Iodine-catalyzed highly effective pictet-spengler condensation: An efficient synthesis of tetrahydro-β-carbolines

Article abstract of DOI:10.1080/00397910802369547

Molecular iodine was found to be an efficient catalyst for the two-component Pictet-Spengler condensation of tryptamine with aldehydes, which leads to the formation of tetrahydro-β-carbolines in high yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802369547

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Iodine-Catalyzed Highly
Effective Pictet–Spengler
Condensation: An Efficient
Synthesis of Tetrahydro-β-
carbolines
a
a
Dipak Prajapati & Mukut Gohain
a
Medicinal Chemistry Division, North East Institute
of Science and Technology , Jorhat , Assam , India
Published online: 07 Nov 2008.
To cite this article: Dipak Prajapati & Mukut Gohain (2008) Iodine-Catalyzed
Highly Effective Pictet–Spengler Condensation: An Efficient Synthesis of
Tetrahydro-β-carbolines, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:24, 4426-4433, DOI:
10.1080/00397910802369547
To link to this article: http://dx.doi.org/10.1080/00397910802369547
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Synthetic Communications , 38: 4426–4433, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369547
Iodine-Catalyzed Highly Effective Pictet–
Spengler Condensation: An Efficient Synthesis
of Tetrahydro-b-carbolines
Dipak Prajapati and Mukut Gohain
Medicinal Chemistry Division, North East Institute of Science and
Technology, Jorhat, Assam, India
Abstract: Molecular iodine was found to be an efficient catalyst for the two-
component Pictet–Spengler condensation of tryptamine with aldehydes, which
leads to the formation of tetrahydro-b-carbolines in high yields.
Keywords: Pictet–Spengler condensations, molecular iodine, tetrahydro-b-
carbolines
INTRODUCTION
The Pictet–Spengler condensation involving an intramolecular Mannich
reaction of b-arylethylamines with carbonyl components is now estab-
lished as one of the most powerful methods toward the synthesis of
[
1,2]
tetrahydro-b-carbolines and tetrahydro-isoquinolines.
The tetrahydro-
b-carboline template possesses multiple sites for modification, allowing
it to be ideally suited to combinatorial elaboration. The World Drug
Index for instance, contains more than 200 listings of this heterocycle,
[
3]
which is usually assembled by the Pictet–Spengler reaction. Combina-
tions of various reactions with Pictet–Spengler condensation in a sequen-
[
4,5]
tial=tandem fashion has been studied by several research groups.
Ganesan et al. reported an efficient one-pot synthesis of acylated
Received March 20, 2008.
Address correspondence to Dipak Prajapati, Medicinal Chemistry Division,
Northeast Institute of Science and Technology, Jorhat 785 006, India. E-mail:
dr_dprajapati2003@yahoo.co.uk
4
426

