Microwave-accelerated synthesis of psychoactive deuterated N,N-dialkylated-[α,α,β,β-d4]-tryptamines

Article abstract of DOI:10.1002/jlcr.1557

A large number of N,N-dialkylated tryptamines are known to induce psychoactive effects in humans. This has resulted in their increased attention within clinical and forensic communities. Deuterated tryptamines are ideal for use as internal standards during MS bioanalysis or of use in biochemical NMR studies. The present study reports on a microwave-enhanced synthesis of 22 N,N-dialkylated-[α,α,β,β-d4]-tryptamines via the reduction with lithium aluminium deuteride of glyoxalylamide precursors obtained by the procedure of Speeter and Anthony. Syntheses were carried out using a single-mode system under elevated pressure conditions where anhydrous tetrahydrofuran was used as the solvent at 150°C. Good yields were obtained within 5 min. Copyright

Full text of DOI:10.1002/jlcr.1557

Research Article
Received 17 July 2008,
Revised 10 September 2008,
Accepted 24 September 2008
Published online 3 November 2008 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1557
Microwave-accelerated synthesis of
psychoactive deuterated N,N-dialkylated-
[a,a,b,b-d4]-tryptamines
Ã
Simon D. Brandt,a Sri Subha Tirunarayanapuram,a Sally Freeman,b
Nicola Dempster,a Steven A. Barker,c Paul F. Daley,d Nicholas V. Cozzi,e
f
´
and Claudia P. B. Martins
A large number of N,N-dialkylated tryptamines are known to induce psychoactive effects in humans. This has resulted in
their increased attention within clinical and forensic communities. Deuterated tryptamines are ideal for use as internal
standards during MS bioanalysis or of use in biochemical NMR studies. The present study reports on a microwave-enhanced
synthesis of 22 N,N-dialkylated-[a,a,b,b-d4]-tryptamines via the reduction with lithium aluminium deuteride of
glyoxalylamide precursors obtained by the procedure of Speeter and Anthony. Syntheses were carried out using a
single-mode system under elevated pressure conditions where anhydrous tetrahydrofuran was used as the solvent at
1501C. Good yields were obtained within 5 min.
Keywords: Hallucinogens; Microwaves; Deuteration; Clinical; Forensic
Due to a renewed interest in the role of such compounds in
understanding mechanisms of perception, there is a need for a
Introduction
Numerous tryptamines, such as serotonin (5-hydroxytryptamine,
5-HT), melatonin, and several related compounds play an
important part in the neurochemistry of the human brain.
Furthermore, N-monomethyltryptamine and N,N-dimethyltryp-
tamine (DMT), have been identified in various human tissues.1–3
A large number of N,N-dialkylated tryptamine derivatives,
including DMT, are capable of inducing altered states of
consciousness in humans and the term ‘hallucinogen’ is often
used in an attempt to describe their powerful impact on
perception, mood and cognition. Several N,N-dimethylated
tryptamines are found in various plants and fungi which have
been used since ancient times for recreational and religious
purposes, and this has led to a long-standing interest in the
chemistry and biological activity of these compounds. The
most common naturally-occurring representatives include DMT,
O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (psilocybin), 5-
methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-hydroxy-
N,N-dimethyltryptamine (bufotenin).4,5 (Scheme 1A)
In recent years, DMT and psilocybin have been the focus of
intense research within the pharmacology, neuroscience, and
psychiatry communities and has included human clinical
studies of these and related compounds.6–11 Psychoactivity is
greatly affected by substitution on the indole ring, the side-
chain carbons and by alkylation of the side-chain nitrogen.
Most of the psychoactive N,N-disubstituted derivatives may
show oral activity, due to their refractoriness to metabolism
by monoamine oxidases (MAOs). Homologation of the
N,N-dialkyl substituents appears to diminish potency and only
derivatives possessing N,N-dimethyl substituents exist
naturally.12–15
fast and simple preparation of deuterated N,N-dialkylated
tryptamine standards. This is based, in part, on the presence
of several dimethylated derivatives in human biofluids and
tissues and the question about their function is not fully
resolved.1,3,16–18 Rat brain levels of DMT and 5-MeO-DMT have
been determined successfully following intraperitoneal (IP)
injection and an isotope dilution method was successfully
employed using deuterated DMT and 5-MeO-DMT as internal
standards.19 The use of a,a,b,b-d4 derivatives provided indica-
tions for a differential pharmacological response when
compared with nondeuterated tryptamines which merits further
aInstitute for Health Research, School of Pharmacy and Chemistry, Liverpool
John Moores University, Byrom Street, Liverpool, L3 3AF, UK
bSchool of Pharmacy and Pharmaceutical Sciences, The University of
Manchester, Oxford Road, Manchester, M13 9PT, UK
cDepartment of Comparative Biomedical Sciences, School of Veterinary
Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
dAddiction Pharmacology Research Laboratory, California Pacific Medical Center
Research Institute, St. Luke’s Campus, 3555 Cesar Chavez Street, San Francisco,
CA 94120, USA
eDepartment of Pharmacology, University of Wisconsin School of Medicine and
Public Health, 1300 University Avenue, Madison, WI 53706, USA
fCentre for Instrumentation and Analytical Science, The University of
Manchester, Sackville Street, PO Box 88, M60 1QD, UK
*Correspondence to: Simon D. Brandt, School of Pharmacy and Chemistry,
Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
E-mail: s.brandt@ljmu.ac.uk
J. Label Compd. Radiopharm 2008, 51 423–429
Copyright r 2008 John Wiley & Sons, Ltd.

S. D. Brandt et al.
R4
R2
N
Instrumentation
R1
R3
NMR spectra were recorded using a Bruker Avance 300
spectrometer at 300.1 MHz (1H-NMR) or 75.5 MHz (13C-NMR).
Tryptamine spectra were taken in CDCl3 and chemical shifts are
reported relative to TMS at d = 0 ppm. NMR spectra were
obtained by 1H, proton decoupled 13C, DEPT-135, HSQC and
HMBC experiments. When d6-DMSO was used, chemical shifts
were determined relative to the residual solvent peak at d = 2.51
(1H-NMR) and d = 39.6 ppm (13C-NMR).
