(Hive Bee)
07-05-03 10:34
No 444717
      DMT to 5-MeO-DMT
(Rated as: excellent)

The Chemistry of Indoles. CIII.
Simple Syntheses of Serotonin, N-Methylserotonin, Bufotenine, 5-Methoxy-N-methyltryptamine, Bufobutanoic Acid, N-(Indol-3-yl)methyl-5-methoxy-N-methyltryptamine, and Lespedamine Based on 1-Hydroxyindole Chemistry

Masanori SOMEI, Fumio YAMADA, Takashi KURAUCHI, Yoshiyuki NAGAHAMA, Masakazu HASEGAWA, Koji YAMADA, Sakiko TERANISHI, Haruhiko SATO, and Chikara KANEKO
Chemical & Pharmaceutical Bulletin 49(1), 87-96 (2001) (

Application of regioselective nucleophilic substitution reactions of 1-hydroxytryptamines to novel and simple syntheses of serotonin (1a), N-methylserotonin (1b), bufotenine (1c), 5-methoxy-N-methyltryptamine (2a), bufobutanoic acid (3a), N-(indol-3-yl)methyl-5-methoxy-N-methyltryptamine (4), and lespedamine (5) are described. Effective syntheses of 5-benzyloxytryptamine and 1-methoxy-2-oxindoles are also reported.

In the above article the authors present a route for the conversion of tryptamines to the corresponding 5-methoxy/hydroxy-dimethyltryptamines (5-MeO-DMT) via an indoline intermediate.

The first step is of rather academical interest as trifluoracetic acid and triethylsilane are expensive and difficult to handle but several other reagents reduce indoles to indolines (e.g. Na(CNBH3), Zn(BH4)2, Pd/C, ...)

2,3-Dihydro-N,N-dimethyltryptamine (7e) from N,N-Dimethyltryptamine (6e)
Et3SiH (0.51 ml, 3.19 mmol) was added to a solution of 6e (201.4 mg, 1.07 mmol) in TFA (20.0 ml) and the mixture was stirred at 55 °C for 2 h.
After evaporation of the solvent under reduced pressure, the residual oil was made basic (pH 11) by adding 8% NaOH and the whole was extracted with CH2Cl2–MeOH (95 : 5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give 7e (189.4 mg, 93%).

1-Hydroxy-N,N-dimethyltryptamine (8e) from 7e
A solution of Na2WO4·2H2O (132.5 mg, 0.40 mmol) in H2O (4.0 ml) was added to a solution of 7e (378.9 mg, 1.98 mmol) in MeOH (40.0 ml). To the resultant solution was added 30% H2O2 (2.0 ml, 19.6 mmol) at 0 °C with stirring.
After stirring at room temperature for 20 min, H2O was added to the reaction mixture and the whole was extracted with CH2Cl2–MeOH (95 : 5, v/v).
The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give unreacted 7e (19.1 mg, 5%) and 8e (223.5 mg, 55%) in the order of elution. 8e: mp 179.5—180.0 °C (colorless needles, recrystallized from MeOH-H2O).

5-Methoxy-N,N-dimethyltryptamine (2e), 1c, and 6e from 8e
c-H2SO4 (5.0 ml) was added to a solution of 8e (421.2 mg, 2.06 mmol) in MeOH (45.0 ml) and the mixture was refluxed for 29 h with stirring. After cooling, the reaction mixture was made basic (pH 10) by adding 30% NaOH and the whole was extracted with CHCl3–MeOH (95 : 5, v/v).
The extract was dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO2 repeatedly with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) and acetone–hexane–28% aq. NH3 (20 : 10 : 0.3, v/v) to give 6e (44.2 mg, 11%), 2e (256.4 mg, 57%), and 1c (27.3 mg, 7%) in the order of elution. 2e: mp 68—70 °C (colorless prisms, recrystallized from Et2O–hexane).

1c: 5-hydroxy-DMT

The candle that burns twice as bright burns half as long
(Chief Bee)
07-05-03 15:41
No 444769
      The Chemistry of Indoles, Part CIII.     

Wow, what a paper you have found! A must-read article!

What about the title? "The Chemistry of Indoles, Part CIII." - does that mean the same authors have written 102 other papers on indole chemistry?
(Hive Bee)
07-06-03 22:19
No 445120
      Part CIII     

What about the title? "The Chemistry of Indoles, Part CIII." - does that mean the same authors have written 102 other papers on indole chemistry?