Iodine-Catalyzed Pictet–Spengler Reaction
4427
tetrahydro-b-carboline en route to dimethoxyfumit-remorgin C through
acylation of the imine with Fmoc-L-proline and acid chloride.
Katzenellenbogen recently reported a vinylogous Pictet–Spengler cycliza-
[
3,6]
[
tion as the key step to prepare breast tumor imaging agents. It has also
7]
been employed as the key reaction in the preparation of b-carboline-
[
8]
3
-carboxylic acid esters which are active at the benzodiazepine receptor.
Reports appeared in the literature describing b-carboline synthesis on
[9]
solid support using strong acidic conditions. However, protic acid–
catalyzed Pictet–Spengler reactions of tryptamine often feature harsher
[10]
conditions and poor yields.
In a very recent finding, Muller et al.
investigated a four-component coupling–amination–aza-annulation–
Pictet–Spengler (CAAPS) sequence of acid chloride, terminal alkynes,
tryptamine derivatives, and acryloyl chloride, which provides one-pot
[
11]
access to tetrahydro-b-carbolines in moderate to good yields.
In recent years, molecular iodine has received considerable attention
as an inexpensive, nontoxic, readily available catalyst for various organic
[
12]
transformations.
bond-formation reactions,
In continuation of our studies on carbon–carbon
we show that molecular iodine is an effi-
[13]
cient catalyst for the synthesis of 1,2,3,4-tetrahydro-b-carbolines via
Pictet–Spengler condensation.
RESULTS AND DISCUSSION
When tryptamine 1 was treated with an equimolar amount of aldehyde 2
in the presence of a catalytic amount of molecular iodine (1 mol%) in
acetonitrile and stirred at ambient temperature, after completion, the
corresponding tetrahydro-b-carboline 4b was obtained (Scheme 1). Com-
plete conversion was observed with 0.5 mol% and thus optimized. All the
products thus obtained were characterized by spectral analyses (IR,
NMR, MS) and finally by comparison with literature data. Among many
solvents utilized, acetonitrile was found to be the best. The reaction also
proceeded smoothly under solvent-free conditions to afford the corre-
sponding tetrahydro-b-carbolines, although the yield was comparatively
less (83%). To demonstrate the generality of this reaction, we next studied
the scope of this reaction under the optimized conditions (acetonitrile,
1 mol% iodine, rt), and the results are summarized in Table 1. But with
furfural and 5-nitrofurfural, the reaction did not yield any tetrahydro-
b-carbolines, rather corresponding imines 3k and 3l were isolated in
7
0–72% yields (Table 1). An attempt to cyclize these imines by increasing
the reaction time and temperature (5 h, reflux) or use of excess of catalyst
20 or 30 mol%) also failed, and decomposition of starting materials
occurred. In conclusion, we have developed a mild and efficient route
(

4428
D. Prajapati and M. Gohain
Scheme 1. Iodine-catalyzed synthesis of tetrahydro-b-carbolines.
for the synthesis of 1,2,3,4-tetrahydro-b-carbolines utilizing molecular
iodine as a new catalyst via Pictet–Spengler condensation.
EXPERIMENTAL
Melting points were determined by using a Buchi melting-point appara-
tus and are uncorrected. IR spectra were recorded on a Perkin-Elmer
ꢀ
1
40 C analyzer using KBr disks. H NMR spectra were recorded on
2
9
units (ppm) relative to Me Si as internal standard. The 100-MHz NMR
0-MHz spectrometers, and chemical shift values were recorded in d
4
spectra are recorded with tetramethylsilane (TMS) as internal standard
(by RSIC, Shillong). Mass spectra were recorded in an AEIMS-30
spectrometer. Elemental analyses were performed on a Hitachi 026
CHN analyser. Silica gel G (E-Merck, India) was used for thin-layer
chromatography (TLC).
Iodine-Catalyzed Pictet–Spengler Condensation at Room Temperature
A mixture of tryptamine (0.16 g, 1 mmol) and p-nitrobenzaldehyde
(0.152 g, 1 mmol) was added to a 50-ml round-bottomed flask containing
a catalytic amount of molecular iodine (0.025 g) in acetonitrile (15 ml).
The resulting mixture was then stirred at room temperature for 4.5 h.
After completion of the reaction (monitored by TLC), acetonitrile was

Iodine-Catalyzed Pictet–Spengler Reaction
4429
Table 1. Molecular iodine-catalyzed Pictet–Spengler reaction and synthesis of
tetrahydro-b-carbolines
a
Products Reaction time (h) Yield (%)
Entry
1
Carbonyl compounds, 2
[
14]
4a
4b
4c
4d
4e
4f
3.5
4.5
4.0
4.0
4.0
4.0
4.5
4.5
90
2
3
4
5
6
7
8
92
89
86
88
87
88
80
4g
4h
9
4i
4j
4.5
4.5
85
83
1
0
(
Continued )

