A Novel Preparation of alpha-Substituted Tryptamines from Isatins.

by C. S. Franklin and A. C. White

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Recent interest in the neuropharmacology of tryptamines, such as alpha -methyltryptamine (II; R = H, R' = Me), led us to seek new methods for their preparation. Dioxindoles (I) were readily obtained by base-catalysed condensation of isatins with ketones [1]. Reduction of their oximes with lithium aluminum hydride gave the required tryptamines (II; seven examples) which probably arose by spontaneous dehydration of the intermediate hyroxyindoles. alpha- Substituted have also been prepared recently by reduction of the oximes of oxindoles (III) with sodium and ethanol [2]; and since our work was completed, indoles have been prepared by reduction of 3-substituted oxindoles with lithium aluminum hydride in ether [3].

The present reductions were also carried out with sodium borohydride- aluminum chloride complex which proved especially useful for the trifluoromethyl analog (II; R = 7-CF3, R' = Me) since lithium aluminum hydride reduced the trifluoromethyl group to methyl. The reduction of oximes to amines with sodium borohydride - aluminum chloride has not been apparently reported before.

In the preliminary experiments, we used oxindole as a model compound for reduction and in our hands, the only product isolated was indole. However, Smith and Yu[4] reported that their reduction of this substance with lithium aluminum hydride gives indoline whereas Julian and Printy [5] were unable to reduce oxindole even at elevated temperatures.


3-Acetonyl-3-hydroxyoxindole (I; R = H; R' = Me).
To a stirred suspension, at room temperature, of isatin (294 g., 2 mol.) in acetone (1 L) was added diethylamine (100 ml.) in one portion. The solid dissolves exothermally during 30 min., to give a dark green solution. The mixture was stirred for for a further 5.5 hr., and the solid which separated was filtered off. The filtrate was evaporated to dryness on a steam-bath; the combined residues were triturated with water, collected, washed with cold acetone, and dried to give the dioxindole as a buff solid (350 g., 85%), m.p. 167 - 168 C (decomp.) [Braude and Lindwall [6] give m.p. 167 - 168 C (decomp.)]

In a similar manner, the following were prepared:

3-acetonyl-3-hydroxy -trifluoromethyloxindole
(I; R = 7-CF3, R' = Me) from 7- trifluoromethylisatin [7], as pale yellow needles (43%) (from 50% aqueous ethanol), m.p. 199 - 200 C (Found: C, 52.75; H, 3.7; N, 5.1; F, 20.2) 3-acetonyl- 3-hydroxy-5-methoxyoxindole (I; R = 5-OMe, R' = Me) as yellow needles (40%), m.p. 176 C (decomp.) [Pietra and Tacconi [8] give m.p. 171 - 172 C (decomp.)].

(I; R = 7-Me, R' = Me) from 7-methylisatin as rhombes (51%) (from acetone), m.p. 201-202 C (decomp.)(Found: C, 65.3; H, 5.8; N, 6.2)

(I; R = 5-F, R' = Me) (made by Miss L. Kruszynska), from 5-fluoroisatin [9] as a yellow solid (64%) (from acetone) m.p. 147 - 149 C (decomp.) (Found: C, 59.8; H, 4.55; N, 6.9)

(I; R = H, R' = Ph) from isatin and acetophenone, as yellow needles (55%), m.p. 165 C (decomp.)[Lindwall and Maclennon [?] give m.p. 169 - 172 C (decomp.)], and 3-hydroxy-3-(3-methyl-2-oxobutyl)oxindole (I; R = H, R' = Pr) (made by Dr. S. C. R. Meacock), from isatin and isopropyl methyl ketone as a cream powder (60%) (from benzene), m.p. 128 - 129 C (Found: C, 66.5; H, 6.3; N, 6.5) Calculated for C13H15NO2 : C, 66.9; H, 5.6; N, 6.0%) (Pietra and Tacconi [2] report m.p. 138 - 139 C)

To 3-acetonyl-3-hydroxyoxindole (321 g., 1.6 moles) in hot 96% ethanol (2 L.) was added hydroxylamine hydrochloride (118 g., 1.7 moles) in water (1 L.), followed by sodium acetate (209 g., 2.6 moles) in water (1 L.). The solution was kept at room temperature for 1 hour, then evaporated to a small volume in vacuo in a water bath. A solid separated which was filtered off and crystallized in water to give the oxime as needles (288 g., 82%), m.p. 179-180 C (decomp.) (Found: C, 60.4; H, 5.5; N, 13.1)