Microwave-accelerated syntheses were carried out using a
monomode CEM Explorer (UK) microwave system. Operation
settings were: microwave power 250 W, temperature 1501C,
maximum pressure 280 psi, ramp time 5 min, hold time 5 min.
Reactions were performed in glass microwave tubes, closed with
Intellivent caps (CEM) and contents of the vessel were
continuously stirred by a Teflon-coated magnetic stir bar
(10 Â 3 mm). Temperature, pressure and power profiles were
monitored using the ChemDriver software version 3.6.0. Each
reaction was carried out in duplicate.
N
H
(a)
R1 = OH; R2 = R3 = R4 = H: Serotonin
R
1 = H; R2 = R3 = Me; R4 = H: DMT
R1 = H; R2 = R3 = Me; R4 = H2O3PO: Psilocybin
R1 = MeO; R2 = H; R3 = CH3CO; R4 = H: Melatonin
R
R
1 = MeO; R2 = R3 = Me; R4 = H: 5-MeO-DMT
1 = OH; R2 = R3 = Me; R4 = H: Bufotenin
O
R2
N
R2
N
O
D
D
ii
iii
i
Cl
Ar
R3
Ar
R3
Ar
Ar
D
D
O
(b)
O
Scheme 1. (a) Commonly found naturally-occurring tryptamine derivatives. (b)
Synthesis of deuterated N,N-disubstituted tryptamine derivatives via the synthetic
route of Speeter & Anthony. i. oxalyl chloride; ii: amine; iii: LiAlD4; R2 = R3 = alkyl;
Ar = 5-methoxyindole or indole. For structures of tryptamines 1–22, see Table 1.
A Micromass LCT orthogonal acceleration time-of-flight mass
spectrometer (Micromass, UK) equipped with an electrospray
ionisation source was operated in positive mode. Samples were
introduced using a flow injection method via a Harvard
Apparatus (Pump 11) (Massachusetts, USA) syringe pump at
20mL/min. The instrument was tuned and calibrated in the mass
range of 100–1000 Da using a sodium formate solution (0.005M
in 50:50 acetonitrile-water). Exact mass measurements of the
tryptamine products were based on the protonated molecules
[M1H]1. Both N,N-diallylglyoxalylamides were detected as
sodiated adducts [M1Na]1. Leucine enkephalin (1 mg/mL) was
used as lock mass standard after instrument calibration.
Operation settings were: capillary voltage: 3000V, sample cone
voltage: 30V, RF lens: 250 V, desolvation temperature: 1501C,
source temperature: 1001C, acceleration: 200 V, cone gas flow:
22L/h, desolvation gas flow: 602 L/h. Data acquisition was carried
out using MassLynx version 4.0 SP2. Isotopic purities were
determined after direct infusion and integration of mass peak
areas.
investigations. This has been attributed to the in vivo kinetic
isotope effect where, for example, d4-DMT was observed to
exhibit prolonged behavioural effects in rats.20 Correspondingly,
deuteration also affected pharmacokinetic parameters which
resulted in significantly increased rat brain levels following IP
injections. This allowed for the identification of minor metabolic
pathways without the use of pharmacological intervention such
as MAO inhibition.21,22 Further, the fact that a number of
N,N-dialkylated tryptamines are often classified as controlled
substances results in an increased demand for deuterated
standards for forensic purposes.
A convenient method for the synthesis of N,N-dialkylated
tryptamines is based on the route of Speeter and Anthony.23
This involves acylation of an indole with oxalyl chloride followed
by reaction with the appropriate amine to give an indol-3-
yl-glyoxalylamide. This amide is then reduced with lithium
aluminium hydride to the tryptamine product. Replacement of
the metal hydride with lithium aluminium deuteride (LAD)
conveniently affords the desired a,a,b,b-d4 derivatives
(Scheme 1B). Previous studies have focused on the preparation
of N,N-dimethylated or mono-methylated derivatives only via
the Speeter and Anthony procedure.12,24–29
General procedure for the microwave-accelerated synthesis
of N,N-disubstituted [a,a,b,b-d4]-tryptamine derivatives
(1–22)
Microwave-accelerated reactions are increasingly used in drug
discovery and organic synthesis because they allow for a high-
throughput approach in which syntheses can be carried out
within minutes.30–32 To the best of the authors’ knowledge, this
study appears to be the first application of a microwave-
accelerated reduction of glyoxalylamides using LAD, to give a
range of novel symmetrically and asymmetrically substituted
a,a,b,b-d4 derivatives.
Tryptamines were synthesised in duplicate by the reduction of
the appropriate indol-3-yl-N,N-dialkylated glyoxalylamides (avail-
able from previous work 33) with lithium aluminium deuteride
(LAD). The preparation of 5-MeO-d4-DALT 11 and d4-DALT 22
required the syntheses of the corresponding glyoxalylamides,
which are reported here
The appropriate indole (5.44 mmol; 5-methoxyindole: 800 mg;
indole: 637 mg) was dissolved in 150 mL anhydrous ether and
stirred on ice for 30 min. Oxalyl chloride (2.07 g, 16.3 mmol) was
added dropwise, stirred for 30 min on ice, and kept at À201C for
4 h. The crystalline orange or yellow a-oxo acid chlorides were
filtered and washed three times with cold anhydrous ether
(50 mL) and dried in vacuo for 3 h at room temperature to give a
yield of 1.19 g (5.00 mmol, 92%) for 5-methoxyindol-3-yl-
glyoxalyl chloride and 1.02 g (4.90 mmol, 90%) for indol-3-yl-
glyoxalyl chloride, respectively.
Experimental
Materials
Silica gel for flash chromatography (particle size 40–63 mm), silica
gel aluminium thin-layer chromatography (TLC) plates were
obtained from VWR (UK). All other solvents, reagents, and
lithium aluminium deuteride (98 atom %) were purchased from
Aldrich (UK) and were of analytical grade.