4430
D. Prajapati and M. Gohain
Table 1. Continued
Carbonyl compounds, 2
a
Products Reaction time (h) Yield (%)
Entry
11
3k
5.0
70
12
3l
5.0
72
a
All the yields refere to isolated pure compounds.
distilled off and 5% Na S O solution was added. The product was
2
2
7
extracted with ethylacetate (3 ꢁ 20 ml) and then dried over anhydrous
Na SO overnight, which upon evaporation and to column chromatogra-
4
2
phy (1:6 hexane–ethylacetate) gave 1-(p-nitrophenyl)-1,2,3,4-tetrahydro-
ꢀ
b-carboline, 4b, mp 170–171 C in 92% yield. Similarly other substituted
carbonyl compounds and tryptamine were reacted together with molecu-
lar iodine, and the results are summarized in Table 1. All the compounds
1
obtained were characterized fully by spectral analysis (IR, H NMR, and
MS) and finally by comparison with authentic samples.
Data
1
-(p-Nitrophenyl)-1,2,3,4-tetrahydro-b-carboline (4b)
ꢀ
ꢂ1
1
Mp 170–171 C. IR (KBr): n
2
¼ 3310, 3415, 1515 cm ; H NMR: d
max
.68–2.90 (m, 2H), 3.10 (m, 1H), 3.22 (m, 1H), 5.32 (s, 1H), 6.90–7.25
(
m, 4H), 7.48 (d, 2H), 7.82 (br, 1H), 8.06 (d, 2H); MS: m=z ¼ 293
(M þ). Anal. calcd. for C H N O : C, 69.63; H, 5.12; N, 14.33%.
1
7
15
3
2
Found: C, 69.74; H, 5.01; N, 14.41%.
1
-(p-Tolyl)-1,2,3,4-tetrahydro-b-carboline (4c)
ꢀ
ꢂ1
1
Mp 192–193 C. IR (KBr): n
(
7
¼ 3315, 3400 cm ; H NMR: d 2.20
max
s, 3H), 2.54–2.76 (m, 2H), 3.18 (m, 1H), 3.32 (m, 1H), 5.40 (s, 1H),
.05–7.35 (m, 4H), 7.52 (d, 2H), 7.90 (br, 1H), 8.13 (d, 2H); MS:
m=z ¼ 262 (M þ). Anal. calcd. for C H N : C, 82.44; H, 6.87; N,
1
8
18
2
1
0.69%. Found: C, 82.53; H, 6.75; N, 10.76%.

