A facile and efficient synthesis of tetrahydro-β-carbolines

Article abstract of DOI:10.1016/j.tetlet.2013.04.107

This Letter describes a convenient, efficient, and clean synthesis of various tetrahydro-β-carbolines catalyzed by propane phosphonic acid anhydride T3P under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2013.04.107

Tetrahedron Letters 54 (2013) 3554–3557
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A facile and efficient synthesis of tetrahydro-b-carbolines
⇑
Matthieu Desroses , Tobias Koolmeister, Sylvain Jacques, Sabin Llona-Minguez,
Marie-Caroline Jacques-Cordonnier, Armando Cázares-Körner, Thomas Helleday, Martin Scobie
Science for Life Laboratory, Unit of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21
Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes a convenient, efficient, and clean synthesis of various tetrahydro-b-carbolines cata-
lyzed by propane phosphonic acid anhydride T3PÒ under microwave irradiation.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 8 April 2013
Revised 18 April 2013
Accepted 26 April 2013
Available online 3 May 2013
Keywords:
Propane phosphonic acid anhydride
T3PÒ
Microwave irradiation
Cyclization
Heterocycles
Medicinal chemistry
The Pictet–Spengler reaction is a widely used method for the syn-
thesisofthetetrahydro-b-carbolineringsystem.Ingeneral,thisreac-
tion proceeds in two steps, one is a condensation reaction between a
b-phenylethylaminederivativeandanaldehyde, togeneratethecor-
responding imine; and one is an intramolecular cyclization to give
the tetrahydro-b-carboline.1 Mechanistically, it is well known that
anacidic catalystactivates theimineintermediate before cyclization
into the tetrahydro-b-carboline. Several Lewis [calcium complexes,
Yb(OTf)3, AuCl3/AgOTf] or Brönsted acids (o-benzenedisulfonimide,
H+ Montmorillonite, trifluoroacetic acid, p-toluenesulfonic acid,
aqueous perfluorooctanesulfonic acid, and chiral phosphoric acids)
have been reported as catalysts for the Pictet–Spengler reaction.2
However, these reaction procedureshave some disadvantages, nota-
bly the use of strong acidic media and/or long reaction times.
The tetrahydro-b-carboline ring system is observed in numer-
ous natural and synthetic organic compounds. Their broad spec-
trum of biological and pharmacological activity has led to
considerable interest in their synthesis. For instance, tetrahydro-
b-carbolines are interesting hypnotic, anxiolytic, antimicrobial,
antiviral, anti-tumor, and anticonvulsant compounds.3
Table 1
Optimization of the reaction conditions
NH2
NH
CHO
T3P (50% in EtOAc)
MW
+
N
H
N
H
1a
2a
3a
Entry
T3PÒ (equiv)
Time (min)
T (°C)
Conversiona(%)
1
2
3
4
5
6
7
8
9
10
1.5
3
2.5
2
2.5
2.5
2.5
2.5
2
20
20
20
20
15
10
10
5
100
100
100
100
100
100
110
110
110
110
35
98
98
93
95
95
98
87
82
0b
10
10
0
a
Determined by LC/MS at 254 nm.
Only the intermediate (noncyclized compound) was observed.
b
We recently reported the use of propane phosphonic acid anhy-
dride T3PÒ as a mild acidic catalyst and efficient dehydrating re-
agent in acid-catalyzed reactions, such as the Fischer indole
synthesis4 and the synthesis of pyrazolones.5
We now employ this reagent in the Pictet–Spengler reaction to
develop a new, mild, and expedient protocol for the synthesis of
tetrahydro-b-carbolines.6
In a prototype reaction, a mixture of tryptamine (1a, 0.5 mmol)
and benzaldehyde (2a, 0.5 mmol), in the presence of an excess
(1.5 equiv) of T3PÒ (50% solution in EtOAc) was heated at 100 °C
under microwave irradiation for 20 min (Table 1, entry 1). We
observed that T3PÒ did indeed catalyze the formation of the de-
sired tetrahydro-b-carboline, albeit in low yield (35%). To optimize
the reaction conditions, we studied the influence of the T3PÒ stoi-
chiometry, the reaction time, and the reaction temperature on the
⇑
Corresponding author.
E-mail address: matthieu.desroses@scilifelab.se (M. Desroses).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.107

