 4-OH-tryptamines via glyoxylamides.
J. Het. Chem. 18, 175 1981 D. B. Repke e.a.: synthesis of 4-MeO-indole, reaction with 1-dimethylamino-2-nitroethylene, LAH reduction to tryptamines.
Synth. 437 1985 S. Andersson: a high yield PTC phenolether cleavage procedure! Many substrates! A must!
Heterocycles 16, 1119 1981 L. I. Kruse: synthesis of 4-NH2 / COOCH3 / CH3 / OH / MeO / BnO-indoles.
Heterocycles 22, 797 1984 M. Somei: 4-OH-indole-3-carbaldehyde from indole-3-carbaldehyde via 4-thallium-bistrifluoroacetate.
Chem. Pharm. Bull. 29, 3145 1981 M. Somei e.a.: 4-OH-indole from 4-aminoindole from 4-nitroindole from 2,6-dinitrotoluene.
Org. Synth. Coll. Vol. VIII, 493 1993 J. Bergmann: 4-nitroindole from 2-methyl-3-nitroaniline.
Tet. Lett. 24, 3665 1983 J. Bergmann: 4-nitroindole from 2,6-dinitrotoluene.
Chem. Pharm. Bull. 29, 726 1981 M. Somei e.a.: 4-subst. Indoles, 4-aminoindole from indole (!).