N,N-Diallylamine (760mg, 7.81mmol, 0.966 mL) was added
dropwise to an ice-cold solution of 5-methoxyindol-3-yl-glyoxalyl
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 423–429

S. D. Brandt et al.
chloride (619 mg, 2.60mmol) or indol-3-yl-glyoxalyl chloride chromatography (CHCl3/MeOH/NH4OH: 8/2/0.1). The free base
(540 mg, 2.60 mmol) dissolved in 100 mL anhydrous tetrahydrofur- products were dried overnight in vacuo over P2O5 to yield the
an (THF). The mixture was stirred on ice for 4h. The solvent was desired, mostly solid, tryptamine derivatives.
evaporated under reduced pressure to give a crude solid that was
purified by flash chromatography (CH2Cl2-MeOH, 9:1). The solvent 5-Methoxy-N,N-dimethyl-[a,a,b,b-d4]-tryptamine (1)
was evaporated under reduced pressure and recrystallised from
Yield: 82 mg (0.37 mmol, 74%). 1H-NMR: 8.00 (NH-1, br s), 7.23
methanol/ethyl acetate and dried overnight under vacuum.
(1H, d, H-7, J 8.7 Hz,), 7.05 (1H, d, H-4, J 2.3 Hz), 6.99 (1H, d, H-2,
J 2.3 Hz), 6.85 (1H, dd, H-6, J 8.7, 2.3 Hz), 3.86 (3H, s, OCH3), 2.37
(6H, s, N-CH3). 13C-NMR: 153.8 (C-5), 131.6 (C-7a), 127.9 (C-3a),
5-Methoxyindol-3-yl-N,N-diallylglyoxalylamide
122.5 (C-2), 113.7 (C-3), 111.9 (C-6 and C-7), 100.8 (C-4), 56.0
Yield: 64%. 1H-NMR (d6-DMSO): 12.18 (NH-1, br s), 8.03 (1H, s,
(OCH3), 45.4 (N-CH3). HRESIMS theory [M1H]1: 223.1748;
H-2), 7.62 (1H, d, H-4, J 2.4Hz), 7.44 (1H, d, H-7, J 8.5 Hz), 6.92 (1H,
observed: 223.1740.
3
3
dd, H-6, J 8.9, 2.4 Hz), 5.89 (1H, ddt, Jtrans 16.7 Hz, Jcis 10.7 Hz,
3
3
3J 5.7 Hz, CH==CH2), 5.74 (1H, ddt, Jtrans 17.2 Hz, Jcis 10.3 Hz,
3J 5.7 Hz, CH==CH2), 5.27 (1H, ddtꢀdq, J 7.2, 1.5 Hz, CH==CH), 5.24-
5.22 (1H, m, CH==CH), 5.16 (1H, ddtꢀdq, J 12.9, 1.5Hz, CH==CH),
5.135 (1H, ddtꢀdq, J 5.7, 1.5, CH==CH), 4.03 (2H, d, N-CH2, J 5.7 Hz),
3.86 (2H, d, N-CH2, J 5.7Hz), 3.81 (3 H, s, OCH3). 13C-NMR: 185.8
(CO-b), 167.3 (CO-a), 155.9 (C-5), 137.0 (C-2), 133.2 (CH==CH2), 132.7
(CH==CH2), 131.6 (C-7a), 125.8 (C-3a), 118.3 (CH==CH2), 117.7
(CH==CH2), 113.4 (C-7), 113.3 (C-6), 112.8 (C-3), 102.7 (C-4), 55.3
(OCH3), 49.2 (N-CH2), 45.6 (N-CH2). HRESIMS theory [M1Na]1:
321.1215; observed: 321.1230.
5-Methoxy-N-methyl-N-ethyl-[a,a,b,b-d4]-tryptamine (2)
Yield: 95 mg (0.40 mmol, 80%). 1H-NMR: 7.96 (NH-1, br s), 7.23
(1H, d, H-7, J 8.5 Hz,), 7.05 (1H, d, H-4, J 2.4 Hz), 7.00 (1H, d, H-2,
J 2.3 Hz), 6.85 (1H, dd, H-6, J 8.7, 2.4 Hz), 3.86 (3H, s, OCH3), 2.57
(2H, q, N-CH2, J 7.2 Hz), 2.37 (3H, s, N-CH3), 1.13 (3H, t, N-CH2-
CH3, J 7.2 Hz). 13C-NMR: 153.8 (C-5), 131.5 (C-7a), 127.9 (C-3a),
122.4 (C-2), 113.8 (C-3), 111.9 (C-6 and C-7), 100.8 (C-4), 56.0
(OCH3), 51.3 (N-CH2), 41.6 (N-CH3), 12.3 (N-CH2-CH3). HRESIMS
theory [M1H]1: 237.1905; observed: 237.1917.
5-Methoxy-N-methyl-N-n-propyl-[a,a,b,b-d4]-tryptamine (3)
Indol-3-yl-N,N-diallylglyoxalylamide (22a)
Yield: 96 mg (0.38 mmol, 76%). 1H-NMR: 7.94 (NH-1, br s), 7.23
(1H, d, H-7, J 8.5 Hz,), 7.05 (1H, d, H-4, J 2.4 Hz), 7.00 (1H, d, H-2,
J 2.3 Hz), 6.85 (1H, dd, H-6, J 8.8, 2.1 Hz), 3.86 (3H, s, OCH3), 2.45
(2H, m, N-CH2-CH2), 2.38 (3H, s, N-CH3), 1.56 (2H, sext, N-CH2-
CH2, J 7.5 Hz), 0.93 (3H, t, N-CH2-CH2-CH3, J 7.5 Hz). 13C-NMR:
153.8 (C-5), 131.6 (C-7a), 127.9 (C-3a), 122.5 (C-2), 113.9 (C-3),
111.9 (C-6 and C-7), 100.8 (C-4), 59.8 (N-CH2-CH2), 56.0 (OCH3),
42.2 (N-CH3), 20.4 (N-CH2-CH2), 12.1 (N-CH2-CH2-CH3). HRESIMS
theory [M1H]1: 251.2061; observed: 251.2051.