M. Desroses et al. / Tetrahedron Letters 54 (2013) 3554–3557
3555
Table 2
Scope of the reaction using tryptamine (1a)
Entry Aldehyde
Product
Time
T
Yielda Entry Aldehyde
Product
Time
T
Yielda
(min) (°C) (%)
(min) (°C) (%)
CHO
CHO
Cl
NH
NH
NH
NH
Cl
1
10
10
110 97b
9
10
10
110 91
N
H
N
H
2a
2i
2j
3i
3j
3a
3b
CHO
CHO
S
2
110 96
10
110 93
N
H
N
H
2b
S
O
CHO
O
NH
NH
NH
NH
NH
NH
H
3
4
10
10
110 98
11
12
10
10
110 97
N
H
3k
N
H
2k
2c
O
3c
CHO
CHO
O
110 92
110 94
O
N
H
N
H
2l
2d
3l
3d
CHO
O
F
F
H
O
N
H
N
H
2e
5
10
110 95
13
30
120 91
2m
F
3m
F
3e
F
F
10
20
110
120
CHO
NH
NH
NH
NH2
O2N
N
H
N
H2N
6
10
110 98
14
15
/
2f
H
2n
3n
3f
NO2
10
20
110
120
CHO
CHO
O
NH
NH
Cl
Cl
N
H
N
H
7
8
10
10
110 93
/
2g
2h
3o
2o
3g
Cl
110 96
N
H
Cl
3h
a
Isolated yield.
Reaction on a 5 mmol scale.
b
synthesis of 1-phenyl-1,2,3,4,-tetrahydro-b-carboline (3a). The re-
sults are summarized in Table 1.
110 °C, we obtained a maximum conversion of 98% in 10 min
(Table 1, entry 7).
The optimum number of equivalents of T3PÒ was determined by
carrying out the experiments with 1.5, 3, 2.5, and 2 equiv. We found
that 2.5 equiv gave the best conversion (98%, Table 1, entry 3). Nota-
bly, no improvementin the yield was obtained using 3 equiv of T3PÒ.
We next investigated the influence of the reaction time by con-
ducting the reaction over 15 and 10 min. No significant difference
was observed between these two reaction times (Table 1, entries 5
and 6). Finally, by conducting the reaction at a temperature of
Decreasing the reaction time from 10 to 5 min led to a reduction
of the conversion by 10% (Table 1, entry 8). Similarly, the use of
only two equivalents of T3PÒ at 110 °C gave an 82% conversion
(Table 1, entry 9).
In order to confirm that our results were due to the catalytic
activity of T3PÒ and not to a thermal effect, the reaction was con-
ducted at 110 °C for 10 min without the addition of T3PÒ. Under
these conditions, only the imine intermediate was obtained (Ta-

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M. Desroses et al. / Tetrahedron Letters 54 (2013) 3554–3557
Table 3
Scope of the reaction using substituted tryptamines and benzaldehyde
NH2
NH
CHO
T3P (50% in EtOAc)
MW
R
R
+
N
H
N
H
1 equiv
1b-1e
1 equiv
3p-3s
2a
Entry
1
Tryptamine
Product
Time (min)
T (°C)
Yielda (%)
NH2
NH
10
10
10
20
110
95
N
H
3p
N
H
1b
NH2
NH2
NH2
NH
2
3
110
110
110
87
82
74
N
H
N
O
O
O
O
H
1c
1d
3q
NH
N
H
N
H
3r
Br
NH
Br
4
N
H
3s
N
H
1e
a
Isolated yield.
ble 1, entry 10), indicating that T3PÒ was required for this
cyclization.
Having optimized these parameters, we next explored the scope
of these conditions. A variety of substituted aldehydes were trea-
ted with tryptamine (1a) in the presence of T3PÒ using the opti-
mized conditions [T3PÒ (2.5 equiv), MW, 10 min., 110 °C]. The
results are summarized in Table 2.
As shown in Table 2, a variety of aromatic aldehydes bearing
electron-donating (entries 2–4) or electron-withdrawing (entries
5–9) substituents were successfully employed to prepare the cor-
responding tetrahydro-b-carboline derivatives in good to excellent
yields. Electron-withdrawing or electron-donating substituents on
the aldehyde had little influence on the yield or on the rate of the
reaction.
Tryptamines substituted with electron-donating groups such as
7-methyl, or 5- and 6-methoxy, produced the desired compounds
in good to high yields (Table 3, entries 1–3). On the other hand,
although the reaction was successful using 5-bromotryptamine
hydrochloride (1e), a longer reaction time was needed (20 min)
and the yield was lower (entry 4).
In conclusion, we have developed a new method for the synthe-
sis of tetrahydro-b-carbolines which can be conveniently con-
ducted on a wide variety of aldehyde substrates.8 This simple
process, which features short reaction times, is a useful alternative,
and occasionally superior, way to produce these building blocks by
comparison to literature reports. Efforts to use this new method to
synthesize novel biologically active compounds are underway in
our laboratory.
Heterocyclic and aliphatic (cyclic or linear) aldehydes (entries
10–13) were also well tolerated. Notably, when pivaldehyde
(2m) and tryptamine (1a) were used as substrates, the synthesis
of 1-tert-butyl-2,3,4,9-tetrahydro-1H-b-carboline (3m) required a
longer reaction time (30 min) and a higher temperature (e.g.,
120 °C), presumably reflecting a steric effect on the reaction
rate.
Acknowledgments
Technical support from The Laboratories for Chemical Biology
at Karolinska Institutet (LCBKI) (http://www.cbcs.se/lcbki/) and
ChemAxon
(http://www.chemaxon.com)
is
gratefully
acknowledged.
It is well known that ketones are often problematic in the Pic-
tet–Spengler reaction and sometimes fail to react.7 When we
investigated the use of ketones (acetophenone) or amides (benza-
nilide) using the optimum conditions, or at 120 °C for 20 min, we
recovered only unreacted starting materials. The difficult
formation of the imine intermediate may have impaired the reac-
tion, even in the presence of T3PÒ (entries 14 and 15).
We subsequently examined the substrate scope of this reaction
with respect to a variety of substituted tryptamines (Table 3).
Supplementary data
Supplementary data (experimental details and NMR spectra for
compounds 3a–m and 3p–s) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.04.107.

