The synthesis of 1,1-disubstituted tetrahydro-β-carbolines induced by iodine

Article abstract of DOI:10.1016/j.tetlet.2007.06.099

A mild access to 1,1-disubstituted tetrahydro-β-carbolines is described. Tryptamine is subjected to Pictet-Spengler cyclization with various ketones using iodine.

Full text of DOI:10.1016/j.tetlet.2007.06.099

Tetrahedron Letters 48 (2007) 7243–7245
The synthesis of 1,1-disubstituted tetrahydro-b-carbolines
induced by iodine
Y. Lingam,a,* D. Muralimohan Rao,b Dipal R. Bhowmik,a Pachore Sharad Santu,a
K. Raghavendra Raoa and Aminul Islama
aCustom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500 049, India
bCollege of Engineering, Jawaharlal Nehru Technological University, Kakinada 533 003, Andhra Pradesh, India
Received 3 February 2007; revised 12 June 2007; accepted 18 June 2007
Available online 24 June 2007
Abstract—A mild access to 1,1-disubstituted tetrahydro-b-carbolines is described. Tryptamine is subjected to Pictet–Spengler cycli-
zation with various ketones using iodine.
Ó 2007 Elsevier Ltd. All rights reserved.
The b-carboline moiety is the core structure in various
synthetic pharmaceuticals displaying a broad spectrum
of biological activities.1–5 Tetrahydro-b-carbolines are
conformationally constrained tryptamine analogues,
and are of considerable interest due to their diverse
pharmacological properties.
stituted tetrahydro-b-carboline or tetrahydroisoquino-
line. Only a few ketones have shown satisfactory
results.8
A number of recent approaches for the preparation of
1,1-disubstituted tetrahydro-b-carbolines have been
reported, including microwave-accelerated,9 polymer-
bound10 and using titanium isopropoxide.11 However,
there is still a need to develop a cost effective, safe and
environmentally friendly method. Our method provides
an easy access to 1,1-disubstituted tetrahydro-b-carbo-
lines and is depicted in Scheme 1.
A search of the World Drug Index revealed 222 cita-
tions on these compounds in a number of therapeutic
areas.6
Since its discovery, the Pictet–Spengler reaction7 has
been extensively studied and is used in areas such as
the preparation of new heterocycles for combinatorial
applications. The Pictet–Spengler reaction is an acid-
catalyzed intramolecular cyclization of an intermediate
In recent years, I2 has been used extensively as a reagent
due to its inherent low toxicity, electrophilicity and ease
of handling.12 We have developed an iodine-induced
Pictet–Spengler reaction yielding 1,1-disubstituted tetra-
hydro-b-carbolines as the only products.
imine formed by condensation with
a carbonyl
compound. Most examples of Pictet–Spengler reactions
are with aldehydes or activated ketones such as 1,2-
dicarbonyl compounds. Simple ketones are much less
reactive at room temperature (typical reaction time in
days) or are sluggish under reflux, whilst some aryl
ketones do not react at all. This low reactivity may be
attributed firstly to slow imine formation and then to
a sterically sensitive, if not totally prohibited, cyclization
of the resulting imine to produce a congested tetrasub-
The results presented in Table 1 clearly show that all the
studied ketones participated in Pictet–Spengler reactions
with tryptamine in short reaction times affording good
yields of products.
1
2
R COR
I /EtOH
NH
R
NH
2
2
2
1
N
H
N
H
R
Keywords: Pictet–Spengler cyclization; 1,1-Disubstituted tetrahydro-b-
carbolines; Iodine; Ketones and tryptamine.
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
4044; e-mail: lingamy@drreddys.com
Scheme 1. General scheme for the Pictet–Spengler reaction induced by
iodine.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.099

7244
Y. Lingam et al. / Tetrahedron Letters 48 (2007) 7243–7245
Table 1. Pictet–Spengler cyclization induced by iodine
Entry
1
Ketone
Product
Yield (%)
47
Reaction time (h)
NH
NH
PhCOCH3
5
N
H
1
2
2
CH3COCH3
56
67
11
12
N
H
O
NH
O
N
O
O
O
13
N
N
H
3a
O
O
O
O
3
NH
N
H
4
5
PhCOPh
71b
8
7
4
NH
NH
O
O
O
N
H
66
O
O
5
O
O
O
N
H
6
72
8
O
O
6
I
O
NH
I
N
H
7
8
77
64
9
8
H2N
NH2
7
NH
N
H
O
8
9
NH
O
S
N
H
9
78
44
8
S
N
O
N
H
10
11
NH2
10
a See Ref. 13 for the synthesis of the starting ketone.
b The same reaction run without iodine as a catalyst led to no conversion.