Yield: 621 mg (2.87 mmol, 55%). 1H-NMR (d6-DMSO): 12.28
(NH-1, br s), 8.14-8.12 (1H, m, H-4), 8.1 (1H, s, H-2), 7.58-7.52 (1H,
m, H-7), 7.29 (1H, td, H-6, J 7.2, 1.8 Hz), 7.26 (1H, td, H-5, J 7.2,
3
3
1.5 Hz), 5.89 (1H, ddt, Jtrans 16.7 Hz, Jcis 10.7 Hz, 3J 5.7 Hz,
3
3
CH==CH2), 5.74 (1H, ddt, Jtrans 17.2 Hz, Jcis 10.3 Hz, 3J 5.7 Hz,
CH==CH2), 5.27 (1H, ddtꢀdq, J 7.2, 1.5 Hz, CH==CH), 5.24-5.22
(1H, m, CH==CH), 5.16 (1H, ddtꢀdq, J 12.9, 1.5 Hz, CH==CH), 5.14
(1H, ddtꢀdq, J 5.7, 1.5 Hz, CH==CH), 4.03 (2H, d, N-CH2, J 5.7 Hz),
3.86 (2H, d, N-CH2, J 5.7 Hz). 13C-NMR: 185.9 (CO-b), 167.3 (CO-a),
137.1 (C-2), 136.8 (C-7a), 133.1 (CH==CH2), 132.7 (CH==CH2),
124.9 (C-3a), 123.5 (C-6), 122.5 (C-5), 120.9 (C-4), 118.3
(CH==CH2), 117.7 (CH==CH2), 112.9 (C-7), 112.6 (C-3), 49.2
(N-CH2), 45.6 (N-CH2). HRESIMS theory [M1Na]1: 291.1109;
observed: 291.1092.
5-Methoxy-N-methyl-N-isopropyl-[a,a,b,b-d4]-tryptamine (4)
Yield: 96 mg (0.38 mmol, 76%). 1H-NMR: 7.96 (NH-1, br s), 7.23
(1H, d, H-7, J 8.8 Hz,), 7.06 (1H, d, H-4, J 2.4 Hz), 7.00 (1H, d, H-2,
J 2.1 Hz), 6.85 (1H, dd, H-6, J 8.7, 2.3 Hz), 3.86 (3H, s, OCH3), 2.97
(1H, sept, N-CH, J 6.6 Hz), 2.37 (3H, s, N-CH3), 1.07 (6H, d, N-CH-
CH3, J 6.6 Hz). 13C-NMR: 153.9 (C-5), 131.5 (C-7a), 128.0 (C-3a),
122.3 (C-2), 114.2 (C-3), 112.1 (C-6), 111.8 (C-7), 100.9 (C-4), 56.0
(OCH3), 53.6 (N-CH), 30.3 (N-CH3), 18.0 (N-CH-CH3). HRESIMS
theory [M1H]1: 251.2061; observed: 251.2075.
To a microwave tube were added a stirrer bar and the
corresponding glyoxalylamide (0.5 mmol). Ice-cold anhydrous THF
(3 mL) was added under a stream of nitrogen and LAD (126 mg,
3 mmol) was added under a stream of nitrogen with vigorous
stirring on ice. The tube was sealed and the reaction mixture was
heated in the microwave system under the conditions described
above. At the end of the reaction the mixture was transferred to a
conical flask and cooled on ice. The tubes were then rinsed with
3Â 8 mL THF and the washings were added to the flask. Excess
deuteride was destroyed by the dropwise addition of 5 mL water,
followed by 4 mL 20% NaOH and 5 mL water. The volume of THF
was increased by adding another 20 mL. The precipitated inorganic
salts were removed by filtration and washed with 30 mL THF. The
filtrate was evaporated under reduced pressure and the resulting
oily residue was dissolved in 60 mL chloroform, 1 mL 20% NaOH,
and 10 mL water, and thoroughly shaken in a separating funnel.
The organic layer was separated and two additional chloroform
extractions (20 mL) from the remaining alkaline aqueous phases
were carried out. The combined organic fractions were then
pooled and washed with distilled water (2 Â 40 mL) with saturated
aqueous NaCl (40 mL). The organic phase was evaporated under
reduced pressure and the resulting product was purified by flash
5-Methoxy-N,N-diethyl-[a,a,b,b-d4]-tryptamine (5)
Yield: 97 mg (0.39 mmol, 78%). 1H-NMR: 7.98 (NH-1, br s), 7.23
(1H, d, H-7, J 8.9 Hz,), 7.06 (1H, d, H-4, J 2.4 Hz), 6.99 (1H, d, H-2,
J 2.3 Hz), 6.85 (1H, dd, H-6, J 8.9, 2.4 Hz), 3.86 (3H, s, OCH3), 2.70
(4H, q, N-CH2, J 7.2 Hz), 1.12 (6H, t, N-CH2-CH3, J 7.2 Hz). 13C-NMR:
153.9 (C-5), 131.5 (C-7a), 127.9 (C-3a), 122.2 (C-2), 114.4 (C-3),
112.1 (C-6), 111.8 (C-7), 100.8 (C-4), 55.9 (OCH3), 46.9 (N-CH2),
11.8 (N-CH2-CH3). HRESIMS theory [M1H]1: 251.2061; observed:
251.2074.
5-Methoxy-N-ethyl,N-n-propyl-[a,a,b,b-d4]-tryptamine (6)
Yield: 95 mg (0.36 mmol, 72%). 1H-NMR: 7.98 (NH-1, br s), 7.23
(1H, d, H-7, J 8.7 Hz,), 7.05 (1H, d, H-4, J 2.3 Hz), 6.99 (1H, d, H-2,
J 2.1 Hz), 6.85 (1H, dd, H-6, J 8.7, 2.4 Hz), 3.86 (3H, s, OCH3), 2.69
J. Label Compd. Radiopharm 2008, 51 423–429
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S. D. Brandt et al.
(2H, q, N-CH2-CH3, J 7.2 Hz), 2.55 (2H, m, N-CH2-CH2), 1.56 (2H, m, 114.3 (C-3), 112.1 (C-6), 111.8 (C-7), 100.8 (C-4), 56.9 (N-CH2),
N-CH2-CH2), 1.11 (3H, t, N-CH2-CH3, J 7.2 Hz), 0.92 (3H, t, N-CH2- 55.9 (OCH3). HRESIMS theory [M1H]1: 275.2061; observed:
CH2-CH3, J 7.3 Hz). 13C-NMR: 153.9 (C-5), 131.5 (C-7a), 128.0 275.2050.