M. Desroses et al. / Tetrahedron Letters 54 (2013) 3554–3557
3557
7. Cesati, R. R., III; Katzenellenbogen, J. A. Org. Lett. 2000, 2, 3635–3638.
8. Typical procedure (example 3a, Table 2, entry 1): T3PÒ (50% in EtOAc) (2.5 equiv,
1.25 mmol) was added to mixture of tryptamine (1a, 0.5 mmol) and
References and notes
a
1. Cox, E. D.; Cook, J. Chem. Rev. 1995, 95, 1797–1842.
2. Barbero, M.; Bazzi, S.; Cadamuro, S.; Dughera, S. Tetrahedron Lett. 2010, 51,
6356–6359.
3. Tang, J. G.; Liu, H.; Zhou, Z. Y.; Liu, J. K. Synth. Commun. 2010, 40, 1411–1417.
4. Desroses, M.; Wieckowski, K.; Stevens, M.; Odell, L. R. Tetrahedron Lett. 2011, 52,
4417–4420.
benzaldehyde (2a, 0.5 mmol) in a microwave vial. The reaction volume was
then adjusted to 0.5 mL with EtOAc and the vessel was sealed. The mixture was
heated under microwave irradiation (Biotage Initiator) at 110 °C for 10 min. The
residue was diluted with EtOAc and washed successively with a saturated
solution of NaHCO3 (2 Â 5 mL) and brine (5 mL). The organic layer was dried
over Na2SO4. Evaporation of the solvent afforded the expected product in
sufficient purity. Yield: 120 mg (97% yield, white solid). 1H NMR (400 MHz,
MeOD) d (ppm): 7.55 (d, 1H, J = 7.9 Hz), 7.51 (m, 3H), 7.44 (m, 2H), 7.31 (d, 1H,
J = 7.9 Hz), 7.17 (td, 1H, J = 7.9 Hz, 1.1 Hz), 7.10 (td, 1H, J = 7.9 Hz, 1.1 Hz), 5.88
(s, 1H), 3.64 (m, 1H), 3.56 (m, 1H), 3.27 (m, 1H), 3.17 (dt, 1H, J = 8.1 Hz, 5.5 Hz).
LCMS [M+H]+ m/z 249.
5. Desroses, M.; Jacques-Cordonnier, M. C.; Llona-Minguez, S.; Jacques, S.;
Koolmeister, T.; Helleday, T.; Scobie, M. Eur. J. Org. Chem. 2013. http://
dx.doi.org/10.1002/ejoc.201300380, submitted.
6. T3PÒ has recently been used as
a catalyst in a Pictet–Spengler reaction
but not starting from tryptamine derivatives; see Augustine, J. K.;
Bombrun, A.; Alagarsamy, P.; Jothi, A. Tetrahedron Lett. 2012, 53, 6280–
6287.