Y. Lingam et al. / Tetrahedron Letters 48 (2007) 7243–7245
7245
12. Gogoi, P.; Konwar, D. Tetrahedron Lett. 2006, 37, 5633–
5636.
13. Prabhakar, C.; Vasanth Kumar, N.; Ravikanth Reddy,
M.; Sarma, M. R.; Om Reddy, G. Org. Proc. Res. Dev.
1999, 3, 155–160.
Tryptamine was reacted with various ketones and a cat-
alytic amount of iodine in ethanol to produce 1,1-disub-
stituted tetrahydro-b-carbolines in short reaction times
at room temperature.14 The optimized conditions were
subsequently applied to several other ketones (Table 1).
14. Synthesis of 1,1-disubstituted tetrahydro-b-carbolines (1–
10); General procedure: Tryptamine (200 mg, 125 mmol)
was dissolved in ethanol (10 ml) and ketone (1 equiv) was
added to the reaction mixture. Next, a catalytic amount of
iodine (0.001 equiv) was added to the reaction mixture. The
reaction was maintained at room temperature for 3–12 h
and the progress monitored by TLC. After completion, the
solvent was evaporated and the product purified by column
chromatography using silica gel (230–400 mesh), eluting
with 10% ethyl acetate and petroleum ether to yield the
products in good to moderate yields (44–78%). For
previously known compounds, 1H NMR and mass spectral
data were consistent with those reported in the literature.
For new compounds 1H NMR, mass and elemental
analysis data are provided.
When compared to other methods for the synthesis of
1,1-disubstituted tetrahydro-b-carbolines, the iodine-
induced reaction tolerates the sensitive indole unit well.
In summary, we have developed a novel, simple and
one-pot synthesis of 1,1-disubstituted tetrahydro-b-
carbolines and the use of these products for natural
product synthesis will be reported in due course.
Acknowledgements
The authors thank Dr. Reddy’s Group of companies for
supporting this work and Mr. Abijit Mukherjee and Dr.
Vilas Dahanukar of Custom Pharmaceutical Services,
for their constant help and encouragement. Cooperation
extended by all colleagues of the analytical division is
gratefully acknowledged.
Ethyl 5-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)-2-(1-methyl-
1,2,3,4-tetrahydro-carbolin-1-yl)-pentanoate 3: Yield 67%.
Yellow solid; mp 237–239 °C; 1H NMR (200 MHz,
CDCl3) d 7.88 (d, ArH, J = 3.34 Hz), 7.70 (d, ArH,
J = 7.4 Hz), 4.04 (q, 2H, J = 7.4 Hz), 3.70 (t, 3H,
J = 7 Hz), 3.50 (t, 3H, J = 7.4 Hz), 1.86 (m, 2H), 1.69
(m, 2H), 1.37 (s, 3H), 1.2 (m, 1H), 0.9 (m, 2H); Anal. Calcd
for C27H29N3O4: C, 70.57; H, 6.36; N, 9.14. Found: C,
70.77; H, 6.20; N, 9.27. MS (CI) 460 (M+1).
References and notes
1,1-Diphenyl-1,2,3,4-tetrahydro-b-carboline 4: Yield 71%.
1
Light brown solid; mp 163–165 °C; H NMR (200 MHz,
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CDCl3) d 7.92 (s, 1H), 7.62 (d, ArH, J = 7.8 Hz), 7.47 (d,
ArH, J = 11.8 Hz), 3.75 (t, 3H, J = 7.4 Hz), 3.13 (t, 3H,
J = 7.8 Hz); Anal. Calcd for C23H20N2: C, 85.15; H, 6.21;
N, 8.63. Found: C, 85.27; H, 6.32; N, 8.54. MS (CI) 325
(M+1).
Methyl 2-(1-isopropyl-1,2,3,4-tetrahydro-b-carbolin-1-yl)
acetate 5: Yield 66%. Light yellow solid; mp 173–176 °C;
1H NMR (200 MHz, CDCl3) d 8.80 (s, 1H), d 8.07 (s, 1H),
7.59 (d, ArH, J = 7.2 Hz), 7.38 (d, ArH, J = 7.2 Hz), 3.73
(s, 3H), 3.63 (t, 2H, J = 21.6 Hz), 3.08 (t, 2H, J = 7.4 Hz),
2.57 (m, 1H), 1.07 (d, 6H, J = 7.8 Hz); Anal. Calcd for
C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.22;
H, 7.62; N, 9.67. MS (CI) 287 (M+1).
Ethyl 2-(1-methyl-1,2,3,4,-tetrahydro-b-carbolin-1-yl) ace-
tate 6: Yield 72%. Brown solid; mp 227–229 °C; 1H NMR
(200 MHz, CDCl3) d 8.65 (s, 1H), d 8.43 (s, 1H), 7.57 (d,
ArH, J = 7.2 Hz), 7.26 (m, ArH), 4.17 (m, 2H), 3.73 (t, 3H,
J = 7 Hz), 3.44 (t, 2H, J = 7.8 Hz), 2.99 (d, 1H, J =
7.2 Hz), 1.82 (s, 2H), 1.27 (t, 3H, J = 11.2 Hz), 1.07 (d, 3H,
J = 12.8 Hz), Anal. Calcd for C16H20N2O2: C, 70.56; H,
7.40; N, 10.29. Found: C, 70.02; H, 7.32; N, 10.42. MS (CI)
273 (M+1).
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