(C-3a), 122.3 (C-2), 114.2 (C-3), 112.1 (C-6), 111.8 (C-7), 100.8
(C-4), 56.0 (OCH3), 55.5 (N-CH2-CH2), 47.5 (N-CH2-CH3), 20.1 N,N-Dimethyl-[a,a,b,b-d4]-tryptamine (12)
(N-CH2-CH2-CH3), 12.0 (N-CH2-CH2-CH3), 11.7 (N-CH2-CH3). HR-
Yield: 77 mg (0.40 mmol, 80%). 1H-NMR: 8.13 (NH-1, br s), 7.60
(1H, d, H-4, J 7.7 Hz,), 7.34 (1H, d, H-7, J 7.5 Hz), 7.18 (1H, td, H-6,
ESIMS theory [M1H]1: 265.2218; observed: 265.2230.
J 7.5, 1.3 Hz), 7.10 (1H, td, H-5, J 7.3, 1.2 Hz), 7.00 (1H, d, H-2,
J 2.4 Hz), 2.19 (6H, s, N-CH3). 13C-NMR: 136.5 (C-7a), 127.5 (C-3a),
5-Methoxy-N-ethyl-N-isopropyl-[a,a,b,b-d4]-tryptamine (7)
1
Yield: 94 mg (0.36 mmol, 72%). H-NMR: 7.93 (NH-1, br s), 7.23 121.8 (C-6 and C-2), 119.0 (C-5), 118.8 (C-4), 113.9 (C-3), 111.3
(1H, d, H-7, J 8.7 Hz,), 7.06 (1H, d, H-4, J 2.4 Hz), 7.00 (1H, d, H-2, (C-7), 45.3 (N-CH3). HRESIMS theory [M1H]1: 193.1643; ob-
J 2.3 Hz), 6.85 (1H, dd, H-6, J 8.7, 2.4 Hz), 3.86 (3H, s, OCH3), 3.10 served: 193.1655.
(1H, sept, N-CH, J 6.6), 2.62 (2H, q, N-CH2, J 7.2 Hz), 1.14 (3H,
t, N-CH2-CH3, J 7.2 Hz), 1.06 (6H, d, N-CH-CH3, J 6.6 Hz). 13C-NMR: N-Methyl-N-ethyl-[a,a,b,b-d4]-tryptamine (13)
153.9 (C-5), 131.5 (C-7a), 128.0 (C-3a), 122.3 (C-2), 114.4 (C-3),
Yield: 80 mg (0.39 mmol, 78%). 1H-NMR: 8.08 (NH-1, br s), 7.61
112.1 (C-6), 111.8 (C-7), 100.9 (C-4), 55.9 (OCH3), 50.6 (N-CH), 44.2
(1H, d, H-4, J 7.7 Hz,), 7.34 (1H, dt, H-7, J 7.9, 1.1 Hz), 7.18 (1H, td,
H-6, J 7.5, 1.1 Hz), 7.11 (1H, td, H-5, J 7.7, 1.1 Hz), 7.01 (1H, d, H-2,
J 2.4 Hz), 2.57 (2H, q, N-CH2, J 7.2 Hz), 2.38 (3H, s, N-CH3), 1.13
(N-CH2), 18.5 (N-CH-CH3), 14.0 (N-CH2-CH3). HRESIMS theory [M1
H]1: 265.2218; observed: 265.2232.
(3H, t, N-CH2-CH3, J 7.2 Hz). 13C-NMR: 136.3 (C-7a), 127.6 (C-3a),
121.8 (C-6 and C-2), 119.1 (C-5), 118.8 (C-4), 114.4 (C-3), 111.3 (C-
5-Methoxy-N,N-di-n-propyl-[a,a,b,b-d4]-tryptamine (8)
1
Yield: 103 mg (0.37 mmol, 74%). H-NMR: 7.91 (NH-1, br s), 7.24 7), 51.3 (N-CH2), 37.2 (N-CH3), 12.3 (N-CH2-CH3). HRESIMS theory
(1H, d, H-7, J 8.7 Hz,), 7.05 (1H, d, H-4, J 2.4 Hz), 6.99 (1H, d, H-2, [M1H]1: 207.1799; observed: 207.1808.
J 2.4 Hz), 6.85 (1H, dd, H-6, J 8.7, 2.4 Hz), 3.86 (3H, s, OCH3), 2.55
(4H, m, N-CH2), 1.56 (4H, m, N-CH2-CH2), 0.91 (6H, t, N-CH2-CH3, J N-Methyl-N-n-propyl-[a,a,b,b-d4]-tryptamine (14)
7.3 Hz). 13C-NMR: 153.9 (C-5), 131.5 (C-7a), 128.0 (C-3a), 122.3 (C-
Yield: 82 mg (0.37 mmol, 74%). 1H-NMR: 8.06 (NH-1, br s), 7.60
2), 114.3 (C-3), 112.1 (C-6), 111.8 (C-7), 100.8 (C-4), 56.1 (N-CH2),
(1H, d, H-4, J 7.7 Hz,), 7.34 (1H, d, H-7, J 7.7 Hz), 7.18 (1H, td, H-6,
56.0 (OCH3), 20.1 (N-CH2-CH2), 12.0 (N-CH2-CH3). HRESIMS theory
J 7.9, 1.3 Hz), 7.11 (1H, td, H-5, J 7.7, 1.3 Hz), 7.01 (1H, d, H-2,
[M1H]1: 279.2374; observed: 279.2360.
J 2.4 Hz), 2.45 (2H, m, N-CH2), 2.38 (3H, s, N-CH3), 1.56 (2H, m,
N-CH2-CH2), 0.92 (3H, t, N-CH2-CH2-CH3, J 7.3 Hz). 13C-NMR: 136.3
5-Methoxy-N,N-diisopropyl-[a,a,b,b-d4]-tryptamine (9)
(C-7a), 127.5 (C-3a), 122.0 (C-6), 121.5 (C-2), 119.2 (C-5), 118.8 (C-
Yield: 108 mg (0.39 mmol, 78%). H-NMR: 7.92 (NH-1, br s), 7.23 4), 114.3 (C-3), 111.1 (C-7), 59.7 (N-CH2-CH2), 42.1
1
(1H, d, H-7, J 9.2 Hz,), 7.06 (1H, d, H-4, J 2.6 Hz), 6.98 (1H, d, H-2, (N-CH3), 20.3 (N-CH2-CH2), 12.0 (N-CH2-CH2-CH3). HRESIMS
J 2.3 Hz), 6.85 (1H, dd, H-6, J 8.9, 2.4 Hz), 3.86 (3H, s, OCH3), 3.13 theory [M1H]1: 221.1956; observed: 221.1944.
