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introducing the group after formation of the indole. chain and the indole nucleus to yield a range of substi-
The benzylic- or -carbon of 2- or 3-substituted tuted tryptamines.
indoles can show enhanced susceptibility to radical In a related cyclisation Julia and Tchernoff [100] used
reactions, characteristic of many aromatic compounds. N-methylaniline and ethyl 4-bromoacetoacetate to give
Stabilisation of the radical intermediate by its participa- ethyl 3-indoleacetate (Fig. 21). There is a number of
tion in the overall aromatic structure is enhanced in the routes from 3-indoleacetic acid (Fig. 21), either reduc-
indoles by participation of the ring nitrogen, an effect tion with NaBH4 via the Me- or Et-ester, or direct
enhanced by N-deprotonation. This facilitates a group reduction and reduction with Na EtOH to tryptophol
S. Freeman, J.F. Alder / European Journal of Medicinal Chemistry 37 (2002) 527 539 537
(indol-3-yl-2-ethanol). Conversion of tryptophol to 6. Possible future trends in recreational drug
clandestine synthesis
N,N-disubstituted tryptamines is possible by conversion
to the alkyl- -Br derivative with PBr3 then reaction
Many of the references given in this review are to
with secondary amines. It is also reported that direct
relatively old literature, reflecting the maturity of many
refluxing of tryptophols in benzene or xylene with
synthetic methods for the amphetamines and
secondary amines over a nickel catalyst gives high
tryptamine psychotropic agents. It also reflects the con-
yields of the tertiary amines [101].
servatism of the clandestine synthetic chemists and the
Conversion of tryptophan to tryptamine is achieved
dependence they have on certain precursor chemicals.
by heating at reflux in a high boiling solvent in the
That conservatism will undoubtedly evolve slowly, as is
presence of a ketone (Fig. 22) [102]. A method had been
seen in the discussions on the web sites, with new ideas
proposed to convert tryptamine to N,N-dimethyl-
gradually being adopted. There is presently very exten-
tryptamine using methyl iodide in the presence of
sive research in the general area of indole pharmaceuti-
sodium hydroxide and a phase transfer catalyst [67].
cal chemistry. Many indole derivatives are biologically
This method appears to be flawed, at least for dimethy-
active and many natural products contain indole nuclei.
lation. Recent discussions on the websites indicate the
One can expect, therefore, research in this area to
more likely product as being the tri-methylated quater-
unearth new psychotropic and psychotomimetic mate-
nary ammonium salts. Work in our own laboratory
rials. Whether these will find themselves in the recrea-
supports that proposition [103]. Fig. 22 also shows an
tional drug community repertoire will depend at least in
alternative N-methylation step using formalin solution,
part upon the market forces that drive that scene. The
which the present authors have not yet attempted.
current amphetamine products seem to hold favour
Indigo is a source of indole that has been identified
with the illegal recreational drug community at present
by the clandestine drug community [104]. It is broken
[109] due to their availability and familiar blend of
down by nitric acid or CrO3 to isatin, indole-2, 3-dione psychomotor and hallucinogenic properties, whilst
[105] and there is a more recent report on isatin from being relatively less harmful in the shorter term than
indigo using oxygen and ozone in sodium hydroxide heroin and cocaine. There is still active research in this
DMF [106]. Isatin is susceptible to base catalysed addi- area too, to develop new analytical methods for possi-
ble regioisomeric and homologous compounds of the
tion of a ketone to the 3-position, which can lead to a
amphetamine family [110 112].
series of ring and side chain substituted tryptamines
The fact that all of these materials occasionally cause
[107] (Fig. 23). As a specific example, Franklin and
sudden death, and appear to cause longer term mental
White [108] reacted 5-methoxyisatin with acetone. Re-
and physical damage to the user, seems not to be a
action of the ketone product with hydroxylamine gave
particular concern to the generally younger cohort who
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