Looks like it.
The chemistry of indoles. Part 92. Novel formations of 6-mesyloxytryptamines and 1-substituted 3a-(4-chlorobutoxy)-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]indoles in the reaction of Nb-substituted 1-hydroxytryptamines with mesyl chloride
Heterocycles, 52 (1): 483-491 Jan 1 2000

In-fact they seem to be up to:
The chemistry of indoles. CVII. A novel synthesis of 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles and a new finding on Pictet-Spengler reaction.
Chem. Pharm. Bull Tokyo, 49 (9): 1159-1165 Sep 2001

Got democracy?
(Hive Bee)
11-21-03 09:34
No 472281
      A General Synthesis of N-Hydroxyindoles
(Rated as: excellent)

J. Org. Chem.; 2003; ASAP Web Release Date: 18-Nov-2003

A General Synthesis of N-Hydroxyindoles

Audrey Wong,* Jeffrey T. Kuethe, and Ian W. Davies

Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065

Received September 12, 2003

Abstract: A general method for the formation of N-hydroxyindoles is demonstrated through a lead-promoted intramolecular reductive cyclization of o-nitrobenzyl ketones and aldehydes under transfer hydrogenation conditions. The N-hydroxyindoles are isolated in high purity and excellent yield (>90%) in an operationally simple procedure. This new method is exemplified by a two-step synthesis of the naturally occurring 1-methoxyindole-3-carboxaldehyde, which is pivotal in many alkaloid total syntheses.

The synthesis of N-hydroxyindoles and their derivatives has received considerable attention in recent years.1
The biological role of N-hydroxyindoles is still an area of significant investigation. A range of N-hydroxyindoles has been shown to have antimicrobial or fungicidal activity. In addition, biologically inactive indoles have been rendered biologically active when the N-hydroxyindole analogues were prepared.1 Due to their ability to direct lithiations at the indole 2-position and also undergo both nucleophilic and electrophilic substitutions, N-hydroxy- and N-alkoxyindoles have served as useful precursors to highly functionalized indoles.1 N-Hydroxyindoles are also convenient precursors to isatogens which have been shown to spin trap hydroxyl radicals2 and exhibit a wide range of biological activities.3 The ability to fully profile biological activity of N-hydroxyindoles has been somewhat limited by the currently available methods which suffer from low yields and competing side reactions. Although some of these limitations have been addressed by the Somei “tungstate method”,4mild synthetic methods which would provide rapid assembly of the N-hydroxyindole ring from simple precursors would give access to an array of highly functionalized N-hydroxyindoles would be highly desirable. Reactions leading to increasing molecular complexity and methods which tolerate a wide range of functionality are important synthetic tools. It was envisioned that reductive cyclization of substituted o-nitrobenzyl ketones would be an attractive method for the construction of N-hydroxyindoles. In this paper, we demonstrate an efficient method for the synthesis of N-hydroxyindoles which is mild, high yielding and tolerates a wide range of functionality. While the reduction of o-nitrobenzyl ketones or aldehydes has been reported to give N-hydroxyindoles in the presence of Zn/NH4Cl,5 Pd/NaBH4,6 or Pd/H2,7 these reactions are generally intolerable to many functional groups, low yielding, and substrate limited. Often, further reduction of the N-hydroxyindole to the corresponding indole is observed. The reduction of aromatic nitro compounds with triethylammonium formate (TEAF) in the presence of palladium on carbon leads to the formation of anilines.8 Very recently, Gowda reported the reduction of nitro compounds to azo compounds using Pb/TEAF in methanol.9 Under these reaction conditions, the initial reduction of the nitro group to a hydroxylamine was observed, and in certain cases the hydroxylamine was isolated in up to 30% yield. We envisioned that reductive cyclization of a suitably substituted o-nitrobenzyl ketone 1 mediated by Pb/TEAF might provide the appropriate chemoselectivity to provide N-hydroxyindoles 3 via the cyclization of intermediate 2 (Scheme 1).

Scheme 1

To examine the Pb/TEAF-promoted reductive cyclization to N-hydroxyindoles, nitroketone 410 was treated with Pb/TEAF in MeOH at 55 °C for 12 h and gave 2-phenyl-N-hydroxyindole 5 as the sole product in 94% isolated yield. There was no detectable amount of 2-phenylindole present in the crude reaction mixture (HPLC and 1H NMR) as evidenced by comparison with an authentic sample. With this extremely gratifying result, we set out to examine the scope of the reaction. The method proved to be general and allowed access to a diverse array of highly functionalized N-hydroxyindoles in good to excellent yield (Table 1). Rapid two-step entry to substituted tricyclic systems of tetrahydrocyclopenta[b]indoles (entry 8) and tetrahydrocarbazoles (entry 9) and the tolerance of a number of important functional groups have been demonstrated. In all cases, isolation of the product was achieved in a straightforward, simple fashion. The insolubles were removed by filtration, followed by concentration of the MeOH (or EtOH), and filtration through a small plug of silica gel which afforded the products as stable crystalline solids.
Isolated from the Cruciferae family of plants,1,14 1-methoxyindole-3-carboxaldehyde 22 has been utilized as a building block for the synthesis of a number of other natural products.15 The synthesis of 22 using the leadpromoted reductive cyclization required only two synthetic steps from commercially available 2-nitromalondialdehyde 20 and occurred in 89% overall yield (Scheme 2).