(2H, sept, N-CH, J 6.6 Hz), 1.09 (12H, d, N-CH-CH3, J 6.6 Hz). 13C-
NMR: 153.9 (C-5), 131.4 (C-7a), 128.1 (C-3a), 122.2 (C-2), 114.8 (C- N-Methyl-N-isopropyl-[a,a,b,b-d4]-tryptamine (15)
3), 112.0 (C-6), 111.8 (C-7), 101.0 (C-4), 55.9 (OCH3), 49.2 (N-CH),
Yield: 82 mg (0.37 mmol, 74%). 1H-NMR: 8.04 (NH-1, br s), 7.61
(1H, d, H-4, J 7.7 Hz,), 7.35 (1H, d, H-7, J 8.1 Hz), 7.19 (1H, td, H-6,
J 8.0, 1.1 Hz), 7.12 (1H, td, H-5, J 7.5, 1.1 Hz), 7.03 (1H, d, H-2,
J 2.4 Hz), 2.98 (1H, sept, N-CH, J 6.6 Hz), 2.38 (3H, s, N-CH3), 1.07
20.7 (N-CH-CH3). HRESIMS theory [M1H]1: 279.2374; observed:
279.2390.
5-Methoxy-N,N-diisobutyl-[a,a,b,b-d4]-tryptamine (10)
(6H, d, N-CH-CH3, J 6.6 Hz). 13C-NMR: 136.3 (C-7a), 127.6 (C-3a),
Yield: 119 mg (0.39 mmol, 78%). H-NMR: 7.79 (NH-1, br s), 7.23 121.8 (C-6), 121.6 (C-2), 119.1 (C-5), 118.8 (C-4), 114.4 (C-3), 111.3
1
(1H, d, H-7, J 8.7 Hz,), 7.03 (1H, d, H-4, J 2.4 Hz), 6.97 (1H, d, H-2, (C-7), 53.5 (N-CH), 37.2 (N-CH3), 18.1 (N-CH-CH3). HRESIMS theory
J 2.4 Hz), 6.84 (1H, dd, H-6, J 8.8, 2.4 Hz), 3.87 (3H, s, OCH3), 2.20 [M1H]1: 221.1956; observed: 221.1967.
(4H, d, N-CH2, J 7.3 Hz), 1.73 (2H, non, N-CH2-CH, J 6.8 Hz), 0.90
(12H, d, N-CH2-CH-CH3, J 6.6 Hz). 13C-NMR: 153.8 (C-5), 131.4 (C-
7a), 128.1 (C-3a), 122.2 (C-2), 114.7 (C-3), 112.0 (C-6), 111.8 (C-7),
101.0 (C-4), 63.9 (N-CH2), 56.0 (OCH3), 26.9 (N-CH2-CH), 20.1 (N-
CH2-CH-CH3). HRESIMS theory [M1H]1: 307.2687; observed:
(1H, d, H-4, J 7.7 Hz,), 7.34 (1H, d, H-7, J 7.9 Hz), 7.18 (1H, td, H-6,
N,N-Diethyl-[a,a,b,b-d4]-tryptamine (16)
Yield: 85 mg (0.39 mmol, 78%). 1H-NMR: 8.11 (NH-1, br s), 7.61
J 7.0, 1.3 Hz), 7.11 (1H, td, H-5, J 7.0, 1.3 Hz), 7.00 (1H, d, H-2,
J 2.3 Hz), 2.68 (4H, q, N-CH2, J 7.2 Hz), 1.11 (6H, t, N-CH2-CH3, J
7.2 Hz). 13C-NMR: 136.3 (C-7a), 127.6 (C-3a), 121.9 (C-6), 121.4 (C-
2), 119.2 (C-5), 118.8 (C-4), 114.5 (C-3), 111.1 (C-7), 46.9 (N-CH2),
11.8 (N-CH2-CH3). HRESIMS theory [M1H]1: 221.1956; observed:
221.1966.
307.2673.
5-Methoxy-N,N-diallyl-[a,a,b,b-d4]-tryptamine (11)
1
Yield: 95 mg (0.34 mmol, 68%). H-NMR: 7.87 (NH-1, br s), 7.24
(1H, d, H-7, J 8.8 Hz,), 7.02 (1H, d, H-4, J 2.4 Hz), 6.97 (1H, d, H-2,
J 2.4 Hz), 6.84 (1H, dd, H-6, J 8.7, 2.3 Hz), 5.93 (2H, ddt, 3Jtrans 17.1
Hz, 3Jcis 10.2 Hz, 3J 6.6 Hz, CH==CH2), 5.23 (2H, ddd, 3Jtrans 17.1 Hz,
N-Ethyl-N-n-propyl-[a,a,b,b-d4]-tryptamine (17)
2J 3.3 Hz, 4J 1.5 Hz, CH==CHcis), 5.16 (2H, ddt, Jcis 10.2 Hz,
3
2J 2.2 Hz, J 1.1 Hz, CH==CHtrans), 3.85 (3H, s, OCH3), 3.23 (4H, dt,
4
Yield: 91 mg (0.39 mmol, 78%). 1H-NMR: 8.04 (NH-1, br s), 7.60
(1H, d, H-4, J 7.7 Hz,), 7.35 (1H, d, H-7, J 8.1 Hz), 7.18 (1H, td, H-6,
J 7.5, 1.3 Hz), 7.11 (1H, td, H-5, J 7.3, 1.1 Hz), 7.01 (1H, d, H-2, J 2.4
3J 6.6 Hz, J 1.2 Hz, N-CH2). 13C-NMR: 153.9 (C-5), 135.9 (N-CH2-
CH), 131.4 (C-7a), 127.9 (C-3a), 122.3 (C-2), 117.4 (CH==CH2),
4
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 423–429