Iodine-Catalyzed Pictet–Spengler Reaction
4431
1
-(m-Nitrophenyl)-1,2,3,4-tetrahydro-b-carboline (4d)
ꢀ
ꢂ1
1
Mp 143–145 C. IR (KBr): n
2
1
¼ 3310, 1525 cm ; H NMR: d 2.70–
max
.94 (m, 2H), 3.06 (m, 2H), 5.30 (s, 1H), 7.02–7.22 (m, 2H), 7.34 (d,
H), 7.58 (d, 1H), 7.72 (t, 1H), 7.82 (d, 1H), 8.12 (s, 1H), 8.25 (d, 1H);
MS: m=z ¼ 293 (M þ). Anal. calcd. for C H N O : C, 69.67; H, 5.16;
1
7
15
3
2
N, 14.35%. Found: C, 69.59; H, 5.07; N, 14,47%.
1
-(p-Methoxyphenyl)-1,2,3,4-tetrahydro-b-carboline (4e)
ꢀ
ꢂ1
1
Mp 205–206 C. IR (KBr): n
2
6
¼ 3330, 3420 cm ; H NMR: d 2.62–
max
.85 (m, 2H), 3.08 (m, 1H), 3.32 (m, 1H), 3.86 (s, 3H), 5.40 (s, 1H),
.90–7.32 (m, 4H), 7.52 (d, 2H), 7.92 (br, 1H), 8.10 (d, 2H); MS:
m=z ¼ 278 (M þ). Anal. calcd. for C H N O: C, 77.70; H, 6.47; N,
1
8
18
2
1
0.07%. Found: C, 77.61; H, 6.58; N, 10.16%.
1
-(p-Chlorophenyl)-1,2,3,4-tetrahydro-b-carboline (4f)
ꢀ
ꢂ1
1
Mp 207–208 C. IR (KBr): n
2
7
¼ 3210 cm ; H NMR: d 2.66–3.00 (m,
max
H), 3.05 (m, 1H), 3.32 (m, 1H), 5.12 (s, 1H), 6.95–7.15 (m, 2H), 7.20–
.34 (m, 2H), 7.40–7.54 (m, 4H), 7.72 (br, 1H), 7.92 (m, 1H); MS:
m=z ¼ 282 (M þ). Anal. calcd. for C H N Cl: C, 72.34; H, 5.32; N,
1
7
15
2
9
.93%. Found: C, 72.42; H, 5.25; N, 9.82%.
1
-(p-Bromophenyl)-1,2,3,4-tetrahydro-b-carboline (4g)
ꢀ
ꢂ1
1
Mp 215–216 C. IR (KBr): n
2
2
¼ 3190 cm ; H NMR: d 2.72–2.98 (m,
max
H), 3.10 (m, 1H), 3.28 (m, 1H), 5.20 (s, 1H), 7.02–7.16 (m, 2H), 7.22 (m,
H), 7.30–744 (m, 4H), 7.78 (br, 1H), 7.94 (m, 1H); MS: m=z ¼ 327
(
C, 62.46; H, 4.48; N, 8.63%.
M þ). Anal. calcd. for C H N Br: C, 62.39; H, 4.59; N, 8.56%. Found:
1
7
15
2
1
-(Benzopyranyl)-1,2,3,4-tetrahydro-b-carboline (4h)
ꢀ
ꢂ1
1
Mp 190–191 C. IR (KBr): n
(
¼ 3250 cm ; H NMR: d 2.46–2.76
max
m, 2H), 3.00 (m, 1H), 3.16 (m, 1H), 5.24 (s, 1H), 6.90–7.25 (m, 4H),
7.35–7.56 (m, 4H), 7.82 (br, 1H), 8.06 (s, 1H); MS: m=z ¼ 316 (Mþ).
Anal. calcd. for C H N O : C, 75.95; H, 5.06; N, 8.86%. Found: C,
20 16 2 2
7
5.88; H, 5.15; N, 8.77%.

4432
D. Prajapati and M. Gohain
1
-(p-Flurophenyl)-1,2,3,4-tetrahydro-b-carboline (4i)
ꢀ
ꢂ1
1
Mp 139–140 C. IR (KBr): n
2
2
¼ 3160 cm ; H NMR: d 2.74–3.02 (m,
max
H), 3.10 (m, 1H), 3.32 (m, 1H), 5.22 (s, 1H), 6.98–7.12 (m, 2H), 7.20 (m,
H), 7.34–7.45 (m, 4H), 7.56 (br, 1H), 7.74 (m, 1H); MS: m=z ¼ 266
(
M þ). Anal. calcd. for C H N F: C, 76.69; H, 5.64; N, 10.52%. Found:
1
7
15
2
C, 76.79; H, 5.59; N, 10.61%.
1
-(Napthyl)-1,2,3,4-tetrahydro-b-carboline (4j)
ꢂ1
1
IR (KBr): nmax ¼ 3210 cm ; H NMR: d 2.68–2.90 (m, 2H), 3.10 (m,
H), 3.22 (m, 1H), 5.32 (s, 1H), 6.90–7.25 (m, 4H), 7.45–7.88 (m, 8H);
MS: m=z ¼ 298 (M þ). Anal. calcd. for C H N : C, 84.56; H, 6.04; N,
1
2
1
18
2
9
.40%. Found: C, 84.65; H, 6.11; N, 9.52%.
ACKNOWLEDGMENTS
We thank the Department of Science and Technology (DST), New Delhi,
for financial support and the director, Northeast Institute of Science
and Technology (NEIST), Jorhat, for his keen interest and constant
encouragement.
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