The same method gave analogous oximes containing also the following substituants: 7-trifluoromethyl, needles (72%) (from water), m.p. 99 - 102 C. 5-methoxy- pale yellow rhombs (77%) (from aqueous ethanol) m.p. 162 - 163 C, 5-fluoro- cream needles (47%) (from aqueous methanol), m.p. 156.5 - 157 C (decomp.), and 7-methyl (83%), m.p. 200 - 201 C, (decomp.). 3-hydroxy-3-(beta- hydroxyiminophenethyl)oxindole formed needles (76%) (from ethanol), m.p. 203 - 204 C (decomp.) and 3-hydroxy-3-(2-hydroxyimino-3-methylbutyl)oxindole (73%) (from benzene- methanol) had m.p. 139 - 140 C (decomp.)


(II; R = H, R' = Me). (A) 3-Hydroxy-3-2'-hydroxyiminopropyl-oxindole (10 g., 0.05 mol.) in tetrahydrofuran (250 ml.) was added dropwise to a stirrred suspension, at room temperature, of lithium aluminum hydride (10 g., 0.28 mol.) in tetrahydrofuran (200 ml.): a vigorous reaction occurred. The red-brown mixture was refluxed for 12 hr., then cooled and treated with water (40 ml.), and the resulting suspension was filtered, evaporated to a small volume in vacuo on a water-bath, and extractdd with ether. The organic phase was dried (MgSO4 and distilled to afford the base (2.7 g., 34%), b.p. 137 C @ 0.3 mm/Hg (bath 175 C), giving a picrate, red-orange needles (from ethanol), m.p. and mixed m.p. 226 C.

(B) To a stirred suspension of the oxime (44 g., 0.2 mol.) in freshly distilled bis-2-methoxyethyl ether (400 ml.), at room temperature, was added sodium borohydride (29.6 g., 0.8 mol.): an exothermic reaction occured and all the solid dissolved. When a solution of aluminum chloride (37.6 g.) in the ether (200 ml.) was added a complex separated. The mixture was heated at 100 C for 48 hr., cooled, and filtered, and the residue was decomposed with 10N sodium hydroxide and extracted with chloroform. Distillation of the extract yielded a-methyl-tryptamine (10.1 g., 29%).

The above mentioned oximes were reduced by one or other of the foregoing methods to give the following tryptamine: 5-methoxy-a-methyl-T (A) (45%), b.p. 187 - 190 C @ 0.3 mm/Hg [hydrochloride, plates (from ethyl acetate-methanol) , m.p. and mixed m.p. 112 - 113 C], 7-methyl-a-methyl-T (A) (44%), b.p. 156 - 158 C @ 0.2 mm/Hg, plates, m.p. and mixed m.p [2] 226 - 227 C (decomp.)]; a-phenyl (A) [hydrochloride pale orange needles, m.p. [2[ 250 -253 C (decomp.)], a-isopropyl (A) [from benzene-light petroleum (b.p. 40 - 60 C)], m.p. [2] 108 -110 C (found: C, 59.4; H, 5.8; N, 11.4 ; F, 23.0

Reduction of oxindole To a stirred suspension of lithium aluminum hydride (6 g.) in ether (250 ml) at room temperature was added oxindole (14 g.) in ehter (1.5 L). The mixture was refluxed for 10 hr., then cooled and decomposed with water (25 ml.). The resulting suspension was filtered and distilled, affording indole (2.55 g., 20%), b.p. 126 @ 15 mm/Hg. [1,3,5-trinitro-benzene adduct, yellow needles (from ethanol), m.p. and mixed m.p 166 - 169 C]

The authors thank Dr. R. E. Bowtnam for his advice and encourangemetn, Mr. C. A. Paterson for technical assistand, and Mr. F. H. Oliver for the microanalysis.

The Research Department, Parke, Davis & Company, Hounslow, Middlesex. [Received, September 19th, 1962.]


[1] Elderfield, "Hetrocyclic Compounds," New York, 1952, Vol. III, p. 222.
[2] Pietra and Tacconi, Farmaco (Pavia), 1958, 13, 893; 1961, 16 483, 492.
[3] Bettembourgh and David, Bull. Soc. chim. France, 1962, 772
[4] Smith and Yu, JACS, 1952, 76, 1096.
[5] Julian and Printy, JACS, 1949, 71, 3206.
[6] Braude and Lindwall, JACS, 1933, 55, 325.
[7] Maginnity and Gaulin, JACS, 1951, 73, 3579.
[8] Lindwall and Maclennan, JACS, 1932, 54, 4742