Scheme 2

In summary, a general, high-yielding method of preparation of N-hydroxyindoles through the lead-promoted intramolecular reductive cyclization of o-nitrobenzyl ketones and aldehydes has been demonstrated. The reaction conditions are mild and tolerant of a wide range of functional groups. Increased access to o-nitrobenzylcarbonyl substrates through recent advances by Buchwald, 12 Rawal,16 RajanBabu,17 and others18 and the present sequence should allow for the generation of previously inaccessible N-hydroxyindoles in a remarkably straightforward manner.

Supporting Information Available: Experimental procedures and compound characterization for all new compounds. This material is available free of charge via the Internet at

(1) For reviews on N-hydroxyindoles and their derivatives, see:
(1) (a) Somei, M. Adv. Heterocycl. Chem. 2002, 82, 101.
(1) (b) Somei, M. Heterocycles 1999, 50, 1157.
(1) (c) Acheson, R. M. Adv. Heterocycl. Chem. 1990, 51, 105.
(1) (d) Somei, M. Yuki Gosei Kogaku Kyokaishi 1991, 49, 205.
(1) (e) Acheson, R. M. In New Trends in Heterocyclic Chemistry; Mitra, R. B., Ayyanger, N. R., Gogte, Y. N., Acheson, R. M., Cromwell, N., Eds.; Elsevier Science Publishers: New York, 1979; p 1.
(2) (a) Rosen, G. M.; Tsai, P.; Barth, E. D.; Dorey, G.; Casara, P.; Spedding, M.; Halpern, H. J. J. Org. Chem. 2000, 65, 4460.
(2) (b) For reference on the synthesis of isatogens, see: Bristow, T. H. C.; Foster, H. E.; Hooper, M. J. Chem. Soc., Chem. Commun. 1974, 677.
(3) Adams, D. B.; Hooper, M.; Swain, C. J.; Raper, E. S.; Stoddart, B. J. Chem. Soc., Perkin Trans. 1 1986, 1005 and references therein.
(4) (a) Somei, M.; Kawasaki, T. Heterocycles 1989, 29, 1251.
(4) (b) Kawasaki, T.; Kodama, A.; Nishida, T.; Shimizu, K.; Somei, M. Heterocycles 1991, 32, 221.
(5) (a) Somei, M.; Inoue, S.; Tokutake, S.; Yamada, F.; Kaneko, C. Chem. Pharm. Bull. 1981, 29, 726.
(5) (b) Somei, M. Chem. Pharm. Bull. 1986, 34, 4109.
(5) (c) Mousseron-Canet, M.; Boca, J.-P. Bull. Soc. Chim. Fr. 1967, 1296.
(6) Coutts, R. T.; Wibberley, D. G. J. Chem. Soc. 1962, 4610.
(7) Reboredo, F. J.; Treus, M.; Este´vez, J. C.; Castedo, L.; Este´vez, R. J. Synth. Lett. 2002, 999.
(8) Cortese, N. A.; Heck, R. F. J. Org. Chem. 1977, 42, 3491.
(9) Srinivasa, G. R.; Abiraj, K.; Gowda, D. C. Tetrahedron Lett. 2003, 44, 5835.
(10) Strazzolini, P.; Giumanini, A. G.; Runcio, A.; Scuccato, M. J. Org Chem. 1998, 63, 952.
(11) (a) Bond, C. C.; Hooper, M. Synthesis 1974, 443.
(11) (b) Patterson, D. A.; Wibberley, D. G. J. Chem. Soc. 1965, 1706.
(12) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168.
(13) Allais, A.; Meier, J.; Mathieu, J.; Nomine, G.; Peterfalvi, M.; Deraedt, R.; Chifflot, L.; Benzoni, J.; Fournex, R. Eur. J. Med. Chem. Chim. Ther. 1975, 10, 187.
(14) Monde, K.; Takasugi, M.; Shirata, A. Phytochemistry 1995, 39, 581.
(15) (a) Somei, M.; Ohnishi, H.; Shoken, Y. Chem. Pharm. Bull. 1986, 34, 677.
(15) (b)Acheson, R. M.; Hunt, P. G.; Littlewood, D. M.; Murrer, B. A.; Rosenburg, H. E. J. Chem. Soc., Perkin Trans. 1. 1978, 1117.
(16) Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org. Lett. 1999, 1, 673.
(17) (a) RajanBabu, T. V.; Reedy, G. S.; Fukunaga, T. J. Am. Chem. Soc. 1985, 107, 5473.
(17) (b) RajanBabu, T. V.; Chenard, B. L.; Petti, M. A. J. Org. Chem. 1986, 51, 1704.
(18) Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org Lett. 2003, 5, 2497.

General Procedure for the Preparation of N-Hydroxy-Indoles

To a solution containing 1.00 g of the appropriate nitroketone in 10 mL of either MeOH or EtOH was added 4.00 g of lead powder (325 mesh) and 4 mL of HCO2HNEt3. The mixture was stirred at 50 °C for 12 h, cooled to rt, and filtered over a pad of Celite. The solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography to give the product.

The candle that burns twice as bright burns half as long