S. D. Brandt et al.
Hz), 2.69 (2H, q, N-CH2-CH3, J 7.2 Hz), 2.55 (2H, m, N-CH2-CH2), 13C-NMR: 136.3 (C-7a), 135.8 (N-CH2-CH), 127.6 (C-3a), 121.9
1.56 (2H, m, N-CH2-CH2), 1.11 (3H, t, N-CH2-CH3, J 7.2 Hz), 0.92 (C-6), 121.4 (C-2), 119.2 (C-5), 118.9 (C-4), 117.4 (CH==CH2), 114.6
(3H, t, N-CH2-CH2-CH3, J 7.3 Hz). 13C-NMR: 136.3 (C-7a), 127.6 (C-3), 111.1 (C-7), 56.9 (N-CH2). HRESIMS theory [M1H]1:
(C-3a), 121.8 (C-6), 121.5 (C-2), 119.1 (C-5), 118.8 (C-4), 114.4 245.1956; observed: 245.1969.
(C-3), 111.2 (C-7), 55.6 (N-CH2-CH2), 47.5 (N-CH2-CH3), 20.2
(N-CH2-CH2), 12.2 (N-CH2-CH2-CH3), 12.1 (N-CH2-CH3). HRESIMS Results and discussion
theory [M1H]1: 235.2112; observed: 235.2125.
The reduction of indol-3-yl-glyoxalylamides with lithium alumi-
nium deuteride (LAD) provides a convenient method for the
preparation of a,a,b,b-d4 N,N-dialkylated tryptamines. This is
N-Ethyl-N-isopropyl-[a,a,b,b-d4]-tryptamine (18)
1
Yield: 89 mg (0.38 mmol, 76%). H-NMR: 8.01 (NH-1, br s), 7.61
(1H, d, H-4, J 7.9 Hz,), 7.35 (1H, dt, H-7, J 8.1, 1.1 Hz), 7.17 (1H, td,
H-6, J 7.5, 1.1 Hz), 7.11 (1H, td, H-5, J 7.7, 1.2 Hz), 7.03 (1H, d,
H-2, J 2.2 Hz), 3.10 (1H, sept, N-CH, J 6.6 Hz), 2.65 (2H, quart, N-
CH2, J 7.2 Hz), 1.14 (3H, t, N-CH2-CH3, J 7.2 Hz), 1.07 (6H, d, N-CH-
CH3, J 6.6 Hz). 13C-NMR: 136.3 (C-7a), 127.6 (C-3a), 121.8 (C-6),
121.5 (C-2), 119.1 (C-5), 118.9 (C-4), 114.7 (C-3), 111.1 (C-7), 50.5
(N-CH), 44.2 (N-CH2), 18.6 (N-CH-CH3), 14.0 (N-CH2-CH3).
HRESIMS theory [M1H]1: 235.2112; observed: 235.2101.
typically carried out by heating at reflux in an anhydrous aprotic
solvent (e.g. THF) for 2–16 hours.12,24–29 There have also been
examples where diethyl ether has been employed but the low
boiling point of this solvent can result in significantly prolonged
reaction times and incomplete reduction.34 In cases where
deuteration on the indole nucleus was desired, platinum-
catalysed exchange reactions have been employed for the
preparation of d5-DMT and d5-bufotenin. These included a 24 h
reflux with deuterated acids. 17,19,35 Two examples have recently
been reported for the synthesis of N,N-d10-DET and N,N-d6-DPT
via tryptamine alkylation with d5-iodoethane and 1,1,1-d3-3-
bromopropane, respectively. In both cases the reaction mixture
was stirred for 5 days.28
N,N-Di-n-propyl-[a,a,b,b-d4]-tryptamine (19)
1
Yield: 98 mg (0.39 mmol, 78%). H-NMR: 8.05 (NH-1, br s), 7.60
(1H, d, H-4, J 7.9 Hz,), 7.34 (1H, d, H-7, J 8.0 Hz), 7.18 (1H, td, H-6,
J 8.0, 1.3 Hz), 7.11 (1H, td, H-5, J 7.5, 1.1 Hz), 7.00 (1H, d, H-2,
J 2.3 Hz), 2.53 (4H, m, N-CH2), 1.54 (4H, m, N-CH2-CH2), 0.91 (6H,
t, CH3, J 7.3 Hz). 13C-NMR: 136.3 (C-7a), 127.6 (C-3a), 121.9 (C-6),
121.4 (C-2), 119.2 (C-5), 118.8 (C-4), 114.6 (C-3), 111.1 (C-7), 56.2
(N-CH2), 20.3 (N-CH2-CH2), 12.2 (CH3). HRESIMS theory [M1H]1:
249.2269; observed: 249.2280.
In an attempt to apply a rapid method for the glyoxalylamide
reduction
a microwave-based procedure was developed.
Previous work in this laboratory indicated that under the
microwave-accelerated conditions used, reaction times above
20 min did not appear to increase yields. Correspondingly, this
method was applied to the synthesis of a,a,b,b-d4-DMT
Table 1. Structures of synthesised tryptamines 1–22, and
commonly used abbreviations.
N,N-Diisopropyl-[a,a,b,b-d4]-tryptamine (20)
1
Yield: 99 mg (0.40 mmol, 80%). H-NMR: 7.97 (NH-1, br s), 7.61
R2
(1H, d, H-4, J 8.1 Hz,), 7.35 (1H, d, H-7, J 8.1 Hz), 7.18 (1H, td, H-6,
J 7.5, 1.1 Hz), 7.11 (1H, td, H-5, J 7.5, 1.1 Hz), 7.02 (1H, d, H-2,
J 2.3 Hz), 3.13 (2H, sept, N-CH, J 6.6 Hz), 1.10 (12H, d, N-CH-CH3, J
6.6 Hz). 13C-NMR: 136.3 (C-7a), 127.8 (C-3a), 121.9 (C-6), 121.4 (C-
2), 119.2 (C-5), 119.1 (C-4), 115.1 (C-3), 111.2 (C-7), 49.2 (N-CH),
20.9 (N-CH-CH3). HRESIMS theory [M1H]1: 249.2269; observed:
249.2283.
D
D
4
7
R1
N
3a
R3
3
2
5
6
D
D
7a
N1
H
No.
R1
R2
R3
Name
1
2
3
4
5
6
7
8
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
Me
Et
Pr
iPr
Et
Pr
iPr
Pr
iPr
iBu
allyl
Me
Et
Pr
iPr
Et
Pr
iPr
Pr
iPr
iBu
allyl
5-MeO-d4-DMT
5-MeO-d4-MET
5-MeO-d4-MPT
5-MeO-d4-MIPT
5-MeO-d4-DET
5-MeO-d4-EPT
5-MeO-d4-EIPT
5-MeO-d4-DPT
5-MeO-d4-DIPT
5-MeO-d4-DIBT
5-MeO-d4-DALT
d4-DMT
d4-MET
d4-MPT
d4-MIPT
d4-DET
d4-EPT
d4-EIPT
d4-DPT
d4-DIPT
N,N-Diisobutyl-[a,a,b,b-d4]-tryptamine (21)
1
Yield: 104 mg (0.38 mmol, 76%). H-NMR: 7.90 (NH-1, br s), 7.59
(1H, d, H-4, J 7.7 Hz,), 7.34 (1H, d, H-7, J 7.9 Hz), 7.18 (1H, td, H-6,
J 8.0, 1.1 Hz), 7.11 (1H, td, H-5, J 7.7, 1.1 Hz), 7.00 (1H, d, H-2,
J 2.3 Hz), 2.20 (4H, d, N-CH2, J 7.3 Hz), 1.73 (2H, non, N-CH2-CH, J
6.8 Hz), 0.90 (12H, d, N-CH2-CH-CH3, J 6.6 Hz). 13C-NMR: 136.2 (C-
7a), 127.6 (C-3a), 121.8 (C-6), 121.4 (C-2), 119.0 (C-5), 118.8 (C-4),
114.9 (C-3), 111.0 (C-7), 63.8 (N-CH2), 26.8 (N-CH2-CH), 21.0 (N-
CH2-CH-CH3). HRESIMS theory [M1H]1: 277.2582; observed:
277.2592.
Et
Et
Pr
9
iPr
iBu
allyl
Me
Me
Me
Me
Et
10
11
12
13
14
15
16
17
18
19
20
21
22
N,N-Diallyl-[a,a,b,b-d4]-tryptamine (22)
1
Yield: 85 mg (0.35 mmol, 70%). H-NMR: 7.96 (NH-1, br s), 7.59
Et
Et
Pr
(1H, d, H-4, J 7.7 Hz,), 7.33 (1H, d, H-7, J 7.9 Hz), 7.18 (1H, td, H-6,
J 8.1, 1.1 Hz), 7.10 (1H, td, H-5, J 8.1, 1.1 Hz), 6.99 (1H, d,
3
H-2, J 2.3 Hz), 5.93 (2H, ddt, Jtrans 17.1 Hz, Jcis 10.2 Hz,
3
iPr
iBu
allyl
3
3J 6.6 Hz, CH==CH2), 5.23 (2H, ddd, Jtrans 17.1 Hz, 2J 3.3 Hz,
H
H
d4-DIBT
d4-DALT
3
4J 1.5 Hz, CH==CHcis), 5.16 (2H, ddt, Jcis 10.2 Hz, 2J 2.2 Hz, 4J
1.1 Hz, CH==CHtrans), 3.23 (4H, dt, 3J 6.6 Hz, 4J 1.2 Hz, N-CH2).
J. Label Compd. Radiopharm 2008, 51 423–429
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org

S. D. Brandt et al.
Table 2. Isotopic purities of synthesised tryptamines 1–22.
minimise the amounts of LAD employed. Since the microwave
system used in this study was equipped with a 24 vessel
autosampler, scale-up considerations were not significantly
hampered.
No.
D0 (%)
D1 (%)
D2 (%)
D3 (%)
D4 (%)
1
0.35
0.25
0.39
0.03
0.21
1.25
0.86
0.46
2.13
0.31
0.54
0.21
0.15
1.95
0.93
0.99
0.18
0.36
1.75
0.75
0.41
1.22
0.60
0.76
0.26
0.03
0.54
0.59
0.49
0.26
0.77
0.30
0.20
2.74
1.40
0.82
0.44
0.77
0.34
0.23
0.53
0.31
0.44
1.04
2.89
0.45
0.52
1.35
0.43
0.87
0.60
0.49
1.23
0.77
0.34
0.92
0.50
0.41
2.77
0.92
0.21
0.29
0.60
0.24
1.39
0.92
2.34
1.72
1.92
1.77
1.82
1.77
1.63
1.94
1.55
1.79
0.56
1.57
1.65
1.68
1.09
1.66
0.25
1.78
1.59
1.55
1.64
1.51
93.83
96.82
96.92
97.52
97.01
95.52
96.43
96.85
94.30
96.83
98.35
94.56
96.35
95.15
94.78
95.68
97.23
97.33
95.53
97.15
96.11
95.31
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Conclusion
Application of a microwave-accelerated procedure to the reduc-
tion of glyoxalylamides with lithium aluminium deuteride was
suitable for the preparation of deuterated psychoactive trypta-
mines. The advantage of a pressurised vessel microwave system
was that the reaction only required 5 min, whereas traditional
heating under reflux conditions take 2–16h for the same
reduction. This procedure gave good yields and a rapid approach
for the production of deuterated tryptamines that can be used for
future forensic, pharmacologic and pharmacokinetic studies.
Acknowledgement
The synthetic work was carried out under a Home Office licence.
Grateful thanks are extended to Dr. Jochen Gartz for his very
helpful discussions on tryptamine chemistry.
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(Table 1).36 When this was compared with shortened reaction
times of 5, 10, and 15 min, it was interesting to observe that
comparable yields and product purities were obtained (HPLC
analysis, data not shown). These findings led to the application
of a 5 min reduction to the preparation of 22 N,N-dialkylated
a,a,b,b-d4-tryptamines (Table 1) with good yields.
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Reactions were carried out using a single-mode microwave in
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